Psychopharmacology 4
typical exponential rate
first order elimination kinetics
1960s-70s
many new synthetic amphetamine-derived hallucinogens, such as DOM, were discovered
History of synthetic cathinones 1930s
methcathinone used as antidepressant in USSR
History of synthetic cathinones 1960s
pyrovalerone (Centroton®) developed to combat fatigue
1925
The 2nd International Opium Convention in 1925 banned the non-medical sale of morphine and diacetylmorphine (heroin), followed soon by the development of other morphine analogues
new psychoactive substances (NPS
The United Nations now refers to new synthetic drug analogues as
Projection neurons (PN)
receive sensory signals and relay them to the brain
History of synthetic cathinones 2000s
reports of mephedrone, MDPV, methylone use surface in Europe
Ethyl alcohol
(ethanol, EtOH, alcohol) is the type that is found in alcoholic beverages
Synthetic steroids
(hydrocortisone, prednisone, etc.) also reduce inflammation (not via COX inhibition), but long term use is harmful to the immune system
Methyl alcohol
(methanol, wood alcohol) is metabolized to toxic chemicals such as formaldehyde, which can cause blindness, coma, and death
History of opiate drugs 1979-now
Geopolitical crises in Afghanistan and other middle eastern countries often involve opium production and export
nociception
the perception of pain
Mechanisms of cannabis-induced analgesia
>When stimulated, -CB2 receptors located on immune cells can suppress secretion of nociceptor-activating pro-inflammatory molecules -CB1 receptors located on free nerve endings reduce activity of pain-sensitive neurons -CB1 receptors located on synaptic terminals of sensory neurons inhibit neurotransmitter release in the dorsal horn, and reduce ascending pain signals to the brain within the spinothalamic tract
Alcohol excretion
>~95-97% of alcohol ingested is metabolized by the liver, and its metabolites are excreted through the urine via the kidneys >~3-5% of alcohol ingested is excreted unchanged via the lungs, regardless of the route of consumption >Trace amounts of alcohol are excreted in sweat and feces
Maintenance
psychological and group therapy (Narcanon) in combination with opioid substitution therapies such as methadone or Suboxone
nociceptors
types of receptors for stimuli (chemical, mechanical, thermal) that result in pain perception; located on free nerve endings in skin, muscle, organs, but not in the brain
FDA Safety & Innovation Act of 2012
which contained the Synthetic Drug Abuse Prevention Act, declared all synthetic cannabinoids (cannabimimetics), two "bath salt" drugs, and 9 "2C-type" hallucinogens to be Schedule I controlled substances
Non-steroidal anti-inflammatory drugs
(NSAIDs, such as aspirin, ibuprofen, naproxen, acetaminophen, etc.) produce pain relief by inhibiting COX activity and reducing prostaglandin formation
Physiological effects of opiates
-Analgesia -Respiratory Depression -Euphoria -Relaxation and sleep -Tranquilization -decreased blood pressure -Constipation -Pupil constriction -Hypothermia -Drying of secretions -Reduced sex drive -Flushed and warm skin -Narcosis
Alcohol absorption
-After oral consumption of alcohol, ~20% is absorbed into the bloodstream via the stomach, and ~80% is absorbed into the bloodstream via the small intestines -Absorption is slowed in the presence of food -Absorption is accelerated by carbonation -BACs peak ~45-60 min after ingestion -Occasionally, other routes of intake are used
Alcohol metabolism
-Alcohol is first metabolized to acetaldehyde by alcohol dehydrogenase (ADH) -Acetaldehyde is then metabolized to acetic acid by acetaldehyde dehydrogenase (ALDH) -There are many genetic variants of ALDH across ethnicities (i.e., ~10% of Asians have genes that code for an inactive form of ALDH) -Acetic acid is then converted to CO2, H2O, and energy (i.e., ATP)
Alcohols
-Alcohols are a class of chemicals produced by the natural process of fermentation by yeast cells -During fermentation, glucose is broken down to form energy (i.e., ATP) and several intermediates prior to forming alcohol -Ethyl alcohol -Isopropyl (rubbing) alcohol -Methyl alcohol
Synthetic cannabinoids
-Also known as herbal alternatives, incense, synthetic weed, potpourri, Spice, K2, etc. -Typically consist of "blends" of 10+ psychoactive compounds -Either THC analogues or structurally unrelated chemicals that are agonists at the CB1 cannabinoid receptor -The first synthetic cannabinoids were created decades ago by John W. Huffman (JWH) of Clemson University for (true) research purposes -Synthetic cannabinoids do not contain cannabidiol to buffer their effects, and as a result carry a higher probability of producing adverse psychiatric or toxic effects
Effects of synthetic cannabinoids
-At low doses, the subjective effects of synthetic cannabinoids are similar to marijuana (euphoria, relaxation, sedation, altered consciousness, increased sensory experience) -At high doses, adverse effects can occur include nausea, hypertension, tachycardia, seizures, hyperventilation, agitated delirium, delusions and paranoia, and death -The high incidence of toxicity is likely a result of the absence of cannabidiol
Forms of marijuana-based medicine
-Botanical cannabis -THC-based medications -dronabinol (Marinol) synthetic THC -nabilone (Cesamet) synthetic THC -Sativex spray form of THC + CBD
Buprenorphine/Suboxone
-Buprenorphine (Buprenex, Butrans) is a partial agonist at mu opioid receptors (half-life 24-48 hr) -Suboxone is an abuse-deterrent combination of buprenorphine and naloxone >when taken orally (as prescribed), the naloxone that reaches brain concentrations that are very low (poor bioavailability) >when taken intravenously (i.e., abused) naloxone reaches brain concentrations high enough to block opiate receptors and reduce effects of buprenorphine -Zubsolv is a sublingual form of Suboxone Monthly depot injections currently in clinical trials
Two typies of cannabinoid receptors
-CB2 receptors -CB1 receptors -Both are inhibitory G-protein coupled receptors -Both were discovered as the primary target of THC prior to the discovery of AEA and 2-AG -THC is an agonist of both CB1 and CB2 receptors -Cannabidiol (CBD) buffers the effects of THC, but research so far has found that CBD does not act as a CB receptor antagonist, so its mechanisms of action are still unknown
Cannabidiol (CBD) based medicines
-CBD is generally thought to buffer the effects of THC, but its precise pharmacology is unknown -CBD does not appear to interact directly with CB receptors, but perhaps other neurotransmitter receptors or ion channels -CBD appears to be a potentially effective anticonvulsant and possible therapeutic for other disorders -The current legal status of CBD is very complicated and murky >its is not specifically listed as a Schedule I controlled substance, but is considered a marijuana extract and therefore Schedule I
Approved medical uses of marijuana in AZ
-Cancer -Glaucoma -HIV/AIDS -Hepatitis C -Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) -Crohn's disease -Agitation of Alzheimer's disease -A chronic disease that causes: >wasting syndrome (cachexia) >severe chronic pain >severe nausea >seizures/epilepsy >Severe muscle spasms, incl. MS
Anti-emetic effects of cannabis
-Cancer patients frequently use cannabis to relieve chemotherapy-induced nausea and vomiting (CINV) -Many regions of the brainstem regions receive neural inputs from the GI tract, vestibular system, and internal chemical trigger zones to regulate vomiting (emesis) -Cannabis-induced activation of CB1 receptors in the brainstem inhibits the activity of these regions, producing anti-emetic effects
Over-the-counter (OTC) pain relievers
-Cyclooxygenase (COX) -After tissue injury, prostaglandins activate nociceptors on free nerve endings -Non-steroidal anti-inflammatory drugs (NSAIDs) -Synthetic steroids
The designer/synthetic drug cycle
-DEA places the drug on a special surveillance list for monitoring potential abuse and threats to public safety -If sufficient evidence for either exists, the DEA can utilize its emergency scheduling authority to place the substance into a temporary schedule for up to a year, after which the Controlled Substances Act must be amended by Congress -Drug makers alter the chemical structure by as little as a single atom with the intent of making it a new chemical entity -The new synthetic drug, of unknown potency and mixed with unknown chemicals, becomes available on the streets/internet and is sold as a "legal high" on the "gray market"
Kratom
-Derived from Mitragyna speciosa, a plant native to southeast Asia -Primary psychoactive substances are mitragynine and 7-hydroxymitragynine (7-HMG), which are mu opioid receptor agonists that are >10x more potent than morphine, but chemically unrelated to opiates -7-HM also has affinity for 5-HT2A and alpha-adrenergic receptors -Mitragyna speciosa also contains rhynchophylline, an NMDA antagonist -In August 2016 the DEA announced its intention to place Kratom into Schedule I status due to over 600 poison control center reports from 2010-2015 of adverse effects and overdose -Due to a strong public outcry and petitions for its potential medicinal use (especially as an alternative opioid substitution therapy), the DEA withdrew its statement of intent in October 2016 -Although some states have banned its sale and use, Kratom remains unregulated by the DEA, for now...
Krokodil
-Desomorphine is an opiate that was patented in 1930's as a sedative/analgesic (now Schedule I) it is a cheap, synthetic opioid receptor agonist that is 8-10x more potent than morphine -Desomorphine is synthesized from codeine (which is sold OTC in countries such as Russia) with the use of harsh chemicals such drain cleaner, gasoline, hydrochloric acid, and paint thinner -Nicknamed Krokodil or the "flesh-eating drug" due to the scaly effects it produces on the skin -The drug itself is not toxic at normal doses, but contaminants from synthesis that cause necrotizing fasciitis, gangrene, osteonecrosis, etc.
Treatment of opiate addiction
-Detoxification -Maintenance
Alcohol distribution
-During early stage distribution, organs with a rich blood supply such as the lungs, kidneys, liver and brain will initially receive a proportionally higher amount of alcohol than tissues with lower blood flow -Eventually alcohol reaches equilibrium across all tissues
Endocannabinoids (ECBs)
-Endogenous cannabinoids (endocannabinoids, ECBs) are fatty acid-derived molecules that include anandamide (AEA) and 2-arachidonylglycerol (2-AG) -Anandamide comes from the Sanskrit word ananda meaning "bringer of inner bliss and tranquility" -ECBs act as retrograde messengers to inhibit neurotransmitter release by acting on inhibitory presynaptic CB1 receptors -ECBs are enzymatically degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)
Endogenous opioid peptides
-Endogenous opioids are neuropeptides (amino acid chains of varying lengths) -They include the endorphins (a contraction of the term "endogenous morphine", endomorphins, enkephalins, dynorphins, and others -Opioid peptides bind to and activate opioid receptors, which include , , and receptors (i.e., MOR, DOR and KOR) -All opioid receptors are inhibitory G-protein coupled receptors
The origins of the term "420"
-In 1971, a group of friends in San Rafael, CA calling themselves the Waldos regularly met at a Louis Pasteur statue on the grounds of San Rafael H.S. at 4:20 pm prior to embarking on daily treks to harvest marijuana plants from local fields -They colloquially referred to this as "4:20 Louie", and eventually just "420" -California Senate Bill 420, which amended a prior bill (SB 215, Compassionate Use Act of 1996), was passed in 2003 and was one of the first legislative acts to establish a state medical marijuana program -Contrary to popular belief, it was Colorado Amendment 64 that legalized marijuana for recreational purposes, not Proposition 420 -420 is now largely used by the marijuana culture as a reference to the drug
Actions of synthetic cathinones
-In addition to different mechanisms of action, individual synthetic cathinones have different durations of action and potencies (i.e., MDPV is 10x more potent than methylone, 10x longer acting than cocaine)
Mechanisms of opiate-induced analgesia
-In spinal analgesia, opiates act in the dorsal horn of the spinal cord, where they reduce incoming pain signals by inhibiting presynaptic terminals of primary afferent Adelta and C fibers -However, opioid receptors are not found on Abeta or other non-nociceptive afferents, leaving normal sensations intact -In supraspinal analgesia, opiates inhibit pain signal processing in various brain regions including the thalamus and cerebral cortex
The current opioid epidemic
-In the last two decades, opiate addiction and overdose rates have risen dramatically due to: >increasing opiate prescription rates >restrictions on amounts of opioids that can be dispensed per prescription increased availability and lower costs of heroin >Adulteration of heroin with highly potent opioid agonists such as fentanyl and its derivatives such as furanylfentanl and acetylfentanyl
Common arguments for marijuana legalization
-Increased tax revenue -Legitimate medical purposes -Allows for greater regulation -Weakening of drug cartels -Reductions in burden on law enforcement and criminal justice system -Reduced health care costs -Less addictive or harmful than other drugs
Anti-migraine medications
-Medieval treatments for migraine included trepanation (drilling a hole in skull), placing a hot iron on the head, and bloodletting -Up until recently, the etiology of migraines was thought to be due to dilation and inflammation of dural blood vessels -More recent evidence suggests that migraines may originate from within the brain via abnormal neural activity (cortical spreading depression) in brainstem regions such as the trigeminocervical complex (TCC) -The first effective medication developed was ergotamine which constricts blood vessels by activating 1 and 5-HT1 receptors -Current anti-migraine medications belong to the triptan family (sumatriptan (Imitrex), zolmitriptan (Zomig), eletriptan (Relpax), etc., which cause vasoconstriction via stimulation of 5-HT1B receptors on blood vessel walls and inhibit pain signal transmission by activating 5-HT1B/1D receptors in the brainstem
Methadone
-Methadone is a long-acting mu opioid receptor full agonist (half-life 15-60 hr) taken in a pill or liquid form -Has abuse potential and side effects, but withdrawal is generally less severe than heroin -Administration is usually supervised at methadone clinics -Deaths can occur as a result of drug accumulation due to long half-life
Common arguments against marijuana legalization
-Negatively affects driving and cognitive performance -Carcinogenicity and neurotoxicity uncertain -Increased regulatory burden -Cartels will continue by trafficking other drugs Increases in dubious medical practices -Marijuana is a "gateway" drug -Will lead to equivalent of "Big Tobacco"
Abuse-deterrent prescription opiates
-New formulations of morphine, oxycodone, hydrocodone, etc., such as Embeda, MorphaBond, Xtampza, Arymo, Acurox, etc. are designed to: >produce an aggregate when crushed >release naltrexone if taken non-orally >form a viscous gel that is difficult to draw into a syringe -Others contain irritants such as sodium dodecyl sulfate that are benign to the stomach but are painful to the skin or nasal passages if snorted -Some contain niacin which causes an unpleasant flushing reaction if too many pills are taken
Synthetic cannabinoids look like pot, but aren't
-Often imported from China where they are mass produced -Put into liquid form and sprayed onto dried and otherwise inert plants to give them a marijuana-like appearance -Do not actually contain marijuana -Newer versions come in liquid form intended for use with in e-cigarettes
Opiate suppression of neuronal activity
-Opiates reduce neuronal activity through post-synaptic or neurotransmitter release by presynaptic inhibition -In some brain circuits, such as the mesolimbic reward pathway, this can cause disinhibition ("releasing the brake") of firing of other types of cells
Treatment of opiate overdose
-Opioid overdose is usually treated with broad spectrum opioid receptor antagonists such as naloxone (Narcan) -The FDA recently approved naloxone as a nasal spray without the need for a prescription -Deaths due to opioid overdose primarily result from inhibition of neuronal activity in brainstem respiratory regions
Ascending and descending pain pathways
-Pain signals are transmitted to the brain primarily via the spinothalamic tract -Pain perception can be modulated by descending inputs to the dorsal horn, such as NE/5-HT projections from the locus coeruleus/raphe nuclei -As a result, SSRI, SNRI, NRIs can alleviate chronic pain in some patients
Pain Fibers
-Sensory information is carried to the central nervous system via various types of primary afferent neurons, which enter the spinal cord via the dorsal root ganglion into the dorsal horn -Adelta fibers -C fibers -A beta -Projection neurons
Structure of synthetic cathinones
-Synthetic cathinones are chemical derivatives of cathinone, a naturally occurring stimulant found in the Khat plant in the Horn of Africa and Arabian Peninsula -Also known as β-ketone amphetamines (note the structural similarity to amphetamine) -First to emerge were MDPV, mephedrone, and methylone ->100 have now emerged, including alpha-PVP ("flakka", "gravel"), and hundreds more likely in the future
Pharmacodynamics of THC
-THC is very lipid soluble and penetrates the BBB rapidly -The elimination half-life of THC depends on body compartment (plasma <2-3 hours, brain ~24 hr, fatty tissue ~10-13 days), and frequency of use (overall average 1 day in infrequent user, 5-10 days in frequent users) -Metabolized by liver primarily into the active metabolite 11-hydroxy-THC as well as the inactive metabolite 11-norcarboxy-THC and many others, all of which have relatively long half-lives -As a result of its lipophilicity, THC and its some metabolites are stored in fatty tissue, which can be detected for 6-8 weeks after last use
Current legal status of marijuana in the U.S.
-The Controlled Substances Act placed marijuana and its components into federal Schedule I status, where it has remained ever since -This includes marijuana extracts such as tetrahydrocannabinols (THCs) -However, certain parts of the plant (stalk, fiber, and sterilized seeds) and their extracts, are exempt from this classification -Numerous states now have varying degrees of marijuana legalization for medical and recreational purposes -In August 2016, the DEA denied a petition to reschedule marijuana
Is marijuana addictive or neurotoxic?
-The best evidence for marijuana dependency is the emergence of withdrawal symptoms following chronic use: -Symptoms include anxiety, insomnia, anorexia, irritability, tremor, depression, headache, and craving for the drug -Dependence occurs in ~9% of users -There is no consensus one way or the other as to whether marijuana permanently damages the brain
Opiate tolerance
-The development of tolerance to the analgesic and euphoric of opiates is a major contributor to their misuse -When activated, opioid receptors inhibit the production of the cellular messenger cyclic AMP (cAMP) -During withdrawal from chronic opiate use (i.e., morphine, M) , relief of this suppression causes a rebound over-production of cAMP, altering cellular homeostasis -Opiate tolerance is likely a result of drug-induced receptor endocytosis (removal of receptors from cell surface) -Depending on the degree of overstimulation, internalized receptors can either be recycled back to the membrane (for future use), or degraded (if no longer needed)
Psychoactive components of marijuana
-The marijuana plant contains >400 unique chemical substances, excluding biochemical and macromolecules needed for basic cellular function ->100 of these are cannabinoids such as delta 9-tetrahydrocannabinol (delta9-THC), delta8-THC, cannabinol (CBN), cannabidiol (CBD), and cannabitriol (CBT) ->200 additional chemicals are formed after combustion (pyrrolysis), including some that may be carcinogenic (i.e., polycyclic aromatic hydrocarbons) -Marijuana can also contain pesticides and fungi
Possible anti-tumor effects of cannabis
-There are case reports of cannabis use reducing tumor growth including brain tumor size -Cannabis may have anti-tumor properties by inhibiting growth of new blood vessels (angiogenesis), cancer cell proliferation, or cancer spread (metastasis, via disrupting cancer cell adhesion, migration or invasion)
Pot and schizophrenia
-There is a long-standing debate as to whether marijuana use, particularly during adolescence, increases the risk of developing psychosis and schizophrenia -However, evidence for this appears to be limited to individuals who are genetically susceptible (i.e., monozygotic twin of an affected individual) or carrying a genetic variant that might predispose that person to mental illness
Alcohol clearance
-Unlike most drugs, alcohol is eliminated at a linear rate (also known as a zero order elimination kinetics), rather than at a typical exponential rate (first order elimination kinetics) -This occurs as a result of saturation by alcohol of the multiple enzymatic steps involved in alcohol metabolism -Because of this, alcohol is not generally considered to have an elimination half-life (t1/2) -The clearance rate of alcohol in the blood varies from person to person depending on genetics, body mass, gender, drinking history, etc., but typical elimination rates are about 1 drink per hour (~0.015% BAC)
Adverse effects of synthetic cathinones: Psychological
-agitated delirium, often requiring general anesthetics or other extreme measures for sedation -severe and lasting hallucinations and delusions -suicidal and homicidal ideation -violent paranoia
Bath salts
-are common names for synthetic cathinones, which are amphetamine-like molecules sold as fictitious retail products -Other common fictitious names included plant food, glass cleaner, iPod cleaner, ladybug attractant, research chemical, etc. -They are taken orally, intranasally, intravenously or smoked -They are not actually "bath salts" for bathing - these are normally epsom salts
Adverse effects of synthetic cathinones: Physiological
-hypertension -appetite suppression -tachycardia -motor abnormalities -rhabdomyolysis and kidney failure -cardiac arrest -death
Major classes of designer drugs
-synthetic cannabinoids -phenethylamine (2C) and tryptamine-based hallucinogens -mu opioid agonists (fentanyl analogues, U-47700) -ketamine analogues -piperazine-based stimulants -bath salts and other amphetamine analogues
Detoxification
-ultra-rapid (anesthesia-assisted) detoxification, which consists of administering a high dose of an opiate receptor antagonist such as naloxone or naltrexone while the patient is under general anesthesia for several hours to remove opiate drugs from their receptors and precipitate withdrawal -accelerated (stepped or rapid) detoxification, which consists of administering naloxone and withdrawal symptom minimizing medications (i.e., benzodiazepines or NE receptor antagonists such as clonidine) while conscious but under medical supervision
History of synthetic cathinones Pre 1900's
Catha edulis (Khat, Qat) plant, which contains the chemical cathinone, used recreationally for centuries
mephedrone, methylone
DA/NE/5-HT releasers, similar to amphetamines
MDPV, "mu-PVP"
DA/NE/5-HT transporter blockers, similar to cocaine
History of synthetic cathinones 2014-ores
DEA places additional synthetic cathinones into temporary Schedule I status, later moved to permanent status
Adventures in buying "research chemicals"
Drug turned out to be 4-methylethcathinone (4-MEC), which has profoundly different potency and effects compared to mephedrone
History of opiate drugs 1874
Heroin first synthesized from opium
History of opiate drugs 1850s
Hypodermic syringe and needle are invented
History of synthetic cathinones 2011
MDPV, mephedrone, and methylone classified by DEA as Schedule I controlled substances on a temporary basis while further research is conducted
History of synthetic cathinones 2013
Methylone permanently classified as Schedule I controlled substance
Prevalence and type of designer drugs (NPS)
More NPS have been developed in the past decade than the number of all previous substances scheduled by the DEA
History of opiate drugs 1804
Morphine isolated from opium
History of synthetic cathinones 2012
Obama signs into law the Synthetic Drug Abuse Prevention Act, which bans MDPV and mephedrone along with 20 synthetic cannabinoids and 9 synthetic hallucinogens
History of opiate drugs 1839-1860
Opium wars between Britain and China
History of opiate drugs ~4000 B.C
Recorded history of medical opium use
1980s
The term "designer drugs" was coined in the 1980s in response to the increased development of synthetic fentanyl and meperidine analogues (i.e., MPPP), as well as amphetamine derivatives such as MDMA
Types of opiates
The terms opiates and opioids are often used interchangeably when referring to either chemicals derived from the opium poppy, or endogenous opioids like endorphins
anesthetic
a substance that reduces perception by all senses (pain, touch, temperature, pressure, etc.)
analgesic
a substance that reduces the perception of pain
Opiate narcotic drugs
all bind with varying affinities to and are agonists at mu,delta or k opioid receptors
linear rate
also known as a zero order elimination kinetics
anesthesia
absence of all sensory perception
analgesia
absence of pain
A beta
and other fibers carry convey normal touch and pressure signals
CB2 receptors
are highly expressed in the immune system, and have a much more restricted distribution in the brain
ADelta fibers
are myelinated and carry information about quick, sharp pain
C fibers
are unmyelinated and carry information about dull, burning, or aching pain
CB1 receptors
are widespread throughout the CNS
History of synthetic cathinones 1985
buproprion (Wellbutrin, Zyban, a synthetic cathinone) approved
History of synthetic cathinones 1993
cathinone listed as Schedule I by DEA
The Federal Analogue Act of 1986
declared that chemical substances that structurally or pharmacologically similar to Schedule I or II controlled substances shall be treated as if they were actually substances in those schedules, if they are intended for human consumption
Isopropyl (rubbing) alcohol
is a denatured form of alcohol used for medical and cleaning purposes
Cyclooxygenase (COX)
is an enzyme that produces prostaglandins in skin and other types of cells
History of opiate drugs 1680
tinctures (mixture of plant extracts and alcohol) such as laudanum and paregoric (containing opium and wine) are introduced