Diet-induced Changes in n-3- And n-6-derived Endocannabinoids and Reductions in Headache Pain and Psychological Distress

J Pain. 2015 Aug;16(8):707-16. doi: 10.1016/j.jpain.2015.04.007. Epub 2015 May 7.


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: (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Diet*
  • Endocannabinoids / administration & dosage
  • Fatty Acids / administration & dosage
  • Fatty Acids, Omega-3 / metabolism*
  • Fatty Acids, Omega-6 / metabolism*
  • Female
  • Headache / diet therapy*
  • Headache / metabolism
  • Humans
  • Male
  • Middle Aged
  • Psychological Tests
  • Quality of Life
  • Stress, Psychological / diet therapy*
  • Stress, Psychological / metabolism
  • Young Adult


  • Endocannabinoids
  • Fatty Acids
  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6

Associated data