Immunomodulation by cannabinoids: Current uses, mechanisms, and identification of data gaps to be addressed for additional therapeutic application

The endocannabinoid system plays a critical role in immunity and therefore its components, including cannabinoid receptors 1 and 2 (CB₁ and CB₂), are putative druggable targets for immune-mediated diseases. Whether modulating endogenous cannabinoid levels or interacting with CB₁ or CB₂ receptors directly, cannabinoids or cannabinoid-based therapeutics (CBTs) show promise as anti-inflammatory or immune suppressive agents. Herein we provide an overview of cannabinoid effects in animals and humans that provide support for the use of CBTs in immune-mediated disease such as multiple sclerosis (MS), inflammatory bowel disease (IBD), asthma, arthritis, diabetes, human immunodeficiency virus (HIV), and HIV-associated neurocognitive disorder (HAND). This is not an exhaustive review of cannabinoid effects on immune responses, but rather provides: (1) key studies in which initial and/or novel observations were made in animal studies; (2) critical human studies including meta-analyses and randomized clinical trials (RCTs) in which CBTs have been assessed; and (3) evidence for the role of CB₁ or CB₂ receptors in immune-mediated diseases through genetic analyses of single nucleotide polymorphisms (SNPs) in the CNR1 and CNR2 genes that encode CB₁ or CB₂ receptors, respectively. Perhaps most importantly, we provide our view of data gaps that exist, which if addressed, would allow for more rigorous evaluation of the efficacy and risk to benefit ratio of the use of cannabinoids and/or CBTs for immune-mediated diseases.