Cannabidiol exerts anti-inflammatory effects but maintains T effector memory cell differentiation in humans

Abstract

BACKGROUND: Cannabidiol (CBD) is increasingly used for pain management, including in transplant recipients with limited analgesic options. Its immunomodulatory effects in humans are not well defined at a single cell level at CBD steady state with concomitant tacrolimus treatment. METHODS: In a Phase 1 ex vivo study, peripheral blood mononuclear cells from 23 participants who received oral CBD (Epidiolex®) up to 5 mg/kg twice daily for 11 days were collected before CBD (pre-CBD) and at steady state (post-CBD). Lymphocytes were isolated and stimulated with anti-CD3/CD28 antibodies, with or without tacrolimus (5 ng/mL). Pharmacodynamic responses were assessed using CellTiter-Glo® proliferation, single-cell/nucleus RNA sequencing, cytokine assays, and flow cytometry. Steady-state plasma concentrations of CBD were quantified via tandem mass spectrometry. RESULTS: We identified an increased proportion of T effector memory (TEM) cells post-cannabidiol (22% increase), which correlated with CBD plasma concentrations (R = 0.77, P-value = 0.01). Cannabidiol reduced proliferation of T (37% decrease) and CD70hi B (17% decrease) lymphocytes with additive immunosuppressive effects to tacrolimus. Single-cell RNA sequencing revealed reduced IL2 and TNF signaling and altered receptor-ligand networks in TEM cells. Post-cannabidiol cytokine assays revealed elevated proinflammatory IL-6 protein levels and anti-inflammatory IL-10 levels, with reduced TNF-α, LTA, and IL-2. In flow cytometry, the proportion of TEM and TEMRA increased post-cannabidiol with tacrolimus. CONCLUSION: Cannabidiol exhibits mixed immunomodulatory effects with pro- and anti-inflammatory signals. Understanding the clinical safety of cannabidiol use is important given the paucity of pain control options available for immunocompromised transplant populations.