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 to 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<0.001) and docosahexaenoylethanolamine (+99%, p<0.001), and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, p=0.001). 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.

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

“…Indeed, endocannabinoids have the ability to lower the excitability of nociceptors and thus reduce the intensity of the nociceptive information [165]. A recent study interestingly demonstrated that ω-3 rich diet was able to reduce physical pain and that this relief was significantly correlated to an increase in DHEA and 2-DHG, the two DHA-derived endocannabinoids [84] (Figure 4). This reinforces the hypothesis that ω-3 dietary PUFAs favor 'good' endocannabinoids, derived from ω-3 PUFAs (Figure 4).…”

“…It has been suggested that these ethanolamides could serve as 'entourage molecules' to modulate the signaling of AEA [59]. Finally the ω-3 derived endocannabinoid 2-docosahexanoylglycerol (2-DHG) is sometimes evoked in the literature [83,84], but there is a crucial lack of data about the enzymatic pathways and the binding affinity of this bioactive lipid (Figure 2). 4.…”

Transmission of risk from parents with chronic pain to offspring: an integrative conceptual model

“…Higher BMI is a risk factor in and of itself for the persistence of chronic musculoskeletal 8 or headache pain 57,112 in children and adolescents and is associated with activity limitations in youth with pain. 162 In addition, dietary interventions have been shown to reduce pain in adults with irritable bowel syndrome, 55 and pain and psychological distress in adults with headache, 110 suggesting that diet and nutrition habits within a family might influence pain outcomes. Health care utilization may also play a role, as parental health status has been associated with pain-related medical visits in children, 141 and mother and child health care visit frequency are positively correlated in families in which the mother has irritable bowel syndrome.…”

Lowering dietary n-6 polyunsaturated fatty acids

“…Ramsden et al [66,71 && ] report that increasing dietary n-3 concurrent with decreasing linoleic acid has more pronounced effects, decreasing concentrations of linoleic acid, ARA and their mediators while increasing those produced from EPA and DHA. An important thing to consider in interpreting this work is that levels of ARA and DHA in the blood may be under homeostatic control.…”