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Psychopharmacology

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Title: Psychopharmacology


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2
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)

3
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)

4
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.

5
13.3 The potent form of cannabis called hashish
6
Hash Oil
7
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.

8
  • 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

9
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

10
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.

11
Basic Pharmacology of Marijuana
  • Israeli researchers Gaoni and Mechoulam (1964)
    identified THC as the major active ingredient of
    Cannabis Sativa.

12
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

13
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.

14
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

15
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.

16
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

17
  • 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).

18
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

19
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

20
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

21
  • 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

22
  • 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

23
  • 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.

24
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

25
  • 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

26
13.9 Retrograde signaling by endocannabinoids
reduces GABAergic inhibition
27
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

28
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.

29
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

30
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.

31
  • 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

32
  • 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

33
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

34
  • 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

35
  • 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.

36
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

37
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

38
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

39
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

40
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

41
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

42
  • 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

43
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

44
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.
45
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

46
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

47
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.

48
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?

49
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.

50
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

51
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

52
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

53
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

54
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

55
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

56
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

57
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

58
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.

59
  • 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

60
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.

61
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

62
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

63
13.16 Desensitization of cannabinoid receptors
produced by chronic THC exposure
64
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

65
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.

66
13.17 Time course of overall withdrawal
discomfort in heavy marijuana users
67
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

68
  • 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

69
  • 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
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