Modulation of the Immune System in Cannabis Users

KEYWORDS:
• cannabis
• cell-mediated immunity
• cytokines
• immunity, cellular
• interleukins
• marijuana smoking

To the Editor: In vitro studies and experiments in animal models have found that cannabinoids modulate immune cell function.¹ However, investigations of immune effects in human subjects are scarce and contradictory. Gene expression of cannabinoid receptors in peripheral blood mononuclear cells may be altered among marijuana users.² Experimental data in healthy persons have found abnormalities in T lymphocyte and natural killer (NK) cell function, but have not confirmed that these alterations might affect susceptibility to infections.³ We sought to investigate cell-mediated immune response and cytokine release in cannabis users.

Methods. Participants were recruited by word of mouth and gave written consent to participate in the study, which was approved by our institutional ethical committee and conducted in accordance with the Declaration of Helsinki. Volunteers were deemed healthy after a full medical history and examination. They were then interviewed about their recent use of illicit drugs, and their statements were confirmed by urine testing. A psychiatric screening excluded drug abuse or dependence (except for cannabis or nicotine) or psychiatric disorders according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

A blood sample was obtained between the hours of 8 and 11 AM to determine blood cell count and differential, lymphocyte immunophenotyping, lymphocyte proliferative response to mitogenic stimulation (stimulation index with phytohemoagglutinine [SI-PHA] or concanavaline A [SI-ConA]), and levels of interleukin 2 (IL-2), interleukin 10 (IL-10), and transforming growth factor β-1 (TGFβ1), as described previously.⁴ Comparisons between cannabis exposure categories were performed using χ² tests or analysis of variance. Multivariate linear regression models were fitted for each immune parameter to analyze the effects of cannabis consumption after adjusting for sex, as well as consumption of coffee, tobacco, and alcohol.

Results. According to total cannabis consumption and frequency of use during the previous 6 months, participants were classified as controls (n = 32), occasional users (eventual to monthly use, n = 13) and regular users (weekly to daily use, n = 16). Sex, tobacco smoking, and alcohol consumption were unequally distributed between groups (Table 1).

Cannabis use was associated with a decrease in NK counts, lymphocyte proliferative response by SI-PHA and SI-ConA, and levels of IL-2, and an increase in levels of IL-10 and TGFβ1. No differences were found in counts of total lymphocytes or CD4, CD8, and CD19 cells (TABLE). The significant effect of cannabis consumption on immune measures persisted after multivariate analysis controlling for the possible confounding effects of sex and use of coffee, tobacco, and alcohol. A significant dose-response relationship was found between cannabis exposure (total life consumption, as the log-transformed number of cannabis "joints") and the decrease in counts of total lymphocytes, CD4 or NK cells, and IL-2 levels, or the increase in IL-10 levels.

Comment. Cannabis use was associated with a decrease in levels of IL-2, a T_H1-type cytokine related to cell-mediated immunity, and an increase in levels of IL-10, a T_H2-type cytokine related to humoral immunity. The decrease of proinflammatory (IL-2) cytokines and the augment of anti-inflammatory (IL-10 and TGFβ1) cytokines was associated with a marked reduction in lymphocyte functionality, and a decrease in the number of NK cells. The suppression of immediate and innate responses of the immune system together with the disruption of T_H1/T_H2 balance might increase the susceptibility and promote the progression of infectious diseases and tumors, although the clinical relevance of these findings has not been clearly demonstrated in humans.^{3, 5} It also has been suggested that immunomodulatory effects of cannabinoids on inflammatory and autoimmune disorders could lead to new therapeutic interventions.⁶