Chronic Edible Dosing of Δ9-tetrahydrocannabinol (THC) in Non-human Primates Reduces Systemic Platelet Activity and Function

S.E. Reitsma¹, J. Johnson¹, J. Pang¹, I. Parra-Izquierdo^1,2, H. Hara Sudhan Lakshmanan¹, A.R. Melrose^2,1, M. T. Hinds¹, J.E. Aslan^2,1, O.J. McCarty¹, J.O. Lo³

¹Oregen Health and Science University, Portland, United States, ²Knight Cardiovascular Institute, Portland, United States, ³Department of Obstetrics and Gynecology, Portland, United States

Abstract Number: LPB0132

Meeting: ISTH 2021 Congress

Theme: Platelets and Megakaryocytes » Platelet Signaling

Background: Medical cannabis is administered for chronic pain treatment based on the premise that the endocannabinoid system signals desensitize pain sensor neurons and produce anti-inflammatory effects. The major psychoactive ingredient of cannabis is Δ9-tetrahydrocannabinol (THC) which signals through cannabinoid receptor-1 (CBr); beyond neurons, CBr is expressed in tissues ranging from skin to blood cells including platelets. In vitro, CBr-mediated signaling acutely inhibit platelet activation downstream of the immunotyrosine activation motif (ITAM) platelet collagen receptor GPVI. The systemic effects of chronic THC administration on platelet activity and function is unknown.

Aims: Determine the effects of chronic THC administration on platelet function in non-human primates (NHPs).

Methods: Seven female rhesus macaques (Macaca mulatta) were fed THC edibles daily, titrated up to 2.5mg/7kg/day, equivalent to a heavy medical dose in humans, over 3 months. Blood was collected every 3 weeks and platelet function was analyzed by flow cytometry and aggregometry in response to the platelet agonists collagen-related peptide (CRP-XL; GPVI/ITAM agonist), TRAP-6 (GPCR protease-activated receptor-1 agonist), ADP (GPCR P2Y12 agonist) and the Toll-like receptor 2, Pam2CSK4. In parallel, human washed platelets were pretreated with a CBr agonist followed by CRP-XL stimulation; phosphorylation was analyzed by Western blot.

Results: Chronic THC administration in NHPs decreased platelet aggregation in a dose-dependent manner in response to CRP-XL and ADP. Platelet thromboxane production was reduced by ≥70% in THC-treated animals. Granule secretion as measured by P-selectin expression was reduced in a THC dose-dependent manner compared to untreated animals in response to CRP-XL, TRAP-6, and ADP. Platelet activation induced by Pam2CSK4 remained unchanged. In vitro, a CBr agonist inhibited GPVI-mediated phosphorylation of Akt and MAPK substrates while increasing PKA-substrate phosphorylation.

Conclusions: Chronic administration of THC edibles desensitized platelet activity and function in response to ITAM- and GPCR-based activation by interfering with primary and secondary feedback signaling pathways.

To cite this abstract in AMA style:

Reitsma SE, Johnson J, Pang J, Parra-Izquierdo I, Hara Sudhan Lakshmanan H, Melrose AR, Hinds MT, Aslan JE, McCarty OJ, Lo JO. Chronic Edible Dosing of Δ9-tetrahydrocannabinol (THC) in Non-human Primates Reduces Systemic Platelet Activity and Function [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/chronic-edible-dosing-of-%ce%b49-tetrahydrocannabinol-thc-in-non-human-primates-reduces-systemic-platelet-activity-and-function/. Accessed December 8, 2021.

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