1. Marijuana

2. CANNABIS SPECIES Cannabis sativa Cannabis sativa grows worldwide grows worldwide Tall plant with long, thin light green leaves Tall plant with long, thin light green leaves used for fibers to make cloth and rope, but also used for psychoactive properties. used for fibers to make cloth and rope, but also used for psychoactive properties. Cannabis indica Cannabis indica Plentiful in Mideast, India, and Central Asia Plentiful in Mideast, India, and Central Asia Short plant with broad dark leaves Short plant with broad dark leaves Mainly used for psychoactive resins. Mainly used for psychoactive resins. Cannabis ruderalis Cannabis ruderalis grows primarily in Eastern Europe (Russia, Poland) grows primarily in Eastern Europe (Russia, Poland) Short weedy plant, less THC content than others Short weedy plant, less THC content than others

3. CANNABIS Primary psychoactive agent in Cannabis Primary psychoactive agent in Cannabis delta-9-tetrahydrocannabinol (THC) delta-9-tetrahydrocannabinol (THC) Various preparations from Cannabis Various preparations from Cannabis Charas (in India) or Hashish Charas (in India) or Hashish the pure resin from the leaves and stems the pure resin from the leaves and stems avg. concentration of THC is 3% to 7%, as high as 20% avg. concentration of THC is 3% to 7%, as high as 20% Ganja (in India) or Sinsemilla (Spanish, without seeds) Ganja (in India) or Sinsemilla (Spanish, without seeds) dried tops of female plants (without seeds) dried tops of female plants (without seeds) THC concentration 7 – 12% THC concentration 7 – 12% Bhang Bhang dried, ground up remainder of the plant dried, ground up remainder of the plant avg. concentration of THC is 1% to 2% avg. concentration of THC is 1% to 2%

4. Early History of Cannabis Cannabis probably originated in central Asia Cannabis probably originated in central Asia Cultivated and widely dispersed before recorded history. Cultivated and widely dispersed before recorded history. Scythians were probably responsible for spreading its use to Egypt and north to Europe and Russia. Scythians were probably responsible for spreading its use to Egypt and north to Europe and Russia. In China, Cannabis probably known since ~4000 B.C. In China, Cannabis probably known since ~4000 B.C. Cultivated for fiber, seed, as well as intoxicating and medicinal properties. Cultivated for fiber, seed, as well as intoxicating and medicinal properties. Social use began in North Africa by ~1000 A.D. Social use began in North Africa by ~1000 A.D.

5. Recent History of Cannabis Use Widespread industrial use of hemp in western Europe and American colonies Widespread industrial use of hemp in western Europe and American colonies psychoactive properties not widely recognized until 19 th century psychoactive properties not widely recognized until 19 th century 19th Century: Romantic Literature and the New Science of Psychology 19th Century: Romantic Literature and the New Science of Psychology Use expanded into Europe and was widespread among artists and writers. Use expanded into Europe and was widespread among artists and writers. The new science of psychology also introduced the use and study of psychoactive agents. The new science of psychology also introduced the use and study of psychoactive agents.

6. HISTORY “Marijuana, Assassin of Youth” “Marijuana, Assassin of Youth” Sensationalized stories in the news media Sensationalized stories in the news media e.g., blaming marijuana for violent crimes e.g., blaming marijuana for violent crimes 36 states in U.S. had laws regulating the use, sale and/or possession of marijuana by 1935. 36 states in U.S. had laws regulating the use, sale and/or possession of marijuana by 1935. The Marijuana Tax Act of 1937 The Marijuana Tax Act of 1937 Did not outlaw Cannabis, but taxed it Did not outlaw Cannabis, but taxed it After the Marijuana Tax Act After the Marijuana Tax Act New York Academy study showed no physical or mental deterioration with long- term use. New York Academy study showed no physical or mental deterioration with long- term use.

7. PHARMACOLOGY Cannabinoid Chemicals Cannabinoid Chemicals Over 400 chemicals in marijuana Over 400 chemicals in marijuana 61 unique to the cannabis plant 61 unique to the cannabis plant called cannabinoids called cannabinoids Pharmacokinetics Pharmacokinetics THC is a weak acid with a pKa of 10.6 THC is a weak acid with a pKa of 10.6 not ionized at pH of bodily fluids not ionized at pH of bodily fluids When smoked, rapid absorption When smoked, rapid absorption Peak effects within 5-10 min. Peak effects within 5-10 min. When ingested, peak effects ~90 min. When ingested, peak effects ~90 min. Half-life ~ 19 hours, longer for metabolites (20-30 hrs) Half-life ~ 19 hours, longer for metabolites (20-30 hrs) Main metabolite: 11-hydroxy-delta-9-THC, which may be more active than delta-9-THC Main metabolite: 11-hydroxy-delta-9-THC, which may be more active than delta-9-THC

8. NEUROPHARMACOLOGY Mechanisms of Action Mechanisms of Action CB receptors discovered in brain, 1990 CB receptors discovered in brain, 1990 CB1 receptors: in CNS CB1 receptors: in CNS primarily in cortex, hippocampus, cerebellum, basal ganglia primarily in cortex, hippocampus, cerebellum, basal ganglia CB2 receptors: spleen, immune system CB2 receptors: spleen, immune system Endocannabinoids were discovered soon after. Endocannabinoids were discovered soon after. Anandamide, 2-arachidonylglycerol (2-AG) Anandamide, 2-arachidonylglycerol (2-AG) Neuromodulators of multiple neurotransmitters, including monoamines, GABA, ACh and endorphins Neuromodulators of multiple neurotransmitters, including monoamines, GABA, ACh and endorphins Signaling between postsynaptic and presynaptic cells Signaling between postsynaptic and presynaptic cells Interactions with opioid peptides to modulate DA transmission in mesolimbic structures Interactions with opioid peptides to modulate DA transmission in mesolimbic structures

9. Acute Physiological Effects Cardiovascular and Peripheral Effects Cardiovascular and Peripheral Effects Increased heart rate Increased heart rate Variable effects on blood pressure Variable effects on blood pressure Dry mouth, “bloodshot” eyes Dry mouth, “bloodshot” eyes Effects on Sleep Effects on Sleep Drowsiness, increased sleep time Drowsiness, increased sleep time High doses can produce insomnia. High doses can produce insomnia.

10. Cognitive/Behavioral Effects Low to moderate doses produce euphoria, a pleasant state of relaxation, laughter Low to moderate doses produce euphoria, a pleasant state of relaxation, laughter Some loss of coordination and balance Some loss of coordination and balance Simple reaction times relatively unaffected Simple reaction times relatively unaffected Complex and choice reaction time, accuracy but not speed affected. Complex and choice reaction time, accuracy but not speed affected. Impaired short-term memory Impaired short-term memory Reduced sustained attention Reduced sustained attention Impaired visuo-spatial and temporal processing Impaired visuo-spatial and temporal processing

11. Adverse Behavioral Effects Moderate to high doses may produce mild anxiety to panic and paranoia Moderate to high doses may produce mild anxiety to panic and paranoia A few rare cases have been reported of cannabis-induced psychoses, delusional and bizarre behavior, and hallucinations A few rare cases have been reported of cannabis-induced psychoses, delusional and bizarre behavior, and hallucinations These reactions occur most frequently in individuals who are under stress, anxious, depressed or borderline schizophrenic. These reactions occur most frequently in individuals who are under stress, anxious, depressed or borderline schizophrenic.

12. Driving Performance The ability to perform complex tasks, such as driving, may be impaired while under the influence of marijuana. The ability to perform complex tasks, such as driving, may be impaired while under the influence of marijuana. Laboratory studies with non-regular marijuana users show significant impairments. Laboratory studies with non-regular marijuana users show significant impairments. Results suggest that marijuana has little effect on ability to control a car, but impairs the driver’s ability to attend to peripheral stimuli. Results suggest that marijuana has little effect on ability to control a car, but impairs the driver’s ability to attend to peripheral stimuli. Effects of THC on driving ability are amplified when combined with alcohol. Effects of THC on driving ability are amplified when combined with alcohol.

13. Critical Thinking Skills Marijuana has been found to have a negative impact on critical thinking skills. Marijuana has been found to have a negative impact on critical thinking skills. Impairment can affect: attention, memory, learning. Impairment can affect: attention, memory, learning. An unresolved question is whether these impairments are due to acute drug effects or long-term consequences of regular use. An unresolved question is whether these impairments are due to acute drug effects or long-term consequences of regular use.

14. Behavioral Effects in Nonhumans Unconditioned Behavior Unconditioned Behavior Biphasic effect on motor activity; initial increase, then depressant effects. Biphasic effect on motor activity; initial increase, then depressant effects. Stimulatory effects represent an exaggerated response to environmental stimuli. Stimulatory effects represent an exaggerated response to environmental stimuli. High doses produce ataxia. High doses produce ataxia. Reduced aggressive behavior Reduced aggressive behavior Conditioned Behavior Conditioned Behavior Interference with tasks that assess short term memory Interference with tasks that assess short term memory THC decreases avoidance responding, like depressants THC decreases avoidance responding, like depressants Unlike depressants, THC does not increase punished behavior. Unlike depressants, THC does not increase punished behavior.

15. Behavioral Effects in Nonhumans Drug Discrimination Drug Discrimination Rats readily learn to discriminate THC Rats readily learn to discriminate THC Some evidence for partial generalization to depressants, but not to any other drug classes Some evidence for partial generalization to depressants, but not to any other drug classes THC discrimination is blocked by CB1 antagonists. THC discrimination is blocked by CB1 antagonists. Self-Administration Self-Administration Due to low solubility in water, I.V. self-administration of THC has been difficult to study. Due to low solubility in water, I.V. self-administration of THC has been difficult to study. Water soluble synthetic cannabinoids are self- administered. Water soluble synthetic cannabinoids are self- administered. THC also establishes Conditioned Place Preference in rats. THC also establishes Conditioned Place Preference in rats.

16. Health Risks Abuse/Dependence Potential Abuse/Dependence Potential Tolerance occurs when high levels are used over long periods. Tolerance occurs when high levels are used over long periods. Physical dependence has been observed under certain heavy use conditions. Physical dependence has been observed under certain heavy use conditions. Psychological dependence does not occur for most users, but can occur with frequent heavy use. Psychological dependence does not occur for most users, but can occur with frequent heavy use. Withdrawal symptoms occur within 1 day and persist 4-12 days Withdrawal symptoms occur within 1 day and persist 4-12 days Anxiety, restlessness, depression, irritability, disrupted sleep, decreased food intake, sometimes increased aggression Anxiety, restlessness, depression, irritability, disrupted sleep, decreased food intake, sometimes increased aggression

17. Health Risks Chronic Lung Exposure Chronic Lung Exposure Similar chemicals to tobacco Similar chemicals to tobacco Levels of exposure differ from tobacco Levels of exposure differ from tobacco Marijuana as a causal factor in COPD or lung cancer is still debated Marijuana as a causal factor in COPD or lung cancer is still debated Reproductive Effects Reproductive Effects Effects noted but significance not known Effects noted but significance not known Immune System Effects Immune System Effects No relationship established between marijuana use and overall death rate No relationship established between marijuana use and overall death rate

18. MEDICAL USES OF CANNABIS China China First mention in 2737 B.C. was medical use First mention in 2737 B.C. was medical use Cannabis mixed with wine was used for anesthetic 2900 years later (A.D. 200) Cannabis mixed with wine was used for anesthetic 2900 years later (A.D. 200) Europe Europe Almost no mention until 1800s Almost no mention until 1800s 1839, W.B. O’Shaughnessy reported on anticonvulsant and appetite stimulant effects. 1839, W.B. O’Shaughnessy reported on anticonvulsant and appetite stimulant effects. Several publications followed regarding numerous other medical uses (e.g., tetanus, neuralgia, dysmenorrhea, asthma, gonorrhea, migraine, alcohol addiction). Several publications followed regarding numerous other medical uses (e.g., tetanus, neuralgia, dysmenorrhea, asthma, gonorrhea, migraine, alcohol addiction).

19. MEDICAL USE OF CANNABIS United States United States Some early medicinal use in 1800s Some early medicinal use in 1800s Minimal uses until Marijuana Tax Act of 1937 resulted in withdrawal of existing products Minimal uses until Marijuana Tax Act of 1937 resulted in withdrawal of existing products Renewed interest following a 1972 report showed help for glaucoma patient and a 1975 report noted reduced nausea in chemotherapy patients. Renewed interest following a 1972 report showed help for glaucoma patient and a 1975 report noted reduced nausea in chemotherapy patients.

20. MEDICAL USE OF CANNABIS Suggested medical uses of marijuana include Suggested medical uses of marijuana include Reduced intraocular pressure Reduced intraocular pressure Antiemetic Antiemetic Appetite stimulant Appetite stimulant Pain management Pain management Reduced muscle spasticity Reduced muscle spasticity Recent developments with synthetic derivatives of THC (e.g., Marinol) and oral preparations from cannabis extracts (e.g., Savitex). Recent developments with synthetic derivatives of THC (e.g., Marinol) and oral preparations from cannabis extracts (e.g., Savitex).