Marijuana and the Cannabinoids

By: Coley Genger, and Sara Heizer, Kaitlin McClimon

Cannabis• From Cannabis sativa

o 60+ cannabinoids in resino Δ9-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 poten

to 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 1900so 1930s: Harry Anslingero 1937: Marijuana Tax Act

• Overturned in 1969o 1970: Controlled Substance Acto Today: Gateway drug or medical

marvel?

Pharmacology

• THC identified in 1964

• Smoking:o 1 cigarette contains 0.5 to

1g of cannabiso 20% absorbed by lungso Rapid rise in blood

concentration• Oral consumption

o Prolonged but poor absorption

• Converted to metaboliteso 11-hydroxy-THCo 11-nor-carboxy-THC

• Accumulates in fat stores o T1/2 = 20-30 hours

• Removal from body: o 1/3 excreted as urineo 2/3 eliminated in feces

Cannabinoid Receptors• Identified CB1 and CB2 genes

o Both G-protein coupled o When active, release of many NTs is inhibited

• CB1 (metabotropic)o On axon terminalso Inhibits cAMP formation and voltage-gated Ca2+

channels, activates K+ channelso In basal ganglia, cerebellum, hippocampus, &

cerebral cortex• CB2

o Only in immune system• THC-antagonist: SR 141617 (rimonabant)

o Potent and selective, orally active

Endocannabinoids

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)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 1o CB1o Effects were significantly inhibited by prior

treatment with CB1 antagonist

• To fully block the effects of marijuana o Higher dose of antagonisto Possibly an additional mechanism involved?

Physiological Responses Increased blood flow to the skinHeart rate is stimulated Increases hunger

o “Munchies”o Therapeutic use

Varied responseso Dose, Setting, Exposure, Expectations

Kirk et al., 1998o Subjects given a pill with THC or placeboo Half were informed of possible cannabinoids in the capsuleo 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 performanceo Low doses produce few aversive effectso Moderate to high doses results in impaired functioningo 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 systemso Opioid receptor antagonist naltrexone reduces THC self-

administration o µ-opioid receptor activation mediates reinforcing effectso 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

o Antidepressants- buprophin, refazodoneo Mood stabilizer- divalproexo 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 peerso Dislike of school- poor performanceo 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 Cannabis use may lead to persistent cognitive deficitso 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 monoxideo Increased risk of bronchitis- cough and phlegm productiono Cell abnormalities: possible, but not proven and haven’t linked with

lung cancero Reproduction: suppressed release of LH, not in regular userso Lower sperm count: only heavy use, dissipate in 3-4 weeks