THC/Marijuana Marijuana/THC Overview (an intoxicant) • Cannabis Sativa native to Central Asia, cultivated for thousands of years for fiber, seeds, medicine, drug use • Main psychoactive ingredient, delta- 9-tetrahydrocannabinol (THC), from resin on unfertilized flowers • 421 chemicals (60-70 cannabinoids) • Psychoactive uses: euphoria, sedative, altered state of consciousness Marijuana Smoke vs. Tobacco Smoke • Which is more harmful? • Each type has more of certain toxins and carcinogens than other • Mitigating factors – Filtration – Additives – Frequency of use – Method of inhalation World Cannabis Highlights • Archaelogical record of hemp cord (~8000 B.C.) • Documentation of medical use in China (~2700 B.C.) • Religious use in India (~2000 B.C.) • Hashish use in Arab world (~1000 A.D.) • Western World learns of psychoactive use (mid 1800s) U.S. Cannabis History • Harvested for hemp in American colonies • Smoking introduced in 1850s by Mexicans and West Indians • Portrayed as evil in 1920s, laws passed to outlaw use • By mid-1930s, considered a “narcotic” • Marijuana Tax Act (1937): made illegal • By 1940 public convinced that it – Induced violent crimes – Led to heroin addiction – Was a great social menace U.S. Cannabis History continued • THC isolated from marijuana (1964) • Hippie era (1960s) • Synthetic marijuana - Marinol (1980) • First cannabinoid receptor isolated and cloned (1990) • Endogenous ligand (anandamide) isolated (1992) • Voters in CA, AZ approve medical use (1996) • Marinol as Schedule 3 (1999) THC Pharmacokinetics • Absorption – Inhaled (smoked) – Oral (tea, food) • Distribution – Peak blood levels in about 10 minutes – Significant depot binding due to high lipid solubility THC Pharmacokinetics continued • Metabolism and Elimination – Metabolized almost entirely by liver – Half-life 20-30+ hours (1-10 days) – More than 24 metabolites, some of which are psychoactive (e.g. 11-hydroxy-delta-9-THC) – Testing done on THC-COOH (an inactive metabolite), can be detected for several weeks – Excreted via feces (2/3) and urine (1/3) THC Pharmacodynamics • Mimics action of endogenous anandamide and sn2 arachidonylglycerol (2-AG) • Direct agonist for cannabinoid (CB) receptors, found in both CNS (CB1) and periphery (CB2) •CB1 receptors are – Metabotropic – Primarily presynaptic heteroreceptors – Mostly inhibitory • Inhibits Ach, Glu • Complex dose-related effects on reuptake and release of DA and NE • Location-specific effects on DA CB Receptor Localization • Cortex • Thalamus • Hippocampus • Cerebellum • Striatum • Accumbens • Amygdala •VTA •Retina Acute Effects • Analgesia • Euphoria • Disinhibition • Disrupted attention • Sedation • Impaired short-term • Increased appetite memory and learning • Antiemesis • Impaired multi-tasking • Altered control of motor • Altered sensory awareness movements/coordination • Hallucinations (at high • Increased heart rate and doses) blood pressure • Anxiety, fear, panic (at high doses) Chronic Effects • Respiratory system • Emotion – bronchitis, pneumonia – amotivational syndrome • Immune system • Intellect – increased likelihood of – impaired thinking/reasoning becoming ill – difficulty maintaining • Reproductive system attention – decreased sperm count • Psychological – menstrual irregularities – increasing tolerance – drug craving/seeking – addiction Possible Roles for Anandamide and 2-AG • Broaden Attentional Spotlight – Effects on cortex, thalamus, cerebellum – Wider distribution of resources – More processing of “irrelevant” stimuli • Facilitate Selective Forgetting – Effects on hippocampus –Block LTP – Facilitate rejection of “irrelevant” stimuli Medical Uses (National Academy of Sciences, 1999 •AIDS – reduces nausea, vomiting, and loss of appetite • Glaucoma – reduces intraocular pressure • Cancer – reduces side effects of chemotherapy • Multiple Sclerosis – limits muscle pain and spasticity; relieves tremors • Epilepsy – prevents seizures • Chronic Pain – alleviates pain caused by many disorders Chronic Health Effects • Cardiovascular: speeds heartbeat; risk for those with heart rhythm or blood pressure problems (but may provide protection against strokes) • Pulmonary: damage from smoke; lung cancer • Immunosuppression (but significance unclear) • Reproductive: reductions in sex hormones (sperm counts); reduces sperm mobility • Extrapolating from animal experiments, TI is estimated to be on order of 1000 Tolerance and Withdrawal • Tolerance to cardiovascular effects in both light and heavy users, but to psych effects more in heavy users • Mechanism: CB receptor downregulation and desensitization • Withdrawal precipitated in animals receiving high doses, seen in chronic heavy users who abstain: – Restlessness – Reduced food intake – Irritability – Insomnia – Agitation – Sleep disturbances – Anxiety –Nausea –Depression –Cramping .