**6. Cannabis**

Multiple lines of evidence support the important role of the endocannabinoid system in mod‐ ulating pain and inflammation [47–54]. The potential value of the cannabinoids for medicinal purposes arose from the discovery of endogenous cannabinoid receptors: CB1 (mostly in the central nervous system) and CB2 (mostly in peripheral tissues) [55, 56]. The best‐studied can‐ nabinoids in *Cannabis* involved in having potential analgesic properties are tetrahydrocan‐ nabinol (THC) and cannabidiol (CBD).

CB1 is predominantly responsible for the psychoactive effects of THC, and the stimulation of this receptor plays a role in regulating pain, stress responses, energy regulation and lipogenesis, and immune function. CB2 is expressed on immune cells, so it is thought to serve an important role in immune function and inflammation. CBD, lacking psychoactivity compared to THC, agonist activity at CB2 receptors seems to account for its anti‐inflammatory properties.

These cannabinoids are rapidly metabolized in the liver and intestine, undergoing extensive hepatic first‐pass metabolism. Cannabinoids are distributed throughout the body; they are highly lipid‐soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for their prolonged elimination half‐lives [57, 58].

Precaution must be taken when CBD is used in conjunction with many other drugs due to its inhibition of several cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4) and efflux transporters (P‐glycoprotein). This is important in the management of chronic pain, since many conventionally used analgesics (opioids, SNRIs and SSRIs) are metabolized via these pathways (mainly CYP2D6 and CYP3A4) and/or are efflux transporters substrates [59, 60].

The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in the treat‐ ment of pain for which current drugs do not fully address the patients' need.
