Introduction

The endogenous cannabinoid signaling system (ECS) is a highly conserved, ubiquitous, pleiotropic biochemical system known as a gatekeeper in immune homeostasis.¹ A multitude of ECS-mediated immunosuppressive effects have been demonstrated to date, including inhibition of immune cell proliferation, migration and antibody production, induction of apoptosis, and cytokine suppression (via downregulation of immunoregulatory genes). Given these effects, are phytocannabinoids helpful or harmful for immune competency in the context of the current coronavirus disease 2019 (COVID-19) pandemic?

The plant cannabinoid delta9-tetrahydrocannabinol (THC) mimics the actions of endogenous cannabinoids (ECB) as a nonselective partial agonist (higher affinity than ECBs) at cannabinoid receptors 1 and 2 (CB₁ and CB₂). Both receptors are expressed on immune cells, with CB₂ exclusively expressed in human immune cells and tissues. Agonism of these receptors on immune cells has been shown to reduce the production and secretion of inflammatory mediators.² Cannabidiol (CBD) acts as a negative allosteric modulator with very low affinity at both cannabinoid receptors. CBD has also been shown to be immunosuppressive through diverse (non-ECS-mediated) mechanisms.³ The dietary sesquiterpenoid beta-caryophyllene, found in Cannabis and other plants, and alkylamides in Echinacea purpurea activate the CB₂ receptor (Ki: 100 and 60 nM affinity, respectively).^4,5