Diet-induced changes in n-3- and n-6-derived endocannabinoids and reductions in headache pain and psychological distress

Abstract

Omega-3 and omega-6 fatty acids are biosynthetic precursors of endocannabinoids with antinociceptive, anxiolytic, and neurogenic properties. We recently reported that targeted dietary manipulation-increasing omega-3 fatty acids while reducing omega-6 linoleic acid (the H3-L6 intervention)-reduced headache pain and psychological distress among chronic headache patients. It is not yet known whether these clinical improvements were due to changes in endocannabinoids and related mediators derived from omega-3 and omega-6 fatty acids. We therefore used data from this trial (N = 55) to investigate 1) whether the H3-L6 intervention altered omega-3- and omega-6-derived endocannabinoids in plasma and 2) whether diet-induced changes in these bioactive lipids were associated with clinical improvements. The H3-L6 intervention significantly increased the omega-3 docosahexaenoic acid derivatives 2-docosahexaenoylglycerol (+65%, P < .001) and docosahexaenoylethanolamine (+99%, P < .001) and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, P = .001). Diet-induced changes in these endocannabinoid derivatives of omega-3 docosahexaenoic acid, but not omega-6 arachidonic acid, correlated with reductions in physical pain and psychological distress. These findings demonstrate that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids in humans and suggest that 2-docosahexaenoylglycerol and docosahexaenoylethanolamine could have physical and/or psychological pain modulating properties.

Trial registration: ClinicalTrials.gov (NCT01157208) PERSPECTIVE: This article demonstrates that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids and that these changes are related to reductions in headache pain and psychological distress. These findings suggest that dietary interventions could provide an effective, complementary approach for managing chronic pain and related conditions.

Keywords: 2-arachidonoylglycerol; 2-docosahexaenoylglycerol; Endocannabinoids; docosahexaenoylethanolamine; headache; psychological distress.

Conflict of interest statement

Conflicts of Interest: The authors declare no conflicts of interest.

Published by Elsevier Inc.

Figures

Figure 1. Model depicting diet-induced alterations in n-3 and n-6 derived endocannabinoids

(A) Dietary n-3 and n-6 polyunsaturated fatty acids compete for enzymatic conversion into their respective elongated and desaturated products, notably n-3 DHA and n-6 AA. (B) n-3 DHA and EPA and n-6 AA and LA compete for esterification into cell membranes. (C) Membrane n-3 DHA and n-6 AA are converted to their respective glycerol-ester and N-acylethanolamine endocannabinoids in proportion to available substrate. (D) n-3 and n-6 fatty acids can be converted to numerous other lipid autacoids with pro- or anti-nociceptive properties (eg, prostaglandins, EETs, HODEs, lipoxins, resolvins, protectins). DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LA, linoleic acid; AA, arachidonic acid; DHG, docosahexaenoylglycerol; DHA-EA, docosahexaenoylethanolamine; AG, arachidonoylglycerol; AEA, arachidonoylethanolamine; EET, epoxyeicosatrienoic acid; HODE, hydroxyoctadecadienoic acid; CB, cannabinoid; TRPV1, transient receptor potential cation channel, subfamily V, member 1.

Figure 2. Precursor fatty acids and their n-3 and n-6 endocannabinoid products in plasma after 12 weeks

Plots are post-estimations of linear regression models for the effect plasma fatty acids on each endocannabinoid after 12 weeks on the Chronic Daily Headache Study (n=55), adjusting for the baseline value of each respective endocannabinoid and fatty acid. Endocannabinoids are measured in ng/mL. The shaded areas around regression lines are 95% confidence intervals. DHG, docosahexaenoylglycerol; DHA-EA, docosahexaenoylethanolamine; 2-AG, 2-arachidonoylglycerol; AEA, arachidonoylethanolamine; DHA, docosahexaenoic acid; n-6, omega-6; HUFA, highly unsaturated fatty acids.