Cannabinoids

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:

Cannabinoid 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.

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.