The Potential Role of Cannabinoids in Modulating Serotonergic Signaling by Their Influence on Tryptophan Metabolism

Abstract

Phytocannabinoids present in Cannabis plants are well known to exert potent anti-inflammatory and immunomodulatory effects. Previously, we have demonstrated that the psychoactive D9-tetrahydrocannabinol (THC) and the non-psychotropic cannabidiol (CBD) modulate mitogen-induced Th1-type immune responses in peripheral blood mononuclear cells (PBMC). The suppressive effect of both cannabinoids on mitogen-induced tryptophan degradation mediated by indoleamine-2,3-dioxygenase (IDO), suggests an additional mechanism by which antidepressive effects of cannabinoids might be linked to the serotonergic system. Here, we will review the role of tryptophan metabolism in the course of cell mediated immune responses and the relevance of cannabinoids in serotonergic signaling. We conclude that in particular the non-psychotropic CBD might be useful for the treatment of mood disorders in patients with inflammatory diseases, since this cannabinoid seems to be safe and its effects on activation-induced tryptophan degradation by CBD were more potent as compared to THC.

Keywords: cannabidiol; indoleamine-2,3-dioxygenase; tryptophan; Δ9-tetrahydrocannabinol.

Figure 1

In the course of the adaptive immune response, activated T-helper (Th)1-type immune cells produce cytokines such as interleukin-2 or interferon-γ (IFN-γ). Pro-inflammatory cytokine IFN-γ stimulates several antiproliferative effector functions in monocyte-derived macrophages (MΦ), such as production of reactive oxygen species (ROS) and the activity of indoleamine-2,3-dioxygenase (IDO) and GTP-cyclohydrolase I, which are responsible for the conversion of tryptophan to kynurenine and the production of neopterin, respectively. Formation of ROS trigger redox-sensitive signal transduction cascades including the production of tumor necrosis factor-α (TNF-α), which enhances sensitivity of macrophages to pro-inflammatory IFN-γ. Continuous release of ROS may overwhelm the antioxidant capacity of cells, whereby oxidative stress and inflammation develop.

Figure 2

Associations between neopterin production and kynurenine to tryptophan ratio (Kyn/trp; shown in log scale) in phytohemagglutinin (PHA; open symbols) and concanavalin A(Con A; solid symbols)-stimulated peripheral blood mononuclear cells (PBMC) pretreated with Δ9-Tetrahydrocannabinol (THC; triangles) or cannabidiol (CBD; squares) at doses of 1-10 µg/mL. Neopterin production was positively associated with Kyn/trp in PHA-stimulated PBMC pretreated with THC (rs = 0.868; p < 0.001; n = 30) or CBD (rs = 0.909; p < 0.001; n = 30), as well as in Con A-stimulated PBMC pretreated with THC (rs = 0.962; p < 0.001; n = 26) or CBD (rs = 0.909; p < 0.001; n = 30). Tryptophan and kynurenine concentrations were measured by high-performance liquid chromatography (HPLC) [20], and concentrations of neopterin by a commercially available enzyme linked immunosorbent assay (BRAHMS, Hennigsdorf, Germany). Non-parametric correlations were calculated using Spearman’s rank test.