Chronic edible dosing of Δ9-tetrahydrocannabinol (THC) in nonhuman primates reduces systemic platelet activity and function

Abstract
Cannabis usage has steadily increased as acceptance is growing for both medical and recreational reasons. Medical cannabis is
administered for treatment of chronic pain based on the premise that the endocannabinoid system signals desensitize pain sen sor neurons and produce anti-inflammatory effects. The major psychoactive ingredient of cannabis is D9-tetrahydrocannabinol
(THC) that signals mainly through cannabinoid receptor-1 (CBr), which is also present on nonneuron cells including blood plate lets of the circulatory system. In vitro, CBr-mediated signaling has been shown to acutely inhibit platelet activation downstream
of the platelet collagen receptor glycoprotein (GP)VI. The systemic effects of chronic THC administration on platelet activity and
function remain unclear. This study investigates the effects of chronic THC administration on platelet function using a nonhuman
primate (NHP) model. Our results show that female and male NHPs consuming a daily THC edible had reduced platelet adhe sion, aggregation, and granule secretion in response to select platelet agonists. Furthermore, a change in bioactive lipids (oxyli pins) was observed in the female cohort after THC administration. These results indicate that chronic THC edible administration
desensitized platelet activity and function in response to GPVI- and G-protein coupled receptor-based activation by interfering
with primary and secondary feedback signaling pathways. These observations may have important clinical implications for
patients who use medical marijuana and for providers caring for these patients.