7–17 In medicinal use, these adverse effects may be prevented or mitigated by avoiding THC entirely in favor of other non-psychoactive cannabinoids.18 For instance, prolonged exposure to the non-psychoactive phytocannabinoid, cannabidiol (CBD), at doses of 3–4 mg/kg/d, both in human volunteers and those with epilepsy, revealed no adverse effects or evidence of

toxicity.19 However, adequate precaution must be taken when CBD is used in conjunction with many other drugs due to its inhibition of several cytochrome P450 isoenzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2D6, and Inhibitors,research,lifescience,medical CYP3A4. This is especially important in the management of chronic pain, since many conventionally used analgesics (opioids and non-opioids) are metabolized via these pathways (most notable CYP2D6 and CYP3A4).20 Therefore, the key relevant clinical issues for practitioners dealing Inhibitors,research,lifescience,medical with populations of Liver X Receptor agonist patients in pain have to do with questions about effects of specific cannabinoids, their various modes of delivery and absorption, Inhibitors,research,lifescience,medical potential indications, and their respective risks and tolerability.21 Based on relatively new but limited scientifically based literature, it is now only possible to speculate about mechanisms of action and what the future may hold for phytocannabinoids as effective analgesics across the vast and

varied cohorts of people living with chronic pain. With that in mind, this review will proceed

with a summary of what is known about Inhibitors,research,lifescience,medical different cannabinoid congeners on various types of pain (efficacy and tolerability) and the putative role of commonly available “generally regarded as safe” (GRAS) ingredients that may enhance the effectiveness of certain phytocannabinoids. CANNABIS AND CANNABINOIDS: PAST Inhibitors,research,lifescience,medical TO PRESENT Cannabinoid refers to a pharmacological class of about 60 naturally occurring compounds (phytocannabinoids) found in plants of the genus Cannabis (i.e. marijuana and hemp) and structurally related synthetic analogues (e.g. Δ3,4-tetrahydrocannabinol and HU-210, which is 100–800 times more potent psychoactively than natural THC22). This classification has been generalized to include a wide range of exogenous and endogenously produced compounds that exhibit similar pharmacodynamic properties as the phytocannabinoids or demonstrate activity at the same receptor binding sites. over Cannabis sativa has two subspecies, indica and sativa. A variety of the former, hemp, has industrially and nutritionally useful qualities. Hemp has a very low amount of the psychoactive constituent Δ9-tetrahydrocannabinol (THC) but higher quantities of cannabidiol (CBD) which may offer a range of medicinal benefits without the cognitive effects and abuse potential associated with THC.23 Cannabis has a long and storied social and medicinal history dating back thousands of years.