Marijuana/Cannabis

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Marijuana/Cannabis

• Chapter 11

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History of Marijuana

• Oldest non-food crop cultivated by man/woman
• Originated in central Asia
• Cultivated dispersed before written history
• 2700 BC - first written record in China
• Used for medicinal properties

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History of Marijuana

• Major cannabis spread about 200 BC with Scythians
• warlike Middle Eastern tribe, gave us word
  cannabis
• used in cleansing ceremony after funerals
• threw hemp seeds on heated rocks inside tents
  inhaled vapors

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History of Marijuana

• Hebrews also used cannabis
• (Old Testament in Exodus)
• God told Moses to make holy oil containing
  cannabis
• Most infamous use by Muslim sect founded by
  Hasan-Sabbah (Hashishin)
• secret assassination
• gave us words hashish assassin

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History of Marijuana

• France in mid 1800s with "Club des Hachichins"
• writer Gautier offered reward to anyone who
  invented a new pleasure was given hashish by a
  doctor
• Victor Hugo, Alexander Dumas
• consumed large quantities of hash-like material
• wrote accounts of their experiences

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History of Marijuana

• In U.S., primarily for rope (George Washington)
• Introduced by Mexican laborers in early 1900s
  (group targeted by 1st laws)
• 1920s 1930s - major attention - drug of violent
  crime danger to society
• Commissioner of Narcotics, Harry Anslinger
  -crusade against marijuana

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History of Marijuana

• 1937 Marijuana Tax Act
• made possession of marijuana without having paid
  special tax illegal
• Early 1940s
• NYC Mayor Fiorello La Guardia
• set up commission of experts to determine
  consequences of marijuana use
• Final report - marijuana fairly minor intoxicant
  with few side effects even when used excessively
• Report ridiculed by Anslinger

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History of Marijuana

• Marijuana comeback late 1950s to early 1960s
• Now most broadly used illicit substance in U.S.
• 35-40 of Americans having tried
• Numerous states have compassionate use laws

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Preparations of Marijuana

• Leaves, stems and flowering buds of cannabis
  sativa
• Most of the THC is in the buds

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Preparations of Marijuana

• Hashish - processing of plant to yield dried
  resin - more concentrated THC content
• resins scraped/ plants harvested (female)
• beaten down/ rolled in carpets/ leaf substance
• collected and
• placed in tubs
• containing alcohol
• evaporated off
• pressed into bars
• content 5 - 20

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Preparations of Marijuana

• Hash Oil - boil with solvent, solvent then
  strained out
• THC concentration as high as 60 - 70
• Becoming more popular - ease of smuggling

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Various Uses
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Active Agents
?-9-THC ?-8-THC Cannabidiol Active Metabolites
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Active Agents

• Cannabidiol - slows metabolism of THC increase
  duration
• converted to THC when burned
• may have neuroprotective, anticonvulsant and
  anti-psychotic effects

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Pharmacokinetics

• Administration
• Inhalation Smoke
• Oral Tincture, Eating, Tea
• Marinol
• Oral-mucosal
• Sativex

• Absorption
• Smoking rapid and complete
• Oral Half that of smoking
• Distribution
• Everywhere as it is highly lipophilic
• Flies across BBB

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Metabolism Clearance

• Binds to proteins and fats
• Slow metabolism in liver
• Metabolites for a week three weeks
• Primary metabolic product is more potent
• (11-OH- 9-THC)
• Delay between peak plasma levels and high

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Mechanism of Action

• Mostly unknown until the late 1980s
• 1988 Isolated the receptors
• 1992 Discovered the first neurotransmitter for
  that receptor
• THC binds to cannabinoid receptors
• Its and Agonist
• Anandamide 2-AG are the NTs for cannabinoid
  receptors
• Works as a retrograde NT
• It modulates the activity of many
  neurotransmitters
• This is way it has such broad effects

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Two Receptor Types

• CB-1 Receptor

• CB-2 Receptor

• Mostly in periphery
• Found primarily in immune system
• Found on heart protects from inflammation?

• Located in CNS and PNS

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Red abundant CB1 receptor expression Black
moderately abundant CB1 receptor expression
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Low - Moderate Doses

• Disinhibition
• Relaxation
• Drowsiness
• Exhilaration, euphoria
• Sensory - perceptual changes
• Overestimate time passage

• STM impairment
• Balance impaired
• Decreased muscle strength
• Small tremor
• Poor on complex tasks (e.g., driving)

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Higher Doses

• Psychotomimetic
• Pseudo hallucinations
• Synesthesias
• Paranoia
• Agitation
• Disorganized thoughts
• Confusion

• Impaired executive function
• Increased impulsivity
• Impaired judgment, slower RT
• Pronounced motor deficits

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Physiological Effectsof Marijuana

• Physiological effects
• Increase in pulse rate slight drop in BP
• Produces dry mouth occasional dizziness
• Reddening of eyes (dilation of vessels in cornea)
• No permanent adverse cardiovascular
• People with heart disease should abstain
• Increased risk for heart attack four an hour
  after smoking
• Appetite increased
• Hypothalamus
• Hedonic Hotspot specific area of NAC when
  stimulated by cannabinoids there is an increase
  in the reward value of natural rewards.

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Side Effects of Marijuana

• THC suppresses immune system, but not enough to
  increase risk of infection it appears.
• Lowers testosterone levels sperm count as well
  as estrogen
• Crosses placental barrier
• Lower birth weight
• Some evidence suggests a relation between mother
  smoking while pregnant and childhood cancer
• Most severe side effects
• Respiratory - can lead to asthma bronchitis
• Anxiety/panic in some users

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THC Toxicity

• Almost impossible to OD
• 1-1.8 kg w/5 taken orally in a female
• THC not toxic in this sense
• Pot smoke contains more tar than cigarette smoke
• Does one smoke the same?
• Cancer and respiratory possibilities
• Data on cancer is very mixed recent studies
  show no relationship
• THC found to kill cultured hippocampal cells, but
  so far not in other cells high in CB receptor
  density
• Effect reversed with NSAIDS
• Possible mechanism for memory loss

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THC Tolerance Dependence

• Tolerance develops with heavy long-term use
• Reverse tolerance in consistent users
• Cross tolerance with sedatives - alcohol
• Dependence mild (like SSRIs)
• Mild withdrawal symptoms in humans, with
  irritability, depression, sleep disturbances,
  nausea, diarrhea, sweating, tremors, reduced food
  intake, and salivation
• 50 of heavy users may experience it
• 30 mg THC / 4 hrs / 10-20 days (unusual levels of
  intake)
• Begin within 48 hours after cessation and lasts
  2 10 days

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Highly Debated Effects

• Amotivational Syndrome
• Most research has not found this to be true
• Is it a HOST effect?
• It may be psychopathology independent of use
• Gateway Drug
• Most well-designed studies suggest this is false.
• Common liability model is a better explanation
• Alcohol and cigarettes are stronger gateway drugs
  if one accepts the data

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Medical Marijuana

• Many states have compassionate use laws
• California, Washington, Oregon, Nevada, Alaska,
  Vermont, Maine, Colorado, New Mexico, Montana,
  Rhode Island, Maryland
• Physicians recommend marijuana and patient buy
  it at buyers clubs.
• Would lose license if prescribed
• 2003 Gallup Pole 75 for medical use, 66
  against legalization
• 2005 study of physicians' attitudes
• 36 were in favor of legal prescription
• 26 were neutral

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Medical Marijuana

• 1998 IOM report concluded that there is
  scientific evidence for the medical use of
  marijuana
• Analgesic Next slide
• Anti-emetic
• Anti-spastic
• Appetite Stimulant
• Glaucoma
• Tumor suppression (lung cancer)
• Siezures? THC Cannibidiol protect against
  neurotoxicity
• Cannabinoid Antagonists?
• - Ramonabant

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THC and Analgesia

• Likely mediated through CNS/PNS mechanism as well
  as non-NS systems
• RVM Part of brainstem
• THC increases activity of pain suppressing
  neurons and decreases activity of pain enhancing
  neurons
• Inhibits glutamate release
• Increases dynorphin release
• CB receptors located on peripheral sensory nerves
• Reduce pain signaling from the site of damage
• Inhibits prostaglandin synthesis

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How to administer THC

• Studies show smoking is superior to oral
  administration of either synthetic or natural THC
• Significant problems w/smoking however
• Tar and toxins
• Respiratory problems
• Cancer? Want to make sure its not an issue

• Vaporizers
• Heat pot to 180-200 degrees
• Releases active drugs, but does not produce
  toxins
• Sativex THC spray
• Delivered as a mist
• Used in Western Europe and Canada
• Studies are positve

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Medical Marijuana

• The Empirical View.
• There is a medical use for THC
• Medical use does not require legalization
• You can be anti-drug and pro-medicalization
• Saying there is no medical value is a statement
  based in either politics or ignorance/stupidity
• There are ways to get the gains of smoked THC
  without smoking
• Like many other medicines, there are risks and
  the a potential for abuse

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The debate continues