Marijuana Chapter 11 Cannabis sativa Tetrahydrocannabinol

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Marijuana
Chapter 11

• Cannabis sativa
• Tetrahydrocannabinol (THC)

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History of Marijuana

• Oldest non-food crop cultivated by man/woman
• Earliest archaeological records from Taiwan,
  10,000 yr (stone age) evidence of hemp fiber use
• Pottery, clothes, shoes, bow strings, paper (105
  A.D.)
• Tsai Lun ridicule!
• Use Spread throughout Asia, the mid East, and
  eventuallyEurope.

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History of Marijuana- Religious and Medical use

• Also originating in Chinaspread 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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Early History

• India
• Bhang--tea
• Ganjapipe
• Charas--hashish/hash

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History of Marijuana

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

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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 Early U.S., primarily for rope and canvas
  (George Washington), Minor medicinal use
• Prohibition increased use of MJ..NYC Tea Pads!

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The Bureau of Narcotics
Commissioner of Narcotics, Harry Anslinger
-crusade against marijuana 1920s 1930s - major
attention - drug of violent crime danger to
society
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History of Marijuana

• 1937 Marijuana Tax Act
• made possession of marijuana without having paid
  special tax illegal
• classified marihuana as a controlled substance.
  Needless to say most doctors and dentists stopped
  using products covered by this law.

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What we have lost
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Various Uses
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History of Marijuana

• 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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A harder attitude- 1950s-60s

• VI. THE 1950's HARSHER PENALTIES AND A NEW
  RATIONALE-THE "STEPPING STONE" THEORY
• 1951 Congress passed -the Boggs Act . .much
  harsher penalties for all drug violators.
  marijuana and other narcotics were lumped
  together
• First offense 2 - 5 years
• Second offense 5 - 10 years
• Third and subsequent offenses 10 - 20 years
• Fine for all offenses 2,000.00
• Boggs stated "We need only to recall what we
  have read in the papers in the past week to
  realize that more and more younger people are
  falling into the clutches of unscrupulous dope
  peddlers . . . .
• Perhaps Commissioner Anslinger best described the
  prevailing climate when he stated
• Short sentences do not deter. In districts where
  we get good sentences the traffic does not
  flourish....
• There should be a minimum sentence for the second
  offense. The commercialized transaction, the
  peddler, the smuggler, those who traffic in
  narcotics, on the second offense if there were a
  minimum sentence of 5 years without probation or
  parole, I think it would just about dry up the
  traffic

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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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Marijuana use exploded in the 1960s
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And use continued at high rates into the 70s
through today
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Time/CNN Poll 2006

• 80 approve of medical use of marijuana
• 72 say that marijuana possession should lead to
  fine, not jail
• 47 say that they have tried marijuana at least
  once

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A changing Attitude? Law Reforms

• 2006, Recreational Marijuana use on ballot in
  Colorado and Nevada
• Defeated in both cases
• January 02, 2009 Massachusetts On Nov. 4, a
  majority of voters in Massachusetts chose to
  decriminalize possession of small amounts of
  marijuana. Those in possession of less than an
  ounce of marijuana are no longer charged with a
  criminal offense, but instead face a 100 fine.

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U.S. Drug laws TODAY
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The International perspective-The Dutch Experience

• Marijuana is NOT legal, but laws are not enforced
  for Coffee shops in Amsterdam
• Over 1000 shops are now licensed in the
  Netherlands
• Cannot advertise
• Cannot sell to minors

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Current MJ World Laws
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The Future?/ Politics of Marijuana
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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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Cannabis Preparations
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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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Active Agents
?-9-THC ?-8-THC Cannabidiol Active Metabolites
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Active Agents

• Cannabidiol - slows metabolism of THC increases
  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

• Distribution
• Everywhere as it is highly lipophilic
• Flies across BBB

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Pharmacokinetics of THC

• Rapid absorption in lung
• 2-4 hr duration of action
• Erratic absorption after oral admin.
• Great persistence in tissue up to 30 days after
  a single dose
• Detection in urine 10-14 days after a single
  dose gt21 days after chronic use
• Distribution
• Everywhere as it is highly lipophilic
• Flies across BBB

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Metabolism Clearance
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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 and agonizes cannabinoid receptors
• Anandamide 2-AG are the NTs for cannabinoid
  receptors
• Anandamide The brains own marijuana (from
  Ananda Hindu word for bliss)
• Works as a neuromodulator/ and retrograde NT

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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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CB1 receptor hot spots
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THC is a retrograde CB1 agonist- works on the
presynaptic terminal to modulate NT release
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Physiological Effectsof Marijuana

• Physiological effects
• Increase in HR drop in BP
• Produces dry mouth occasional dizziness
• Reddening of eyes (dilation of vessels in cornea)
• No permanent adverse cardiovascular effects
• People with heart disease should abstain
• Increased risk for heart attack four an hour
  after smoking
• Appetite increased
• May be related to actions on the Hypothalamus
• or nucleus accumbens- when stimulated by
  cannabinoids there is an increase in the reward
  value of natural rewards.

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PSYCHOLOGICAL EFFECTSLow - Moderate Doses

• Disinhibition
• Relaxation
• Drowsiness
• Exhilaration, euphoria
• sharpened humor
• 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/panic
• Disorganized thoughts
• Confusion

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

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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
• THC not toxic in this sense
• Pot smoke contains more tar than cigarette smoke
• Data on cancer is very mixed recent studies
  show no relationship
• Does one smoke the same?
• 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
• 5 of heavy users may experience it
• 30 mg THC / 4 hrs / 10-20 days 15 joints per day
  (unusual levels of intake)
• Begin within 48 hours after cessation and lasts
  2 10 days

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Highly Debated Effects

• Amotivational Syndrome
• Amotivational Syndrome is a theoretical condition
  that proposes the heavy use of marijuana may
  alter a smokers motivations, goals, and possibly
  personality.
• Most research has not found this to be true
• When it appears to exist, It may be
  psychopathology independent of use

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What is Amotivational Syndrome?

• Amotivational Syndrome is a theoretical condition
  that proposes the heavy use of marijuana may
  alter a smokers motivations, goals, and possibly
  personality.
• Better put, this syndrome may cause "... apathy,
  loss of effectiveness, and diminished capacity or
  willingness to carry out complex, long-term
  plans, endure frustration, concentrate for long
  periods, follow routines, or successfully master
  new material. Verbal facility is often impaired
  both in speaking and writing. Some individuals
  exhibit greater introversion, become totally
  involved with the present at the expense of
  future goals and demonstrate a strong tendency
  toward regressive, childlike, magical thinking.
  McGlothin, W.H.

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History of Amotivational Syndrome

• The 1960s are associated with an explosion of
  the use of marijuana.
• Peak use was surveyed in 1979 with 24 million
  smokers.
• Before this time, any record of amotivational
  syndrome was completely nonexistent.

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Case Histories

• The concept of this syndrome first appeared in
  the 1960s with a few case histories.
• However, these case histories were unable to
  show
• How common amotivational syndrome is.
• Whether marijuana caused the change in
  motivation.
• If a change did occur, did it effect all facets
  of motivation or is it specific only to certain
  forms of motivation.
• What do you think?

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What is the culprit?

• The big question is which comes first, the
  marijuana or the loss of motivation?
• Lets look at a few surveys conducted on college
  and high school students.

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Evidence continued

• A study among workers suggests that marijuana use
  can be hazardous to working or to a motivation to
  work
• Users had 55 more accidents, 85 more injuries,
  and a 75 increase in absenteeism
• (National Institute on Drug Abuse)

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Survey Research

• A survey was conducted on 2000 college students
  in 1974 by Brill, N. et al.
• The researchers concluded that there was no
  difference in grade point average or academic
  success between smokers and non smokers.
• However, the marijuana smokers surveyed did have
  more trouble deciding on career goals and many
  did not pursue professional degrees.

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Laboratory Studies

• Mendelson et al, 1974, conducted an experiment in
  which 10 casual and 10 heavy cannabis smokers
  were observed for 31 days.
• They were given access to as many marijuana
  cigarettes as they earned through a simple
  operant task which involved pressing a button to
  move a counter.
• The researchers found that all subjects earned
  the maximum amount of points each day and output
  was unaffected by marijuana smoking.
• Mendelson et al concluded that "our data
  disclosed no indication of a relationship between
  decrease in motivation to work at an operant task
  and acute or repeat dose effects of marihuana"

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The Jamaican Study ( 1976)

• A study performed by Rubin and Comitas 1976,
  examined the effects of marijuana on the
  performance of Jamaican farmers who regularly
  smoked marijuana in the belief that it enhanced
  their physical energy and work productivity.
• They used videotape to track the farmers
  movements and biochemical measures of exhaled
  breath to asses caloric expenditures before and
  after getting high.
• After smoking ganja the workers engaged in more
  intense and concentrated labor.
• but this was done less efficiently, especially by
  heavy users. Looking for your pencil when its
  behind your ear?
• "In all Jamaican settings observed, the workers
  are motivated to carry out difficult tasks with
  no decrease in heavy physical exertion, and their
  mistaken perception of increased output is a
  significant factor in bolstering their motivation
  to work. -Comitas

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Debatable issues- Gateway Drug

• The gateway hypothesis holds that consumption of
• abusable drugs progresses in orderly fashion
  through several
• discrete stages
• Young et al. observed that marijuana was the
  first drug used by 42 of
• a sample of delinquent youths.

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Debatable issues- Gateway Drug- Most
well-designed studies suggest this is false.

• The entire sequence, which is exhibited by only a
  small minority of drug users, begins with beer or
  wine and moves progressively through hard liquor
  or tobacco, marijuana, and finally hard drugs.
  Each stage is thus a component of both a temporal
  sequence and a hierarchy.
• This claim has not been empirically supported,
  however. Researchers have reported that marijuana
  use is not a requirement for progression to hard
  drugs.
• Golub and Johnson (5) found that 75 of
  inner-city heavy drug users began using cocaine
  before using marijuana. These authors also report
  that14 of hard drug users skipped both the
  alcohol/tobacco and marijuana stages (6).
• Mackesy-Amiti et al. (7) reported that 39 of
  their sample started using marijuana after they
  had used hard drugs.
• Blaze-Temple and Lo (8) reported that 29 of
  their sample began using marijuana after having
  used heroin, stimulants, or LSD.
• Common liability model is a better explanation
• Alcohol and cigarettes are stronger gateway drugs
  if one accepts the data

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Debatable issues- Gateway Drug vs common
liability model

• Alternatively, abuse of illicit drugs,
• whether or not preceded by use of licit
  compounds, may
• be more parsimoniously explained by their
  availability in
• the social environment and the level of the
  individuals liability
• that is common to all abusable substances. For
  example,
• conduct problems in childhood presage consumption
• of all classes of abusable drugs. Genetic (912),
• neurophysiological (13, 14), neurochemical (15,
  16), and
• behavioral (17, 18) investigations have shown
  that the
• same factors are associated with consumption of
  licit and
• illicit drugs. Indeed, 100 of the genetic
  variance in the
• risk for diagnosis of substance use disorder is
  common
• acros

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Medical Marijuana

• 1998 IOM (inst of Med.) report concluded that
  there is scientific evidence for medical use
• Analgesic
• Anti-emetic
• Anti-spastic
• Appetite Stimulant
• Glaucoma-not particularly effective
• Tumor suppression? (lung cancer)
• Seizures? THC Cannibidiol protect against
  neurotoxicity

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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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The debate continues
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Adverse Effects of Marijuana Chronic Effects

• Lung damage-Bronchitis Lung cancer?

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Carcinogens in smoke

• Marijuana
• Vinyl Chloride 5 ng
• D-M nitrosamine 75 ng
• M ethylnitrosamine 27 ng
• Benz-anthracene 75 ng
• Benz-pyrene 31 ng

• Tobacco
• Vinyl Chloride 12 ng
• D-M nitrosamine 84 ng
• M ethylnitrosamine 30 ng
• Benz-anthracene 43 ng
• Benz-pyrene 21 ng

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Dependence on Marijuana

• Tolerance
• Withdrawal syndrome
• Irritability, mood changes
• Sleep disturbances
• Loss of appetite, nausea
• 5 heavy users 15 joints per day more or less
  permanently stoned House of Lords Cannabis
  report (2000)

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Adverse Effects of Marijuana Chronic Effects

• Cognitive deficits?

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Cognitive deficits

• Deficits on tests of memory, learning, word
  fluency (producing words in a particular
  category), and processing speed persist 48 hours
  after last use in chronic marijuana users (Croft,
  et al., 2001)
• Heavy users who begin smoking before age 17 show
  more severe deficits (Pope et al., 2003)but many
  accounts are possible

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Costa Rican Study

• This study performed by Carter et al. 1980 that
  compared Costa Ricans employment history of
  heavy users to non-users.
• The comparison showed that non-users were more
  likely to have a stable employment history, have
  received promotions and raises, and to be in
  full-time employment
• Users were more likely to spend more than their
  incomes

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Costa Rica cont.

• However, when comparing only users, a
  relationship between average daily marijuana
  consumption and employment presents a conflicting
  amotivational hypothesis.
• Those "who had steady jobs or who were
  self-employed were smoking more than twice as
  many marijuana cigarettes per day as those with
  more frequent job changes, or those who were
  chronically unemployed", indicating that "the
  level of consumption was related more to relative
  access than to individual preference"

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What does this all mean?

• Evidence of Amotivational syndrome from these
  field studies are usually interpreted as failing
  to demonstrate the existance of an actual
  syndrome.
• Here are a few problems with the evidence
• Sample sizes are too small to exclude the
  possibility of an effect occurring among a
  minority of heavy users.
• Cohen (1982) argues that the heavy users come
  from socially marginal groups.
• Therefore, the cognitive and motivational demands
  of their everyday lives were insufficient to
  detect any impairment caused by chronic cannabis
  use.

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Laboratory Criticism

• There are a few obvious weaknesses in Mendelsons
  experiment.
• The period of heavy use was only 21 days, which
  is inconclusive with the amount of years that
  many of the subjects in the field studies
  endured.
• The subjects were all healthy, young cannabis
  users with a mean IQ of 120 and nearly three
  years of college education.
• During debriefing, many of the subjects reported
  that they were motivated to perform well to
  demonstrate that marijuana does not have any
  affect on their performance.

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In Conclusion

• The evidence of Amotivational Syndrome is
  extremely vague in all facets of research.
• The small number of field and experimental
  studies were unable to show convincing evidence
  to support such a syndrome.
• In conclusion, if there is such a syndrome, it is
  specific only to a few heavy users and is a very
  rare occurance.