Cannabis sativa

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Cannabis sativa

• Cannabis sativa has been used for many years for
  recreational and therapeutic applications
• The drug form is usually derived from the
  flowering part of the female plant of a slow
  maturing variety of the same species whose rapid
  maturing variety is used to produce fibres for
  rope.
• The female plant produces a resin which traps the
  pollen from male plants.

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Cannabis sativa

• Most common form used in USA and Europe is
  marijuana the dried leaves and flowers of the
  plant, usually smoked as a cigarette, but
  sometimes cooked into cakes (brownies)
• In India, a distinction is made between bhang and
  ganja.
• Bhang is the dried leaves of uncultivated plants,
  and is not very potent
• Ganja is made from the tops of female plants, and
  is 3-4 times more potent than bhang

• In the West Indies, cannabis was imported from
  India, and the Indian term Ganja is used rather
  than marijuana, but in Jamaica, Ganja refers to
  the whole plant, not just the flowers
• Hashish, also known as Charas in India, refers to
  the dried resin.
• Frequently this is smoked with tobacco
• A purified form of hashish is hash oil, prepared
  by boiling hashish in alcohol, and may contain up
  to 50 THC

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Cannabis sativa

• The main active ingredient of cannabis is
  ?9-tetrahydrocannabinol (?9-THC)
• There are many other psychoactive ingredients,
  perhaps up to 60 cannabinoids, which probably
  contribute to its effects.
• Other cannabinoids include cannabinol and
  cannabidiol (CBD).
• CBD is converted to ?9-THC during burning

• Marijuana samples seized in the 1960s contained
  about 1.5 THC.
• THC content increased during the 1980s to about
  3.0 3.5
• By 1994, the content was 5.4
• Hydroponic cultivation has led to levels as high
  as 20 in varieties such as Netherwood and
  Sinsemilla.

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Active Ingredients

• ?-9- THC also ?-8-THC (lower quantities)
• Cannabinol cannabidiol
• not active in own right
• cannabidiol - slows metabolism of THC increase
  duration
• cannabinol - increases rate of metabolism
• both inhibit THC binding
• increase brain THC
• cannabidiol converted to THC when burned
• THC converted to cannabinol with time
• (refrigerate when not in use)

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Cannabis sativa

• THC hardly dissolves in water, and when marijuana
  is taken orally, it is absorbed very slowly.
• Absorption is enhanced if oil is added to the
  plant preparation before ingestion. Easily
  achieved by baking it in food with oils or fats,
  such as brownies.
• Effects felt 1-3h after ingestion, and may last
  5h or longer

• A typical joint contains between 0.5 and 1 g of
  cannabis.
• Smoking results in about 25 of THC in a
  cigarettte entering the lungs, and practically
  all of that is absorbed into the blood.
• Blood levels peak within 15 mins.
• Effects felt within a few minutes, and peak in
  30-60 mins.

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Cannabinoid system

• Cloning of two subtypes of the cannabinoid
  receptor, CB1 and CB2 (Matsuda, 1990 Munro,
  1993).
• CB1 receptor is located mainly centrally, while
  the CB2 receptor is peripheral, mainly in the
  immune system.
• CB1 receptors are mainly localised to axons and
  nerve terminals

• Areas of high concentration of receptors include
  cortex, striatum (including accumbens),
  cerebellum, hypothalamus, anterior cingulate
  cortex
• No brainstem cannabinoid receptors, so vegetative
  functions are not affected directly by THC.

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Cannabinoid system

• Recent discovery of endogenous cannabinoid agents
  - anandamide and 2-arichidonylglyceryl ether
• endocannabinoids

• Anandamide is the NT for cannabinoid receptor
• Sanskrit for bliss

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How do cannabinoids work?

• Enhance extracellular DA in forebrain loci,
  possibly by facilitating release.
• This effect is antagonised by opiate antagonists
  such as naloxone.
• Thus cannabinoids appear to act in part by
  enhancing the effects of endogenous opioid
  peptides.

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How do cannabinoids affect reward?

• Also enhance firing of dopamine neurones in
  mesolimbic, nigrostriatal, and mesocortical
  pathways. Effects most prominent in mesolimbic
  pathways.
• Activation of the opioid receptors in the VTA by,
  for example, morphine or heroin blocks the
  activity of the GABAergic interneurons, thereby
  producing disinhibition and increased firing of
  the dopaminergic neurons, and, in turn, enhanced
  dopamine release in the nucleus accumbens.

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• One possible mechanism in the VTA-nucleus
  accumbens pathway is cannabinoid-induced
  inhibition of GABAergic interneurons within the
  VTA, leading to disinhibition of dopamine cell
  firing
• Alternatively, might be an interaction with the
  endogenous opioid system, known to modulate the
  dopamine release.
• Increase in dopamine concentration in accumbens
  evoked by 9-THC is prevented by the mu1 opioid
  receptor antagonist naloxonazine.

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How do cannabinoids work?

• Why should an opiate antagonist block THC
  effects, when we know THC works at its own CB1
  receptors?
• CB1 receptors are co-localised with mu opioid
  receptors in accumbens.
• Both coupled to similar postsynaptic signalling
  mechanisms involving Gi proteins, and subsequent
  inhibition of adenylyl cyclase and decreased
  cyclic AMP production.
• Thus effects are likely to be additive, and
  blocking one will reduce the effectiveness of the
  other.

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How do cannabinoids work?

• However, in drug discrimination experiments, the
  stimulus properties of cannabinoids do not
  generalise to other abused drugs ( but do
  generalise to other cannabinoids)

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Amotivational Syndrome

• Shift or decline in ambition
• unproductiveness
• aimlessness
• poor class attendance
• lack of goals

• Poor school performancesluggish in physical
  responses
• disorientation
• physical exhuastion
• depression

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Effects of cannabis

• Cannabis produces euphoria and relaxation, and is
  reported to increase the intensity of ordinary
  sensory experiences such as eating, watching
  films, and listening to music.
• At high doses cannabis acts as a hallucinogen,
  but at doses normally used in the UK the drug
  gives a pleasurable high

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Effects of cannabis

• Bloodshot eyes caused by dilation of small blood
  vessels in the sclera.
• Drooping eyelids (stoned)
• Dry mouth and compulsion to drink often
  resulting in alcohol use in conjunction with
  marijuana smoking
• An intense feeling of hunger, known as the
  munchies, strongest about 3h after smoking, when
  other effects have declined
• Increase in heart rate up to 160 beats/min
• Unpredictable fluctuations in blood pressure and
  body temperature
• Nausea and vomiting

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Effects of cannabis

• Most unpleasant side effects are anxiety and
  panic reactions
• Mostly confined to naïve users, or to experienced
  users taking an unusually large amount
• No confirmed cases of death from cannabis
  poisoning
• However, large doses of THC produce confusion,
  amnesia, delusions, hallucinations and agitation

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Effects of cannabis

• A prospective study of 50000 Swedish conscripts
  found a dose-response relationship between
  frequency of cannabis use by age 18, and risk of
  schizophrenia over the next 15 years.
• Probable that cannabis exacerbates schizophrenia
  symptoms, rather than causing schizophrenia.

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Therapeutic Actions of Cannabinoids

• Nausea and vomiting associated with cancer
  chemotherapy
• Appetite stimulants to counteract the AIDS
  wasting syndrome
• Multiple sclerosis
• Glaucoma

• Epilepsy
• Bronchial asthma
• Mood disorders and sleep
• Drug abuse and dependence?

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Mood Changes

• Swings of mood from euphoric gaiety and hilarious
  laughter to placid dreaminess referred to as
  being high.
• Nearly always pleasant, but occasionally
  associated with anxiety and foreboding
• Frequently felt that perceptions are keener, and
  sensory events more intense, and more enjoyable.
  Mundane thoughts are viewed as deep insights.
• Although users consistently report enhanced mood,
  when mood scales such as POMS are used, no
  consistent data obtained on scales for euphoria
  or positive mood states.

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Mood Changes

• Possibly due to these tests being carried out in
  unsympathetic environments, and in non-social
  situations
• After smoking marijuana, people may become more
  susceptible to being influenced by the moods of
  others

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Perception

• Although users claim heightened sensory
  sensitivity, objective tests show decreases, or
  no change in auditory, visual and tactile
  thresholds
• Increases in subjective time rate (experiencing
  time passing more quickly) can be shown reliably.
• Impaired short term memory attributable to a rush
  of distracting thoughts may relate to distorted
  time perception
• Deficits in tasks of vigilance and sustained
  attention, again because easily distracted.
• Little effect on ability to control a car, but
  impairs ability to attend to peripheral stimuli

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Cannabinoids and Reward

• Many drugs pleasurable to humans have been shown
  to have positive reinforcing properties in animal
  behavioural models
• However
• Difficult to demonstrate the rewarding properties
  of cannabis and ?9-tetrahydrocannabinol (?9-THC)
  in the currently used rodent models of addictive
  behaviour.
• Several studies have failed to show
  self-administration of cannabis or THC in rodents
  or primates (Corcoran Amit, 1974 Harris et
  al., 1974 Leite Carlini, 1974 Mansbach et
  al., 1994 Van Ree et al., 1978)

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Cannabinoids and Reward

• Several studies of cannabis self-administration
  by humans.
• Mendelson et al (1976) allowed subjects to press
  a button to obtain points which they could
  exchange for joints, or for money. Carried on for
  26 days
• About 30 mins work was necessary to obtain one
  joint. Casual users smoked about 2 joints at the
  beginning of the experiment, increasing to 3 by
  the end. Heavy users increased from 4 to 7 over
  the experiment.
• No evidence of withdrawal at end of experiment

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CB1 agonists and Reward

• CB1 cannabinoid receptor agonists show a
  different profile compared to other drugs of
  abuse
• Controversial data concerning the ability of CB1
  receptor agonists to reinforce behavioural
  responses in experimental animals, i.e.
• to lower self-stimulation thresholds
• to support self-administration
• to support conditioned place preference

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THC and Reward

• However
• Some other studies have shown
• a facilitation of brain-stimulation reward
  (Gardner et al., 1988 Lepore et al., 1996)
• sustained self-administration (Takahashi
  Singer, 1979 Tanda et al., 2000) and
• conditioned place preference (Chaperon et al.,
  1998 Lepore et al., 1995 Mallet Benninger,
  1998 Valjent Maldonado, 2000)

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Endogenous cannabinoid system and drugs of abuse

• Key role of the endogenous cannabinoid system in
  the reinforcing properties of other drugs of
  abuse??????
• Indeed, studies have shown an important role of
  cannabinoids on addictive drugs (Arnold et al.,
  1998 Braida Sala, 2002 Chaperon et al., 1998
  de Vries et al., 2001 Fattore et al., 1999
  Ferrari et al., 1999 Lamarque et al., 2001
  Pontieri et al., 2001(a) Pontieri et al.,
  2001(b) Pryor et al., 1978)

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Does cannabis cause dependence?

• Withdrawal from drugs of dependence is associated
  with changes in brain stimulation rewards, so
  that more current is needed to support
  self-stimulation.
• Withdrawal from as little as 1 mg/kg THC
  increases BSR thresholds, similar to other abused
  drugs.
• Withdrawal from THC also reduces firing rates of
  mesolimbic dopamine neurones Diana et al, 1998),
  and dopamine release in accumbens shell (Tanda et
  al, 1999).
• With high doses and continuous administration,
  withdrawal symptoms including hot flashes, runny
  nose, loose stools and sweating have been
  described in people.

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Progression to other drugs the gateway hypothesis

• Virtually all heroin users have used marijuana
  before they adopted heroin (Golub
  Johnson,1994).
• The extent of other drug use is correlated with
  marijuana use (Mullins et al, 1975)
• Problem of causality virtually all alcohol
  users have previously drunk lemonade does
  lemonade cause alcohol use?
• No pharmacological basis for progression?
• More likely that marijuana users come into social
  situations where they are likely to meet heroin
  users, or that personalities who use marijuana
  are also those that use other drugs.

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Relevant literature

• Wickelgren, I (1997) Science 2761967-8
• Hall Solowij (1998) Lancet 352 1611-1616
• Gardner EL (2002) Chemistry and Physics of Lipids
  121 267 290
• Ameri A (1999) Progress in Neurobiology 58 315
  348.

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How do cannabinoids affect reward?

• Also enhance firing of dopamine neurones in
  mesolimbic, nigrostriatal, and mesocortical
  pathways. Effects most prominent in mesolimbic
  pathways.
• These effects are blocked by selective CB1
  antagonists, but not by opiate antagonist
  naloxone..