Neurophysiology of Cannabinoids

The cannabis plant contains at least 60 different phytocannabinoids with variable proportions of these biochemicals based on the strain of plant. [Koppel: 2014] These cannabinoids are structurally related, yet distinct, and easily cross the blood-brain barrier due to their lipophilic nature. Within the central nervous system, they function through the complex endocannabinoid system, which is composed of chemicals called endocannabinoids and their receptors. Activation of this system, either through endogenous (endocannabionoids) or non-endogenous (cannabis-derived chemicals) sources results in multifactorial neuro-modulatory effects with modulation of region-specific, long-term synaptic potentiation and depression. [Rosenberg: 2015]
The 2 main cannabinoid receptors are CB1, which is widely distributed and primarily inhibits neurotransmitter release, and CB2, which is less prevalent and not as well understood. [Fine: 2013] Some believe that phyto- and endo- cannabinoids also work on additional target sites and receptors, which adds to the complexity of a process. Furthermore, the system is felt to be dynamic with chronic hyperexcitability leading to changes in the pathway. [Rosenberg: 2015] Cannabinoids work through synaptic depolarization and hyperpolarization, which activate receptors that then modulate the release of other neurotransmitters. [Fine: 2013] The endocannabinoid system, and its ability to function as feedback inhibition, thus presents an inherent potential target for management of neurologic disease.
While the complex nature of the system makes cannabis an attractive potential therapy for multiple ailments, it also creates difficulties in targeting the correct receptors and desired effects. This is further complicated by the variability of strains, preparations, and ratios of phytocannabinoids. The most studied of the phytocannabinoids are tetrahydrocannabinol (THC) and cannabidiol (CBD).
THC is a partial agonist of cannabinoid receptors, and it is felt to be responsible for the majority of cognitive and psychotropic effects of cannabis. Functioning mainly through CB1 and CB2, it has been shown to be involved in the regulation of neuronal excitability and the release of anti-inflammatory cytokines. [Rosenberg: 2015]
CBD, on the other hand, seems to function through non-endocannabinoid signaling, with antioxidant, anti-inflammatory, and neuroprotective properties.[Devinsky: 2014] The effect of a cannabis preparation, therefore, depends on the ratio THC to CBD, and CBD in and of itself is thought to modulate the psychoactive effects of THC. [Koppel: 2014]

Authors & Reviewers

Initial publication: December 2018; last update/revision: December 2018
Current Authors and Reviewers:
Author: Jennifer Goldman, MD, MRP, FAAP
Contributing Authors: Carey A. Wilson, MD
Francis M. Filloux, MD

Page Bibliography

Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D.
Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.
Epilepsia. 2014;55(6):791-802. PubMed abstract / Full Text

Fine PG, Rosenfeld MJ.
The endocannabinoid system, cannabinoids, and pain.
Rambam Maimonides Med J. 2013;4(4):e0022. PubMed abstract / Full Text

Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D.
Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.
Neurology. 2014;82(17):1556-63. PubMed abstract / Full Text
A systematic review of medical marijuana (1948-November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders.

Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O.
Cannabinoids and Epilepsy.
Neurotherapeutics. 2015;12(4):747-68. PubMed abstract / Full Text
This provides a review of current understanding of the endocannabinoid system, the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and evidence from pre-clinical and clinical trials of cannabinoids in epilepsy.