Cannabinoids

  • Cannabis sativa, the hemp plant: Tetrahydrocannabinol (THC) is the main active principle of cannabis
  • The most abundant cannabinoids are THC,
  • its precursor cannabidiol, and cannabinol, a breakdown product formed spontaneously from THC
  • Cannabidiol and cannabinol lack the psychoactive properties of THC but can exhibit anticonvulsant activity.

Three general types of  cannabinoids:

  • Endogenous  cannabinoids
  • Herbal  cannabinoids à present in the Cannabis plant
  • Synthetic cannabinoids

Cannabinoid receptors

  • Two types – CB1 receptors and CB2 receptors

Location

CB1 not homogeneously distributed, being concentrated in the

  • hippocampus (relevant to effects of cannabinoids on memory),
  • cerebellum (relevant to loss of coordination),
  • the hypothalamus (important in control of appetite and body temperature),
  • substantia nigra, mesolimbic dopamine pathways à implicated in psychological ‘reward’
  • the relative paucity of CB1 receptors in the brain stem, consistent with the lack of serious depression of respiratory or cardiovascular function by cannabinoids.

CB2 receptor

  • located mainly in lymphoid tissue (spleen, tonsils, and thymus as well as circulating lymphocytes, monocytes, and tissue mast cells).
  • also present on microglia – immune cells in the CNS which when activated contribute to chronic pain
  • typical members of the family of G protein-coupled receptors
  • CB1 receptors are linked via Gi/o to inhibition of adenylyl cyclase and of voltage-operated calcium channels, and to activation of G protein-sensitive inwardly rectifying potassium (GIRK) channels, causing membrane hyperpolarization.
  • CB1 receptors are located in the plasma membrane of nerve endings and inhibit transmitter release from presynaptic terminals, which is caused by depolarization and Ca2+ entry.

PHARMACOLOGICAL EFFECTS

  • Actions on the central nervous system include both depressant and psychotomimetic effects
  • A sensation of relaxation and well-being, similar to the effect of ethanol but without the accompanying recklessness and aggression.
  • impairment of short-term memory and simple learning tasks
  • impairment of motor coordination (e.g. driving performance)
  • catalepsy – the adoption of fixed unnatural postures
  • hypothermia
  • analgesia
  • antiemetic action 
  • increased appetite
  • reduction of intraocular pressure
  • bronchodilatation.

TOLERANCE AND DEPENDENCE

  • Tolerance to cannabis and physical dependence occur only to a minor degree and mainly in heavy users.
  • Cannabinoids are less liable than opiates, nicotine or alcohol to cause dependence but may have long-term psychological effects.

ENDOCANNABINOIDS

  • Anandamide CB1 > CB2
  • Virodhamine CB2 > CB1
  • They are eicosanoid mediators
  • The main enzyme that inactivates anandamide is fatty acid amide hydrolase (FAAH).
  • FAAH ‘knockout’ mice have an increased brain content of anandamide and an increased pain threshold; selective inhibitors of FAAH have analgesic and anxiolytic properties, implicating endocannabinoids in nociception and anxiety

SYNTHETIC CANNABINOIDS and their clinical application

  • Cannabinoid receptor agonists were developed in the 1970s in the hope that they would prove useful nonopioid/ non-NSAID analgesics respectively, for limitations of opioids and NSAIDs), but adverse effects, particularly sedation and memory impairment, were problematic
  • Nabilone: sometimes used clinically for nausea and vomiting caused by cytotoxic chemotherapy if this is unresponsive to conventional antiemetics
  • The first selective CB1 receptor antagonist, rimonabant à was licensed in Europe for treating obesity,
  • was withdrawn because it caused psychiatric problems including depression.
  • both the UK and the USA cannabinoids have been used as antiemetics
  • encourage weight gain in patients with chronic diseases such as HIV-AIDS and malignancy.
  • Cannabis extract (Sativex) is used to treat spasticity in patients with multiple sclerosis

Cannabidiol

  • Approved June 2018
  • specifically indicated for the treatment of seizures associated with Lennox Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients 2 years of age and older.
  • the anticonvulsant effect in humans is unknown.
  • Cannabidiol DOES NOT appear to exert its anticonvulsant effects through interaction with cannabinoid receptors.

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