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-9tetrahydrocannabinol (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
World Cannabis Highlights
• 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)
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 and
carbon 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
Devane et al., 1988
• Inhibits Ach, Glu
• Complex dose-related effects on reuptake and release of DA
and NE
• Location-specific effects on DA
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
DSI was discovered in 1992 by Vincent et al., (1992)
DSI: a reduction in inhibitory GABA release
DSE: a reduction in excitatory glutamate release;
endocannabinoid role not as clear
Acute Effects
• Analgesia
• Euphoria
• Disinhibition
• Disrupted attention
• Sedation
• Increased appetite
• Impaired short-term
memory and learning
• Antiemesis
• Impaired multi-tasking
• Altered control of motor
movements/coordination
• Altered sensory
awareness
• Increased heart rate and
blood pressure
• Hallucinations, loss of
control (at high doses)
• Anxiety, fear, panic (at
stimulation  tranquility high doses)
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
P300
Solowij et al., 1995
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
Inactive cannabinoid
vehicle