DIETARY OMEGA-6 FATTY ACID LOWERING INCREASES THE BIOAVAILABILITY OF PLASMA OMEGA-3 FATTY ACIDS IN HUMAN PLASMA LIPID POOLS. With Dr. Christopher Ramsden, we evaluated the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, altered unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA. TARGETED ALTERATIONS IN DIETARY N-3 AND N-6 FATTY ACIDS IMPROVE LIFE FUNCTIONING AND REDUCE PSYCHOLOGICAL DISTRESS AMONG PATIENTS WITH CHRONIC HEADACHE: A SECONDARY ANALYSIS OF A RANDOMIZED TRIAL. In a randomized trial, we demonstrated that targeted dietary manipulation-increasing omega-3 fatty acids with concurrent reduction in omega-6 linoleic acid (the H3-L6 intervention)-produced major reductions in headache compared with an omega-6 lowering (L6) intervention. Because chronic pain is often accompanied by psychological distress and impaired health-related quality of life (HRQOL), we used data from this trial to examine whether the H3-L6 intervention favorably impacted these domains. In the intention-to-treat analysis, participants in the H3-L6 group experienced statistically significant reductions in psychological distress and improvements in SF-12 mental and physical health summary scores. Dietary manipulation of n-3 and n-6 fatty acids, previously shown to produce major improvements in headache, also reduced psychological distress and improve HRQOL and function. LOW UNESTERIFIED : ESTERIFIED EICOSAPENTAENOIC ACID (EPA) PLASMA CONCENTRATION RATIO IS ASSOCIATED WITH BIPOLAR DISORDER EPISODES, AND OMEGA-3 PLASMA CONCENTRATIONS ARE ALTERED BY TREATMENT. Based on our finding that chronically administered mood stabilizers reduced turnover and metabolism of n-6 arachidonic acid, but not of n-3 docosahexaenoic acid in rat brain phospholipids, with Dr. Erika Saunders at Penn State Hershey School of Medicine, we hypothesized that plasma concentrations of n-3 PUFAs would be lower and of n-6 PUFAs higher in BD patients compared to healthy controls (HC) and would correlate with symptom severity, and that effective treatment would increase n-3 but lower n-6 PUFA levels. We compared HC and symptomatic BD subjects when ill and after symptomatic recovery (follow-up). Plasma concentrations of fatty acids were measured in esterified (E) and unesterified (UE) forms. UE EPA was lower in BD than HC, with a large effect size at p < 0.002 that was not statistically significant after correction for multiple comparisons. Mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. In conclusion, there was large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state, which may contribute vulnerability. Altered n-3 PUFA ratios indicate changes in PUFA metabolism concurrent with symptom improvement. OMEGA-3 AND OMEGA-6 POLYUNSATURATED FATTY ACIDS IN BIPOLAR DISORDER: A REVIEW OF BIOMARKER AND TREATMENT STUDIES. With Dr. Erika Saunders at Penn State Hershey, I am reviewing data on PUFA as biomarkers in bipolar disorder (BD) and n-3 PUFA used as treatment for BD. Data Sources are PubMed and CINAHL. Results of n-3 PUFA dietary supplementation trials for BD in open-label trials indicate efficacy in treatment for mania or depression, efficacy in treatment of depression in 1/7 randomized controlled trials, and signal detected for treatment of depression in one meta-analysis. Biomarker studies of PUFA and treatment studies of n-3 PUFA in BD show a way forward in understanding and treating BD. QUANTIFYING WHOLE BODY SYNTHESIS OF LONG CHAIN OMEGA (N-3) POLYUNSATURATED FATTY ACIDS IN HUMANS FROM CIRCULATING ALPHA-LINOLENIC ACID (ALA). Rodent data and human trials suggest that long chain omega (n)-3 polyunsaturated fatty acids (PUFAs), namely eicosapentaenoic (EPA) and docosahexaenoic (DHA), are critical for brain and heart function. They can be obtained from dietary fish products, or be synthesized from the circulating shorter chain nutritionally essential precursor, alpha-linolenic acid (ALA), which is found in vegetable oils. I have published a kinetic model to evaluate their whole body synthesis rates , and have shown significant rates in unanesthetized rodents using 2 hours of continuous intravenous radiolabeled ALA infusion. On this basis, I have initiated with NIAAA scientists an IRB approved clinical protocol (No. 11-AA-0028) to extrapolate the rodent infusion method and thereby quantify synthesis-secretion rates of EPA and DHA from circulating unesterified ALA in humans consuming an average US diet. We have completed studies demonstrating significant synthesis rates in two human volunteers, and are preparing a Methods paper for human use.. PATHWAYS OF POLYUNSATURATED FATTY ACID UTILIZATION: IMPLICATIONS FOR BRAIN FUNCTION IN NEUROPSYCHIATRIC HEALTH AND DISEASE. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. In a critical review with Dr. Elizabeth Sublette of Columbia University, we provided an overview of physiologic factors regulating PUFA brain utilization, highlighting their relevance to neuropsychiatric disease.

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Saunders, Erika Fh; Reider, Aubrey; Singh, Gagan et al. (2015) Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment. Bipolar Disord 17:729-42
Ramsden, Christopher E; Faurot, Keturah R; Zamora, Daisy et al. (2015) Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized trial. Pain 156:587-96
Liu, Joanne J; Green, Pnina; John Mann, J et al. (2015) Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. Brain Res 1597:220-46
Taha, Ameer Y; Cheon, Yewon; Faurot, Keturah F et al. (2014) Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins Leukot Essent Fatty Acids 90:151-7
Yuan, Zhi-Xin; Rapoport, Stanley I; Soldin, Steven J et al. (2013) Identification and profiling of targeted oxidized linoleic acid metabolites in rat plasma by quadrupole time-of-flight mass spectrometry. Biomed Chromatogr 27:422-32
Ramsden, Christopher E; Ringel, Amit; Feldstein, Ariel E et al. (2012) Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans. Prostaglandins Leukot Essent Fatty Acids 87:135-41