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

2. 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

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?
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

4. 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 = 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

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

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
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

7. Therapeutic Uses
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

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”
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

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?
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.

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
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

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
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

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