Cannabidiol Alters Circulating Lymphocytes Composition in a Concentration-Dependent Manner: A Single-Cell Study in Humans

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Background: Cannabidiol (CBD) is available over the counter and often used for pain management. Post-organ transplantation (POT) recipients cannot use non-steroidal anti-inflammatory drugs (NSAIDs) due to their nephrotoxicity. CBD may serve as an option for pain control in kidney POT recipients who often receive immunosuppressive regimens, including tacrolimus (TAC), as both substances are involved in the deregulation of nuclear factor of activated T-cells (NFAT). Methods: We conducted a human pharmacokinetic study of CBD (N=22) and compared immune cell distribution in the blood of pre-CBD (baseline) and post-CBD (steady-state) subjects. Participants received oral CBD (up to 5 mg/kg, twice daily) for 12 days. Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies. Responses were assessed via CellTiter-Glo® (viability/proliferation, N=19, t-test), scRNA-seq (gene expression, N=10, Wilcox, BH), cytokine assays (immune mediators, N=3, limma t-test, BH FDR), and flow cytometry (surface/intracellular markers, N=3, Fisher’s Exact, BH-FDR). After Day 12, subjects were monitored for 48 hours with 10 time-point samples to assess steady-state CBD pharmacokinetics (N=10, Pearson Cor; t-test). Results: scRNA-seq analysis of immune cells showed an increased proportion of CD8+ effector memory T (CD8 TEM) cells in the stimulated post-CBD condition compared to baseline (21%, CI[18, 25]), indicating enrichment. CBD blood levels correlated with CD8 TEM cell proportions (Cor= 0.77, P < 0.01). Cytokine assays revealed elevated IL-6 protein levels post-CBD (adj.P < 0.05), a cytokine known for its proinflammatory effects. In flow cytometry of CD8 T, the proportion of CD45RO+CD45RA− increased expression post-CBD (adj.P < 0.05) with greater GzmA within effector memory CD8 populations. Other enriched lymphocyte populations included TREGs and CD4 memory cells. CBD reduced overall CD4 and B lymphocyte proliferation. Conclusion: CBD exhibits mixed immunomodulatory effects with pro- and anti-inflammatory signals. Understanding the safety of CBD use in POT recipients and chronic kidney disease populations is important given the paucity of pain control options available to these populations. Funding: Other NIH Support - R01 AT011463/AT/NCCIH

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