PBSI 336 - Chapter 10 (Marijuana)

3 Cannabis Species

sativa, indica, ruderalis (first two grown for consumption).

Cannabinoids are especially concentrated...

In the sticky, yellow resin secreted at the flowering top of the female plant.

Cannabis contains...

Over 110 cannabinoids, many of which are psychoactive.

Δ9-tetrahydrocannabinol (Δ9-THC or "THC")

The most important psychoactive compound, identified in 1964.

Other cannabinoids

Δ8-THC, cannabinol, cannabidiol (CBD)

Marijuana

Refers to dried cannabis and contains a mixture of leaves, small stems, and flowering tops

THC content

Varies with strain (breeding) and growing conditions. If pollination and seeding in female plants are prevented, THC content is increased (sinsemilla = "without seeds").

THC content in seized marijuana

Has increased over the decades (1960s: 1-3%, 1990s: 3-5%, 2010s: 8-12% typical, up to 30%).

Hashish

A dried resin concentration consisting of trichomes (small outgrowths from the top of the female plant; the plant part with the highest THC content). 20-60% THC.

Hash oil

An alcoholic extract from hashish.

Dab

includes other extractions from cannabis, including via butane. Forms of dab: wax, butane, honey oil, shatter. Can be >90% THC.

Smoking marijuana

Most common form, 20-30% of the THC can be absorbed.

Vaporizing

Includes dabbing, Inhalation of vapor; cannabinoids evaporate at ~200°C • Heat a drop of concentrated THC (e.g., hash oil, dab) using a lighter/tinfoil, a "volcano," a vape pen, a dab rig.

Eating marijuana

Dissolve in oils contained in food (e.g., brownies, gummies). Low absorption of THC due to first-pass metabolism in the stomach and liver (but metabolic products are even stronger).

Cannabis sativa

Also known as hemp, one of the earliest cultivated non-food plants.

Hemp

Among the strongest natural fibers. Used for ropes and canvas sails on ships.

1800s marijuana

Marijuana was legal and widely available. Used as an analgesic, appetite stimulant, and muscle relaxant.

1930s marijuana

Marijuana was targeted by Harry Anslinger (director of new Federal Bureau of Narcotics). Anti-marijuana propaganda was created. Spread false info that it was a social menace that would lead to violent crimes and other drugs ("gateway drug").

1960s - 1970s marijuana

Attitudes toward marijuana became more lenient, and cannabis use became very popular among the counterculture.

1970 marijuana

President Nixon established the Controlled Substances Act and designated marijuana as Schedule I. Despite the laws, cannabis use has remained popular since the 1960s.

Cannabis

Currently, the most popular U.S. illicit drug. Typically first used in adolescence.

Potential medical uses

Treatment of glaucoma - to decrease intraocular pressure

Antiemetic - to reduce nausea and vomiting (cancer patients)

Appetite stimulant (AIDS patients)

Anticonvulsant - to reduce seizures

Analgesic - to reduce pain

Medical marijuana

Many U.S. states have legalized medical marijuana, and some have legalized recreational marijuana. But, still illegal at the federal level (Schedule I).

Cannabidiol (CBD)

Thought to have similar benefits as THC without strong psychoactive effects (still Schedule I though). Highly lipid soluble.

2018 Farm Bill

Allows "hemp" cultivation. Hemp cannot contain >0.3% THC. Significant state and federal regulations.

Synthetic THC

Approved in the U.S. for the treatment of nausea and anorexia in AIDS and cancer patients.

Nabiximols (Sativex®)

THC and CBD mouth spray. Approved in Canada, the UK, and several European countries. Used for spasticity and neuropathic pain in multiple sclerosis.

CBD medication

Approved in the U.S. for severe childhood epilepsy.

Epidiolex® - plant-based CBD liquid medication.

THC absorption/distribution

Reaches the brain quickly after inhalation (experienced users can distinguish from placebo within ~ 1-2 minutes). Then, distributed to fat stores (depot binding), causing a rapid decrease in blood concentration.

Oral THC

Has slower effects. Onset 30-60 min; peak 3-4 hours.

THC half-life

Long (20-30 hours). Drug tests can detect single use >2 weeks later (even longer with frequent use).

THC metabolization

Mostly in the liver.

11-hydroxy-THC

Active metabolic product after oral consumption of Δ9-THC (first-pass metabolism), more potent than Δ9-THC itself.

11-nor-9-carboxy-THC

Inactive metabolite used in a drug test.

THC behavior and mood effects (Low/moderate doses)

Disinhibition, relaxation, drowsiness, floating sensation. Enhanced feeling of well-being, euphoria. Impaired short-term memory. Impaired time estimation and reaction time.

THC physiological effects (Low/moderate doses)

Increased hunger ("munchies") - very reliable effect. Decreased muscle strength, small tremor, Increased heart rate (pounding), increased blood flow (causes red eyes, good for glaucoma).

Effects vary with...

Dose, setting, past exposure, and expectations.

THC behavior & mood effects (High doses)

Increasingly disorganized thoughts, confusion, paranoia, agitation, and anxiety (dependent on setting). Synesthesias and pseudohallucinations.

THC physiological effects (High doses)

Pronounced motor impairment. Not lethal even at very high doses.

Cannabis withdrawal

Symptoms peak for 1-2 weeks after chronic use in humans (and are opposite to the acute effects of cannabis): Irritability, Anxiety, Depressed mood, Sleep disturbances, Heightened aggression, Decreased appetite.

Factors contributing to increased risk of addiction

Early onset of use (young age) and daily use.

behavioral tolerance to repeated cannabis

For many, cannabis is an "acquired taste" - learn to find the effects pleasant. First-time users show more impairments.

pharmacodynamic tolerance of repeated cannabis

After repeated use, desensitization and downregulation of CB1 receptors in the brain, where cannabinoids act. Reduced CB1 receptor availability correlated with withdrawal severity.

Reduced CB1 receptor availability

Correlated to withdrawal severity.

Effects of repeated cannabis use while still using the drug

Amotivational syndrome (similar to depression), Impaired attention and memory (impairment often lasts until all cannabinoids are completely cleared from the body (weeks, months)), and Reproductive system impairments in males (lower testosterone, sperm counts, and sperm motility).

Spice and K2

Herbs laced with synthetic cannabinoids, sold under several names and marketed as "safe" legal alternatives to marijuana. Not safe or legal. Intoxication, withdrawal, psychosis, and overdose death have been reported after consumption (placed on Schedule I list).

Cannabis pharmacodynamic mechanism

cannabis/marijuana acts at cannabinoid receptors.

CB1 cannabinoid receptors

Located on presynaptic terminals for retrograde signaling.

Endogenous ligands for CB receptors

These are endocannabinoids (CB1 and CB2).

Endocannabinoids (endogenous cannabinoids)

Chemical structures unrelated to THC, except that all have high lipid solubility. Lipid neurotransmitters and retrograde messengers.

Two endocannabinoids

Anandamide and 2-AG

Anandamide

Partial agonist for CB1 receptors.

2-AG (2-arachidonoylglycerol)

Full agonist for CB1 and CB2

Do endocannabinoids have vesicles?

No, they're too lipid-soluble to be stored in vesicles. Synthesized on demand in the post-synaptic side of the synapse.

Endocannabinoids signaling

Travel retrogradely to the pre-synaptic terminal and bind to CB1 receptors. Inactivation via Degradation by enzymes.

Two known cannabinoid receptors

CB1 receptor (discovered 1990) and CB2 receptor (1993).

Both metabotropic, coupled to Gi proteins.

CB1 receptor expression

Mostly in the brain (basal ganglia, hippocampus, cerebellum, cortex) and spinal cord.

CB2 receptor expression

Mostly in the immune system, but also in bone, adipose tissue, the GI tract, and some brain (microglia).

CB1 receptor

Important for rewarding effects and "high" from cannabis. Exceptionally high densities (the most abundant GPCR in mammalian brain).

Gi protein from CB1

Acts to reduce the activity of voltage-gated Ca++ channels, thus inhibiting calcium-mediated neurotransmitter release.

Endocannabinoids are involved in...

Both short-term plasticity (seconds to minutes) and long-term plasticity (hours +) (LTP/LTD, a component of learning).

Endocannabinoids function

They are the principal components of retrograde synaptic signaling.

Cannabinoid effects: Reward (Low doses of THC)

Conditioned place preference (CPP) and self-administration.

Cannabinoid effects: Reward (High doses of THC)

Conditioned place aversion (CPA) and no self-administration.

Cannabinoids and dopamine

Cannabinoids can increase dopamine, which is partially involved in rewarding effects, but also have non-dopamine mechanisms of reward.

CB1 agonists

increase DA firing in VTA and increase DA release in NAc -- via disinhibition (inhibition of GABA inputs onto DA neurons).

Animals with CB1 agonists

Animals will self-administer CB1 agonists (like THC or 2-AG) directly into VTA or NAc.

Cannabinoids effect in feeding

Cannabinoids injected i.v. or into NAc cause pleasurable reactions to tastes: "munchies".

Cannabiniods effect in memory

Cannabinoids (right: "CP") injected i.v. or into the hippocampus cause deficits in working memory (increased errors on cognitive tasks). Blocked by CB antagonist rimonabant into the hippocampus (right: "Rim").

What are endocannabinoids normally involved in?

Reward, feeding, and learning.

CB1 antagonists or CB1 gene knockout

Block self-administration of THC, but also decrease self-administration of other drugs (alcohol, opioids, cocaine, nicotine). Decrease sensitivity to all rewards (food or drugs) and decrease NAc dopamine release.

CB1 antagonist AM6545

Decreased food consumption in animals. Also reduced motivation and reward (probably due to general effects).

CB1 knockout mice

Show normal fear learning but impaired extinction learning (they keep freezing). Also show enhanced retention of other types of memory. Retain recognition memory for longer.

What does impaired extinction learning show in CB1 knockout mice?

Indicates that endocannabinoids are important for extinction learning (probably due to their role in LTD at synapses).

THC effects in mice

Rewarding, increases feeding (pleasure), Impairs learning/memory, and is Hypoalgesic (reduces pain). All blocked by the CB1 antagonist.

CB1 antagonist or knockout effects

Reduces reward, decreases feeding (motivation), Impairs extinction learning, and causes hyperalgesia (enhanced pain).

Indicates that THC mimics and amplifies...

The normal role of endocannabinoids in reward, feeding, and memory.

cannabis use can lead to...

Addiction. Treatment options are mostly centered on psychosocial therapy.

What are the long-lasting effects of repeated cannabis use that remain even after long abstinence/withdrawal periods?

It may reduce cognitive function, but certainly increases risk for psychosis.

Occasional or low use of marijuana

No clear evidence of long-term lung problems.

Adverse effects: reduced cognitive function?

Some impairments to decision making, concept formation, and planning, even after 3 weeks+ of abstinence since last use. Heavy users have the most enduring effects.

Marijuana users grey matter levels

Significantly reduced gray matter in areas of the orbitofrontal cortex (even with similar IQ).

Rats were exposed to a synthetic CB agonist (CP) only during adolescence. In adulthood, they showed...

Reduced cognitive (memory) function and reduced dendritic complexity in the prefrontal cortex (dendrite number and length).

Conclusion from rats exposed to a synthetic CB agonist (CP)

CB1 receptors are important in neurodevelopmental changes during adolescence.

Greatest predictors of psychosis risk

Daily use and high-potency cannabis (5-fold odds ratio). Psychosis risk increases even more during early abstinence/withdrawal

Cannabis-induced psychosis

Greatly enhances the risk of transitioning to chronic psychosis (schizophrenia spectrum disorder) within 3 years (particularly for young males).

January 2017

Comprehensive review of recent research on health effects of recreational and therapeutic use (last report was 1999).

From 2002 to 2015, past-month cannabis users in the U.S. (aged >12)...

Increased from 6.2 to 8.3%.

Significant barriers to research

Schedule I classification

Therapeutic effects from comprehensive review (2017)

Reduced pain symptoms in patients. Reduced nausea/vomiting for chemo patients.

Risks from comprehensive review (2017) - Immediate effects

Increased risk of motor vehicle accidents, Impaired learning, memory, and attention.

Risks from comprehensive review (2017) - repeated use

No increased risk of cancer (but newer reports find otherwise), but frequent use is associated with chronic bronchitis and worse respiratory symptoms. Increased risk of developing schizophrenia and psychoses. Increased risk of social anxiety disorder; increased thoughts of suicide.