Marijuana and the Cannabinoids

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Marijuana and the Cannabinoids
By: Coley Genger, and Sara Heizer, Kaitlin McClimon
Cannabis
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From Cannabis sativa
o 60+ cannabinoids in resin
o Δ9-tetrahydrocannabinol (THC)
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Forms:
o Marijuana (dried leaves, stems, flowering tops)
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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)
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Consumption: smoked or eaten
Potency depends on preparation
Hash oil = alcoholic extract, highly potent
History
• Origin: Central Asia
• Western interest: early to midnineteenth 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 T1/2 = 20-30 hours
• Removal from body:
o 1/3 excreted as urine
o 2/3 eliminated in feces
Cannabinoid Receptors
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Identified CB1 and CB2 genes
o Both G-protein coupled
o When active, release of many NTs is inhibited
CB1 (metabotropic)
o On axon terminals
o Inhibits cAMP formation and voltage-gated Ca2+
channels, activates K+ channels
o 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
 Arachodonic Acid derivatives
 Rise in intracellular Ca2+ triggers release
 Highly lipid soluble
o Made and released as needed
 Activate CB1 receptors
o 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- 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 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 Subjects given a pill with THC or placebo
o Half were informed of possible cannabinoids in the capsule
o 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 selfadministration
o µ-opioid receptor activation mediates reinforcing effects
o 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
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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 useo 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
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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 deficits
o 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
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