Marijuana and the Cannabinoids

By: Coley Genger, and Sara Heizer, Kaitlin McClimon

Cannabis

• • From Cannabis sativa o 60+ cannabinoids in resin o Δ 9 -tetrahydrocannabinol (THC) Forms: o 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 o Hashish (relatively pure resin or leaf extracts) • • • Consumption: smoked or eaten Potency depends on preparation Hash oil = alcoholic extract, highly potent

History

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

Pharmacology

• • •

THC identified in 1964 Smoking:

o 1 cigarette contains 0.5 to 1g of cannabis o 20% absorbed by lungs o Rapid rise in blood concentration

Oral consumption

o Prolonged but poor absorption •

Converted to metabolites

o 11-hydroxy-THC o 11-nor-carboxy-THC • Accumulates in fat stores o T 1/2 = 20-30 hours • Removal from body: o 1/3 excreted as urine o 2/3 eliminated in feces

Cannabinoid Receptors

• • • • Identified CB 1 o and CB 2 genes Both G-protein coupled o When active, release of many NTs is inhibited CB 1 (metabotropic) o On axon terminals o Inhibits cAMP formation and voltage-gated Ca channels, activates K + channels 2+ o In basal ganglia, cerebellum, hippocampus, & cerebral cortex CB 2 o Only in immune system THC-antagonist: SR 141617 (rimonabant) o Potent and selective, orally active

Endocannabinoids

       Arachodonic Acid derivatives Rise in intracellular Ca 2+ triggers release Highly lipid soluble o Made and released as needed Activate CB 1 o  receptors 2-arachiodonoylglycerol (2-AG) Generated from arachodonic acid o Anandamide  Similar to arachodonic acid Taken up by specific transport proteins Metabolized by FAAH Retrograde messengers in hippocampus and cerebellum o Increased pyramidal cell firing in hippocampus

Therapeutic Uses

• • • • 1896- 1 st 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

Subjective and Behavioral Effects

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

Subjective and Behavioral Effects

• •

Partially mediated by cannabinoid receptor type 1

o CB1 o Effects were significantly inhibited by prior treatment with CB1 antagonist

To fully block the effects of marijuana

o Higher dose of antagonist o Possibly an additional mechanism involved?

Physiological Responses

    Increased blood flow to the skin Heart rate is stimulated Increases hunger o “Munchies” o Therapeutic use Varied responses o Dose, Setting, Exposure, Expectations  Kirk et al., 1998 o o o 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

Cognitive and Psychomotor Effects

• • Cognition o 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 o Low doses produce few aversive effects o Moderate to high doses results in impaired functioning o Marijuana use combined with alcohol, even at low doses, reduces functioning • Risk factor in car accidents

Reinforcing Effects

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

Mechanism of Reinforcement

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

Tolerance

• • • • Humans- variable results, need further research Animals- show tolerance in behavioral and physical effects In 3 weeks, gradual reductions in regional CB 1 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 CB 1 receptors so no euphoria

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

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 o Antidepressants- buprophin, refazodone o Mood stabilizer- divalproex o Oral THC- reduce cravings, only short term

Early Usage

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

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?

o o Cannabis use may lead to persistent cognitive deficits Little evidence linking cognitive deficits to school performance

Health Effects

• • No one has ever died of an O.D.

Damage possible: o Smoking: produce irritants and carcinogens, carbon monoxide o Increased risk of bronchitis- cough and phlegm production o Cell abnormalities: possible, but not proven and haven’t linked with lung cancer o Reproduction: suppressed release of LH, not in regular users o Lower sperm count: only heavy use, dissipate in 3-4 weeks