title: 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.
  
  
  BACKGROUND
  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.
authors.affiliation: Section on Nutritional Neurosciences, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina, Chapel Hill, North Carolina. Electronic address: chris.ramsden@nih.gov.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Ramsden
authors.affiliation: Department of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Daisy
authors.initials: D
authors.lastname: Zamora
authors.affiliation: Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts.
authors.forename: JodiAnne T
authors.initials: JT
authors.lastname: Wood
authors.affiliation: Department of Neurology, Program on Integrative Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: J Douglas
authors.initials: JD
authors.lastname: Mann
authors.affiliation: Department of Physical Medicine and Rehabilitation, Program on Integrative Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Keturah R
authors.initials: KR
authors.lastname: Faurot
authors.affiliation: Nutrition Research and Metabolism Core, North Carolina Translational Clinical Sciences Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Beth A
authors.initials: BA
authors.lastname: MacIntosh
authors.affiliation: Section on Nutritional Neurosciences, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sharon F
authors.initials: SF
authors.lastname: Majchrzak-Hong
authors.affiliation: Anesthesia Section, Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jacklyn R
authors.initials: JR
authors.lastname: Gross
authors.affiliation: Nutrition Department, Clinical Center, National Institutes of Health (NIH), Bethesda, Maryland.
authors.forename: Amber B
authors.initials: AB
authors.lastname: Courville
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: John M
authors.initials: JM
authors.lastname: Davis
authors.affiliation: Section on Nutritional Neurosciences, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Hibbeln
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004032:Diet; D063388:Endocannabinoids / Q000008:administration & dosage; D005227:Fatty Acids / Q000008:administration & dosage; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D043371:Fatty Acids, Omega-6 / Q000378:metabolism*; D005260:Female; D006261:Headache / Q000178:diet therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011581:Psychological Tests; D011788:Quality of Life; D013315:Stress, Psychological / Q000178:diet therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D063388:Endocannabinoids; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6
keywords: 2-arachidonoylglycerol; 2-docosahexaenoylglycerol; Endocannabinoids; docosahexaenoylethanolamine; headache; psychological distress