The future of cannabinoids as analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic overview

For thousands of years, physicians and their patients employed cannabis as a therapeutic agent. Despite this extensive historical usage, in the Western world, cannabis fell into disfavor among medical professionals because the technology available in the 1800s and early 1900s did not permit reliable, standardized preparations to be developed. However, since the discovery and cloning of cannabinoid receptors (CB1 and CB2) in the 1990s, scientific interest in the area has burgeoned, and the complexities of this fascinating receptor system, and its endogenous ligands, have been actively explored. Recent studies reveal that cannabinoids have a rich pharmacology and may interact with a number of other receptor systems-as well as with other cannabinoids-to produce potential synergies. Cannabinoids-endocannabinoids, phytocannabinoids, and synthetic cannabinoids-affect numerous bodily functions and have indicated efficacy of varying degrees in a number of serious medical conditions. Nevertheless, despite promising preclinical and early clinical data, particularly in the areas of inflammation and nociception, development challenges abound. Tetrahydrocannabinol (THC) and other CB1 receptor agonists can have an undesirable CNS impact, and, in many cases, dose optimization may not be realizable before onset of excessive side effects. In addition, complex botanically derived cannabinoid products must satisfy the demanding criteria of the U.S. Food and Drug Association's approval process. Recent agency guidance suggests that these obstacles are not insurmountable, although cannabis herbal material ("medical marijuana") may present fatal uncertainties of quality control and dosage standardization. Therefore, formulation, composition, and delivery system issues will affect the extent to which a particular cannabinoid product may have a desirable risk-benefit profile and acceptable abuse liability potential. Cannabinoid receptor agonists and/or molecules that affect the modulation of endocannabinoid synthesis, metabolism, and transport may, in the future, offer extremely valuable tools for the treatment of a number of currently intractable disorders. Further research is warranted to explore the therapeutic potential of this area.