cannabis

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cannabis
See Dennis Hopper and Peter Fonda and Jack
Nicholson in Easy Rider (1969)
CHAPTER 15
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Cannabis sativa

• Two phenotypes (subspecies)
• cultivated for fiber (hemp), low content of
  active ingredients
• cultivated for psychoactive ingredients
  (marijuana)
• Identifiable by distinctive leaf
• Male and female plants
• Female must be fertilized by pollen from male
• Resin
• Sticky, yellow
• Flowering tops of female plants

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Forms of Cannabis

• Marijuana (dried leaves and flowers)
• Smoked, baked into brownies or cookies
• 60s 1.5 THC
• 80s 3.0-3.5 THC
• 90s 5.4 THC
• Hashish (dried resin from female plant)
• Smoked, baked in candies or cookies
• Hash oil (60 cannabinoids)
• Boiling hashish in alcohol, filtering out
  residue, evaporating alcohol
• Colour related to purity
• Synthetic
• Nabilone, Marinol
• Used to treat chemotherapy-induced nausea

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Sativex is extracted THC from cannabis
SR-141716A rimonabant (Acomplia, Zimulti,
Slimona, Obitone) is a cannabinoid receptor
blocker marketed as an appetite suppressant
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THE CANNABINOIDS

• ACTIVE INGREDIENT
• Usually reported as
• ?9- tetrahydrocannabinol
• (delta-9-THC or ?9-THC)
• But an entire family (gt60) of
• drugs (cannabinoids) exists in
• cannabis and may contribute to
• its effects
• - ?8-THC
• - cannabinol (CBN)
• - cannabidiol (CBD)
• CBN CBD dont have behavioural effects on
  their own

Electron micrograph of cannabis leaf
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THE CANNABINOIDSBut wait

• Active ingredients depend upon preparation
  and route of administration
• Burning cannabis (during smoking) changes many of
  the cannabinoids and appears to create new ones
  with increased potencies and effects
• CBD is effective when burned (converted into
  ?9-THC)
• Also, new cannabinoids are created during
  digestion and metabolism
• Content of marijuana can change over time,
  especially if exposed to light and air (THC gets
  converted into CBN)

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History Cannabis has been known from prehistoric
times in India and China
Gautier
Baudelaire
Cub des Hachichins
Dumas
De Balzac
Moreau de Tours
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Marijuana gets a bad reputation
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Grown as hemp in northern climates for rope. In
more temperate climates a different phenotype was
developed for active ingredient. Grown by the
British in the American Colonies Marijuana was
introduced to the US by Mexican laborers and was
used furtively by minorities and jazz
musicians. In 1937 the US passed the Marijuana
Tax Act. In Canada it was included in the
Narcotic Control Act.
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Used as a folk remedy . In 1839, medicinal
properties were investigated by W.B.
OShaughnessy and in 1845 was used to treat
mental illness by J.J. Moreau de Tours In 1970,
the American Medical Association supported the
position of the US government and declared that
marijuana had no medical use and had a high
potential for abuse.
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ABSORPTION
ORAL

• THC
• Weak acid
• pKa 10.6
• Extremely lipid soluble
• Soluble in EtOH
• Wont dissolve in water
• Absorbed slowly in the
  digestive system
• Adding oil speeds absorption (brownies, cookies)
• Synthetic THC is dissolved in sesame oil
• First pass metabolism (consume larger amounts)
• Peak 1-3 hr after consumption (last gt 5 hr)

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ABSORPTION
INHALATION

• JOINT, CIGAR, BONG
• water pipe, cools smoke and prevents loss of
  drug in sidestream smoke
• 10-25 of cannabinoids in joint enter lungs/body
• Blood levels peak within 15 min
• Subjective effects generally last 30-60 min
• Depth of inhalation vs. holding smoke in

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DISTRIBUTION

• Lipid solubility
• Distributed throughout body depending on blood
  flow
• Some concentration in
• Lungs, kidneys, liver
• Peak subjective effects usually lag behind plasma
  concentration
• At peak blood levels, only 1 of administered
  dose enters brain
• Brain levels of THC continue to rise for several
  hrs after consumption

Blood THC levels
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EXCRETION

• Most metabolism occurs in liver
• METABOLITES
• ?9-THC converted to 11-hydroxy-delta-THC (more
  active than ?9-THC, penetrates BBB more easily)
• Numerous others metabolites - most are less lipid
  soluble and more easily excreted
• CBD slight effect on its own, but blocks the
  enzyme that metabolizes ?9-THC (prolonged action)
• CBN speeds metabolism of ?9-THC
• CBD and CBN also displace bound THC in blood,
  increasing amount available to reach brain

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EXCRETION

• INITIAL phase
• - ?9-THC levels in blood fall rapidly
  (redistribution)
• - Half-life 30 min
• LATER phase
• - Slower metabolism- dependent on the rate at
  which THC is released from lipid stores
• - Half-life 20-30 hrs
• - Traces of THC may be detected in blood for up
  to 30 days

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CB2 immune system
CB1 - CNS
Cannabinoid receptors
coupled to cAMP second messenger system
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Cannabinoid receptors
Cortex White matter
CB1 concentration Green high Yellow - low
globus plallidus (GP), substantia nigra (SN)
cerebellum (Cer), hippocampus (H), caudate
nucleus (C), putamen (P), hypothalamus (Hy), and
amygdala (Am)
Few CB1 receptors in medulla
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NEUROPHARMACOLOGY

• Endocannabinoids endogenous THC
• Anandimide ananda internal bliss
• First endocannabinoid discovered by Devane and
  Mechoulam (1994)
• Effects on CB receptor not as profound as THC
• Two other endocannabinoids have been found,
  others very likely exist

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• Act as neuromodulators (like endogenous opioids)
• Alter neurotransmitter/receptor functioning
• NE
• DA
• 5-HT
• ACh
• GABA
• Histamine
• Endogenous Opioids

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depolarization-induced suppression of inhibition
Relax, eat, sleep, forget and protect
In the CA1 field of the hippocampus, membrane
depolarization (1) opens voltage-activated Ca2
channels in pyramidal neurons, producing (2) an
elevation of intracellular Ca2 concentrations.
Ca2 can (3) stimulate the synthesis of
anandamide The newly formed endocannabinoids
might travel across the synapse to interact with
(4) CB1 receptors on axon terminals of GABA (
-aminobutyric acid) interneurons, leading to
depolarization-induced suppression of inhibition,
or (5) 'CB3' sites on glutamatergic terminals,
leading to depolarization-induced suppression of
excitation.
depolarization-induced suppression of excitation
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Dopamine Neuron
GABA Neuron
THC binds to GABA autoreceptors which inhibits
further release of GABA (feedback mechanism)
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• Cannaboinoid Receptors
• Within nucleus accumbens
  increase activity of mesolimbic
  DA system (reward)
• Found in same region as
  opiate receptors

RECALL The NAcc and VTA form the brains Reward
System The VTA stimulates the NAcc by releasing
dopamine Cells in the NAcc send axons back to VTA
and release GABA and endogenous opiates
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EFFECTS ON THE BODY
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Medically Useful Effects

• Glaucoma THC reduces pressure of fluid in the
  eyeball
• Antiemetic stops nausea and vomiting
  (useful in chemotherapy patients)
• Antiepileptic/anticonvulsant
• Movement and Spasticity Disorders
• multiple sclerosis, epilepsy, spinal cord injury
• Pain CNS pain centres are less responsive to
  pain after cannabinoid administration
• As effective as morphine at reducing pain
  responses in rats
• Blocking CB1 spinal cord receptors increases
  sensitivity to pain

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Why Not Use Medical Marijuana?

• There are few systematic, controlled studies to
  properly evaluate marijuana (or any other
  cannabinoid) as a treatment for disease
• No cannabinoid has yet been found that doesnt
  produce a subjective high and cause detrimental
  effects on memory

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Effects of Marijuana

• SLEEP
• Low dose Drowsiness, increased sleep time
• High dose Restlessness, insomnia
• PERCEPTION
• Loss of sensitivity to pain
• Perceptions keener, sensory effects more intense
  and enjoyable
• Increases in subjective time rate (people
  experience time passing more quickly)
• MOOD
• Swings from euphoric gaiety with hilarious
  laughter to placid dreaminess, almost always
  pleasant
• being High
• Mood greatly affected by environment
• Mood of others present is vital mood ratings do
  not correlate with ratings of intoxication but
  with mood of others present (high or not)

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Systematic studies of Mood POMS shows Increased
stimulation and sedation! No change in euphoria
or positive affect. Many novice users report
little effect. Those who show a positive effect
the first time are more likely to reuse.
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Effects of Marijuana

• MEMORY
• No problem with recall of already-learned
  material
• Problem in short-term memory
• temporal disintegration loss of the ability
  to retain and coordinate information for a
  purpose
• - person will forget thought mid-sentence (leads
  to very disjointed conversations in a room full
  of marijuana smokers!)
• - similar to symptoms of Korsakoffs Psychosis
  (alcohol)
• caused by damage to limbic system
  hippocampus
• cannabis blocks functioning of hippocampus
• ATTENTION
• Deficit on tasks requiring vigilence or sustained
  attention
• People are easily distractible
• Rotary Pursuit Task one subject stopped
  following the moving dot and drew pictures on the
  screen with the dot that he controlled

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Effects of Marijuana

• DRIVING
• Marijuana has little effect on the ability to
  control a car (no effect on reaction time)
• HOWEVER, marijuana does impair a drivers ability
  to attend to peripheral stimuli (might not notice
  things they need to stop for)
• Attending to internal events rather than whats
  happening on the road
• Driving in real traffic low doses of THC caused
  significant impairment
• Impairment amplified by small doses of alcohol

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Screening tests Standardized Field Sobriety
Test gaze nystagmus walk and
turn balance Nonhumans Taming
effect Interferes with tasks that involve short
term memory Matching to Sample and
timing Blocks avoidance at doses that do not
block escape No increase in punishment suppressed
behavior Asymmetrical dissociation demonstrated
in humans
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Nonhumans Taming effect Interferes with tasks
that involve short term memory Matching to
Sample and timing Blocks avoidance at doses that
do not block escape No increase in punishment
suppressed behavior Asymmetrical dissociation
demonstrated in humans
Delayed matching to sample test
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Discriminative Stimulus Properties Effective
discriminative stimulus Delta9 generalizes to
delta 8 and 11 hydroxy, but not to CBD, some
generalization to CBN Will generalize poorly to
anandamide, only at high doses CBD can enhance
or prolong the effect of THC Partial
generalization to sedatives, no generalization to
any other drug.
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Tolerance to some behavioral effect in
nonhumans. No sensitization in laboratory studies
with humans. Tolerance to subjective effect for
both high and low dosed four times a day for four
days. No tolerance to increased food
consumption. Asymmetrical dissociation
demonstrated in humans
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WITHDRAWAL

• Withdrawal in Humans (1976)
• Volunteers took high doses of oral
  THC every 4 hr for 12 days
• Results after Cessation
• inner unrest after 6 hr
• By 12 hr following last dose Hot flashes,
  sweating, runny nose, loose stools, hiccups, loss
  of appetite
• Irritability, restlessness and insomnia
• Recent research (1999)
• Withdrawal symptoms to smoked and oral THC after
  only 4 doses/day for 4 days
• Anxiety, irritability, decreased food intake,
  decreased quality/quantity of sleep

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Haney, Hart, Vosburg, Nasser,Bennett, Zubaran and
Foltin (2004)
Placebo pills placebo MJ except before bed
Placebo MJ either placebo pills or THC
Placebo pillsreal MJ
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Self-administration Earlier attempts used too
high a dose and administered it in a solvent that
was not appropriate. Gianluigi Tanda, Patrik
Munzar and Steven R. Goldberg (2000) Blocked by
a cannabinoid receptor antagnist, SR141716A
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EPIDEMIOLOGY

• Social drug (1970s) - group, ritual-like
• Recently, more solitary use, less ritual
• From 1985-1992 steady decline in U.S. (9.3-4.3)
• Increased and remained steady thereafter
• Marijuana and ER visits (DAWN) 126 increase in
  marijuana related accidents (1995-2000) likely
  due to increased potency

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EPIDEMIOLOGY

• Cultural differences
• Amount
• North Americans consume low amounts vs. India,
  Egypt, Greece, Morocco, Jamaica extensive doses
  daily
• NA casual user stoned on 5-6 mg
• Avg. user daily consumption (U.S.) 50 mg/day
• Avg. user daily consumption (Eastern countries)
  200 mg/day
• Longitudinal Use
• Westerners decrease use with age,
  eventually quit
• Eastern countries extensive use for
  20-40 years

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HARMFUL EFFECTS
1936 Anti-Marijuana film
The plot revolves around the tragic events that
follow when high school students are lured by
pushers to try marijuana a hit and run accident,
manslaughter, suicide, rape, and descent into
madness all ensue.
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HARMFUL EFFECTS

• VIOLENCE and AGGRESSION
• No systematic data to support ?ed violence and
  aggression
• In fact, marijuana has been used to ? aggression
• MENTAL DISTURBANCE
• Marijuana psychosis marijuana can precipitate
  full-blown psychosis in people with psychotic
  tendencies
• Intensify schizophrenic and paranoid symptoms
  that already exist
• High doses
• - paranoia, anxiety
• - Freak Out psychotic reaction, panic,
  hallucinations, perceptual distortions, loss of
  reality, feel insane.
• Freak outs occur when drug is taken in
  higher-than- normal doses or in unusual or
  stressful circumstances
• - ER Patients can be talked down or given BDZs

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HARMFUL EFFECTS

• INTELLECTUAL IMPAIRMENT BRAIN DAMAGE
• North Africa (where cannabis is used for long
  periods at high doses) cannabis dementia
• British study shrinking of the brain
• Rats
• THC in large doses, daily for 6 months
  results in impaired maze
  learning,
  remained 2 months after marijuana
  (permanent brain damage)
• Monkeys
• 4-5 low-medium potency joints inhaled through
  mask every day for 1 year produced no detectable
  differences in behaviour, hippocampal volume,
  neuron size, anatomy of synapse or dendrites
• Comparisons between rats, monkeys, humans
• 3 months in rat 3 years in monkey 7-10 years
  in human

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HARMFUL EFFECTS

• INTELLECTUAL IMPAIRMENT BRAIN DAMAGE
• Review (1998) little evidence that long-term
  heavy use produces severe debilitating impairment
  of cognitive functioning
• May produce subtle impairments in higher
  cognitive functions such as memory, attention,
  integration of complex information (related to
  duration and extent of use)
• Reversible ????

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Amotivational Syndrome

• Systematic changes in persons lifestyle,
  ambitions,
• motivation, personality
• Apathy
• ? effectiveness
• ? Long-term goals
• ? concentration
• ? ability to endure
  frustration
• ? follow routines
• Impaired verbal ability
• Introversion, regressive,
  
• childlike, magical thinking
• Monkeys
• Marijuana every day for 1 yr
• Lower breaking point for banana-flavoured food
  pellets

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• Claims that marijuana is a gateway drug or
  stepping stone toward using more
  dangerous drugs
• Golub and Johnson (1994) All heroin users
  in study had used
  marijuana
• Mullins et al. (1975) The more a person uses
  marijuana, the greater the likelihood of using
  other drugs
• Main Problem Causal relationship? (correlation
  doesnt imply cause)
• Soda before alcohol
• Boredom hypothesis people tolerate to the mild
  effects of marijuana
• People seldom abandon marijuana when using
  stronger drugs
• Social hypothesis Heavy marijuana use provides
  social setting, motivation, and opportunity to
  use other drugs

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Reproduction

• ? - ? testosterone levels
• Mice anandamide works as a chemical messenger
  between embryo and uterus during implantation
• THC could interfere with the implantation
  process, prevent pregnancy
• Study 1984-1989 (7,000 women- 11 users during
  pregnancy)
• No association with birth weight or prematurity
• Functional disturbances in children prenatally
  exposed to marijuana
• Abnormal sleep patterns in newborns, lasted until
  3 yrs old

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• IMMUNITY
• Clearly shown that marijuana decreases immune
  system activity
• tissue transplant success
• more research needed
• CANCER
• Marijuana smoke
• 50-70 more carcinogenic material than tobacco
  smoke
• Inhale more deeply, hold smoke in lungs longer
• Marijuana likely accelerates carcinogenic effects
  of tobacco smoke
• Lung cancer patients (lt45) 100 marijuana use
• Confounds
• Many marijuana smokers also smoke tobacco
• Cannabidiol and ?9-THC are also antioxidants
  (reduce DNA damage by free radicals which can
  lead to cancer)
• - More research needed