History of Cannabis Use

Cannabis is thought to have originated in Central Asia or China, its use then spread quickly to Africa, India, Arabian and Mediterranean countries. Historical data on the use of Cannabis dates back to 6000 BC, with the first real description given in a medical book by the legendary Chinese emperor Shen Nung in 2737 BC.

The use of cannabis for purposes of healing predates recorded history. Cannabis pollen was found on the mummy of Ramesses II, who died in 1213 BC. Prescriptions for cannabis in Ancient Egypt included treatment for the eyes (glaucoma), inflammation, and cooling the uterus, as well as administering enemas.

The use of Cannabis spread rapidly throughout the world, in colonial times it was known as the hemp plant, while today in the US it is called marijuana, in Jamaica its ganja, bhang in India and dagga in South Africa. The leaves and buds of the cannabis plant have natural therapeutic properties, which have been used for centuries in the treatment of numerous life-threatening diseases.

In the early 20th century cannabis was used as a sedative in insomnia, mania and melancholia. It was also used for tetanus, rabies, hay fever, bronchitis, coughs, and gonorrhea and bladder spasms. Its uses also included analgesic for migraine, menstrual cramps, brain tumors, dental pain and gastric ulcer.

It was not until 1964 however, that delta-9-tetrahydrocannabinol (THC) was isolated and identified by scientists in Israel, as the main component responsible for the ‘high’ and many of the medicinal activities of Cannabis sativa L. Identification of THC inevitably led scientists on a journey to discover THC receptors in the body and the endogenous ligands that activate these receptors.

The Endocannabinoid System

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FIGURE 1 | Cannabinoids and endocannabinoids.

Towards the use of cannabinoids as antitumour agents. Guillermo Velasco, Cristina Sánchez & Manuel Guzmán. Nature Reviews Cancer 12, 436-444 (June 2012)

The identification of the major compound in the cannabis plant, THC, led to the discovery of the cannabis receptor type 1 (CB1) and later cannabis receptor type 2 (CB2). CB1 receptors are present mainly in the central and peripheral nervous system and are major mediators of health and disease, while CB2 receptors have prevalence in the peripheral tissues of the immune system. This led further to the discovery of endogenous ligands (endocannabinoids). Endocannabinoids are produced naturally in the body and target the same receptors as plant cannabinoids. The two most common endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG). These are short lived molecules that are produced on demand or when needed by the body and are then deactivated by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

The term endocannabinoid system refers to the endocannabinoids, their targets and their deactivators. The endocannabinoid system is responsible for maintaining homeostasis of a variety of physiological processes including sleep, appetite, analgesia and spasticity by binding to CB1 or CB2 receptors and thereby regulating the release of various neurotransmitters.

Activity of the endocannabinoid system is not limited however to CB1 and CB2 receptors and endocannabinoids and plant cannabinoids are able to produce an effect by binding at various receptor sites. This increases and improves the potential medicinal use of cannabinoid compounds.

Cannabinoid Compounds

Cannabinoids may be endogenous (naturally produced in the body), phytocannabinoids (derived from cannabis plant material) or synthetic.

Endocannabinoids

Endocannabinoids are produced from cell membrane and arachidonic acid derivatives in response to a disturbance in a physiological process maintained by the endocannabinoid system.  There are several endocannabinoids of which anandamide and 2-arachidonoylglycerol (2-AG) are the most important.

Phytocannabinoids

There are over 60 different cannabinoids present in the cannabis plant. Of this number delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most researched.  THC is the most common phytocannabinoid is the drug type plant and possesses psychoactive and therapeutic properties mediated by its partial agonism of CB1 and CB2 receptors. The second most common compound in the drug type and the most common compound in the hemp fibre plant, cannabidiol (CBD), has low affinity for both CB1 and CB2 receptors.

Research has shown that both THC and CBD have important pharmacological activity. THC mimics the actions of anandamide and acts as an analgesic, anti-inflammatory, appetite stimulant, anti-spasmodic and anti-emetic. CBD has been shown to possess anti-inflammatory, anti-convulsant, anxiolytic, anti-cancer and neuroprotective properties as well as it attenuates the psychotropic effects of THC.

Other phytocannabinoids include:

  • Cannabinol is the breakdown product of THC and has shown anti-inflammatory and anti-convulsant activity.
  • Cannabigerol is a potent analgesic and acts as an antibiotic agent.
  • Tetrahydrocannabivarin has shown anti-inflammatory and anti-convulsant activity.
  • Cannabidivarin has shown anti-seizure activity in research.

Mechanism of Action

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Discovery of an endocannabinoid system in the body has sparked renewed interest into research and subsequent medicinal opportunities of cannabis. Phytocannabinoids target the same receptors as endocannabinoids and therefore act as neuromodulators of a variety of physiological processes.  Cannabinoids target CB1 and CB2 receptors mainly and THC acts as a partial agonist at these receptors. CBD has lower affinity for these receptors and recent research has shown that the activity of CBD may be mediated by a group of new cannabinoid receptors for which CBD may have greater affinity.

Cannabinoids are released from the postsynaptic neuron when neurotransmitters that are released from the presynaptic neuron signal a series of chemical changes that result in the onsite synthesis of either anandamide or 2-arachidonoylglycerol (2-AG). The cannabinoids then diffuse across the synaptic cleft and bind to presynaptic cannabinoid receptors. This binding to the CB receptors on the presynaptic neuron inhibits further neurotransmitter release.

Endocannabinoids are inactivated by hydrolysis by the enzyme fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid and ethanolamine or monoacylglycerol lipase (MAGL) which cleaves 2-AG into arachidonic acid and glycerol.

Phytocannabinoids are metabolized by liver enzymes while some is stored in fat tissues. Some metabolites may be present in the body up to several weeks after administration.

 

References

Batkai, S., Kunos, G., Pacher,P. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological Reviews 2006; 58(3):389-462

Lowe, H., Morrison, E (2013) Ganja: The Jamaican and Global Connection. Jamaica, W.I.:  Pelican Publisher

Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008 February; 4(1): 245–259

Russo EB, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Medical Hypotheses. 2006; 66(2):234-46.