Psychopharmacology

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Background and History of Marijuana

• Produced from the flowering hemp (Cannabis
  Sativa).
• Hemp was historically important as a major source
  of fiber for rope making
• Shipping
• Contains more than 60 unique compounds
  collectively known as cannabinoids
• Some of these compounds are psychoactive
• ?9 tetrahydrocannabinol (THC)

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Background and History

• Cannabis can be obtained in a number of forms
• Marijuana mixture of dried leaves, small stems,
  and flowering tops of Cannabis plants
• Usually smoked
• Can be consumed (often in baked goods cookies
  or brownies).
• Potency varies depending on
• genetic strain
• growing conditions
• If you prevent pollination (which prevents seed
  production in female plants) you can achieve
  higher potency
• Known as sinsemilla (without seeds)

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Background and History

• Hashish
• Collected and pressed plant resin
• Can be smoked or eaten
• Potency depends on how collected, but it is
  generally more potent than marijuana
• Hash oil
• An even more potent extract of the marijuana
  plant resin
• Sometimes a drop is placed on a typical cigarette
  and smoked.
• Or a drop can be added to a marijuana cigarette
  to increase its dose.

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13.3 The potent form of cannabis called hashish
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Hash Oil
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Background and History

• Cannabis is thought to have originated in central
  Asia (probably China).
• There is evidence of hemp rope dating back to
  8,000 B.C.

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• Western interest did not begin until the early to
  mid nineteenth century.
• Napoleons soldiers thought to have brought
  hashish back to France from Egypt
• French physician Jacques-Joseph Moreau also
  brought hashish back to Paris after traveling to
  the Middle East.
• club of hashish eaters
• Writers and artists

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Background and History in US

• Dates back to colonial era
• George Washington was a hemp farmer
• Unlikely aware of psychoactive effects
• Grown for fiber
• Practice of smoking marijuana likely brought into
  the US in the early 1900s
• Mexican/American border
• Mexican immigrants
• New Orleans and other ports on the Gulf of Mexico
• Caribbean sailors
• West Indian immigrants

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Background and History in US

• Marijuana use spread rapidly in the US
• Marijuana tax act in 1937
• Overturned by Supreme Court in 1969
• Controlled substances Act of 1970
• Schedule 1 drug.

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Basic Pharmacology of Marijuana

• Israeli researchers Gaoni and Mechoulam (1964)
  identified THC as the major active ingredient of
  Cannabis Sativa.

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Basic Pharmacology of Marijuana

• A typical joint consists of around 0.5 grams to 1
  gram of cannabis.
• THC content can be around 4 or higher
• If about 4 then a 1 gram joint contains about 40
  mg of THC
• Burning causes the THC to vaporize and enter the
  smokers lungs in small particles
• Only about 20 of the original THC content gets
  absorbed
• There can be substantial variation in the amount
  of THC absorbed based on
• The potency of the marijuana
• The amount smoked
• The pattern of smoking

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Basic Pharmacology of Marijuana

• Experienced marijuana users regulate the volume
  and frequency of puff to control the behavioral
  effects of the drug.
• Interestingly controlled experimental studies
  have failed to show a substantial effect of
  breath holding
• Though Block et al. (1998) found that there was a
  modest subjective effect of breath holding for 15
  seconds rather than 7 seconds.
• So there may be something to the practice of
  holding the smoke in.

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Basic Pharmacology of Marijuana

• THC is absorbed through the lungs
• Causes rapidly rising levels of THC in blood
  plasma
• After peak levels are reached, Plasma THC levels
  begin to decline
• Metabolism by liver
• Accumulation of the drug in fat stores

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Basic Pharmacology of Marijuana

• Oral consumption of marijuana
• Leads to prolonged but poor absorption of THC
• Results in low and variable plasma concentrations
• Probably due to degradation in stomach, and first
  pass metabolism by the liver.
• THC is converted into several metabolites
• 11-hydroxy-THC
• 11-nor-carboxy-THC (THC-COOH)
• These metabolites are excreted in feces and urine
• Blood levels of marijuana decline quickly
• But elimination from the body is much slower.
• The drug persists in fatty tissue
• Sensitive urine screening tests can detect
  THC-COOH more than 2 weeks following last use.

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Mechanism of Action

• It wasnt until 1988 that the receptors for
  cannabanioids were discovered
• Subsequently, it was discovered that cannabinoid
  receptors were expressed in many brain regions,
  including the
• Basal ganglia
• Cerebellum
• Hippocampus
• Cerebral cortex
• Especially frontal cortex
• Also limbic system
• Hypothalamus
• Anterior cingulate cortex
• Absence of receptors in brain stem may explain
  low toxicity (hard to overdose).
• Key for image
• CB1 receptor densities
• YellowgtRedgtBlue

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• Not surprisingly the location of cannabinoid
  receptors correspond with the behavioral effects
  of cannabinoids
• Locomotor activity
• Coordination
• Memory
• There are 2 forms of the cannabinoid receptors
• CB1 in the CNS
• CB2 in the periphery (seems to be involved in
  immune system).

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CB1 receptors

• Metabotropic
• Inhibition of cAMP
• Inhibition of voltage sensitive CA channels
• Activation of K channels
• Excitation or Inhibition?
• Typically the receptors exist on the axon
  terminal rather than on the postsynaptic cell.
• Affects many neurotransmitter systems
• Acetylcholine
• Dopamine
• Norepinephrine
• Serotonin
• Glutamate
• GABA

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Agonists and Antagonists

• THC is of course the classic cannabinoid receptor
  agonist
• First useful antagonist was developed in 1994
• SR 141716 (rimonabant)
• Selective antagonist for CB1 receptors
• Orally active (thus, easy to administer to
  humans)
• We will discuss the effects of this drug later

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Endocannababinoids

• The existence of cannabinoid receptors led
  researchers to search for an endogenous
  neurotransmitter
• Israeli scientists Devane et al. (1992)
• Arachidonoyl ethanolamide
• Anandamide
• From Sanskrit - ananda bringer of inner bliss
  and tranquility
• Other endogenous substances have now been found
• Collectively referred to as the endocannabinoids

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• The endocannabanoids are generated from
  arachidonic acid
• A fatty acid found in the cell membrane
• Unlike classic neurotransmitters they are very
  lipid soluble
• Cant be stored in vesicles
• Would pass right through the membrane
• Believed they are made and released as needed
• One mechanism appears to be a rise in
  intracellular Ca levels.
• Enzymes involved in generation of
  endocannabinoids are Ca sensitive

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• After release endocannabinoids are taken up from
  the extracellular fluid by specific transporters
• Seems to inactivate endocannabinoids
• Inhibition of this transporter (AM 404) enhanced
  the effects anandamide in animals
• Once in the cell endocannabinoids are metabolized
  be enzymes
• Fatty acid amide hydrolase (FAAH)
• Genetic knock out mice that lack FAAH show
  elevated anandamide levels in the brain

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• Endocannabinoids appear to work by modulating
  the effects of other neurotransmitter systems
• Either by suppressing inhibition of interneurons
• Depolarization induced suppression of inhibition
  (DSI)
• Suppress activity of GABA releasing neurons
• Or by suppressing excitation of interneurons
• Depolarization induced suppression of excitation
  (DSE)
• Suppress activity of Glutamate releasing neurons.

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Depolarization-induced Suppression of Inhibition
- DSI

• Depolarization-induced suppression of inhibition
  (DSI)
• Known to occur for some time.
• A form of fast acting retrograde signaling
• Remember nitric oxide?
• Prominent effect in the hippocampus and
  cerebellum
• Endocannabinoids appear to be retrograde
  messengers
• The are synthesized and released in response to
  depolarization of the post synaptic cell
• Influx of Ca through voltage gated channels
• Following release they cross the synaptic cleft
  and activate CB1 receptors
• They then inhibit neurotransmitter release from
  the presynaptic terminal

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• In the hippocampus (an example)
• Endocannibinoids are generated by pyramidal
  neurons (principle output neurons of the
  hippocampus)
• Diffuse to nearby GABAergic interneurons and
  inhibit them
• Inhibition of GABA release allows the pyramidal
  cells to fire more rapidly
• Inhibition of inhibition excitation
• Similar mechanisms likely occur in other brain
  regions and other neurotransmitter systems

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13.9 Retrograde signaling by endocannabinoids
reduces GABAergic inhibition
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Evidence that endocannabinoids play a role in DSI

• Ohno-Shosaku et al. (2001)
• Cultured hippocampal neurons
• Found that depolarization of the postsynaptic
  neurons lead to suppression of inhibition in
  about 2/3 of neuron pairs
• Due to inhibition of GABA
• Those neurons that displayed DSI responded to the
  CB1 synthetic agonist (WIN55, 2122)
• Mimicked DSI
• Rimonabant blocked this effect

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Evidence that endocannabinoids play a role in DSI

• Varma et al. (2001)
• DSI was completely absent in hippocampal slices
  prepared from CB1 receptor knockout mice
• There is also a phenomenon known as
  depolarization-induced suppression of excitation
  (DSE).
• This involves suppression of typical excitation
  produced by glutamate
• Cannabinoids appear to play a role here as well.

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Iversen 2003

• These findings suggest that endocannabinoids are
  involved in the rapid modulation of synaptic
  transmission in the CNS via a retrograde
  signaling system.
• Causing inhibitory effects on both excitatory and
  inhibitory neurotransmitter release that persists
  for tens of seconds
• When we take cannabinoids they cause long-lasting
  activation of CB1 receptors in all brain regions
• Rather than short localized effects
• This will temporarily override any modulatory
  effects that cannabinoids normally cause

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Acute Behavioral Effects

• Iversen (2000) separates the subjective effects
  of moderate doses of marijuana into four stages
• 1) The buzz
• A brief period of initial responding
• Lightheaded
• Perhaps slightly dizzy
• Tingling sensation in extremities is fairly
  common
• 2) The high
• Feelings of euphoria and exhilaration
• Sense of disinhibition
• Often manifested as increased laughter.

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• 3) stoned
• Calm, relaxed, dreamlike state
• Sometimes people report
• Floating sensation
• Enhanced visual and auditory perception
• Visual illusions
• Tremendous slowing of time passage
• Some feel increased sociability others feel a
  desire to be alone

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• 4) comedown
• Often preceded by hunger, or empty feeling in
  stomach munchies
• People report feeling tired, listless, weak.
• Everyone initially very talkative, but as they
  comedown conversations slows and people become
  sleepy
• Usually leads to sleep sometimes with colorful
  dreams
• Marijuana can cause strong feelings of anxiety,
  panic, or paranoia.
• More likely to be reported by first time users,
  or the result of taking large doses of the drug

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Acute Physiological effects

• Increased blood flow to the skin
• Sensation of warmth or flushing
• Increased heart rate
• Pounding pulse
• Increase in hunger
• Munchies
• Recognized as a therapeutic effect of marijuana

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• Expectations about the drug can influence the
  effects of the marijuana
• Kirk et al. (1998)
• Some given THC capsules
• Some given placebo
• Some informed
• Some uninformed
• Informed group gave higher ratings for liking the
  drug and wanting more drug
• This was also true for the group that received
  placebo, but were told they received THC

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• The subjective effects of marijuana are at least
  partially mediated by CB1 receptors.
• Self reports of feeling high or stoned were
  significantly inhibited by the antagonist SR
  141716
• Notice the same sort of effects occurred for
  heart rate (a less subjective measure).
• Unknown if there is more than one mechanism of
  marijuana effects, or if they didnt use a high
  enough dose of antagonist to fully block the
  effects.

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Therapeutic uses of cannabinoids

• Antiemetic effects
• There are presently synthetic forms of THC that
  are prescribed to treat the nausea and emesis
  (vomiting) associated with chemotherapy
• Dronabinol
• Nabilone
• Animal Studies have shown that this effect
  appears to be CB1 dependent.
• In fact in one susceptible species (the shrew)
  the CB1 antagonist rimonabant is emetic.
• This effect can be blocked by THC or WIN55,2122

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Appetite stimulant

• Dronabinol is also approved for use as an
  appetite stimulant in AIDS patients suffering
  from anorexia-cachexia (wasting syndrome).
• THC also stimulates food intake in experimental
  animals
• For high-fat or sweet high-fat diets
• Not for lab chow
• This effect is blocked by rimonabant
• Rimonabant given on its own suppresses food
  intake
• Led to reduced body weight in adult non-obese
  rats.
• Implicates CB1 receptors
• Perhaps a treatment for obesity?
• These effects may work through the appetite
  suppressing hormone leptin.
• hypothalamus

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Cannabinoids and pain

• Cannabis was widely used in the 19th century for
  pain relief
• Cannabinoid receptors exist at various levels in
  the pain pathway
• Peripheral nerve endings in the spinal cord
• Anterior cingulate cortex

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Animal studies

• Animal studies show that THC and synthetic
  cannabinoids have anti-nociceptive effects.
• Have to rule out motor effects
• Cannabinoids decrease activity
• Typically measure how quickly an animal will
  avoid pain
• Hot plate
• Tail flick
• Could be same pain but less movement

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Cannabinoids, pain relief, animal studies

• Shown that cannabinoids suppress
  electrophysiological responses of spinal cord
  neurons to pain
• Shown that cannabinoids work when injected
  directly into spinal cord, brain stem, or spinal
  cord
• Localized effects that should be less likely to
  affect activity levels
• The anti-nociceptive effects of cannabinoids are
  blocked by rimonabant
• Showing that CB1 receptors are directly involved
• Pain increases release of anandamide in the
  periaquaductal grey

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Cannabinoids and pain relief

• There is evidence that there may be an
  interaction between the cannabinoid and the
  opioid system in the relief of pain
• The systems seem to potentiate each other
• This potentiation can be blocked by rimonabant or
  naloxone
• Indicating that both CB1 and opiate receptors are
  involved

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• There is also evidence that cannabinoids may have
  some benefit for
• Glaucoma (pressure in the eye)
• Multiple sclerosis
• Spinal cord injury
• Traumatic brain injury
• Development of cannabinoid clinical applications
  has been slow
• Why?
• Lack of large scale controlled clinical studies
• Federal government tends to discourage efforts to
  develop and license new cannibinoid medicatons
• Concerns about psychoactivity
• cannabinoids are psychoactive even if taken
  orally
• This leads some physicians to be concerned about
  abuse
• Route of administration
• Works best if smoked
• Daily smoking can cause respiratory issues
• Nevertheless, some states have legalized smoking
  marijuana

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Marijuana use can lead to deficits in cognition

• Clinical accounts of marijuana intoxication have
  noted deficits in thought processes and verbal
  behavior
• Illogical disordered thinking
• Fragmented speech
• Difficulty remaining focused on a given topic of
  conversation
• Experimental assessment
• There are decrements on a variety of tasks
• Verbal
• Recall and recognition of word lists

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Cognitive deficits

• Spatial working memory Ilan et al. (2003)

A dot stimulus was displayed in one of six
positions on each trial. Subjects had to decide
whether the spatial location of the dot on each
trial matched the location of the dot two trials
before. Because which dot occurred two trials
before changes with each passing trial, this task
requires frequent manipulation of
to-be-remembered items.
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Cognitive deficits

• Time estimation
• Lieving et al. (2006)
• Asked to push one button for a short sample (2-s)
  and a different button after a long sample (4-s)
• train until performing well
• Test with a variety of samples between 2- and 4-s
• Those on marjiuana were more likely to judge time
  samples as long.
• Indicating that time had sped up for the
  individual - making short intervals seem long

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Cognitive deficits

• Explicit memory
• Oral Dronabinol (Marinol)
• Subjects listened to a short written passage
• Similar to a news bulletin on the radio
• Tested before and after drug or placebo
  administration
• 1 hour before 0 point on next graph
• They were then tested again 2 and 6 hours after
  treatment

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Cognitive deficits

• Low dose of THC did not affect memory
• High dose clearly did
• Memory for the content of a story compares nicely
  with real world task of following a conversation.

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Cognitive deficits

• Clearly there are many cognitive effects of
  marijuana intoxication
• There is evidence that prior usage of marijuana
  can reduce these adverse cognitive effects
• Behavioral cognitive tolerance?
• Learn to focus / pay more attention?

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Psychomotor performance

• Low doses of marijuana do not affect psychomotor
  performance much
• Higher doses do, even for regular users
• Particularly for demanding tasks
• Like driving.

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Animal studies

• Early studies show that THC can cause motor
  impairments, cataplexy (lack of voluntary
  movement), hypothermia, and analgesia.
• Most of the behavioral effects of THC are
  abolished in CB1 receptor knockout mice.
• Indicating these effects are mediated by CB1
  receptors

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Effects on animal learning and memory

• Cannabinoids disrupt performance on several
  learning tasks
• Radial arm maze
• Morris water maze
• Delayed non-match-to-position task.
• Left or right bar
• Insert one
• When rat responds the bar is retracted
• Impose delay
• Insert both bars
• Must choose the 1 that was not presented
  initially
• Considered a test of short term memory

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Effects on animal learning and memory

• Cannabinoids can impair radial arm maze
  performance when injected directly into
  hippocampus
• It has also been shown that activation of CB1
  receptors in the hippocampus decreases
  hippocampal synaptic transmission and interferes
  with long-term potentiation
• Perhaps the effects in humans are also due to
  impaired hippocampal functioning

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Effects on animal learning and memory

• There is evidence that CB1 receptors may be
  involved in extinction or reversal learning
• Varvel and Lichtman (2002) found the CB1 knockout
  mice show impaired reversal learning in the
  Morris Water Maze
• Perseverate?
• Damage to which brain area tends to cause
  perseveration?
• There is also evidence that humans exposed to
  marijuana have a decreased ability to inhibit
  responding

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Cannabinoids are reinforcing to both humans and
other animals

• Chait and Zacny (1992) found that regular
  marijuana users could discriminate marijuana from
  placebo cigarettes
• All preferred marijuana if given a choice
• Same effects occurred with pure THC taken orally
  compared to placebo
• Also shown that marijuana users preferred 1.95
  THC content to 0.63 THC

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Marijuana and reward in animals

• It was initially thought that animals did not
  find marijuana rewarding.
• Perhaps early studies used too high of doses
  leading to aversive reactions
• Squirrel monkeys have been shown to
  self-adminster THC
• These studies used lower doses within the range
  of a single drag of marijuana
• Lever pressing was blocked with pretreatment with
  SR 141716
• Indicating that the reinforcement depended on CB1
  receptors

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Marijuana and reward in animals

• Rats and mice
• Will self administer low doses of WIN 55,212-2
  (synthetic CB1 receptor agonist).
• Mice also show CPP to THC injection
• Only for the low dose
• Only if preexposed to THC in their home cage
• Indicates that first exposure to THC may be
  somewhat aversive regardless of dose
• Also indicates that the animals found high doses
  to be aversive

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Mechanisms of cannabinoid reinforcement

• One factor may be activation of the mesolimbic DA
  system.
• Cannabinoids have been shown to stimulate firing
  of DA neurons in the VTA
• Also to enhance DA release in NA

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Mechanisms of cannabinoid reinforcement

• There is evidence that the close interaction of
  the cannabinoid and opioid systems may play a
  role in reward
• For both cannabinoids and opiates
• Systemic Naltrexone reduced THC
  self-administration in squirrel monkeys
• CPP to low doses of THC did not occur in µ-opioid
  receptor knock out mice
• CPA to high doses of THC did not occur in
  ?-opioid receptor knock out mice
• Microinfusion of µ-opioid antagonist naloxonazine
  into the VTA of rats blocked DA release in NA
• by heroin
• also by THC.

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• Recently knockout and SR 141716 studies have
  provided evidence that the endocannabinoid system
  may play a role in the process of reinforcement,
  dependence, and relapse of a number of drugs
  including
• Ethanol
• Opioids
• Cocaine
• Nicotine
• Perhaps future treatments for drug addiction may
  involve the endocannabinoid system

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Cannabis use

• Cannabis is one of the most widely used
  intoxicants
• Almost half of all 18 year olds in the USA and in
  most European countries admit to having tried it
  at least once
• About 10 of that age group are regular users
• The number of new marijuana users per year has
  remained fairly steady (1995-2001).
• Suggests government efforts to dissuade use has
  not been very effective.

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Cannabis use

• Initial use of marijuana use typically occurs in
  adolescence
• Peak age for trying marijuana is 17
• People who have not tried the drug by mid
  twenties are unlikely to begin use

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Marijuana tolerance

• Human literature is variable
• Some studies have shown tolerance
• But many have shown that the high produced by a
  given dose of THC is similar for heavy or light
  users
• Animal literature is more consistent
• Animals exposed repeatedly to THC develop a
  profound tolerance
• Appears to be pharmacodynamic tolerance
• Rats given daily THC injections over a 3-week
  period
• Showed gradual reductions in CB1 receptor
  densities
• Also reduced responsivity of receptors to
  cannabinoid agonists
• Measured by G-protein activation reduced as
  exposure increased

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13.16 Desensitization of cannabinoid receptors
produced by chronic THC exposure
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Marijuana Dependence

• For many years cannabis was not considered a drug
  of addiction
• Withdrawal did not lead to any obvious physical
  symptoms in people or animals
• These attitudes have changed recently
• The DSM IV definitions of substance dependence
  and substance abuse may have played a role
• Certainly high proportions of regular cannabis
  users would meet these definitions
• Swift et al (2001)
• 10641 Australians 18 or older
• Estimate 1/3 of regular cannabis users fell
  within the definition of substance abuse (11) or
  substance dependence (21)
• US survey (Anthony et al., 1994)
• 46 admitted trying
• estimate that 9 of those users became dependent

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Marijuana Dependence

• There is some evidence for a mild withdrawal
  syndrome as well
• Symptoms include
• Craving for cannabis
• Decreased appetite
• Sleep difficulty
• Strange dreams
• Weight loss
• Sometimes emotional issues
• Anger
• Aggression
• Irritability
• These symptoms are similar to that seen with
  nicotine
• Symptoms are greatest during first 1 or 2 weeks
  of withdrawal.

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13.17 Time course of overall withdrawal
discomfort in heavy marijuana users
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Effects of Chronic Cannabis use

• There is a negative correlation between cannabis
  use and educational performance in young people
• Poorer grades
• Negative attitude about school
• Increased absenteeism
• Increased drop-out rates
• Amotivational syndrome?
• Correlation and causation

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• Health effects
• No overdose
• Lung damage?
• Dont smoke as much as cigarettes
• But - higher concentration of tar and other
  carcinogens
• Thus heavy smoking is linked to
• Increased risk for bronchitis
• Cellular abnormalities in lungs
• Some considered precancerous
• Clear link to lung cancer not determined

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• Immune system
• THC can suppress the immune system
• Impairs resistance to bacterial and viral
  infections
• Mostly in-vitro studies
• Difficult to know if it has real life effects
• Reproductive function?
• Can suppress luteinizing hormone (LH) in women
• Not present in regular users (Tolerance)
• Can decrease sperm count
• Only under very heavy conditions (10 joints per
  day for 4 weeks)
• Went away after a few weeks of abstinence
• No convincing evidence that reproductive problems
  stem from marijuana use