THC/Marijuana

By Any Other Name…

• Pot, herb, weed, grass, widow, ganja, hash, dank, mota/moto, hierba, pasto, reefer, old man, sinsemilla, bhang, dagga, etc.

Marijuana/THC Overview(an intoxicant)

• Cannabis Sativa (hemp) and Cannabis Indica native to Central Asia, cultivated for thousands of years for fiber, seeds, medicine, drug use

• Main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), from resin on unfertilized flowers (which protects plant from excessive heat)

• 483 chemicals (60-70 cannabinoids)

• Psychoactive uses: euphoria, sedative, altered state of consciousness

STRUCTURE OF THC

• Archaelogical record of hemp cord (~8000 B.C.)

• Documentation of medical use in China (~2700 B.C.)

• Religious use in India (~2000 B.C.)

• Hashish use in Arab world (~1000 A.D.)

• Western World learns of psychoactive use (mid 1800s)

World Cannabis Highlights

U.S. Cannabis History

• Harvested for hemp in American colonies

• Smoking introduced in 1850s by Mexicans and West Indians

• Portrayed as evil in 1920s, laws passed to outlaw use

• By mid-1930s, considered a “narcotic”

• Marijuana Tax Act (1937): made illegal; overturned in 1960s.

• By 1940 public convinced that it– Induced violent crimes– Led to heroin addiction– Was a great social menace

U.S. Cannabis History (cont)

• THC isolated from marijuana (1964)

• Hippie era (1960s)

• Synthetic marijuana - Marinol (1980)

• First cannabinoid receptor isolated and cloned (1990)

• Endogenous ligand (anandamide) isolated (1992)

• Voters in CA, AZ approve medical use (1996)

• Marinol as Schedule 3 (1999)

Marijuana Smoke vs. Tobacco Smoke

• Which is more harmful?• Each type has more of certain toxins and carcinogens than

other• Mitigating factors

– Filtration– Additives– Frequency of use– Method of inhalation

Normal Lungs and Physiology

Lungs are the site of gas exchange: oxygen enters blood andcarbon dioxide leaves blood

Healthy Lung Diseased Lung

Marijuana Use

Marijuana Use

THC Pharmacokinetics

• Absorption– Inhaled (smoked)– Oral (tea, food)

• Distribution– Peak blood levels in about 10

minutes– Significant depot binding due

to high lipid solubility

THC Pharmacokinetics (cont)

• Metabolism and Elimination– Metabolized almost entirely by liver

– Half-life 20-30+ hours (1-10 days)

– More than 24 metabolites, some of which are psychoactive (e.g. 11-hydroxy-delta-9-THC)

– Testing done on THC-COOH (an inactive metabolite), can be detected for several weeks

– Excreted via feces (2/3) and urine (1/3)

Endocannabinoids

– First receptor discovered in 1988• 1992 first endocannabinoid discovered• arachidonyl ethanolamide- named anandamide

- CB1 receptors expressed in the brain, especially in the hippocampus, cortex, cerebellum, and the basal ganglia.

- CB2 receptors are absent from the brain but are expressed in the immune tissues.

- New evidence suggests a “CB3” receptor.

THC Pharmacodynamics

• Mimics action of endogenous anandamide and sn2 arachidonylglycerol (2-AG)

• Direct agonist for cannabinoid (CB) receptors, found in both CNS (CB1) and periphery (CB2)

• CB1 receptors are– Metabotropic– Primarily presynaptic heteroreceptors– Mostly inhibitory

• Inhibits Ach, Glu• Complex dose-related effects on reuptake and release of DA

and NE• Location-specific effects on DA

Devane et al., 1988

CB Receptor Localization

• Cortex• Thalamus• Hippocampus• Cerebellum• Striatum• Accumbens• Amygdala• VTA• Retina

CB(1) receptor is densely distributed in areas of the brain related to motor

control, cognition, emotional responses, motivated behavior and homeostasis

Depolarization-induced suppression of inhibition (DSI) – short term plasticity

DSE: a reduction in excitatory glutamate release; endocannabinoid role not as clear

DSI was discovered in 1992 by Vincent et al., (1992)

DSI: a reduction in inhibitory GABA release

Acute Effects

• Analgesia• Disinhibition• Sedation• Increased appetite• Antiemesis• Altered control of motor

movements/coordination• Increased heart rate and

blood pressure

• Euphoria• Disrupted attention• Impaired short-term

memory and learning• Impaired multi-tasking• Altered sensory

awareness• Hallucinations, loss of

control (at high doses)• Anxiety, fear, panic (at

high doses)stimulation tranquility

Chronic Effects• Respiration

– bronchitis, pneumonia, lung cancer

• Cardiovascular– speeds heartbeat; risk for

those with heart rhythm or blood pressure problems

• Immune system – Suppressed; increased

likelihood of becoming ill• Reproduction

– decreased sperm count; mobility

– menstrual irregularities

• Emotion– amotivational syndrome

• Intellect– impaired

thinking/reasoning– difficulty maintaining

attention• Psychological

– increasing tolerance– drug craving/seeking– addiction

Hormone Problems Associated with Marijuana Use

• Altered hormone levels (prolactin)

• Enlarged breasts in males (gynecomastia)

Possible Roles for Anandamide and 2-AG

• Broaden Attentional Spotlight– Effects on cortex, thalamus, cerebellum– Wider distribution of resources– More processing of “irrelevant” stimuli

• Facilitate Selective Forgetting and promote hippocampal neurogenesis– Effects on hippocampus– Block LTP and gamma synchrony– Facilitate rejection of “irrelevant” stimuli– Limit memory retention– Ensure adequate coping with stressful

situations

Effects on Performance

Leirer et al., 1991

Solowij et al., 1995

P300

Marijuana and Attentional Load

Chang et al., 2006

Medical Uses(National Academy of Sciences, 1999)

• AIDS – reduces nausea, vomiting, and loss of appetite

• Glaucoma– reduces intraocular pressure

• Cancer– reduces side effects of chemotherapy

• Multiple Sclerosis– limits muscle pain and spasticity; relieves tremors

• Epilepsy– prevents seizures

• Chronic Pain– alleviates pain caused by many disorders

Tolerance and Withdrawal

• Tolerance to cardiovascular effects in both light and heavy users, but to psych effects more in heavy users

• Mechanism: CB receptor downregulation and desensitization

• Withdrawal precipitated in animals receiving high doses, seen in chronic heavy users who abstain:

– Restlessness– Irritability– Agitation– Anxiety– Depression

– Reduced food intake– Insomnia– Sleep disturbances– Nausea– Cramping

1mg/kg cannabinoid

3mg/kg cannabinoid

10mg/kg cannabinoid

10mg/kg THC

vehicle

Inactive cannabinoid