Modulation of Human Peripheral Blood Mononuclear Cell Signaling by Medicinal Cannabinoids

Abstract

Medical marijuana is increasingly prescribed as an analgesic for a growing number of indications, amongst which terminal cancer and multiple sclerosis. However, the mechanistic aspects and properties of cannabis remain remarkably poorly characterized. In this study we aimed to investigate the immune-cell modulatory properties of medical cannabis. Healthy volunteers were asked to ingest medical cannabis, and kinome profiling was used to generate comprehensive descriptions of the cannabis challenge on inflammatory signal transduction in the peripheral blood of these volunteers. Results were related to both short term and long term effects in patients experimentally treated with a medical marijuana preparation for suffering from abdominal pain as a result of chronic pancreatitis or other causes. The results reveal an immunosuppressive effect of cannabinoid preparations via deactivation of signaling through the pro-inflammatory p38 MAP kinase and mTOR pathways and a concomitant deactivation of the pro-mitogenic ERK pathway. However, long term cannabis exposure in two patients resulted in reversal of this effect. While these data provide a powerful mechanistic rationale for the clinical use of medical marijuana in inflammatory and oncological disease, caution may be advised with sustained use of such preparations.

Cannabinoid Signal Transduction Explains Disconnect of Cannabis Effects in Experimental and Clinical Colitis

“…Recently we published a study in which volunteers and pancreatitis patients were challenged with medical cannabis preparations, and the kinomes of blood lymphocytes before and after medical cannabis were contrasted. 2 Especially prominent in our observations was that pro-inflammatory p38MAP kinase signalling and mTOR signalling were constrained following cannabis challenge. Importantly, p38MAP kinase inhibitors-although partially effective in chemical colitis-are not useful for treating clinical Crohn's disease.…”

From Beef to Bees: High-Throughput Kinome Analysis to Understand Host Responses of Livestock Species to Infectious Diseases and Industry-Associated Stress

“…A critical advantage of PBMCs is the opportunity to collect samples pre-and post-treatment which provides a valuable control to minimize the contributions of the individualspecific kinome profiles. For example, recent efforts for kinome profiling of human PBMCs have investigated responses to acute stress in the form of bungee jumping (107) while another investigation of human PBMCs facilitated investigation of signaling responses activated by consumption of marijuana (108). Important phenotypic differences between individuals, in particular with respect to immune function, may also manifest in unique signaling profiles of PBMCs.…”

Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges

“…However, a more recent study, which aimed to assess the effects of medical cannabis ingestion on peripheral blood mononuclear cells, revealed an immunosuppressive effect of cannabinoid preparations via deactivation of signaling through the proinflammatory p38 MAP kinase and mTOR pathways and a concomitant deactivation of the promitogenic p42/p44 extracellular signal-regulated kinase (ERK)-1/2 signaling. However, it should also be noted that long-term cannabis exposure in two patients resulted in reversal of this effect ( 173 ). Similar to these data, a significant decrease in serum immunoglobulin (IgG and IgM) levels, in C3 and C4 complement protein concentrations, as well as in absolute numbers of T and B lymphocytes and natural killer (NK) cells was observed in bhang (an edible form of cannabis) users as compared to controls.…”