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

Cannabis Δ9-tetrahydrocannabinol (THC) From Cannabis sativa Forms: 60+ cannabinoids in 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 Cannabis sativa: flowering hemp plant Cannabinoids are found in resin secreted by flowering tops THC = main psychoactive cannabinoid

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? Path: Central Asia -> China -> Arab world Western: Napolean’s soldiers brought back from Egypt and France US: Washington was a hemp farmer! Little awareness of intoxicating effects at time US smoking start: Mexican immigrants, Caribbean seamen, and West Indian immigrants Harry Anslinger: “social menace capable of destroying the youth of American” MJ Tax Act: national registration and taxation sys discouraged commercial, recreational, and medicinal use Harry Anslinger: appointed as the first Commissioner of the U.S. Treasury Department's Federal Bureau of Narcotics (FBN) on August 12, 1930 where he served until 1962. 1937 MJ Tax Act: levied a tax of roughly $1 to anyone commercially dealing cannabis, hemp, or marijuana. violation of handling procedures could result in a fine up to $2000 and 5 yrs in prison 1970 Controlled Sub. Act: All substances placed into 1 of 5 schedules, act strictly regulates manufacture and distribution of controlled substances

Pharmacology Converted to metabolites 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 THC identified by Ganoi and Mechoulam as active ingredient in Cannabis sativa Potency depends on a number of factors: genetic strain and growing conditions in particular Burning marijuan causes THC to vaporize and enter lungs to be absorbed To improve high: smokers adjust puff volume and frequency, but studies are inconclusive as to whether or not this actually helps Blood concentration rises b/c almost completely bound by plasma proteins, but drug is quickly metabolized by liver Orally not well absorbed b/c of 1st pass metab by liver, low & variable blood plasma concentrations Accumulation is why it can be detected in urine screens for up to 2 weeks after consumption on one occasion

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 inhibit release of Ach, NE, DA 5-HT, glutamate, and GABA CB1: 1988, Devane et al. affects locomotor activity, coordination, and memory basal ganglia include: striatum, globus pallidus, entropeduncular nucleus, and substantia nigra

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 Arachodonic acid is found in the phospholipid membrane Enzymes involved in synthesis of derivates are Ca2+ sensitive Endocann. Can’t be stored in vesicles Anandamide aka arachidonoyl ethanolamide discovered in 1992 by Raphael Mechoulam lipid FAAH: fatty acid amide hydrolase, breaks down anandamides Cravatt et al. showed genetic knockout mice lacking FAAH had elevated levels of anandamide Retrograde b/c released from post-syn neurons to acts on axonal terminals Summary: synthesized and released in resopns to depol of post-syn cell due to Ca2+ influx thru volt-gated channels, bind to CB1 of pre-syn terminals to inhibit release of nts Hippocampus: endocann. Generated by pyramidal neurons and diffuse to terminals on GABAergic interneuron that suppress firing of pyramidal cells. Therefore GABA release is inhibited and pyramidal cells fir more rapidly

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

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” Moreau was a French physician who wanted to see if there was a correlation between hashish intoxication and characteristics of mental illness. Logically, the only way he could get reliable data was to record his and his students experiences after consuming hashish When they consumed large amounts they experienced profound personality changes and even hallucinations Lower doses, like those found in marijuana cigarettes, produce more modest effects and that is what we’re going to focus on

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? It has been found that the subjective effects of marijuana use are partially mediated by CB1 When treated with 90 mg of the CB1 antagonist, the drug users reported the effects were significantly inhibited. Similar results were found for the heart-rate elevating effects.

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 As with many drugs the responses that every person has are different Some of the differences can come from the dose, the setting, previous exposure, and expectations they have about possible drug effects

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

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 At first it seemed that cannabinoids didn’t follow the general rule that animals liked the same drugs as humans. Then it was discovered that a lot of the earlier studies showing these results were compromised for several reasons, the main one being that the animals were given really high doses and were experiencing aversive effects

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

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

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

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

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

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