Food and Behaviour Research

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

Ramsden C, Zamora D, Makriyannis A, Wood J, Mann J, Faurot K, MacIntosh B, Majchrzak-Hong S, Gross J, Courville A, Davis J, Hibbeln J (2015) The Journal of Pain 16(8) 707-16. doi: 10.1016/j.jpain.2015.04.007 

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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.


Changing the diet to include more long-chain omega-3 fats (EPA and DHA) and less omega-6 fats was shown in an earlier clinical trial to be a successful way to reduce chronic daily headache pain, and associated psychological distress.

Here, the researchers examined blood biochemical data from that trial to investigate possible mechanisms behind these effects. 

Results showed that reductions in both headache pain and psychological distress caused by the dietary changes were associated with changes in blood levels of endocannabinoids - substances made within the body from these long-chain omega-3 and omega-6 fats.

The endocannabinoids were only discovered in the 1990s, but these bioactive substances are involved in numerous aspects of brain and nerve signalling.  In addition to their roles in modulating pain - for which this study provides yet more evidence - they are also involved in the regulation of appetite, temperature regulation, sleep, mood, perception and cognition. They also play critical roles in brain development and 'plasticity' (the remodelling of brain connections in response to experience).

The balance of different endocannabinoids produced depends on the balance of long chain omega-3 and omega-6 fats from which they are made.  This study adds to the evidence that imbalances in these substances may contribute to pain and psychological distress - and helps to explain why these symptoms can be reduced by correcting the dietary deficiencies of omega-3 relative to omega-6 fats found in modern, western-type diets. 

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