drugs

ephedrine

-Indirect general sympathetic agonist -Releases stored catecholamines -Nasal decongestion, urinary incontinence, hypotension. Ma huang is indeed the source of several natural psychostimulant compounds, one of which is ephedrine. Ephedrine was purified from its plant form in 1885 by Nagayoshi Nagai, an organic chem-ist at Tokyo University. Nagai's work, and subsequent research stemming from his findings, was published only in Japanese or German, and the drug remained unknown

schiz

1 % of pop 18-32 years old onset environmental factors like vitamin d deficiency

medical weed

1998 report anelgesic anti-emetic anti-spastic appetite stimulant glaucoma tumor suppresion-maybe lung cancer siezures?-cannabonoids and thc protect against neurotxicity

cigs

6-11 mg nic goes to lungs with tar 70-80 % transformed to cotinine by cytochrome p450 1A6 enzyme excreted in pee

withdrawal

WitHdraWal Animal research suggests there may be some withdrawal after repeated use of PCP. The symp-toms include vocalizations, grinding of the teeth, diarrhea, difficulty staying awake, anxiety, tremors, memory impair-ment, and depressive-like symptoms (Nabeshima, Mouri, Murai, & Noda, 2006). Reports of withdrawal symptoms in humans following the prolonged use of ketamine or

Agrannulocytosis

With regard to clozapine specifically, a major problem is increased risk of a disorder called agranulocytosis, a potentially fatal loss of white blood cells and decline in immune system function due to the suppression of bone marrow activity. It occurs in 1 to 2% of all patients receiv-ing clozapine and can happen at any time. For this reason, patients taking clozapine must be carefully and continu-ously monitored with frequent blood testing. This serious side effect kept clozapine off the market for many years.

cotunine

alkaloid in tobacco predominant metabolite in nic studied for some disorder now

thc toxicity

almost impossible to od -1-1.8 kg w/ 5% taken orally by female weed smoke more tar than boges -data on cancer very mixed thc kills cultured hippocampal cells, not in other cells in high in cb reciptor dencity -could cause medical loss

debated effects

amitovational syndrome -most research untrue gateway drug -most studies suggest false -common liability model a better explanation alc and nic better represent gateway drugs

addiction via smoking

additives sensory cues smokers have greater number of nicotinic receptors -could be due to decrease in turnover rate-desinsitization inhalation makes it cross blood brain barrier most rapidly

differences in vaper absorption

and what other chemicals or flavorings have been added. The age of the ENDS device (whether it is "first" or later generation); how much use it has had (most of the nicotine content is delivered during the first 150-180 puffs, despite manufacturer claims that the solution will last up to 500 puffs; Goniewicz et al., 2013; Pagano et al., 2016); and the features of its engineering, such as its battery power and resultant capacity to heat the atomizer for aerosol produc-tion, also determine the speed and efficiency with which nicotine is delivered (Etter, 2015; Lisko, Tran, Stanfill, Blount, & Watson, 2015; Martinez, Dhawan, Sumner, & Williams, 2015; Talih et al., 2015). Finally, the experience level of the vaper is important. Naïve users tend to vape as if they are smoking a cigarette, with short, hard draws, whereas experienced vapers take longer puffs, inhaling a greater volume of vapor. These differences in puffing tech-nique translate into experienced vapers receiving more nicotine from their ENDS device (Farsalinos et al., 2015; Schroeder & Hoffman, 2014). A comparison of first-time and 4-week e-cigarette use found that practice generated a 24% increase in peak plasma concentrations and a 79% increase in overall nicotine intake (Hajek et al., 2015).

performance

Reports of the effects of typical antipsychotics on attention and cognitive performance have been variable. Most stud-ies examining acute effects show impairment, probably related to the sedative actions of antipsychotics. Tolerance to these effects has been reported to occur within about two weeks of regular use. Clozapine and remoxipride, both atypical antipsychotics, have been shown to interfere with performance. The findings with sulpride, however, have been mixed (King, 1993). Surprisingly, few studies of the effects of antipsychotics on cognitive functioning have been conducted. Those that were done have been inconclu-sive, reporting no effect, deficits, or improvements (Judd, Squire, Butters, Salmon, & Paller, 1987)

persistent depressive disorder

Some individuals experience a chronic sense of being "down in the dumps" without meeting full diagnostic cri-teria for major depressive disorder. These people may be diagnosed with persistent depressive disorder (or dysthymia) which tends to onset prior to adulthood and is associated with a higher likelihood of comorbid substance use 291

hash oil

boiled with solvent solvent strained out 60-70 percent thc popular bc easy to smuggle

side effects of marijuana

thc suppresses immune system-does not increase infection risk lowers testosterone, sperm count, estrogen crosses placental barrier -lowers birth weight -some link to childhood cancer respitory -bronchitis, astma anxiety/panic

glutamate hypothesis

the idea that schizophrenia may be caused, in part, by understimulation of glutamate receptors found out pcp and ketamine can mimic symptoms nmda doin shit sympotms of pcp directly relate to binding to nmda glutamate receptor genetic disposition to glutamate receptor could play a role cerebral spinal fluid w. glutamate hyperactivity similiar to those without

history of tea

credits the discovery of the beverage to the Chinese emperor Shen Nung around 2700 bce. It is known that tea was cultivated and sold commercially in China by 780 ce when the book Ch'a Ching, or Tea Classic, was written. The book was sponsored by a group of merchants and its pur-pose was to promote tea drinking (Forrest, 1973). Tea was first mentioned in print in Europe in 1559, but it was not until 1606 that the Dutch began shipping tea to Europe. By the 1630s, the Dutch were sending tea on a reg-ular basis to satisfy a growing demand in their country as well as in Germany and France. Tea was also becoming popular in Portugal, which had an extensive Oriental trade of its own. In the 1640s and 1650s, tea enjoyed a brief phase of popularity in France but the French soon turned to cof-fee in the 1660s. During this time, tea was not extensively consumed in England. It did not become fashionable there until Charles II married the Infanta Catherine, who brought tea drinking with her from Portugal in 1662. Tea also became popular in the 13 British colonies of North America. In fact, by 1760, tea was the third largest export from England to the colonies and this figure represented only a quarter of the total tea imported; the rest was smuggled. Smuggling was a lucra-tive enterprise due to the tea tax impose

effects on body

dilation, vasodilation (dilation of the blood vessels), and bronchodilation (dilation of air passages in the lungs). Their ability to open up the lungs and ease breathing made them historically useful as medicines for people suffering from asthma. When stimulants are used for their psycho-active properties, most of the sympathomimetic effects are considered unpleasant. Methamphetamine has stronger CNS effects and fewer peripheral effects than d-and l-amphetamine or cocaine. At high doses, the amphet-amines can cause abdominal cramps, nausea, vomiting, tremors, and exacerbate motor tics (Heal et al., 2013). Khat chewing delays gastric emptying and reduces intestinal absorption of nutrients, which can lead to malnutrition (Valente et al., 2014). Amphetamine and other psychomotor stimulants decrease food consumption. The mechanism responsible for this effect is not well understood, and may be achieved secondarily through the drugs' impact on other behaviors. In laboratory animals, amphetamine stimulates engage-ment in many behaviors other than eating, which contrib-utes to the reduction in food intake. The missed opportunity is later compensated for by excessive eating. Anorectic (appetite-suppressing) drugs are capable of cre-ating a satiety response which generates a sequence of behaviors that, in rats, involves grooming and resting and, in humans, the feeling of having had a full meal. It is thought that activity at serotonin 5-HT1B and 5-HT2C receptor

low moderate doses

dishinbition, relaxation, drowsiness, eyphoria, sensory changes, decreased strenght, tremors, balance impairment

fda and nicotine

district court decision. Tobacco companies sued and, in 2000, the U.S. Supreme Court ruled in a 5 to 4 decision that the FDA cannot regulate tobacco products until given authority by Congress. Finally, in June of 2009, the U.S. Senate passed the Family Smoking Prevention and Tobacco Control Act, which put tobacco products under FDA con-trol in the United States (Mundy & Etter, 2009). The Act, signed into law by President Obama, enables the FDA to regulate the marketing and promotion of tobacco products and to set performance standards for tobacco products in order to protect public health. The FDA can mandate a reduction or elimination of harmful substances and regu-late nicotine content if there is a public health concern, but it cannot ask for the complete removal of nicotine from products. Under the Act, the sale of cigarettes characteriz-ing flavors such as cherry, vanilla, or grape is prohibited, though menthol-flavored cigarettes and non-cigarette tobacco products are excluded from the ban. The FDA also has the authority to approve products introduced after February, 2007, and to force tobacco manufacturers to pay fees to fund FDA product reviews. The Act applies to ciga-rettes, cigarette tobacco, roll-your-own tobacco, and smoke-less products, but does not cover e-cigarettes as several courts have ruled that because e-cigarettes are not sold as therapeutic devices for smoking cessation, they are not "tobacco products" and are not covered by the Act (Cobb & Abrams, 2011; Peterson, 2011). In April, 2014, the FDA proposed extending its author-ity over tobacco to include additional, unregulated prod-ucts that are deemed to be subject to the Family Smoking Prevention and Tobacco Contro

Classic hallucinogens

lassic hallucinogens. Classic hallucino-gens can be divided into two main structural classes: the indolamines, whose molecular structures bear resemblance to that of serotonin (5-HT), and the phenethylamines, which are structurally similar to molecules of dopamine (DA) or norepinephrine (NE). The chemical structure of LSD, for instance, is similar to that of serotonin and the drug there-fore belongs in the indolamine class, whereas mescaline has a molecular structure more closely resembling the cate-cholamines (DA and NE) and therefore belongs with the phenethylamines. Despite their structural differences, the indolamine and phenethylamine classic hallucinogens overlap considerably in their subjective effects, so they will be discussed together in this section. The main differences that exist amongst the classic hallucinogens lie in their selectivity for certain serotonin receptor subtypes, varying potencies, and durations of action (Halberstadt, 2015). In addition to LSD, members of the indolamine class of hallucinogens include: • lysergic acid amide (LSA)—an ergoline chemical com-pound (like LSD) found in the seeds of the flowering plant species known as morning gl

Aripiprazole (Abilify)

le (Abilify), for the treatment of schizophrenia. Aripiprazole has a mechanism of action unlike its prede-cessors and, for that reason, is sometimes referred to as a third-generation antipsychotic. It is a DA receptor partial agonist—it modulates, rather than blocks, dopamine activity at D2, D3, and D4 receptor subtypes. Recall from Chapter 4 that a partial agonist has a high affinity for the receptor to which it binds, but it activates that receptor to a lesser degree than would the natural ligand (i.e., dopamine). Because of this, in regions of the brain where dopamine activity is too low (i.e., in the prefrontal cortex where the mesocortical pathway terminates), aripiprazole acts as an agonist by binding to and increasing the activation of DA receptors. In regions of the brain where dopamine activity is too high (i.e., in the nucleus accumbens where the meso-limbic pathway terminates), aripiprazole acts as an antag-onist by preventing DA from binding to its receptors and activating those receptors to a lesser degree. Aripiprazole also acts as a partial agonist or antagonist at various 5-HT receptor subtypes and affects histamine and alpha-adrenergic receptor function. Because aripiprazole stabi-lizes dopamine activity, it is able to treat positive, negative, and cognitive symptoms of schizophrenia. Though it is not the most efficacious of the newer antipsychotic medica-tions, its greater tolerability and fewer side effects make it a superior treatment for many patients (Khanna et al., 2014). In terms of their efficacy in relieving positive, nega-tive, and cognitive symptoms of schizophrenia and their ability to increase quality of life and improve one's overall mental state, the atypicals are not overwhelmingly supe-rior to the typicals (Jones et al., 2006). In some cases and for certain symptoms, they may in fact be less efficaciou

dissovalbles

less nic higher ph. looks like food for kids The most recent smokeless tobacco product to hit North American markets—the dissolvables—has created worry amongst public health and medical workers. Their total nico-tine content is in the range of 3.1-4.5 mg/g, which is less than many other tobacco products, but their pH values are roughly 7.8-8.1. At these alkaline values, roughly 36-55% of the nicotine is readily absorbable. The major source of con-cern is how these products look, especially to children. Camel Orbs, which contain 1 mg of nicotine per pellet, resemble Tic Tacs or M&Ms, and Camel strips provide 0.6 mg of nicotine in a thin cinnamon-or mint-flavored film that looks like Listerine breath strips. Camel sticks contain 3.1 mg of nicotine and appear similar to a toothpick. The esti-mated minimum lethal dose of nicotine for a child is 1 mg per kg of body weight (Connolly et al., 2010). As such, a typi-cal 2 year old weighing 28 lb would need to ingest only 12 Camel Orbs to reach a potentially lethal dose of nicotine.

theories together

likely a combo

routes of admin

inhalation snuffing chewing

nic admin

inhale, nazal, oral, transdermal

subjective

pleasure-rapid absorption into blood rather than "high" and steady dose smokers lower wellbeing and moodiness

humans

pleasure/increased performance tremors/muscle weakness increase heart rate, blood pressure laxitive increases dopamine stimulate release of epinephrin-increase breatjing, yak

animal behavior

possible discrimination-but discrimination not great only saline at high doses but generalizes to other antipsychotics lowers aggression unconditioned self admin-low, adversive-lack of abuse potential

distribution

prmarily metabolized in liver females metsbolixe faster

later gen problems

problems, headache, dizziness, sweating, nervousness, and agitation, but these symptoms tend to dissipate with time. These side effects likely result from SSRI effects on 5-HT2 receptors. In contrast with the MAOIs, the SSRIs decrease appetite, promote weight loss, and are sometimes used to treat obesity (Boyer & Feighner, 1991). Most of the side effects associated with third-genera-tion antidepressants are due to this class's antagonism of acetylcholine and histamine receptors and enhancement of 5-HT2-3 receptor activity. These side effects include increased appetite and weight gain, changes in blood pres-sure, dizziness, dry mouth, and gastrointestinal problems. Side effects associated with bupropion include restlessness and agitation, tremor, constipation, nausea, headache, dry mouth, and loss of appetite. An additional, dangerous side effect of bupropion is that, like some TCAs, it increases the risk of seizure. The reason nefazodone (Serzone) is no lon-ger sold in Canada or the United States is because of the risk of liver damage. It is, however, available in other countries and in generic form in North America.

animals

readily discriminated mPFC responsible similiar to amphetimines- increase reward sensitivity effects cognition-increased response rate facilitates working memory animals reluctant to self-adminster-unlike humans condition reinforcemernti important then

positive effects

reduced anxiety cognitive enhancement-debated cerebro-vasodilation neuroprotection anelgesia anti-psychotic

pharmokynetics-entry through lungs/mouth muccus membranes

researchers to believe that absorption of nicotine through vaping must be occurring primarily in the mucous mem-branes of the mouth, rather than in the lungs (Cobb & Abrams, 2011). In an attempt to better understand the pharmacokinetics of vaped nicotine, Hajek and colleagues (2015) measured nicotine concentration in participants' blood after 5 minutes of ad libitum vaping. Peak venous blood plasma nicotine concentrations reached 5.7 ng/ml in practiced users within 5 minutes of the start of vaping. Other researchers have reported similarly quick rises in blood nicotine levels after 5 minutes of vaping (Dawkins & Corcoran, 2014; Spindle et al., 2015; Vansickel & Eissenberg, 2013). Peak nicotine levels varied across studies from ~6 ng/ml to 19 ng/ml following 10 puffs or 5 minutes of vaping. This wide range is not surprising, given the above discussion, and at the upper end begins to approach the level of nicotine delivery from a tobacco cigarette. The con-sistency of these studies, in terms of the rapidity with which vaped nicotine reaches venous blood, suggests a pulmonary route of absorption. Buccal absorption would not permit nicotine to reach the bloodstream so quickly. It is the case, though, that in addition to absorption in the lungs, nicotine from tobacco smoke or vapor may enter the bloodstream through mucous membranes of the mouth (buccal membranes). Because nicotine is a weak base with a pKa of about 8.0, absorption by this route is determined by changes in the pH of saliva. In general, cigarettes are made from flue-cured tobacco with a pH of about 6.0 or less. Burning produces an increasingly acidic smoke tha lowers the pH of saliva to about 5.3 from its normal range of ~6.2-7.4. At pH levels below ~6.2, the nicotine contained in tobacco smoke is highly (790%) ionized, which reduces its absorption (Brunnemann & Hoffman, 1974). To be absorbed, the nicotine from cigarette smoke must be inhaled into the lungs, which are so efficient that pH has no effect on absorption. By contrast, pipe and cigar tobacco is usually air-cured, a process that results in a more basic or alkaline smoke. Smoking a pipe or cigar will raise the pH of saliva to about 8.5, well within the range where ion-ization of nicotine is less than 50%, and absorption is rapid. Compared to cigarettes, cigar and pipe tobacco contain higher levels of nicotine, in the realm of 30-50 mg (Taghavi et al., 2012). Consequently, substantial amounts of nicotine in the smoke from cigars and pipes can be absorbed from the mouth, and inhalation into the lungs is not necessary (Armitage, 1973; Jones, 1987). The pH of ENDS e-liquids ranges across products, from about 4.8 to 9.6 in regular solutions and 8.2-9.6 in mentholated solutions (Lisko et al., 2015; Pagano et al., 2016; Stepanov & Fujioka, 2015). Nicotine from the more alkaline solutions is more readily absorbed through buccal membranes. Tobacco taken in the form of traditional dry snuff is sniffed into the nostrils. With this route of administration, most of the nicotine is absorbed through the mucous mem-branes of the nasal cavity rather than through the lungs, although some tobacco eventually gets into the lungs as well as the stomach. Dry snuff is not commonly used in modern times and absorption from this route of adminis-tration has been studied far less extensively than absorp-tion through the mucous membranes of the mouth.

Third gen antidepressants

ressants, the third-generation antidepressants, sometimes called the atypicals, are the more recently approved medi-cations used to fight depression. These drugs include the serotonin and norepinephrine reuptake inhibitors (SNRIs) that affect the functioning of both of those monoamines. Enhancing NE activity, through stimulation of the reticular activating system, is helpful for those individuals who exhibit symptoms of fatigue and loss of energy associated with depression. Third-generation antidepressants do not alter the functioning of muscarinic acetylcholine receptors and therefore do not produce some of the side effects asso-ciated with older antidepressants. Some of the atypicals do affect nicotinic acetylcholine and histamine receptor func-tioning and influence the dopamine system. Examples of these drugs and their mechanisms of action can be found in Table 13-2 (some of these may not be approved for use in parts of Europe or North America).

dopamine theory

result from excessive dopamine in limbic pathways haloperidol is a dub for this theory-medicine doesnt bind to d2

human self admin

s The use of consciousness-altering substances, including classic hallucinogens like DMT, mescaline, and psilocybin, is an ancient and near-universal practice in human cultures. However, the use of these drugs is quite different from that of most others. First, classic hallucino-gens are never consumed in a continuous manner. They are indulged in sporadically and on special occasions. The use of hallucinogens in most societies is usually associated with religious ceremonies, cultural practices, or therapeu-tic interventions. In many cultures, these drugs are taken only by priests and shamans for the purpose of divination, talking to the dead, or seeking direction from a deity. Even in modern Western culture, hallucinogens are usually taken episodically. Unlike other heavily used drugs such as alcohol or nicotine, the use of classic hallucinogens does not usually escalate over time. This is likely due, in part, to the rapid development of tolerance that occurs with repeated use.

strains

sativa-cerebral indica-indacouch -research shows not a lot of differences-mixed evidence in effects expentamcy plays a role

trends in use

stimulant drug, at some point during the past year, out-side of a physician's recommendation. The graph illus-trates the percentage of young adults between the ages of 19 and 28 years who reported past-year stimulant use in surveys conducted between 1991 and 2014. As you can see, some trends in drug use (such as those of crystal methamphetamine and crack cocaine) have remained rather stable or decreased slightly since the early 1990s. Others are marked by more dramatic declines in use, as in the case of methamphetamine and Ritalin. Annual rates of cocaine use illustrate a bumpy trend; there was a large spike in use in the early 1980s (not illustrated on this graph), followed by a gradual decline until the mid-1990s when use seemed to level off. There was a mild resurgence in the early-and mid-2000s, followed by a subsequent decline to mid-1990s levels. Data from 2014 show a significant increase in prevalence of use over 2013 levels, but additional years of data are needed to determine whether this marks the beginning of a resur-gence in cocaine use. A similar bumpy pattern of annual use can be seen for amphetamine. Widespread use throughout the 1980s (not shown) was followed by a decline during the early 1990s. In the early 2000s, there was a slight resurgence in the use of amphetamine which, in recent years, has grown far more prevalent. The increasing use of amphetamine is mirrored by the trend in Adderall use, which is now at its highest point since its first year of survey measurement in 2009 (Johnston, O'Malley, Bachman, Schulenberg, &

stimulus properties

stimulus ProPerties Dissociative anesthetics appear to have unique stimulus properties. Animals trained to discriminate PCP and ketamine from saline do not generalize responding to any other class of drugs, including stimulants, depressants, or hallucinogens, and no drug has been found to antagonize their stimulus prop-erties. Animals generalize responding only to other drugs also known to block NMDA receptors, such as dextro-methorphan (see later in this chapter), indicating that this effect is likely the basis for the drugs' stimulus proper

two sides of same coin

stress hormones interact in complex ways with mono-amine systems, including DA, NE, and 5-HT. For example, dopamine and glucocorticoid receptors coexist in neurons of the ventral tegmental area that project to the nucleus accumbens (Ahima & Harlan, 1990). Under chronic stress, heightened cortisol levels encourage DA release and struc-tural change within the mesolimbic DA system. One such change is an upregulation of DA receptors in the ventral tegmental area (Czyrak, Maćkowiak, Chocyk, Fijał, & Wedzony, 2003). Sensitization of the stress system (or, what George Koob calls the antireward system), and its interac-tion with the dopamine system, may also contribute to the depressive, anxious, and irritable symptoms that appear during drug withdrawal and craving, thereby increasing the propensity for drug addiction (Wise & Koob, 2014). CRH neurons originating in the amygdala are directly and indirectly connected to areas of the hindbrain and midbrain, including the serotonin-containing raphe nuclei and the norepinephrine-containing locus coeruleus. During stressful events, amygdala activity overrides that of the prefrontal cortex and activates stress pathways in the hypothalamus and brainstem, leading to increased lev-els of monoamines and perhaps even upregulation of their receptors. Therefore, any change in the structure or activity of the amygdala has the potential to produce changes in the functioning of monoamine systems. Changes in glucocorticoid levels are also strongly associated with changes in 5-HT function. You have read that depressed individuals often demonstrate abnormali-ties in the number and function of 5-HT1A receptors, but the exact nature of this relationship is hotly debated. One finding that is well established is the link between stress, high levels of HPA-axis stress hormones, and a reduction in both number and function of postsynaptic 5-HT1A recep-tors in the hippocampus (Drevets et al., 2007). Adrenalectomy (the surgical removal of the adrenal glands, thereby clearing the body of cortisol) increases 5-HT1A receptor densities and binding (Grino et al., 1987), whereas 2 weeks of chronic stress (and elevated levels of cortisol) decreases 5-HT1A receptor densities and binding in the rat hippocampus (López, Chalmers, Little, & Watson, 1998). This suggests that changes in 5-HT neuro-transmission may actually be the result of hypersecretion of stress hormones, especially cortisol. Research in patients with major depressive disorder suggests that abnormal HPA-axis function precedes the onset of clinical symptoms of depression. It may be that cer-tain individuals are genetically predisposed to develop HPA-axis hyperactivity. In a study that spanned two decades, researchers discovered that the number of child-hood and adolescent stressful experiences correlated with the development of depression and suicidal ideation. Moreover, this correlation was strongest in individuals with the short form of the 5-HT transporter protein gene (Casp

effects on humans

subjective and cognitive effects A dose of 75-100 mg of MDMA induces a subjective state similar to that caused by marijuana or low doses of phencyclidine (PCP), with no hallucinations, and an enhanced awareness of emotions and sensations—effects similar to the entac-togenic effects described earlier in Section 15.1.4 (Lamb & Griffiths, 1987; Siegel, 1986). The MDMA "high" is also characterized by disinhibited social interactions, extrover-sion, and an openness of spirit; increased self-confidence, self-esteem, and sense of well-being; enhanced feelings of closeness, emotional warmth, and empathy toward oth-ers; improved mood and euphoria; increased vigilance and sharpened sensory perceptions; and wakefulness, energy, and endurance (Iversen, 2006; Moratalla et al., 2015). As with LSD, these effects are subject to rapid acute tol-erance, which generally means that ecstasy is unlikely to be used continuously. Tolerance to MDMA's acute effects dissi-pates within a few days. Though the majority of users report acute effects of MDMA that are largely positive, up to one-quarter of MDMA users experience at least one adverse reaction (Davison & Parrott, 1997; Moratalla et al., 2015). Negative drug experiences often include apprehension, anx-iety, a loss of control over thoughts, the feeling of having too much energy, and skepticism about the drug experience (Cohen, 1998; Parrott, 2010). As with psilocybin and LSD, the use of MDMA can also lead to the development of hal-lucinogen persisting perception disorder (Litjens et al., 2014).

chronic effects of nicotien

survey in the United Kingdom has shown that smokers have lower levels of psychological well-being than nonsmokers and ex-smokers (West, 1993). In addition, even though it is typically found that mood worsens when a person stops smoking, it slowly returns to the normal smoking level after 3 or 4 weeks. What's more, it then continues to improve even further during the following 10 weeks, so the person's mood becomes better than it was while he or she was smoking (Hughes, Higgins, & Hatsukami, 1990).

Punding

A disorder of stereotypic motor behavior in which there is intense fascination with repetitive handling and examining of mechanical objects n 1965, a Swedish psychiatrist named Gosta Rylander described a peculiar behavior shown by high-dose users of phenmetrazine, an amphetamine-like drug used to pro-mote weight loss. These users were grinding up phenmet-razine pills and injecting them intravenously to experience a rush. The behavior Rylander noticed was what the users called punding—the repetitive performance of some (usu-ally purposeless) act for an extended period. Typical acts included taking apart and putting together a watch or a telephone, sorting and resorting things in a handbag, or cleaning and re-cleaning an apartment. When users are punding, they often won't take the time to eat or drink or even go to the bathroom, and they become annoyed if the activity in which they are engaged is interrupted (Rylander, 1969). Similar behavior is common among amphetamine users. Punding is considered the human equivalent of ste-reotyped behavior seen in laboratory animals after high-dose injections of amphetamines. It is quite likely that both punding and stereotyped behavior are caused by stimula-tion of the nigrostriatal DA system, which has input into the extrapyramidal motor system (see Chapter 4

lethal dose

A lethal dose of ketamine taken intranasally is estimated to be about 2700 mg, nearly 40 times greater than the usual effective dose (Gable, 2004b). Although toxic effects vary between individuals, high doses have been found to cause respiratory arrest, convulsions, and coma. Kidney failure and brain hemorrhage have also been reported. The lethal effects of PCP and ketamine are potentiated by the co-presence of other CNS-depressant drugs, such as alco-hol and barbiturates, in the bod

factors of elimination

A number of factors affect the rate of caffeine metabo-lism and elimination from the body. Individual genetic variation is one such factor. The CYP1A2 gene carries instructions for building the caffeine-metabolizing cyto-chrome P450 enzyme. There are two forms of the gene. Individuals who express the CYP1A2*1A gene form are rapid caffeine metabolizers while those who carry the CYP1A2*1F gene form are slow caffeine metabolizers. The same amount of caffeine will have a greater effect on a slow metabolizer of caffeine than on a fast metabolizer and may be more likely to have adverse effects. The CYP1A2 enzyme can also be stimulated or inhib-ited by various foods and medications. For example, caf-feine metabolism is slowed by alcohol and grapefruit juice but speeded by broccoli, and smokers eliminate caffeine nearly twice as quickly as nonsmokers (James, 1991; Parsons & Neims, 1978). The fluoroquinolones, a family of antibiotic drugs, can also slow caffeine metabolism by inhibiting the CYP1A2 enzyme. In females, caffeine metabolism is impacted by hor-mone levels. Caffeine half-life is prolonged during the luteal phase (after ovulation) compared to during the fol-licular phase (before ovulation) of the menstrual cycle (Arnaud, 1993). Taking oral contraceptives also extends the half-life of caffeine, nearly doubling it (Callahan, Robertson, Branfman, McComish, & Yesair, 1983). Caffeine elimination slows progressively during pregnancy. During the first trimester, caffeine half-life is similar to that of non-pregnant women, but increases to about 10 hours near the end of the second trimester. By the end of pregnancy, half-life is extended up to 18 hours, leading to a decrease in total clearance and an accumulation of caffeine in the mother and fetus (Ådén, 2011). These changes in caffeine pharmacokinetics seem due to reductions in enzyme activ-ity (Ådén, 2011). Half-life returns to its normal range within 3 to 15 weeks postpartum (Gaohua, Abduljalil, Jamei, Johnson, & Rostami-Hodjegan, 2012). Newborns are not proficient metabolizers of caffeine, due to immaturity of the liver's CYP1A2 enzyme system, and they excrete about 85% of caffeine unchanged in urine. The half-life of caffeine averages about 100 hours in an infant, but can range from ~40 to 230 hours with premature and young infants demonstrating longer caffeine half-lives (Ådén, 2011; Fredholm et al., 1999). An adult-like pattern of caffeine metabolism and excretion does not develop until about 7 to 9 months of age (Aldridge, Aranda, & Neims, 1979). In nonhuman species, caffeine is metabolized differ-ently, using different enzymes and creating different metabolites (Arnaud, 2011; Berthou et al., 1992; Bonati & Garattini, 1984). Some metabolites created in other species may be more active or toxic than those created in humans (Stavric & Gilbert, 1990). In addition, metabolic rates differ across species. For instance, in a rat or mouse, the half-life of caffeine is only about 42-72 minutes. A dose of 10 mg/kg in a rat is thought to be the rough equivalent of a 3.5 mg/kg dose in a human (Fredholm et al., 1999). For a 70 kg indi-vidual, that's about 250 mg of caffeine. One must always be cognizant of these interspecies differences when inter-preting effects of the methylxanthines in nonhuman animals.

benefits from caffeine

A number of health benefits appear to result from the reg-ular consumption of caffeine. Coffee drinkers show a low-ered risk of developing type 2 diabetes. In those who consume at least six cups of coffee per day, risk is reduced by 35% compared to those who consume less than two cups per day (van Dam & Hu, 2005). A comparison of caf-feinated and decaffeinated coffee consumption found that the decaffeinated coffee also offered some protection against type 2 diabetes. Though the reduction in risk was not as great for the decaffeinated coffee drinkers, it was significant enough to suggest that some ingredient in the coffee, other than caffeine, might be the beneficial agent (Heckman, Weil, & Gonzalez de Mejia, 2010). Caffeine may also cause weight loss, or at least prevent weight gain and obesity, due to its role in increasing metabolic rate, energy expenditure, lipid degeneration, and thermogene-sis (Greenberg, Boozer, & Geliebter, 2006; Turk et al., 2009). Consumption of 300 mg of caffeine daily corresponds with an increased energy expenditure of 79 kcal (Rudelle et al., 2007). There is growing, albeit still contentious, evidence of an association between coffee and tea intake and reduced risk of various forms of cancer, including endo-metrial, hepatocellular, colorectal, gastrointestinal, lung, prostate, breast, and skin cancer (Gardner et al., 2007; Hashibe et al., 2015; Lambert, 2013; Ludwig et al., 2014). Not all studies support these findings, however, and those that do acknowledge that some of the benefit may be due to coffee or tea constituents other than caffeine, such as polyphenols catechins, and flavonoids. Coffee and tea are also credited with reducing risk of coronary heart disease, congestive heart failure, arrhythmia, stroke, and even mor-tality in general, though these benefits are related to dose and less likely to occur with extremely low or highly exces-sive intake (Gardner et al., 2007; Ludwig et al., 2014; O'Keefe et al., 2

caffiene self adminastration and reinforcer

A number of human self-administration studies have reported a preference for caffeinated coffee and capsules containing caffeine, suggesting that caffeine serves as a reinforcer. An individual's history of caffeine use seems to play a role in determining its reinforcing value. For instance, a study conducted with moderate coffee drinkers revealed a distinct preference for caffeinated over decaf-feinated coffee. This preference could be detected in some people at doses as low as 25 mg per cup and was greatest when the participants reported caffeine withdrawal (Hughes, Higgins, Bickel, & Hunt, 1989; Hughes, Higgins, Gulliver, & Mireault, 1987). In another study, when permit-ted to consume caffeine freely for 1 week prior to preference testing, people reliably preferred caffeinated coffee. However, people who were not permitted to have any caf-feine for 1 week, and were presumably not physically dependent on caffeine, showed considerable individual variation in caffeine preference (Griffiths & Woodson, 1988). Using a within-subjects design, Garrett and Griffiths (1998) examined the effects of caffeine dependence by maintaining participants, for 9 to 12 days, on a daily dose of caffeine (300 mg of caffeine/70 kg of body weight/day; caffeine-dependent phase) or on a daily dose of a placebo (caffeine-nondependent phase). When switched from the caffeine-dependent to the caffeine-nondependent phase of the experiment, participants demonstrated typical with-drawal symptoms (e.g., fatigue and shifts in mood). Caffeine-dependent participants were also willing to for-feit money to avoid placebo administration and to pay more money for caffeine compared to participants in the nondependent phase. When dependent, they were twice as likely to take a dose of caffeine versus a placebo as when they were nondependent. This study clearly shows that varies between people and activity

glucocorticoid theory of depression

A system that has become a major focus of depression research is the hypothalamic-pituitary-adrenal (HPA) axis, illustrated in Figure 13-1. It is an important part of the neuroendocrine system that controls the body's response to stress. Stress is the most influential environmental fac-tor that predisposes an individual to depression, so it is not surprising that research would veer in this direction. The HPA-axis response to stress is organized hierarchi-cally so that the physiological changes that take place are like a domino effect. The stress response starts in the hypothalamus where neurons secrete corticotropin-releas-ing hormone (CRH). The release of CRH, in turn, initiates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which ultimately stimulates the secretion of glucocorticoids (cortisol in humans) from the cortex of the adrenal glands, which sit above the kidneys. The stress response is important for survival since it mobilizes us for "fight or flight" and helps us escape dan-ger. Once a stressful experience ends, the HPA-axis response is terminated. This is achieved through a series of negative-feedback loops—cortisol binds to glucocorticoid receptors in the pituitary, hypothalamus, and especially in the hippocampus, which then sends a signal to the hypo-thalamus to stop releasing CRH. In individuals who expe-rience frequent or chronic stress, the HPA axis may become hyperactive. Animal research suggests that chronic-stress-induced overactivity of the HPA axis is due, at least in part, to a downregulation of glucocorticoid receptors in the hip-pocampus (Meyer, van Kampen, Isovich, Flügge, & Fuchs, 2001). Overactivity of the HPA axis, indicated by high lev-els of CRH and cortisol, is a frequent finding in patients with major depressive disorder and in suicide victim Neurons that contain CRH are present, not only in the hypothalamus, but also in areas of the limbic system. Recall that the limbic system plays an important role in emotion and mood. One such limbic area is the prefrontal cortex which, like the hippocampus, contains receptor sites for CRH and cortisol and sends inhibitory projections to the hypothalamus. Another limbic area is the amygdala which, you will recall, plays an important role in fear and anxiety. The amygdala also contains receptors for HPA-axis stress hormones but sends excitatory projections to the hypothalamus. A very common finding in patients with depression is structural change in areas of the limbic sys-tem. These changes are believed to result from high levels of cortisol circulating through the bloodstream and enter-ing the brain. In depression, both the prefrontal cortex and he hippocampus lose volume (i.e., they atrophy), whereas the amygdala increases in volume. The increases in metab-olism and blood flow to the amygdala are related to the severity of depressive symptoms (Peluso et al., 2009). Because the prefrontal cortex, hippocampus, and amygdala are interconnected with the hypothalamus, struc-tural changes in these brain regions lead to a loss of balance between inhibition and excitation of the stress system, resulting in heightened stress hormone release. Heightened HPA-axis activity and resulting elevation of stress hormone levels substantially increases one's risk of depression and suicide. Investigation of the therapeutic potential of CRH receptor antagonists has produced mixed results. In some clinical trials, patients with major depressive disorder experienced significant reduction of depressive symptoms with CRH antagonists. In other trials, CRH receptor antag-onists fared no better than a placebo. It may be that CRH antagonists benefit only those individuals whose depres-sion is brought on by stress and resulting hyperactivity of the HPA axis (Paez-Pereda et al., 2011).

neuropharmacology

Acetylcholine (ACh) is a neurotransmitter used widely in both the peripheral and central nervous systems. Recall from Chapter 4 that there are two basic types of receptors for ACh: muscarinic and nicotinic. Nicotinic receptors (nAChRs) are the ones stimulated by nicotine. In the peripheral nervous system (PNS), where they were first discovered, nAChRs act at neuromuscular junctions of striated muscles and control voluntary muscle action. In the central nervous system (CNS), they participate in many cognitive functions, including learning and memory.

conditioned behavior-like amphetamine

After an initial suppression of all behavior at higher doses, the effects of nicotine on both positively and aversively motivated behavior are similar to those of amphetamine in that they are dependent on control rate; high rates are depressed, and low rates are increased (Morrison, 1967; Pradhan, 1970). Like amphetamine, nicotine does not appear to increase responses that have been suppressed by response-contingent shock (Morrison & Stephenson, 1973). Also like amphetamine, nicotine lowers the threshold of responding for intracranial electrical self-stimulation (ICSS) of the medial forebrain bundle. Extracts prepared from moist snuff and snus, when injected subcutaneously in rats, also produce reinforcement-enhancing (i.e., ICSS threshold-lowering) effects (Harris et al., 2015). The increase in reward sensitivity can last for more than a month following cessation of nicotine self-administration (Kenny & Markou, 2006). Nicotine does disrupt rats' ability to withhold responding on a DRL (differential reinforcement of low response rate) schedule in a manner similar to amphet-amine. This effect does not appear on initial exposure to the drug, but after repeated doses (Kirshenbaum et al., 2011), and can be blocked by the nAChR antagonist, meca-mylamine. The pronounced similarity between the effects of nicotine and amphetamine on operant behavior suggests that many are likely brought about by a similar mechanism. Because amphetamine increases activity at catecholamine synapses and nicotine causes a general release of epinephrine and stimulates DA and NE syn-apses, it is possible that many of these behavioral effects of nicotine are catecholamine-related (Pradhan, 1970). This increase in catecholamine activity depends, however, on nicotine's action at its receptor sites because most of these behavioral effects can be blocked by mecamylamine (Morrison, 1967). There is considerable interest in studying the effects of nicotine in laboratory animals on tasks that model aspects of human cognition that are improved by nicotine. Popke and colleagues (2000) used such tasks to examine the effects of nicotine on cognition in rats. In one test, a repeated incremental acquisition task, rats were required to learn a sequence of lever presses on three levers. The session started with presses on one lever producing rein-forcement, but eventually required the rat to learn a spe-cific pattern of six lever presses on the three levers to earn reinforcement. On this task, nicotine failed to affect accu-racy, but did increase speed of responding. Similarly, nico-tine enhanced speed of performance on a conditioned discrimination task, which is like a matching to sample task. In this task, animals are presented with one of two stimuli (e.g., either a loud sound or a soft sound). After a delay, they are required to press a particular lever for rein-forcement. The animal must remember which stimulus was presented to know which lever to press. Increasing doses of nicotine increased the speed of pressing the lever, but had no effect on accuracy. Another test used by

sleep

All classes of antidepressants have been found to affect sleep. The MAOIs can cause either insomnia or sedation. Strangely, the tricyclics cause drowsiness, although this may have more to do with their anticholinergic properties than their monoamine-stimulating effects. Unlike the anti-depressant effect, which takes days to develop, a single dose of a tricyclic can cause sleepiness and is sometimes prescribed to treat insomnia. The drug does not, however, increase total sleeping time. High doses of tricyclics at bed-time can cause nightmares. Many antidepressants, like fluoxetine and venlaxafine, significantly reduce REM (rapid eye movement) sleep time. Reduction in REM sleep may be associated with a drug's antidepressant effects because sleep deprivation, particularly REM deprivation, has been shown to decrease symptoms of depression (Ravindran et al., 2009), and sleep can worsen the symptoms of depression (Janicak, Davis, Preskorn, & Ayd, 1993). The beneficial effects of REM deprivation build with time and even persist after depriva-tion ceases. Not all antidepressants reduce REM sleep time (Spiegel & Aebi, 1981); bupropion actually increases it (DeVane, 1998). Patients often report that fluoxetine increases the viv-idness of their dreams. While some enjoy this side effect, others find it disturbing. SSRIs have also been found to produce insomnia in some individuals. Many third-gener-ation antidepressants, such as mirtazapine, have antihista-minergic actions and cause sedation and sleepiness, while others, like bupropion, can produce insomn

first gen neuro

All monoamine neurons produce the enzyme monoamine oxidase (MAO). This enzyme degrades monoamine mole-cules that float freely (i.e., those that are outside of vesicles) in the cytosol of the axon terminal, thereby diminishing available neurotransmitter. The MAOIs do exactly what their name implies—they inhibit (block) the activity of monoamine oxidase so that molecules of DA, NE, and 5-HT that float freely in the cytosol are not destroyed but, instead, are available for vesicle storage and later release. Thus, MAOIs increase the availability and activity of DA, NE, and 5-HT. There are actually two types of MAO: MAO-A degrades all three monoamines, whereas MAO-B is most active in metabolizing DA. The effect of the older MAOIs was nonselective and irreversible—they inhibited both MAO-A and MAO-B, and their effects persisted for several days or weeks, even when the drug was not taken, until enzyme stores were replenished. Because both forms of MAO enzymes are present throughout the body, the nonselective MAOIs produced numerous unpleasant side effects. Some newer MAOIs, such as selegiline, act selec-tively on MAO-B at low doses but, at higher doses, also affect MAO-A. In addition, some newer MAOIs are revers-ible, meaning they can detach from MAO rather than deac-tivate it permanently. Although they are grouped with the MAOIs as first-generation antidepressants, the tricyclics are actually more similar in function to the second-and third-generation SSRIs and SNRIs. Their principal mechanism of action is to block reuptake transporter proteins on the axon terminals of 5-HT and NE neurons so that, after these monoamines are released into the cleft by an action potential, their reup-take is inhibited and their duration of action on the post-synaptic cell is prolonged. At one point it was believed that all tricyclics worked in the same way, but there are now many drugs that have the three-ring structure of the tricyclics but produce various effects on the functioning of other monoamines (Ordway, Klimek, & Mann, 2002). In addition, the TCAs affect other transmitter systems—they act as anticholinergics, blocking muscarinic acetylcholine receptors, and they antagonize histamine and a1 adrener-gic receptors. Although the TCAs are a safer and some-times more effective alternative to the MAOIs, these additional actions can produce unpleasant and even dan-gerous side effects in some people.

seratonin

All of the three monoamines are probably involved in some aspect of mood, and they interact with each other in complex ways, but the monoamine that has received the most focus over the past couple of decades is serotonin. Decreased activity in the serotonin system, although it may not be the direct cause of depression, certainly appears to play a role in vulnerability to depression. Many lines of research support this idea. For example, individuals diag-nosed with major depressive disorder have low cerebrospi-nal-fluid levels of 5-HT, its amino acid precursor tryptophan, and its major metabolite 5-H1AA. Below-normal levels of 5-H1AA also correspond with a nearly fivefold increase in suicide risk (Pompili et al., 2010). Treatments that have been shown to be effective in relieving depression ultimately increase transmission at serotonin synapses. SPECT imaging data indicate that depressed individu-als also exhibit decreased numbers of 5-HT reuptake trans-porter proteins in the brainstem (Malison et al., 1998). At first glance, this appears counterintuitive. Because reuptake transporter proteins rid 5-HT from the synapse, a reduction in their quantity would seem like a protective mechanism, decreasing vulnerability to depression. Moreover, antide-pressants such as the SSRIs are effective because they inhibit the action of serotonin reuptake transporter pro-teins; with chronic treatment, SSRIs significantly reduce (i.e., by 30-40%) the amount of 5-HT transporter protein mRNA in the raphe nuclei (Lesch et al., To understand this finding, we must consider the big-ger picture—what this deficiency in 5-HT transporter pro-teins actually illustrates. Quite possibly, it indicates a pathological reduction in the sheer number of serotonin neurons (upon which the transporter proteins reside). Even a slight reduction in the number of raphe serotoner-gic neurons would translate into an exponentially greater loss of 5-HT release in projection areas, such as the cortex. It may also be an indication of a more widespread dysreg-ulation of serotonin system function. In support of this explanation, genetic research has isolated a portion of a gene, found on chromosome 17, responsible for 5-HT transporter protein production. This portion of the gene, called a promoter region, regulates the number of 5-HT transporter proteins that get made. It comes in two forms—long and short. Possessing the short form of this portion of gene is associated with having significantly fewer 5-HT transporter proteins and a heightened risk of developing depression, whereas possessing the long form appears to create a protective effect. Finally, a reduction in 5-HT reup-take transporter protein quantity could indicate a compen-satory mechanism, an attempt by neurons to overcome a preexisting state of synaptic 5-HT hypoactivity by reduc-ing 5-HT reuptake activity (Malison et al., 1998

self-administration

Although caffeine can serve as a reinforcer in laboratory animals, it does so only under limited circumstances and does not seem to be able to support a lot of behavior. In one primate study where bar pressing delivered an intra-venous caffeine infusion, only two out of six monkeys self-administered the caffeine spontaneously. The four monkeys that did not voluntarily self-administer caffeine were then given automatic infusions of caffeine for a period of time. This procedure succeeded in establishing caffeine as a reinforcer in three of the four remaining monkeys (Deneau, Yanagita, & Seevers, 1969). The pat-tern of self-administration was irregular, with periods of voluntary abstinence, and there was no tendency to increase the dose over time. Likewise, in baboons and rats, caffeine is self-administered erratically and irregu-lar periods of abstinence occur. The reinforcing nature of caffeine is demonstrated, however, because rates of responding decline to near zero when a placebo is substi-tuted (Griffiths & Mumford, 1995). Other researchers have also demonstrated modest reinforcing effects with caffeine, but they were limited to specific doses and par-ticular animals (Griffiths, Bigelow, & Liebson, 1979). When given the opportunity to consume caffeine orally, few animals do so spontaneously, and a period of forced consumption is usually required before caffeine is self-administered (Vitiello & Woods, 1975). Still other studies have not been able to demonstrate reinforcing effects of caffeine at all, although these studies used only one dose of caffeine or tested for only a short time (Hoffmeister & Wuttke, 1973).

lower subjective liking and abuse liaboloty of methylphenidate

Although methylphenidate's binding sites and mechanisms of action are nearly identical to those of cocaine, intrave-nously or intranasally administered methylphenidate takes much longer to reach peak brain levels, compared to cocaine, and has a much longer half-life, compared to cocaine (Frölich et al., 2014; Romach, Schoedel, & Sellers, 2014). This helps to explain the lower subjective liking and abuse liability of methylphenidate. Khat chewers, like users of the amphetamines or cocaine, report euphoria and elation, enhanced self-esteem, and an increased ability to concentrate, associate ideas, and communicate accompanied by energetic discussions and social interactions (Valente et al., 2014; Wabe, 2011). The elevation in mood experienced during the first hours of use is often followed by agitation, restlessness, anxiety, and depression as the hours-long chewing session reaches its end (Valente et al., 2014)

performance

Although stimulant drugs can improve performance, this improvement may be limited to simple tasks, like sustained vigilance, or over-learned and overpracticed tasks, like simple reaction time tests. Some investigators have suggested that stimulants may actually impair performance on tasks that require cognitive flexibility and the ability to adopt new strategies (Judd, Squire, Butters, Salmon, & Paller, 1987). As men-tioned earlier, even low doses of amphetamine may create a tunnel vision effect by concentrating attention on only one feature of the environment. At higher doses, most of the simple beneficial effects of stimulants are lost and peo-ple become impatient, more easily distracted, and show impaired judgment. athletic Performance In one early study, Smith and Beecher (1959) gave amphetamine to competitive swimmers who were then timed while performing in the event for which they were training. The researchers found rmance, their use by athletes is banned by most national sports federations, and urine samples supplied by athletes at sporting events are screened for these drugs. As mentioned earlier, ephedrine is a psychomotor stimulant closely related to amphetamine. Ephedrine and similar drugs act as bronchodilators and are found in cold prepara-tions, cough syrups, and decongestants. Athletes should carefully check the ingredients contained in these medi-cines as taking them could result in urine samples testing positive for a banned substance. One such incident occurred at the 2002 Olympic Games in Salt Lake City, Utah, when a British alpine skier was stripped of his bronze medal in the slalom event. The athlete failed the drug test due to the presence of trace amounts of metham-phetamine in his urine. The compound was the l-isomer of methamphetamine, which is found in the American (but not European) formulation of Vicks Vaporub inhaler, which the skier used in the days prior to the event to treat a cold. Though l-methamphetamine has no CNS (and no performance-enhancing) effects, the anti-doping analysis did not distinguish between drug isomers and, despite an appeal, the athlete's medal was not returned (Appendino et al., 2014). Some other banned stimulant-like substances found in cold medicines include norpseudoephedrine, methoxyphenamine, isoprenaline, isoproterenol, and methylephedrine

atypical antipsychotics

Although their individual profiles vary considerably, they share an important property: a very weak affinity for the D2 receptor. That is, they bind to D2 receptors very loosely and have dissociation constants that are signifi-cantly higher than those of dopamine or the typicals (Seeman, 2002). Examples of such drugs include amisul-pride, clozapine, olanzapine, quetiapine, remoxipride, sertindole, and ziprasidone (Seeman, 2002). Because of this property, adverse EPS are atypical effects of these drugs. Positron emission tomography research reveals that about 60 to 80% of D2 receptors must be occupied in the striatum of the basal ganglia to produce EPS (Seeman, 2002). Because of their weak affinity for the D2 receptor, atypical antipsychotics avoid the problem of blocking dopamine in the nigrostriatal system and, therefore, pro-duce far fewer EPS compared to the typicals. They are also more effective than the typicals in treating a wider range of schizophrenic symptoms. Instead, the atypicals have high affinities for D3 and D4 receptors. Neither of these receptor subtypes is found in high quantities in the basal ganglia. The D3 receptor is local-ized largely in the nucleus accumbens, the terminal point of the mesolimbic projection, with many fewer receptors in the basal ganglia (Landwehrmeyer, Mengod, & Palacios, 1993). The D4 receptor is localized largely in the cortex, amygdala, and hippocampus—regions that are important in cognition, emotion, and learning. There are very few, if any, D4 receptors in human motor systems (Primus et al., 1997). Thus, it is possible for the atypical antipsychotics to depress dopamine activity in the mesolimbic system and treat psychoses without having a great effect on the nigros-triatal system and causing Parkinsonian side effects. Another major difference between the typicals and the atypicals is the extent to which they bind to 5-HT recep-tors, especially the 5-HT2A subtype. Both classes of anti-psychotics have some 5-HT2A blocking ability, but this activity is much higher for the atypicals. As a general rule,

atypical affects on humans

Although they produce far fewer EPS than do the typi-cals, the atypicals have their own set of problematic or even life-threatening side effects. Like the typicals, long-term use of atypicals is associated with disturbances in glucose metabolism and fat regulation, significant weight gain, and the onset of diabetes (Üçok & Gaebel, 2008). People taking atypical antipsychotics also experience thermodysregula-tion, dry mouth, dizziness, nausea, and are more prone to developing cataracts. Increases in triglycerides and choles-terol have also been found in individuals taking clozapine and olanzapine. Like the typicals, the atypicals can produce abnormal cardiac function that can be life threatening, espe-cially in older adults (Mehta, Chen, Johnson, & Aparasu, 2011). The U.S. Food and Drug Administration warns against treating dementia-related psychotic symptoms in the elderly with olanzapine or risperidone due to a near doubling of risk of death related to cardiac dysfunction or respiratory infections. Aripiprazole has a relative absence of most of the side effects mentioned earlier and, for that reason, has a higher compliance rate compared to typicals and many of the atypicals. Its most significant side effects are nausea and dizziness (Melnik et al., 2010).

modern smoking trends use

Although tobacco use is declining in industrialized nations, its consumption has been rising in developing countries of the world by about 1.4% per year. It appears that tobacco manufacturers, pressured by shrinking tradi-tional markets, have turned their attention to populations not well educated about the health risks of smoking (Greenlees, 2005; Hurt, Murphy, & Dunn, 2014). In response, many developing countries have been resisting aggressive marketing with stringent rules and controls but find themselves in frequent court battles with the tobacco industry (Wilson, 2010). Of the more than one billion smokers worldwide, 80% live in low-or middle-income countries. In China alone, there are 300 million smokers—the near-equivalent of the entire U.S. population. Two-thirds of Chinese men smoke, though smoking prevalence amongst Chinese women is low (65%). At these rates, annual smoking-related deaths are projected to rise in China from 1 million in 2010 to 2 million in 2030 and reach 3 million by 2050 (Chen et al., 2015). If current smoking trends continue, annual smoking-related mortality will reach 8.3 million people worldwide by the year 2030, 80% of whom will be in poor and developing countries (American Lung Association, 2011).

effects on behavior

Animals trained to discriminate GHB from saline show only a partial generalization of responding to morphine, LSD, and chlordiazepoxide; an even lesser degree of gen-eralization to amphetamine and alcohol; and do not gener-alize responding at all to barbital and PCP-like compounds. Animals will fully generalize responding to other drugs that are GABAB agonists, suggesting that this mechanism of action is likely responsible for GHB's unique interocep-tive effects. Any generalization of responding between GHB and drugs of other classes is highly dose-specific. For instance, rats trained to discriminate alcohol from saline will generalize responding to GHB, but only at a very nar-row range of intermediate doses. GHB has sedative properties and, at high doses, acts as an anesthetic. Animal research suggests that the state of anesthesia produced by GHB is more similar to cata-lepsy (a trancelike condition marked by immobility and diminished responsiveness) than to anesthetization. Brainwave activity is seizure-like in pattern, and the non-responsive state achieved with high doses of GHB is more characteristic of petit mal seizures than that pro-duced by anesthesia. At higher doses, body jerks and out-ward signs of seizure become apparent. With prolonged GHB administration, animals show cognitive impair-ments, including deficits in spatial learning and memory, that are distinct from the typical amnesia that can result during and after drug use (Sircar, Wu, Reddy, Sircar, & Basak, 2011). In pigeons, GHB increases punished responding to an extent comparable to that of pentobarbital (Frawly & McMillan, 2008). This finding suggests that, like the barbi-turates and benzodiazepines, GHB has anxiolytic proper-ties that may contribute to its abuse liability (Frawly & McMillan, 2008). Microinjection of GHB directly into the ventral tegmental area of rats produces a conditioned place preference, though GHB was not able to maintain operant responding for intravenous self-administration (Watson et al., 2010). A study involving baboons found that high-dose GHB was self-administered by two-thirds of the animals tested, suggesting the drug has some abuse potential. The animals that demonstrated the highest rates of responding for GHB were those that had a recent his-tory of self-administering other drugs, including cocaine. This suggests that a history of drug use is important to the reinforcing effects of GHB (Goodwin, Kaminski, Griffiths, Ator, & Weerts, 2011). 15.7.4: Effects of GHB on Human Behavior At low doses, GHB produces alcohol-like intoxication, char-acterized by mild euphoria, disinhibition, relaxation, drows-iness, slurred speech, dizziness, headache, nausea, and visual distortions. GHB is also reputed to be an aphrodi-siac, increasing libido and enhancing sexual pleasure; how-ever, such effects may depend more heavily on GHB's ability to reduce sexual inhibitions than on a true physio-logical aphrodisiac quality. When combined with alcohol or other CNS depressants, the effects of GHB are greatly enhanced. Often, users experience more debilitating symptoms of GHB intoxication, including abdominal pain, disorien-tation and confusion, hallucination, tremor and muscle twitching, ataxia (a lack of voluntary muscle coordina-tion), hypotonia (a decrease in muscle tone), hyporeflexia (a reduction or absence of reflexes), and amnesia for events that occurred both during and after drug use (Busardò & Jones, 2015; Miotto et al., 2001). Less often, GHB users develop vertigo, delusions, and extrapyrami-dal side effects (like those associated with the use of some antipsychotic medications; see Chapter 12). An Australian study reported that 99% of GHB users experienced adverse drug effects at least once, including profound sweating (58%), vomiting (53%), unconscious

other effects

Antipsychotic drugs are useful in the treatment of other medical conditions and forms of mental illness. They are effective antiemetics; that is, they prevent nausea and vom-iting and are useful in the treatment of motion sickness. In addition, they were originally developed by Laborit as presurgical and preanesthetic medications and are still used for that purpose. A number of movement disorders thought to result from excessive dopamine activity in the brain can, not surprisingly, be treated effectively with anti-psychotics. These disorders include Huntington's chorea, an inherited degenerative disease. Huntington's is fatal, but antipsychotics help control some of the symptoms. Antipsychotics are also useful in treating Tourette's syn-drome; Tourette's patients show involuntary muscle tics, twitches, and vocalizations. Surprisingly, antipsychotics are also used to treat tardive dyskinesia. Antipsychotics have also been used to treat hiccups, stuttering, delirium tremens caused by alcohol with-drawal, and psychotic behaviors induced by psychomotor stimulants, LSD, and other hallucinogens. Atypicals, including aripiprazole, have been used in the treatment of major depressive disorder, bipolar disorder, mania, and irritability in autistic children

dissasociativer and discriminative stimulus

Animals trained under the influence of amphetamine demonstrate partial forgetting of what they learned when the effects of the drug wear off, suggesting that amphet-amine causes dissociation. This may be bad news for stu-dents who use amphetamines to help them stay awake and alert to cram for exams (Roffman & Lal, 1972). The effects of khat on learning and memory are dissociable and appear to be dose-related; low doses have no effect on learning but impair memory, whereas high doses impair learning but improve memory (Geresu, 2015). Rats learn to discriminate amphetamine and cocaine from saline with moderate ease, although they are not as easily discriminable as barbiturates or benzodiazepines (Overton, 1982). Animals generalize the amphetamine response to cocaine, methylphenidate, cathinone, and some monoamine oxidase (MAO) inhibitors (Glennon, 1987; Glennon, Young, Martin, & Dal Cason, 1995; Huang & Ho, 1974; Porsolt, Pawalec, & Jalfre, 1982; Schechter & Glennon, 1985). In rats, amphetamine responses do not generalize to caffeine, nicotine, the barbiturates, chlor-promazine, atropine, or any of the common hallucinogens (Seiden & Dykstra, 1977). The discriminative effects of amphetamine can be blocked by dopamine D1 and D2 recep-tor antagonists administered within regions of the mesolim-bic, but not the nigrostriatal, dopamine system (Callahan, De La Garza, & Cunningham, 1997). Norepinephrine and serotonin appear to play a far lesser role in amphetamine discrimination (Brauer, Goudie, & de Wit, 1997). Like cocaine and methamphetamine, cathinone acts as a discriminative stimulus in a food-reinforced, two-lever operant task—rats distinguish cathinone from saline but generalize responding to cocaine, amphetamine, and methamphetamine (Goudie, Atkinson, & West, 1986; Schechter & Glennon, 1985). Even direct microinjection of cathinone into the nucleus accumbens of rats produces dis-criminative stimulus effects (Schechter, Schechter, & Calcagnetti, 1992). Methcathinone produces discriminative stimulus effects similar to those of cocaine and metham-phetamine (Gatch, Rutledge, & Forster, 2015). Rats do not generalize responding from cathinone to opioids, benzodi-azepines, or fenfluramine (Goudie et al., 1986)

entactogenic

Another commonly reported effect is that the classic hallu-cinogens seem to provide insight into one's past and mind, revealing repressed thoughts and unrecognized feelings. Such insights are similar to those that psychoanalysis attempts to achieve through psychotherapy. It was this effect that inspired Humphry Osmond to suggest that hal-lucinogens might be useful tools in psychotherapy, a belief that still exists today (Nichols, 2016; Tupper et al., 2015). This effect also prompted the use of the term entactogenic ("touching within"). Here is a description of the experi-ences of psychologist Bernard Aaronson, who took LSD as part of an experiment:

Methamphetamine

Another member of the amphetamines family is meth-amphetamine, introduced in 1944 under the trade name Methedrine and used for the treatment of narcolepsy, alcoholism, hay fever, and other conditions (Wood et al., 2014). Like amphetamine, both d-and l-isomers of meth-amphetamine exist; the l-isomer has little CNS activity and is used in nasal decongestants, including the Vicks Vaporub inhaler. The d-isomer, alone or in combina-tion with the l-isomer, continues to be prescribed medically, as a generic drug or under the trade name Desoxyn. It is used to treat ADHD and obesity, but its medical use is not widespread; approximately 16,000 prescriptions are issued each year in the United States (U.S. Drug Enforcement Administration, 2013). Methamphetamine is far more well-known as a drug of abuse. It dominates the illicit amphet-amines market and has numerous street names, including meth, speed, ice, crank, and glass. Methamphetamine's popularity is owed in part to its relatively easy synthesis from legally available ingredients, specifically ephedrine or pseudoephedrine. Additional required reagents include lithium (from lithium batteries), liquid ammonia (a fertil-izer), and toluene (from paint thinner). Methamphetamine is manufactured in large quantities in illegal "superlabs" and on a smaller scale by aspiring chemists in clandestine laboratories. Production without proper laboratory equip-ment and safety measures is particularly dangerous, with fires, explosions, toxic fumes, and long-lasting contamina-tion of a house or apartment being common occurrences (Appendino, Minassi, & Taglialatela-Scafati, 2014). Methamphetamine is sold in a waxy form known as base or paste, and as a tablet or powder. When the powder is recrys-tallized to form chunks of concentrated d-methamphetamine hydrochloride (HCl) intended for smoking, it is referred to by the street names ice, glass, and crystal meth. Yaba is a street name for tablets containing methamphetamine and caffeine which are most commonly sold at raves.

first gen antidepressants

Antidepressant Medications There are several different classes or types of antidepres-sant drugs, examples of which can be found in Table 13-1 (some of these drugs may not be approved for use in parts of Europe or North America). The first pharmaceuticals successfully used to treat depression were the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). Consequently, these two classes are referred to as first-generation antidepressants. The first antidepressant ever marketed was an MAOI called iproniazid, developed in the late 1950s. Before its anti-depressant properties were realized, iproniazid was used in the treatment of tuberculosis (TB). Physicians noticed a great improvement in the mood of TB patients that was separate from the relief of their TB symptoms, and the drug was redeveloped for its antidepressant properties. When MAOIs were first introduced, they became widely used. But in a few years, the initial enthusiasm waned due to sev-eral factors. To begin with, iproniazid was taken off the market soon after it was released because of reports that it caused liver damage. It turned out that the liver damage occurred only because the administered doses were too high. In addition, some clinical studies concluded that MAOIs were ineffective. Once again, these reports were unfounded. The studies used inadequate research design, and we now know that the doses employed in these studies were too low. It has since become clear that MAOIs are just as effective as any other treatment for depression. Up to 70% of patients who fail to respond to newer classes of anti-depressants show improvements in mood when given MAOIs. New MAOIs are more specific in their actions, they are reversible, they are much less likely to interact with diet (discussed later), and they do not cause liver damage at therapeutic doses. For these reasons, this class of drugs is regaining prominence as an effective and relatively safe treatment for depression. The tricyclic antidepressants are so named because their molecular structure contains three rings of atoms. The efficacy of these compounds in alleviating depression was also discovered serendipitously, during research on antipsy-chotic drugs (see Chapter 12); the first of these was imipra-mine. In the late 1950s, imipramine was tested on psychiatric patients, and although it did not improve the positive symp-toms of schizophrenia, it did elevate the mood of depressed patients. Because the tricyclics were considered safer than the early MAOIs, many more were developed, and their use became common in the treatment of depression.

distribution

Antidepressants readily cross the blood-brain and placen-tal barriers. They tend to become concentrated in the lungs, kidneys, liver, and brain. Some antidepressants can be found in significant quantities in breast milk

other problems with typicals

Antipsychotics also seem to cause the body to have trouble regulating temperature, which becomes easily influenced by changes in the environment. In hot environ-ments, patients are more susceptible to heat stroke; in cold climates, they are more vulnerable to hypothermia. The skin also develops an oversensitivity to the sun so that it burns quickly. Other side effects of typical antipsychotics include weight gain, changes in cardiac function and blood pressure (due to the effect of these drugs on NE receptors), dry mouth, impaired vision, dizziness, constipation (due to anticholinergic effects), and jaundice. In certain suscep-tible individuals, there is an increased risk of seizu

sleep

Antipsychotics at therapeutic doses have very little effect on sleep, but some antipsychotics that have sedating effects (e.g., chlorpromazine, quetiapine) will increase sleep time when given at high doses or when first adminis-tered. The antipsychotics do not alter sleep cycles or REM sleep (Spiegel & Aebi, 1981). There is evidence that the atypicals may increase the risk of obstructive sleep apnea (Shirani, Paradiso, & Dyken, 2011).

reproduction

Antipsychotics can have serious effects on reproductive functions. In males, antipsychotics reduce sexual interest, an effect that may arise from their sedative properties. Sexual performance may also be impaired. The primary difficulty is a failure to ejaculate; erection and orgasm are unaffected. These problems arise from the cholinergic, adrenergic, histaminergic, and dopaminergic properties of the antipsychotics and their effects on hormone levels (Üçok & Gaebel, 2008; Woods, 1984). Recall from Chapter 4 that, in the tuberoinfundibular pathway, dopamine acts as a neurohormone to inhibit the release of prolactin from lactotroph cells of the pituitary. Prolactin suppresses male sexual activity. Drugs like cocaine, which activate this sys-tem, can stimulate male sexual performance by suppressing prolactin release, but the antipsychotics, which block D2 receptors on lactotroph cells, cause excess release of prolac-tin. This is less of a concern with the atypicals, although ris-peridone elicits elevations in prolactin levels to a similar extent as the typicals (Üçok & Gaebel, 2008). In females, there may be abnormal menstrual cycles and infertility. In both males and females, there is sometimes an enlargement of the breasts and fluid discharge from the nipples (Woods, 198

redosing/stacking

As is also reported by cocaine and methamphetamine users, mephedrone users engage in binges during which they repeatedly administer the drug; this practice is called redosing or stacking. These binges usually take place in social settings—at a friend's home, a party, or at a dance club or rave. A typical stacking session lasts approximately 9-10 hours, though they can extend over a number of days (Carhart-Harris, King, & Nutt, 2011; Penders, Gestring, & Vilensky, 2012; Winstock et al., 2011a, 2011b). On average, 6 doses of mephedrone are administered during a typical, 10-hour stacking session, with 30-120 minutes elapsing between each dose (German et al., 2014). Self-reported total dosages of mephedrone taken during a typical stacking session usually range from 500-1000 mg, at an average rate of about 100-200 mg per hour (Kelly, 2011; Valente et al., 2014). Dosing is less frequent, and the amount taken is significantly lower, when individuals ingest the drug orally as compared to snorting it. While the 500-1000 mg total dosage is "typical" or "average," individual reports of the total amount of mephedrone consumed during a stacking session is enormously wide-ranging, from 25 mg to 9000 mg (German et al., 2014). It is common for users to mix routes of administration during a single mephedrone stacking session in order to achieve the rapid effects that occur following intranasal administration, combined with the more long-lasting effects of oral administration (Dybdal-Hargreaves, Holder, Ottoson, Sweeney, & Williams, 2013; Valente et al., 2014). Additionally, mephedrone is commonly co-ingested with other drugs, including alcohol, cocaine, ecstasy, cannabis, and ketamine (German

shared neuropharmocilogy of psychomotor stimulants

As stated at the start of this chapter, drugs classified as psychomotor stimulants share a common ability to impact neurotransmission at monoaminergic synapses. However, the mechanisms by which stimulant drugs

later gens neuro

As their name suggests, the SSRIs, through blockade of reuptake transporter proteins, diminish the ability of pre-synaptic cells to reabsorb and recycle 5-HT. This causes a buildup of 5-HT in the synaptic cleft, thereby prolonging postsynaptic receptor stimulation. This action is specific to 5-HT; the SSRIs have minimal effect on other monoamines or other neurotransmitters, such as histamine and acetyl-choline. SSRIs are not selective with regard to the subtype of serotonin receptor to which they bind. It is believed that the antidepressant effects of the SSRIs result from altera-tions to 5-HT1A receptor functioning whereas the unpleas-ant side effects of the SSRIs may be due to activation of 5-HT2 receptors. The SNRIs and atypicals block the reuptake of 5-HT, NE, and in some cases DA. For example, the cathinone derivative bupropion, which inhibits DA reuptake trans-porter proteins, is used to treat depression (Wellbutrin) and is also marketed as a smoking cessation aid (Zyban) In addition to its dopaminergic actions, bupropion affects the functioning of NE and ACh. Some newer antidepres-sants, like mirtazapine, act by antagonizing autoreceptors, specifically for NE and 5-HT, to prevent inhibitory feed-back to the cell and thereby increase the amount of trans-mitter released. In addition, mirtazapine and some other atypicals block histamine receptors to induce sedation and drowsiness. This can be a beneficial effect for patients who experience difficulty falling and staying asleep.

perception

As you have learned, people who use LSD frequently report that their perceptions are much keener and that their sight and hearing have become more acute. There have been a few studies of the effects of LSD on visual sensory thresholds, but their results are inconsistent. In general, however, impairments in sensory functions attributable to LSD are reported more often than improvements (Hollister, 1978). Although it is clear that LSD increases the enjoyment of music, it has not yet been established whether there are any changes in auditory thresholds. The perception of the passage of time is distorted in most individuals; however, the direction of distortion is not consistent. In most cases, time is perceived as slowing down (10 seconds seem more like 20), but in some experiments the reverse has been reported (Hollister, 1978).

unconditioned behavior

At low and intermediate doses, amphetamines increase spontaneous locomotor and exploratory activity in rats. At higher doses, there is an increase in locomotion at first, but after about an hour, the animals start to show increased sniffing and a variety of other stereotyped behaviors. These behaviors are usually simple, brief acts with no par-ticular purpose; they are invariably repeated, over and over, to the exclusion of other behaviors. In rodents, stereo-typed behavior may take the form of up-and-down head bobbing, sniffing in a corner, rearing on the hind legs, or gnawing and biting. The consumption of khat leaves or administration of cathinone increases spontaneous loco-motor activity in rats to a degree nearly equivalent to that of amphetamine (Kimani & Nyongesa, 2008). Methcathinone is particularly potent, increasing locomotor activity of mice for up to 6 hours (Gatch et al., 2015). Similarly, cathinone produces stereotyped behavior in rats (Wabe, 2011). Repeated oral administration of cathinone leads to strong behavioral sensitization and increases in locomotion, rearing, sniffing, and turning behaviors (Banjaw & Schmidt, 2005). Both khat and cathinone enhance aggressive behavior of isolated rats (Banjaw, Miczek, & Schmidt, 2006). In monkeys, psychostimulant-induced stereotyped behavior is generally more complex than in rodents and varies between individual animals. One monkey may examine its hands; another may shuffle sideways. These behaviors will reappear in the same individual when the drug is re-administered. In humans, stimulant-ind

bath salts

Bath salts products may contain a variety of synthetic cathinones, including mephedrone (4-methylmethcathinone), methylone (3,4-methylenedioxymethcathinone), and MDPV (3,4-methylenedioxyprovalerone). Although these repre-sent the most commonly abused cathinone derivatives, they are but a few of the more than 80 compounds that, between 2005 and 2014, were reported to the European Union Early Warning System (European Monitoring Centre for Drugs and Drug Addiction, 2015). Further infor-mation about these drugs will be provided in Chapter 15, along with club drugs. The only cathinone derivative currently approved for medical use in North America

effects on human behavior

Bath salts users often compare the acute subjective effects of synthetic cathinones to those of cocaine, amphetamine, and MDMA. These effects include: heightened alertness and awareness, boundless energy, excitement, increased motivation, euphoria, enhanced mood, a sense of relax-ation, mild empathogenic effects, openness in communica-tion, sociability and talkativeness, intensification of sensory experiences, greater appreciation of music, increased sexual arousal and sensual enhancement, perceptual distortions, time distortion, and reduced appetite. At high doses, bath salts can produce hallucinogenic effects (Dybdal-Hargreaves et al., 2013; Kelly, 2011; Musselman & Hampton, 2014; Van Hout, 2014a; Zawilska & Wojcieszak, 2013). A British survey conducted in 2009, one year prior to mephedrone being declared illegal in the United Kingdom, found that 42% of clubbers had used mephedrone, most within the previous month, thus giving bath salts the repu-tation of a club drug (Morris, 2010). With very large or multiple doses (such as those self-administered during a stacking session), toxic exposure to bath salts compounds can lead to a variety of adverse effects. These include strong sympathomimetic actions, owing largely to enhanced norepinephrine levels in the peripheral nervous system, and other acutely harmful or life-threatening, as well as potentially long-lasting, physi-ological and psychological effects. Examples include: car-diovascular symptoms (hypertension, heart palpitations, chest pain, cardiac arrest); gastrointestinal symptoms (nausea, vomiting, abdominal pain, loss of appetite, weight loss); sympathomimetic symptoms (dry mouth, sweating, dehydration, pupil dilation, blurred vision); cognitive symptoms (confusion, mental fatigue, disorien For patients visiting hospital emergency rooms due to adverse effects of bath salts, MDPV is one of the com-pounds most frequently reported as having been used. This is likely due to the ease with which MDPV penetrates the blood-brain barrier and its high potency at DATs (which can lead to psychotic symptoms) and at NETs (pro-ducing adverse sympathomimetic actions; Spiller, Ryan, Weston, & Jansen, 2011). Anxiolytic drugs (i.e., benzodiaz-epines, such as lorazepam and diazepam) and antipsy-chotic medications (such as haloperidol and risperidone) are used alone or in combination to treat agitation and psy-chotic symptoms of synthetic cathinone overdose (Mas-Morey, Visser, Winkelmolen, & Touw, 2013). When used chronically, consumption of mephedrone is linked to an increased risk of valvular heart disease, likely caused by stimulation of 5-HT2B receptors in heart muscle (Rothman & Baumann, 2002). Synthetic cathinones also produce toxic effects on liver cells (Araújo, Valente, et al., 2015). MDPV use has been implicated in numerous deaths, even when taken in isolation from other drugs (Kesha et al., 2013; Murray, Murphy, & Beuhler, 2012; Ross, Reisfield, Watson, Chronister, & Goldberger, 2012). The same is true of mephedrone and "second generation" bath salts compounds, such as a-PVP (Kelly, 2011; Wood et al., 2010; Zawilska & Andrzejczak, 2015). Death may result from hyperthermia (core body temperatures of more than 42.1°C have been reported; Levine, Levitan, & Skolnik, 2013); cardiac arrest; multiorgan failure; lethal interaction with other illicit drugs, such as GHB or her-oin; serotonin syndrome, resulting from co-ingestion o

self-administration

Because the self-administration of nicotine in humans is so persistent and widespread, it is surprising that laboratory animal self-administration is much less robust and restricted to a limited set of conditions. There are some anecdotal accounts of tame monkeys smoking. Indeed, Charles Darwin, in The Descent of Man (1882), claimed to have seen monkeys "smoke tobacco with pleasure" (p. 7). Darwin used these observations to support his contention that the sense of taste and the nervous systems of humans and monkeys are similar. Surprisingly, however, early sys-tematic research from laboratories found monkeys to be reluctant smokers (Jarvik, 1973). Monkeys have been taught to inhale cigarette smoke, but the procedure involved a period of forced consumption in which the thirsty monkeys were reinforced with drinking water for sucking on a tube through which they received tobacco smoke. After this training, some animals seemed to prefer sucking on a tube that delivered tobacco smoke over one that delivered only air. This procedure is not highly valid, in terms of representing situations that elicit human tobacco use, and nonhuman animals do not normally initi-ate smoking on their own (Jarvik, 1973). Laboratory animals will work for intravenous infu-sions of nicotine, though early studies had difficulties showing reliable self-administration. These difficulties were due to several factors, perhaps the most significant of which is that nicotine acts as a reinforcer only within a rather narrow range of concentrations. Doses that are too low are not reinforcing, and doses that are too high stimu-late a5 nAChR subunits, which is known to produce ave monkeys using a second-order schedule where the nico-tine infusion was preceded by a colored light. They found that monkeys would respond at a higher rate for the com-bination of light presentation and nicotine infusion than for the nicotine infusion alone. They also showed that the monkeys would persistently respond for the light alone, even if it was only occasionally paired with the nicotine infusion. It appears that the presence of conditioned reinforce-ment arising from stimuli paired with nicotine infusions is very important in the reinforcing properties of nicotine. Anthony Caggiula at the University of Pittsburgh, Eric Donny at Johns Hopkins School of Medicine, and their col-leagues have extensively explored this effect. They designed a series of experiments in which rats were trained to lever press for infusions of nicotine in combination with a discriminative cue and then systematically removed each element to examine its importance to responding (Caggiula et al., 2001). Specifically, during the first phase of the experiment—the "acquisition" phase—rats were trained to lever press on an FR5 schedule for infusions of nicotine. Each infusion was paired with presentation of a 1-second cue light, followed by a 1-minute time-out period during which the house light (the overhead light in the chamber) was extinguished. After 20 days of acquisition training came the second phase of the experiment—the "extinc-tion" phase, which lasted 12 days. During extinction, the trained rats were split into three separate groups. For one group (the Saline + Cues group), saline was substituted for nicotine, but the cue light continued to be presented dur-ing the saline infusion and the hou

tardive dyskinesia

Because the typicals accumulate in brain tissue, pro-longed use can lead to a neurological condition called tar-dive dyskinesia. It is characterized by involuntary, tic-like, repetitive movements of the face, such as muscle twitching, smacking of the lips, or flicking of the tongue, sometimes dozens of times per minute. Unfortunately, for some indi-viduals, the symptoms of tardive dyskinesia are permanent and do not dissipate even after the drug is stopped (Enna & Coyle, 1983). Rates of tardive dyskinesia tend to be higher in elderly individuals and in women. In contrast to the typ-icals, the atypicals are far less fat-soluble and bind only briefly to D2 receptors. As a result, their likelihood of caus-ing tardive dyskinesia is extremely low (Seeman, 2002).

medical absorption

But when used for medicinal purposes, the methylxanthines are usu-ally given as salts, which can be absorbed even more read-ily. Aminophylline (a bronchodilator used to treat asthma) is the most widely used methylxanthine preparation. It is a mixture of theophylline and ethylenediamine. The latter substance is considered therapeutically inert, but it increases the amount of dissolved theophylline by 20 times and thereby speeds absorption in the lungs. Oxtriphylline (Choledyl or choline theophylline) is also widely u

N. tabacum l

By far, the principal source of tobacco is the species N. tabacum L., which is cultivated in temperate climates all over the world. The plants of N. tabacum are usually about 2 meters tall and have long, broad, pointed leaves that are harvested two or three at a time from the bottom of the plant as they mature, although for some types of curing the entire plant is cut at one time. Species of N. rustica are not widely grown commercially. While it has a higher nicotine content (up to 9%), it is harder to cultivate. Wild N. rustica has been widely used as a medicine and for shamanistic rituals by Indigenous Peoples of North and South America. In addi-tion to nicotine, it contains other psychoactive substances such as the hallucinogen harmine (see Chapter 15). Cultivated strains of tobacco have much higher nicotine content than wild members of the same genus. The nico-tine content of a cured, commercially grown tobacco leaf may reach as high as 6.2%

extent of methyxamine use

Caffeine and the other methylxanthines are the most widely used class of behaviorally active substances. Approximately 80% of the world's population and 90% of North Americans consume caffeine regularly (Frary, Johnson, & Wang, 2005; Ogawa & Ueki, 2007). The average caffeine consumption of the world's population is about 70-76 mg per person per day, though average intake ranges widely between countries (Gilbert, 1984; Fredholm, Bättig, Holmén, Nehlig, & Zvartau, 1999). About 90% of caffeine is consumed in the form of coffee and tea. Across the globe, coffee is the second-most common beverage, after water (Ludwig et al., 2014), with an estimated 1.6 billion cups consumed daily (Cappelletti, Daria, Sani, & Aromatario, 2015), 400 million of which are consumed in the United States alone (National Coffee Association USA, 2015). Clearly, the production and sale of methylxanthine-containing products is big business. According to the United Nations International Trade Statistics Yearbook, worldwide exports of coffee, tea, maté, chocolate, cocoa, and cocoa-containing foods totaled nearly 88.3 U.S. dollars in 2013 (United Nations, 2014). Among these, coffee was the most extensively traded and valuable export. During the 2014 crop season, 141.7 million 60-kg bags of coffee beans were produced worldwide, of which roughly 60% was arabica and 40% was robusta. An esti-mated 149.2 million 60-kg bags of coffee beans were con-sumed globally in 2014 (International Coffee Organization, 2015). Brazil, Germany, Vietnam, Switzerland, and Columbia are the largest coffee-exporting countries (United Nations, 2014). The largest importers of coffee beans are the United States, Germany, France, Japan, and Italy (United Nations, 2014). Global export values and per capita consumption of tea is less than that of coffee. Sri Lanka, China, Kenya, and India are the top exporting countries, while Russia, the United States, the United Arab Emirates, and the United Kingdom are the top importers of tea (United Nations, 2014). On average, the world's inhabitants consume about 120 ml (approximately 4 fl. oz.) of tea per person per day. Ireland and Great Britain are the greatest per capita tea drinkers, at about 540 ml (approximately 19 fl. oz.) per person per day, which is roughly 10 times higher than con-sumption levels in the United States and Canada (Gardner, Ruxton, & Leeds, 2007). The Irish and British also consume a great deal of chocolate, at approximately 16.3 lbs per capita per year for each country. These numbers are exceeded only by the Swiss and the Germans (who con-sume 19.8 and 17.4 lbs per person per year, respectively; Euromonitor, 2015). Recently conducted

methyxanthines in chocolate

Caffeine and theobromine are the principal methylx-anthines found in chocolate, though small amounts of the-ophylline are also present. In their dried, raw form, cocoa beans contain approximately 2.5% caffeine by weight (Ashihara et al., 2008).content found in various forms of processed chocolate. Theobromine content in cocoa products is even higher than that of caffeine

sources

Caffeine is available from a wide variety of sources. Table 9-1 lists common sources and provides an estimate of the amount of caffeine they contain. Some of these sources, especially teas and chocolate, also contain theophylline and theobromine, though their amounts are seldom reported. In addition, energy drinks contain a variety of methylxanthine-containing plant ingredients (such as guaraná and maté

harmful effects of caffeine-reproduction

Caffeine passes easily across the placental barrier and, at a dose of 200 mg in the mother, reduces blood flow to the pla-centa by 25% (Kirkinen, Jouppila, Koivula, Vuori, & Puukka, 1983). Studies in animals have shown that caffeine adminis-tration, even at low doses, slows both embryonic and neo-natal growth (Dunlop & Court, 1981). The effects of caffeine on human reproduction and fetal growth are of increasing concern, especially as new highly caffeinated products are being marketed. A large British prospective study, examin-ing more than 2,600 pregnancies, found that maternal caf-feine intake was related to deceleration in fetal growth (CARE Study Group, 2008). Women who voluntarily reduced caffeine consumption from 300 mg to less than 50 mg per day during the first trimester of pregnancy had babies weighing an average of 161 g heavier than women who did not reduce their caffeine consumption. Daily caf-feine consumption of 200 mg or more throughout preg-nancy corresponded with an average decreased birth weight of 60 to 70 g. There are also reports in the literature of increased risk of miscarriage in women consuming more than 150 mg of caffeine per day (Fernandes et al., 1998; Weng, Odouli, & Li, 2008). Li and colleagues (2015) report a 19% increased risk of pregnancy loss for every 150 mg increase in caffeine intake. Even at high doses, however, caf-feine is not shown to cause congenital malformations (Brent, Christian, & Diener, 2011). The potentially adverse effects of caffeine on fetal growth and development seem restricted primarily to the first trimester of pregnancy (Ådén, 2011). In a review of the effects of caffeine consumption on reproductive outcomes, Peck, Leviton, and Cowan (2010) point out a common problem with such studies: caffeine con-sumption during pregnancy is often confounded with morn-ing sickness and vomiting experienced during the first trimester. Women who experience these "pregnancy signal" symptoms are more likely to have normal pregnancies and healthy babies. They are also the women who are most likely to reduce their consumption of coffee, tea, and other distinc-tive-tasting beverages because they feel sick and develop aversions to caffeine-containing drinks. This could make it appear as though there is a positive relationship between caf-feine consumption and negative pregnancy outcomes. A large proportion of studies examining the relationship between caf-feine consumption and spontaneous abortion, prematurity, fetal death, and fetal malformations do not measure or ade-quately control for the confounding effect of morning sick-ness. In light of this confound, combined with the uncertainties stemming from the oftentimes flawed measures of caffeine consumption, Peck and colleagues concluded there was no convincing evidence that caffeine has any detrimental effect on reproductive success. As they and others point out, con-trolling for the presence of "pregnancy signal" would allow researchers to limit their assessments of the impact of caffeine to healthy pregnancies (Brent et al., 2011; Peck et al., 2010).

caffiene in soda

Caffeine-containing sodas first appeared in 1885 with the introduction of Coca-Cola. At that time, caffeine was sourced naturally from the kola nut. Today, more than 60% of sodas on the market contain caffeine, most of which is synthetically manufactured. Some of these beverages are listed in Table 9-1. In the United States, the Food and Drug administration (FDA) considers caffeine to be a GRAS (Generally Recognized as Safe) ingredient that can be added to "cola-type beverages" at levels below 200 parts-per-million (0.02%; U.S. FDA, 2014). In a typical 12-fl.oz can or bottle of soda, that translates into a maximum per-missible level of 71 mg of caffeine. In 1985, Jolt Cola was introduced in the United States with the slogan "All the sugar and twice the caffeine." Whereas most cans of soda contain 35 to 50 mg of caffeine, Jolt Cola contained the maximum permissible 71 mg. In the 1990s, several manu-facturers started marketing caffeinated drinks as dietary supplements, rather than as food products, to circumvent regulations on caffeine content. Currently, the most popu-lar of these caffeine-containing dietary-supplement and beverage products are energy drinks and energy shots.

withdrawal

Cessation of recreational amphetamine or cocaine use is not usually associated with a severe or medically serious withdrawal syndrome. After a single dose of amphetamine or cocaine, the high is typically followed by a crash or comedown—a period of depression and lethargy. The depression is immediately relieved by another administra-tion of the drug. Withdrawal symptoms tend to appear within about half an hour of taking cocaine, but are delayed for a number of hours after the use of amphetamine. After chronic heavy use, abrupt discontinuation of amphetamine or cocaine will lead to the appearance of withdrawal symp-toms within 24 hours of the last dose. In this case, the severity of the depression is related to the dose and dura-tion of the intake period and may be quite severe, accom-panied by suicidal thoughts and suicide attempts (Meredith, Jaffe, Ang-Lee, & Saxon, 2005; Scott et al., 2007). Withdrawal-related depression can be treated with antide-pressant medications. If the period of stimulant use has been long enough to interfere with sleep and eating, there will also be a compensatory increase in these behaviors. During withdrawal, sleep quality tends to be poor, marked by insomnia, vivid and unpleasant dreams, and frequent awakenings. The initial phase of withdrawal can last for up to a week, but the increased appetite, sleep disturbances, and depression may continue for many weeks or even months (Gawin & Kleber, 1987; McGregor et al., 2005). Cessation of methamphetamine use also produces with-drawal symptoms that include disturbed sleep, marked by vivid and unpleasant dreams; depression and suicidal ide-ation; anxiety, agitation, and panic; drug craving; and cog-nitive impairment (Cruickshank & Dyer, 2009). thdrawal from psychomotor stimulants can also disrupt performance. In the early stages of abstinence, methamphetamine addicts demonstrate decision-making deficits on a two-choice procedure task that requires switching from a losing to a winning strategy. This perfor-mance deficit correlates with reduced dorsolateral prefron-tal cortical activation (important for working memory, reward evaluation, and behavioral shifting) and a failure to activate the ventromedial cortex (which plays a role in emotion and the dysfunction of which is implicated in depression; Paulus et al., 2002). Following at least 1 year of amphetamine abstinence, PET imaging studied demon-strated a continued decreased in dorsolateral prefrontal cortical activation in association with decision-making in risky situations (Ersche et al., 2005)

subjective affects of typicals

Chlorpromazine, when given to healthy individuals, causes a very pronounced feeling of tiredness, slowed and confused thinking, difficulty concentrating, and feelings of clumsiness. People also report a need for sleep, dejection, anxiety, and irritability. Simple tasks such as walking seem to take great effort. Haloperidol is not as sedating as chlor-promazine but, along with other atypical antipsychotic drugs, it makes people feel internally aroused and exter-nally sedated at the same time; that is, they feel restless and want to do something but also feel restrained and have difficulty moving (Spiegel & Aebi, 1981). The subjective effects of antipsychotics are often described as unpleasant and these drugs are rarely abused. In fact, the antipsychotics represent a group of drugs for which there is considerable difficulty gaining patient com-pliance. Compliance refers to the extent to which a patient adheres to a regimen of medical treatment. In the case of typical antipsychotics, compliance is frequently poor; patients often stop taking their medication with the usual result being that their symptoms reappear. It is for this rea-son that various administration techniques have been devel-oped that do not depend on the patient adhering to a strict dosing schedule. Depot injections, for instance, slowly release the drug into the bloodstream and maintain thera-peutic drug levels. Noncompliance is slightly less of a prob-lem with the atypical antipsychotics, such as clozapine (Meltzer, 1992). There are reports of quetiapine, olanzapine, and other atypical antipsychotics being used recreationally, mainly for their strong sedating actions. They can be crushed and snorted, or injected intravenously either alone or in combination with a psychostimulant drug. A mixture of quetiapine and cocaine is referred to on the street as a Q-Ba

tolerance

Chronic administration of caffeine causes an upregulation in both the number and sensitivity of adenosine receptors (Hirsh, 1984). Tolerance to the behavioral effects of caffeine has been demonstrated in rats. One study showed that a 100 mg/kg injection of caffeine could depress bar pressing on an FI schedule to about 40% of saline control rates (Wayner, Jolicoeur, Rondeau, & Barone, 1976). After eight injections of caffeine, this dose could only depress responding to 75% of baseline. It has also been demonstrated, in a study of operant responding in rats, that chronic treatment with caffeine shifted the caffeine dose-response curve to the right by a fac-tor of 6. This means that after long-term exposure to caffeine on nondrinkers. In one experiment, 150 to 300 mg of caffeine produced complaints of jitteriness, nervousness, and upset stomach in nonusers, but users reported increased alertness, decreased irritability, and a feeling of contented-ness (Goldstein, Kaizer, & Whitby, 1969). While results like these are probably demonstrating tolerance, it is also possi-ble that individuals who are most resistant to the effects of caffeine might also be the ones who become heavy coffee drinkers. The sleep-disrupting effects of caffeine show toler-ance within 7 days and the subjective effects are tolerated within 4 days (Evans & Griffiths, 1992). The effects of caf-feine on the body also build tolerance at different rates. For example, cardiovascular effects fade within 2 to 5 days, but caffeine-induced increases in urination may take consider-ably longer or never show complete tolerance. In general, many effects of caffeine seem to disappear within a week at usual levels of consumption. Some acute effects of caffeine—the effect on spontaneous motor activity and susceptibility to convulsions—actually reverse with chronic treatment

chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) can be caused by air pollution and industrial exposure to dust and airborne chemicals, but 80 to 90% of all cases in the United States result from smoking. COPD is marked by shortness of breath, cough, and increased mucus produc-tion resulting from inhalation of noxious particles or gases triggers a heightened inflammatory response in the lung (Rabe et al., 2007), restricting airflow to the lungs. Both cig-arette smoking and e-cigarette vaping increase lung flow resistance and decrease levels of exhaled nitric oxide (NO), an inflammatory signaling molecule whose levels also decrease in cases of cystic fibrosis and pulmonary hyper-tension as a result of damage to NO-producing epithelial cells of the lungs (Marini, Buonanno, Stabile, & Ficco, 2014; Schober et al., 2014; Vardavas et al., 2012). The composition of tobacco smoke is 92% gaseous chemicals and 8% tar components. When inhaled, the ash and tars are deposited on the moist membranes on the inside surface of the lung, through which oxygen and carbon dioxide must pass to and from the blood. Normally, particles are cleared from the lungs by small hairs called cilia, which agitate and work the pollutants upward until they are ejected by coughing. Another line of defense against inhaled particles is the action of phagocytes. The phagocytes attack, surround, and destroy foreign matter in the lungs. Smoking reduces the actions of both the cilia and the phagocytes, leaving the lungs more vulnerable to the toxic effects of inhaled pollutants and infections by bacteria and viruses. As a result, the relative risk of developing COPD is greatly increased by smoking, to 25.0 for women and 27.8 for men (Carter et al., 2015). COPD is the third leading cause of death in the United States (Kochanek, Murphy, Xu, & Arias, 2014). While there is no cure, smoking cessa-tion is one of the most important factors in slowing the progression of the disease. Quitting smoking can signifi-cantly reduce the rate of deterioration in lung function and delay the onset of disability and death. The vapors inhaled from ENDS devices contain ultra-fine particles and chemical compounds known to irritate the mouth, throat, and lungs, dry mucous membranes, and produce coughing (Callahan-Lyon, 2014). Sweet-flavored e-liquids (e.g., butterscotch, caramel, bubblegum, or cinna-mon) contain diacetyl and propionyl which are approved additives to food but that, when inhaled, can adversely affect the respiratory system. The flavoring with the most toxic effects is cinnamon (Behar et al., 2014). Inhalation of vegetable glycerin can cause lipid pneumonia (McCauley, Markin, & Hosmer, 2012). Long-term effects, such as increased risk of COPD and lung cancer, are as yet unknown.

self admin

Cocaine has a long history of self-administration, starting with the native people of South America who consumed the drug orally, as noted earlier in this chapter. Their pat-tern of use was very different from the modern North American patterns of self-administration of pure cocaine or amphetamines. With pure cocaine, continuous use is rare. When snorted or injected, cocaine is usually taken in large quantities for brief periods of time that are followed by periods of abstinence. This is sometimes called the run-abstinence cycle. This pattern is also seen with crack addicts. Cocaine is often taken in conjunction with other drugs. The most usual mix is the speed ball, a combination of cocaine (or amphetamine) and heroin. Users claim that the heroin reduces the jitteriness that cocaine arouses by stim-ulating the sympathetic nervous system, and the cocaine diminishes the sleepiness or nod caused by heroin. Cocaine is also regularly mixed with sedatives such as benzodiaze-pines or with hallucinogens such as ketamine or PCP for the same reason. Like cocaine, the amphetamines tend to be self-administered sporadically, in run-abstinence cycles rather than continuously. The pattern of use may, how-ever, depend on the effect for which the drug is taken. Because it is longer-lasting than cocaine, amphetamine allows for an easier maintenance of constant drug levels in the blood over an extended period of time. This is help-ful when amphetamine is being used to enhance perfor-mance or prevent sleep, as might be the case for truck drivers on a long haul or students cramming for final exams. When the need is over, use of the drug is usually discontinued, and the person recovers from its effects by sleeping for a prolonged period. When amphetamines are taken for their euphoric effects, much higher doses are usually taken, and the route of administration is most likely intravenous or inhalation. In the 1960s, this pattern of use characterized the peak user or speed freak who might inject amphetamine every few hours for days on end. During such runs, the user typically sleeps and eats very little, and may demonstrate signs of amphetamine psy-chosis, such as punding and paranoia. Eventually, the drug runs out or the user reaches the point of physical and emotional exhaustion, and they crash. After crashing, it is common to sleep for a long time (24 to 48 hours) and to then awaken, consume a large meal, and resume drug seeking to begin another run

coke pharmakinetics

Cocaine has a pKa of 8.6. Traditionally, the Indigenous peoples of the Andes rolled coca leaves into a ball, stuck a wad in the cheek, and sucked it. It is also common for those who self-administer coca in this way to mix the leaves with wood ashes or ground shells, which are alka-line (Schultes, 1987); this practice raises the pH of the saliva and the digestive tract, consequently reducing drug ionization and increasing its absorption through buccal and gastrointestinal membranes. Peak blood plasma levels of cocaine are reached within about 25 minutes to 2 hours of chewing (Bortolotti, Gottardo, Pascali, & Tagliaro, 2012). Despite the long tradition of coca-leaf chewing, it is very unusual for pure cocaine to be taken orally. Rather, to improve absorption and enhance subjective effects, it is nearly always injected, snorted, or smoked. Dried coca leaves contain up to 2% cocaine by weight, which can be extracted to yield a variety of products—a sulfate paste, a hydrochloride (HCl) salt, and a freebase or crystalized "crack" (Dinis-Oliveira, 2015). The first cocaine product yielded by the extraction process is a sulfate paste, made by crushing and submerging coca leaves in a mix-ture of lime water and kerosene, and then using sulphuric acid and more lime to extract the cocaine as a sticky, d cocaine product that often contains vari-ous impurities, resulting from the refining process, or is deliberately diluted or "cut" with other cheaper sympa-thomimetic substances in order to add bulk and increase profit (Phillips, Epstein, & Preston, 2014). One method used to assess the purity of the drug is to place some of the powder on a sheet of tinfoil and heat it. Pure cocaine HCl has a very high melting point and does not vaporize easily; when it vaporizes, it leaves little residue. Because heat degrades the drug before it reaches the point of vaporiza-tion, cocaine HCl is most often snorted or dissolved in water and injected intravenously, rather than smoked. When snorted, its bioavailability is roughly 60% (Phillips et al., 2014). For the purpose of smoking, cocaine HCl can be converted back to a freebase, derived by chemically treating the powder with ammonia or baking soda (sodium bicarbonate) which are alkaline. When added to cocaine HCl salt, either ammonia or baking soda will free the HCl base from the salt, thereby removing the ionic charge from the molecules of cocaine, and increasing its lipid solubility. When the water evaporates, crystalline chunks of freebase cocaine are produced for sale as crack or rock. Freebase cocaine has a much lower melting point and can be heated in pipes or other devices, and its vapors inhaled. The term crack comes from the popping or crackling sound made er and cannot be injected or snorted. When injected intravenously or smoked as crack, peak blood plasma levels of cocaine are reached very quickly, within 2-5 minutes (Allain, Minogianis, Roberts, & Samaha, 2015; Cone, 1998). Peak subjective effects are felt within 1-2 minutes of smoking crack and within 3-4 minutes of injecting cocaine (Hatsukami & Fischman, 1996; Volkow et al., 2000). Bioavailability of smoked crack cocaine is about 70%, with the remainder being lost as sidestream smoke or through drug degrada-tion by heat (Cone, 1998). Snorting cocaine results in higher (~94%) bioavailability, but a slower (~30-60 minute) attainment of peak blood plasma concentrations and lower peak concentrations (Allain et al., 2015; Cone, 1998). When snorted, peak subjective effects are felt within 10-15 minutes. The absorption of methylphenidate varies consider-ably between individuals. Bioavailability of the drug in children ranges from 11 to 53%, with peak blood levels attained within about 1-3 hours after oral administration (Frölich et al., 201

cocaine

Cocaine is extracted from the leaf of a small tree known as the coca bush (Erythroxylum coca), native to South America. It is well adapted to high elevations and thrives on the slopes of the Andes Mountains of Peru and Bolivia. It grows in both wild and cultivated forms from northwestern Argentina to Ecuador. It is believed that Indigenous Peoples of South America have been chewing coca leaves for millennia. Legendary tales from Indigenous Colombians tell of how their people came from the Milky Way in a canoe drawn by an anaconda. In addition to a man and a woman, the canoe contained several psychoac-tive plants, including coca (Schultes, 1987). Coca leaves have been found in middens in Peru that date back to 2500 bce. Large stone monolithic idols found in Colombia and dating to 500 bce have the puffed-out cheeks charac-teristic of a coca chewer. The Incas started to use the plant when they conquered the region in about the tenth cen-tury. Under the Incas, coca became sacred. It was used pri-marily by priests and nobility for special ceremonies and was not consumed daily by the common folk.

cocoa

Cocoa is made from seeds found in the seedpods of the cacao tree, Theobroma cacao, which is native to the dense, tropical Amazon rain forest. (The name cacao refers to the tree and its seeds; the term cocoa is used to refer to the pro-cessed products of the bean. Do not confuse either of these terms with coca, the bush that is the source of cocaine; see Chapter 10.) Cocoa is now cultivated mainly in Central and South America, the West Indies, and West Africa. The mature tree grows seedpods from the trunk and main branches. These pods, about 6 to 10 inches long and 3 to 4 inches in diameter, contain 20 to 40 seeds (beans) sur-rounded by pulp. The seeds are removed and put into boxes or piles for fermentation. During this process, which lasts 5 to 6 days, the pulp ferments, becomes very watery, and separates from the seed. Fermentation of the pulp heats the beans, causing them to germinate, but the ongo-ing fermentation process soon kills the newly germinated seed. The beans are then dried in the sun or in commercial driers. This fermentation and drying process takes place on the grounds of the cocoa plantation. After drying, the beans are shipped to manufacturing plants for further processing. They are roasted for enhanced flavor and then crushed and the husks of the shells are removed. The resulting product is sold as unsweetened chocolate, which has a high fat content but is not very appealing in its raw state. In 1828, in the Netherlands, a Dutchman named C. J. Van Houten invented a press that could remove most of the fat, or cocoa butter, from the unsweetened chocolate. This invention was a major breakthrough in the processing of cocoa. In nvented a press that could remove most of the fat, or cocoa butter, from the unsweetened chocolate. This invention was a major breakthrough in the processing of cocoa. In addition to creating the press, the Dutch learned to alkalize cocoa, which gives it a stronger flavor and a darker color and makes the powder disperse better in water. In the production of cocoa powder, the unsweetened chocolate is pressed into cakes. This process removes a large portion of the cocoa butter. The cakes are then ground to produce the dry cocoa powder. Chocolate is made by mixing the roasted, alkalized, and refined beans with sugar and cocoa butter and, in the case of milk chocolate, with milk or milk solids. The details of the mixing process are complicated and vary according to the type and pro-posed use of the chocolate being produced (Minifie, 1970

coffee

Coffea, which contains approximately 70 species. The two most commonly cultivated species are arabica, which accounts for 60-80% of the world's coffee production, and canephora (also called robusta), which accounts for 20-40% (Ludwig, Clifford, Lean, Ashihara, & Crozier, 2014). These species are native to Ethiopia but are now widely culti-vated on coffee plantations throughout Africa and South America and in tropical climates all over the world, includ-ing Hawaii, Jamaica, and Vietnam. The coffee bean is a seed kernel of the coffee berry (or cherry), which grows in clumps along the branches. Each berry contains two seeds within its pulp. Usually, the berry is picked and dried briefly in the sun before the seeds are removed from inside the pulp. In preparation for making coffee, the beans are roasted to enhance their flavor, then crushed or ground and mixed with boiling water. The caffeine content of a cup of coffee can vary considerably depending a number of factors, such as: the species of the coffee plant (arabica beans contain 0.9-1.3% caffeine by dry weight whereas robusta beans con-tain about twice as much at 1.5-2.5%; Ashihara, Sano, & Crozier, 2008; Ludwig et al., 2014), the method of brewing (drip brewing of roasted, ground coffee beans extracts nearly 100% of the caffeine, whereas only 75% extraction results from traditional boiling methods; D'Amicis & Viani, 1993), and not surprisingly, the size of the cup! Most sources state that, on average, a cup of coffee contains 100 mg of caf-feine. As you can see in Table 9-1, this is an underestimat

meth od

Common signs of methamphetamine overdose include dilated pupils, shivering, high fever, hypertension, rapid or (Cruickshank & Dyer, 2009). Seizures are possible, but occur in only about 3-4% of overdose cases. Altered mental status is common in methamphetamine poisoning and most often include agitation, suicidal ideation, and psycho-sis. The fatal dose of methamphetamine is wide-ranging, estimated at between 140 and 1650 mg of drug taken orally (Gable, 2004b). However, overdose deaths have occurred after as little as 20 mg of methamphetamine administered intravenously (Ago, Ago, Hara, Kashimura, & Ogata, 2006), whereas one individual survived a 640 mg intrave-nous injection, albeit with transient psychosis (Bell, 1973). Overdose fatalities most commonly result from multisys-tem organ failure, pulmonary congestion, cerebrovascular hemorrhage, and acute cardiac failure, though deaths have also been attributed to sepsis resulting from dirty injections and by asphyxia by aspiration of vomit (Cruickshank & Dyer, 2009; Vearrier et al., 2012). Combined, homicide and suicide account for more than 40% of methamphetamine-associated deaths (Logan, Fligner, & Haddix, 1998). The death rate from all causes among users of amphetamines and cocaine is about six times higher than that of the gen-eral population. It is even higher among intravenous users and those who experience psychiatric symptoms (Arendt, Munk-Jørgensen, Sher, & Jensen, 2011)

MDPV

Compared to mephedrone and methylone, MDPV is a much more potent compound, producing effects at doses as low as 3-5 mg. A typically administered dose of MDPV ranges from 5-20 mg; however, when doses higher than ~10-15 mg are taken, some users report extremely unpleas-ant "come-down" effects (Psychonaut WebMapping Research Group, 2009). Single, acute intakes of more than 200 mg of MDPV have been reported and, as with mephedrone, redosing within a single session is common. The onset of MDPV effect can be felt within 15-90 minutes after intranasal or oral administration, and the drug expe-rience tends to last from 2.0 to 3.5 hours when snorted and from 7 to 8 hours when taken orally (Psychonaut WebMapping Research Group, 2009; Karila & Reynaud, 2011; Musselman & Hampton, 2014; Ross, Watson, & Goldberger, 2011). With the stimulating dose of MDPV being so much lower than that of mephedrone or methy-lone, and stacking being common practice, the risk of over-dose is significant. This is especially true when the presence or amount of MDPV in a bath salts product is unknown. Packages frequently contain as much as 500 mg of product and some labels suggest escalating the dose to more than 50 mg (Zawilska & Wojcieszak, 2013). All synthetic cathinones exhibit good penetration of the blood-brain barrier, though they are generally less lipophilic than the amphetamines which is why they must be taken in much higher doses to achieve equivalent psy-chostimulant effects (Kelly, 2011; Valente et al., 2014). The chemical structure of MDPV makes this compound less polarized and more highly lipophilic compared to other synthetic cathinones, allowing its molecules to easily cross the blood-brain barrier (Valente et al., 2014). Its high tran

cocaine elimination

Compared to the amphetamines, cocaine has an extremely short half-life, averaging about 60 minutes (Jufer, Wstadik, Walsh, Levine, & Cone, 2000), though this varies rather widely between individuals and also depends on the pH of the urine as well as on the route of administra-tion. Intravenous administration of cocaine results in half-lives ranging from about 15 minutes to 3.5 hours. The detection time of cocaine in the blood is 4-6 hours after 20 mg and 12 hours after 100 mg of intravenously adminis-tered drug (Maurer, Sauer, & Theobald, 2006). When cocaine is taken intranasally, half-lives vary from about 30 minutes to 4.8 hours. A single oral dose of cocaine results in a much more uniform half-life of just under 1 hour. Cocaine is also cleared from the brain much more quickly than the amphetamines, which corresponds with its shorter period of subjective "high" (Fowler, Volkow, et al., 2008). Very little cocaine (~1-9%) is eliminated from the body unchanged in urine (Goldstein, DesLauriers, & Burda, 2009). The half-lives of cocaine's metabolites are consider-ably longer than the parent drug, from about 14.5 hours to more than 52 hours (Jufer et al., 2000). The principal metab-olite of cocaine can be detected in urine for 2-3 days after 100 mg administered intranasally or 1.5 days after a single 20 mg intravenous injection, but up to 10 days after chronic 8 g/day intravenous doses (M

binding potential of 5ht1a receptors

Depressed individuals also exhibit abnormalities in the functioning and quantity of 5-HT receptors, particu-larly for the 5-HT1A receptor subtype. Much of this evi-dence comes from PET imaging studies that measure the binding potential of 5-HT1A receptors. Differences in recep-tor binding potential could indicate an upregulation or downregulation in the density of receptors present on neu-rons, a change in the sensitivity of the receptors to neu-rotransmitter molecules, or it could indicate an increase or decrease in the presence of neurons containing those receptors. This area of research is hotly debated because some evidence suggests increases and some suggests decreases in 5-HT1A receptor binding potential in depres-sion. The debate may be, at least in part, due to the differ-ent brain regions analyzed by researchers and to the varying roles 5-HT plays in those brain regions. Remember that 5-HT1A receptors act not only as post-synaptic receptors, but also as autoreceptors. In the raphe nuclei, 5-HT1A receptors are mostly autoreceptors, located on the presynaptic neuron. Stimulation of those receptors inhibits cell firing and reduces 5-HT activity. In other brain regions, such as the hippocampus, hypothalamus, amyg-dala, and cortex, 5-HT1A receptors are located postsynapti-cally. Stimulation of those receptors increases serotonin neurotransmission. Changes in the sensitivity or number of 5-HT1A receptors could result from genetic makeup, render-ing the individual more vulnerable to depression. Or, these changes might represent an adaptive response to depres-sion—a way for the brain to compensate for abnormal levels of serotonin activity, perhaps triggered by some The increase in serotonin transmission produced by antidepressant medications appears to be a necessary, but not sufficient, condition for alleviating depression. It is believed that, in serotonergic synapses at least, increased levels of neurotransmitter do not result in an immediate increase in cell firing. Through the action of autoreceptors, the presynaptic cell detects the excessive amounts of transmitter in the cleft caused by the antidepressant medi-cation and, in response, inhibits the release of more 5-HT (typically by reducing the influx of calcium at the termi-nal). Thus, acute administration of reuptake inhibitors like the SSRIs does not cause an immediate increase in con-duction at 5-HT synapses. It takes a few weeks for the autoreceptors to habituate to the presence of excess 5-HT, and only then does serotonergic conduction at the syn-apse actually increase. With chronic treatment, antidepres-sants are able to enhance the sensitivity and functioning of 5-HT1A postsynaptic receptors, leading to increased mono-amine activity (Drevets et al., 2007). In addition, there is a downregulation and desensitization of 5-HT1A autorecep-tors, which acts to decrease cell inhibition resulting from the antidepressant-induced rise in monoamine levels and thereby enhance monoamine neurotransmission. The delay experienced with other classes of antidepressants may result from similar adjustment mechanisms. The bulk of evidence supports the theory that depres-sion is a result of diminished activity in the 5-HT system in the brain, which runs from the raphe nuclei through the medial forebrain bundle to the forebrain. The situation is very complicated, however, and many other explanations of depression exist. In the mid-1990s, antidepressant med-ications that target both serotonin and norepinephrine were introduced. Like 5-HT, NE activity is also dysregu-lated in depression, and more recently developed antide-pressants target the NE system. In addition, altered transmission of serotonin, and perhaps even norepineph-rine and dopamine, may be caused by, and may in turn cause changes in, activity of other transmitter systems—even some that do not use monoamines. Alternate theo-ries of depression cite the importance of different neurotransmitters, such as GABA, acetylcholine, opioid peptides, and cannabinoids, and the balance achieved among levels of these neurotransmitters (Uppal, Singh, Gahtori, Ghosh, & Ahmad, 2010). Activity at monoamine synapses may in fact be only one link in a long and com-plex chain of neurological deficiencies that cause depres-sive disorders. Still other theories suggest the involvement of second messengers, biological rhythms, hormone lev-els, and the immune system. Among these, one theory that has garnered substantial support and warrants

Neuropharmacology

Despite the strong association between a drug's hallucino-genic properties and its capacity to stimulate the serotonin 5-HT2A receptor subtype (Halberstadt, 2015), salvinorin A does not bind to serotonin receptors. Instead, it is a highly selective kappa (k)-opioid receptor agonist. This is remark-able, not only because its hallucinogenic effects are pur-portedly mediated through the opioid system, but because salvinorin A shares little structural similarity with the endogenous k-receptor ligand, dynorphin, or any other known compound that binds to k receptors (Cunningham, Rothman, & Prisinzano, 2011). Some researchers have reported that salvinorin A directly affects other neurotransmitter systems, including that it allosterically modulates the mu (m) opioid receptor (Rothman et al., 2007) and that it acts as a partial agonist at the D2 dopamine receptor (Seeman, Guan, & Hirbec, 2009), but no independent replications of these findings have since been published. There is strong evidence that sal-vinorin A interacts indirectly with other neurotransmitter systems, including dopamine (Zhang, Butelman, Schlussman, Ho, & Kreek, 2005), norepinephrine (Grilli et al., 2009), and endocannabinoids (Braida et al., 2008). In animal research, salvinorin A has been found to inhibit the release of DA in the mouse striatum and prefrontal cortex as well as in the rat nucleus accumbens (Carlezon et al., 2006). It also inhibits the release of 5-HT and stimulates the release of NE in the hippocampus (Grilli et al., 2009). Impairment of the mesolimbic dopamine system is postu-lated to be involved in salvinorin A induced dysphoria (Grilli et al., 2009) whereas a decrease in 5-HT activity might be involved in the sedating effects of the drug (Ansonoff et al., 2006; Fantegrossi, Kugle, Valdés, Koreeda, & Woods, 2005).

mix

Deterioration of brain regions, including limbic structures and prefrontal areas, likely begins in utero and continues throughout childhood, becoming fast-tracked during the synaptic pruning that takes place prior to and during adolescence. This process likely leads to a progres-sive and substantial loss of glutamate synapses, resulting in NMDA receptor hypoactivity and glutamate dysregula-tion. To understand the implications of glutamate dysfunc-tion on dopamine systems, you must understand that NMDA receptor activity regulates dopamine function. In the prefrontal cortex sit the cell bodies of glutamate neurons whose axons project to the ventral tegmental area. There, they synapse with dopaminergic neurons that form both the mesocortical and mesolimbic pathways. Recall that the most current conceptions of the dopamine hypoth-esis of schizophrenia state that the negative and cognitive symptoms of schizophrenia result from hypoactivity of the mesocortical pathway. Normally, cortical glutamate neu-rons projecting to the ventral tegmental area produce a tonic (steady, constant) excitation of mesocortical dopa-mine neurons (Geisler, Derst, Veh, & Zahm, 2007; Geisler & Wise, 2008). These dopamine neurons, in turn, project their axons back to the prefrontal cortex (this is the mesocortical pathway) where they release dopamine in response to this excitation. This glutamate-dopamine interaction is illus-trated in Figure 12-1, panel A. Additionally, prefrontal cortical glutamatergic neu-rons form synapses with GABAergic interneurons within the ventral tegmental area. The axons of these GABAergic interneurons project to and inhibit the activity of the dopa-minergic neurons that, in turn, project their axons to the nucleus accumbens (this is the mesolimbic pathway). Stimulation of glutamate neurons in the prefrontal cortex results in the inhibition of dopamine neurons that form the mesolimbic pathway, due to the presence of the GABAergic neurons that act as a chronic braking system. This glutamate-dopamine interaction is illustrated in Figure 12-1, panel B. Recall that the positive symptoms of schizophrenia are believed to be the result of hyperactivity of the mesolimbic dopamine pathway. When cortical glutamate activity is diminished, due to a blockade of NMDA receptors by PCP or ketamine or resulting from neurodevelopmental pathology, this leads to a loss of NMDA receptors or glutamate connectivity and understimulation of ventral tegmental area dopamine neu-rons. As a result, the mesocortical dopamine pathway becomes hypoactive and, at the same time, the mesolimbic dopamine pathway becomes hyperactive. These glutamate-dopamine interactions may explain why, with progressive deterioration of neurons and glutamate functionality, we see the emergence of negative and cognitive, followed by positive, symptoms of schizophrenia.

Dextromethorphan

Dextromethorphan (DXM) is a synthetic antitussive (cough-suppressant) drug found in more than 120 over-the-counter cough-and-cold formulations, most of which have trade names that end in "DM." Chemically, DXM is the dextro (d-) isomer of levomethorphan, a semisynthetic mor-phine derivative, and is therefore structurally similar to the opioids (see Chapter 11). Many years ago, DXM was considered safe after research indicated that its potential for abuse was not as serious as that of the opioids. Since those early studies, however, there have been numerous reports of people consuming large quantities of over-the-counter cough medicines, such as Robitussin or Coricidin, for their psychoactive effects. This practice is known as Roboing, Robo-tripping, or skittling. Evidence of the drug's abuse has led to in-depth examination of dextrometho-rphan's behavioral pharmacology, as well as that of its metabolite, dextrorphan (DXO).

human effects

Dextromethorphan has been used as a cough suppressant for many decades. At normal therapeu-tic doses (15-30 mg taken once every 6-8 hours), it is an effective antitussive and produces few side effects and no PCP-like effects. However, the use of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhib-itors (MAOIs) alongside DXM can increase the likelihood of negative side effects (Ziaee et al., 2005). Recreational dextromethorphan users report varying intensities of behavioral effects produced by the drug. These are described as "plateaus" that are achieved accord-ing to the dose ingested. The first plateau, attained after a 100-200 mg dose of DXM, involves mild stimulation, simi-lar to that resulting from MDMA use. The second plateau is reached after ingesting a 200-400 mg dose of DXM and involves mild hallucination, giggling or laughing, and euphoria, similar to that induced by the combined admin-istration of alcohol and cannabis. The third plateau, achieved with a dose of 300-600 mg of DXM, is marked by a loss of motor control, distorted visual perceptions, and a dissociative "out-of-body" state similar to that elicited by a low recreational dose of ketamine. The fourth and final plateau consists of sedation and a fully dissociative state, similar to that produced by ketamine intoxication, and is achieved after administration of 600-1500 mg of DXM. The usual effective dose for recreational purposes is 150 mg (typical range: 100-300 mg), while the usual lethal dose is about 1500 mg (Gable, 2004b). In addition to the above, physical symptoms, such as tachycardia, hypertension, vomiting, dizziness, pupil dila-tion, sweating, and nystagmus (jerky, involuntary eye movements), may occur with lower intoxication plateaus. With higher levels of intoxication, users may demonstrate "zombie-like" walking, characterized by a plodding, ataxic gait (Burns & Boyer, 2013). They may also become extremely agitated. Experienced recreational dextrometho-rphan users report rapid tolerance to the drug's effects. Whether this is the result of alterations to cytochrome P450 enzyme functioning, or some other mechanism, is unknown (Boyer, 2004). Although dextromethorphan is not believed to be highly addictive, susceptible individuals may develop craving and compulsive use of the drug (Burns & Boyer, 2013). 15.7: GHB GHB (gamma-hydroxybutyrate) is a naturally occurring substance, found at extremely low concentrations within the human central nervous system, blood, urine, and pe

withdrawal

Doses as high as 600 mg per day can cause physical dependence after only 6 to 14 days of exposure. Withdrawal symptoms can also be seen at daily exposures of as little as 100 mg per day over a longer period of time (Griffiths & Mumford, 1995). Withdrawal symptoms usually start within 12 to 28 hours since the last caffeine intake, peak at 20 to 51 hours, and last 2 to 9 days (Griffiths & Mumford, 1995; Griffiths & Woodson, 1988; Juliano & Griffiths, 2004). Abstinence from regular use of high-dose (e.g., 7900 mg/day) caffeine may delay the onset of withdrawal to 24 hours or more. Figure 9-1 shows the across-day subjective Figure 9-1 Changes in subjective ratings of headache (top) and energy (bottom) across 24 days of study participation. On each of the first and last 6 days of the study, participants consumed ten 10-mg caffeine tablets, one per hour, throughout the day. During the middle 12 days of the study, placebo capsules were substituted for caffeine. The y-axis of each graph portrays mean ratings (0 = not at all; 3 = very much) for headache and energy level. Caffeine withdrawal caused increases in reported headaches and a decrease in energy that lasted as long as a week. (From Griffiths et al., 1990.) 1.2 0.2 0.4 0.6 0.8 1 0 0 2 2 4 6 8 10 12 14 16 18 20 22 24 CONSECUTIVE DAYS ratings of headache (top graph) and energy level (bottom graph) during daily use of 100 mg of caffeine, 12 days of pla-cebo substitution, and a return to 100 mg daily caffeine con-sumption (Griffiths et al., 1990). Ratings of headache increased and ratings of energy decreased substantially, especially during the preliminary days of placebo substitu-tion. Though headache scores approached baseline levels by the end of the 12-day placebo substitution period, some researchers report that withdrawal-related headache can persist for up to 3 weeks (Richardson et al., 1995). Given expectation and placebo effects (described in Caffeine Placebo Caffeine Chapter 2), is it possible that withdrawal symptoms from caffeine might be explained by such nonpharmacological factors (Dews, O'Brien, & Bergman, 2002)? This possibility was investigated by Juliano and Griffiths (2004), who pointed out that most of the studies that have found clini-cally significant withdrawal from caffeine were double-blind studies where the participants did not know that they were experiencing caffeine withdrawal. In some stud-ies, participants did not know that the experiment involved caffeine at all, so it is unlikely that expectancy and placebo effects are responsible for withdrawal symptoms. Given that a high percentage of the population regu-larly consumes caffeine, caffeine withdrawal could be a possible (though often overlooked) diagnosis when people report headache, fatigue, and mood disturbances in cir-cumstances where normal diet, including caffeine

synaptic pruning

During childhood and adolescence, the brain under-goes a period of synaptic pruning where weak, unused syn-apses are eliminated and strong, frequently used synapses remain and grow even stronger. Some researchers believe that, in schizophrenia, this process is pathologically exag-gerated so that too many connections are pruned and cer-tain populations of neurons dwindle in number. These populations include, but are not necessarily limited to, dopaminergic and glutamatergic neurons, which you will learn more about shortly

substrate recognition site

Each MAT protein contains a sub-strate recognition site—a receptor located on the outer mem-brane of the transporter complex that binds its relevant monoamine. Because the concentration of any monoamine will be much higher inside the axon terminal relative to outside in the synaptic space, simple gradient forces will not move the monoamine to the inside of the cell. Instead, MATs additionally bind Na+ and Cl-ions, which form a chemical complex with the monoamine, and rely on the motive force of the inward-directed Na+ ion gradient to transport molecules of monoamine into the neuron, against their own outward-directed concentration gradi-ent (Heal et al., 2014).

reproduction

Early studies indicated that the tricyclic antidepressants can interfere with male sexual functioning, but suggested that the problems are not extensive (Harrison et al., 1986). A study published soon after, however, found evidence that the impact may be more serious than first thought. Monteiro and colleagues (1987) compared a group of men and women receiving the tricyclic clomipramine to treat obsessive-compulsive disorder with a placebo control group. In response to general questions about sexual func-tioning, there did not appear to be any difference between the drug group and the controls, but when questioned more closely in a structured interview about changes in sexuality, nearly all (96%) of the drug group reported severe difficulties in achieving orgasm. No difficulties were reported in the control group. This effect did not seem to be a result of sedation or fatigue and did not show any tolerance. Delayed or impaired ejaculation has also been reported with the MAOIs (Woods, 1984). Individuals taking newer antidepressants, including the SSRIs and SNRIs, also frequently report delayed ejaculation and a loss of interest in sex. The atypical bupropion does not affect 5-HT function to the same magnitude as other anti-depressants and is unlike the others in that it is not associ-ated with sexual dysfunction; it may, in fact, enhance sexual activity through its dopaminergic effects. Drug use during pregnancy is always a concern as any molecule capable of entering the bloodstream and passing through the blood-brain barrier is also capable of reaching the developing fetus. It is not surprising, given that young adults comprise the age group most likely to experience depression, that the condition occurs in up to 13% of preg-nant women (Bennett, Einarson, Taddio, Koren, & Einarson, 2004). The safety of antidepressant use du

subjective effects

Early studies on the subjective effects of caffeine were con-fusing. In some cases, participants reported negative effects of caffeine such as increased anxiety, tension, jitteri-ness, and nervousness. Other studies documented an array of positive effects, such as increased sense of well-being, energy, motivation for work, and self-confidence. Griffiths and Mumford (1995), and Rush, Sullivan, and Griffiths (1995), explain this discrepancy by proposing that the posi-tive effects of caffeine are more reliably detected under a restricted set of conditions. First, they are seen when caf-feine is administered to people who are not caffeine users or to caffeine users who have been deprived at least over-night. The fact that positive effects are seen in coffee abstainers indicates that these effects are not simply a ematter of alleviating caffeine withdrawal (Childs & de Wit, 2006; Richardson, Rogers, Elliman, & O'Dell, 1995). Second, positive effects are more likely to be seen at low doses (from 20 to 200 mg). The higher the dose, the more likely it is that unpleasant effects will be reported. Finally, positive effects are most likely to be reported by individu-als for whom caffeine acts as a positive reinforcer, which is perhaps a reflection of genetic predisposition (Meredith, Juliano, Hughes, & Griffiths, 2013). In a study by Mumford and colleagues (1994), partici-pants were given 178 mg of caffeine, and scores on a mood scale were determined at various time points thereafter. The drug caused increases in well-being, magnitude of drug effect, energy, affection for loved ones, motivation to work, self-confidence, social disposition, alertness, and concentra-tion, and decreases in sleepy and muzzy feelings. These changes were evident within 30 minutes and remained higher than placebo levels for at least 8 hours. The same study also examined the subjective effects of theobromine. A dose of 100 mg produced positive changes in energy, moti-vation to work, and alertness but to a much smaller extent than caffeine. The time course for these changes was similar to caffeine, but at 5 to 10 hours after ingestion, participants reported unpleasant effects such as headache and lethargy

eoute of admin

Ecstasy is usually taken orally at a dose of ~100-120 mg. Its effects are felt within 30-60 minutes and peak blood concentrations, as well as peak subjective effects, are achieved within about 1-2 hours after ingestion. The dura-tion of principal effects is roughly 4-6 hours (Nutt, 2012; Parrott, 2014). MDMA has an elimination half-life of about 8 hours, thus taking roughly 40 hours for 95% of the drug to be eliminated. For this reason, many of the effects of MDMA can persist for several days after use. The majority of the drug is either excreted unchanged in the urine or metabolized to MDA

energy drinks

Energy drink labels or manufacturer websites may cite comparable or even lower levels of caffeine than a similar-sized cup of Starbucks or Dunkin' Donuts coffee, but energy drinks also contain other stimulating ingredients likely not included in the caffeine count. Manufacturers add plant extracts such as guaraná, kola nut, maté, green tea, cocoa, acai berry, milk thistle, Ginkgo biloba, ginseng, yohimbine, and St. John's wort—some of which provide additional amounts of caffeine and other methylxanthines. This extra caffeine content is not included on the label, or in the caffeine amounts given in Table 9-1, so it is difficult to determine the exact dose of caffeine contained in an energy drink. Energy drinks may also contain: amino acids, such as taurine, tyrosine, L-carnitine, L-tryptophan, L-arginine, and L-theanine; vitamins, including A, B, C, and E; minerals, such as iron or calcium; various other substances, including glucuronolactone, carnitine, citico-line, creatine, 1,3-dimethylamylamine, malic acid, and vin-pocetine; carbohydrates, such as glucose; and artificial flavors, colors, and other sweeteners. Many of these ingre-dients are GRAS and have no maximum limits imposed on them, nor are they required to be listed as ingredients. In Canada, energy drinks are regulated by Health Canada whose guidelines state that a single-serving container (...591 ml/20 fl.oz.) must not contain more than 180 mg of caffeine (Health Canada, 2011a). There are no limits imposed on other energy-drink ingredients that may exert caffeine-like effects. As of the writing of this chapter (in September, 2015), the U.S. FDA does not have regulations related specifically to energy drinks

driving

Epidemiological studies have shown that people under the influence of amphetamines are 2.3 times more likely to be killed in an automobile accident compared to a sober driver (Drummer et al., 2004). A recent meta-analysis reported that the odds of being involved in a road traffic crash are 18 times greater after amphetamine use, and that amphetamine and methamphetamine are associated with higher risk of road traffic crash than any other drug (Gjerde, Strand, & Mørland, 2015). The odds ratio of road traffic crash also increases with cocaine use, but the asso-ciation is weaker than that of the amphetamines. High doses of amphetamines impair self-perception and critical judgement, and at the same time increase risk-taking behavior. As the drug wears off, increased fatigue, anxiety, and irritability may further impact driving ability (Gjerde et al., 2015). Observed behaviors of drivers under the influence of amphetamines include drifting out of the la

non-nic factors in the dual reinforcement model

Figure 8-3, Caggiula and colleagues (2001) showed that cues associated with nicotine infusions can acquire rein-forcing properties and maintain self-administration. It is possible that many of the sensory experiences associated with smoking, such as the smell, taste, and the motor activ-ities of smoking, can also acquire reinforcing properties and may be important in both maintaining smoking and in relapse to smoking after quitting. We have seen as well that smokers report considerable satisfaction from smoking denicotinized cigarettes, which can relieve craving and other symptoms of nicotine withdrawal for up to 96 hours, despite a lack of drug (Buchhalter, Acosta, Evans, Breland, & Eissenberg, 2005; Butschky, Bailey, Henningfield, & Pickworth, 1995). In a study of the subjective effects of vap-ing versus smoking, Vansickel and colleagues (2010) mea-sured blood plasma nicotine levels and cigarette craving at various time points following participants' use of an e-cigarette or own brand of tobacco cigarette. The vaping devices used in the study were "first-generation" cig-a-likes, which were notoriously inefficient nicotine delivery systems and indeed failed to raise blood plasma nicotine levels from baseline. Yet, the act of vaping significantly reduced tobacco abstinence symptom ratings, most notably the sense of "craving a cigarette" and "urge to smoke." At the same time, participants reported higher subjective ratings of "satisfy-ing," "taste good," "calm," and "pleasant" after vaping. Even the resemblance of an ENDS device to a tobacco ciga-rette (a white as opposed to red cig-a-like) influences crav-ing and withdrawal symptoms, despite similar levels of ristoforou, Olumegbon, & Soar, 2016). A better understanding of the role these non-nicotine-related factors play in maintaining smoking behavior will improve strategies, such as nicotine replacement therapy (NRT), for treating tobacco addiction. NRT provides nico-tine via other routes of administration, such as the patch or a nicotine inhaler, but does not provide the sensory cues of smoking. The role of smoking-related sensory and motoric cues has been explored extensively by Jed Rose and his colleagues at Duke University. In one experiment, Rose (2006) administered nicotine intravenously to smokers, either continuously or in 2-second burst infusions, over a 4-hour period. The burst infusions were designed to mimic the dose of nicotine one would get from taking a puff of a cigarette. At the same time, some participants inhaled

distribution

Following absorption, caffeine is widely distributed throughout the body's tissues and reaches all organs, although the rates of entering and leaving the organs may vary. In a recent case study of death by caffeine overdose, Yamamoto and colleagues (2015) reported high concentra-tions of caffeine within the stomach, kidneys, liver, lungs, heart, brain, skeletal muscles (quadriceps), skin, urine, and blood of the deceased. About 10 to 30% of caffeine in the blood becomes bound to protein and trapped in the circu-latory system (Arnaud, 1993; Axelrod & Reichenthal, 1953). Caffeine also crosses the blood-brain and placental barriers without difficulty and is present in all body fluids, including breast milk. Theophylline and theobromine are less lipid soluble than caffeine and are slower to pass through the blood-brain barrier

neuropharmacology-MATS

Following monoamine release and receptor-activation, neurotransmission is terminated both by the activity of spe-cific enzymes in the synaptic cleft, such as monoamine oxi-dase (MAO) and catechol-O-methyltransferase (COMT), and by the reabsorption of neurotransmitter molecules into the presynaptic neuron. Reabsorption is achieved via special reuptake transporter molecules called monoamine transport-ers (MATs). These transporters are large protein molecules that span the membrane of the presynaptic axon terminal and actively move monoamines from the synaptic cleft, across the membrane, and into the cytosol of the presynap-tic cell. Each monoamine has its own special transporter; there is a dopamine transporter (DAT), a norepinephrine transporter (NET), and a serotonin transporter (SERT). MATs are structurally very similar to one another and are therefore capable of transporting molecules of each other's neurotransmitter; for instance, DATs will transport norepi-nephrine, and NETs will also transport dopamine. However, the transporters have a lower affinity for monoamines other than their own, so under normal circumstances they mostly transport their designated neurotransmitter. MATs belong to a family of transporter proteins called Na+/Cl-dependent substrate-specific neuronal membrane trans-porters. Recall from Chapter 4 that ions are unevenly dis-tributed across the cell membrane; in the case of Na+ and Cl-, higher concentrations are found outside relative to inside the cell. Na+/Cl-dependent substrate-specific neu-ronal membrane transporters use the power of the ionic gradient that exists between the outside and inside of a neuron to transport molecules of neurotransmitter from the synaptic cleft into the presynaptic axon terminal (Heal, Gosden, & Smith, 2014). Each MAT protein contains a sub

problems

For example, we know that antidepressant medications pro-duce an immediate physiological effect. That is, as soon as the drug reaches monoamine synapses, it increases neu-rotransmitter levels. But, as with antipsychotic medications, despite their immediate action, antidepressants need to be taken continuously before any relief from depression is felt. The lag time between the start of antidepressant treatment and the alleviation of depressive symptoms can be as much as 4 to 6 weeks. Up to 12 weeks may pass before the antide-pressants reach their full effectiveness. In the context of the original monoamine theory, which simply stated that depres-sion is a result of diminished monoamine activity, this does not make sense. Another finding that cannot be explained by the original monoamine theory is that the above-mentioned correlation between tryptophan depletion and depression does not hold true for everyone. In individuals with no per-sonal or family history of depression, tryptophan depletion has no effect on mood (Riedel, Klaassen, & Schmitt, 2002). This suggests that other physiological differences must exist between those individuals who are susceptible to depression and those who are not. Therefore, the monoamine theory, in its simple form, is not tenable—the neurophysiological changes associated with depression are much more compli-cated than first imagined. A wealth of research has advanced our understanding of the role monoamines play in mood disorders, and the monoamine theory in its updated form continues to receive much attention and support.

adhd treatment

For more than half a century, the psychomotor stimu-lants (first d-amphetamine, then methylphenidate, and most recently lisdexamfetamine) have been the drugs of choice for the treatment of ADHD. In 2005, an estimated 9% of boys and 4% of girls in the United States were taking some form of stimulant medication as part of their ADHD treatment. These drugs primarily target catecholamine neu-rotransmitter systems (dopamine and norepinephrine), which are believed to be dysfunctional in individuals with ADHD. It may seem strange and even counterintuitive that drugs classified as "psychomotor stimulants" are used to treat a disorder marked by "hyperactivity." However, indi-vidual differences in resting-state catecholamine levels seem to explain why these drugs work (Volkow et al., 2002). Recall that methylphenidate and amphetamine are catecholamine blockers; they competitively inhibit the activity of dopamine and norepinephrine reuptake trans-porter proteins (DATs and NETs), which leads to a signifi-cant accumulation of DA and NE in the synaptic cleft. The role of dopamine in ADHD has received the most research attention, and elevations in extracellular DA levels appear to be responsible for the therapeutic effects of psychostim-ulants (Frölich et al., 2014). When DAT blockade prevents the reuptake of dopamine, molecules accumulate in the extracellular space which leads to an increase in the stimu-lation of presynaptic D2 autoreceptors. By way of negative feedback, the outcome is a reduction in the amount of DA released from synaptic vesicles in response to an action potential. This, in turn, dampens DA signaling at postsyn-aptic D1 and D2 receptors, thereby reducing motor hype activity (Seeman & Madras, 1998). Additionally, methylphenidate-induced DAT blockade dampens the amount of "background noise" created in the brain by tonic (steady) dopamine-cell firing, and amplifies the sig-naling of task-related (i.e., action-potential-elicited) dopamine-cell firing. This is believed to be the mechanism of action by which methylphenidate improves sustained focus and attention (Volkow et al., 2001). Increases in extra-cellular dopamine levels might also enhance the motiva-tional salience of a cognitive task in which an individual is engaged, facilitating interest in the activity and thus improving performance (Volkow et al., 2001). The relationship between catecholamine activity levels and cognitive functioning follows an inverted U-shape curve; deficits, as well as excesses, of DA and NE can impair cognition. Methylphenidate is therapeutically ben-eficial for individuals whose baseline (tonic) release of DA is too high; those with low baseline release, or low DAT availability, might not respond well to psychostimulant treatment (Volkow et al., 2002). Indeed, approximately 25-30% of ADHD patients fail to benefit from Psychostimulants are not cognitive-enhancing magic bullets. While they do seem to enhance sustained attention in individuals with attention deficit, they tend to worsen selective attention and distractibility (ter Huurne et al., 2015). They do not improve the short-term acquisition of information, though there is some evidence that long-term memory may be enhanced in people with pre-existing severe deficits (Advokat, 2010). Stimulants do not improve (in fact, they may even worsen) cognitive and behavioral flexibility (Advokat, 2010). Moreover, an increase in cate-cholamine levels may lead a person to believe that his or her levels of energy and attention are enhanced and that cognitive performance has improved when in fact it has not (Ilieva, Boland, & Farah, 2013; Ilieva & Farah, 2013). In fact, the use of unprescribed stimulants has been found to com-promise study habits, lower motivation, and contribute to attention problems (Ilieva & Farah, 2015). In considering the research, it seems rather unwise to rely on "smart pills" (as Adderall, Ritalin, and Concerta are called on the street) as a substitute for well-planned, effective study beha

GHB

GHB (gamma-hydroxybutyrate) is a naturally occurring substance, found at extremely low concentrations within the human central nervous system, blood, urine, and peripheral tissues (Meyer & Maurer, 2011). It is both a pre-cursor for, and a metabolite of, the brain's principal inhibi-tory neurotransmitter, gamma-aminobutyric acid (GABA), and acts in the brain as a neurotransmitter and as a neuro-modulator (Busardò & Jones, 2015; Castelli, 2008). GHB is also a drug of abuse, GHB has sedative qualities, similar but more potent than those of alcohol and sedative-hypnotic drugs (see Chapters 6 and 7). In 1874, a Russian chemist named Alexander Saytzeff was the first person to synthesize a compound called GBL (gamma-butyrolactone), a precursor of GHB (and currently used as a "legal high" alternative to GHB). In the 1960s, Henri Laborit, the French military surgeon famed for his research on the antipsychotic drug chlorpromazine (see Chapter 12), became interested in the physiological effects of GHB and its potential as a surgical anesthetic. Laborit's research revealed that GHB exerts potent pharmacological actions. Unlike GABA, it crosses the blood-brain barrier and is effective when administered orally. At high doses, it produces sedation and unconsciousness, without depress-ing cardiovascular or respiratory functions, and causes no deleterious effects on the kidneys or liver (Busardò & Jones, 2015). Clinical assessment of the drug's potential as an anesthetic proved disappointing, however. GHB exerted insufficient analgesic effects, and unconscious patients often vomited or suffered convulsions while under the drug's influence. Additionally, it was difficult to determine and control adequate dosages of the drug. Thus, investigation of the GHB's potential as an anesthetic was abandoned in favor of pursuing a safer alternative, such as ketamine (Busardò & Jones, 2015). In the 1970s and 1980s, GHB was sold in health-food stores as a nutritional supplement. It became popular with dieters, who were told that the drug would burn fat, and with body builders, who believed GHB would promote the production of growth hormone and cause them to build muscle. Throughout the 1980s and into the 1990s, users reported that, at low doses, GHB enhanced libido, lowered inhibitions, and produced euphoria, making it a popular drug choice among dance-club and rave attend-ees. The popularity of GHB as a club drug grew signifi-cantly during the early 1990s. It was in this context that GHB also gained notoriety as a "date rape drug"—a sub-stance slipped into an unsuspecting person's drink, inca-pacitating them and facilitating sexual assault. GHB makes people feel drowsy, lowers their inhibitions making it more likely that they will engage in untypical behaviors, and produces anterograde amnesia so that it becomes difficult to recall events that took place while under the drug's influence (Busardò & Jones, 2015). Because of GHB's rapid metabolism and excretion from the body, forensic analysis of sexual assault survivors' bodily fluids is of little use in determining whether GHB has been administered. ance beginning in the early 2000s. When sold on the street, GHB has many names including Georgia Home Boy, juice, liquid X, liquid ecstasy, liquid G, fantasy, mils, GBH (grievous bodily harm), scoop, cherry meth, blue nitro, easy lay, and more than 30 others (O'Connell, Kaye, & Plosay, 2000). While its recreational use is prohibited, GHB is sanctioned for legit-imate medical purposes. It is approved for use in its sodium salt form, sold under the generic name sodium oxybate and under the trade name Xyrem. Xyrem is used for the treatment of cataplexy (the brief loss of muscle tone, often brought on by emotional arousal) that occurs in individuals with the neurological disorder, narcolepsy (a sleep disorder characterized by excessive daytime sleepiness). In the United States, GHB is a Schedule I drug, but Xyrem is a Schedule III drug. The classifications assigned to GHB and Xyrem are similar to those assigned to cannabis (Schedule I) and Marinol (Schedule III), a THC-containing preparation with medical use (see Chapter 14). In Italy and Austria, GHB is marketed in its sodium oxybate form as Alcover—an adjunctive pharma-cotherapy used to treat the symptoms of alcohol detoxifi-cation and withdrawal. It has also been found to reduce craving for alcohol and is as effective as naltrexone or disulfiram in preventing r

admin

GHB is available as a colorless, clear liquid that tastes slightly salty, or as a white powder that is most often mixed into a beverage and ingested orally. When mixed with alcohol, as is often the case, GHB's effects are greatly intensified. GHB is usually packaged in small vials or bot-tles in liquid form and sold at bars or raves by the capful, known as a swig. When taken orally, GHB is rapidly absorbed from the gastrointestinal tract, producing behav-ioral and subjective effects within 15-30 minutes of inges-tion. Its peak effects are reached within 20-40 minutes. GHB is also rapidly eliminated from the body. When taken in low therapeutic doses, its half-life is 30-50 minutes. Within 150-250 minutes following ingestion, blood plasma concentrations of GHB will have declined to the point of being barely measurable (Busardò & Jones, 2015). Depending on the dose ingested, the effects of GHB are felt for 1-6 hours. Between 95% and 98% of GHB is metabo-lized in the liver by GHB hydrogenase, producing no active metabolites. The dose-effect curve for GHB is extremely steep, meaning that tiny increases in dose produce profound increases in the drug's subjective and behavioral effects, as well as a heightened risk of toxicity to the user (Busardò & Jones, 2015). It is not unusual for a recreational user of GHB to go from feeling fine and alert to becoming inca-pacitated and losing consciousness in a matter of minutes. When used for recreational purposes, a usual dose ranges between 1.4-3.0 g (Busardò & Jones, 2015; Gable, 2004b). This amount of GHB is sufficient to produce feelings of euphoria and well-being. Larger doses will cause drowsi-ness, slurred speech, and motor incoordination. The usual lethal dose of orally administered GHB is approximately 16 g, but the range of lethal doses is rather large, from 5.4 to 24 g (Gable, 2004b). Because of the narrow safety margin that exists between a recreational and a lethal dose of GHB, mortality rates stemming from GHB abuse are relatively high. In a review of 226 GHB-related deaths, 94% were due to cardiorespiratory arrests and 65% involved the co-administration of another drug (Zvosec, Smith, Porrata, Strobl, & Dyer, 2011). Given the illegal status of GHB, a market exists for a similar-acting, easily available, alternative "legal high." GBL (the compound synthesized in Russia in 1874) and a similar compound, 1,4-butanediol (BD), appear to have filled this niche. Both GBL and BD are precursors (or prodrugs) that, when ingested, are rapidly (within ~1 minute) converted into GHB. As GBL and BD both have cosmetic and industrial applications, to classify these compounds as drugs of abuse and to regulate their possession and sale would prove problematic (Busardò & Jones, 201

swallowed tobacco

However, with certain forms of moist snuff, snus, and dissolvable products where spitting is uncommon, nicotine that is not absorbed through buc-cal membranes is swallowed in saliva. Nicotine is a weak base, so it will not have many lipid-soluble molecules when dissolved in solutions with a pH lower than 6. Conse-quently, this ionized nicotine is not readily absorbed from the acidic environment of the digestive system. Swallowed nicotine has another disadvantage for absorption because the blood from capillaries of the digestive tract must first pass through the liver before it achieves general circulation throughout the body. Because nicotine is rapidly metabo-lized in the liver, much of what is swallowed is metabolized during this first pass before reaching the rest of the body.

discrimination

Humans can quite readily learn to discriminate amphet-amine and other psychomotor stimulants from a placebo (Chait, Uhlenhuth, & Johanson, 1986; Sevak et al., 2009). In one experiment, participants completed training sessions during which they received a monetary reward if they could learn to discriminate between a capsule containing 10 mg of methamphetamine and one containing placebo. Following the training phase, participants were tested with capsules containing various doses of methamphet-amine, d-amphetamine, and methylphenidate. They were also administered capsules containing doses of triazolam (a benzodiazepine). The test doses of these drugs, which are displayed along the x-axis of Figure 10-3, are within the range of those commonly prescribed for therapeutic pur-poses. The results of the test phase are also illustrated in Figure 10-3. As you can see, the methamphetamine response generalized completely to d-amphetamine and methylphenidate, indicating that the participants could not distinguish between them (Sevak et al., 2009). Triazolam, on the other hand, was easily discriminated.

self administration

In 1968, Roy Pickens and Travis Thompson, then at the University of Minnesota, published the first detailed account of cocaine self-administration in nonhumans (the first cocaine self-administration experiments were actually done by G. A. Deneau and his colleagues at the University of Michigan, but these were not published until 1969). Pickens and Thompson showed that rats, implanted with intravenous catheters, would bar press on an FR schedule to self-administer cocaine (this experiment was described in detail in Section 5.3.4 of Chapter 5). This discovery was an important milestone, for several reasons. It was the first demonstration of self-administration of a drug other than morphine, and it established that a drug with no readily apparent withdrawal symptoms could act as a reinforcer confirming that the reinforcing effects of drugs do not hinge on a fear of withdrawal. Since this early experiment, there have been many demonstrations of nonhumans responding, not only for cocaine infusions, but for many other psychomotor stimulants, across different species, and via a variety of routes of administration. Deneau and colleagues (1969) published data from monkeys, demonstrating the erratic pattern of cocaine self-administration that results when the drug is made freely available, 24 hours a day, for 3 weeks. A monkey quickly learns to self-administer the drug and soon begins taking it at levels high enough to cause convulsions. There is consid-erable fluctuation from day to day; on some days, very little drug is taken whereas, on others, considerable quantities are infused. As an example of the typical run-abstinence cycle noted by Deneau, one monkey self-administered cocaine at doses of up to 110 mg/kg/day and then stopped responding entirely for a 28-hour period (on day 17 of self-administration) before resuming injections the next day (Deneau et al., 1969). This pattern of cocaine self-administration is similar to the binge-abstinence cycles engaged in by human stimulant users. If no restrictions are placed on cocaine intake and the drug is freely available, laboratory animals will often administer cocaine to the point of lethal overdose (Bozarth & Wise, 1984). The pattern of self-administration is quite different when daily access to cocaine is limited; that is, when there is a long time-out period after each infusion, or when access to cocaine is limited to brief sessions during the day. Under these conditions, laboratory animals self-administer

personality

In 1990, fluoxetine (Prozac) attracted national attention by appearing on the cover of Newsweek. Quoted in that issue was a psychiatrist, Peter Kramer, who had written about giving fluoxetine to people, not to treat depression, but to modify their personalities. Prozac "seemed to give social confidence to the habitually timid, to make the sensitive brash, and to lend the introvert the social skills of a sales-man" (Kramer, 1993, p. xv). Kramer quoted one of his patients as saying that the drug had made him feel "better than well." He also coined the term cosmetic psychopharma-cology, suggesting that people could take drugs such as fluoxetine to cover, by neurochemical means, some aspect of their personality they were not satisfied with in the same way that facial blemishes could be hidden by makeup or the shape of a nose could be made more attrac-tive by cosmetic surgery It is well-established that fluoxetine and other SSRIs are useful in treating people with diagnosed personality disorders, such as obsessive-compulsive personality disor-der, and with compulsive behaviors (Gitlin, 1993). However, the use of fluoxetine and SSRIs as a personality cosmetic for people who do not have a diagnosed disor-der, but are simply not happy with their personality, is a matter of some debate. The practice raises a number of interesting issues, not the least of which concerns the ori-gins of personality. If a drug can cause such immediate and profound changes in personality, this effect has far-reaching implications for the way we view personality. Is our personality determined by our past, our childhood experiences, and the like, as many theorists have long believed, or is it determined by 5-HT levels in the raphe nuclei (Kramer, 1993)

caffeine and dsm-5

In Chapter 5, you read the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) key features of substance use dis-order. In Chapters 6, 7, and 8, you learned that those criteria can be applied to diagnose alcohol, sedative-hypnotic, and tobacco use disorders. Are the methylxanthines like other drugs in their potential for abuse? Can caffeine use reach a pathological level, leading to risky behavior, a loss of self-control, and social impairment the way that heroin or cocaine can? The unequivocal answer to these questions is: maybe. Of all the classes of drugs you will learn about in this text, caffeine is the only one that the American Psychiatric Association (APA) acknowledges can produce intoxication and withdrawal syndromes, but excludes from potentially causing a "use disorder." In stark contrast, the World Health Organization does include caffeine dependence syndrome in its classification system, the ICD-10 (WHO, 2015). The APA's decision to set caffeine apart from other intoxicating and withdrawal-producing substances was made for a number of reasons. Caffeine is used by the large majority of the world's population who tend to self-administer daily doses that fall well within safe limits and who generally suffer no harmful effects. In fact, chronic caf-feine consumption has health benefits not afforded by daily use of most other non-prescribed drugs. The majority of individuals who regularly use caffeine function just fine, managing to fulfill their major social, work, and interper-sonal obligations. Yet, despite these facts, the possibility remains that some people may self-administer caffeine in a disordered manner and much more investigation of caf-feine's abuse potential is requir

antisphycotic termonologies

In North America, they are most often referred to as antipsychotics because their primary beneficial effect is to diminish the symptoms of psychosis. The term major tranquilizer is some-times used to refer to the antipsychotics because they have a calming and sedating effect, not only in agitated patients experiencing symptoms of psychosis, but also in healthy individuals. This term is inaccurate, however, because it suggests that the utility of these drugs stems from their capacity to tranquilize agitated patients. While there is a tranquilizing effect, the major benefit of the antipsychotics results from their direct inhibition of psychotic symptoms, which in turn reduces agitation. Another problem with using the term major tranquilizer is that it implies these drugs are simply a stronger (more potent) version of the minor tranquilizers, a name sometimes applied to the class of drugs that includes the benzodiazepines and barbiturates (see Chapter 7). This terminology is misleading because it suggests that both "major" and "minor" tranquilizers exert similar effects, with one group simply being more powerful than the other. In fact, there is very little similarity, in chem-istry or effect, between the barbiturates and benzodiaze-pines on the one hand and the antipsychotics on the other. In Europe, neuroleptic (meaning clasping the neuron) is the preferred name used in reference to antipsychotic drugs. Neuroleptic denotes the capacity of these drugs to cause extrapyramidal signs and symptoms, such as rigid-ity in the limbs and difficulty of movement, similar to those symptoms seen in people suffering from Parkinson's This property of these drugs is a persistent and bothersome side effect, and it is indeed strange that a fam-ily of drugs should be named after a side effect rather than its most useful therapeutic effect. The term neuroleptic may have become the name of choice because, at one time, it was believed that both EPS and therapeutic effects were related; that is, people believed that these drugs would not relieve psychosis unless they produced neuroleptic effects as well. It is now known that the two types of effects are independent (Creese, 1983). In fact, many of the more recently developed, highly effective antipsychotic drugs have few, if any, neuroleptic (EPS) effects. Although the term neuroleptic is probably more common than

nicotine as a discriminative stimulus-cocaine

In a drug state discrimination task, low-dose nicotine is an effective cue for laboratory animals that will not generalize to various doses of epinephrine, pentobarbital, physostig-mine, chlordiazepoxide, or caffeine. Caffeine is, in fact, able to potentiate the discrimination of nicotine in rats (Gasior, Jaszyna, Munzar, Witkin, & Goldberg, 2002). The stimulus properties of nicotine can be blocked by mecamylamine (Morrison & Stephenson, 1969; Stolerman, Pratt, & Garcha, 1982) or by a low dose of alcohol (Korkosz et al., 2005), although alcohol does not seem to affect nicotine discrimi-nations in humans (Perkins, Fonte, Blakesley-Ball, Stolinski, & Wilson, 2005). Humans sometimes describe the effect of intravenous nicotine as being similar to that of cocaine and, in rats, nic-otine will fully substitute for cocaine. The effect, though, is not bidirectional; cocaine will only partially substitute for nicotine in trained animals. Desai, Barber, and Terry (2003) used various antagonist drugs to further explore this rela-tionship and concluded that nicotine's ability to mimic cocaine is due to its stimulation of dopamine release, an effect it shares with cocaine. The subjective similarity is not due to cocaine's effect on cholinergic systems that are also affected by nicotine

other neurotransmitter systems involved

In addition to dopamine and glutamate, there may be other neurotransmitter systems that are rendered dysfunctional in schizophrenia. These include, but are not limited to, sero-tonin (Rasmussen et al., 2010), GABA (Lewis, Hashimoto, & Volk, 2005), acetylcholine (Lester, Rogers, & Blaha, 2010; Sarter, Nelson, & Bruno, 2005), and histamine (Ito, 2009). Research into neurotransmitter systems and their interac-tions continues to advance our understanding of the mech-anisms that underlie the development of psyc

akathisia

In addition, about 20% of patients show akathisia, a condition characterized by uncontrolled restlessness, constant compulsive movement, and sometimes a protruding tongue and facial grimacing

brain responsible for discriminatability

In an attempt to determine which regions of the brain are responsible for nicotine's discriminative properties, Miyata, Ando, and Yanagita (2002) trained rats to discrimi-nate nicotine and then tested for generalization of the response when nicotine was administered into various brain locations. They found that the nicotine response fully generalized to nicotine administrations into the medial prefrontal cortex and only partially to administrations into the nucleus accumbens and the ventral tegmental area, which indicates that the cortex, rather than reinforcement systems, is the primary mediator of nicotine's discriminability.

unconditioned behavior

In both rats and mice, locomotor activity in an open field is increased by injection of caffeine, paraxanthine, and the-ophylline, but not theobromine (Orrú et al., 2013; Seale et al., 1984). The impact of the methylxanthines on locomo-tion follows an inverted-U shape dose-response curve. Maximum increases in activity are observed at 30 mg/kg doses of paraxanthine and caffeine whereas higher doses greatly decrease motor behavior (Orrú et al., 2013). In rats, paraxanthine has the strongest stimulating effect on motor activity, which is proposed to result from increased dopa-mine release in the striatum (Orrú et al., 2013). Chronic treatment with caffeine results in a depression of sponta-neous activity (Fredholm, 1995). The LD50 of caffeine is approximately 200-250 mg/kg which is fairly consistent across species, including humans (Barnes & Eltherington, 1973; Dews, 1982; Eichler, 1976). Death is often due to convulsions though some animals die, even at lower doses of caffeine, from bleeding as a result of attacking themselves. Automutilation has been observed in rats when caffeine was given at a dose of 185 mg/kg for 14 days. The rats bit their tails and paws, even though they seemed to retain their normal sense of pain. When a ball of wire was placed in their cage, they temporarily attacked it but soon returned to biting them-selves. When picked up, they did not bite the hand of the experimenter, but they did attack other rats placed with them in a cage (Peters, 1967).

harm

In comparison to life-long non-smokers, risk of mortal-ity among current smokers is increased by 200-300% (Carter et al., 2015). According to the 2014 Surgeon General's report, cigarette smoking is responsible for nearly 500,000 deaths annually in the United States (USDHHS, 2014). As the report takes into account only those deaths resulting from the 21 specific cancer-, cardiovascular-, metabolic-, and pulmonary-related diseases formally acknowledged as being directly caused by smoking, half a million deaths may be a gross underestimate. Worldwide, smoking kills 5.5 million people every year, a toll that is expected to climb to 8 million by the year 2030 and 1 billion for the twenty-first century, mostly in the newly targeted develop-ing world (Jha, 2009). In addition to the health conse-quences of cigarette smoking, accumulating evidence points to potential harmful effects resulting from smokeless tobacco use, including snuff, snus, and dissolvables. Electronic nicotine delivery devices, being relatively new to the market, have become the subject of intensive study, in part because of manufacturers' claims that they are a health-ier, safer option to conventional cigarettes and an effective smoking cessation device (Zhu et al., 2014). Though e-cigarettes likely are safer than tobacco cigarettes, given that they do not deliver carbon monoxide and some of the carcinogens found in combustible tobacco, a full under-standing of their long-term health effects has not yet been reached. Some short-term negative outcomes have been

types of khat psychosis

In countries such as Yemen and Ethiopia where khat chewing is customary, two forms of khat psychosis are rec-ognized. Manic psychosis is similar to the manic phase of bipolar disorder. It is marked by hyperactivity, talkative-ness, shouting, grandiose delusions, flight of ideas and tangential thought processes, and a highly liable mood that fluctuates from euphoria to anger (Wabe, 2011). The second form, schizophreniform psychosis, resembles amphet-amine or cocaine psychosis. It is marked by schizophrenia-type symptoms: paranoid, persecutory, and referential delusions; thought alienation; auditory hallucinations; a tendency to isolate oneself from others; fear and anxiety; a hostile perception of the environment; and aggressive behavior (Wabe, 2011). Khat psychosis may also be accom-panied by violent outbursts, depressive symptoms, and suicidality (Geresu, 2015; Wabe, 2011). Both forms of psy-chosis are exceptional and are associated with chewing large amounts of khat, typically more than two bundles per day. Symptoms most often disappear without treat-ment when khat use is ceased (Nielen, van der Heijden, Tuinier, & Verhoeven, 2004; Wabe, 2011)

conditioned behavior

In general, the antipsychotic drugs cause a decrease in responding on schedules maintained by positive rein-forcement, although at lower doses there are reports that low response rates may be increased. This rate-dependent effect is similar to that seen with many other drugs, including amphetamine. When chlorpromazine was first being tested on humans in the early 1950s, Simone Courvoisier and her associates at the Rhöne-Poulenc com-pany discovered that the drug would decrease avoidance at doses that had no effect on escape from shock, an effect now known to be shared by antianxiety drugs such as the barbiturates and benzodiazepines (Courvoisier, Fournel, Ducrot, Kolsky, & Koetschet, 1953). In fact, this was the first time that the shock avoidance-escape task had been adopted for use in testing drugs, and it has since become a widely used screening device for new psychotherapeutics

elimination

In humans, roughly 1% of caffeine molecules are excreted unchanged in urine (Moffat, Osselton, Widdop, & Watts, 2011). The remaining 99% is metabolized almost exclu-sively in the liver by the cytochrome P450 superfamily enzyme: CYP1A2. Approximately 80-84% of caffeine mol-ecules are metabolized to paraxanthine, 12% to theobro-mine, and 4-7% to theophylline (Atia, York, & Clark, 2009; Safranow & Machoy, 2005). Levels of these metabolites peak at about 6-8 hours following caffeine ingestion, after which they are further broken down by the liver and grad-ually excreted from the body (Lang et al., 2013). Within an individual, the half-life of a given dose of caffeine is fairly consistent. But between individuals, caffeine elimination rates can vary substantially with the half-life ranging from 2.5 to more than 7.5 hours and averaging about 5 hours (Arnaud, 2011; Lang et al., 2013). There is evidence that caffeine's half-life may be dose-dependent. At concentra-tions of 70 to 100 mg, caffeine clearance from the body pro-ceeds at a linear (constant) rate of about 1-2 mg/min/kg (Moffat et al., 2011). But, at larger doses of 250 to 500 mg, caffeine elimination slows and its rate of clearance becomes nonlinear, prolonging its half-life (Kaplan et al., 1997). The addition of guaraná, which itself contains 4-8% caffeine by weight, may prolong the half-life of caffeine (Seifert, Schaechter, Hershorin, & Lipshultz, 2011). The half-lives of caffeine's primary met

tolerance

In humans, tolerance to the effects of LSD and related drugs develops extremely rapidly. When LSD is taken repeatedly at daily intervals, tolerance is observed after 1-3 days and a near-complete loss of response even-tually ensues so that the drug no longer produces any desired effect. The ability of LSD to disrupt the operant behavior of nonhumans also shows rapid tolerance. Such tolerance appears to be mediated by an acute down-regulation of serotonin 5-HT2A receptors (Gresch, Smith, Barrett, & Sanders-Bush, 2005) and is one reason why clas-sic hallucinogens are seldom taken continually. The abrupt tolerance to hallucinogens dissipates quickly, however, and sensitivity returns within a week. Cross-tolerance has been observed between LSD, psilocybin, and mescaline but not between LSD and d-amphetamine or THC (Brown, 1972). As an exception to the rule, tolerance does not build to the effects of DMT, nor does the repeated administration of this drug lead to a downregulation or desensitization of 5-HT2A receptors (Halberstadt, 2015). During ayahuasca ceremonies, the decoction may be taken repeatedly across multiple nights, and is each time capable of producing psychedelic effects

cognitive performance

In investigating the impact of caffeine on cognitive func-tion and performance, researchers must take into account a number of mitigating factors. To begin with, you just learned that caffeine can improve mood and increase self-confidence which makes tasks seem easier. This often leads research participants to believe that performance has improved when it actually has not and, for that reason, subjective reports of enhanced performance after caffeine intake are not reliable. As an example, in an early experi-ment by Goldstein, Kaizer, and Warren (1965), participants were asked to rate the effects of caffeine on their alertness, physical activity, and wakefulness. Then they were given caffeine and tested on their ability to detect a number in an array of numbers flashed on a screen for 1/32 of a second. They were also tested on coordination in a line-drawing task. The participants' assessment of their alertness and physical activeness did not correlate with their actual abili-ties as measured by these various tasks; though all partici-pants thought they were doing better, caffeine produced no real improvement. Similarly, participants in a more recent study reported increased vigor and reduced fatigue after consuming a 5-Hour Energy shot, but objective mea-surement of reaction times on a cued go-no go task did not support the subjective reports (Marczinski et al., 2014). The effect of caffeine on performance may also be influenced by placebo effects, so careful placebo controls are impor-tant and instructions to participants must be worded so as to avoid creating expectations (Fillmore & Vogel-Sprott,

self admin

In line with the lack of abuse liability indicated by ICSS and conditioned place preference research, the antipsy-chotic drugs appear to produce aversive effects in animal studies of self-administration. In one experiment, monkeys learned to bar press to avoid infusions. At first, the mon-keys did not respond to avoid chlorpromazine; after a week, they were successfully avoiding 90% of the pro-grammed infusions. It appears that the aversive properties of chlorpromazine develop slowly, with repeated doses (Hoffmeister & Wuttke, 1975).

peripheral nervous system

In the PNS, nico-tinic receptors are located at neuromuscular junctions where motor neurons synapse onto skeletal muscle fibers to cause muscle contraction. The deadly effect of a high dose of curare results from a blocking of these receptors (remember, curare is a nAChR antagonist) and a paralysis of the diaphragm. The victim can no longer breathe and dies of asphyxiation. Nicotine's stimulation of nAChRs at neuromuscular junctions can cause tremor and muscle weakness. In the autonomic nervous system, acetylcholine is important in the functioning of both the sympathetic and parasympathetic divisions. Acetylcholine nicotinic recep-tors are responsible for preganglionic transmission in both systems, as well as postganglionic parasympathetic trans-mission. As such, stimulation or blocking of nAChRs alters autonomic nervous system functioning. The biphasic effect of nicotine on cholinergic transmission is reflected in the ability of nicotine to stimulate, and then inhibit, transmis-sion of autonomic ganglia as nicotinic receptors enter their desensitized state. These two effects, however, are modified because nicotine causes the release of other neu-rotransmitters that affect the PNS. One such neurotrans-mitter is epinephrine, which produces sympathetic stimulation. When this is combined with neuromuscular and parasympathetic stimulation and blocking, the result is a very complicated array of PNS changes. In general, at doses encountered in tobacco smoking, e-cigarette vaping, or snus use, nicotine produces increases in heart rate and blood pressure (Digard et al., 2013; Orellana-Barrios, Payne, Mulkey, & Nugent, 2015; Rhee that the skin of smokers tends to wrinkle and age faster than that of nonsmokers (Daniell, 1971). The reduced blood flow to the skin also explains why smokers do not blush easily. This lack of skin color prompted one judge in the 1930s to accuse cigarettes of "deadening the sense of shame" and corrupting the morals of young people. Nicotine also inhibits stomach secretions and stimulates the activity of the bowel. For this reason, especially for someone with little tobacco tolerance, a cigarette can act as a laxative.

synthetic cathinones in west

In the mid-to-late 2000s, synthetic cathinones infil-trated the illicit drug market in Europe, North America, and Oceania as legal alternatives to controlled psychostim-ulants, like methamphetamine and MDMA. Synthetic cathinones were sold over the Internet and in head shops, adult bookstores, gas stations, truck stops, tattoo parlors, and elsewhere, but are far less readily available now that they have been declared illegal in most affected countries. Products containing these compounds are collectively known in North America as bath salts, as plant food or plant feeders in Europe, and also by various other labels, includ-ing fertilizer, research chemicals, screen cleaner, stain remover, or insect repellant (Musselman & Hampton, 2014; Zawilska & Wojcieszak, 2013). Most synthetic cathinones originate in China and, to a lesser extent, India, and are sold as white, yellow, or brown powder or fine crystals, and as tablets or capsules (Zawilska & Wojcieszak, 2013). Tablets are branded with names like meow meow, bubbles, and top cat, while powdered synthetic cathinones are sold as ivory wave, white lightening, and vanilla sky (German, Fleckenstein, & Hanson, 2014). Powdered or crystalized bath salts products can be smoked, snorted, dissolved and consumed in a beverage, wrapped in a cigarette paper and swallowed (a practice known as "bombing"), inserted into the rectum (known as "booty bombing" or "keystering"), or injected intravenously or intramuscularly to produce psychostimulant effects (German et al., 2014). The prod-ucts were considered "legal highs" and their packages marked "not for human consumption" in an attempt to exploit a loophole created by the vaguely worded 1986 amendment to the U.S. Controlled Substances Act which made it illegal to manufacture, sell, or possess certai

Neuropharmacology

In therapeutic doses (i.e., those used to treat a cough), dex-tromethorphan and dextrorphan bind with high affinity to sigma (s) receptors, a poorly understood class of receptors once thought to be a subtype of opioid receptor, but since confirmed to be a non-opioid receptor that binds diverse classes of psychotropic drugs (Hayashi & Su, 2005). Sigma receptors can be divided into two subtypes: s1 and s2 receptors. Dextromethorphan and dextrorphan bind with higher affinity to the s1 subtype, which is found predomi-nantly in the central nervous system (Hayashi & Su, 2005). This mechanism of action likely explains the antitussive effects of DXM, as s1 receptor activation is associated with cough-suppression in guinea pigs (Brown, Fezoui, Selig, Schwartz, & Ellis, 2004). Animal behavior studies indicate that s1 receptors also play a role in learning and memory processes, psychosis, depression, and drug dependence (Hayashi & Su, 2005). In large doses (i.e., those abused recreationally), dex-tromethorphan and dextrorphan act as potent blockers of the glutamate NMDA-receptor ion channel, similar to PCP and ketamine. Dextrorphan has a greater affinity for the NMDA receptor binding site than does dextrometho-rphan and consequently produces a greater PCP-like sub-jective effect. It is this mechanism of action that is believed to be responsible for the dissociative "out-of-body" expe-riences associated with the use of DXM (Burns & Boyer, 2013). Dextromethorphan also enhances serotonin levels in the brain and, when taken alongside serotonergic drugs such as antidepressant medications, can produce dangerous outcomes including serotonin syndrome (

withdrawal

In varying degrees of intensity, chronic smokers expe-rience the following nicotine withdrawal symptoms during abstinence: decreased heart rate; increased eating causing weight gain; an inability to concentrate; insomnia and increased awakenings from sleep; craving for cigarettes and urge to smoke; and alterations in mood, including anxiety, irritability, restlessness, anger, frustration, aggression, and depression (APA, 2013; Hughes, Gust, Skoog, Keenan, & Fenwick, 1991; Hughes, Higgins, & Bickel, 1994). Other reported symptoms include nervousness, tremor, head-aches, dizziness, nausea, light-headedness, and drowsiness (Jarvik, 1979). The drowsiness experienced by nicotine-dependent individuals who abstain from tobacco for 10 to 24 hours corresponds with a slowing in brainwave activity to levels normally seen during light sleep (Herning, Jones, & Bachman, 1983). Approximately half of tobacco users who abstain from nicotine for 2 or more days will develop symptoms of tobacco withdrawal. Occasional or light smokers (those who smoke five or fewer cigarettes per day) tend to experi-ence minimal or no symptoms of withdrawal during absti-nence (Shiffman, 2009). In those with higher cigarette use, withdrawal symptoms typically emerge over the first 24-48 hours of nicotine abstinence, peak within the first week, and then gradually decrease to pre-abstinence levels rily, by the sensory components of smoking—the sight, taste, smell, and feel of tobacco smoke in the throat or the hand-to-mouth actions of smoking. For instance, denico-tinized cigarettes are as effective as tobacco cigarettes in reducing smokers' "desire for sweets," "hunger," and "urges to smoke" evoked by 5 days of nicotine abstinence (Buchhalter et al., 2005). Denicotinized cigarettes are also as effective as tobacco cigarettes at decreasing measures of tobacco withdrawal and craving in 12-hour tobacco-deprived smokers (Butschky et al., 1995). Craving for ciga-rettes and withdrawal-induced negative affect can be alleviated in smokers by the use of a nicotine-free, tobacco-smoke flavored citric acid inhaler (Behm, Schur, Levin, Tashkin, & Rose, 1993). Finally, cig-a-like vaping in the absence of significant nicotine absorption reduces the urge for a cigarette (Vansickel et al., 2010). Unlike most other drugs that cause physical depen-dence, nicotine withdrawal severity does not seem to be related to dose; heavy and light smokers report equally severe withdrawal. Nor is withdrawal severity related to length of time smoking, previous attempts at quitting, sex, age, education, or alcohol and caffeine use (Hughes et al., 1991). However, severity of withdrawal does seem to be related to one's rate nicotine metabolism, which is geneti-cally influenced. Fast metabolizers show more severe withdrawal symptoms than do slow me

effects on humans

Inhalation of smoked or vaporized salvinorin A produces a rapid onset of intense perceptual and mood effects that can be extremely pleasurable for some users while evoking feelings of anxiety and disorientation in others. Some of the intoxication symptoms users report as being positive or desirable include: an altered state of consciousness and highly modified perception of external reality; an altered sense of the passage of time; feelings of dissociation, depersonalization, and derealization (i.e., an "out of body" experience); spiritual experiences; a sense of relaxation, dreaminess, and calm; a floating feeling; improvement in mood and sense of well-being; increased talkativeness and laughter; heightened sense of creativity, insight, and self-confidence; intense psychedelic effects, including vivid visual and auditory hallucinations; synesthesia (a crossing of sensory modalities); and increased appreciation of aes-thetics (Addy, 2012; González et al., 2006; Zawilska & Wojcieszak, 2013). The "trip" is not always pleasant, however, and users also report negative experiences associated with the use of salvinorin A. These include: a loss of control over, and dif-ficulty integrating, experiences; racing thoughts; irritability, anxiety, panic attack, and terror; acute psychosis and para-noia; social withdrawal; dysphoria; physical exhaustion and drowsiness; dizziness, headache, and a sense of heavi-ness in the head; mental fatigue, confusion, and disorienta-tion; psychomotor agitation, fidgeting, and a lack of motor coordination; temporary language impairment; amnesia; profound sweating, flushing, and chills; and nausea, vomit-ing, and abdominal pain (Addy, 2012; Zawilska & Wojcieszak, 2013). Headache and drowsiness may last for hours or even days after drug use. In a study of the acute and aftereffects of salvinorin A, 87% of participants reported experiencing aftereffects that lasted less than 24 hours after smoking the drug. These included enhanced reflection, empathy, intuition, and awareness of beauty, but also headache, fatigue, and difficulty concentrating (Addy, 2012). Additionally, 70% of participants reported enduring longer-lasting aftereffects, including a headache that per-sisted for 3 days, feeling somewhat unsure of things, and being impatient and moody (Addy, 2012). Salvinorin A produces profound perceptual altera-tions. In a double-blind, placebo-controlled study, the hal-lucinogenic and mystical effects of vaporized salvinorin A were found to be similar to those resulting from intrave-nously administered DMT or orally administered psilocy-bin (Johnson et al., 2011). Visual hallucinations are often characterized by perceived changes in bodily form; the merging of objects with their surroundings; relocation to a different place; intensely colorful visions of objects and designs that are often fractal, vine-like, or geometric in pat-tern; and complex, realistic-looking three-dimensional scenes. Users also report seeing cartoon-like imagery; com-municating and interacting with other-worldly entities or beings; and re-experiencing childhood memories, visually and auditorily (MacLean et al., 2013). These hallucinations often take on a recurring theme across sessions of salvino-rin A use. It is also common for users to describe spatial adjustments to their body, such as being dragged, pulled, or pushed in a particular direction, or spinning, flipping, twisting, and stretching (MacLean et al., 2013). As found in animal research, salvinorin A does not exert significant effects on heart rate or blood pressure and

Schizophrenia

It instead refers to a disconnect between thought, emotion, and behavior—different aspects of a single personality. The psychoses are defined in the DSM-5 by a constellation of abnormalities in one or more of the percep-tual, cognitive, emotional, and behavioral domains. Key defining features of the psychotic disorders, including schizophrenia, are briefly described in Box 12-1. A diagno-sis of schizophrenia requires that two or more key features be present, and that at least one of these be among the first three listed. The first four diagnostic features, or criteria, are classified as positive symptoms—traits that are abnormally present in psychosis. The fifth feature, negative symptoms, incorporates a variety of traits that are abnormally absent in psychosis. Negative symptoms manifest in only about 20% of individuals diagnosed with schizophrenia (Chue, 2013; Cohen, Natarajan, Araujo, & Solanki, 2013), though they are not exclusive to the psychotic disorders—they may be exhibited in a variety of conditions, including major depres-sive disorder, neurocognitive impairments, or traumatic brain injury. In addition to the positive and negative symptoms outlined above, neurocognitive and executive deficits may emerge that include an inability to sustain attention, prob-lems with learning and memory, difficulties with problem solving and abstract thinking, and a slowing of neuromus-cular actions. Schizophrenia spec

self admin

It is generally accepted that LSD and simi-lar monoamine-like hallucinogens are not readily self-administered by nonhumans. In fact, classic hallucinogens appear to have aversive effects in laboratory animals, and they will work to avoid being given LSD. In one experi-ment, rhesus monkeys learned to press a lever to turn off a stimulus that normally preceded an infusion of LSD, thus preventing the infusion (Hoffmeister & Wuttke, 1975). In an interesting twist, a study published in 2004 reported transient self-administration of DMT, mescaline, and psilocybin by some monkeys with a history of self-administering MDMA (Fantegrossi, Woods, & Winger, 2004). These findings suggest that the occasional use of classic hallucinogens might be reinforcing in some indi-viduals with a history of drug use. In their natural envi-ronment, animals are known to occasionally consume plants that contain LSD-like compounds.

reproduction

It is now clearly established that smoking can decrease fer-tility in both men and women. In men, smoking reduces semen volume and sperm count, rapid progressive motil-ity, and viability (Soares & Melo, 2008; Zhang et al., 2013). Women who smoke more than 20 cigarettes per day are 1.7 to 3.2 times more likely to be infertile than nonsmokers. It appears, though, that this effect is reversible: fertility returns to normal after cessation of smoking (Baird, 1992). Maternal smoking increases the odds of a baby being born with a birth defect. This likelihood can be measured in terms of an odds ratio (OR) which is a little more compli-cated than relative risk (RR) you learned about previously. OR is the probability that an event will happen relative to the probability that an event will not happen and is calcu-lated using the formula [A/(1-A)]/[B/(1-B)]. In terms of the odds of maternal smoking causing a birth defect, we would compare the odds of the treatment group (in this case, maternal smokers—Group A) divided by the odds of the control group (maternal non-smokers—Group B). An odds ratio greater than 1.0 indicates that a birth defect is more likely in mothers who smoked during pregnancy. In a review of 101 studies involving over 173,000 birth-defect cases compared with 11.7 million controls, it was shown that maternal smoking was positively and significantly correlated with many birth defects: cardiovascular/heart defects (OR = 1.09); musculoskeletal defects (OR = 1.16); limb reduction defects (OR = 1.26); missing/extra digits (OR = 1.18); clubfoot (OR = 1.28); craniosynostosis (an abnormally shaped head; OR = 1.33); facial defects (OR = 1.19); eye defects (OR = 1.25); orofacial clefts (OR = 1.28); gastrointestinal defects (OR = 1.27); and unde-scended testes (OR = 1.13). There was a reduced risk for hypospadias (having the urinary opening on the underside of the penis, rather than at the end; OR = 0.90) and skin defects (OR = 0.82). For all defects combined, the OR was 1.01, due to including defects with a reduced risk and those with no association (Hackshaw, Rodeck, & Boniface, 2011). Many years of research have clearly established that babies born to women who smoke during pregnancy are likely to be anywhere from 150 to 200 grams lighter at birth than babies born to nonsmoking mothers. This effect is dose-dependent; birthweight is decreased by about 11 grams for every cigarette smoked per day by the mother. Lower birthweight may result because smokers do not put on as much weight during pregnancy as nonsmokers do; therefore, their babies are lighter as less energy is available for fetal growth. Another possibility might be that the developing fetus receives less oxygen from the body of a smoking mother because of the reduced oxygen-carrying capacity of her blood (Russell, Taylor, & Law, 1968). Women who smoke during pregnancy are also more likely to miscarry or give birth prematurely, and their children are more likely to be ill or die (Dietz et al., 2010; USDHHS, 2014). It has been estimated that if maternal smoking could be eliminated altogether, the overall

conditioned behavior

Ivan Pavlov (1927) was the first person to experiment with the effects of caffeine on conditioned behavior. He showed that the drug could disrupt conditioned discriminations by increasing responses to the negative stimulus. After ingest-ing caffeine, the animals responded to stimuli that did not signal food in the same way that they had responded to stimuli that did signal food. He concluded that the drug produced "an increase in excitability of the Central Nervous System." The profile of effects of caffeine on operant behavior is very similar to, though not exactly the same as, the profile caused by the psychomotor stimulants (McKim, 1980). Preexposure to caffeine enhances the rate at which rats learn to self-administer cocaine. In addition, caffeine administration increases operant responding for low-dose cocaine and reinstates responding previously maintained by cocaine (Garrett & Griffiths, 1997). These similar effects of caffeine and cocaine on operant responding are likely the result of caffeine's ability to increase catecholamine release and dopamine activity in the brain's reward path-ways (Garrett & Griffiths, 1997). The methylxanthines also share the psychomotor stimulants' ability to increase responding for intracranial self-stimulation (ICSS) of the medial forebrain bundle (Lazenka, Moeller, & Negus, 2015). The abuse liability of caffeine and paraxanthine appears less than that of amphetamine and cocaine, how-ever, as peak ICSS facilitation by methylxanthines was lower than that produced by amphetamine or cocaine (Lazenka et al., 2015). There is some evidence that caffeine at 30 mg/kg in a rat will increase food-reinforced responding that has been suppressed by punishment with electric shock (Morrison, 1969). If this observation is true, it makes this effect of caf-feine more similar to the barbiturates than to amphet-amine. In general, caffeine appears to increase avoidance responding. Increases were seen on nondiscriminated avoidance responding of squirrel monkeys at a dosage of 1 to 30 mg/kg of caffeine; these increases were almost as great as those seen with amphetamine (Davis, Kensler, & Dews, 1973)

ketamine admin

Ketamine is available in the form of a colorless, taste-less liquid that may be injected, dripped onto a cigarette and smoked, or mixed into a drink and consumed orally. The liquid can be heated and turned into a white powder that can be smoked or mixed into a drink. After oral administration, ketamine is slowly absorbed from the gas-trointestinal tract and highly susceptible to degradation by first-pass metabolism, which is why the drug is often administered intranasally by recreational users. Users snort small lines of ketamine called bumps, which typi-cally contain about 75-125 mg of drug. A typical oral dose of ketamine is 175 mg, and a typical intranasal dose is 70 mg (Gable, 2004a, 2004b). The effects of ketamine are relatively short-lived, lasting between 30 and 60 minutes

ketamine

Ketamine was first synthesized in 1962 and marketed in 1969 as a safer alternative to PCP. Compared to PCP, ket-amine is a less potent anesthetic, has a faster onset, a shorter duration of action, and milder emergence effects. Ketamine is sold under numerous trade names, including Ketalar, Ketaset, and Vetamine. It continues to be used as a pediatric anesthetic, a sedative in intensive care, and a vet-erinary anesthetic. Its street names include K, Special K, KitKat, and cat Valium, and it is most often used as a club drug at parties or raves. Ketamine also has the reputation of being a "date rape drug." Some of the ketamine sold on the street is probably diverted from legitimate veterinary use, however much of it comes from illicit drug labs based mainly in Mexico

neuropharmacology of classic hallucenogens

LSD is known to act as a serotonin receptor blocker in the peripheral nervous system, but in the central nervous sys-tem it acts as a serotonin receptor agonist (Halberstadt, 2015; Rolland et al., 2014). Likewise, the phenethylamine hallucinogens agonize serotonin receptors in the central nervous system, demonstrating highly selective binding for 5-HT2A as well as 5-HT2B and 5-HT2C receptor subtypes (Araújo, Carvalho, et al., 2015; Halberstadt, 2015). LSD and other indolamine hallucinogens, such as psilocybin and DMT, also act as 5-HT2 receptor agonists, but they are far more promiscuous in their binding and stimulate addi-tional serotonin receptor subtypes, such as the 5-HT1 receptor series (Araújo, Carvalho, et al., 2015; Tylš, Páleníček, & Horáček, 2014). In cortical neurons, LSD and other hallucinogenic compounds trigger a particular intra-cellular signaling cascade that is distinct from that trig-gered by other 5-HT2A receptor agonists (González-Maeso et al., 2007). This neuropharmacological action appears to be one of the reasons why these compounds cause halluci-nations. Additionally, the ergot hallucinogens (LSD and LSA) exert actions at dopaminergic and adrenergic recep-tors (Halberstadt, 2015

discovery of treatment

Laborit theorized that surgical shock was caused by excessive release of transmitters such as acetylcholine and histamine. He therefore tested drugs known to block the actions of these substances—atropine, curare, and antihistamines—to determine whether they would reduce the likelihood of surgical shock. The first antihistamine Laborit tested was promethazine, which was supplied by the Rhöne-Poulenc company. Like most antihistamines, it has sedating proper-ties and Laborit was encouraged by the results he obtained. In 1951, Rhöne-Poulenc requested that Laborit test another antihistamine that had been synthesized several years earlier but subsequently rejected because the com-pound's sedating properties were found to be too strong. The drug was chlorpromazine, and Laborit's results were impressive. His patients did not lose consciousness but became sleepy (sedated), lost interest in things going on around them (that is, they felt tranquilized and calm), and could be anesthetized with a reduced dose of general anes-thetic. Laborit described the state induced by chlorproma-zine as artificial hibernation. He recognized the significance of this effect and immediately suggested to psychiatrist colleagues that the drug might prove useful in treating agi-tated, mentally disturbed patients. Two Parisian psychia-trists named Delay and Deniker learned about these trials and requested that Rhöne-Poulenc provide them with samples of chlorpromazine. The psychiatrists adminis-tered the drug to their patients in higher doses and with-out combining it with other compounds, which other astonishingly positive results; in 1953, the drug was mar-keted in Europe as Largactil (Sneader, 1985; Snyder, 1986; Spiegel & Aebi, 1981). Chlorpromazine was marketed in the United States in 1955 as Thorazine, with great success. At that time, the number of patients in mental hospitals had been climbing steadily, but with the introduction of chlorpromazine, admissions began to decline dramatically. Over the next 3 decades, the resident population of mental institutions in the United States dropped by 80% (Hollister, 1983), largely as a result of the use of antipsychotics.

mdma

MDMA (3,4-methylenedioxy-methamphetamine) was originally synthesized in Germany by the Merck pharma-ceutical company and patented in 1914. At that time, the compound was used as an intermediate substance in the development of another drug and was not tested pharma-cologically. The first toxicological studies were performed in the United States in the early 1950s, but remained unpublished until the early 1970s (Hardman, Haavik, & Seevers, 1973). The use of MDMA was extremely limited at this point. The situation changed in 1977 when Alexander Shulgin, a U.S. biochemist, introduced the drug to a psychotherapist named Leo Zeff. Zeff decided to test whether MDMA might prove beneficial to his patients during therapy sessions. He was so thoroughly impressed by the drug's capacity to enhance his patients' emotional sensitivity, communication, intimacy, and connectedness to others that he spread word of the drug's wondrous effects to other psychotherapists in the United States who also began giving MDMA to their patients (Benzenhöfer & Passie, 2010). The terms entactogen and empathogen were coined with MDMA in mind and continue to refer to drug compounds with MDMA-like effects (Adler, Abramson, Katz, & Hager, 1985; Verebey, Alrazi, & Jaffe, 1988). Despite early enthusiasm, in 1985, the World Health Organization's Expert Committee on Drug Dependence recommended banning the use of MDMA, even for psychotherapeutic purposes. The committee cited the pharmacological simi-larity of MDMA to other (illegal) drugs of abuse, as well as a lack of well-defined therapeutic benefit, as partial basis for their recommendation. The governments of sever

Neuropharmacology

MDMA impacts the functioning of monoamine neurotrans-mitter systems by acting both as a reuptake inhibitor and as a substrate-releasing agent. Molecules of MDMA bind to all three monoamine reuptake transporter proteins (DATs, NETs, and SERTs) to prevent the recapture of DA, NE, and 5-HT from the synaptic cleft, thus increasing extracellular levels of these neurotransmitters in multiple brain regions Gudelsky & Yamamoto, 2008; Verrico, Miller, & Madras, 2007). In rats and mice, MDMA exhibits the highest binding affinity for SERTs and lower affinities for DATs and NETs (Rudnick & Wall, 1992; Steele, Nichols, & Yim, 1987). The binding affinity of MDMA to SERTs, DATs, and NETs in humans has been examined in vitro (i.e., in human cells incu-bated on plates in a laboratory) with inconsistent results. Some researchers report that MDMA binds most strongly to NETs and has lower but similar binding affinities for SERTs and DATs (Verrico et al., 2007). Others have found that MDMA's binding affinity for SERTs is many times stronger than that for DATs (Simmler et al., 2013). Notwithstanding these findings, the degree to which MDMA is capable of eliciting the release of monoamines by reversing the direc-tion of transporter protein function is greatest for SERT-expressing neurons (Reneman et al., 2001a; Reneman, Booij, Majoie, Van Den Brink, & Den Heeten, 2001b). MDMA increases extracellular levels of 5-HT to a far greater extent than it elevates DA and NE levels (Iversen, White, & Treble, 2014; Simmler et al., 2013; Verrico et al., 2007). Like the amphetamines, MDMA disrupts the proton gradient that exists between the synaptic vesicles and cyto-sol within the neuron's axon terminal (Eshleman et al., 2013). This gradient is pivotal in maintaining the proper functioning of vesicular monoamine transporter 2 (VMAT2) proteins—those transporters that capture mole-cules of monoamine floating in the cytosol and package them in synaptic vesicles. The disruption in proton grad ent reverses the direction of VMAT2 action, causing the transporters to spill molecules of monoamine from vesicles into the cytosol, and preventing the transporters' packag-ing of monoamine molecules in vesicles (see Panel C of Figure 10-1, as MDMA's actions on VMAT2s are similar to those of amphetamine; Cozzi, Sievert, Shulgin, Jacob, & Ruoho, 1999; Rudnick & Wall, 1992). Cytosol concentra-tions of monoamine neurotransmitter molecules are even further enhanced by MDMA's ability to partially inhibit monoamine oxidase type B enzymes (MAO-B), which are responsible for breaking down free-floating monoamines in the cytosol of neurons (Leonardi & Azmitia, 1994). In addition to increasing serotonin release, MDMA enhances neurotransmission by selectively interacting with 5-HT2 receptors (Liechti, Baumann, Gamma, & Vollenweider, 2000; Liechti & Vollenweider, 2001). It is this direct receptor interaction that is believed to be the mecha-nism by which MDMA produces an excited emotional state and mild hallucinogenic perceptual alterations (Liechti et al., 2000; Liechti & Vollenweider, 2001). The stimulant and euphoriant effects of MDMA are mediated indirectly through increases in dopamine neurotransmission (Liechti & Vollenweider, 2000; Liechti & Vollenweider, 2001). In addition to its impact on monoamine neurotra oxytocin, a hormone involved in social bonding and build-ing trust, is believed to be responsible for ecstasy's empa-thogenic and entactogenic properties (Dumont et al., 2009). In humans, MDMA-induced increases in oxytocin levels correspond with a heightened sense of social affiliation, decreased identification of negative facial expressions (reflecting cognitive empathy), blunted responses to social rejection, enhanced responses to others' positive emotions (reflecting emotional empathy), and increased social approach (Kamilar-Britt & Bedi, 2015). MDMA also stimulates the body's principal stress-response system, the hypothalamic-pituitary-adrenal (HPA) axis, amplifying levels of the stress hormone cortisol. Under normal circumstances, the HPA axis releases cortisol as a means of coping with acute, short-term stressors. However, chronic elevations in cortisol levels impair the homeostatic feedback mechanism that dampens acute stress-hormone release, thus prolonging the HPA-axis response. This state of "chronic stress" is associated with a variety of adverse health consequences, including a heightened propensity for psychosis (Borges, Gayer-Anderson, & Mondelli, 2013; Shah & Malla, 2015). Compared to pre-drug baseline lev-els, MDMA users exhibit an 800% increase in salivary cor-tisol levels after clubbing (Parrott et al., 2014). Heavy MDMA users show a 400% increase in hair cortisol levels 3 months after discontinuing drug use (Parrott et al., 2014). In these individuals, impairment is reflected by deficits in core psychological functions, including memory, cogni-tion, sleep, and well-

effects on animal behavior

MDMA increases locomotor activity in rats. The effect becomes even more pronounced (that is, it sensitizes) with intermittent repeated exposure, but less pronounced (it tolerates) with high-dose exposure (Schenk & Bradbury, 2015). Locomotor activity is likewise amplified following MDMA administration to macaque monkeys, who also demonstrate increased social grooming behavior and reduced inhibition to manipulate a novel object in the pres-ence of other macaques (Ballesta, Reymond, Pozzobon, & Duhamel, 2016). An increase in anxiety-like and avoidant behaviors has been documented in adolescent rats follow-ing short-term repeated MDMA administration (Cox et al., 2014). Longer-term repeated MDMA exposure leads to behavioral disinhibition and an impairment in object rec-ognition memory in adolescent rats (Piper & Meyer, 2004; Piper, Fraiman, & Meyer, 2005). Animal paradigms used to assess the abuse liability of MDMA have produced conflicting results. For instance, MDMA produces a conditioned place aversion in rats (Cox et al., 2014), and while it facilitates responding for intracra-nial self-stimulation (ICSS), it does so only across a narrow range of doses with maximum stimulation of ICSS levels approaching less than 130% that of baseline levels (Bauer, Banks, Blough, & Negus, 2013). Research with rhesus mon-keys has likewise shown that the reinforcing effects of MDMA are strongest at moderate doses, while lower and higher doses are ineffective reinforcers (Fantegrossi, Ullrich, Rice, Woods, & Winger, 2002). These findings suggest that MDMA does not have a great deal of addictive potential. In contrast, when appropriate doses are used, MDMA is readily self-administered by primates (Lamb & Griffiths, 1987) and rodents (Ball & Slane, 2014; Creehan, Vandewater, & Taffe, 2015; Trigo, Panayi, Soria, Maldonado, & Robledo, 2006). Interestingly, there seems to be a great deal of indi-vidual difference in rats' behavioral and locomotor responses to MDMA and these differences predict subse-quent patterns of drug-taking and drug-seeking (Ball & Slane, 2014). Animals that, over time, develop tolerance to the locomotor stimulating effects of MDMA also esca-late their level of MDMA self-administration across days and exhibit a cue-induced reinstatement of MDMA seek-ing following extinction. In contrast, rats that develop locomotor sensitization to repeated MDMA injection maintain stable levels of self-administration across days and show no cue-induced reinstatement of drug-seeking following extinction (Ball & Slane, 2014). Extension of these and similar animal findings to humans strongly suggests that certain individuals are biologically predis-posed to the compulsive use of MDMA whereas others are not (Ball

amphetamine

Many years earlier, in 1887, Lazăr Edeleanu, a Romanian chemist working at the University of Berlin, had synthesized what we now know as amphetamine. But he had failed to explore the com-pound's properties and it remained untested until 1910, when Gabriel Barger and Sir Henry Dale published a tech-nical paper describing the effects of amphetamine and other sympathomimetic drugs on the body. The signifi-cance of Barger and Dale's paper was not grasped until 1927 when Gordon Alles, a young chemist at a research laboratory in Los Angeles, suggested that amphetamine would be a far less costly and more easily manufactured substitute for ephedrine Amphetamine never surpassed ephedrine as a bron-chodilator, though it was also used to treat many other medical conditions (discussed below). Sales of ephedrine peaked in the 1940s and 1950s but began to decline with the emergence of other bronchodilating drugs, such as the methylxanthines and corticosteroids. However, this was not the end for ephedrine. The late 1970s marked the begin-ning of ephedrine's popularity as a weight-loss aid, energy booster, and exercise performance enhancing dietary sup-plement, contained in formulations with caffeine or other methylxanthines such as guaraná, green tea, and kola nut (Gurley, Steelman, & Thomas, 2015). These dietary supple-ments were sympathomimetic and concerns over their safety led to the removal of herbal Ephedra-containing prod-ucts from U.S. markets in 2004. Ephedra sinica also contains pseudoephedrine, which has less pronounced CNS effects compared to ephedrine. Today in the United States and Canada, ephedrine and pseudoephedrine are dispensed by pharmacists or sold over-the-counter, without prescription, in decongestants and anti-asthmatics such as Bronkaid, Primatene, Sudafed, and Sinutab. These medications can be used as starting materials in the illicit production of the synthetic psychostimulants

mescaline

Mescaline is a catecholamine-like drug, belonging to the phenethylamine class of hallucinogens. It too has many effects in common with LSD but is about 1/2,000th as potent. Mescaline is a naturally occurring, psychoactive alkaloid compound found in the peyote cactus (Lophophora williamsii), which is native to the deserts of Mexico and the

methylone admin

Methylone is generally taken in oral doses ranging from 100 to 300 mg; doses higher than 250 mg are consid-ered "heavy" consumption (Kelly, 2011; Valente et al., 2014). The effects of methylone are felt within 15-30 minutes of administration and usually last for 3-5 hours (Musselman & Hampton, 2014; Valente et al., 2014), though

Absorption/distribution

Most antipsychotic drugs are readily absorbed from the digestive tract. Once absorbed, they are distributed throughout the body and easily cross placental and blood-brain barriers. Blood protein binding is considerable, and the drugs tend to be absorbed into body fat and released very slowly. With regularly scheduled injections, oil-based depots can take weeks or even months to reach steady-state levels and are very slowly eliminated from the body. Depot injections of the atypicals, because they are not dis-solved in oil, do not accumulate in body fat over time. Long-acting risperidone reaches peak release at about 28 days. Long-acting olanzapine and paliperidone show peak blood levels after about 2 to 4 days (Haddad et al., 2011).

discrimination

Neither the MAOIs nor the TCAs are discriminable at doses that produce most of their behavioral effects, though they can be discriminative at very high doses. There does not appear to be any generalization between the antide-pressants and the antipsychotics or other drug classes (Stewart, 1962). In contrast, the SSRIs and the SNRIs/ atypicals do have discriminate stimulus properties at ther-apeutic doses. Dekeyne and Millan (2003) trained rats to discriminate citalopram, bupropion, and reboxetine. They also found that antidepressants that blocked both sero-tonin and norepinephrine would substitute for either cital-opram or reboxetine, but SSRIs generalize only to citalopram. Bupropion did not substitute for either citalo-pram or reboxetine. Taken together with the observation that the MAOIs and the TCAs do not appear to have any discriminable properties, this suggests that the stimulus properties of antidepressant drugs do not arise from their antidepressant effects. The stimulus properties of citalo-pram were blocked by drugs that block 5-HT2C receptors, and the reboxetine cue was blocked by NE a1 antagonists, suggesting that the stimulus properties of these drugs arise from interactions with very specific receptors

absorption with replacement therapies

Nicotine chewing gum was the first nicotine replacement product developed as a smoking-cessation aid. Approxi-mately 44-64% of the nicotine contained in a 4 mg piece of gum is absorbed within 30 to 45 minutes of use, pro-viding a ~9-13 ng/ml peak blood plasma level of nicotine (Digard et al., 2013; Lunell & Curvall, 2011). The rise and fall in blood nicotine levels with gum use resembles the pattern caused by smoking, although peak levels are much lower. Nicotine nasal sprays and lozenges have also been developed for absorption through mucous membranes. The nasal spray produces the most rapid absorption. Within only 10 minutes of administration, a 3 mg spray of nicotine leads to a peak blood concentration of ~4.7 ng/ml (Fishbein et al., 2000). The ability of nicotine to be absorbed transdermally (through the skin) allowed for the develop-ment of the nicotine patch. Nicotine-containing patches are available in various concentrations and are typically placed on the skin covering the deltoid muscle. Peak blood nicotine levels are achieved within about 4 hours of admin-istration (Dempsey, St. Helen, Jacob, Tyndale, & Benowitz, 2013) and much more easily maintained at a steady state, compared to nicotine gu

nicotine poisining

Nicotine is rapidly absorbed through the lungs, mucous membranes, and skin and, at high doses, it is toxic. The lethal dose (LD50) of orally administered nicotine is esti-mated to be 6.5-13 mg/kg (Mayer, 2014), though lower doses (1.0 mg/kg) may be toxic in children (McGuigan, 2003). Each year, children die of nicotine poisoning after eating cigarettes, smokeless tobacco products, and nicotine gum or by handling transdermal nicotine patches (Ordonez, Kleinschmidt, & Forrester, 2015). With the intro-duction of candy-like dissolvables and highly concentrated e-liquids, the potential for harm has increased. There are reports of children and infants being poisoned by inges-tion of tobacco orbs and snus (Connolly et al., 2010). ENDS liquid may pose an even greater risk. E-cigarette refill car-tridges hold between 10 and 1000 ml of e-liquid and may contain up to 720 mg of nicotine (Cameron et al., 2014; Etter, Zather, & Svensson, 2013). The most commonly pur-chased e-liquid concentration is a 20 ml bottle containing 18 mg of nicotine per milliliter of fluid (Etter & Bullen, 2011) though it is possible to purchase e-liquids with con-centrations of up to 36 mg/ml (Breland, Spindle, Weaver, & Eissenberg, 2014). Ingestion or transdermal absorption of only a few milliliters could prove toxic, especially in chil-dren. Reports from a Texas poison center document the exponential increase in e-liquid poisonings between 2009 and 2014. Most (53%) occurred in children under the age of 5 years and 78% of poisonings resulted from oral ingestion (Ordonez et al., 2015). Symptoms of nicotine poisoning included vomiting, nausea, headache, eye irritation, dizzi-ness, and lethargy (Ordonez et al., 2015). There have also been reports of purposeful ingestion of e-liquid as a means of committing suicide (Cervellin, Luci, Bellini, & Lippi, 2013; Christensen, van't Veen, & Bang, 2013

pentametric

Nicotinic receptors are pentameric—made up of five subunits, organized as a ring around a central pore. Each subunit is encoded by a specific gene. When activated by an agonist like nicotine, the configuration of all five subunits changes and the pore is opened, allowing the flow of positively charged ions (primarily Na+ and K+) to pass through, thus creating an excitatory postsynaptic potential (see Figure 8-2). nAChR activation also increases the neuron's permeability to Ca2+ ions. When the receptor is located presynaptically, this causes the release of neu-rotransmitters. Thus, nAChRs are involved in excitatory synaptic transmission when they are located postsynapti-cally whereas, when they are located presynaptically, they function as neuromodulators, stimulating the release of other neurotransmitters. The receptive and functional characteristics of each nAChR are determined by the specific combination of the subunits of which it is composed. There are 17 different receptor subunits that have been identified, 12 of which are used by nAChRs in neurons, so a great many types of nico-tinic receptors are possible. In neurons, the subunits are named alpha 2 to 10 (a2-a10) and beta 2 to 4 (b2-b

withdrawal

No withdrawal symptoms for LSD or any similar drugs have been documented. This may be because the drugs are seldom taken continuously for any period of time and do not lead to physical depen-dence. However, adverse effects of the hallucinogens can persist for some time after cessation of use. One such effect is a rare perceptual disorder called halluci-nation persisting perception disorder (HPPD; colloquially known as "flashbacks"). HPPD is discussed further in Section 15

subjective affects of atypicals

Noncompliance is slightly less of a prob-lem with the atypical antipsychotics, such as clozapine (Meltzer, 1992). There are reports of quetiapine, olanzapine, and other atypical antipsychotics being used recreationally, mainly for their strong sedating actions. They can be crushed and snorted, or injected intravenously either alone or in combination with a psychostimulant drug. A mixture of quetiapine and cocaine is referred to on the street as a Q-Ball.

the law of thirds

Observation that schizophrenic patients' response to antipsychotic drugs falls into one of three categories in approximately a 1:1:1 ratio: The patient may show minor symptoms and lead a relatively normal life; the patient may show symptoms at various times and need help with tasks of daily living; or the patient may show major symptoms, spend significant time in mental hospitals, and need constant help in daily life.

crash

Once the intoxicating effects of MDMA subside, an acute state of neurochemical depletion is believed to be responsible for the ensuing crash or comedown, similar to that experienced following cocaine or amphetamine use (see Chapter 10). This post-MDMA "neurochemical recov-ery" period is marked by feelings of anhedonia, lethargy, irritability, anger, and depression (Parrott, 2014). Other short-term recovery symptoms include insomnia and dis-rupted sleep pattern, unpleasant dreams, difficulty con-centrating, deficits in memory and higher-order cognition, heightened sensitivity to pain, reduced appetite, psycho-logical distress, increased aggression and violence, higher perceived levels of stress, and reduced happiness (Parrott, 2014). Recreational MDMA users refer to this recovery period as the "midweek blues" (Parrott, 2014, p. 39). Generally speaking, regular users of MDMA exhibit a greater number of psychiatric symptoms, including depression (Brière, Fallu, Janosz, & Pagani, 2012; MacInnes, Handley, & Harding, 2001), and discontinuing the use of ecstasy leads to improved psychiatric functioning and reduced feelings of depression in the majority of recre-ational users (Parrott, 2014; Verheyden, Maidment, & Curran, 2003). In chronic, heavy MDMA users, some impairments (including disordered sleep, depressed mood, impulsivity, and impairments in attention, episodic memory, working memory, and executive functioning) continue well beyond the acute withdrawal period, per-haps for many months (Morgan, 2000; Murphy, Wareing, Fisk, & Montgomery, 2009). Elevations in anxiety and hos-tility may persist for up to a year (Morgan, 2000).

Hallucinogen Persisting Perception Disorder

One additional adverse outcome of classic hallucino-gen use is that their perceptual effects may briefly reoccur, days, months, or even years after using the drug, an expe-rience that is often (understandably!) accompanied by panic. Whereas the acute perceptual alterations caused by hallucinogens typically wear off as the drug is metabolized and excreted from the body, for a subset of individuals, these perceptual alterations do not fade away (Litjens, Brunt, Alderliefste, & Westerink, 2014). These episodes are commonly known as flashbacks, and the condition is listed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (the DSM-5; APA, 2013) as Hallucinogen Persisting Perception Disorder (HPPD). Symptoms of HPPD are similar to those perceptual changes experienced while intoxicated with a hallucinogen, and may include: geomet-ric or kaleidoscopic visual images; false perceptions of movement in peripheral visual fields; flashes of color; an intensification of colors; trailing phenomena, in which a moving object is followed by a series of stationary images that trail along its trajectory; palinopsia, in which a moving object leaves a continuous "smear" in its path; positive afterimages, in which objects continue to be "seen" after they have gone; the appearance of "halos" around objects; macropsia, in which objects appear larger than they actually are; and micropsia, in which objects appear smaller than they really are (APA, 2013; Litjens et al., 2014

performance

One of the difficulties in measuring human performance under the influence of hallucinogens is maintaining the motivation of the par-ticipant to engage in the study. Like marijuana, halluci-nogens frequently cause people to become inattentive to the task and so caught up in internal experiences that they lose their motivation to perform, as well as they are able, on tasks that they may feel are irrelevant at the time. The available data show mostly that LSD impairs reaction time. Functioning on intellectual tasks is also impaired. Like THC, LSD causes a deficit in short-term (working) memory. Other impairments are seen in problem-solving and cognitive functions, such as mental addition and sub-traction, color naming, concentration, and recognition (Hollister, 1978). Claims have been made that LSD-like hallucinogens improve creativity, but again, as with THC, these are diffi-cult to substantiate experimentally. There is little doubt that LSD changes the sort of work done by artists, but it is debatable whether these changes are improvements.

brain structure and functional abnormalities

One of the most noticeable abnormalities is the size of the lateral and third ventricles, cavities in which cerebrospinal fluid is produced and flows to cushion, cool, and nourish the brain. In individuals with schizophrenia, these ventricles are nearly twice as large as those of individuals unaffected by the illness. Most likely, a loss of brain tissue leads to this enlargement—the cerebrospinal-fluid-filled ventricles take over space opened due to the deterioration of neurons. Compared to nonschizophrenic controls, individuals with schizophrenia have less tissue volume in up to 50 dif-ferent brain regions (Kubicki et al., 2007). This deteriora-tion is most pronounced in the corpus callosum, cerebellum, and areas of the frontal and temporal lobes, including structures of the limbic system, such as the hippocampus, amygdala, and cingulate gyrus (Borgwardt, McGuire, & Fusar-Poli, 2011). The deficits in brain volume are small in the beginning stages of the illness but become progressively greater as symptoms worsen. For example, MRI research shows that, as the cingulate gyrus deterio-rates, there is a corresponding decrease in the ability to function socially (e.g., to perform social cognition, to attri-bute emotion to facial expressions; Fujiwara et al., 2007). Loss of volume in the dorsolateral prefrontal cortex is associated with impaired cognitive functioning and defi-cits in working memory cal processes are at play? Researchers suggest that the abnormal neurophysiological processes that underlie schizophrenia may begin even before birth and continue throughout childhood and adolescence. Children who have a parent with schizophrenia and who are, thereby, at an increased risk of developing the illness, often exhibit cognitive and behavioral warning signs of neurophysio-logical abnormalities. For example, high-risk individuals who, as adults, developed schizophrenia showed speech and neuromotor deficits and delays, a lack of motor coor-dination, problems with social adjustment and compe-tence, cognitive deficits, poor academic performance, attentional problems, short-term and verbal memory defi-cits, and problems with smooth-pursuit eye movements in childhood (Erlenmeyer-Kimling et al., 2000; Nicolson et al., 2000; Niemi, Suvisaari, Tuulio-Henriksson, & Lönnqvist, 2003; Schiffman et al., 2004; Schiffman et al., 2009).

subjective effects

One of the most noticeable effects of the amphetamines is that they make people feel good; they improve mood. Users report that the drug causes "a sense of well-being and exhilaration," feelings of "high spirits," and "bubbling inside." Most people report a decrease in fatigue and an increase in energy; a clear, organized mind; and a desire to get to work and accomplish things (Grinspoon & Hedblom, 1975, p. 62). Systematic, double-blind studies confirm these anecdotal reports (Gunne & Anggard, 1973; Johanson & Uhlenhuth, 1980). In laboratory studies, most healthy indi-viduals without a history of stimulant use report pleasur-able effects and a positive mood following amphetamine administration. However, a small minority of participants report unpleasant drug effects, mainly anxiety. The emo-tional effects of the drug strongly predict whether partici-pants will choose to take it again when given an opportunity during subsequent experimental sessions (de Wit & Phillips, 2012). Survey research shows that indi-viduals who report "liking" and "wanting" cocaine upon initial exposure are more likely to abuse and develop a dependence for cocaine in later life (Lambert, McLeod, & Schenk, 2006). Figure 10-2 illustrates results of a study examining the subjective effects of orally administered methamphet-amine, d-amphetamine, methylphenidate, and triazolam

heat and dehydration

One particularly dangerous effect is ecstasy's ability to interfere with the body's heat-loss mechanisms, thus pre-venting it from regulating core temperature. In comfort-able ambient temperatures, this effect may not be of any serious consequence. However, at a dance club or rave, where MDMA use is combined with prolonged periods of physical exertion in a hot and crowded environment, an impairment in the body's ability to dissipate excessive heat can lead to severe hyperthermia. This, in turn, can cause muscle-tissue damage, kidney failure, and liver damage. The mechanisms by which MDMA impairs the body's dis-sipation of heat are complex and not entirely understood, but very likely involve elevations in the release of 5-HT, DA, and NE (Shankaran & Gudelsky, 1999; Sprague, Banks, Cook, & Mills, 2003). One proposed mechanism involves MDMA's ability to induce vascular restriction (a narrowing of vessels and consequent reduction in blood flow and tissue oxygenation) via activation of serotonin 5-HT1B and 5-HT2A receptors, which would interfere with peripheral thermoregulatory mechanisms (Gudelsky, Koenig, Jackman, & Meltzer, 1986). In addition, prolonged dancing and physical exertion in a hot environment leads to profuse sweating that can result in dehydration and a loss of large amounts of sodium. Unfortunately, the "common-sense" suggestion to drink plenty of water in order to counteract dehydra-tion fails to replace the lost sodium. This can dilute the blood and create an electrolyte imbalance which, in turn, can cause organs (including the brain) to swell, resulting in tissue damage and seizures (Nutt, 2012). A literatu

sleep

One reason for the widespread use of amphetamines by soldiers during World War II, and by the general public in the 1950s, is that they temporarily prevent fatigue and the need for sleep. In addition to their ability to increase alert-ness, energy, and attention, amphetamines improve con-centration, which makes them popular among students as a study aid (Hall, Irwin, Bowman, Frankenberger, & Jewett, 2005) and among long-distance truck drivers and military pilots on extended missions (Emonson & Vanderbeek, 1995). Systematic, laboratory studies have shown that amphetamine use causes insomnia. Figure 10-3 Dose-dependent effects of methamphetamine (METH), d-amphetamine (d-AMP), methylphenidate (MPH), and triazolam (TRZ) on percentage of methamphetamine-appropriate responding in humans trained to discriminate methamphetamine. PL = placebo. Statistical analysis revealed that response rates for METH, d-AMP, and MPH did not differ from one other but that all three curves differed from TRZ. (Sevak et al., 2009, Figure 1, p. 1011.) 100 80 60 40 20 0 PL 2.5 10 5 15 METH 2.5 10 5 15 d-AMP Dose (mg) 5 20 10 30 MPH 0.06 0.25 0.13 0.38 TRZ Amphetamine, methylphenidate, and modafinil are all used in the treatment of narcolepsy, a sleep disorder that causes excessive sleepiness and frequent daytime sleep attacks. Khat chewing likewise increases alertness and vig-ilance (Kelly, 2011; Valente et al., 2014), though these effects dissipate after a few hours of chewing. Users leave khat chewing sessions feeling exhausted, yet often experience insomnia and are lethargic, sleepy, and irritable the next day (Al-Motarreb et al., 2002; Valente et al., 2014).

other sources of methylxanthines

Other natural sources of caffeine include the ilex plant of the Amazon region of South America and the cassina of North America. The ilex plant, Ilex paraguariensis, is a holly (related to the Christmas holly) whose young leaves con-tain nearly 1% caffeine by dry weight (Ashihara et al., 2008). It is infused to make a tea called yerba maté or maté which is popular in rural regions of Brazil, Uruguay, Argentina, Paraguay, and other South American countries. It is reported that, each morning, men of the Peruvian Achuar Jivaroan peoples drink a strong herbal tea made from the ilex plant that contains the caffeine equivalent of five cups of coffee, after which they vomit in order to avoid overdose symptoms. It is considered to be part of a masculine ritual passed down through the ages (Science News, 1992). Cassina is another type of holly, Ilex vomitoria, from which a beverage known as yaupon, cassina tea, or black drink is made. Yaupon is not consumed today, but at one time it was widely consumed by Indigenous Peoples of the southeastern United States. It was considered a noble bev-erage, and its use was restricted to great men and chiefs. Cassina tea enjoyed a revival during the American Civil War and World War I, when coffee and tea were either not available or very expensive. Guaraná is a paste made from the seeds of Paullinia cupana, which, at 4.3% caffeine by dry weight, is a potent natural source of caffeine (Ashihara et al., 2008). The plant grows in regions of the Amazon, Orinoco, and Negro riv-ers in South America. The paste is molded into sticks or bars or even sculptures and dried in the sun. For use, it is powdered and mixed with water. Because it has an

pcp admin

PCP and ketamine are weak, lipid-soluble bases. PCP comes in the form of a liquid, tablet, capsule, or a white or colored crystalline powder that readily dissolves in water or alcohol and can be consumed orally. The drug can also be injected, snorted, or smoked. Smoking is the most common method of recreational PCP use and usually involves saturating plant material, such as mint, parsley, or oregano, with PCP and rolling it into a cigarette. A marijuana joint or tobacco cigarette dipped in liquid PCP is called a dipper. The effects of a typical (5-10 mg) dose of PCP are felt within 2-5 minutes after smoking or within 30-60 minutes after oral administration. Peak effects usually occur within 10-90 minutes of drug use, and overall effects typically last for 4-8 hours. Following absorption, blood levels of the drug decline rapidly at first, as PCP is distributed to body fat, however low levels may persist in the blood for several weeks as the drug is released from storage in bodily tis-sues (Gorelick & Balster, 2000). This explains why some users report experiencing subjective effects of PCP for as long as 24-48 hours after administration

harmful effects

PCP and ketamine have an unfounded reputation for caus-ing violence and uncontrollable behavior. An examination of the literature does not provide systematic evidence to support the belief that these drugs in particular evoke vio-lent or criminal behavior. It is true, however, that the psy-chotic state induced by large doses of dissociative anesthetics is marked by disorientation, agitation, and hyperactivity, and that these effects have the potential to lead to injury, either to the individual using the drug or to others nearby. Long-lasting psychotic behavior has been reported following PCP use, even in individuals without prior psychotic tendencies. This PCP psychosis may last several months in some individuals and is indistinguish-able from schizophrenia, as it includes positive, negative, and cognitive symptoms (Javitt, 2007). It is highly unlikely, however, that PCP or ketamine is capable of turning people into dangerous and violent criminals (Brecher, Wang, Wong, & Morgan, 1988; Gorelick & Balster, 2000). Laboratory research even suggests that PCP may have a taming effect on normally aggressive animals (Balster, 1987). Acute behavioral effects of PCP and ketamine can sometimes be responsible for injury and death. For exam-ple, because the drugs are anesthetics, rather severe injuries have been tolerated or self-inflicted without pain or any effort at avoidance. Although the exact frequency of this sort of event has not been documented, it is probably more likely to happen with PCP than with LSD and the other classic hallucinogens. As with many other drugs of abuse, it appears that chronic ketamine use is associated with long-term neurological changes. In a study of chronic ket-amine users, researchers observed a significant reduction in gray matter volume in regions of the frontal cortex that is correlated with the duration of drug use (Liao et al., 2011). genetic damage and reProduction In preg-nant women, the use of PCP has been found to slow the growth of the fetus, precipitate labor, and cause fetal dis-tress. Children born to mothers who use PCP often show muscle stiffness, tremor, irritability, and impaired atten-tion and behavior control that may last for several years. It is difficult to determine with certainty that these adverse effects are due solely to PCP, as mothers often report co-occurring use of other drugs (Gorelick & Balster, 2000). Evidence from animal research, however, allows for stronger conclusions. The use of PCP and ketamine has been linked to widespread cell death in the developing rat brain. The block-ing of NMDA receptors by PCP or ketamine for even a few hours during prenatal development appears to induce sig-nificant neurodegeneration (Ikonomidou et al., 1999).

withdrawal

Physical dependence, if it occurs at all, is rare or mild. There are reports of muscular discomfort, exaggeration of psychotic symptoms and movement disorders, and diffi-culty sleeping when some antipsychotics are suddenly withdrawn, but such effects are not normally seen even after years of use at normal doses. It is possible that the failure to notice withdrawal symptoms is due to the extremely slow excretion of the drug from the body (Baldessarini, 1985). In an examination of 28 patients who abruptly discontinued clozapine use, 11 showed no with-drawal symptoms at all, 12 showed mild symptoms that included headache and nausea, 4 experienced more signif-icant symptoms including vomiting and diarrhea, and 1 experienced a rapid reemergence of psychotic symptoms (Shiovitz et al., 1996)

study of subjective effects of various stimulants

Participants received various doses of these drugs, as shown along the x-axis of each graph. The drug doses are contrasted against placebo administration, illustrated at the far left of the x-axis. Triazolam (Halcion) is not a psy-chomotor stimulant drug like the others; it is a benzodiaz-epine with sedative-hypnotic and anxiolytic properties (see Chapter 7) and was included for comparison. The y-axis shows the subjective rating scale used by partici-pants to indicate the degree to which the dose of a particu-lar drug made them feel "stimulated," "talkative and friendly," "sluggish, fatigued, and lazy," and how much they "like the drug." As you can see in the figure, all three psychomotor stimulants have similar effects: they cause dose-dependent increases in ratings of drug liking, stimu-lation, and feeling talkative and friendly, and they dose-dependently decrease feelings of sluggishness, fatigue, and laziness. These subjective effects peaked at 2 hours for the amphetamines and at 3 hours for methylphenidate, and had largely disappeared by 5 hours, even when adminis-tered at the higher doses. In contrast, triazolam caused only a slight increase in most positive scales even when administered at the higher doses, and a very large increase in participants' sense of sluggishness and fatigue (Sevak, Stoops, Hays, & Rush, 2009). Other studies have found that some of the subjective effects of amphetamine are even greater if the individual is expecting to receive the drug (Mitchell, Laurent, & de Wit, 1996), but the effects appear to be similar regardless of whether participants are tested alone or in social groups (de Wit, Clark, & Brauer, 1997).

discriminative stimulus

Rats can be trained to discriminate between caffeine and saline in a two-lever Skinner box. At a dose of ~30 mg/kg, rats generalize the caffeine-induced state to lower doses of caffeine and to paraxanthine and theophylline, but not to theobromine or nicotine (Carney, Seale, Logan, & McMaster, 1985; Modrow, Holloway, & Carney, 1981; Orrú et al., 2013). Rats trained to discriminate theophyilline from saline gen-eralize responding to caffeine, but not to paraxanthine (Carney et al., 1985). Caffeine appears to share some of the subjective effects of the psychomotor stimulants. There is partial generalization to cocaine and amphetamine in rats trained to discriminate low, but not high, doses of caffeine, and vice versa. These discriminative effects of caffeine can be blocked by antagonizing dopamine receptors (Garrett & Griffiths, 1997) and adenosine A1 receptors, but not A2A receptors. In fact, A2A receptor blockade counteracts tability of an A1 receptor blocker to interfere with the stimu-lus effects of caffeine (

america and coffee use

Recently conducted population surveys provide detailed information about the sources and average amounts of caffeine consumed by American adults, adoles-cents, and children. Of the nearly 25,000 U.S. adults (aged 19 years and older) who responded to the most recent (2010) National Health and Nutrition Examination Survey, 89% reported that they are regular consumers of caffeine. This percentage is similar to that found in surveys of caf-feine consumption conduced in the 1970s and 1980s (Barone & Roberts, 1996). On average, these individuals ingested 211 mg of caffeine per day, though this amount differed by gender with men consuming more caffeine (240 mg) per day than women (183 mg). Caffeine consump-tion also differed by age, with the highest consumption levels occurring in men aged 51-70 years (275 mg/day) and the lowest levels in women aged 19-30 years (132 mg/day; Fulgoni, Keast, & Lieberman, 2015). Approximately 14% of respondents reported that their usual daily caffeine intake exceeded the 400 mg/day safe-intake limit proposed by Health Canada. Beverages were the source of 98% of the caffeine con-sumed by respondents. Unsurprisingly, coffee was the most popular source of caffeine (~64%), followed by sodas (~18%) and tea (~16%). Surprisingly, consumption of energy drinks accounted for only about 1% of caffeine intake in 2010, though that percentage rose to 3% within respondents 19-30 years of age (Fulgoni et al., 2015). Energy drinks are consumed by a far greater percentage of college and university students than by individuals in the general population, with use reported by approximately one-third to nearly two-thirds of young people surveyed on U.S. campuses (Gallucci, Martin, & Morgan, 2016; Malinauskas, Aeby, Overton, Carpenter-Aeby, & Barber-Heidal, 2007; Pettit & DeBarr, 2011). Among individuals who regularly consume energy drinks, daily intake aver-ages about 160 mg of caffeine (Bailey, Saldanha, & Dwyer, 2014). Energy drinks are a rapidly growing market in the United States. In 2012, for the first time, caffeine-containing energy drinks outsold bottled water in the United States (Beverage Industry, 2012). Conservative estimates of 2014 energy-drink sales in the United States amount to more than $12 billion, with Red Bull at the top ($2.88 billion), followed by Monster ($2.47 billion), Rockstar ($647 million), and NOS ($294 million). The energy shot industry was dominated by 5-hour Energy, which garnered more than $732 million in U.S. sales in 2014 (Caffeine Informer, 2015b).

Salvia Divinorum

Salvia divinorum produces hallucinogenic and disso-ciative effects that share some similarities with symptoms of intoxication resulting from the cannabis, ketamine, or high doses of classic hallucinogens. However, experi-enced hallucinogen users report that intoxication by sal-vinorin A is unique and particularly intense (MacLean, Johnson, Reissig, Prisinzano, & Griffiths, 2013). Salvinorin A is indeed unique, as it is the first known diterpene halluci-nogen. Chemically, it does not resemble other psychedelic compounds like LSD or mescaline, which are alkaloids. Dried Salvia divinorum leaves contain about 0.18% sal-vinorin A (Ott, 1995) which, by weight, makes this com-pound the most potent of the natural hallucinogens. The effects of salvinorin A can be felt after doses as small as 200 micrograms (mg), which is comparable to the effective dose of a synthetic or semisynthetic psychoactive drug, like LSD (Sheffler & Roth, 2003). When used recreation-ally, Salvia products are typically sold in packages that contain either the leaf or another absorbent material impregnated with an extract of salvinorin A (Halpern & Pope, 2001; Miller, Griffin, Gibson, & Khey, 2009). Street names for the drug include magic mint, Sally D, lady sally, Maria Pastora, and puff. The use of Salvia divinorum is controlled in many countries around the world, includ-ing Italy, Japan, Russia, Spain, Sweden, Australia, Canada, and some U.S. state

freud

Sigmund Freud. Freud smoked cigars (upward of 20 per day) for most of his life, despite the fact that he suffered from heart pains and cancer of the mouth as a direct result. Toward the end of his life, he was in constant pain, having undergone a total of 33 operations related to his cancer. Freud died of cancer at the age of 83. For 45 years, he had tried to quit his cigar habit but was unable to do so for any longer than a year or so (Brecher & Editors of Consumer Reports, 1972, p. 215). Freud, of course, is not alone. About half of current smokers or users of smokeless tobacco products meet DSM criteria for tobacco use disorder or ICD criteria for tobacco dependence (Hughes, Helzer, & Lindberg, 2006). As Freud's case shows, tobacco smoking can be a difficult habit to break, but the degree of agony he suffered is not typical. Perhaps Freud was a fast metabolizer of nicotine or had a genetic abnormality of nAChR subunits, which amplified his severity of withdrawal from nicotine. For some people, quitting is much easier. A large British sur-vey conducted in the late 1980s, before there were many smoking cessation therapies and no pharmacotherapies had been developed, found that quitting is not necessarily grim; 53% of ex-smokers reported that stopping was "not at all difficult," 27% said it was "fairly difficult," and only 20% said it was "very difficult" (Marsh & Matheson, 1983). Many tobacco users who want to quit are successful at doing so "cold-turkey" (without the aid of behavioral of pharmacotherapeutic interventions). In fact, roughly two-thirds to three-quarters of ex-smokers report having qui

environmental tobacco

Smoking has negative health consequences, not only for smokers, but also for those who live with them. In 1992, the U.S. Environmental Protection Agency (USEPA) released a document reviewing what was known at that time about the dangers of being exposed to environmental tobacco smoke (ETS), also known as secondhand smoke (SHS). Breathing this smoke is referred to as passive smoking or involuntary smoking and is estimated to be responsible for more than 50,000 American and 600,000 worldwide deaths every year (Oberg, Jaakkola, Woodward, Peruga, & Prüss-Ustün, 2011). SHS comes from two sources: (a) the exhala-tion of mainstream smoke (MS) inhaled by a smoker, and (b) the sidestream smoke (SS) released from a burning cigarette between puffs. Both types of smoke contain more than 4000 toxic gaseous chemicals (including polycyclic hydro-carbons and volatile nitrosamines) but the concentration of these substances is higher in the unfiltered SS than in exhaled MS (Flouris, Vardavas, Metsios, Tsatsakis, & Koutedakis, 2010). For example, the concentration of one carcinogen, 4-ABP, is 30 times greater in SS than in MS. Levels of 4-ABP in the blood of nonsmokers have been measured at 10 to 20% that of smokers, even though the smoke they inhale is much less concentrated (USEPA, 1992). The U.S. Surgeon General estimates that living with a smoker increases a nonsmoker's chances of developing lung cancer by 20 to 30%. The renowned British physiolo-gist and epidemiologist, Sir Richard Doll, remarked "An hour a day in a room with a smoker is nearly a hundred times more likely to cause lung cancer in a non-smoker than 20 years spent in a building containing asbestos" (cited in Flouris et al., 2010). There is evidence that second-adults and the risk of leukemia, lymphoma, and brain tumors in children (USDHHS, 2006). Exposure to secondhand smoke irritates the airways and has immediate harmful effects on a person's heart and blood vessels. It may increase the risk of heart disease by an estimated 25-30% (USDHHS, 2006, 2010) and is thought to cause about 46,000 heart disease deaths each year (California Environmental Protection Agency, 2005). There may also be a link between exposure to secondhand smoke and the risk of stroke and hardening of the arteries. Even though the health dangers of ETS are present for all age groups, children are particularly vulnerable. Oberg and colleagues (2011) estimate that 40% of children world-wide have been exposed to secondhand smoke. It is responsible for between 150,000 and 300,000 cases of bron-chitis and pneumonia in infants up to 18 months of age and worsens the severity of asthma symptoms in 200,000 to 1 million children per year (Spitzer et al., 1990; USEPA, 1992). There is also a strong link between ETS and sudden infant death syndrome (SIDS) where infants die suddenly and unexpectedly between the ages of 1 month and 1 year (Schoendorf & Kiely, 1992; USDHHS, 2006). The risk of SIDS death is between 1.6 and 7.7 times greater for babies of smoking mothers than for babies of nonsmokers and is proportionally related to the number of cigarettes smoked in the home. Compared to in a nonsmoking home, the odds ratio of an infant dying of SIDS is 2.4 in a home where 1-10 cigarettes are smoked daily and increases to 22.7 in a home where 21 or more cigarettes are smoked daily (Nicholl & O'Cathain, 1992; USDHHS, 2006). Elimination of maternal smoking would decrease the risk of SIDS death

acute affects of nicotine

Smoking is a pleasurable experience for many people (de Wit & Zacny, 1995). In pioneering research designed to assess whether nicotine is psychoactive and liable to be abused, volunteers smoked tobacco cigarettes or received nicotine via intravenous infusion, and their subjective responses were measured using the Addiction Research Center Inventory (ARCI). While nonsmokers did not enjoy the experience, smok-ers reported increased liking scores and subjective effects similar to those caused by morphine and amphetamine. The effects peaked about 1 minute after administration, were gone within a few minutes, and could be blocked by mecamylamine (Henningfield, Miyasato, & Jasinski, 1985; Henningfield, Miyasato, Johnson, & Jasinski, 1983; Jasinski, Johnson, & Henningfield, 1984). In another experiment, smokers were deprived begin-ning in the evening and given cigarettes with different lev-els of nicotine on the morning after. They were asked to smoke the cigarettes and push a button if they experienced "a rush, a buzz, or a high." Eighty-six percent of partici-pants smoking the high-concentration cigarette experi-enced at least one such sensation, the frequency and duration of which were related to blood nicotine levels. On average, the sensations lasted for about 11 seconds and occurred with a delay of about 30 seconds after a puff (Pomerleau & Pomerleau, 1992). Humans' ability to dis-criminate between identical-looking cigarettes that vary in nicotine content (Kallman, Kallman, Harry, Woodson, & Rosecrans, 1982) and to detect the presence of nicotine in nasal spray must be centrally mediated, since it is blocked by mecamylamine but not by a blocker of PNS nAChRs. Interestingly, men are more sensitive than women to the stimulus properties of nicotine (Perkins, 2009). More recently, Mello, Peltier, and Duncanson (2013) explored the temporal relationship between ratings of "high" on a visual analog scale (VAS) and the pharmacoki-netic profile of nicotine after smoking a 15.5 mg nicotine cigarette. Maximum ratings of "high" were reported after 4 minutes (8 puffs) of smoking as blood plasma nicotine level increased significantly from baseline. Once blood nico-tine level exceeded 14 ng/ml, which occurred after 6 minutes (12 puffs) of smoking, VAS ratings of "high" declined and proceeded to fall as nicotine concentration continued to increase to a peak value of 23.9 ng/ml after 14 minutes of smoking. This temporal dissociation between ratings of "high" and blood plasma levels of nicotine suggests that the pleasure of smoking is more the result of rapid absorption of nicotine into the blood (and, consequently, the brain) than it is of achieving and maintaining a high steady-state concen-tration of nicotine in the body. It is well established that the rate at which a drug enters the brain affects one's subjective experience; the faster the entry, the more intense the positive sensations of "high" or "liking" (de Wit, Bodker, & Ambre, 1992; Henningfield & Keenan, 1993; Lunell & Curvall, 2011). Nicotine appears to be no exception to this general rule. Neuroimaging studies help elucidate changes in neuro-transmission that occur during smoking and related subjec-tive changes. Nicotine causes the release of NE, DA, and other neurotransmitters in the brain. PET im [11C]raclopride, which binds to D2 receptors, demonstrates a relationship between the pleasurable effects of smoking and dopamine system activity. Participants who reported increases in euphoria while smoking their usual brand of cigarette showed significant decreases in [11C]raclopride binding potential in the caudate region of the dorsal stria-tum (Barrett, Boileau, Okker, Pihl, & Dagher, 2004). Decreases in radiotracer binding potential demonstrate that receptor sites are occupied by dopamine. Conversely, participants who reported experiencing smoking-induced decreases in euphoria demonstrated increased [11C]raclopride binding (indicating decreased dopamine binding) in the caudate.

chronic tolerance/sensitization

Some of the effects of amphetamines and cocaine build tol-erance with a more prolonged period of repeated adminis-tration. In humans, the appetite-suppressing effect of psychomotor stimulants usually disappears within about 2 weeks, and the drugs' effects on the heart and blood pres-sure also diminish somewhat over time. As such, the lethal effects of cocaine and amphetamine show tolerance with repeated use. Chronic amphetamine users are able to increase their dose to extremely high levels without experi-encing a fatal overdose. In one such case, a 15,000-mg dose of amphetamine was administered to an individual over in a 24-hour period; this is ~1,000 times the usual therapeutic dose and several times the estimated LD50 for nontolerant humans. Some effects of stimulants, such as their ability to prevent sleep, show no tolerance. Tolerance to the effects of methamphetamine are also quickly established. A chronic user typically administers four-to five-times higher doses compared to non-regular users (Vearrier et al., 2012). Some of the effects of psychomotor stimulants show reverse tolerance, or sensitization, with repeated use. Stereotyped and psychotic behaviors appear more fre-quently after repeated doses, even well beyond the period of last use (Ujike & Sato, 2004). In rats, chronic administra-tion of cocaine lowers the threshold for convulsions (Stripling & Ellinwood, 1976), and stereotyped behavior and spontaneous motor activity also increase in frequency and intensity (Post, Weiss, Pert, & Uhde, 1987

violence and suicide

Soon after fluoxetine was introduced to the U.S. market, there were reports that it induced intense, violent suicidal preoccupations in some patients (Teicher, Glod, & Cole, 1990). In fact, Prozac-induced violence became a defense in some courtrooms and was the subject of extensive cov-erage by television talk shows. There have since been many high-profile court cases where fluoxetine in partic-ular has been blamed by defense attorneys for causing many terrible crimes. Despite their increased safety over first-generation antidepressants and growing popularity, public health officials worried that the SSRIs may be hav-ing unintentional effects, especially on young people. In 2004, the U.S. FDA thoroughly reviewed clinical trial data, both published and unpublished, involving more than 4,000 children and adolescents. The review revealed that those taking antidepressant medications were twice as likely as those taking placebos to have sui-cidal ideations and to attempt suicide (4% of those in the drug group vs. 2% in the placebo group). European and The FDA mandated a black box warning, the most serious type of warning, to be placed on all antidepressant medi-cations prescribed to children and adolescents. Friends and family members should closely monitor young patients for worsening depression, indications of sui-cidal thoughts, and changes in behavior. In 2007, this warning was widened to include young adults up to age 24. In subsequent studies, researchers did not find signifi-cant evidence that suicidal ideation increases with antidepressant drug use but, instead, that the benefits of antidepressant treatment for young people outweighed the risks (Bridge et al., 2007). Yet, European and North American warnings prompted discontinuation of antide-pressant treatment in many children and adolescents, and far fewer new prescriptions were written. Between 2003 and 2005, suicide rates increased dramatically (by 14% in the United States; by 49% in the Netherlands) as young people were not treated for their depression (Gibbons et al., 2007). One reason why there is such confusion surrounding this issue is because it is inherently difficult to research. Antidepressant drugs are often prescribed for people who are already very agitated, depressed, and suicidal. Suicide and violence after taking an antidepressant drug may rep-resent only a lack of effect—an inability to restore seroto-nergic functioning and prevent suicide, not a drug-induced effect (Bortolato et al., 2013; Walsh & Dinan, 2001). In addi-tion, if a drug causes suicide and violence in only a small number of people but re

nicotine and unconditioned behavior

Spontaneous motor activity (SMA) of rats is initially depressed by 0.8 mg/kg of nicotine but, after 7 days of repeated testing, this dosage produces an increase in SMA that builds until it is similar to that elicited by 0.8 mg/kg of amphetamine. The initial depression in SMA results from nicotine's influence on ACh transmission in the brain, an effect that disappears after a few days as tolerance grows. Once the ACh effect decreases, the nicotine-induced increase in epinephrine enhances SMA in a manner similar to amphetamine (Morrison & Stephenson, 1972; Stolerman, Fink, & Jarvik, 1973).

reproduction

Studies examining the impact of stimulant use during pregnancy on fetal outcomes are inherently confounded by the lack of prenatal care, poor diet, and high rates of nicotine use that often coincide with amphetamine abuse (Golub et al., 2005). Some studies have examined the effects of orally administered amphetamine-like drugs on fetal abnormali-ties. Most of these were conducted with women who u stimulant drugs (mainly, ephedra) to control appetite dur-ing pregnancy. They provided some evidence linking chronic, low-dose use with a higher-than-average incidence of birth abnormalities. Keeping in mind the potential impact of additional mediating variables, various other studies have also linked amphetamine use during pregnancy with low birth weight, increased pregnancy complications, pre-term delivery, and perinatal infant mortality (Cruickshank & Dyer, 2009). Supporting evidence comes from animal stud-ies indicating that the administration of amphetamines dur-ing pregnancy can cause behavioral and physical problems in offspring (Grinspoon & Hedblom, 1975). Infants born to amphetamine-abusing mothers exhibit poor feeding, drows-iness, and tremor that is less severe than that seen in alcohol-or opioid-exposed infants and tends to resolve within about a week (Thaithumyanon, Limpongsanurak, Praisuwanna, & Punnahitanon, 2005). Methamphetamine abuse is associated with increased maternal risk during labor and delivery (Vearrier et al., 2012). Prenatal exposure to methamphetamine has been linked to fetal growth restriction; placental insufficiency, hemorrhage, and abruption; and premature delivery. Other adverse outcomes associated with maternal methamphet-amine use include neonatal birth defects, such as hydro-cephalus, brain lesions, and heart malformations; toxic hepatitis; and Down's syndrome (Cruickshank & Dyer, 2009; Vearrier et al., 2012). The frequency of these extremely adverse effects is low, however, and it is difficult to deter Many studies, but not all, have found that maternal cocaine use retards fetal growth; babies are smaller and more likely to be premature (Zuckerman & Frank, 1994). Other studies have found that pregnant women who used cocaine were almost 10 times more likely to have abruptio placentae (the placenta detaches prematurely; Shiono et al., 1995). As is the case with amphetamines, studies of possi-ble long-term developmental and behavioral effects of pre-natal exposure to cocaine are plagued with methodological difficulties, not the least of which is accurately measuring cocaine exposure and separating its effect from other con-founding factors such as the use of other drugs and the quality of pre-and post-natal care (Zuckerman & Frank, 1994). There is some evidence that prenatal exposure to cocaine affects childhood IQ, short-term memory, and ver-bal reasoning, particularly in male offspring (Bennett, Bendersky, & Lewis, 2008). Several studies have conclud

worse than coffee

Table 9-1 shows that a container of energy drink or energy shot lists the caffeine content as being no higher than that of a large cup of premium coffee, yet their conse-quences for health can be far more grave. There are a num-ber of reasons for the potentially detrimental health impact of energy drinks and shots. First, because energy drinks and shots are neither highly carbonated nor hot, they tend to be consumed much more quickly than a can of soda or cup of coffee which are likely to be sipped. Energy shots, in their highly concentrated form, are even easier to consume rap-idly. It is not uncommon for these products to be "chugged" as a quick pick-me-up. Second, energy-drink marketers tar-get adolescents and young adults (especially males), tout-ing the near-miraculous performance-enhancing an stimulating properties of the product. Energy drinks have become the fastest-growing product in the U.S. beverage and dietary-supplement market (Heckman, Sherry, & Gonzalez de Mejia, 2010). Drinking them is viewed as socially appealing and is even considered an illustration of one's masculinity (Miller, 2008). With increased desirability and use comes increased potential for adverse effects. Third, consumers interested in using energy drinks, but who also want to track their caffeine and stimulant-ingredient intake to maintain safe levels, would find the task extremely diffi-cult, if not impossible. The Nutrition Facts Panel on food packages and bev-erage containers is required by regulation to list dietary information for nutrients, but caffeine is not a nutrient. Though energy-drink and energy-shot manufacturers often list the amount of caffeine added to their product (it is, after all, a major selling-point), the caffeine or caffeine-like content stemming from additional herbal and syn-thetic ingredients is typically not provided. Guaraná, for instance, contains caffeine, theophylline, and theobromine. One gram of guaraná exerts a stimulating effect equivalent to that of 40 mg of caffeine but with an even longer dura-tion of effect (Finnegan, 2003). Yet, the 160 mg caffeine con-tent listed on a can of Monster, Rockstar, NOS, or Full Throttle (as shown in Table 9-1) does not include the caf-feine provided by guaraná or any other added plant extract, for that matter. Furthermore, a 2012 investigation by Consumer Reports Magazine found that nearly one-third of the energy-drink products that listed caffeine content on their labels contained 20% higher total values of caffeine than stated, and the remaining two-thirds of produ

canada and nicotine

The Canadian Food and Drugs Act regulates nicotine-containing products, including some not yet under the authority of the FDA, such as cigars and cigarillos. Health Canada's Tobacco Act regulates the manufacture, packag-ing and labeling, sale, and advertising, promotion, and sponsorship of tobacco products. In March of 2009, Health Canada issued a Notice—To All Persons Interested in Importing, Advertising or Selling Electronic Smoking Products in Canada. It stated that electronic smoking products for the vaporization and administration of inhaled doses of nicotine fall within the scope of the Food and Drugs Act and therefore require market authorization before being imported, advertised, or sold in Canada. Market authori-zation is granted by Health Canada only "following suc-cessful review of scientific evidence demonstrating safety, quality, and efficacy with respect to the intended [emphasis added] purpose of the health product" (Health Canada, 2009). To date, no ENDS product has been authorized for sale in Canada, as full scientific evaluation has not been completed, and distributers of e-cigarettes have been warned to cease sales immediately. However, the Notice issued by Health Canada in 2009 applies only to e-cigarettes "intended" to deliver nicotine, which created a regulatory grey zone that has since been widely exploited. E-cigarettes that do not make a health claim and do not contain nicotine may be sold legally in Canada. Nicotine-containing e-cigarettes are currently banned in several other countries, including Australia, New Zealand, Sweden, Mexico, Brazil, Argentina, and Columbia but are permitted (and regulated) in other regions, such as the European Union.

elimination

The MAOIs have a short half-life of 2 to 4 hours (Preskorn, 1993). Some MAOIs may be taken once a day because they have an irreversible effect on MAO and their effects persist long after they are eliminated from the body. Newer MAOIs, like moclobemide, have a reversible effect, and two or three daily doses are required. The TCAs have a half-life of about 24 hours and, in most people, reach a steady-state level after about 5 days of use. Usually, only a single daily dose is needed. Most second-and third-generation antidepressants have shorter half-lives than the tricyclics and often require more frequent dosing (Richelson, 2001). Newer SSRIs gen-erally have a short to medium half-life (15 to 25 hours) and do not have active metabolites. With these drugs, a steady-state blood level can be achieved in a few days with once-daily dosing. One major exception is fluoxetine, which has an extremely long half-life—nearly 4 days—and an active metabolite (norfluoxetine) that blocks the enzyme respon-sible for its destruction. The half-life of norfluoxetine is 7 to 15 days, substantially longer than that of its parent com-pound (Richelson, 2001). It may take as long as 75 days for the drug and its metabolite to reach a steady-state level in tabolite to be completely eliminated from the body after the drug is discontinued (Lane & Baldwin, 1997). There is considerable variability between individuals in the pharmacokinetics of antidepressant drugs. After a fixed daily dose of a tricyclic, steady-state blood levels may be as much as 36-times higher in some individuals than in others because some people have a genetic defi-ciency in one of the enzymes the body uses to metabolize these drugs. In these individuals, antidepressants can have extremely long half-lives (Preskorn, 1993; Rudorfer & Potter, 1987). Thus, optimal doses vary substantially across individuals and, in many cases, blood levels must be mon-itored. Swanson and colleagues (1997) reported two deaths caused by tricyclics taken at normal clinical doses. These individuals seem not to have cleared the drug from the body as rapidly as most people, and the metabolites built up to a toxic level. Like many other genetic factors, ethnic-ity has been found to influence levels of metabolizing enzymes (Sramek & Pi, 1996

absorption

The MAOIs, tricyclics, and many second-and third-gener-ation antidepressants have similar absorption pharmacoki-netics. The TCAs reach maximal blood concentrations in 1 to 3 hours (although some TCAs may take as long as 8 hours). The absorption of SSRIs and SNRIs is slower; 4 to 8 hours are needed to reach maximum concentrations. Antidepressants generally have high levels of protein binding (e.g., over 95% for fluoxetine; DeVane, 1998). A significant proportion of the dose of most antide-pressants is destroyed by the digestive system and liver before it reaches the bloodstream. This first-pass metabo-lism is inhibited by alcohol; as a result, alcohol will greatly increase the amount of drug absorbed from a specific dose. Overdoses of TCAs are much more serious when taken in conjunction with alcohol. SSRIs and SNRIs are exceptions; they appear to have little interaction with alcohol. In fact, SSRIs have been suggested as a treatment for alcoholism

history of cocao

The Mayans of the Yucatán Peninsula, the Aztecs of Mexico, and the Incas of Peru cultivated the cacao tree long before Europeans came to North America. The Indigenous Peoples believed cocoa to be a gift of the gods. This belief is the origin of the genus name of the cacao bush, Theobroma, which is Greek for food of the gods. Among the Indigenous Peoples of America, chocolate was a food generally reserved for the wealthy and powerful. It was believed to be an aphrodisiac and was used at wedding feasts and by wealthy noblemen who could afford to support, and had to please many wives. It is reported, for example, that Montezuma, emperor of the Aztecs at the time of contact with Cortés, consumed 50 golden goblets of the drink each day. He called it chocolatl, but what he drank must have been quite different from modern chocolate.

central nervous system

The actions of nicotine in the CNS are diverse. In addition to its direct effects at syn-apses, nicotine stimulates the release of epinephrine from various sites in the PNS, including the adrenal glands, which causes CNS arousal. Arousal is also produced by direct stimulation of the reticular activating system. At low levels, nicotine increases breathing rate via both direct and indirect stimulation of the respiratory centers in the brainstem. Prenatal nicotine exposure has been found to induce impairments in this cholinergic system that have been linked to an increased risk of sudden infant death syndrome (SIDS) and sleep apnea (Shao & Feldman, 2009). Respiratory arrest caused by nicotine overdose is due to blockade of nAChRs within these centers, as well as of the neuromuscular junctions that control the muscles used in breathing. Another brainstem center that is stimulated both directly and indirectly by nicotine is the vomiting center. This effect is most noticeable in naïve smokers who have no tolerance and lack the experience to control dos-age appropriately. The first tobacco use makes most young people nauseous and "green about the gills." This effect is subject to tolerance, but even experienced smokers can feel a bit "green" if they consume more than their accustomed amount of nicotine. Nicotine's ability to increase dopamine activity within brain reward pathways is responsible for its reinforcing effects (Benowitz, 2010; Dani & Balfour, 2011). This occurs via direct stimulation of dopamine neurons within the nucleus accumbens and through potentiation of excitatory glutamatergic connections to dopamine neurons in the ven-tral tegmental area and nucleus accumbens. Through a Through acti-vation of both presynaptic and postsynaptic nAChRs located on midbrain glutamate neurons, nicotine stimulates glutamate release which, in turn, excites the dopamine neu-rons onto which the glutamate afferents project. Nicotine also augments GABA release, which decreases dopamine neuron activity. However, with chronic nicotine use, GABA-mediated inhibitory tone diminishes whereas glutamate-mediated excitation persists so that dopamine neuron responsiveness to nicotine is enhanced (Benowitz, 2010). The nAChRs residing on dopaminergic neurons that project from the ventral tegmental area to the nucleus accumbens contain the b2 subunit. It is possible to reeding knockout (KO) mice that lack the genetic instruc-tions to express it. b2 knockout mice do not demonstrate a surge in dopamine release in the nucleus accumbens con-sequent to stimulation of the ventral tegmental area and they also do not self-administer nicotine. Maskos and col-leagues (2005) restored b2 subunits to nAChRs in the ven-tral tegmental area of b2 KO mice and found a reversal of both of these effects. The mice showed increased dopa-mine activity in the nucleus accumbens when the ventral tegmental area was stimulated and self-administered nico-tine in the same manner as normal mice. The mice also showed improved cognitive functioning and exploratory behavior, suggesting that the presence of b2 subunits is important in cognition. The presence of the a5 subunit in nAChRs appears to mediate the aversive effects of nicotine that are experienced at higher concentrations. a5 KO mice will self-administer much higher doses of nicotine compared to normal mice. It is known that people who carry a particular form of the gene that makes a5 subunits with diminished function are at a much greater risk of being smokers and of suffering from respiratory disease (Tuesta, Fowler, & Kenny, 2011).

methylxanthines in tea

The amount of methylxanthines contained in a cup of tea can vary substantially depending on many fac-tors, such as the species of plant and amount of tea leaves used, the climate and soil conditions in which the tea is grown, environmental pollution, the season in which the leaves are harvested, whether the tea is loose or bagged, the length of brewing time, and the tempera-ture of the water used to steep the tea. On average, a c

amphetamin history

The amphetamine that was first synthesized by Lazăr Edeleanu and, later, by Gordon Alles is one of a larger group of drugs that do not occur naturally. They include d-amphetamine (dextro-amphetamine or dexamfetamine) and l-amphetamine (levo-amphetamine) which have exactly the same chemical structure, but the molecules are mirror images of each other (technically, they are called optical iso-mers). When the term dl-amphetamine or simply amphetamine is used, it refers to a mixture of both d-and l-isomers. In 1935, the pharmaceutical company Smith, Kline, and French marketed dl-amphetamine under the trade name Benzedrine. The drug was sold over-the-counter in a nasal inhaler, used to treat sinus congestion, or as a pill, used for the treatment of mild depression, sea sickness, Parkinson's disease, the sleep disorder narcolepsy, and a host of other conditions. In 1937, Smith, Kline, and French introduced another, stronger amphetamine drug which they marketed as Dexedrine. It contained only d-amphetamine, the more potent of the two optical isomers (Heal, Smith, Gosden, & Nutt, 2013). Researchers reported the benefits of amphet-amine in enhancing concentration and cognitive perfor-mance and in improving intelligence-test scores, which led to its widespread use by academics and medical profes-sionals (Heal et al., 2013; Wood, Sage, Shuman, & Anagnostaras, 2014). These "pep pills" were also in high demand amongst postsecondary students who had "come to cherish this drug as a gift of the Gods, relying upon it to carry them through prolonged periods of cramming for examinations" (Minkowsky, 1939, p. 351). Benzedrine's efficacy in treating children with severe behavioral

distribution of psychomotor stimulants

The amphetamines, cocaine, and other drugs in this class readily cross the blood-brain and placental barriers and are widely and rapidly distributed throughout the tissues and organs of the body. The highest concentrations of metham-phetamine occur in the kidneys and lungs, followed by the stomach, pancreas, spleen, and liver, with lower concentra-tions in the heart and brain (Volkow, Fowler, et al., 2010). Peak brain concentrations (which correspond with behav-ioral effects and subjective ratings of "high") are achieved within about 9 minutes of smoking or injecting the drug intravenously (Fowler, Volkow, et al., 2008; Volkow, Fowler, et al., 2010). In contrast, cocaine tends to concentrate more in the brain than in other bodily organs, and peak brain con-centrations are reached within about 4.5 minutes of cocaine use. Additionally, a greater total percentage of a cocaine dose enters the brain compared to a dose of methamphetamine (Volkow, Fowler, et al., 2010). Peak brain concentrations of methylphenidate occur within about 1 hour after oral administration, which corresponds with the drug's thera-peutic effects (Volkow et al., 1998). After injection, methyl-phenidate reaches peak brain levels within 8-20 minute

subjective effects

The antidepressants do not produce euphoric or even pleasant effects. Neither the TCAs nor the MAOIs are self-administered unless prescribed by a physician for the treatment of depression. They are seldom sold illicitly on the street and do not appear to be used nonmedically. Apart from their medical application, neither of these classes appear to be reinforcing to either humans or non-humans (Griffiths, Bigelow, & Henningfield, 1980). SSRIs and even the atypicals, which increase dopaminergic activ-ity, do not produce euphoria. Recall from Chapter 5 that both the magnitude and the rate of dopamine surge associ-ated with a drug correspond with individuals' reports of euphoria and pleasure. Because the increases in dopamine activity that result from atypical-antidepressant use are, relative to abused drugs, much lower and achieved slowly, any pleasurable effect one might feel is greatly blunted. At low doses, imipramine's effects are similar to those of the antipsychotics. It causes feelings of tiredness, apathy, and weakness. Higher doses impair comprehension and pro-duce confusion that is described as unpleasant . Amitriptyline causes feelings of calmness and relaxation (Spiegel & Aebi, 198

admin

The antipsychotics are most often taken orally. Preparations are available for intramuscular or intravenous injection, though these routes are seldom used when the drug is given for its antipsychotic effects. Rather, injection is a more common route when the drug is used as a presurgi-cal or preanesthetic medication because of the speed with which it produces sedation. Intravenous injection offers the benefit of avoiding any irregularities or delays in effect arising from erratic absorption from the digestive system. It is doubtful, however, that the antipsychotic effects would be speeded significantly by giving the drug Because antipsychotic drugs are often taken chroni-cally and patients do not always comply with the dosing schedule, they are sometimes given in the form of a slowly dissolving depot injection, as described in Chapter 1. Typical antipsychotics (e.g., fluphenazine, haloperidol, and perphenazine) can be dissolved in an oily base, such as sesame, coconut, or synthetic vegetable oil, and injected intramuscularly. Newer atypical antipsychotics administered as depot injections are not suspended in oil. Instead, risperidone, for example, can be encapsulated in a biodegradable polymeric microsphere preparation, which degrades slowly to release the drug. Olanzapine and paliperidone can be combined with the salt form of pamoic acid (pamoate salt) and suspended in water. Following intramuscular injection, the pamoate salt slowly dissolves to release the drug into the body (Haddad, Lambert, & Lauriello, 2011). A single depot injection of oil-, microsphere-, or crystalline-salt-based preparation may be effective for as long as 4 weeks (Haddad et al., 2011

theraputic index

The antipsychotics produce many side effects, but these drugs are not lethal. In fact, they are extremely safe and have a high therapeutic index of about 100. For some anti-psychotics, the therapeutic index is as high as 1,000 (Baldessarini, 1985). It is practically impossible to induce lethal overdose by ingesting antipsychotics

cathinone elimination

The cathinone absorbed during khat chewing has an elimination half-life ranging from about 2.6-6 hours. There is substantial first-pass metabolism and breakdown of cathi-none in the liver; only about 2-7% of an ingested dose is eliminated unchanged in urine (Geresu, 2015; Valente et al., 2014). The drug is eliminated mainly as its major metabo-lites, cathine and norephedrine. Cathinone is barely detect-able in the body at 7.5 hours after a session of khat chewing, and is not detected at all after 24 hours (Geresu, 2015).

harmful effects

The classic hallucinogens are unlikely to cause life-threatening cardiovascular effects or to damage the func-tioning of the liver or kidneys, as they have little affinity for these or any other biological targets that play a role in drug toxicity and overdose (Araújo, Carvalho, et al., 2015). The usual effective dose of orally administered DMT is ~40 mg (typical range: 34-70 mg; Gable, 2004b). In an aya-huasca ceremony, the usual amount of decoction con-sumed is about 100 ml, which contains roughly 24 mg of DMT (Araújo, Carvalho, et al., 2015). The lethal dose of DMT is estimated to be in the range of 2000 mg, which would require an ayahuasca user to consume more than 8 liters of the liquid in order to attain lethal concentrations (Gable, 2004b). The usual effective dose of LSD is ~100 mg (typical range: 25-200 mg) while the lethal dose is esti-mated to be about 100 mg (Gable, 2004b). Likewise, psilo-cybin's estimated lethal dose (6 g) is 1000-times higher than its usual effective dose (6 mg; Gable, 2004b). Mescaline is usually ingested at a dose of 350 mg (typical range: 200-450 mg) whereas an estimated 8.4 g would be required to produce lethal effects (Gable, 2004b). There are no known cases of anyone dying from an overdose of a classic hallucinogen. This is not true, how-ever, of certain designer hallucinogenic drugs, such as 5-MeO-DIPT, 5-MeO-DALT, and AMT (all psilocybin-like compounds), or MDMA (a mescaline-like com-pound; Araújo, Carvalho, et al., 2015). In some of the fatalities related to designer hallucinogens, the user behaved in a risky manner which, in the end, was th

history of coffee

The coffee bush is native to Ethiopia. According to legend, its properties were discovered by a goat herder around 850 ce (Ludwig et al., 2014). From Ethiopia, its use spread with the slave trade across Arabia, Egypt, and North Africa, around the Mediterranean into Turkey, and then on to Europe in the sixteenth century. William Harvey, the first person to describe the circu-lation of the blood, was one of the first coffee drinkers in England and he promoted the beverage for its therapeutic benefits. Two of his students believed that it was a cure for drunkenness (Austin, 1985). The first English coffeehouse opened in Oxford in 1650 and the concept soon spread throughout England. Coffeehouses were referred to as "schools of the cultured," and coffee was "the milk of chess players and thinkers." Coffee, and the intellectual tradition associated with coffeehouses, soon spread throughout Europe. At one time, coffee drinking gained such popular-ity in England that the consumption of alcoholic bever-ages, particularly cheap gin, started to decline. Coffee has remained popular throughout Europe, but in Great Britain it was eventually replaced by tea. Although tea was the preferred drink in colonial America, coffeehouses were as common as in England and filled the same social function: a meeting place for intellec-tual and political discussion. Boston coffeehouses such as the Brown, the North End Coffee-House, and the Exchange served as headquarters for Whigs and Tories and were the scenes of much plotting and heated debate. On

dopamine hypothesis

The dopamine hypothesis has been the dominant theory of the neurobiological basis of schizophrenia from the 1960s to the present day. The basic tenet of this theory, as originally postulated, was that schizophrenia and other psychotic disorders result from excessive dopamine activ-ity in limbic pathways of the brain (Carlsson & Lindqvist, 1963). Support for this supposition was based mainly on two important observations: (a) drugs that increase dopa-mine activity (e.g., cocaine or amphetamine) can, in high doses or with chronic administration, produce a state almost indistinguishable from the positive symptoms of schizophrenia, and (b) the antipsychotics available at the time (i.e., the typicals) were all dopamine antagonists (more on this later). As research into the role of dopamine in schizophrenia progressed, other lines of supporting evidence emerged. Available antipsychotic medications, such as chlorproma-zine and reserpine, that were effective in reducing symp-toms of schizophrenia also produced severe EPS; in the 1960s, researchers already knew that Parkinson's disease was related to a depletion of dopamine in the brain, and so they extrapolated that antipsychotics must be exerting a similar effect. Also, the most effective antipsychotic drugs were found to be those with the greatest ability to block dopamine receptors. In fact, the correlation between the therapeutic dose of a typical antipsychotic and the drug's affinity for the dopamine receptor was found to be almost

revized dopamine

The dopamine hypothesis, even in its revised form, still could not fully explain the etiology of schizophrenia. For one, there are inconsistencies in the research compar-ing D2 receptor densities in individuals with and without schizophrenia, and no strong evidence that dopaminergic circuits progressively deteriorate along with other neu-rotransmitter circuits. Also, if schizophrenia were due sim-ply to an overabundance of dopamine, antipsychotic drugs (which block dopamine activity as soon as they reach their site of action) should work immediately. Instead, the thera-peutic effect may be delayed for several weeks, suggesting that alleviation of psychotic symptoms involves a more complex mechanism than simply blocking excessive dopa-mine activity (Carlsson, 1994). It may also involve the slow and long-lasting changes in the electrical properties or connectivity of cells, as discussed in Chapter 4. Finally, the negative and cognitive symptoms of schizophrenia do not improve with D2 receptor blockade, suggesting that hyperactivity of D2 receptors does not fully account for all schizophrenia symptoms. Some researchers have sug-gested that perhaps D3 or D4 receptor dysfunction is also involved, as these receptor subtypes act similarly to D2 receptors—their activation inhibits, rather than excites, second messenger activity. An additional revision to the dopamine hypothesis that has garnered a lot of support states that excessive dopamine activity, specifically in the mesolimbic pathway, does indeed explain the positive symptoms of schizophre-nia. However, the negative and cognitive symptoms of schizophrenia result from a lack of dopamine activity, spe-cifically in the mesocortical pathway (Abi-Dargham, 2004), as well as from structural abnormalities (and, thereby, functional deficits) resulting from the degeneration of vari-ous brain regions, including the prefrontal cortex, as described earlier (Roth, Flashman, Saykin, McAllister, & Vidaver, 2004; Brown & Thompson, 2010). Interestingly, psychomotor stimulant drugs, such as methylphenidate and amphetamine which increase mesocortical dopamine activity, have been found to alleviate the negative and cog-nitive symptoms of psychosis in select individuals (Lindenmayer, Nasrallah, Pucci, James, & Citrome, 2013). As you will soon learn, when we put all of the pieces together, hypoactivity of the frontal lobes may actually be the driving force behind hyperactivity of the mesolimbic dopamine system

psychomotor stimulants

The drugs known as psychomotor stimulants share a com-mon neuropharmacological effect: they stimulate trans-mission at synapses that use dopamine (DA), norepinephrine (NE), epinephrine (E), or serotonin (5-HT) as neurotransmitters. These transmitters are called biogenic amines or monoamines. The first three—DA, NE, and E—are very similar in chemical structure. As you learned in Chapter 4 (and saw in Figure 4-15), the body manufactures E from NE in one chemical step, and NE is made by slightly changing the structure of DA. Together, these three are called catecholamines. The odd monoamine is 5-HT. It is an indolamine, which is chemically different from the cate-cholamines, but is influenced by many of the same drugs and destroyed by many of the same enzymes. Psychomotor stimulants are sometimes referred to simply as psychostim-ulants or as sympathomimetic drugs because they stimulate the release of NE and activity of the sympathetic nervous system to mimic sympathetic arousal

synthetic cathinones

The earliest and most commonly abused synthetic cathinones include mephedrone (4-methylmethcathinone), which is most prevalent in the United Kingdom and parts of Europe, and methylone (3,4-methylenedioxymethcathinone) and MDPV (3,4-methylenedioxyprovalerone), which are the most frequently abused synthetic cathinones in the United States and Canada (Gregg & Rawls, 2014). These three are the compounds for which the most extensive scientific research has been conducted, though clandestine chemists have since created many more (80+) substances by chemi-cally altering the core structure of the parent compound, cathinone, and far less is known about their effects (European Monitoring Centre for Drugs and Drug Addiction, 2015). The active compounds contained in bath salts products can vary markedly, both in presence and quantity, even across different batches of the same brand of product. Typically, packages contain 50-500 mg of product, but there is often no indication of how much of a particular substance is present in the package, or what constitutes a safe dose (Musselman & Hampton, 2014; Zawilska & Wojcieszak, 2013). Often, more than one synthetic cathinone compound is present in a bath salts product (Kelly, 2011; Zuba & Byrska, 2013), and other substances, such as caf-feine, are also frequently part of the mix. Because their effects on catecholamine release are known to be synergistic (Cameron, Kolanos, Solis, Glennon, & De Felice, 2013), co-ingestion of multiple synthetic cathinones can pose a sig-nificant threat of toxicity, acute harm, and addiction for users. When they first emerged as recreational drugs of abuse, mephedrone, methylone, and MDPV were "legal highs"—unregulated compounds similar in effect to illegal substances such as cocaine, amphetamines, and MDMA

dissociation

The early antipsychotic drug chlorpromazine has been found in animal studies to cause dissociation. One study, for example, found that rats trained on an avoidance task under the influence of chlorpromazine were unable to remember what they had learned when tested under saline, but could recall the task when returned to the drugged state (Otis, 1964). Antipsychotic-induced disso-ciation may be cause for concern, as the various forms of psychotherapy found to benefit those with psychotic disorders (e.g., cognitive behavioral therapy, family ther-apy, or psychosocial intervention) all require learning, memory, and long-lasting adaptions in cognition and behavior (Tsapakis et al., 2015; Valencia, Fresan, Juárez, Escamilla, & Saracco, 2013). If symptoms improve with treatment, a clinician might opt to lower the pharmaceu-tical dose or discontinue antipsychotic drug treatment altogether, which could result in a loss of psychothera-peutic gains as patients may forget what was learned during therapy

effects on human behacior

The effects of antipsychotics are highly variable, both for an individual taking different drugs and between individuals taking the same drug. Each drug's effectiveness as an anti-psychotic and the sorts and intensity of side effects vary considerably from person to person. This is one reason why so many of these drugs are on the market. Psychiatrists may try giving an individual a number of different drugs at different doses until one is found that produces the most favorable therapeutic effect with the fewest side effects. Though some individuals experience a remission of psychotic symptoms, there is no pharmacological cure for psychosis and treatment is often lifelong. With prolonged use, antipsychotic medications can take a significant toll on the user's body. As we have already seen, the most pro-nounced side effect of the typical antipsychotics is EPS—disturbances in movement that resemble the symptoms of Parkinson's disease. This effect is reported in about 40% of patients taking typical antipsychotics. It includes a dulled facial expression, rigidity and tremor in the limbs, loss of coordinated movement, weakness in the extremities, and a

Neuropharmacology

The effects of the methylxanthines on neural functioning arise from their structural similarity to the neurotransmitter adenosine. Caffeine is an adenosine receptor blocker, exerting its effects mainly at A1 and A2A receptor subtypes. Theophylline and the caffeine metabolite paraxanthine are also highly potent inhibitors of A1 and A2A receptors (Fredholm et al., 1999). A1 receptors are distributed widely throughout the brain with the highest densities found in the hippocampus, cerebellum, cerebral cortex, and certain thalamic nuclei. Moderate densities are found in the sub-stantia nigra, neostriatum, ventral tegmental area, and nucleus accumbens (Fredholm et al., 1999). Receptors are located postsynaptically as well as presynaptically, where they act as heteroreceptors to inhibit neurotransmitter release from neurons producing acetylcholine, GABA, glu-tamate, norepinephrine, serotonin, and dopamine (Fredholm & Dunwiddie, 1988). A2A receptors are concen-trated in dopamine-rich regions of the brain, primarily the dorsal striatum and nucleus accumbens (Fredholm et al., 1999).

the cheese effect

The enzyme monoamine oxidase is responsible not only for metabolizing the monoamine neurotransmitters but also for breaking down some substances found in food. One of these substances is tyramine, found in a variety of foods including: aged hard cheeses; pickled, aged, smoked, or processed meats including fish, poultry, beef, and pork; some beans, peas, fruits, vegetables, and nuts; beer, wine, and other alcoholic beverages; some energy drinks; and chocolate. Tyramine is also produced in the body via the metabolism of tyrosine which, you'll recall from Chapter 4, is the amino acid precursor for the production of the cate-cholamine neurotransmitters. MAO-A, which is present in the intestine, normally metabolizes tyramine immediately after it is consumed. Any tyramine missed by intestinal MAO-A is broken down by MAO-B in the liver and the lungs before it gets into general circulation throughout the body. Normally, less than 1% of tyramine avoids MAO metabolism and enters systemic circulation (Fitton, Faulds, & Goa, 1992). If tyramine-rich foods are eaten while taking MAOIs, the body is unable to break down the tyramine and it accumulates. Although the tyramine ingested in foods cannot cross the blood-brain barrier to produce CNS effects, it is capable of stimulating the release of catechol-amines (NE and E) in the peripheral nervous system. This causes effects that mimic sympathetic nervous system acti-vation, including sweating, nausea, and increased blood pressure, which in turn can produce headaches, internal bleeding, and even stroke or death. This is known as the cheese effect The older MAOIs blocked both forms of MAO, but newer MAOIs are more selective. As an example, moclobemide selectively blocks MAO-A while exerting minimal effects on MAO-B. As a result, tyramine that gets past the inhibited MAO-A in the intestine can still be metabolized by the MAO-B in the liver and lungs. Selective MAO-A inhibitors are, therefore, much safer than non-selective inhibitors and patients do not have to be as care-ful about watching what they eat (Fitton et al., 1992). It also helps if the drug is taken long after eating, allowing any dietary tyramine to be metabolized before the MAOI has its maximum effect. Individuals taking newer, selec-tive MAOIs must still avoid serotonin-enhancing medica-tions or illicit drugs, however, as these cross the blood-brain barrier and deaths have been reported follow-ing the co-administration of moclobemide and MDMA (Vuori et al., 2003).

elimination of amphetamines

The excretion of amphetamines from the body depends a great deal on the pH of the urine. Because it is ionized at low pHs, amphetamine is not reabsorbed from the nephron in acidic urine. But as the urine becomes more basic, more of the drug is reabsorbed, and more of the burden of excre-tion is carried by metabolism in the liver. At normal urine pHs, when taken as Adderall, the elimination half-life of d-amphetamine is slightly shorter (~9.8-11.0 hours) than that of l-amphetamine (~11.5-13.8 hours). More acidic urine decreases amphetamine's half-life while more basic urine prolongs it (Creasey, 1979). Approximately 30-40% of a dose of amphetamine is excreted unchanged in urine, while primary metabolic pathways of the amphetamines lead to additional, behaviorally active metabolites. Amphetamine is also eliminated from the body in sweat and saliva (Britton, El-Wardany, Brown, & Bianchine, 1978; Vree & Henderson, 1980). The half-life of methamphetamine is about 9 hours when taken intravenously or orally, and 11-13 hours when snorted or smoked (Cook et al., 1993; Cruickshank & Dyer, 2009). Methamphetamine is broken down primarily in the liver into metabolites that, although active, are not likely to contribute significantly to the drug's subjective effects (Cruickshank & Dyer, 2009). Approximately 70% of a dose of methamphetamine is excreted in urine within 24 hours: 30-50% as unchanged methamphetamine, 15% as the metabolite 4-hydroxymethamphetamine, and 10% as amphetamine (Cook et al., 1993; Cruickshank & Dyer, 2009). After repeated doses or one large dose, methamphetamine is detectable iurine for up to 1 week and amphetamine (as a metabolite) for even longer. The metabolism of methamphetamine doesn't appear to be altered by repeated drug use, which suggests that escalations in dose are the result of pharmaco-dynamic (neuropharmacological) rather than pharmacoki-netic (enzymatic) alterations (Cruickshank & Dyer, 2009).

clozapine

The first atypical to come onto the market was clozap-ine (Clozaril), which alleviates the positive, negative, and cognitive symptoms of schizophrenia. Though only about one-third of individuals respond well to the drug, it has, for more than 20 years, remained the primary medication used in managing treatment-resistant schizophrenia (Essali, Al-Haj Haasan, Li, & Rathbone, 2009). Clozapine has a high affinity for D4 receptors, as well as multiple 5-HT receptor subtypes, muscarinic acetylcholine recep-tors, and alpha1 adrenergic receptors. As with the other atypicals, clozapine has only a weak affinity for D2 recep-tors. Its primary therapeutic effects are thought to result from antagonism of D4 and 5-HT2A receptors (Meltzer, 1994). Clozapine, and the many other atypicals that have since been developed, are often first used in the United Kingdom or other European countries and are slow to be approved for use in the United States and Canada.

khat and cathinones

The khat plant (Catha edulis) is a hardy perennial shrub, cultivated as a bush or small tree. It is native to the Horn of Africa and the Arabian Peninsula. The plant is commonly called khat (pronounced "cot"), but has many other tradi-tional and region-specific names, including quat or qat in Yemen, tscaht or chat in Ethiopia, qaat or jaad in Somalia, and miraa in Kenya (Al-Mugahed, 2008; Kalix, 1994). The young leaves and shoots of the shrub contain psychostim-ulant compounds, the principal one being cathinone which is structurally related to amphetamine (Wabe, 2011). Cathinone is released by chewing the fresh leaves or by drying and pulverizing the plant material into a powder that is brewed as a tea or mixed with honey and eaten as a paste (El-Menyar, Mekkodathil, Al-Thani, & Al-Motarreb, 2015). The practice of khat chewing is believed to have originated in Ethiopia in the thirteenth century and moved into Yemen early in the fifteenth century, though an Arabian physician reported the medical use of khat much kly into its less potent metabolites norephedrine and norpseudoephedrine (also known as cathine) as the plant wilts and dries within a few days of being harvested. For this reason, consumers prefer to chew fresh leaves of the khat plant, optimally within a few hours of cultivation, as these provide maximal stimulant effect (Al-Motarreb et al., 2002). Farmers wrap the leaves in wet cloths, banana leaves, or plastic wrap to keep them fresh as their commer-cial value drops substantially after harvest day. At best, khat leaves retain active cathinone for a maximum of 5 days after picking (Al-Motarreb et al., 2002). Because cathinone decomposes so quickly, the plant is used pri-marily in the regions where it is grown, though it has been smuggled into European and North American markets (Feyissa & Kelly, 2008). To tap into a broader worldwide market, a number of synthetic derivatives and analogs of cathinone have been created. Methcathinone was the first synthetic cathinone to be created. It was developed in the United States in 1928 as an appetite stimulant, but the research was quickly abandoned due to the drug's adverse effects (Musselman & Hampton, 2014). In the 1930s and 1940s, methcathinone was used as an antidepressant in the Soviet Union where, in the 1970s, it emerged as a drug of abuse under the street names jeff, jee-cocktail, or cosmos (Kelly, 2011). In the early 1990s, the drug (which is als

methylxanthine absorption-non-medical

The methylxanthines are bases; consequently, when they are dissolved in the acidic environment of the digestive tract, you might expect them to be highly ionized and, therefore, not lipid soluble. However, these drugs have a very low pKa—about 0.5. Consequently, at the pH of the digestive system, and at any other pH encountered in the body, the methylxanthines will not be ionized at all. They are, in fact, highly lipid soluble and pass easily through tis-sue membranes. For this reason, following oral ingestion, the methylxanthines are readily and completely absorbed into the bloodstream from the digestive tract. Absorption takes place mainly through the walls of the stomach and along the small intestine. Approximately 90% of the caf-feine present in a cup of coffee is cleared from the stomach within 20 minutes of ingestion and peak blood levels are reached within about 45-75 minutes (Lang et al., 2013; Martínez-López, Sarriá, Baeza, Mateos, & Bravo-Clemente, 2014; Nawrot et al., 2003). Factors that decrease stomach-emptying time, such as the presence of food, will slow methylxanthine absorption. The caffeine in coffee, tea, energy drinks, and choco-late exists and is consumed in its alkaloid form.

Methylxanthines

The methylxanthines are naturally occurring compounds found in nearly 100 plant species belonging to 28 genera and over 17 families. Caffeine is the best-known member of the methylxanthine family, which also includes theophylline and theobromine. These three compounds have similar molecular structures, similar behavioral and physiological effects, and are widely self-administered, mainly in the form of coffee, tea, and chocolate. Caffeine is also typically added to soft drinks and is an ingredient in many over-the-counter painkillers, cold remedies, stimulant pills, and, more recently, energy drinks. Caffeine was first isolated from coffee in 1820 by a German chemist, Ferdinand Runge, who called it Kaffeebase. Runge's interest in coffee was purportedly stim-ulated by Wolfgang von Goethe, the author of Faust, who was a close friend of Runge and a great coffee lover. The term caffeine first appeared in 1823 in a medical dictionary, though the origin of the term is unknown. Theobromine was isolated in 1842 and theophylline in 1888. Most of the basic chemistry of the methylxanthines was worked out and published in 1907 in a book by Emil Fischer, a Nobel prize-winning organic chemist.

effects on body

The methylxanthines stimulate the release of epinephrine from the adrenal glands and increase sympathetic nervous system activity, with accompanying physiological changes in vascular tone, heart rate, and body temperature (Echeverri, Montes, Cabrera, Galán, & Prieto, 2010; Riksen, Smits, & Rongen, 2011). At a dose of 250 mg, coffee consumption increases blood pressure, but only in caffeine-naïve individuals (Corti et al., 2002; Mesas, Leon-Muñoz, Rodriguez-Artalejo, & Lopez-Garcia, 2011). High-dose caffeine consumption can also lead to tachycar-dia and other unpleasant physiological changes in individ-uals unaccustomed to drinking caffeine. At doses of 5 to 10 cups of coffee per day, caffeine can cause sensory distur-bances, such as ringing in the ears and seeing flashes of light, as well as mild delirium and excitement. The regula-tory centers of the medulla are also stimulated by high doses of caffeine, producing an increase in the rate and depth of breathing. This ability of the methylxanthines to stimulate respiration makes them useful in the treatment of babies born with breathing difficulties. Outside the CNS, much of caffeine's effect is due to its direct actions on the muscles: smooth (involuntary) mus-cles tend to relax, and striated (voluntary) muscles increase in strength (Pallarés et al., 2013). Smooth muscle relaxation results in dilation of the bronchi of the lungs and a decrease in airway resistance. Theophylline is the most potent methylxanthine in producing this effect; as a result, it is used clinically in the treatment of asthma. Methylxanthines also reduce the susceptibility of striated muscles to fatigue. complex, as it impacts a variety of mechanisms that act to either dilate or constrict blood vessels. In endothelial cells (those that line arterial walls), caffeine stimulates the production of nitric oxide which results in dilation of those vessels. Adenosine-receptor binding can produce either vasodilation or vasoconstriction, depending on the target organ and the type of receptor activated. In the brain, ade-nosine activity at A2A receptors dilates blood vessels and methylxanthine administration reverses this action (Echeverri et al., 2010; Kusano et al., 2009). At moderate doses (~250 mg), caffeine produces vasoconstriction and can reduce cerebral blood flow by as much as 30% (Cameron, Modell, & Hariharan, 1990). Because dilation of cerebral blood vessels is associated with headache, caffeine administration can alleviate head-ache pain and is added to many over-the-counter analgesics Moderate consumers of caffeine (those who drink 3 to 4 cups of coffee daily) report fewer headaches than those who drink less, but more headaches than those who drink more (Warburton & Thompson, 1994). This finding sug-gests that the relationship between caffeine consumption and headache is somewhat of a double-edged sword. Caffeine intake equivalent to as little as 2 cups of coffee per day for 5 days has been found to upregulate adenosine receptors, increasing their number and sensitivity (Green & Stiles, 1986). Chronic caffeine users who miss their morn-ing cup of coffee will quickly feel the effects of enhanced adenosine activity in the form of what Griffiths and Woodson (1988) called abstinence syndrome—a withdrawal condition marked by fatigue, flushing, nausea, anxiety, and headache. Some of these symptoms are related to dilation of blood vessels in the brain, but others are evoked by the enhanced inhibitory actions of adenosine on the release of other neurotransmitter molecules, including serotonin, norepinephrine, acetylcholine, and dopamine (Guieu et al., 1998). Drinking more coffee will keep these abstinence-related symptoms at bay. Caffeine consumption increases the urgency and fre-quency of urination, decreases the sensation of a full blad-der, and increases flow rate and volume of voided urine (Jura, Townsend, Curhan, Resnick, & Grodstein, 2011). The diuretic effects of caffeinated beverages are explained by the influence of the methylxanthines on adenosine recep-tors, which are important for the regulation of kidney function. Supporting evidence comes from studies

configurations of nAChR

The nAChR takes on three different configurations. First, there is a basal state, in which the ion channel is closed and the receptor has a high affinity for ligands. Second, there is an active state, when the channel is open and there is a low affinity for ligands. Third, there is a desensitized state, when the ion channel is closed and the receptor is unresponsive to ligands. These are illustrated in Figure 8-2. When an agonist occupies its receptor sites (there are two for acetylcholine), the nAChR enters its active configuration and the ion channel opens. When the agonist leaves the receptor sites, the nAChR returns to its closed configuration. If the receptor is repeatedly activated, the receptor will enter its desensitized configuration in which its receptor sites are occupied and it is not sensitive to agonists or antagonists. This state of desensitization, when the ion channel is closed and the receptor is unre-sponsive to stimulation, is thought to play a role in acute tolerance to nicotine. The receptor will return to its inac-tive (basal) state following a period of time during which no agonist is bound to the receptor. The change from rest-ing to active states is fast (in the order of milliseconds), whereas the change to the desensitized state is slow (in the order of tens of milliseconds to minutes). The receptor's return to its normal, sensitized state may take hours

neurotoxicity

The neuropharmacological actions of MDMA are similar to those of other substances, such as cocaine and metham-phetamine, that are known to exert neurotoxic effects in humans (Halpin, Collins, & Yamamoto, 2014; Mohammad Ahmadi Soleimani, Ekhtiari, & Cadet, 2016). Evidence from animal and human studies overwhelmingly supports the potential of MDMA to produce dose-dependent, long-lasting alterations to both dopamine and serotonin brain systems (Halpin et al., 2014; Moratalla et al., 2015). Research in mice indicates that MDMA's neurotoxic effects primarily target the nigrostriatal dopamine path-way (substantia nigra to striatum), while largely sparing the mesolimbic pathway (ventral tegmental area to nucleus accumbens; Moratalla et al., 2015). Specifically, MDMA produces long-lasting degeneration of dopamine-neuron axon terminals in the striatum and a significant decrease in levels of tyrosine hydroxylase (TH), the enzyme responsi-ble for DA biosynthesis. The reduction in TH synthesis is not a direct effect of MDMA, but an indirect result of dam-age to dopamine neurons (Moratalla et al., 2015). The loss of DA axon terminals in the striatum of mice following MDMA administration is similar to the pattern of

Typical Antipsychotics

The older drugs, the typical antipsychotics, were all developed prior to 1975 and are either phenothiazines or butyrophenones. They are primarily D2 receptor blockers and are most effective in treating the positive symptoms of psychosis, rather than the negative or cognitive symptoms (which, in fact, may even be worsened). Approximately one-third of individuals with schizophrenia experience no improvement of symptoms when taking typical antipsy-chotics (Wiersma, Nienhuis, Slooff, & Giel, 1998). Adverse EPS are typical of these drugs, hence the name. Neuroleptic side effects range from merely inconvenient, for some indi-viduals, to producing major, life-long physical disability for others. For this reason, it is often difficult for individu-als to comply with taking their prescribed dose

daily self administration

The pattern of self-administration is quite different when daily access to cocaine is limited; that is, when there is a long time-out period after each infusion, or when access to cocaine is limited to brief sessions during the day. Under these conditions, laboratory animals self-administer the drug in a steady and regular manner, precisely control-ling the amount of cocaine they receive on any given day (Ahmed & Koob, 1998; Bass, Jansen, & Roberts, 2010). For instance, when rats are restricted to three opportunities per hour in which to self-administer cocaine, they do not engage in bingeing and do not infuse all of the cocaine available to them. Rather, their consumption throughout the day fluctuates with their circadian rhythm whereby self-administration occurs mostly during the dark phase of the cycle. However, when cocaine is made more readily available (five times per hour), circadian rhythms are over-whelmed and the rats take every cocaine infusion available for days in a row (Roberts, Brebner, Vincler, & Lynch, 2002). Cocaine self-administration is enhanced by stress, pre-vious experience with cocaine, and by concurrent adminis-tration of caffeine, heroin, or alcohol. If responding for cocaine is extinguished, self-administration can be rein-stated by giving a priming injection of cocaine, a different psychomotor stimulant, or even another class of drug, such as morphine or caffeine. Self-administration is decreased by providing alternative reinforcers, such as sweetened water (Carroll & Bickel, 1998). Interestingly

acute tolerance

The subjective effects of amphetamine tend to be greater when blood levels of the drug are rising compared to when they are falling (Brauer, Ambre, & de Wit, 1996). This is indicative of acute (within-session) tolerance. The same is true for cocaine. In one study, humans were permitted to administer cocaine intravenously, once every 10 minutes for 1 hour. Feelings of positive mood increased after the first infusion but did not increase throughout the remain-der of the session, even though blood levels of cocaine rose steadily after each additional infusion (Fischman & Schuster, 1982). With the pattern of use that occurs during bingeing (e.g., snorting every 20 to 30 minutes for 10 to 12 hours), cocaine quickly loses its ability to cause rushes and gradually becomes incapable of improving mood. This phenomenon, known as a coke-out, is often why runs come to an end. Acute tolerance dissipates rapidly and may be gone within 24 hours (Waldorf et al., 1977). Even though acute tolerance develops to the subjective effects of cocaine and amphetamine, it does not appear to develop to the drugs' cardiovascular effects. If a person increases the fre-quency or dose of a psychomotor stimulant during binge-ing in an attempt to attain subjective effects, he or she may be in danger of reaching drug levels that could cause heart attack or cerebral hemorrhage (Brauer et al., 1996). Evidence of quickly developing tolerance in humans is supported by the results of animal research assessing toler-ance to the discriminative effects of amphetamine. Rats trained to discriminate amphetamine from saline were given a single injection of either 1.5 or 3.0 mg/kg of the drug. Twenty-four hours later, a dose-response curve for the dis-criminative properties of amphetamine was determined. Compared to rats given saline, the dose-response curve was shifted to the right in a dose-dependent manner for rats given the amphetamine on the day prior. The peaks of the dose-response curves, however, were the same between groups, indicating that pre-exposure to amphetamine decreased the drug's potency, but not its effectiveness, as a discriminative stimulus (Barrett, Caul, & Smith, 2004

routes of admin

The synthetic cathinones are most often sold as a powder or fine crystals that can be snorted, smoked, dissolved and consumed in a beverage, wrapped in a cigarette paper and swallowed (a practice known as "bombing"), inserted into the rectum (known as "booty bombing" or "keystering"), or injected intravenously, intramuscularly, or subcutane-ously (German et al., 2014; Zawilska & Wojcieszak, 2013). A British survey of mephedrone users found that the drug is most commonly administered intranasally (Winstock et al., 2011a), despite the extensive nasal burning, clogging of nasal passages, and nasal dripping that results from snorting the powdered synthetic cathinones (Van Hout, 2014a). Mephedrone users who inject the drug intrave-nously report that it causes an intense burning sensation and that repeated attempts at injection can result in blocked veins, skin erosion, localized infections, abscesses, gangrenous tissue, and blood clots. As such, a site of injec-tion can only be used a few times (Van Hout & Bingham, 2012). One young user who injected bath salts developed infection and tissue degeneration that required amputa-tion of her arm, a mastectomy, and scraping of dead tissue from her chest wall (Dorairaj, Healy, McMenamin, & Eadie, 2012). Synthetic cathinones are also available as tab-lets or capsules that can be taken orally (German et al., 2014; Zawilska & Wojcieszak, 2013). These are often sold on the street as ecstasy (Brunt et al., 2011). The oral use of mephedrone does indeed produce subjective effects simi-lar to MDMA, whereas intranasal administration produces more cocaine-like subjective effects and a perceived highe Mephedrone exerts psychostimulant effects at doses of 20-50 mg, though the amount of drug administered by users varies much more widely, from 5-125 mg when taken intranasally (5-75 mg is "typical"), and from 15-250 mg when taken orally (150-250 is "typical"; Kelly, 2011; Valente, Guedes de Pinho, de Lourdes Bastos, Carvalho, & Carvalho, 2014). Snorting mephedrone produces effects that onset rapidly, usually within 10-20 minutes, and that are felt for about 1-2 hours (Kelly, 2011; Valente et al., 2014). When consumed orally, mephedrone's effects take longer to onset (from ~30-120 minutes) but can last for 2-5 hours thereafter (Kelly, 2011; Musselman & Hampton, 2014; Valente et al., 2014; Zawilska & Wojcieszak, 2013). When injected intravenously, mephedrone has a much faster onset of stimulation and peak effects are reached within 10-15 minutes. However, the drug experience is much shorter, lasting less than 30 minutes (Valente et al., 2014).

distribution

The time course of nicotine distribution throughout the body depends largely on the route of administration. When high concentrations enter circulation rapidly, as happens after inhalation, nicotine reaches the brain very quickly. PET studies using [11C]nicotine show that, after a single puff, radiolabeled nicotine enters the brain within 5 seconds, reaches 50% of peak values within 15 seconds, achieves its maximum concentration within 1 minute, and remains in the brain for more than 15 minutes (Berridge et al., 2010). After nicotine leaves the brain, it becomes concentrated in the liver, kidneys, salivary glands, and stomach (Schmiterlow & Hanson, 1965). Once absorbed, nicotine crosses most barriers in the body, including the placenta, and is present in sweat, saliva, and in the milk of nursing wome

tobacco

The tobacco plant provides the only known natural source of the alkaloid nicotine, its active ingredient. Tobacco belongs to the nightshade family of plants (Solanaceae), within which the genus Nicotiana contains two subgenera that are cultivated for their nicotine content: rustica and tabacum. Both subgenera contain many species and variet-ies that differ widely in physical characteristics

tryciclics on body

The tricyclics also affect autonomic nervous system functioning through their anticholinergic effects. Specifically, TCAs inhibit the parasympathetic division of the autonomic nervous system, which uses ACh as a trans-mitter. These effects are characterized by symptoms such as dry mouth, constipation, blurred vision, ringing in the ears, and urine retention. Excessive sweating is also com-mon. Tremors are seen in about 10% of patients taking tri-cyclics. Side effects are usually worse during the first 2 weeks of treatment or when the dose is increased sud-denly. Older patients are more likely to also experience confusion and delirium; incidence can be as high as 50% in patients over 70 (Baldessarini, 1985). Extrapyramidal or Parkinsonian symptoms, similar to the side effects of antipsychotics (see Chapter 12), are unusual with tricyclics, though they have been reported (Gill, DeVane, & Risch, 1997). Dizziness, irregular heart-beat, and postural hypotension may develop because of the influence of TCAs on adrenergic receptor functioning. Patients taking the tricyclics often report increased appe-tite and preference for sweets, accompanied by weight gain. This may be due to the influence of TCAs on hista-mine activity. One study reported an increase of 1.3 to 2.9 pounds per month. In fact, excessive weight gain is a major reason why patients stop taking these drugs. An additional, dangerous side effect is reduction in seizure threshold, which can cause convulsions, especially in those with pre-existing seizure disorders

elimination

The typicals and atypicals undergo extensive metabolism prior to excretion in urine and feces (Sheehan, Sliwa, Amatniek, Grinspan, & Canuso, 2010). There is consider-able individual variability in the metabolism of antipsy-chotics and in the optimal blood concentration. Determining the optimal dose for any individual is largely a matter of trial and error. Because of their strong protein binding and tendency to accumulate in body fat, typical antipsychotics have very long half-lives of 11 to 58 hours, and metabolites can be found in the urine months after treatment. This is not the case for the atypicals. Cytochrome P450 enzymes play a major role in the metabolism of antipsychotics. This could be problematic for individuals taking a variety of additional medications, such as antidepressants, mood sta-bilizers, or anxiolytics, as many of these drugs also rely on cytochrome P450 enzymes for their metabolism. Competition for P450 enzymes can affect the bioavailability of the drugs or potentially lead to the build-up of drug mol-ecules and toxic effects (Guengerich, 2008). Genetic poly-morphisms of the cytochrome P450 system also contribute to determining treatment response and adverse effects of antipsychotic drugs (Brandl, Kennedy, & Müller, 2014).

benefits agaisnt neurodegenerative disease

There is evidence that coffee consumption may have protective effects against neurodegenerative diseases, including Parkinson's and Alzheimer's diseases (Chen & Chern, 2011; Rivera-Oliver & Díaz-Ríos, 2014). In one large prospective study, consumption of caffeine from a variety of sources appeared to reduce the incidence of Parkinson's disease in men (Ascherio et al., 2001). No such benefit resulted from drinking decaffeinated coffee, suggesting that caffeine was indeed the active ingredient. Parkinson's disease is marked by a progressive loss of dopamine-producing neurons in the substantia nigra which project their axons to, and release dopamine in, the dorsal striatum. Caffeine consumption diminishes this loss (Palacios et al., 2012). In those who suffer from Parkinson's, caffeine blocks adenosine A2A receptors and enhances dopamine activity, thereby alleviating some of the motor symptoms of the disease, including tremor and freezing of gait (Blandini, Nappi, Tassorelli, & Martignoni, 2000; Cappelletti et al., 2015; Trevitt, Kawa, Jalali, & Larsen, 2009). A2A-receptor antagonists have emerged as the leading non-dopaminergic pharmacological agents in the treatment of Parkinson's disease, with a number of clinical trials suggesting an even greater effectiveness compared to L-DOPA (Chen, Eltzschig, & Fredholm, 2013). Consumption of 3 to 5 cups of coffee per day in middle-aged adults correlates with a 65% decreased risk of developing a neurocognitive disorder in later adult-hood (Cappelletti et al., 2015). Caffeine appears to protect against the accumulation of protein clumps, called beta-amyloid plaques, around blood vessels in the brain which is a tell-tale marker of Alzheimer's disease. Animal stud-ies indicate that caffeine administration can actually decrease levels of beta-amyloid plaque and reverse the associated cognitive impairment (Dall'Igna et al., 2007; Espinosa et al., 2013; Federico & Spalluto, 2012).

Effectivness

There is little doubt that antidepressant medications are an effective means of combating depression (Linde et al., 2015). Efficacy rates are roughly similar for all classes—MAOIs, TCAs, SSRIs, and SNRIs—although there are significant individual differences as to which class works best, as well as differences in the way that different types of depression respond to the various types of antidepressants. It is likely that the neurochemical and neurophysiological manifesta-tions of depression differ between individuals so that cer-tain classes of antidepressants work better for some than others. The severity of the depression also influences whether antidepressants are effective in relieving symp-toms (Fournier et al., 2010). The presence of a comorbid dis-order, such as anxiety, is an additional important consideration since some newer antidepressants, like the SSRIs and SNRIs, are also used to treat other psychiatric conditions. There are also considerable differences in the severity of side effects between individuals. This is one reason why there are so many antidepressant drugs available. It is often necessary to change a drug treatment several times to find a drug and a dose that works for a specific person (Rush & Ryan, 2002). Advances in the development of anti-depressant medications usually involve finding drugs with fewer side effects, rather than drugs with new or novel mechanisms of action, greater therapeutic effective-ness, or faster onset (Ordway et al., 2002). Comparative tri-als have shown that the SSRIs are far superior to any other antidepressants in terms of patients' remaining compliant to chronic drug regimens. This success is due to We are not yet at the point where we can say that anti-depressants are a cure-all for depression. Approximately 60 to 70% of individuals with major depression get some relief from antidepressant medications, but only 28 to 50% show full remission of symptoms (Trivedi et al., 2006). Moreover, much of the improvement associated with anti-depressant treatment is also evident in patients treated with placebos. Placebo response rates are as high as 30%, which, compared to a 50% response rate in drug-treated individuals, means the mere expectation of improvement can account for up to 75% of the improvement that actu-ally occurs (Mora, Nestoriuc, & Rief, 2011). Placebo response rates vary according to the assessment method; physicians and clinicians are more likely to note improve-ment in depressive symptoms compared to when individ-uals self-report. Placebo effect rates have also grown across the past few decades; with millions of individuals having been prescribed antidepressants, there is a growing belief that they work. So the expectancy that there will be improvement (and, therefore, the placebo effect) is increas-ing. When the effectiveness of tricyclics is compared to that of an active placebo (in this case, the anticholinergic drug atropine, which produces side effects similar to those of the TCAs), the active placebo is as effective in reducing depression as the TCA—patients are convinced they are receiving the antidepressant medication, as opposed to the placebo, because they experience physiological symptoms. The expectation that they will feel better reduces their depression (Moncrieff, Wessely, & Hardy, 2004). Our belief in the effectiveness of antidepressants over placebos is also influenced by the way in which research is ublished. Studies that fail to find benefits of a drug over a placebo are rarely accepted for publication. Therefore, what we read in the literature are mostly the good-news stories. A combined analysis of both published and unpub-lished data sets obtained from clinical trial research revealed that the placebo effect can account for up to 82% of the effectiveness of antidepressant medications (Kirsch et al., 2008). Furthermore, in patients experiencing mild or moderate depression, placebos and antidepressants are equally effective in alleviating symptoms. Only in the most extremely depressed patients is there a relatively small dif-ference in treatment outcome between the placebo and drug groups. This is due to a decreased effectiveness of the placebo rather than an increased effectiveness of the anti-depressant (Kirsch et al., 2008). There has been considerable interest in the use of anti-depressants in treating depression in children and adoles-cents. A number of studies have shown that the TCAs are generally not effective in this population, but the SSRIs do work. As with adults, children show a very high rate of placebo effect (between one-third and one-half of the patients in the placebo group improve). Fluoxetine is the only SSRI that has been shown to be effective at a higher rate than placebos, but there are problems. In these stud-ies, there is a greater incidence of adverse symptoms in the SSRI group than in the placebo group (1-6% vs. 0-4%). These include agitation, hyperactivity, and symptoms of mania. In 2004, the U.S. Food and Drug Administration issued a black box warning against prescribing antidepres-sants to children and adolescents. You will learn more about this in Section 13.8.2

effects on sleep

There is little doubt that the methylxanthines can produce insomnia and impact regular sleep patterns. In one study, 300 mg of caffeine increased the latency of sleep onset from 18 to 66 minutes and reduced total sleep time from 475 to 350 minutes compared to control participants (Brezinová, Oswald, & Loudon, 1975). Caffeine administration also reduces the percentage of time spent in slow-wave (stage 3-4) sleep and alters the ratio of non-REM/REM (rapid eye movement) sleep in a dose-dependent manner (Roehrs & Roth, 2008). As slow-wave and REM sleep are critically important in memory consolidation, the reper-cussions of an altered sleep pattern may extend beyond simple daytime fatigue. In general, people who consume caffeine before going to bed report sleeping less soundly and feeling less rested in the morning. Contributing to poor quality of rest, caf-feine lowers the acoustic arousal threshold while sleeping so that people wake up more easily in response to a sound in the night. This effect varies among individuals; habitual coffee drinkers are less affected than coffee abstainers, which is probably due to tolerance rather than a preexist-ing difference between coffee drinkers and abstainers. Evidence of tolerance to caffeine's sleep-disturbing effects comes from a study by Bonnet and Arand (1992) in which participants' sleep efficiency was measured during 7 days of exposure to thrice-daily 400-mg doses of caffeine. The caffeine produced insomnia and a decrease in sleep effi-ciency but, by the end of the experiment, total sleep time and awakenings had returned to baseline levels. Although the mechanisms that cause sleep are still not fully understood, numerous brain regions are known to be involved. One, which is located in the subcortical preopti

homorenic/heterorenic

These receptors can be homomeric (composed of receptor subunits that are all the same), but most are heteromeric (composed of different types of subunits). A homomeric receptor would be described as (a7)5 if it is made up of five a7 subunits. A heteromeric receptor would be described as (a4)2(b2)3 if it is made of two a4s and three b2s. The different combinations of nAChR subunits determine many of their properties including sensitivity to nicotine, which ions are permitted through the ion channel, and the rate at which they can pass through. nAChRs containing a2, a4, and b2 subunits are believed to be the ones that mediate nicotine's reinforcing effects.

second gen antidepressants

This diverse group of chemicals is often called second-generation antidepressants and includes the selective serotonin reuptake inhibitors (SSRIs). The first and probably most well-known SSRI to be marketed is fluoxetine (Prozac). Its structure is only slightly different from that of imipramine and the other TCAs. Yet, the SSRIs appeared safer with fewer of the bothersome side effects of the first-generation antidepressants and could be Nardil Parnate Marplan Eldepryl Aurorix Tofranil Elavil Norpramin Sinequan Pamelor Anafranil Prozac Celexa Lexapro Paxil Zoloft used to treat a variety of psychiatric conditions that fre-quently co-occur with depression, such as anxiety. Prozac was introduced in the United States in 1987 and soon received considerable attention in the popular media because it was being used, not as a treatment for depression, but as a means of altering one's personality (more on this later). The media also carried reports that the drug could precipitate violent acts and suicide. If such adverse effects occur, however, they are extremely rare. Fluoxetine and other SSRIs are often a first-line treatment for depression. Although many second-generation antide-pressants have been used in Europe, strict drug develop-ment laws have delayed or prevented their use in North America

discrimination

Though early studies reported difficulty establishing antipsychotics as training drugs in discrimination studies, a growing body of research suggests that animals can dis-criminate interoceptive states produced by antipsychotics versus saline, but not easily. For an antipsychotic to act as a discriminative stimulus, large doses are required and many more training trials are needed, compared with most other behaviorally active drugs (Overton, 1987; Overton & Batta, 1977). Once an animal has been trained to discrimi-nate an antipsychotic, the response may generalize to some but not all other drugs of the same class. Generalization of responding also crosses the line between typicals and atypicals—discriminability appears to be more compound-specific as opposed to class-specific. For example, rats rained to discriminate clozapine (an atypical) from saline will fully generalize responding not only to olanzapine (another atypical) but also to chlorpromazine (a typical; Porter & Prus, 2009). At the same time, rats trained to dis-criminate chlorpromazine from saline will generalize responding to haloperidol (another typical) and to olan-zapine, but not to clozapine. Some research findings do support a division along typical-atypical lines. For instance, haloperidol will substitute for chlorpromazine, but not for any of the atypical antipsychotics (Porter & Prus, 2009). Likewise, the discriminative stimulus proper-ties of quetiapine and ziprasidone (atypicals) generalize to other atypicals, but fail to substitute for the typicals (Porter & Prus, 2009). There is no generalization between the anti-psychotics and the antidepressants or any other class of drugs (Stewart, 1962).

regions of brain involved

Three regions of the brain appear to be involved in the effects of the classic hallucinogens: the locus coeruleus (LC), the cortex, and the raphe nuclei. The LC is the source of nearly all noradrenergic projections in the central nervous system. It is involved in fear and emotional responses and appears to function as a novelty detector, as it is extremely responsive to sensory stimuli that are novel or highly arousing (Halberstadt, 2015). The LC receives input from many sensory sources throughout the body, including the raphe nuclei. It sends axons to almost every area of the brain, including the cortex where it promotes the release of NE. Stimulation of 5-HT2A receptors by both indolamine and phenethylamine hallucinogens can sup-press output of the LC, although it occurs through differ-ent mechanisms. In addition, these drugs enhance the response of the LC to novelty. This might explain the com-mon effects of hallucinogenic drugs on perception. After taking mescaline, for example, people often report that it is like seeing things for the first time. In the cortex, hallucinogenic drugs alter the response of large glutamatergic neurons to synaptic input by increasing the duration of excitatory action potentials. This effect is mediated through serotonin synapses and is most prominent in the medial prefrontal cortex, where 5-HT2A receptors are densely concentrated. This area of the cortex is instrumental in information processing and perception and an important site of action for the hallucinogens (Halberstadt, 2015). The raphe nuclei are clustered in the brainstem and release serotonin throughout the rest of the brain. LSD acts as a 5-HT1A receptor agonist in the raphe system, where it inhibits neuronal firing and serotonin release (Passie, Halpern, Stichtenoth, Emrich, & Hintzen, 2008). Because the LC receives input from the raphe nuclei via serotonin neurons, suppression of the raphe system by hallucino-genic drugs may be the precursor to LC suppression and resulting effects.

routes of admin

Tobacco products are typically consumed in three ways. First, the tobacco plant material is burned and the smoke is drawn into the mouth, as with cigars and pipe tobacco, or inhaled into the lungs, as with cigarettes. Inhalation is also the means by which nicotine is delivered using ENDS devices, the difference being that nicotine-containing vapor, rather than smoke, is drawn into the lungs. A second method also involves inhalation, but with-out burning tobacco or vaporizing nicotine solution. Instead, the tobacco plant is dried and ground into fine par-ticles and those are sniffed into the nose, as with dry snuff.The third means of consuming tobacco is by putting it in the mouth, but not swallowing it, as is done with chewing tobacco, varieties of moist snuff, and, recently, dissolv-ables. Other means of nicotine administration exist, but are more commonly used in research, in the case of intrave-nous administration, or in therapeutics, such as the trans-dermal patc

cathinone pharmakinetics

Traditionally, cathinone is taken orally by chewing fresh young leaves and shoots of the khat shrub. The cathinone content of khat leaves is wide-ranging, from about 80 to 340 mg per 100 g of plant material. During a single chewing session, ~100-500 grams of leaves are slowly chewed for several hours (Valente, Guedes de Pinho, de Lourdes Bastos, Carvalho, & Carvalho, 2014). This route of administration is highly efficient; nearly 90% of plant constituents are released by chewing and absorp-tion of cathinone occurs mainly within buccal mucosa, but also through the stomach and small intestine as (unlike with chewing tobacco) the juices are swallowed. The euphoric effects of khat begin within about 30-60 minutes of chewing, as blood levels of cathinone begin to rise, and last for about 3 hours. Peak blood plasma concentrations are attained within about 1.5-3.5 hours of chewing (Geresu, 2015; Valente et al., 2014). Methcathinone is pro-duced as a white or off-white powder that is most com-monly snorted but can also be mixed with water and injected intravenously or consumed orally in a beverage. Compared to the amphetamines, cathinones are less lipo-philic and therefore less able to penetrate the blood-brain barrier, requiring higher doses to produce reinforcing effects (Kelly, 2011; Lewin, Seltzman, Carroll, Mascarella, & Reddy, 2014)

conditioned behavior

Tricyclic antidepressants are even more effective than methamphetamine at increasing operant response rates. In addition, they are capable of further increasing already high rates of responding, whereas amphetamine tends to decrease those rates (Dews, 1962). The tricyclic antidepres-sants tend to decrease avoidance behavior at doses that have no effect on escape behavior (McMillan & Leander, 1976), thus making them similar to the antianxiety drugs and the antipsychotics. The tricyclics do not increase decrease it, making them similar to amphetamine and the psychomotor stimulants in this regard. An antidepres-sant's efficacy in facilitating intracranial self-stimulation (ICSS) of the medial forebrain bundle increases according to the drug's binding selectivity for dopamine versus sero-tonin reuptake transporter proteins. Bupropion, with its high affinity for dopamine transporter proteins, increases the rate of ICSS, whereas citalopram, clomipramine, and fluoxetine, all of which primarily target serotonin trans-porter proteins, decrease the rate of responding for ICSS (Negus & Miller, 2014; Rosenberg, Carroll, & Negus, 2013). The investigational new drug amitifadine and other exper-imental triple reuptake inhibitors also increase the rate of ICSS responding (Miller et al., 2015; Rosenberg et al., 2013). Interestingly, the SSRIs sertraline, fluoxetine, and parox-etine are capable of producing a conditioned place prefer-ence in rats, despite their inability to increase ICSS responding. In contrast, administration of the TCAs imip-ramine and amitriptyline, or the atypical venlafaxine, produces either no contextual conditioning effect or results in the development of a conditioned place aversion (Tzschentke, 2007).

SNDRIS

Triple monoamine reuptake inhibitors, also known as sero-tonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs), are also being developed and tested in animal models of depression and alcohol binge-drinking (Dutta et al., 2014; Golembiowska, Kowalska, & Bymaster, 2012; Miller, Leitl, Banks, Blough, & Negus, 2015; Warnock et al., 2012). One SNDRI in particular, called amitifadine, has been adminis-tered to humans in clinical trials and was found to produce significant antidepressant effects (Tran et al., 2012). Amitifadine is most potent at inhibiting 5-HT reuptake, about half as potent an inhibitor of NE reuptake, and roughly one-eighth as potent at inhibiting DA reuptake. This 1:2:8 ratio produces pharmacological effects roughly equivalent to those elicited by the combined administra-tion of citalopram and bupropion, which has been found to result in favorable outcomes for depressed patients (Tran et al., 2012)

unconditioned behavior

Unlike antianxiety drugs, such as the benzodiazepines, the most remarkable effect of the antipsychotic drugs is that they suppress spontaneous motor activity in an open field, and higher doses render most laboratory animals immo-bile. In fact, these animals take on a sort of plastic immobil-ity, or what the DSM-5 calls waxy flexibility in humans. Their limbs will remain in any position in which they are placed, as though the animals were made out of modeling clay. This immobility gave rise to the name neuroleptic. At doses that do not seem to produce these neuroleptic effects, antipsychotic drugs diminish the frequency and intensity of attack behaviors in most species. This decrease in aggression coincides with an overall decrease in activity, so it is possible that it results from an overall debilitation of motor abilities (Miczek & Barry, 1976).

differences in absorption

Using an uncontrolled, ad libitum procedure, Digard and colleagues (2013) instructed participants to smoke a cigarette (containing 14.6 mg of nicotine), according to their usual method, for 5 minutes or until the cigarette butt reached 30 mm in length. With this short, natural smoking technique, peak nicotine levels of 12.8 ng of nicotine per ml of venous blood plasma were reached within 7 minutes following the start of smoking. Mello, Peltier, and Duncanson (2013) measured nicotine absorption into the blood during and following a controlled smoking proce-dure, in which participants took one 5-second puff of a cigarette (containing 15.5 mg of nicotine) every 30 seconds for a total of 24 puffs over a 12-minutes period (a new ciga-rette was presented after every 4 puffs). They found that venous blood plasma nicotine levels increased signifi-cantly within the first 2 minutes of smoking (after only 4 puffs) to a level of 6 ng of nicotine per ml of blood plasma. Peak nicotine levels (~24 ng/ml) were reached within 14 minutes after the start of smoking andlevels gradually decreased to 9 ng/ml by the end of the 120-minute sampling period.

shift from outward to inward facing

When a molecule of monoamine binds to its recogni-tion site on the transporter, a conformational change is trig-gered that causes the MAT to shift from an outward-facing to an inward-facing conformation. This results in the trans-location of the monoamine molecule (and co-transported ions) across the cell membrane, to the inside of the neuron, where they dissociate from their binding site and are deposited into the cytosol of the neuron's axon terminal. In

nicotine bolus theory

When a smoker takes a puff from a cigarette, it is usually done with one rapid inhalation rather than gradually, as with a normal breath. This sudden filling of the lungs with smoke tends to saturate the lungs' capillaries with nicotine at the moment of inhalation. This concentration of nicotine in the blood, known as the nicotine bolus, stays together as the blood returns to the heart and is pumped to the brain. The nicotine bolus theory, proposed by M. A. H. Russell of the Maudsley Hospital in London, suggests that the sudden delivery of highly concentrated nicotine to the brain intensifies the pleasure and enhances the reinforcing effects of smoking. This is what makes nicotine from ciga-rettes so much more addicting compared to drugs admin-istered via other, slower routes to the brain (Russell, 1976). is consistent with the general finding that the reinforc-ing and pleasurable properties of many drugs can be greatly enhanced by delivering them to the brain rapidly and in high concentrations (de Wit et al., 1992). When drug absorption and delivery to the brain is slowed, the pleasur-able effects are greatly blunted (Parasrampuria et al., 2007). It is theoretically possible that sharp increases in brain nicotine concentration are able to generate an enhanced activation of nAChRs, which contributes to nicotine's sub-jective effects. Recall that nAChRs enter a desensitized configuration when continuously exposed to high concen-trations of an agonist and revert to their basal configura-tion only when the concentration drops. If nicotine were delivered to the receptor as a series of spikes created by each puff, then the rising edge of the spike would be able to activate nAChRs and produce a large effect on the cell before the receptors enter their desensitized configuration (see Figure 8-2). Then, on the declining edge of the spike, the drop in nicotine concentration allows nAChRs to return to their basal configuration in time to respond to the next spike (Rose et al., 2010). The presence of a nicotine bolus in the blood is largely theoretical. Jed Rose of Duke University Medical Center and his colleagues attempted to examine the absorption kinetics of nicotine during cigarette smoking using PET imaging with a 3-second temporal resolution and radiolabeled [11C] nicotine-loaded cigarettes. Both nicotine-dependent ("addicted") smokers (DS) and nondependent ("non-addicted") smokers (NDS) were scanned while they took 10 puffs of a cigarette with 48 seconds between each puff (Rose et al., 2010). The results are shown in Figure 8-4. The most interesting finding was that nondependent smokers showed faster absorption of nicotine than the dependent smokers (see Panel A). In both groups, the effect of each puff can be seen as an increase in the slope of the absorption curve, which was much more noticeable in the nondepen-dent smokers. Panel B illustrates the range of brain-nicotine accumulation in study participants by illustrating data for four individuals—the two DS-group participants and the two NDS-group participants with the most extreme (small-est and largest) oscillations, or changes in the slope of the line, in nicotine absorption. Note that nicotine concentra-tions in the blood continue to accumulate after each puff and do not fall back. There is no spike in brain nicotine, as would be expected by the nicotine bolus theory, but merely an increase in the concentration of nicotine that never falls before the next puff. This finding was unexpected and, while it doesn't mean that the nicotine bolus theory is not important for understanding tobacco addiction, it does show that a decrease in desensitization of nAChRs cannot be the mechanism responsible for puffing behavior. It remains clear that, after each puff, nicotine concen-trations rapidly increase, and rapid increases in drug concentration usually produce an intensified positive sub-jective effect. Because a nicotine bolus can be achieved only by smoking or, within increasingly efficient ENDS, by vaping, this theory explains why the craving for the drug is greater in smokers than in those who take tobacco by other means. It cannot, however, account for the great his-torical popularity of tobacco in its other forms

Amphetamines Pharmacokinetics

When amphetamines are used medically for the treatment of ADHD or sleep disorders, they are always given orally. Because the amphetamines are weak bases with pKa val-ues close to 10, they tend to be ionized in the digestive system, which slows their rate of absorption. When taken on an empty stomach, a single dose of Adderall IR reaches peak blood plasma concentrations in about 3 hours. A dose of d-amphetamine attains peak pharmacological effect in about 1.5-2.0 hours. Adderall XR uses a bead technology to deliver two bolus doses of amphetamine; the first is released immediately upon administration and the second approximately 4 hours later. This extends absorption time so that peak concentrations are reached in about 6-8 hours after administration. Oral administration and a prolonged period of absorption allow for easier maintenance of steady blood levels of the drug. When amphetamines are taken for the rush they produce, they are usually administered by injection or are smoked or snorted, which cause sudden high blood levels of the drug. When administered intravenously, d-amphetamine reaches peak blood plasma concentrations in about 20 minutes (Heal et al., 2013). Within the amphetamines family, methamphetamine has the greatest abuse potential. Its higher lipophilicity, better penetration of the blood-brain barrier, and greater stability against enzymatic degradation by monoamine oxidase (MAO) render it more potent and faster-acting compared to amphetamine (Vearrier, Greenberg, Miller, Okaneku, & Haggerty, 2012). Methamphetamine is a white, bitter-tasting crystalline powder that can be taken orally but is more often snorted, smoked as crystal meth, or dissolved in water or alcohol and injected. The use of anal or vaginal suppositories has also been reported (Vearrier et al., 2012). Following oral administration, meth-amphetamine bioavailability is ~67%. Its psychoactive effects can be felt within about 20-60 minutes following ingestion and reach their peak at about 3 hours. Peak blood plasma levels are reached in roughly 3-5 hours post-ingestion (Cruickshank & Dyer, 2009). When smoked or snorted, methamphetamine is well-absorbed through the lungs or nasal mucosa. These routes result in drug bio-availability of ~80-100% (Cruickshank & Dyer, 2009; Harris et al., 2003). Smoking methamphetamine produces peak subjective effects within about 15-20 minutes as the drug moves rapidly from the alveoli of the lungs into the bloodstream. However, peak blood plasma concentrations are reached much later, within about 2-3 hours after smok-ing, which may be due to the slower absorption of the drug from the upper respiratory tract (Cruickshank & Dyer, 2009). When snorted, cardiovascular and peak sub-jective effects of methamphetamine are felt within 5-15 minutes, though peak blood plasma concentrations are reached nearly 4 hours later (Cruickshank & Dyer, 2009). The dissociation between peak plasma and subjective effects is thought to result from acute tolerance, brought about by molecular processes within the axon terminals of neurons (Cruickshank & Dyer, 2009). When methamphet-amine is injected intravenously, cardiovascular effects aredetectable within 2 minutes, and subjective effects are felt within 10 minutes of infusion (Cruickshank & Dyer, 2009). The effects of methamphetamine can last for up to 8 hours following a single, moderate (30 mg) dose (Cruickshank & Dyer, 2009).

neurotoxic effects

When recreationally abused, the amphetamines (especially methamphetamine) appear to exert neurotoxic effects on cer-tain areas of the brain (Carvalho et al., 2012), particularly those regions that contain dopamine-and serotonin-producing cells. Damage is more readily inflicted by large drug doses and binge-like intake, though a slower trajectory of escalating drug intake also results in deleterious effects, albeit less severe (Volkow et al., 2015). Nonhuman primate research demonstrates that dopamine-system dysfunction can occur after only four methamphetamine administrations given at doses comparable to those used recreationally by humans. PET imaging with a radiolabeled dopamine trans-porter (DAT) ligand revealed that total doses of 2, 4, or 8 mg/g of methamphetamine, injected into baboons in a binge-like manner over 8 hours on a single day, resulted in significant reductions in DAT density in the striatum, as mea-sured 2 to 3 weeks later (Villemagne et al., 1998). The loss of DATs that occurs as a result of methamphetamine use could indicate a downregulation of transporter proteins (Volkow et al., 2015) or may be a reflection of dopamine-cell degenera-tion or death (Villemagne et al., 1998; Wang et al., 2012). In addition to affecting dopamine cells in the striatum, methamphetamine exposure can produce long-term dam-age to dopamine and serotonin cells within the hippocam-pus and prefrontal cortex (Halpin, Collins, & Yamamoto, 2014). Neurochemical markers of toxicity include decreases in the expression of tyrosine hydroxylase and tryptophan hydroxylase (enzymes involved in the biosynthesis of DA and 5-HT, respectively) as well as lower levels of DA and 5-HT transmitter molecules and reduced expression of VMATs, DATs, and SERTs (Halpin et al., 2014). In addition to these neurochemical changes, neuronal death and mor-phological abnormalities, including swollen and distorted nerve terminals, are noted indicators of methamphetamine-induced damage (Halpin et al., 2014). Methamphetamine-induced neurotoxicity is associated with the cognitive, subjective, and psychomotor symptoms of drug abuse. The loss of dopamine cells in the striatum correlates with the presence and severity of psychotic symp-toms, memory deficits, and impaired psychomotor coordi-nation. The severity of psychotic symptoms also correlates with diminished DAT density in the frontal cortex, and reduced SERT density globally throughout the brain. Reduced SERT densities in the anterior cingulate, prefrontal cortex, and temporal cortex correlate with increased levels of aggression (Cruickshank & Dyer, 2009). Brain abnormalities resulting from methamphetamine abuse persist well beyond the period of drug administration. In humans an

effects on body

When taken alone, the MAOIs do not produce serious adverse or life-threatening effects. Some of their most com-mon side effects include tremors, weight gain, blurry vision, dry mouth, and a lowering of blood pressure that may result in postural hypotension—dizziness or fainting when moving to a standing position after being seated or lying down. When taken alongside certain other drugs or even particular foods, however, MAOIs can produce dan-gerous pharmacological interactions. Through their enzyme-inhibiting actions, MAOIs can potentiate the effects of monoamine-stimulating drugs, such as cocaine, MDMA (ecstasy), and ephedrine-or pseudoephedrine-containing decongestants. This can be life-threatening in the case of psychostimulants, for instance, which produce sympathetic nervous system effects (through the actions of NE) that can lead to hypertensive crisis and result in irre-versible organ damage (Lindsey, Stewart, & Childress, 2012). MAOIs also potentiate the hypotensive and CNS-depressant effects of heroin (Lindsey et al., 2012). A particular danger associated with the use of MAOIs, as well as other classes of antidepressants, is the develop-

monoamine psychosis

When taken in high doses or used frequently for extended periods, cocaine, khat, methamphetamine, and amphet-amine can elicit psychotic behavior in otherwise healthy people. This syndrome is called monoamine psychosis or is labeled specifically according to the drug responsible, such as methamphetamine psychosis. Collectively, the symptoms of monoamine psychosis form a syndrome that is virtually indistinguishable from schizophrenia, the key features of which are discussed in Chapter 12. These include positive symptoms, such as auditory and visual hallucinations; delusions of reference, persecution, and grandeur; odd speech; anxiety and agitation; and extreme paranoia that sometimes evokes hostility and violence, triggered by a belief that danger is imminent. Monoamine psychosis can also include negative symptoms, such as flattened affect (a severe reduction in emotional expression) and depression (Srisurapanont et al., 2011).

absorption

When tobacco is burned, nicotine vaporizes and can be found in the smoke and particles of ash that contact and dissolve in the mucous membranes on the inside surface of the lungs. About 90% of the nicotine inhaled from burning tobacco is absorbed into the blood in this way (Armitage et al., 1975). Nicotine absorbed from the lungs is carried directly to the heart; from there, much of the nicotine-containing blood goes directly to the brain. The nicotine content of a tobacco cigarette varies sub-stantially, from ...0.06 to 0.16 mg in "denicotinized" ciga-rettes to about 10-15 mg in conventional cigarettes (Mello, Peltier, & Duncanson, 2013; Taghavi et al., 2012). A single (100 ml) puff of a Marlboro cigarette yields ~152-193 mg of nicotine (1000 mg = 1 mg; Trehy et al., 2011). The total dose of nicotine delivered by smoking a conventional tobacco ciga-rette is in the range of 1.5-2.6 mg (Djordjevic, Stellman, & Zang, 2000), achieved in about 10 to 15 puffs. Nicotine deliv-ery to the user depends, though, on the way in which the cigarette is smoked as much as on its actual nicotine content (Benowitz & Henningfield, 1994). A major determinant of nicotine absorption is the volume of smoke inhaled per puff. Increasing the duration of the inhalation does not signifi-cantly increase nicotine absorption (Zacny, Stitzer, Brown, Yingling, & Griffiths, 1987).

absorption through mouth/digestive system

When tobacco is chewed, held against the cheek or gums as is the habit of moist-snuff users, or dissolved in the mouth from tobacco orbs, films, sticks, or gum, nicotine is absorbed through the buccal membranes in the cheeks and under the tongue. With traditional chewing tobacco, excess juices are spit out, so chewing is not considered a form of oral administration since entry into the digestive tract is minimal.

admin

When used traditionally by Mazatecs, Salvia divinorum is taken orally, either by chewing fresh leaves or by crushing them, blending their juices with water, and ingesting the liquid mixture (Diaz, 2013). Salvinorin A is absorbed through buccal membranes, but any drug that is swal-lowed is fully degraded within the gastrointestinal tract and fails to reach the bloodstream (Casselman et al., 2014). When salvinorin A is administered sublingually in liquid form, it produces no effect on the user, suggesting a lack of bioavailability via this route (Mendelson et al., 2011). When used recreationally, Salvia divinorum leaves are sometimes chewed, but it is much more common to smoke the plant material using a pipe or bong, or to vaporize it and inhale the aerosol mixture into the lungs (Giroud et al., 2000). When chewed, users typically retain the plant mate-rial in the mouth for 15-20 minutes before spitting or swal-lowing it (Baggott, Erowid, Erowid, Galloway, & Mendelson, 2010). When smoked from a pipe, users hold the smoke in their lungs for more than 20 seconds, as is also typical of cannabis smokers (Baggott et al., 2010). In an average session, users will smoke 0.25-0.75 grams of plant material (Baggott et al., 2010). When salvinorin A is absorbed through buccal mem-branes, its effects are detected within about 5-10 minutes, build gradually and are maintained over the next 60 minutes, and then slowly decline during the following 60-minute period (Ott, 1995; Siebert, 1994). When smoked, a 200-500 mg dose of salvinorin A produces rapid effects th inorin A is rapidly distributed throughout the body. A non-human primate PET imaging study using radiolabeled salvinorin A revealed that the drug very quickly crosses the blood-brain barrier and achieves maxi-mum brain concentrations within about 40 seconds of intravenous administration. The highest concentrations of salvinorin A occur in the cerebellum (which plays a role in integrating sensory perceptions with motor control) and in the visual cortex (which contributes to the hallucinogenic properties of the drug; Hooker et al., 2008). Clearance of salvinorin A from the brain is also astonishingly rapid; the half-life from peak is reached in 8 minutes in non-huma primates, which is consistent with the short duration of peak subjective effects reported by humans. It appears that salvinorin A is cleared from the brain by an active trans-port mechanism, however its high lipophilicity also means that its molecules can diffuse rapidly and passively through the blood-brain barrier (Teksin et al., 2009). Salvinorin A is metabolized by both the liver and the gall-bladder to its principle (inactive) metabolite, salvinorin B. Both phase 1 metabolism, which involves the cytochrome P450 family of enzymes, and phase 2 metabolism, which involves the UGT2B7 conjugation enzyme, are responsible for salvinorin A metabolism (Teksin et al., 2009). The half-life of salvinorin A elimination from the body is 56.6 minutes in rhesus monkeys (Schmidt et al., 2005). Levels of salvinorin B are undetectable in the urine of rhe-sus monkeys, even shortly after ingestion, suggesting that the metabolite is either immediately cleared or stored in organs and body tissue (Schmidt et al., 2005).

effects on animals

Whereas methylone and MDPV have little effect on body temperature at ambient room temperatures, acute admin-istration of mephedrone has been found to produce hypo-thermia. In contrast, binge-like intake or high doses of either methylone or mephedrone produce hyperthermia, making them similar in this regard to MDMA (Gregg & Rawls, 2014). Because of its strong influence on norepi-nephrine activity, MDPV has profound sympathomimetic effects in rats, increasing heart rate and blood pressure to a degree far greater than that of cocaine (Baumann et al., 2013). Mephedrone elicits significant increases in heart rate, blood pressure, and cardiac contractility in both guinea pigs and rats (Meng et al., 2012; Varner et al., 2013), and cardiovascular toxicity is a well-known feature of mephedrone abuse in humans. Synthetic cathinones dose-dependently increase loco-motor activity and other stimulatory behaviors, such as head weaving and circling, in rats and mice (Gregg & Rawls, 2014). Methylone is the least potent of the compounds, but is capable of stimulating motor activity at doses lower than those required of cocaine and methamphetamine (Gatch, Taylor, & Forster, 2013; Marusich, Grant, Blough, & Wiley, 2012). The psychomotor stimulant properties of mephedrone are weaker than those of its parent compound, cathinone, but mephedrone produces roughly equivalent levels of hyperactivity as those produced by cocaine. Mephedrone-induced stimulation of locomotor activity has been attrib-uted to increases in extracellular DA and 5-HT in the ventral striatum (Kehr et al., 2011). Repeated administration of mephedrone results in behavioral sensitization of repetitive, stereotyped movements (Gregg, Tallarida, Reitz, McCurdy, & Rawls, 2013). Hyperactivity is especially pronounced and behaviors (Aarde et al., 2013b). In drug discrimination studies, rats and mice are able to distinguish between the interoceptive state produced by saline and those produced by the synthetic cathinones. In rats trained to discriminate between mephedrone and saline, MDMA fully substitutes while cocaine and metham-phetamine near-fully substitute for mephedrone. These findings suggest that mephedrone produces interoceptive effects near-identical to those of MDMA and strongly resembling those of cocaine and methamphetamine (Varner et al., 2013). Methylone fully substitutes for MDMA and amphetamine in drug discrimination studies in rats (Dal Cason, Young, & Glennon, 1997). In mice trained to dis-criminate MDPV from saline, responding fully generalizes to both methamphetamine and MDMA (Fantegrossi, Gannon, Zimmerman, & Rice, 2013). While the latter result may seem strange, given MDMA's strong effects and MDPV's weak effects on serotonin neurotransmission, methamphetamine and cocaine substitute for one another as do cocaine and MDMA, suggesting that neurotransmit-ter systems other than serotonin are more highly involved in discriminating interoceptive cues (Watterson et al., 2013). Experimental paradigms used with animals to assess the abuse liability of drugs provide strong evidence that the synthetic cathinones have addictive potential. Both mephedrone and MDPV support high rates of responding for drug self-administration in rats, matching or even exceeding levels of operant behavior elicited by metham-phetamine (Aarde et al., 2013a, 2013b; Motbey et al., 2013). As is the case for cocaine, amphetamine, and methamphet-amine, rats will escalate their intake level of mephedrone or MDPV if given extended periods of access (Watters

subjective effects of psychostimulant withdrawal

Whereas most psychomotor stimulant drug-discrimination studies have focused on exploring the drugs' primary effects, one interesting experiment exam-ined the subjective effects of psychostimulant withdrawal (Barrett, Caul, & Smith, 2004). In this experiment, rats were trained using a two-lever Skinner box task to discriminate a 0.25 mg/kg injection of amphetamine from a 0.035 mg/kg injection of haloperidol (haloperidol is an antipsychotic drug that blocks D2 receptors; see Chapter 12). Food rein-forcement was associated with pressing only one of the two levers, depending on which drug the rat had been adminis-tered. Thus, the rat had to learn to use drug-induce produce food reinforcement and to discriminate responding accordingly. Following the drug-discrimination training phase, a test dose of 0.25 mg/kg of amphetamine prompted more than 90% of responding to be directed toward the amphet-amine lever. As the test dose decreased, so too did the per-centage of responding on the amphetamine lever. At a dose of 0.125 mg/kg of amphetamine, responding on the amphetamine lever decreased only slightly, to about 90%; at 0.06 mg/kg of amphetamine, responding on the amphet-amine lever fell to 80%; and at 0.03 mg/kg of amphet-amine, responding on the amphetamine lever declined further, to roughly 70%. Likewise, as the test dose of halo-peridol decreased, so too did responding on the haloperi-dol lever. At a dose of 0.035 mg/kg of haloperidol, over 90% of responding was directed toward the haloperidol lever; at 0.015 mg/kg of haloperidol, responding on the haloperidol lever fell to roughly 70%; and at 0.008 mg/kg of haloperidol, only about 64% of responding was directed toward the haloperidol lever. When adminis-tered an injection of saline, rats were found to press both levers at a roughly equivalent ratio (i.e., about 50%). To examine the subjective effects of psychostimulant withdrawal, rats were then given an injection of 3.0 mg/kg of amphetamine and responding in the Skinner box was measured at various intervals from 6 to 72 hours post-injection. At 6 and 8 hours po post-injection, nearly 90% of responding was directed toward the amphetamine lever, indicating that the rats were still experiencing the effects of the amphetamine. As time passed, however, the rats began responding on the haloperidol lever. At 16, 20, 24, and 30 hours post-injection, between 70% and 83% of responses were made on the haloperidol lever. This indicates that the rats were experiencing a subjective state of withdrawal from amphetamine that was similar to the intoxication state induced by haloperidol injection. At 48 hours post-injection, responding on the haloperidol lever had declined to roughly 58%. Finally, at 72 hours, responding had returned to the 50% level, suggesting that withdrawal symptoms had disappeared (Barrett, Caul, & Smith, 2004). This type of finding is precisely as predicted by the Opponent Process Theory of Solomon and Corbit (1974), described in Chapter 3.

haloperidol

With the discovery and marketing of haloperidol in the late 1960s, however, came a problem. Haloperidol was more effective than the other typicals in alleviating the positive symptoms of schizophrenia, yet its affinity for dopamine receptors seemed to be lower. How could this be? The answer came in the late 1970s with the discovery that molecules of dopamine (and antipsychotic medica-tions) could bind to more than one subtype of dopamine receptor. Some of the typicals, like chlorpromazine which belongs to a group of chemicals known as the phenothi-azines, have a high affinity for both D1 and D2 receptor sub-types. Others, like haloperidol which belongs to the pharmacologically similar group of chemicals known as the butyrophenones, have a high affinity for the D2 (but not the D1) receptor subtype. There does not appear to be any relationship between the therapeutic effect of an antipsy-chotic and its affinity for the D1 receptor (Seeman, 2002). In fact, many of the typical antipsychotics, including chlor-promazine, fluphenazine, haloperidol, pimozide, and tri-fluoperazine, have a higher binding affinity for D2 receptors than does dopamine itself (Seeman, 2002). They bind more tightly and have lower dissociation constants, compared to molecules of dopamine. A dissociation con-stant is a measure of the ease with which a ligand, such as a drug molecule, will dissociate or separate from the recep-tor to which it is bound. A lower dissociation constant entails stronger binding, and a higher dissociation con-stant entails weaker binding. With this discovery, the dopamine hypothesis was revised: schizophrenia and other psychoses result from excessive dopamine activity

positive symptoms

abnormal additional symptom-hallucinations, delusions of granduer/persecutions

negative

abnormally absent-social withdrawal, bluneted emotions, loss of pleasure

smokeless tobacco trends

ansnational tobacco companies have focused on manu-facturing and promoting alternative, non-cigarette prod-ucts. In 2012, advertising expenditures by the major U.S. smokeless tobacco companies amounted to more than $435 million and product sales reached 125.5 million pounds, valued at more than 3 billion U.S. dollars (Federal Trade Commission, 2015). Smokeless tobacco products, including dipping, chewing, and dissolvables, were used by roughly 3%, 5%, and 8% of U.S. 8th, 10th, and 12th graders, respectively, during the previous 30 days when surveyed in 2014 (Miech et al., 2015). Amongst U.S. adults, nearly 6% of 18-25 year olds and 3% of those aged 26 or older were current smokeless tobacco users (Center for Behavioral Health Statistics and Quality, 2015).

atypical 5ht2a

azine, haloperidol, and trifluoperazine, have lower disso-ciation constants and greater effects at D2 receptors than at 5-HT2A receptors. The opposite is true of atypical antipsy-chotic drugs, including clozapine, olanzapine, sertindole, and ziprasidone, although there are some notable excep-tions to this rule, such as remoxipride (Seeman, 2002). There is another reason why the effects of atypical antipsychotics on 5-HT2A receptors may be important. Drugs like LSD and psilocybin are agonists at 5-HT2A receptors and produce psychotic symptoms such as hallu-cinations. Metabotropic glutamate (mGlu) receptors inter-act with 5-HT2A receptors to create a functional receptor complex that, when activated by hallucinogenic drugs, triggers unique cellular responses in the cortex (González-Maeso et al., 2008). In untreated schizophrenia, there is an upregulation of 5-HT2A receptors and a downregulation of mGlu receptors, suggesting that an imbalance of 5-HT2A to mGlu receptors may create vulnerability to psychosis. In addition, mGlu knockout mice (mice genetically engi-neered so that the gene coding for the mGlu receptor is inactivated, i.e., knocked out) fail to demonstrate behavioral effects of hallucinogenic drugs (Moreno, Holloway, Albizu, Sealfon, & González-Maeso, 2011). As such, mGlu recep-tors and, specifically, the 5-HT2A-mGlu receptor complex may be ideal targets for antipsychotic medications. In addition to their actions on DA and 5-HT, the atypi-cals affect other neurotransmitter systems, including ace-tylcholine, histamine, norepinephrine, and peptide

seratonin syndrome

cognitive symptoms, including disorientation, confusion, and agitation. Somatic symptoms, some of which can be life-threatening, reflect the dysregulation of autonomic nervous system functioning that occurs in serotonin syn-drome. These include hypertension, rapid and irregular heartbeat, pupil dilation, flushing, shivering, sweating, and diarrhea. Severe headache, a loss of motor coordina-tion, shock, seizures, and unconsciousness are also possi-ble. Serotonin syndrome results from an acute, dramatic increase in serotonergic transmission that is most com-monly caused by the co-administration of multiple sero-tonin-enhancing drugs. Examples of such drugs include the anti-nauseant ondansetron, the anti-seizure drug car-bamazepine, the analgesics fentanyl and meperidine, the mood-stabilizer lithium, herbal remedies such as St. John's wort or tryptophan, and of course other antidepressants (Lindsey et al., 2012). In some cases, a switch in medica-tions can lead to serotonin syndrome if there is an insuffi-cient washout time—the period required for a drug to be completely eliminated from the body (Lane & Baldwin, 1997). This is more likely to happen when patients transi-tion from an antidepressant with a particularly long half-life, such as fluoxetine, to another antidepressant. Serotonin syndrome may also result when patients taking antidepressants use psychostimulant drugs such as amphetamine, cocaine, or MDMA (Vuori et al., 2003).

ENDS trends

d 466 brands of e-cigarette were available for purchase in 2014 (Zhu et al., 2014). Today, nearly all international tobacco companies have developed their own ENDS products (70% of the market is captured by 10 companies). Global sales reached 3 billion U.S. dollars in 2013, surpassing those of nicotine replacement therapy products despite their 35 years on the market. Within the next decade, e-cigarette sales are expected to exceed those of tobacco cigarettes and, by 2030, are projected to have increased by 1700% over current lev-els (Euromonitor International, 2013; Herzog, 2014). Already, e-cigarette use has surpassed that of tobacco ciga-rettes amongst youth. In 2014, 9% of 8th-graders, 16% of 10th-graders, and 17% of 12th-graders reported having vaped nicotine in the previous 30 days (Miech et al., 2015). These are the highest current use rates of any nicotine product and, amongst 8th and 10th graders, are more than double those of traditional cigarettes. Fewer than 15% of youth believe that e-cigarettes pose "great risk" to health (Miech et al., 2015), which has prompted concern in the public health community that the strides made over past decades in reducing tobacco use and nicotine addiction will be largely or entirely offset by the soaring use of ENDS. Amongst U.S. college students and young adults, e-cigarette use is about 10%—currently lower than that of tobacco cigarettes (Johnston, O'Malley, Bachman, Schulenberg, & Miech, 2015)

typical antipsychotics

d2 blockers adverse eps-motor movement

rate dependency effect

decreased responding on a fixed ratio (FR) schedule. The determining factor turned out to be the animal's baseline response rate; methamphetamine increased the rate of responding if it was slow (as in the FI) but decreased the rate of responding if it was fast (as in the FR). This princi-ple, which became known as the rate dependency effect, has since been found to apply to all amphetamine-like drugs, across many species, and to many types of behavior and schedules of reinforcement (Dews & Wenger, 1977). The significance of this observation cannot be overstated; it was one of the first demonstrations that a drug interacts dynamically with ongoing behavior, and illustrates that it is not entirely appropriate to simply classify a drug as a "psychomotor stimulant." Whether a drug stimulates or depresses motor activity is not determined solely by the properties of the drug, but by the behavior being observed. The rate-increasing behavioral effects of cocaine are simi-lar, though not as large, as those of amphetamine (Smith, 1964). In contrast, the principle of rate dependency does not seem to apply to the effect of psychomotor stimulants on behavior suppressed by punishment. Punishment-suppressed behavior usually occurs at a low rate, but most amphetamines and cocaine do not increase the rate. Psychomotor stimulants, including amphetamine, methamphetamine, methcathinone, and cocaine, lower the threshold value and facilitate operant responding for intra-cranial self-stimulation (ICSS) of the medial forebrain bun-dle. These properties are indicative of the drugs' rewarding value. The ability of psychomotor stim

rate of absorption in buccal membranes

depends on ph and amount of free base nic he rate at which nicotine is absorbed across buccal membranes is highly dependent upon the pH of the prod-uct and the amount of "free-base" or un-ionized drug mol-ecules present. Products with higher pH values and greater free-base nicotine content will deliver more drug, more quickly. The various types of smokeless tobacco differ in their pH values. Common brands of moist snuff have pH values ranging between 5.0 and 8.6, with higher (more alkaline) products resulting in considerably faster absorption and a greater boost in nicotine blood levels (Fant, Henningfield, Nelson, & Pickworth, 1999; Henningfield, Radzius, & Cone, 1995; Lauterbach, Bao, Joza, & Rickert, 2011; Pickworth, Rosenberry, Gold, & Koszowski, 2014). Pickworth and colleagues (2014) found that absorption of nicotine from 2 g of moist snuff (pH = 8.3; nicotine content = 12 mg/g) placed in the mouth for 30 minutes led to venous blood plasma concentrations of ~20 ng/ml—a level similar to that achieved following cigarette smoking. Peak levels of nicotine occurred between 20 and 35 minutes after the product was placed in the mouth. In addition to differences in pH, there is considerable variation in the total and free-base nicotine content of vari-ous products. Total nicotine content of long-cut, fine-cut, and pouched moist snuff products ranges from about 10.9 to 13.4 mg/g, but the percentage of free-base nicotine is quite variable, from about 8%-59% of the total weight (Lauterbach et al., 2011). Low-moisture snuff contains less nicotine (~5.5-8.6 mg/g) but between 92% and 98% of it is free-base and easily absorbed. Pouched snus contains about 13.7-24.8 mg/g of nicotine, about 4.5-31% of which is free-base (Lauterbach et al., 2011; Stepanov et al., 2012). Loose and plug chewing tobacco contain 7.7-12.6 mg of nicotine per gram of product, but very little (61%) is free-base and the pH levels are quite acidic, about 4.9-5.9 (Lauterbach et al., 2011). Although the nicotine content of these smoke-less forms of tobacco are within the range, or even below that, of a typical tobacco cigarette, the higher pH levels and greater percentage of free-base nicotine content (which is especially true of low-moisture snuff, but not of chewing tobacco), can result in greater nicotine delivery to the user. Smokeless tobacco users who "dip" 8 to 10 times a day might be exposed to the same amount of nicotine as if they smoked 30 to 40 cigarettes (Centers for Disease Control and Prevention, 1999).

self admin

dogs, baboons, and rats, either by intravenous infusion or taken orally (Balster, 1987; Carroll, 1993; Griffiths, Bigelow, & Henningfield, 1980). PCP injected directly into the nucleus accumbens or frontal cortex has been found to be reinforcing. This effect is not diminished by a dopa-mine antagonist, suggesting it is independent of dopamine transmission (Carlezon & Wise, 1996). Likewise, ketamine is self-administered intravenously by both rats and mon-keys (Moreton, Meisch, Stark, & Thompson, 1977). Humans Patterns of PCP use are similar to those of LSD. Most use is experimental or occasional but, unlike LSD, some occasional users become heavy chronic users, despite the buildup of tolerance to the drug's effects (Linder, Lerner, & Burns, 1981). The use of PCP began to increase alongside a decline in the prevalence of LSD dur-ing the 1970s. Before the use of PCP became popular in its own right, it was often mixed with other drugs or passed off as a different drug. The use of ketamine increased dur-ing the 1980s with the rising popularity of the club scene and, later, raves. Since that time, its use has once again declined. Figure 15-1 illustrates that both PCP and ket-amine are used by less than 1% of young adults annually

extrapyramidal signs and symptoms EPS

dopamine hypothesis The nigrostriatal pathway contains dopamine neurons whose cell bodies reside in the substantia nigra and project to the dorsal striatum of the basal ganglia, which contains the caudate nucleus and the putamen. This dopaminergic system is important for the integration of smooth movements (it is the extrapyramidal motor sys-tem). When there is a deficiency of dopamine at these syn-apses, people show symptoms that resemble those of Parkinson's disease—tremors, slowed motor functions, stiff limbs, and trouble maintaining balance. These are called extrapyramidal signs and symptoms (EPS). Antipsychotic medications (especially the "typicals") block the activity of dopamine in the nigrostriatal pathway, often producing serious EPS that make taking the medication intolerable. In addition, two other dopamine systems are highly impli-cated in the development of schizophrenia. They have cell bodies that reside in the ventral tegmental area and send projections to release dopamine in the cortex (this is the mesocortical pathway) and in the nucleus accumbens and limbic structures, including the hippocampus and amyg-dala (this is the mesolimbic pathway).

banging

doses of psychomotor stimulants enhance sexual desire and sexual pleasure in females (Semple, Grant, & Patterson, 2004), and prolong erection, delay ejaculation, and lead to a particularly intense orgasm in males (Shoptaw & Reback, 2007). Increased sexual pleasure, along with reported drug-induced decreases in sexual inhibition, can sometimes promote unsafe and untypical sexual practices (Semple et al., 2004). People who claim they would not usually do such things may engage in unprotected sex, sex marathons, group sex, and same-sex experiences (Smith, Damman, & Buxton, 1979). Chronic administration of high-dose cocaine, by inhala-tion of crack or freebase or by injection of cocaine, often leads to a disruption in sexual activity in males and periods of dis-interest in sex (Siegel, 1982). Likewise, some male metham-phetamine addicts report that chronic use leads to erectile dysfunction and that drugs such as sildenafil (Viagra) are needed in order to perform sexually (Bang-Ping, 2009). Like cocaine, khat initially increases sex drive in males, but con-tinued use can cause decreased sexual interest and impo-tency (Giannini, Burge, Shaheen, & Price, 1986; Wabe, 2011). In chronic khat chewers, sperm count, motility, and volume are decreased and there is a high percentage of deformed sperm found in samples (Wabe, 2011). Chronic khat chewing can inhibit milk production in nursing mothers.

hasish

dried resin more concentrated thc beaten-rolled-collected and placed in tubs w/ alcohol-evaporated-pressed into bars 5-20 percent thc

elimination

effected by gender and genetic differences. Two pathways in the liver metabolize nicotine into two inactive metabolites: cotinine, which accounts for ~75% of nicotine metabolites, and nicotine-1'-N-oxide. The primary enzyme responsible is the cytochrome P450 2A6 (abbrevi-ated CYP2A6) enzyme. There is considerable inter-individual variability in the excretion rate of nicotine, with half-life estimated to be between 90 and 150 minutes. Smokers are able to metabolize nicotine faster than non-smokers, and females clear nicotine from their bodies faster than males, perhaps because CYP2A6 is induced by estrogen (Higashi et al., 2007). This may explain why females are more susceptible to nicotine addiction and why it is more difficult for them to quit (Perkins & Scott, 2008). Nicotine elimination speeds up during pregnancy and slows with age. Because nicotine metabolism occurs primarily in the liver, it is quickened by a meal because eating causes an increase in blood flow to the liver. Menthol, which is added to some cigarettes, has been shown to inhibit CYP2A6 activity and thereby slow nicotine metabolism and prolong its effects (Hukkanen, Jacob, & Benowitz, 2005; Kramlinger, von Weymarn, & Murphy, 2012). Genetic differences also influence the way in which people metabolize nicotine. About 16-25% of the popula-tion has a genetic variation (in CYP2A6 genes) that decreases their ability to metabolize nicotine. A given dose of nicotine will reach higher levels and last longer in these people, which appears to offer some protection against becoming a smoker. People with a genetic basis for slow metabolism who do become smokers consume fewer cigarettes per day and are more likely to quit smok-ing (Pianezza, Sellers, & Tyndale, 1998; Malaiyandi, Sellers, & Tyndale, 2005). Rapid metabolizers expe Rapid metabolizers experience more severe withdrawal symptoms during abstinence and have a lower likelihood of quitting smoking (Lerman et al., 2006). The amount of nicotine excreted by the kidneys depends on the pH of the urine, as described in Chapter 1. Acidic urine (pH 6 7) tends to ionize nicotine and reduce its reabsorption through the nephron wall. Consequently, as much as 30-40% of administered nicotine may be eliminated in the urine. Reduced ionization at an alkaline pH increases reabsorption into the blood, and the effi-ciency of the kidneys is reduced, thereby shifting the load of excretion to the enzymes of the liver. Nicotine will accu-mulate in the body of a smoker over the course of a day, and if smoking continues until bedtime, there also will be a day-to-day accumulation (Hukkanen et al., 2005)

tolerance

effectiveness. Haloperidol's ability to increase dopa-mine release in the cortex does decline with prolonged use; clozapine does not show tolerance of this sort (Advokat, 2005). Tolerance seems to develop to the initial sedating effects of antipsychotics, as well as to the EPS side effects, which lessens their disabling impact on individuals

ventrolateral preoptic nucleus

egion called the ventrolateral preoptic nucleus (VLPO), is a sleep-inducing center. When it is active, it causes sleep by generating synchronous activity in the cortex, which shows up on an EEG as slow waves. There are several other centers in the brainstem and midbrain that are wak-ing centers. They arouse and desynchronize cortical activ-ity, which wakes up the brain and keeps it active. The waking centers and the sleep center sendto each other so that control of the cortex tends to flip-flop between these centers. After you have been awake for a period of time, the sleep center is triggered to become active, it inhibits the wakefulness centers, and you sleep. After you have slept for a period of time, the wakefulness centers take over, they inhibit the sleep center, and you wake up. There are numerous environmental, neural, and chemical events that can trigger the flip-flop, but a buildup of adenosine is one trigger that can activate the sleep cen-ter. Caffeine blocks or suppresses this activation by block-ing adenosine receptors with the result that you can stay awake longer (Luppi & Fort, 2011).

consequences of energy drinks

eptible individuals, such as those with a heart condition, or in children. Common reactions include elevations in blood pressure and heart rate, and minor cognitive effects such as insomnia. Irresponsible and excessive consumption, how-ever, can be medically hazardous. In 2013, the Drug Abuse Warning Network (DAWN) reported that the number of energy-drink-related emergency-room visits in 2011 had doubled since 2007 and were nearly 1400% higher than in 2005 (Center for Behavioral Health Statistics and Quality, 2013). The majority of patients were aged 18-25 years and most (58%) had consumed energy drinks alone, though the cumulative amounts were not reported. The remaining 42% had consumed energy drinks or shots in combination with other drugs, including pharmaceuticals (e.g., Adderall), alcohol, and illicit drugs including marijuana. The U.S. Food and Drug Administration collects infor-mation, via the Adverse Event Reporting System, regard-ing adverse health consequences of consuming a regulated conventional food or dietary supplement, which includes energy drinks and shots. Between 2004 and 2012, adverse reactions following consumption of Red Bull, Monster, Rockstar, or 5-Hour Energy included: flushing, headache, dizziness, tremor, hyperventilation, renal failure, vomiting, diarrhea, incontinence, fluctuations in blood pressure, fainting, anaphylactic shock, heart palpitations, chest pain, heart attack, hemorrhage, stroke, disorientation, spontaneous abortion, depression, anxiety, aggression, blindness, deafness, hallucinations, and convulsions. This is but a partial list of reported serious and life-threatenin

rush

es of amphetamines produce intense feelings of eupho-ria and pleasure, called rushes. Users describe the sense of rush as "being lifted into the air with feelings of extreme happiness." Another account claims, "The heart starts beating at a terrible speed and his respiration is very rapid. Then he feels as if he was ascending into the cosmos, every fiber of his body trembling with happiness." Many people report that the rush has a strong sexual component. As one user put it, "The shot goes straight from the head to the scrotum" (Rylander, 1969, p. 254). These more powerful subjective effects depend on both the concentration of the drug and the speed with which it reaches the brain (Allain et al., 2015). Intravenous injection and smoking are the two fastest and most efficient methods of getting a drug into the bloodstream and, consequently, into the brain, and these routes of administration tend to produce the greatest rush. Oral and intranasal routes fail to produce a rush because they result in slower absorption rates and, in turn, lower blood concentrations over a longer period of time (Allain et al., 2015)

coke subjective effects

follows cocaine injection is felt within seconds and lasts for less than a minute. As with the amphetamines, the rush is near-universally described in sexual terms analogous to orgasm. The experience is so intense that the user is com-pletely engrossed in the experience and cut off from every-thing and everyone nearby (Waldorf, Murphy, Reinarman, & Joyce, 1977). Peak subjective ratings of "high" occur shortly after the rush dissipates. As with the amphetamines, there is a feeling of energy and a sensation of clear thoughts and perceptions. This lasts for roughly 20-30 minutes and is followed by a mild depression called the crash or comedown. With repeated administrations, cocaine-induced rushes show rapid tolerance. In one study, when intravenous injections of cocaine were given 70 minutes apart, reports of rushes disappeared over the session, though other subjective measures, such as "feeling good," remained unchanged (Kumor, Sherer, Muntaner, Jaffe, & Herning, 1988). The route of cocaine administration determines the intensity and speed of its effect. Subjective reports of "good" effect and "high" are greater after smoking cocaine compared to after injecting it intravenously (Cone, 1995), and the time to reach peak subjective effects is faster for smoked (~1.4 minutes) than for intravenous (~3.1 minutes) cocaine (Volkow et al., 2000). When cocaine is adminis-tered intranasally (i.e., snorted), a numbing sensation called the freeze can be felt within a couple of minutes. This is followed within about 5 minutes by feelings of exhilaration and well-being. Peak subjective effects are reached in just under 15 minutes (Volkow et al., 2000

automutilation/formication

fter high doses of amphetamines and cocaine, it is common for both rodents and monkeys to chew and bite at their own bodies. This self-directed biting is called automu-tilation. Animals may sometimes bite off their fingers, toes, or paws. It is likely that automutilation is a form of stereo-typed behavior because it appears to be repetitious; but it may also be a result of sensory nerve stimulation and tin-gling. In humans, administration of amphetamine or cocaine can produce formication—the sensation of bugs crawling under or on the skin ( formica is Latin for "ant"). The same sensation, when experienced by animals, could cause them to pick or gouge at their skin. The amphet-amines, cocaine, and cathinone produce analgesic effects in rats and mice, which may decrease the pain and aver-siveness of automutilation (Geresu, 2015). Even at low doses, amphetamines and cocaine decrease consumption of both food and water in most spe-cies. This is probably a combination of (a) the effect of the drug on regions of the brain that control appetite and (b) the fact that the drug increases other behavior sequences, thereby interfering with and reducing the time available for eating and drinking. Appetite suppression is not related to the reinforcing effects of these drugs because fenfluramine, a drug similar to amphetamine, is very effec-tive in suppressing appetite but does not appear to have any reinforcing effects (Brady et al., 1987). In fact, fenflura-mine antagonizes the reinforcing effects of amphetamine and cocaine (Wee & Woolverton, 2006). It is possible the effect of psychomotor stimulants on consummatory behav-ior is mediated by alterations in serotonin functioning.

negatives

gastro-intestinal distress hypothermia-constriction of blood vessels emesis hypertension siezures

development

gradually, over a period of 3 to 5 years. Men and women are equally likely to be affected by schizophrenia, although men typically experience signs and symptoms beginning at a slightly earlier age (late teens or early twenties) than do women (twenties or thirties). The first symptoms to emerge are often negative (e.g., asociality, a loss of pleasure and motivation) and may be misdiagnosed as depression. Their appearance is usually, though not always, followed by the onset of positive symptoms, which may take years to develop. Box 12-2 presents an early study of a woman diagnosed with schizophrenia; in her case, major symptoms included delusions and catatonia. This is irrefutable evi-dence that genetic makeup plays a pivotal role in rendering individuals susceptible to developing schizophrenia (van Dongen & Boomsma, 2013). No one particular gene has been flagged as the "schizophrenia gene" and probably never will. Instead, genetic analysis has pinpointed a num-ber of gene mutations on many chromosomes that, together, create vulnerability to develop schizophrenia. These genes are involved in such processes as neuronal migration dur-ing prenatal brain development, neuronal differentiation and growth, axonal projection, and the formation of recep-tors and synapses (Doherty, O'Donovan, & Owen, 2012; Walsh, McClellan, et al., 2008). If schizophrenia were caused purely by genetics, we would expect identical twins (who are genetic clones of one another) to either both exhibit schizophrenia or for nei-ther to be affected. In fact, the likelihood of both identical twins exhibiting schizophrenia, when one is affected, is only about 45%. We can conclude, then, that environmental influences must also play an important role in activating or promoting the expression of genes implicated in schizo-phrenia. Many such genetic triggers have been identified. If a mother contracts a virus while pregnant, especially during the first or second trimester, brain developm In large cities, where viruses are spread more readily, schizophrenia rates are approximately three times higher than those in rural areas. Schizophrenia rates are also higher in individuals whose gestation occurred during the winter flu season. During the dark winter months, levels of vitamin D (the "sunshine" vita-min) also tend to be lower. In pregnant women, vitamin D deficiency may predispose the developing offspring to schizophrenia as vitamin D is important for normal brain development. Other influential environmental factors include birth complications and a lack of oxygen to the infant during labor and delivery, early childhood infection, head trauma, stress, and the use of drugs such as cannabis or methamphetamine, especially during adolescence. Schizophrenia researchers propose that environmental dis-turbance of prefrontal cortical development during either of two critical periods—the early embryonic period, when prefrontal cortical development is characterized by neuro-genesis and cell proliferation, or during adolescence, when maturation of the prefrontal cortex entails a fundamental elimination of excitatory synapses—increases the risk of developing schizophrenia (Selemon & Zecevic, 20

cancer

gree to which smoking affects one's likelihood of devel-oping cancer can be measured in terms of relative risk—the probability that an event (such as a disease or death) will occur in an event-exposed or treatment group (in this case, smokers—Group A) relative to another group that does not experience the event (non-smokers—Group B). Relative risk (RR) ratio is calculated by dividing A/B and a RR of 1.0 means that both groups are equal in risk; values 7 1.0 mean that exposure to the event (smoking) increases one's risk. Higher numbers mean a higher relative ratio of risk. Relative risk of developing cancer of the stomach, colon, pancreas, kidney, or blood (leukemia) range between 1.1 and 1.9 in men and women who smoke. Male smokers are at a higher risk of developing prostate cancer (RR = 1.4), and females smokers at a higher risk of breast cancer, in direct proportion to daily cigarette use (RR = 1.3; Carter et al., 2015). Relative risk of liver and bladder cancer is higher, up to 3.9. The highest relative risks are found for lip, oral cavity (a form of cancer that cigar-loving Sigmund Freud suffered), and esophageal cancer (RR = 3.9-5.7) and cancer of the larynx and lungs (RR = 13.9-103.8; Carter et al., 2015). The risk of lung cancer can be greatly decreased by quitting smoking, and the risk lessens considerably over time after a person stops. Th

absorption

hard to quantify in vape rate absorps depends on ph and free base present snuff could experience greater delivery

monoamine theory of depression

he monoamine theory of depression, in its original form, proposed that depression is a result of reduced levels of activity in monoamine systems. The theory was supported by observations that altering monoamine activity levels affected mood. Drugs like cocaine or amphetamine that enhance monoamine neurotransmission make people feel good. Alternatively, decreased transmission at monoamine synapses is associated with depression. Depression is the most common psychiatric condition in individuals with Parkinson's disease, which is marked by a severe depletion of dopamine (Ravina et al., 2009). The drug reserpine, which was once used to treat high blood pressure, depletes mono-amines by blocking the activity of the vesicular transporter proteins that reside in the axon terminals where they fill syn-aptic vesicles with molecules of monoamine. Coincidently, individuals administered reserpine showed improvement in their hypertensive symptoms, but also developed severe depression which prompted many countries to discontinue use of the drug. Similarly, depleting 5-HT by ridding its amino acid precursor (tryptophan) from the body also pro-duces depression. All of these findings support the mono-amine theory of depression.

Phencyclidine (PCP)

hencyclidine, also known as PCP, is a synthetic drug devel-oped and marketed in 1963 by the Parke-Davis Company as an analgesic and anesthetic. For these purposes, it proved very effective and safe because it did not depress blood pressure or slow heart and respiration rates. The state induced by phencyclidine is more of a trance-like condition than a loss of consciousness, and the drug is clas-sified as a dissociative anesthetic because of its seeming abil-ity to separate people from sensory experiences. In 1965, PCP was withdrawn from the pharmaceutical market because patients reported that, while recovering from the drug, they experienced a state of delirium, disorientation nd agitation referred to as emergence delirium. The use of PCP was then restricted to experimental research in ani-mals and to veterinary purposes. In the same year that its use as a medical drug was halted, PCP appeared on the street as a recreational drug, sold under a variety of names including crystal, angel dust, and hob. However, its use did not become popular until after the 1960s.

Phenethylamine

henethylamines, which are structurally similar to molecules of dopamine (DA) or norepinephrine (NE). The chemical structure of LSD, for instance, is similar to that of serotonin and the drug there-fore belongs in the indolamine class, whereas mescaline has a molecular structure more closely resembling the cate-cholamines (DA and NE) and therefore belongs with the phenethylamines. Despite their structural differences, the indolamine and phenethylamine cla

troubles with quantifying absorption with vaping

ications, as you will see. The dose of nicotine deliv-ered from a single (70-100 ml) puff of an e-cigarette is esti-mated at somewhere between 1.7 and 51.3 mg (Goniewicz, Kuma, Gawron, Knysak, & Kosmider, 2013; Trehy et al., 2011). Assuming that 15 puffs is typical when smoking a tobacco cigarette, the comparable dose of nicotine delivered by vaping an e-cigarette would be about 0.026-0.77 mg—less than that of a tobacco cigarette. The wide range of this estimate is due to the numerous factors that influence nico-tine delivery during vaping. In part, the delivered dose is determined by nicotine concentration, which ranges from about 5-25 mg in the most popular U.S. brands of dispos-able e-cigarette and 18-24 mg/ml in refillable e-liquid (Pagano et al., 2016; Spindle, Breland, Karaoghlanian, Shihadeh, & Eissenberg, 2015). Brands also differ substan-tially in their nicotine transfer efficiency, with one model tested delivering only 14% of its total nicotine content over its lifespan and another delivering 58% (Pagano et al., 2016). A study of rechargeable/refillable e-cigarettes found that, on average, about 50-60% of the nicotine contained in the e-liquid reservoir was aerosolized during vaping, though the range of nicotine vaporization efficiency across products and cartridges was substantial, from 21 to 85% (Goniewicz et al., 2013). The total amount of aerosolized nicotine delivered by 300 puffs (20 series of 15 puffs) also ranged substantially, from 0.5 to 15.4 mg in "high nico-tine" products and from 0.5 to 3.1 mg in "low nicotine" cartridges (Goniewicz et al., 2013) In addition, because there is no regulatory body assessing manufacturers' claims regarding the nicotine content of an e-cigarette, the amount listed on the ENDS label may differ substantially from its actual content. Researchers have found up to a 71% discrepancy between the listed and independently measured nicotine content of an e-cigarette (Goniewicz, Hajek, & McRobbie, 2014; Pagano et al., 2016). Many contained less nicotine than claimed, but some contained significantly more, and nico-tine was even discovered in some "nicotine-free" e-liquids. Even between batches of the same product, nicotine con-centrations have been found to vary by up to 30% (Goniewicz et al., 2014). One recent study estimated the average daily nicotine exposure for regular vapers to be 0.38 mg of nicotine per kg of body weight (Hahn et al., 2014). But with erroneous labeling and such variability between products, it is very difficult for a user to judge, with any degree of certainty, their actual exposure to nicotine. Nicotine delivery from vaping also depends on addi-tional variables including the pH of the solution; the amount of nicotine present in free-base (non-ionized) form

tea

ier cultivation. For the best-quality teas, only the bud and first two young leaves of each twig are plucked. Inferior-quality teas are made from the third and fourth leaves. Caffeine content, as well as quality, decreases in leaves the further they are from the bud. On average, tea leaves contain caffeine levels ranging between 2.0 and 4.8% by dry weight (Gramza-Michałowska, 2014; Wierzejska, 2014). This caffeine content is higher than that of coffee beans, but the extraction of caffeine from tea leaves during brewing is less efficient than that of coffee beans, resulting in less caffeine per cup of beverage (Barone & Roberts, 1984). Soon after they are picked, the tea leaves begin to dry out and wilt, and the process of oxidation begins. The extent to which the leaves oxidize affects the color, flavor, and chemical composition of the tea. Most of the tea con-sumed outside of Asia is black or fermented tea (though fermentation, when used in reference to tea, actually means oxidation). Black tea is produced by crushing or rolling slightly dried green leaves which breaks the leaf mem-brane, exposing its chemical components to oxygen and releasing enzymes that cause oxidation. Over time, the leaves become 100% oxidized and turn black. In semifer-mented teas, such as oolong tea and white tea, the oxidation process is incomplete. White tea is oxidized naturally by the sun to between 8 and 15%. Oxidation of oolong tea

constant blood level theory

in a constant blood level of nicotine (i.e., one high enough to avoid withdrawal symptoms, but below a level that has toxic or aversive effects) comes from research in which the nicotine content of cigarettes is varied and consequent smoking behavior is measured. Early studies had trouble demonstrating dose compensation when researchers mea-sured dose by simply counting the number of high-and low-nicotine cigarettes a person smoked. They soon learned that people control nicotine intake, not by chang-ing the number of cigarettes they smoke, but by changing their smoking behavior; that is, they compensate for low-nicotine cigarettes by taking deeper and more frequent puffs on the cigarette (Benowitz, 1992). A similar learning curve occurs in e-cigarette vapers who compensate for the different dynamics and nicotine-delivery inefficiencies of ENDS devices by changing their puffing behavior (Farsalinos et al., 2015; Hajek et al., 2015). One prediction of the constant blood level theory is that the first few puffs on a cigarette will be rapid and deep as the smoker tries to raise blood nicotine levels that have fallen since the previous cigarette was smoked. As the nic-otine level increases, the puff rate should decrease, and few puffs should be taken near the end of the cigarette. This change in puff rate has been reported by several researchers (Chait & Griffiths, 1982). In addition, the the-ory predicts that people will be highly motivated to smoke when their blood levels are low after a period without smoking. Nicotine accumulates in the body over the course of 6 to 9 hours of regular smoking and drops while the smoker sleeps so that the lowest blood levels occur upon wakening. A British study showed that 14% of smokers light up within 5 minutes of waking in the morning, and 50% do so within 30 minutes. Smoking within 30 minutes of waking and getting up at night to smoke are indicators of nicotine addiction (Baker et al., 2007; Baker, Breslau, Covey, & Shiffman, 2012; Piper, McCarthy, & Baker, 2006). The first 1 to 2 puffs of a cigarette results in a 50% increase in a4b2 nAChR occupancy in a chronic smoker for more than 3 hours. Smoking one or more cigarettes boosts recep-tor occupancy levels to nearly 90% and significantly reduces cigarette craving (Brody et al., 2006). Thus, repeated cigarette use by a daily smoker achieves chronic near-complete saturation (and, thus, desensitization) of a4b2 nicotinic cholinergic receptors, which prevents the onset of withdrawal symptoms (Brody et al., 2006). Even though human smokers attempt to prevent their nicotine blood level from falling to the point where with-drawal symptoms occur and make adjustments for the amount of nicotine delivered by their cigarette, they are unable to compensate completely. Their blood levels then

Indolamines

indolamines, whose molecular structures bear resemblance to that of serotonin (5-HT), and the phenethylamines, which are structurally similar to molecules of dopamine (DA) or norepinephrine (NE). The chemical structure of LSD, for instance, is similar to that of serotonin and the drug there-fore belongs in the indolamine class, whereas mescaline has a molecular structure more closely resembling the cate-cholamines (DA and NE) and therefore belongs with the phenethylamines. Despite their structural differences, the indolamine and phenethylamine classic hallucinogens overlap considerably in their subjective effects, so they will be discussed together in this section. The main differences that exist amongst the classic hallucinogens lie in their selectivity for certain serotonin receptor subtypes, varyin

dual reinforcement model

inforcing effects of smoking. Their dual reinforcement model proposes that there are actually three processes at work during nicotine reinforcement. First, there is the pri-mary reinforcement that stems from nicotine's effects on the mesolimbic dopamine system, as described earlier. Second, there are non-nicotine-related stimuli, such as the taste and smell of the tobacco smoke and the sensation of smoking, which acquire secondary reinforcing properties through conditioning because they are paired with the pri-mary reinforcement derived from nicotine administration. As nicotine enhances midbrain dopamine activity and acts upon memory-related circuits, these conditioned associa-tions become internal motivators that drive smoking behavior (Zhang, Tang, Pidoplichko, & Dani, 2010). Third, the researchers hypothesize that nicotine has "reinforce-ment enhancing" properties—that is, the ability to make a weak reinforcer (such as a sensory cue) stronger—and that these properties enhance the effect of the non-nicotine stimuli. The joint effect of all these processes is tha vaping) is a much more powerful reinforcer than would be predicted by nicotine's primary reinforcing effect. To illustrate nicotine's "reinforcement enhancing" effect, Caggiula and colleagues (2009) performed an exper-iment in which rats were placed in an operant chamber with two levers. One lever produced the same visual stim-uli used in the nicotine studies described earlier (the onset of a 1-second cue light and the offset of the house light for 1 minute) but no infusion of nicotine. The other lever caused an infusion of nicotine but no change in visual stimuli (cue or house light). For one group of rats, only the stimulus lever was active (pressing on the nicotine lever produced no results); for a different group, only the nico-tine lever was active (pressing it produced no changes in visual stimuli). The researchers found that, in both groups of rats, the "active" lever supported low levels of respond-ing. You may find it surprising that visual stimuli alone would be reinforcing given that they had never been paired with nicotine, but it has been known for some time that sensory changes (changes in illumination and sounds) function as weak reinforcers for laboratory animals (this is called sensory reinforcement). It appeared that the reinforc-ing effect of the light changes and the reinforcing effect of nicotine infusions were roughly equivalent; rats press either lever at about the same rate her group of rats was permitted to press both levers in the same session (i.e., both levers were made "active"). In this group, responding on the nicotine lever was just as low as it was in the group that was permitted to press only that lever; however, these rats responded for the visual stimuli at a much higher rate than before. It appears that the nicotine infusions received after press-ing the nicotine lever greatly enhanced the reinforcing properties of the visual stimuli produced by pressing the other lever. Drawing an analogy to cigarette smoking, the ability of nicotine to enhance the reinforcing properties of the smell and taste of tobacco smoke, and the combina-tion of this reinforcement with the primary reinforcement from nicotine, add up to make tobacco smoking a much more powerful reinforcer than the administration of nic-otine alone. These three explanations—the constant blood level theory, the nicotine bolus theory, and the dual reinforce-ment model—are not mutually exclusive. They may all be correct to some extent in different smokers, and the same smoker may, under varying circumstances, be motivated by the need to create a nicotine bolus, avoid nicotine withdrawal, or experience the taste and smell of tobacco smoke. The ability of nicotine to enhance the effects of other reinforcers no doubt increases these motivations and perhaps influences other reinforcers not yet identified or considered

cardiac disease

ion to heart disease is equivocal. In the early 1970s, the Boston Collaborative Drug Surveillance Program published two studies showing that drinking more than six cups of coffee a day doubled the risk of heart attack. Since that time, numerous studies have failed to replicate the finding and contradictory results abound. For example, one study of more than 85,000 women in the United States concluded that coffee was not an important contributor to heart attacks (Willett et al., 1996); while another study of more than 800 women in Boston found that heavy coffee consumption (more than five cups per day) did increase the risk of heart attack (Palmer, Rosenberg, Rao, & Shapiro, 1995). These divergent findings might be explained, at least in part, by the fact that caffeine consumption is usually not measured accurately, and, as a result, risk is consistently underestimated (James, 1991). Another possible explana-tion might be related to the manner in which coffee is pre-pared. One study has shown that boiled coffee contains a substance that raises cholesterol levels, but filtered coffee does not contain this factor (Pirich, O'Grady, & Sinzinger, 1993). Statistical adjustments for other confounding health-related factors, such as smoking status, alcohol use, saturated-fat intake, level of physical activity, and body mass index, result in a lower risk of cardiovascular disease in coffee drinkers (O'keefe et al., 2013). A further confound in this research is the possibility that the link may be genet-ically determined and may exist only for specific popula-tions. Cornelis, El-Sohemy, Kabagambe, and Campos (2006) showed a positive relationship between caffeine consumption and cardiovascular disease, but only in indi--viduals with the "slow metabolizing" form of the CYP1A2 enzyme gene (i.e., the CYP1A2*1F form). These individu-als excrete caffeine slowly. While the issue is far from

overdose

is extremely rare. As described earlier, SSRIs in combina-tion with other antidepressants or psychomotor stimulants can cause serotonin syndrome. If this syndrome is unrec-ognized and untreated, it can ultimately cause respiratory, circulatory, and kidney problems. Serotonin syndrome is relatively common in SSRI overdose, though the incidence of seizures or coma is lower. Both the SSRI citalopram and the SNRI venlafaxine appear to be more dangerous due to their influence on cardiac function (Christoph et al., 2010; Isbister, Bowe, Dawson, & Whyte, 2004). The tricyclics are potentially dangerous medications with a therapeutic index of around 10 to 15. This is a seri-ous concern, especially when these drugs are prescribed for people who are severely depressed and contemplating suicide. The toxicity of the tricyclics is due primarily to their effect on the contractility of the heart muscle. There is considerable variability in the death rates attributed to the various classes of antidepressants. Among the tricyclics, clomipramine is relatively safe, but many deaths have been attributed to amitriptyline. Tranylcypromine, an MAOI, is responsible for a high rate of deaths, but the rate of isocarboxazid fatalities is low (Leonard,

look up the neuropharomacology for this

its hard

revisions

izophrenia results from a lack of glutamate neurotrans-mission, why are measures of cerebrospinal fluid gluta-mate levels similar between individuals with schizophrenia and those without? An additional problem for the original glutamate hypothesis came from animal research showing that injections of NMDA receptor antagonists at doses that produce schizophrenia-like symptoms actually increased, rather than decreased, glutamate release in the prefrontal cortex. Recall that glutamate also binds to another receptor subtype, the AMPA receptor. Researchers also discovered that blockade of AMPA receptors reversed the effects of the NMDA receptor antagonists. So glutamate dysfunction in schizophrenia might be the result of two combined pro-cesses: NMDA receptor hypoactivity and AMPA receptor hyperactivity. How can it be that NMDA receptor blockade increases glutamate activity in the prefrontal cortex? This makes sense if we consider that neurons in the cortex are inhibited by GABA interneurons—if they were not, excitation of some glutamate neurons would set off a domino effect of ever-increasing cortical activation. Blockade of NMDA receptors present on these GABA interneurons decreases their firing; in other words, there is an inhibition of inhibi-tion, or excitation, and increased glutamate release and acti-vation of AMPA receptors. This would not be so at NMDA receptors, since they are antagonized through blockade of the PCP binding site. A disorganized pattern of glutamate neurotransmission may produce a state of "noise" and dis-ruption in which the cortex is unable to properly assess information (Moghaddam & Javitt, 2012). One goal of anti-psychotic drug development is to stabilize NMDA and AMPA receptor glutamate neurotransmission in the cortex. NMDA itself, or direct NMDA agonists, cannot be used as antipsychotic medications because they increase the risk of seizure and brain damage resulting from excitotoxicity, when neurons die from excessive stimulation. However, indirect NMDA agonists, such as glycine and d-serine (an agonist at the NMDA receptor glycine binding site), facili-tate NMDA receptor activity and hold great promise.

bad shit

kills 5.5 million per year linked with cancer 30 % of cancer deaths

atypical antipsychotics

loosely bind to d2 higher affinity to d2 and d3 higher affinity to bind to seratonin receptors -5-HTRs, especially 5-HT2A subtype not that much better at treating sympots, just nice with the side effects

human behavior

low lethality effects greatly vary eps most pronounced effect weight gain sedation people often dont want to take them not giant effects on sleep males reduce sex females abnormal bleeding

subjective and rewarding effects of caffeine

m both direct and indirect actions. Recall from Chapter 4 that low levels of adenosine (and adenosine-receptor activ-ity) correspond with alertness whereas high levels corre-spond with sleepiness. Adenosine levels rise over the course of a day to produce sedation, but adenosine's actions on A1 and A2A receptors can be blocked by the methylxanthines. As a cognitively arousing drug, caffeine is most effective when adenosine activity is high (Fredholm et al., 1999). Through interaction with adenosine receptors, caf-feine indirectly impacts the functioning of additional neu-rotransmitter systems. For instance, acetylcholine neurons are tonically inhibited by adenosine and caffeine conse-quently increases their firing rate. Blockade of adenos-ine's inhibitory effects on glutamate neurons helps explain why high doses of caffeine can lead to seizures. Methylxanthine intake also increases the firing rate of norepinephrine neurons in the locus coeruleus and enhances the turnover of the other monoamines (5-HT and DA) as well. When it comes to understanding caf-feine's psychomotor and reinforcing effects, of greatest interest is the interaction between adenosine and dopa-mine receptors. A1-and A2A-receptor activity modulates levels of dopamine in the brain (Fredholm et al., 1999). For instance, in the ventral striatum (which is highly implicated in reward and addiction), caffeine blocks pre-synaptic A1 receptors located on dopaminergic terminals, the net result of which is an enhanced release of dopa-mine by these neurons (Ferré, 2008). In addition to acting as heteroreceptors, the receptors for adenosine often participate in the formation of recepto mosaics where two or more receptors are attached to each other and consequently influence one another's operation (Fuxe, Marcellino, Guidolin, Woods, & Agnati, 2008). Receptor mosaics may involve the same or several different types of receptors. The operation of receptor mosaics com-prised of adenosine and dopamine (A1-D1 and A2A-D2) receptors is impacted by caffeine so that dopamine neuro-transmission is enhanced in the striatum. In addition, activ-ity of A2A-D2 receptor mosaics regulates transmission of other types of neurons, such as GABA and glutamate, upon which they sit (Ferré, 2008; Ferré et al., 2016). Clearly, the simple act of drinking a cup of coffee results in far-from-simple actions in the brain. In Chapter 6, you learned about the neuropharmacol-ogy of alcohol and the subjective and behavioral effects of combining alcohol with caffeine. By itself, alcohol blocks adenosine reuptake, thereby increasing adenosine levels in the synapse and enhancing neurotransmission (Sharma, Engemann, Sahota, & Thakkar, 2010). However, by antago-nizing adenosine receptors, caffeine prevents the feeling of sedation that would otherwise result from alcohol con-sumption so that the user is more alert and feels less intox-icated. Like caffeine, alcohol enhances dopamine neurotransmission. The joint actions of caffeine and alco-hol on dopamine activity might explain why caffeinated alcoholic beverages lead to a greater desire to drink and higher levels of consumption than when alcohol is co

hedonic hotspot

makes u hungry along with hypothalamus area of nuculues accumens-rewards

thc and anelgesia

mediated through cns/pns mechanism as well as non ns system RVM-part of brainstream -thc decreases pain enhancers increases pain dercreasers -inhibits glutamate release -increases dynorphin release cb receptors on peripheral senrory nerves -reduce pain signalig from sights of damage

effects on behavior

memory and cognition The dissociative anesthet-ics are known to cause amnesia for events that occur while intoxicated. In animal studies, PCP has been found to pro-duce a greater disruption of memory than that caused by LSD, THC, opioids, and many other psychoactive drugs (Balster, 1987). Given the well-established, pivotal role of NMDA receptors in the formation of memories, it is unsur-prising that NMDA antagonists like PCP and ketamine are such powerful amnesic drugs. Prolonged ketamine use leads to the emergence of cognitive deficits, including impairments in the encoding (but not retrieval) of episodic memory, deficits in semantic memory and procedural learning, and problems in the manipulation (but not main-tenance) of working memory (Morgan & Curran, 2006). PCP and ketamine are also capable of inducing symptoms of disordered thought like those exhibited in schizophre-nia (Gilmour et al., 201 PCP and ketamine are not hallucinogenic, in the same sense as the classic hallucinogens. At usual doses, the dis-sociative anesthetics cause relaxation, sedation, immobil-ity, warmth, a tingling feeling, a sense of numbness, analgesia, and euphoria. At low doses or when emerging from anesthesia, there are distortions in body image and a feeling of floating in space. When these effects wear off, they are sometimes followed by a mild depression that may last from 24 hours to 1 week. At higher doses, symp-toms of psychosis may emerge, including catatonic excita-tion, marked by frenzied motor activity, or catatonic stupor, in which the person remains immobile for pro-longed periods of time. There may be sudden mood changes that swing from laughter to crying; disoriented, confused, and delusional thought; and repetitive (stereo-typed) actions. This psychotic state usually disappears as drug levels decline, but sometimes the psychosis requires hospitalization and lasts for weeks. Chronic PCP users also describe impairments in thinking and memory, persistent speech difficulties, anxiety, social withdrawal, depression, suicidal thoughts, and drug craving.

antipsychotics admin

oral depot injection readily absorbed in digestive tract bind well to blood slowly released in fat extensivly metabolisde before getting released very long half lives

time course of subjective high

oral has blunted longer course

heart and pulmanory

moking increases the relative risk of heart disease, aortic aneurysm, and other arterial diseases (RR = 1.9-10.1) and doubles one's risk of stroke (Carter et al., 2015; Centers for Disease Control and Prevention, 2015). Risk of cardiovas-cular disease is increased by exposure to secondhand smoke and in individuals smoking fewer than 5 cigarettes per day (Bjartveit & Tverdal, 2005; Prescott, Scharling, Osler, & Schnohr, 2002). Heart disease caused by tobacco smoke stems largely from the combined actions of nicotine, tar components, and gases, such as carbon monoxide, which produce free radicals (highly reactive, oxygen-containing molecules) that cause oxidative stress and damage to the cardiovascular system (Messner & Bernhard, 2014; Morris et al., 2015). Chronic exposure to tobacco smoke can alter gene expression to promote the aggregation (clumping together) of blood platelets, increasing the risk of thrombus

meth psychosis

more than 300 regular methamphetamine users, 13% screened positive for psychosis using diagnostic scales that assess suspiciousness, unusual thought content, and halluci-nation (McKetin, McLaren, Lubman, & Hides, 2006). This prevalence of psychosis is more than 11 times higher than that of the general population. An additional 23% of users had experienced at least one psychotic symptom within the past year. Individuals who met diagnostic criteria for meth-amphetamine dependence were three times more likely to have experienced psychotic symptoms, compared to nonde-pendent individuals (McKetin et al., 2006). The psychotic symptoms most frequently experienced by regular metham-phetamine users are delusions, hallucinations, and odd speech. The most common types of delusions are persecutory (experienced in 71% of cases of methamphetamine psycho-sis) and referential (in 63% of cases), though the belief that someone is capable of reading one's mind is also common (experienced in 40% of cases; Chen et al., 2003). Methamphetamine-induced hallucinations are most often auditory (experienced in 85% of cases of methamphetamine psychosis), visual (46%), and tactile (21%; Chen et al., 2003).

thc

most in buds

coke overdose

muscle weakness and respiratory depression. The individual may be unable to stand up, or may collapse but not lose con-sciousness (Crowley, 1987). The lethal dose of cocaine depends to a large extent on the route of administration and individual susceptibility to its cardiovascular effects. Based on experimental studies and clinical reports, the usual lethal dose in a non-tolerant, 150-pound individual is about 1200 mg when cocaine is taken intranasally. However, the range of reported lethal doses varies between 20 and 2000 mg (Gable, 2004b). The absolute dose may not be the important variable in determining the lethality; rather, what seems to be important is the sudden increase in drug levels in the brain. Cocaine overdose or caine reaction has two phases: an ini-tial excitement is followed by severe headache, nausea, vom-iting, and then convulsions. This phase is followed by a loss of consciousness, respiratory depression, and cardiac failure causing death. Death may be very rapid, within 2 to 3 minutes, or it may take as long as half an hour. Someone who survives the first 3 hours is likely to recover, but if breath-ing has been depressed too long, there may be brain damage from loss of oxygen (Gay & Inaba, 1976). Seizures caused by cocaine overdose can be treated with diazepam, and respira-tory depression or arrest can be treated with artificial respira-tion. Chlorpromazine, an antipsychotic, is also very effective as an antagonist of the toxic effects of cocaine (Crowley, 1987).

Neuropharmacology

nervous system depressant. Its primary effects are medi-ated through interaction with GABA receptors. However, unlike alcohol and sedative-hypnotic drugs, which bind to ionotropic GABAA receptors, GHB binds to metabo-tropic GABAB receptors where it acts as a full or partial agonist (see Chapter 4; Busardò & Jones, 2015; Filip et al., 2015). The GHB binding site on the GABAB receptor com-plex is distinct from that of GABA; that is, GHB binds to an allosteric site and modulates GABA activity (Castelli, 2008; Wu et al., 2004). Likewise, GABA does not bind to the GHB site on the GABAB receptor complex. Areas in the brain that contain the highest densities of GABAB receptors include the hippocampus, thalamus, cerebel-lum, amygdala, and parts of the cortex (Filip et al., 2015). Because GABAB receptors are found postsynaptically as well as presynaptically, where they function as autorecep-tors and heteroreceptors, GHB is able to modulate both the activity of GABA and that of various other neurotrans-mitters, in all of these brain regions. Given that GHB also acts as a precursor for GABA biosynthesis, its presence can increase GABA levels in the brain. At dopamine syn-apses, GHB has been found to inhibit dopamine release and cause an accumulation of excess dopamine in the pre-synaptic neuron. After a prolonged period of inhibition, or when higher concentrations of the drug are present, GHB is capable of producing a surge in dopamine activ

pcp and ketamine neuropharmacology

neurotransmitter systems, including norepinephrine, epi-nephrine, dopamine, serotonin, opioid, adenosine, and acetylcholine (Baumeister et al., 2015; Kapur & Seeman, 2002). However, their principal effects appear to be medi-ated by their noncompetitive antagonist actions at gluta-mate NMDA receptors. Recall that glutamate is an excitatory neurotransmitter found near-ubiquitously in the brain. PCP and ketamine bind to a site embedded deep within the ion channel of the NMDA receptor. When the binding site is occupied by PCP or ketamine, the NMDA receptor ion channel is blocked, rendering glutamate inef-fective. This mechanism of action is thought to be similar to that of the alcohol molecule (Dinwiddie & Farber, 1995; Gorelick & Balster, 2000; see Chapter 6). When dissociative anesthetics inhibit the functioning of NMDA receptors, especially in the frontal cortex, negative symptoms of psy-chosis appear (Stone et al., 2008). The reinforcing effects of dissociative anesthetics are likely the result of their influ-ence on glutamate activity, and thereby dopamine release, in the mesolimbic and mesocortical pathways, in a manner similar to that of the barbiturates and benzodiazepines (see Chapter 7)

amphetamine perscription

o control the indiscriminate prescribing of amphet-amines by physicians, most countries now limit the medical conditions for which amphetamines are approved and their production and marketing is carefully monitored. Today, the most commonly known prescription amphetamine is likely Adderall IR (immediate-release) or Adderall XR (extended-release), a 3:1 mixture of d:l isomers. It is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) and narcolepsy. Dexedrine is still available, by prescription, for the treatment of ADHD, narcolepsy, and shift-work sleep disorder, and is used by the military to combat fatigue and performance decline caused by sleep-deprivation (Caldwell, Caldwell, & Darlington, 2003). In 2007, the introduction of lisdexamfetamine (trade name Vyvanse) offered a new approach to psychostimulant therapy for ADHD. Lisdexamfetamine is a prodrug—an inactive compound that is rendered pharmacologically active through metabolism. It is comprised of d-amphetamine bound to the naturally occurring essential amino acid, L-lysine. After absorption into the bloodstream from the gastrointestinal tract, red blood cells metabolize the prodrug in

effects of classic haluconegns on behavior

of participants in his mescaline experiments with those of other researchers and noticed that there were strong con-sistencies. Mostly, people described vivid visual images that were not real. If participants closed their eyes, they would see these images against a black background; if they opened their eyes, the images would be projected onto whatever they were looking at. Klüver noticed that the images were frequently geometric, and he identified some common patterns: a grating or lattice; a cobweb; a tunnel, funnel, or cone; and a spiral. Klüver remarked that images of these types also appear in fever deliriums, insulin hypo-glycemia, and states that occur just before drifting off to sleep (hypnogogic states). Unfortunately, Klüver went only as far as to describe the first of two stages of imagery; the second stage, described by other researchers, is more com-plex and involves meaningful images of people, animals, and places. Even during this second phase, there are some common elements between individuals. For example, 60-70% of research participants report seeing small animal or human figures that are friendly and caricature-like, and 72% of all participants report religious imagery. Despite great interest in these observations, no com-prehensive, systematic, or scientific work on them was attempted until the 1970s. The problem was tackled by Ronald Siegel (Siegel & Jarvik, 1975) from the University of California in Los Angeles (UCLA). Siegel adopted a varia-tion of the technique of trained introspection, which was used by the early German schools of psychology. Siegel trained his observers to use a code to describe their expe Whereas the participants who took placebos saw a predominance of random forms, those administered hallu-cinogenic drugs saw far more lattice and tunnel forms, confirming the observations Klüver had documented. During control sessions, participants saw primarily black and violet forms, but in hallucinogenic sessions, they saw more colors, ranging into the yellow, orange, and red end of the color spectrum. Finally, in all conditions, aimless and pulsating movement was reported, but in hallucinogenic sessions there was an increase in "explosive" movement. After demonstrating that all of these drugs appeared to evoke similar types of images, Siegel was also able to show that, at higher doses, people sometimes go through a phase where they see themselves being swept up into their own hallucination. This is followed by a stage where the images lose their geometric quality and become meaningful pic-tures of real objects. These images can change rapidly, as Siegel found that the experiences represented by the Huichols in their yarn images were very similar to those reported by the participants in his laboratory. Siegel then postulated that the nature and structure of hallucinations must be determined by the nature and structure of the visual system and the brain, not by the drug, because (a) these hallucinatory experiences are similar among vastly different drugs; (b) the experiences resemble the effects produced by other nondrug hallucinations, such as those from fever, hypoglycemia, and migraine headaches; and (c) the experiences are similar between cultures. In other words, the hallucinations are a result of nonspecific inter-ference in brain functioning; the drug intensifies what might be considered normal background noise in the per-ceptual systems, and this noise is then organized, by the normal processes of perception and cognition, into images and patterns (Siegel, 1977; Siegel & Jarvik, 1975). Siegel's study addressed only the visual property of the hallucino-genic experience, but LSD can cause entactogenic and empathogenic effects as well. These experiences often have a profound effect on emotions, insight, and feelings, which are not as easily studied and can be conveyed only by less scientific modes of expression, as we shall see.

Theories of Schizophrenia

progressed in leaps and bounds over the past few decades. Various conceptions of the illness can be summed up as follows: schizophrenia is the result of a genetic predisposi-tion triggered by environmental factors. The positive symptoms of schizophrenia result from hyperactivity at mesolimbic dopaminergic synapses; the negative and cog-nitive symptoms result from degenerative processes in the brain that lead to hypoactivity at mesocortical dopaminer-gic synapses. Dysfunctional glutamate neurotransmission also occurs in schizophrenia. Other neurotransmitter sys-tems, including serotonin, GABA, acetylcholine, and hista-mine, have all been implicated as well. Next, you will find details supporting these claims and how, when they are pieced together, our understanding of the etiology of schizophrenia becomes much clearer.

glutamate hypothesis of schizophrenia

proposal that schizophrenia relates in part to deficient activity at glutamate synapses, especially in the prefrontal cortex In the late 1950s, researchers synthesized two dissociative drugs, phencycli-dine (PCP) and ketamine (known by the street name Special K; see Chapter 15). These drugs can elicit symp-toms similar, not only to the positive symptoms, but also the negative and cognitive symptoms of schizophrenia. Some years later, researchers discovered that the PCP bind-ing site (to which ketamine also binds) sits within the ion channel of the glutamate NMDA receptor. The ability of various compounds to produce psychotic symptoms is directly related to the affinity with which these drugs bind to the NMDA receptor's PCP binding site and, thereby, their ability to antagonize glutamate function. Antagonizing the NMDA receptor's binding sites for glu-tamate or for glycine produces similar effects. In contrast to dopaminergic neurons, which exist in distinct pathways and regions, glutamatergic neurons are nearly ubiquitous in the brain. This is not all that All neural messages leaving the cortex or traveling between cortical areas, and most messages entering the cortex, travel through glutamate neurons. So the repercussions of gluta-mate dysfunction are widespread. According to early con-ceptions of the glutamate hypothesis, genetic factors predispose individuals to glutamate hypoactivity, specifi-cally at the NMDA receptor. Many of the genes believed to contribute to the development of schizophrenia interfere with brain plasticity and influence glutamate neuron con-nectivity, synaptogenesis, and neurotransmission at the NMDA receptor (Tsapakis, Dimopoulou, & Tarazi, 2015). Postmortem assessments of glutamate receptor densities and protein-expression levels have found alterations in the binding and presence of glutamate in the prefrontal cortex, hippocampus, and thalamus of individuals with schizo-phrenia (Clinton & Meador-Wooddruff, 2004). Dysfunction in the glutamate system may be the result of neurodevel-opmental abnormalities in which NMDA receptor syn-apses do not form properly, or it may result from synaptic overpruning of glutamate neuronal connections during childhood and adolescence.

higher doses

pseudo hallucinations, synthensias, paranoi, agitation, confusion, impulsivity, slow judgement, motor decifits,

routs of admin

psules or syrup and consumed orally. Within the gastro-intestinal system, dextromethorphan undergoes significant first-pass metabolism by the cytochrome P450 family of enzymes which rapidly convert it to dextrorphan. Dextrorphan is an active metabolite whose potency is even greater than that of dextromethorphan (in this sense, dex-tromethorphan is considered a prodrug). The most intense subjective effects that result from consuming DXM-containing antitussives will therefore be delayed until the metabolic transformation of DXM to DXO takes place. Since the effects of first-pass metabolism are greatest after oral administration, this route of administration is the most effective for producing high levels of DXO and strong sub-jective effects. The neurobehavioral effects of recreational doses of DXM begin within about 30-60 minutes following consumption and last for approximately 6 hours (Burns & Boyer, 2013). Peak blood plasma concentrations of dextro-methorphan are attained within about 2.5 hours after ingestion, and those of dextrorphan are attained within about 1.6 hours after ingestion (Burns & Boyer, 2013). There is considerable inter-individual variation in the body's ability to convert dextromethorphan to dextror-phan. Some individuals are rapid metabolizers and experi-ence profound effects of dextrorphan quickly, while others are slow metabolizers, meaning that DXO will not reach high levels in the blood and the subjective effects of DXM consumption will be diminished and delayed. Rapid metabolizers are more likely to abuse dextromethorphan because they get a quicker, more intense high (Burns &

physiological effects of weed

pulse up blood pressure down dry mouth dizzy dialtion of vessles in cornea-red eye no permanent heart problems -ppl with disease should abstain tho-increase heart attack risk

general neuropharmacology

tidepressants generally work by increasing activity in one or more of the monoamine systems of the brain. There are several ways that they can do this, and antidepressants are usually classified by their principal mechanism of action. In addition, the functioning of other transmitter systems may be affected. Regardless of the class of antide-pressant, alleviation of depressive symptoms comes weeks after treatment begins. It is believed that this lag time is the result of neuroadaptations that must take place (specifi-cally, the downregulation of 5-HT1A autoreceptors and increase in serotonin system function; Uppal et al., 2010) in order for therapeutic effects to be felt.

tolerance

tolerance Like LSD, PCP is typically used sporadi-cally. When the drug is used daily, tolerance develops and there is some evidence of dependence and withdrawal symptoms upon cessation of use (Grinspoon & Bakalar, 1979b). When users first try the drug, they need only a few puffs of a PCP-laced cigarette to get high, but within 2-6 weeks, they may require two full joints to achieve the same effect. Tolerance also seems to develop to the anal-gesic effects of the dissociative anesthetics. The basis for tolerance is likely neurophysiological and behavioral, rather than pharmacokinetic (i.e., metabolic; Balster, 1987; Gorelick & Balster, 2000). Rapid tolerance also develops to the reinforcing effects and discriminative stimulus prop-erties of ketamine in rats (Rocha, Ward, Egilmez, Lytle, & Emmett-Oglesby, 1996)

neuro

two main receptors for acetylcholine -nicotinic -muscerinic nicotinic stimulated by nic three general states for nAChR -basal state-ion channel is closed-recptor high affnity for ligens -active state-open channel, low affinity desinsitized state-channel closed, low affinity

performance

underlying characteristics of the depression or caused by the medication. Acute doses of the TCAs imipramine and amitriptyline appear to exert detrimental effects on the performance of vigilance tasks and can cause cognitive, memory, and psychomotor impairments that seem to be related to the sedating effects of the drug. These drugs should not be used by people who must drive, use heavy equipment, or engage in intellectual work. Some studies have shown improvement in cognitive functioning after chronic drug treatment, suggesting that these impairments show tolerance, while other studies have not (Lickey & Gordon, 1991). An evaluation of SSRIs and SNRIs on epi-sodic-and working-memory task performance, mental processing speed, and motor performance found signifi-cant drug-induced improvements. SNRIs improved mem-ory performance to a greater extent than did SSRIs (Herrera-Guzmán et al., 2009). There is evidence that the MAOI moclobemide impairs psychomotor performance. An investigation of the influ-ence of long-term SSRI or SNRI treatment on driving per-formance found poorer driving (more weaving) in medicated patients than in controls, but attributed the impairment to depressive symptoms, not the medication (Wingen, Ramaekers, & Schmitt, 2006). Collectively, stud-ies published since the late 1990s suggest a significant increase in risk of traffic collision in individuals taking TCAs or SSRIs, especially in the early stages of treatment, though the increase in odds ratios are relatively small com-

structural abnormalities in schiz

ventricular enlargemtn especially lateral ventricals not seen in all patients not correlated with length of illness

Neuropharmacology

ynthetic cathinones affect the functioning of brain mono-amine systems in two principal ways. First, mephedrone and methylone act as potent, non-selective monoamine reuptake inhibitors. Like cocaine, they block the ability of transporter proteins to clear DA, NE, and 5-HT from the synaptic cleft and transport them back into the presynaptic nerve terminal for vesicular repackaging (Simmler et al., 2013). The newer synthetic cathinone, 4-MEC, exerts similar pharmacological effects (Saha et al., 2015). MDPV is also a highly potent reup-take blocker, but is far more selective than mephedrone or methylone. It has a very high affinity for DATs and NETs and is a strong inhibitor of both. However, MDPV exerts negligi-ble effects on 5-HT reuptake transporter proteins (Baumann et al., 2013; Simmler et al., 2013). Compared to cocaine, for instance, MDPV is 10-times less potent at inhibiting SERTs (Cameron et al., 2013). The "second generation" compounds, 4-MePPP and a-PVP, likewise strongly inhibit DATs with lit-tle effect on SERTs (Marusich et al., 2014; Saha et al., 2015). Second, mephedrone and methylone act as mono-amine substrate-releasing agents. They are carried into presynaptic axon terminals through monoamine reuptake transporter proteins and, once inside the neuron, disrupt vesicular storage and stimulate neurotransmitter release by reversing the normal, inward-bound direction of trans-porter action. Like the amphetamines, mephedrone and methylone promote the release of DA through DATs. Mephedrone, in fact, elicits greater dopamine release than does methamphetamine. Like MDMA, mephedrone and methylone promote the release of 5-HT through SERTs, for which they exhibit preferential affinity (Baumann et al., 2012; Watterson, Watterson, & Olive, 2013). These pharma-cological effects explain how mephedrone and methylone are capable of producing subjective effects that are similar to psychomotor stimulants like cocaine and methamphet-amine, and also to entactogens and empathogens like MDMA (Simmler et al., 2013). In contrast, MDPV is not MDMA (Simmler et al., 2013). In contrast, MDPV is not a substrate-releasing agent; it does not cause an efflux of DA, NE, or 5-HT through monoamine transporter proteins (Baumann et al., 2013). Its ability to increase monoamine neurotransmission is driven by its reuptake transporter inhibiting properties. Thus, all of the commonly abused synthetic cathinones increase monoamine neurotransmis-sion, but to varying degrees and via different mechanisms of action. In addition to enhancing extracellular DA and 5-HT in the nucleus accumbens and hippocampus, their ability to increase NE transmission likely contributes to the peripheral sympathomimetic actions of the synthetic cathi-nones, including potentially dangerous cardiovascular effects. This is a particular risk for MDPV which, com-pared to cocaine, is 10-times more potent at blocking NETs (Iversen et al., 2014). The neuropharmacological differences between mephedrone and methylone, on the one hand, and MDPV, on the other, are noteworthy when it comes to considering their subjective, addictive, and toxicological properties. Generally, the subjective effects and relative abuse poten-tial of recreational drugs is highly correlated with the degree to which a particular substance enhances the trans-mission of dopamine as compared to serotonin (Rothman & Baumann, 2006). Drugs that are poten ffects, elicit more compulsive and prolonged patterns of abuse, and exhibit higher addictive potential (Bauer et al., 2013; Rothman et al., 2001). Compared to the commonly abused substance cocaine, MDPV is 50-times more potent at blocking DATs and produces 10-times greater elevations in extracellular DA levels in the nucleus accumbens (Baumann et al., 2013; Cameron et al., 2013; Simmler et al., 2013). In contrast, drugs that produce relatively greater activation of the 5-HT system tend to exert more entacto-genic and empathogenic subjective effects (Liechti et al., 2000) and produce a pattern of episodic or binge-like use, but have lower abuse potential (Rothman & Baumann, 2006). A high affinity for SERTs is also associated with a greater likelihood of experiencing paranoia and hallucina-tions, similar to the intoxication symptoms of classic hal-lucinogens such as psilocybin, mescaline, and LSD. In addition to displacing molecules of serotonin from synaptic vesicles and inhibiting their reuptake, mephedrone and methylone (but not MDPV) are capable of directly stimulating serotonin receptors, specifically the 5-HT2A and 5-HT2B receptor subtypes (Iversen et al., 2013; López-Arnau, Martínez-Clemente, Pubill, Escubedo, & Camarasa, 2012; Martínez-Clemente, Escubedo, Pubill, & Camarasa, 2012). Generally, drugs with high affinity for these sero-tonin receptor subtypes produce hallucinogenic effects when taken in high doses (Halberstadt, 2015; Nelson, Lucaites, Wainscott, & Glennon, 1999). Stimulation of 5-HT2A receptors has also been shown to indirectly enhance DA release (Gudelsky, Yamamoto, & Nash, 1994), which could potentially increase the abuse liability of drugs with this property. Finally, substrate-releasing agents, drugs that greatly increase brain dopamine levels, and those that stim-ulate 5-HT2A receptors have all been found to produce neu-rotoxic effects via various mechanisms (Mohammad Ahmadi Soleimani et al., 2016). In high doses, dopamine itself is toxic to nerve terminals (Mohammad Ahmadi Soleimani et al., 2016). Enhanced release of monoamines can ultimately cause neuronal damage that leads to a deple-tion of dopamine and serotonin and results in symptoms of anhedonia and depression (Valente et al., 2014). However, unlike numerous other substrate-releasing and reuptake-inhibiting agents, the synthetic cathinones, alone or in various combinations, do not appear to be neu-rotoxic to dopamine nerve terminals in the striatum of mice (Anneken, Angoa-Pérez, & Kuhn, 2015), even when administered in a binge-like fashion (Angoa-Pérez et al., 2012; Hadlock et al., 2011). The lack of persistent deficits in dopamine functioning resulting from synthetic cathinone administration is surprising, given the neurotoxic effects of other psychostimulant drugs. Likewise, mephedrone does not appear to be neurotoxic to serotonin nerve endings in the hippocampus, as is true of MDMA (Angoa-Pérez, Kane, Herrera-Mundo, Francescutti, & Kuhn, 2014), though other researchers have reported persistent seroto-nergic deficits following the binge-like administration of mephedrone (Hadlock et al., 2011). Both mephedrone and methylone have been shown to potentiate the neurotoxic effects caused by other illicit drugs, such as methamphet-amine, amphetamine, and MDMA, when administered in combination (Angoa-Pérez et al., 2013). In stark contrast, MDPV protects against the neurotoxic effects of metham-phetamine, amphetamine, and MDMA, as it prevents the uptake of these drugs through monoamine transporter proteins into nerve terminals (Anneken et al., 2015