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Chapter 10 - Marijuana Marijuana Medicinal uses documented back to ancient times… Cannabis sativa There are 2 varieties of this plant: Psychoactive o Growing o Weaker fabric o High cannabinoid content o Delta-9-tetrahydrocannabinol and 66 other cannabinoids. Non-psychoactive (hemp) o Easy and fast growing o Strong plant fiber o Little cannabinoid o Many industrial uses Cannabis sativa L. There are two sub-species: Cannabis sativa: higher THC content. o More euphoria. Cannabis indica: higher Cannabidol (CBD) content. o More medicinal aplications (muscle relaxation, analgesia, sleep aid) Marijuana in America Classified as controlled substance iwht no medicinal value in 1970. Today Most commonly used legal drug. o More than 83 million Americans report trying at least once. 18 million in the past month. o Is associated with cigarette and alcohol use. o The number 1 cash crop in America. 2015 revenue in CO. Cannabis sativa: Psychoactive forms Marijuana: Dried leaves and flowers. o Usually smoked; may be baked into foods. o Wide range of THC content (5-15% THC) o Sinsemilla: without seeds (25 to 35% THC) Bhang: Entire remainder of plant after top has been picked. o Ground into a powder. o Often mixed into drinks. 2 Ganja: Made of the tops of the female plants; resin is still present. Hashish: resign from top of female plant. o Dried and then smoked or baked into foods. Hash Oil: Solvents are used to extract the cannabinoids o Tends to have high THC content (15 to 70%) Dab o Concentrated hash oil Infuse marijuana with butane gas o 80-90% pure THC 20 to 25% Absorption Highly lipid (fat) soluble; will hardly dissolve in water. Oral: o SLOW o Oil in foods help to speed absorption. o Peak effects in 1-3 hours; may last up to 6 hours. Inhalation: o 10 to 25% of cannabinoids are absorbed. o Blood levels peak in 15 minutes. o Effects last 30 to 60 minutes. 3 o Depth of inhalation is more important than length. Distribution Only 1% enters the brain. Distributed all over the body. Where does it work in the brain Currently know about two cannabinoid receptors. o CB 1– Found primarily in brain o CB 2– Found primarily in periphery o These work to influence GABA, endorphins, and dopamine. Endogenous agents: endocannabinoids o Anadamide o 2-AG (2-arachindonoylglycerol) 2-AG is the primary endocannabinoid. Why not develop CB 1 and CB 2(ant)agonists There has been development of various CB1 and CB2 agonists and antagonists. They seem to be less effective than the effects observed from cannabis. o The medicinal value of cannabis is not simply the stimulation of CB 1and CB 2 receptors… 4 Efficacy of cannabis Pharmacodynamic interaction of THC and Cannabidiol (CBD) o THC’s psychotropic effect can be blunted by CBD. o Extremely difficult to mimic medicinal value of cannabis. Excretion Most metabolism takes place in the liver. Converted to metabolites that rapidly cross into the brain. Takes 20-30 hours to remove ½ the dose. May be detected in the body up to 30 days later. Effects of 9 THC Psychological – euphoria, relaxation, sleepiness, “insight” Perceptual – altered perception of space and time, mood changes, introspection, and more “creative”. Physical – increased heart rate, reddening of eyes, increased appetite, decreased coordination, dry mouth, and possible headache. Cognitive Effects: o Impairment of short term memory during use. o Long term is more controversial. May cause damage to neurons in the hippocampus. May cause deficits in the ability to organize and integrate complex information. 5 Long Term Effects Crean et al., 2011 Heavy use impairs cognitive function for 2-3 weeks after stopping. o Attention, concentration, inhibition. Less information is available for 3 weeks and beyond. o Suggests a similar trend. Effects of 9 THC Motivational effects o AMS – amotivational syndrome. Characterized by amotivational, apathetic mood; not achievement oriented. Tolerance Studies suggest tolerance occurs o Develops rapidly in laboratory animals. o Down regulation of cannabinoid receptors in the brain. o Not as clear in humans. Sensitization and novice effects. Hirvonon et al., 2012 (in humans): o Down regulation of CB1 in receptors in cortical areas. o Correlation between smoking frequency and down regulation. 6 o Effect was reversed with 4 weeks of abstincence. Withdrawal Animals: Cannabinoid antagonist results in withdrawal. o Increase in stress hormones. Humans – Maybe with high doses… o Increased anxiety, irritability, decreased appetite. Recent evidence suggest it occurs in about 10% of people who have ever tried it. o Daily users have a 50% chance of developing dependence. Treatment Typically, outpatient treatment Relapse rates are similar to other drugs of abuse. Antidepressants and oral THC may help. Long Term effects of Marijuana Fairly minimal to date. Inflammation and cell injury in lungs. o Contains 50-70% more carcinogens than cirarettes. o May be a risk factor for cancer, but now empirical evidence. THC suppresses the immune system. 7 Reproductive function o Females it decreases gluttonizing hormones. In males it decrease testosterone. Marijuana smoke may be a source of cellular oxidative stress. Long Term Effects in Adolescents Significant relationship between early heavy use and the development of psychotic disorders in adulthood. Regular marijuana may alter adolescent brain development. Possible Therapeutic Value Nausea and vomiting o An effective antiemetic drug (for reducing nausea) associated with chemotherapy. o Marinol, and Cesamet: Available for medical use in oral form of chemotherapy–induced nausea. Other Therapeutic Uses Glaucoma o Reduces fluid pressure. Asthma Multiple Sclerosis (MS) and spinal cord injury. Traumatic brain injury. Marijuana smoke may contain antioxidants. CBD may slow the growth of cancer cells. 8 Chapter 5 – Nicotine Routes of Administration Potent poison and bitter flavor. o Tobacco leaves contain up to 10% nicotine. Snuff: Sniffed into the nostrils Dip: Placed inside the cheek. Chew: Absorbed through membrane of the mouth. o All 3 are absorbed through mucus membranes. Cigarettes and cigars: smoked o Nicotine is vaporized and is in the ash and smoke. o Absorbed in the lungs. Absorption Lungs Heart Brain o Rapid o 90% of nicotine inhaled reaches the brain. Distribution Smoke contains: o Carbon monoxide: Reduces oxygen o Tar: Sticks to cells in the lungs and prevents elimination of foreign materials. o Nicotine: Oily psychoactive compound. 60mg of pure nicotine would kill an adult. 7 to 9 mg in a cigarette. Average about 1 mg per cigarette is absorbed into bloodstream/brain. Distribution and Excretion Half life ~30 minutes. 30 to 40% eliminated in urine. Remaining metabolized in liver. No day to day accumulation. Crosses placenta and is found in breast milk. Where does it work in the brain Binds to nicotine receptors for acetylcholine. o Many different brain regions. Stimulates release of epinephrine, dopamine, and serotonin. Effects Physical: Increases heart rate and blood pressure, constricts blood vessels in the skin (cold touch and wrinkles), laxative, increased respiration, nausea. o Increases metabolic rate and decrease appetite. Nesbitt’s paradox: Causes physiological arousal: yet report relaxation. o For non-users it causes arousal, tension, dizziness and/or nausea. Performance: Improves performance of smokers on tasks that require vigilance and attention. o Speeds information processing. o Improves performance on learning tasks. Tolerance does develop. Withdrawal Decreased heart rate, increased appetite, difficulty concentrating, trouble sleeping, craving, anxiety, anger, depression. Last about 1 month (except for craving). May last up to 6 months. 2 Smoking Cessation Most surveys show that the majority of smokers want to quit… Physical and psychological addiction. Pharmacotherapies Substitution and weaning (reliably increase long term abstinence). o Nicotine patch. o Nicotine gum. o Nicotine inhaler. o Nicotine nasal spray. Other things Zyban (buproprion) – Approved in 1997 for smoking cessation. o Originally an antidepressant (Wellbutrin). o Mechanism of action not well understood. Chantix (varenicline) – approved in 2006 for smoking cessation. o Partial agonist for a portion of the nicotine receptor. o Prevents nicotine from occupying receptors. o Results in sustained low level of dopamine release while preventing withdrawal. Topics Hallucinogens ~14 questions Marijuana ~12 questions Nicotine ~8 questions. 3 Chapter 11 – Alcohol What is a Hallucinogen All drugs that cause users to have hallucinations. Abrams (1996) defined psychedelics: o Any agent that causes alterations in perception, cognition, and mood as its primary psychobiological actions in the presence of an otherwise clear sensorium. Psychedelic drugs Many (but not all) psychedelics structurally resemble one of five neurotransmitters: 1. Serotonin Catecholamine’s 2. Norepinephrine 3. Dopamine 4. Glutamate 5. Opiate LSD LSD – synthesized in 1938 o Serotonin-like psychedelic drug. o Albert Hofmann synthesized a series of lysergic compounds, with no interesting findings. o LSD-25 o Later decided to deliberately ingest 0.25mg. o Recorded the first human experience with LSD in 1943. Uses of LSD: 1953-1966 o LSD used as adjunct to psychotherapy. Initial LSD research Timothy Leary o Clinical Psychologist o Conducted Psilocybin and LSD experiments at Harvard University. o Asked to leave Harvard in 1963. o “Turn on, tune in, and drop out…” Pharmacokinetics o Absorption rapid – oral route most common. o ½ life ~ 3 hours o Metabolized in liver o Only 1% reaches the brain. Tolerance – Develops very rapidly. o Recover is also usually rapid (so weekly use of same dose is possible) Cross tolerance – LSD with psilocybin, mescaline. No obvious withdrawal. Mechanisms of action: o Initially thought LSD worked by action on serotonin (5-HT) receptors. o 5-HT receptors ARE primary, but NOT only binding sites for LSD. Some cases working as agonist and some as antagonist. 2 LSD Experience: o Typically last 6-9 hours. o Mostly visual/perceptual changes. Colored lights, distorted images; synesthesia (see sounds, hear colors… Senses are blended). o Altered sense of time o Depersonalization (outside of themselves). o Dilated pupils, elevated temperature and blood pressure. o Restlessness, euphoria, and sensation that inner tenstion has been released. Adverse Effects: o Panic reaction o Flashbacks. Quite variable and unpredictable. o LSD psychosis Rare and usually occur when the person is: o Unaware of taking the drug. o Mentally unstable before taking the drug. Pharmacology of LSD: o Extremely potent of 0.03-0.1mg o No OD death reported in humans. Serotonin-like 3 LSD Mushrooms (psilocybin) Peyote DMT Ayahuasca Nutmeg Mescaline *Serotonin is a monoamine. Psilsoybin (mushrooms) Mild and doesn’t last long. “Magic mushrooms”. Long history in religions and ceremonial use. Isolated by Albert Huffman and then synthesized it. 4mg yield pleasant experience with relaxation and some bodily sensation. Similar to LSD, but now as potent. Current research with psychedelics Therapy for fear and anxiety. Peyote Mescal buttons 4 Wed in spiritual ceremonies (Native-Americans church) Pharmokinetics Readily absorbed if taken orally, but does not get into the brain easily. 1 2,000 as potent as LSD 1 - ~ 2 hours 2 Effects Nausea and vomiting. Tremors and lack of coordination. After about an hour have LSD-like effects for several hours Death results from seizures and respiration affects. DMT Extremely potent. Serotonin is a monoamine. Typically solid in power form and smoked. Structurally similar to serotonin. Peak during effects very widely by route: o Smoking: 1-5 minutes o Injections: 10-15 minutes (might be more intense). o Orally or pill form: 2-3 hours. 5 5-Med-DMT (cousin) Might be called “foxy”. 4 to 10 fold more potent than DMT. Peak effects about 30-45 minutes after inhalation. Licking Toad Squeeze road and secretes 5-med-DMT. Both DMT and 5-med-DMT are only midley active if taken orally. o Must take in with a monoamine oxidase inhibitor (mao-I, hamaline). o Unlike LSD, both DMT and 5-med-DMT can be fatal if taken in combination and or in combination with MAD-Is o MAO-Monamine oxidase: Enzyme that breaks down monoamines monoamine oxidase destroyes excess monoamines in the terminal so have more serotonin available too much death from heart attack due to rise in blood pressure. Ayahuasca o Drink in South America that combines plants with DMT with plants with MAO-Is o Effects last 6-12 hours 3 phases of the experience 1. Vivid visual imagery. Dizziness and nausea with vomiting. 2. Contact with the spirit world 3. Fading of visions, a decrease in nausea, and exhaustion. Nutmeg 6 Myristin likely active in ingredient. o Can cause changes in visual perceptions, visual hallucinations, depersonalization, euphoria BUT… Need a high dose (at least 1 tablespoon). Side effects; vomiting, nausea, unconsciousness, tremors that last up to 12 hours. Mescaline Found in San Pedro cactus. 5-HT receptor agonist. Rapidly and completely absorbed when taken (orally). Significant concentrations achieved in the brain within 1-2 hours. Trips can last 10 hours. Induces nausea and vomiting. Hallucinogens 2.Catechol hallucinogens Catechols – dopamine and norepinephrine. 3.Other hallucinogens Opiate, glutamate, etc. Salvia divinorum Common effects 7 o Uncontrollable hysterical laughter. o Overlapping realities. The perception that one is in several locations at once. o Salvinorin A – active ingredient Does not work on the same neurotransmitters as other hallucinogens. o Kappa Opioid Receptor Agonist. PCP and Ketamine Both are anesthetic agents Work on the glutamate system o NMDA antagonists o This also results in dopamine release. PCP “Angel dust” Power or pill form Dissociation from the body. Strong emotional response (positive or negative). Cognitive disorganization. Ketamine Less portent than PCP. Short acting (lasts 30-60 minutes). Marked dissociative state. o Lose all contact with body. o Sensation of lights coming through the body. o Complete loss of time. o Altered perception of “body consistency”. o Sudden insight into the mysteries of existence. Compulsive daily use can develop. Tolerance does develop. Repeated use causes neuronal changes, including cell death. Recent studies have found that a single iv dose of ketamine markedly improves depression. 8