Cannabidiol exerts antiinflammatory effects but maintains T effector memory cell differentiation in humans
Debora L. Gisch, Sachiko Koyama, Jumar Etkins, Gerald C. So, Daniel J. Fehrenbach, Jessica Bo Li Lu, Ying-Hua Cheng, Ricardo Melo Ferreira, Evan Rajadhyaksha, Kelsey McClara, Mahla Asghari, Asif A. Sharfuddin, Pierre C. Dagher, Laura M. Snell, Meena S. Madhur, Rafael B. Polidoro, Zeruesenay Desta, Michael T. Eadon
Debora L. Gisch, Sachiko Koyama, Jumar Etkins, Gerald C. So, Daniel J. Fehrenbach, Jessica Bo Li Lu, Ying-Hua Cheng, Ricardo Melo Ferreira, Evan Rajadhyaksha, Kelsey McClara, Mahla Asghari, Asif A. Sharfuddin, Pierre C. Dagher, Laura M. Snell, Meena S. Madhur, Rafael B. Polidoro, Zeruesenay Desta, Michael T. Eadon
View: Text | PDF
Clinical Research and Public Health Clinical Research Immunology

Cannabidiol exerts antiinflammatory 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 I 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 and single-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-CBD (22% increase), which correlated with CBD plasma concentrations (R = 0.77, P = 0.01). CBD 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-CBD cytokine assays revealed elevated proinflammatory IL-6 protein levels and antiinflammatory IL-10 levels, with reduced TNF-α, LTA, and IL-2. In flow cytometry, the proportion of TEM and TEMRA cells increased post-CBD with tacrolimus.CONCLUSION CBD exerts mixed immunomodulatory effects in humans, combining antiproliferative and pro- and antiinflammatory responses. Understanding the clinical safety of CBD use is important given the paucity of pain control options available for immunocompromised transplant populations.TRIAL REGISTRATION ClinicalTrials.gov NCT05490511FUNDING NIH/National Center for Complementary and Integrative Health (R01AT011463); NIH/National Institute of General Medical Sciences (NIGMS) (R35GM145383); Intramural Research Program of the NIH; NIH/NIGMS (T32GM008425).

Authors

Debora L. Gisch, Sachiko Koyama, Jumar Etkins, Gerald C. So, Daniel J. Fehrenbach, Jessica Bo Li Lu, Ying-Hua Cheng, Ricardo Melo Ferreira, Evan Rajadhyaksha, Kelsey McClara, Mahla Asghari, Asif A. Sharfuddin, Pierre C. Dagher, Laura M. Snell, Meena S. Madhur, Rafael B. Polidoro, Zeruesenay Desta, Michael T. Eadon

×

Figure 7

Cytokine levels.

Options: View larger image (or click on image) Download as PowerPoint
Cytokine levels. The effects of CBD treatment and/or tacrolimus (TAC) ex...
The effects of CBD treatment and/or tacrolimus (TAC) exposure on cytokine and chemokine levels were assessed under different conditions. CBD was administered in vivo over 11 days, while TAC exposure was ex vivo. Each panel represents a box plot comparing pre-CBD (yellow) and post-CBD (green) conditions stratified according to No CD3/CD28, CD3/CD28 alone (CD3/CD28), and CD3/CD28 with tacrolimus (CD3/CD28 +TAC). The same 3 participants provided samples for all 6 conditions. Because of the volume needed for the assay, biological samples were pooled, and technical replicates were used for statistics. Protein concentrations (pg/mL) were scaled and are shown as z score–normalized values. Symbols indicate statistical comparisons: black denotes differences between pre- and post-CBD conditions; blue indicates comparisons between CD3/CD28 –TAC and CD3/CD28 +TAC in the absence of CBD; and red indicates the same comparison in the presence of CBD. Statistical significance is represented as follows: *P < 0.05, **P < 0.01, ***P < 0.001. All P values were calculated using the limma package with Benjamini-Hochberg FDR correction. Analytes shown include TNF-α (A), lymphotoxin-α (LTA) (B), GM-CSF (C), IL-4 (D), IL-2 (E), IL-10 (F), IL-1RA (G), IL-8/CXCL8 (H), MCP-1/CCL2 (I), IL-6 (J), IL-9 (K), and IL-7 (L).