Marijuana and the Cannabinoids

1. Marijuana and the Cannabinoids By: Coley Genger, and Sara Heizer, Kaitlin McClimon

2. Cannabis • From Cannabis sativa • 60+ cannabinoidsin resin • Δ9-tetrahydrocannabinol (THC) • Forms: • Marijuana (dried leaves, stems, flowering tops) • Schedule I drug • Consumption: commonly in rolled cigarettes and hollowed cigars, also orally • Potency varies with strain and growing conditions • sinsemilla = withouts seeds, no pollination so highly potent • Hashish (relatively pure resin or leaf extracts) • Consumption: smoked or eaten • Potency depends on preparation • Hash oil = alcoholic extract, highly potent

3. History • Origin: Central Asia • Western interest: early to mid-nineteenth century • US: colonial era • Smoking began in early 1900s • 1930s: Harry Anslinger • 1937: Marijuana Tax Act • Overturned in 1969 • 1970: Controlled Substance Act • Today: Gateway drug or medical marvel?

4. Pharmacology • THC identified in 1964 • Smoking: • 1 cigarette contains 0.5 to 1g of cannabis • 20% absorbed by lungs • Rapid rise in blood concentration • Oral consumption • Prolonged but poor absorption • Converted to metabolites • 11-hydroxy-THC • 11-nor-carboxy-THC • Accumulates in fat stores • T1/2 = 20-30 hours • Removal from body: • 1/3 excreted as urine • 2/3 eliminated in feces

5. Cannabinoid Receptors • Identified CB1 and CB2 genes • Both G-protein coupled • When active, release of many NTs is inhibited • CB1 (metabotropic) • On axon terminals • Inhibits cAMP formation and voltage-gated Ca2+ channels, activates K+ channels • In basal ganglia, cerebellum, hippocampus, & cerebral cortex • CB2 • Only in immune system • THC-antagonist: SR 141617 (rimonabant) • Potent and selective, orally active

6. Endocannabinoids • Arachodonic Acid derivatives • Rise in intracellular Ca2+ triggers release • Highly lipid soluble • Made and released as needed • Activate CB1 receptors • 2-arachiodonoylglycerol (2-AG) • Generated from arachodonic acid • Anandamide • Similar to arachodonic acid • Taken up by specific transport proteins • Metabolized by FAAH • Retrograde messengers in hippocampus and cerebellum • Increased pyramidal cell firing in hippocampus

7. Therapeutic Uses • 1896- 1st found to have therapeutic benefits with discovery of THC • Synthetic THC (dronabnol)- taken per os for nausea, vomiting in chemo patients, or appetite stimulant for AIDS patients • Potential to treat chronic pain and spastic disorders like multiple scelorsis, partial spinal cord injury, glaucoma • In future, may treat brain damage patients as it seems to have neuroprotective effects in brain injured animals

8. Subjective and Behavioral Effects • First clinical studies on effects of marijuana performed by Moreau • 4 stages of effects (Iverson, 2000) • “Buzz,” • Light-headedness, dizziness • “High” • Euphoria, disinhibition, increased laughter • “Stoned” • Calm, relaxed, within a dreamlike state • “Come-down”

9. Subjective and Behavioral Effects • Partially mediated by cannabinoid receptor type 1 • CB1 • Effects were significantly inhibited by prior treatment with CB1 antagonist • To fully block the effects of marijuana • Higher dose of antagonist • Possibly an additional mechanism involved?

10. Physiological Responses • Increased blood flow to the skin • Heart rate is stimulated • Increases hunger • “Munchies” • Therapeutic use • Varied responses • Dose, Setting, Exposure, Expectations • Kirk et al., 1998 • Subjects given a pill with THC or placebo • Half were informed of possible cannabinoids in the capsule • Those who were informed gave higher ratings of pleasurable effects whether they received any THC or not

11. Cognitive and Psychomotor Effects • Cognition • Marijuana use leads to deficits in thought processes and verbal behaviors • Illogical or disordered thinking, fragmented speech, and difficulty remaining focused on a single topic • Does not impair recall of simple, “real-world” information • Psychomotor performance • Low doses produce few aversive effects • Moderate to high doses results in impaired functioning • Marijuana use combined with alcohol, even at low doses, reduces functioning • Risk factor in car accidents

12. Reinforcing Effects • Cannabinoids are reinforcing for both humans and animals • Humans: • Regular users could tell the difference between placebos and cigarettes or pills with THC • All subjects preferred substances with THC • Animals: • Initial studies showed animals did not find cannabinoids reinforcing • Subsequent studies showed self-administration at low doses

13. Mechanism of Reinforcement • Mesolimbic DA system • DA neurons fire in ventral tegmental area (VTA) • Enhance DA release in nucleus accumbens • Interactions between opioid and cannabinoid systems • Opioid receptor antagonist naltrexone reduces THC self-administration • µ-opioid receptor activation mediates reinforcing effects • κ-opioid receptor activation mediates aversive effects • Results may not apply to heavy marijuana smokers

14. Tolerance • Humans- variable results, need further research • Animals- show tolerance in behavioral and physical effects • In 3 weeks, gradual reductions in regional CB1 receptor density (some almost completely desensitized) and cannabinoid agonist mediated receptor activation • Solution: Dexanabinol (non competitive antioxidant used for brain injury treatment), doesn’t bind to CB1 receptors so no euphoria

15. Dependence and Withdrawal • Symptoms- irritability, increased anxiety, depressed mood, sleep disturbances, heightened aggressiveness, decreased appetite • Last 1-2 weeks • Animal test show less withdrawal- cannabinoid receptor remain partially occupied after termination • Precipitated Withdrawal- given chronic THC, challenged with SR when THC terminated- showed abstinence syndrome- shakes, hyperactivity • Decreased DA firing at VTA, increase corticotropin-releasing factor in central nucleus of amygdala

16. Treatment • 4.3 million people- abuse or have dependence • Therapies: Cog/Bxl therapy, relapse prevention training, motivational enhancement therapy • Patients highly vulnerable to relapse • Psychopharmacology- New • Antidepressants- buprophin, refazodone • Mood stabilizer- divalproex • Oral THC- reduce cravings, only short term

17. Early Usage • More than 14 million users, 12+ • Some begin use at 10-11 • peak age is 17 • “gateway” drug • Risk Factors for heavy use- • Emotional problems in family, use in family or peers • Dislike of school- poor performance • Use rates lower in stable families with supervision, strong aspirations, responsibilities

18. Physiological and Neurological Effects • Educational performance poorer, poor grades, negative attitude about school • Higher dropout rates if began earlier in life • Amotivational syndrome: In chronic users- evidence of apathy, aimlessness, loss of achievement, motivation, lack of long range planning, decreased productivity (could be cause of personality not consequence of marijuana) • Does marijuana cause bad characteristics or do bad characteristics cause marijuana use? • Cannabis use may lead to persistent cognitive deficits • Little evidence linking cognitive deficits to school performance

19. Health Effects • No one has ever died of an O.D. • Damage possible: • Smoking: produce irritants and carcinogens, carbon monoxide • Increased risk of bronchitis- cough and phlegm production • Cell abnormalities: possible, but not proven and haven’t linked with lung cancer • Reproduction: suppressed release of LH, not in regular users • Lower sperm count: only heavy use, dissipate in 3-4 weeks