CHAPTER 14-MARIJUANA

What is the Toxicity Potential of Amotivational syndrome effects of marijuana?

- Apathy, diminished capacity or willingness to carry out plans for the future. - Cannabis use is correlated with reduced educational achievement. - Rhesus monkeys show reduced breaking points for banana-flavored food pellets when given marijuana. Reduced appetite or motivation?

What are the Physiological Effects of Marijuana?

- Cardiovasculareffects: > Increases heart rate. Time course differs depending on route of administration. > Reddening of the eyes due to dilation of the small blood vessels in eyes. - Dryness of the mouth and throat. > Leads some users to consume alcoholic beverages. - Initial increase in appetite (aka "the munchies"), but this effect shows tolerance and then appetite is suppressed with continued use. - Muscle relaxation, nausea, vomiting.

What is the distribution for THC?

- Concentrates in lungs, kidneys, bile of liver. - Only 1% of peak concentration enters brain. - Much of it is taken up into fatty tissue and released slowly over time. > Leads to delay in peak "high" after peak blood levels have been reached.

What is the withdrawal of marijuana?

- DSM-5: Cannabis withdrawal added. - Not life-threatening but can be unpleasant; severity depends on usage. - Masked by long half-life of THC and metabolites. - Begins about 1 day after the last dose. - Lasts 4 to 12 days. - Symptoms include anxiety, irritability, disrupted sleep, appetite change, craving for cannabis.

What are the effects Cannabinoid Chemicals?

- Difficult to determine the exact effects elicited by each chemical. -1. Amounts of each cannabinoid varies by preparation and route of administration. -2. Cannabinoids thought to be "inactive" may actually alter the potency or metabolism of other cannabinoids. > CBD slows metabolism of THC; CBN may speed metabolism of THC. -3. New cannabinoids are synthesized when the plant is burned or metabolized. > 11-hydroxy-delta-9-THC, the major metabolite of THC, may be more active than THC and can cross the BBB more readily. -4. Cannabinoid content of marijuana changes over time. > THC may be converted to CBN.

What is the description of the marijuana plant?

- Dried leaves and flowers of cannabis plant; usually smoked and baked into cookies or brownies. - Average THC content increasing; can vary between 5-30%.

What is the Mechanism of Action of the ENDOCANNABINOID SYSTEM-2?

- Endocannabinoids send chemical messages via RETROGRADE TRANSMISSION (reverse of classic neurotransmission). - BLOCK release of other neurotransmitters. - THC is an AGONST at cannabinoid receptors, but is MORE EFFICIENT at activation than endocannabinoids.

What is the Toxicity Potential of Immune system effects of marijuana?

- Findings have been mixed. - Some evidence that marijuana use reduces immunity to infection. - Mortality data do not show a relationship between marijuana use and overall death rate.

Is Marijuana a Gateway Substance?

- Gateway substance > One of the first drugs used by a typical drug user. >Alcohol,tobacco,and marijuana are sometimes considered gateway drugs. - Gateway substances may not be the cause of future drug use. > First drug used is not predictive of pattern of escalation of later drug use. > Not all who use gateway substances will use cocaine or other "harder" drugs. - Gateway substances are perhaps best thought of as: > Drugs that are used early on that indicates a basic pattern of deviant behavior resulting from a variety of risk factors which MAY lead to drug use later in life.

What is the Toxicity Potential of Acute physiological effects of marijuana?

- Increased heart rate. - Possibly risky for someone with preexisting cardiovascular disease. - No human overdose deaths have been reported, but too much at one time can cause panic, anxiety, paranoia.

What is the Toxicity Potential of the Driving ability on marijuana?

- Laboratory studies: significant impairment in infrequent users. - Epidemiological studies: little evidence for impairment.

What is the Toxicity Potential of Chronic lung exposure of marijuana?

- Most recent research indicates that marijuana alone is not associated with respiratory symptoms or lung disease. > However, difficult to know for sure as many marijuana users are also tobacco users as well. - Marijuana smoke contains many of the carcinogens found in tobacco smoke, not yet clear whether marijuana smokers are at increased risk for cancer. > Cigarette smokers typically smoke a greater amount; however, marijuana smoke is not filtered and is deeply drawn into the lungs and held there for a longer period. - Vaporizers are becoming a popular method to inhale cannabis smoke while reducing the amount of carcinogens.

What is Hash Oil?

- Prepared by boiling hashish in alcohol and filtering. - May contain up to 60% cannabinoids.

What is Hashish?

- Pure resin that has been carefully removed from the surface of leaves and stems. - Can be smoked alone or with tobacco; can also be baked. - THC content about 20% on average.

What is the Mechanism of Action of the ENDOCANNABINOID SYSTEM-"classic neurotransmitters" and CB1/CB2?

- RETROGRADE TRANSMISSION to BLOCK release of other "classic" neurotransmitters. - THC is an AGONST at cannabinoid receptors, but is MORE EFFICIENT at activation than endocannabinoids. - CB1 and CB2 receptor localization - explains effects

What is the Toxicity Potential of Reproductive effects of marijuana?

- Reduced testosterone levels in men. - Diminished sperm counts and abnormal sperm in men. - Marijuana use by pregnant women does not appear to be associated with negative birth outcomes (e.g., low birth weight and prematurity); however, not recommended for use during pregnancy as some studies indicate impact on later behavior (e.g., sleep patterns, hyperactivity, impulsivity, problems with learning).

What are the Behavioral Effects of Marijuana?

- Subjective effects: > Euphoria, "high," mellowness, stimulation, alterations in perception. > Mood effects appear to be dependent on the mood of others in surroundings. >Infrequent users experience similar but more intense effects compared with experienced smokers (perhaps due to tolerance). > At high THC concentrations, infrequent users may report negative effects such as mild paranoia. -Verbal behavior: > Verbal exchanges decrease. > Nonverbal social interactions increase. -Sleep: > High doses may interfere with sleep.

What is the Mechanism of Action of the ENDOCANNABINOID SYSTEM-1?

- THC binding sites in brain discovered in 1988. - Endogenous cannabinoid chemicals (endocannabinoids) isolated starting in the early 1990's. > Anandamide was the first in 1992. > 2-arachidonylglycerol (2-AG) and at least 3 others have been discovered since that time. - Endocannabinoids appear to function as neuromodulators of other neurotransmitters. - Endocannabinoids bind to its receptors to block the action potential of the presynaptic neuron and inhibits firing. - Blocks release of "classic neurotransmitters" NE,DA,5-HT,ACh, endorphins, GABA.

How was the Medical Uses of Cannabis during the 1970's to present?

-1970's-present: renewed interest in THC for medical usage. > Glaucoma: marijuana smoking reduces fluid pressure in the eye. > Cancer treatment-related nausea (antiemetic). > Pain relief. > Nerve disorders such as MS and ALS. > Boost appetite. Certain types of obstructive sleep apnea? Overactive vagal nerve activity during sleep stage transitions contributes to muscle weakening of upper airway. THC may help normalize this nerve activity. > CBD may reduce psychotic symptoms of schizophrenia—antianxiety implications? -More research is needed, especially with regards to differential developmental effects.

What are the Cognitive Effects of chronic marijuana users-2?

-Data is mixed but indicates possible developmental vulnerability. > After abstaining for more than a month, regular marijuana use produces few effects on cognition in adult users (Pope et al., 2001). > Habitual marijuana users (followed over 30 years) showed a greater cognitive decline over non-users, with the most significant impairments observed with heavy adolescent use (Meier et al., 2012). > Meta-analysis of imaging studies indicate chronic marijuana usage produces alterations in brain structure and deficits in cognitive function in both adults and adolescents (Batalla et al., 2013). > Small study indicates that recreational, non-dependent, young adult users show dose-dependent structural abnormalities (density, shape, size) of nucleus accumbens and amygdala (Gilman et al., 2014). Impact on behavior and if these effects are reversible are currently unknown.

What are the Cognitive Effects of chronic marijuana users-1?

-Difficult to make definitive statements about effects on long-term cognitive functioning. > Studies have had divergent findings and interpretations.

What is the Marijuana Tax Act of 1937?

-Followed the regulation-by-taxation theme of the 1914 Harrison Act. > Grower, distributor, seller, and buyer were taxed. > Result: administratively almost impossible to deal in Cannabis. > Eliminated the possibility of legitimate medical use. - State laws made possession and use illegal. - Cost of marijuana increased significantly. -LaGuardia Report (1944): > Concluded that marijuana use had less serious effects than commonly believed. > Report elicited strong negative reactions.

What are the Cognitive Effects of frequent marijuana users?

-Frequent users: marijuana causes less dramatic effects. > Slowed cognitive processing. > Frequent users may be tolerant to cognitive effects.

Describe the Marijuana History: U.S. Regulation

-Hemp grown alongside tobacco in American colonies, but not widely perceived to be a recreational drug until early 20th century. - 1926: >Series of news paper articles linked marijuana and crime and violence. > Public interest/concern increased very rapidly. > Legislators associated usage with lower income and minority groups. -1937: > All states had laws regulating the use, sale, and/or possession of marijuana. -Most early regulation efforts: > Based on concerns about use and criminal behavior. > Concerns not based on direct evidence.

What are the Cognitive Effects of Infrequent marijuana users?

-Infrequent users: marijuana disrupts cognitive performance. > Slowed cognitive processing. > Impairedshort-termmemory. > Impairedinhibitorycontrol. > Loss of sustained concentration or vigilance. Impairedvisuospatialprocessing.

What is Marijuana Madness>

-Marijuana Madness: > Some studies have found a correlation between marijuana use and psychotic symptoms. -Causation? > Psychotic symptoms prior to using marijuana? > Influence of other drug use on the psychotic symptoms? -There is evidence that marijuana can increase the likelihood of psychotic episodes in individuals with a history of psychiatric problems. > But also involves environmental risk factors, dosage, genetic risk factors, and age at first use.

What is marijuana and what are the three subspecies?

-Marijuana is a preparation of leafy material from the Cannabis plant that is usually smoked. > Most widely used illicit drug in the world. > Current prevalence of use increasing. > Use of cannabis has been traced back thousands of years. -Three species: > Cannabis sativa: used primarily for its fibers from which hemp rope is made. > Cannabis indica: grown for its psychoactive resins. > Cannabis ruderalis: grows primarily in Russia.

How was the Medical Uses of Cannabis before 1937 Marijuana Tax Act?

-Medical use declined before the 1937 Marijuana Tax Act for several reasons: > New and better drugs were developed to treat most illnesses. > Variability of product. > Active ingredient insoluble in water and thus cannot be injected. > Oral dose has delayed onset of action.

What is the elimination for THC?

-Metabolism: > Most metabolism takes place in the liver, which is limited by the release of THC from body fat. > Most THC is removed from the brain within 30 minutes. > THC has a half-life of 20-30 hours. > Complete elimination of THC and its metabolites may take 2-3 weeks. > Maybe even up to 30 days, depending on body composition. -Excretion: Primarily in feces (55%) and urine (20%). *IMPORTANT NOTES* 1. No easy way to measure blood or urine levels of THC or metabolites and correlate them with behavioral/physiological effects (roadside screening methods are being developed for driving under the influence). 2. Effects of stored THC and metabolites have not been determined.

How potent is resin?

-Potency of Cannabis preparations depends on the amount of resin (dried sap) present. > Most of the resin is in the flowering tops. > Less in the leaves. > Little in the fibrous stalks.

What does the Self-administration indicate for Marijuana Dependence?

-Self-administration > Studies show both animals and humans will self-administer both smoked marijuana and oral THC. > Note: routes of administration of THC that induce a rapid onset of effects (e.g., smoking) may influence the abuse potential.

What are synthetic Cannabinoids?

-Synthetic cannabinoids have similar chemical structures, although not much is known about their effects. > May be more stable, effective, and/or selective. > Therapeutic use (e.g., dronabinol and nabilone) > Recreational use (e.g., K2, spice): at least 5 are currently illegal in the U.S.

What are the cannabinoid chemical two receptors?

-THC and other cannabinoid chemicals bind to two receptors; THC is longer lasting and has greater effects compared to endogenous cannabinoids. -CB1 receptors: - Found primarily in the brain but also throughout the body. - High density in specific brain regions: > Basal ganglia and cerebellum (movement coordination). > Hippocampus (memory storage). > Cerebral cortex (higher cognitive functions). > Nucleus accumbens (reward). -CB2 receptors: > Found mainly in spleen and immune cells; lesser concentration in brain. > Potential role of cannabinoids in the modulation of the immune system. > Activation of CB2 receptors in brain may be protective against neural destruction by the immune system. -Few CB receptors found in medulla; thus, overdose by breathing suppression is not likely.

What is the Absorption for THC?

-THC is highly lipid soluble; can hardly dissolve in water. > More likely to stick in cell membranes rather than move in and around freely -Via inhalation: > Rapid absorption into bloodstream; blood levels peak within 15 minutes. > Vaporizers heat the plants to boil the chemicals in the plant material; cannabinoids are vaporized at lower temperatures and make up more vapor than tars and other carcinogens. -Via oral administration: > THC is absorbed more slowly; can be ↑ by adding oil to plant material. > More is metabolized via first-pass metabolism by the liver before reaching the brain (compared to smoking). > Peak effects occur about 1-3 hours following ingestion. > More likely to cause nausea and vomiting compared to smoking.

What are Cannabinoids?

-There are more than 400 chemicals in marijuana. Over 80 are cannabinoids (chemicals unique to cannabis). -Some cannabinoids: - Delta-9-tetrahydrocannabinol (THC) > Primary psychoactive agent in Cannabis. > Synthesized in 1964. - Cannabinol (CBN) - Cannabidiol (CBD) > May have anxiolytic/antipsychotic effects.

What does Marijuana Dependence indicate Under controlled laboratory conditions?

-Under controlled laboratory conditions: > Marijuana cigarettes with higher THC content are preferred. > Participants choose more oral THC during periods of social interaction.

How was the US After the Marijuana Tax Act?

-Use of marijuana increased throughout the 1950's-1960's. > Scientific research on marijuana stalled at this time. > Use peaked in 1970's (personal freedom, reject authority). - 1969: U.S. Supreme Court declared the Marijuana Tax Act unconstitutional. - Controlled Substance Act of 1970 classified marijuana as schedule I drug at the national level (no accepted medical use and high potential for dependence/abuse). > Still under review for rescheduling. - Marijuana use decreased in the 1980's, but rose again in the 1990's. > Still has not reached the peak of the 1970's. - Decriminalization/legalization movement gaining momentum.

What is the Tolerance of marijuana?

> Tolerance to many marijuana effects develops after high levels of regular use (e.g., effects on cognitive functions). > May not develop uniformly to all effects (e.g., cardiovascular effects). > Associated with a decrease in the number and desensitization of cannabinoid receptors in several brain areas. > Sensitization (reverse tolerance) for some effects has been demonstrated outside the laboratory. > Users learn to inhale more efficiently to require fewer joints to get high, in addition to environmental and experience effects.

What does the data indicate for Marijuana Dependence?

Data indicate: > There is abuse potential of THC. > Remember, there is always a percentage of individuals who have a problem controlling their usage! > Cannabis self-administration is influenced by social factors.