Neurotransmitters

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THC/Marijuana
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By Any Other Name

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

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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-tetrahydroca
  nnabinol (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

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STRUCTURE OF THC
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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)

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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

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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)

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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

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Normal Lungs and Physiology
Lungs are the site of gas exchange oxygen
enters blood and carbon dioxide leaves blood
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Diseased Lung
Healthy Lung
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Marijuana Use
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Marijuana Use
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THC Pharmacokinetics

• Absorption
• Inhaled (smoked)
• Oral (tea, food)
• Distribution
• Peak blood levels in about 10 minutes
• Significant depot binding due to high lipid
  solubility

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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)

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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.

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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
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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
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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
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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
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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

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Hormone Problems Associated with Marijuana Use

• Altered hormone levels (prolactin)
• Enlarged breasts in males (gynecomastia)

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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

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Effects on Performance
Leirer et al., 1991
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P300
Solowij et al., 1995
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Marijuana and Attentional Load
Chang et al., 2006
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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

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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

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1mg/kg cannabinoid
10mg/kg THC
3mg/kg cannabinoid
Inactive cannabinoid
10mg/kg cannabinoid
vehicle
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