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LMBB - Section of Nutritional Neuroscience (NN)
CAPT Joseph R. Hibbeln, MD, Acting Chief
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health
5625 Fishers Lane, Room 3N07:MSC 9410
Bethesda MD 20892-9410
fax: +1 301.402.4617
The central focus of the Section on Nutritional Neurochemistry is to examine the impact of deficiencies in long chain omega-3 fatty acids on adverse neurodevelopmental and psychiatric outcomes. This section translates basic biochemical and biophysical findings into clinical applications. The portfolio of projects include studies in genetic epidemiology, large-scale longitudinal cohort studies, studies of basic metabolism, the development of high throughput high accuracy analytical biochemical methods suitable for population level examinations and randomized placebo-controlled clinical intervention trials among populations potentially affected by insufficient intakes. Active clinical intervention protocols include aggressive subjects with alcohol use disorders, subjects with a history of suicide attempts, pediatric populations with bipolar disorders and disruptive behaviors, and women with severe depressive symptoms in pregnancy. Several military applications are being developed, including compositional analysis of foods currently provided in combat theaters, assessment of increased risk of suicide and Post Traumatic Stress Disorder resulting from inadequate tissue compositions of long chain polyunsaturates and the development of a large-scale prevention trial utilizing omega-3 fatty acids to prevent the development of severe depression, psychiatric distress and adverse outcomes from dramatic brain injury for military personnel in combat theaters.
The first in vivo studies of the essential fatty acid (EFA) metabolism in alcoholics and smokers have been performed within the Section of Nutritional Neuroscience. In addition, our research with infants and adults report some of the first basic studies for normative physiology. Highly sensitive and selective methodology has been developed within our research group allowing for the safe and non-invasive assessment of EFA metabolism in vivo. This approach takes advantage of the stable isotope labeled EFAs, deuterated linoleic and linolenic acids, along with negative, chemical ionization gas chromatography /mass spectrometry to simultaneously measure the precursor and product fatty acids in the blood stream after metabolism and export in the liver. This methodology has advanced with new capabilities to simultaneously measure different components of the EFA pathway and to model the resulting data so as to obtain rate related parameters. Thus, arguably the worldwide lead in the metabolomics of essential fatty acids has been gained.
Our metabolic studies were among the first clinical studies performed in human adults and showed that a diet low in n-3 fats leads to an increase in formation and transport of long chain polyunsaturates to the plasma compartment. Smokers also have somewhat increased activity in this regard. Smoking alcoholics have a further marked increase in the deuterium enrichment of plasma DHA when deuterated alpha-linolenate is orally ingested. Both smoking and alcohol are peroxidative challenges that are hypothesized to lead to increased EFA degradation. The apparently greater level of formation/transport of the fatty acids may, in part, compensate for these losses. When the intensity of the alcohol challenge is too great with respect to its frequency and dosage, metabolism cannot keep pace with the increased catabolism and tissue levels fall, consistent with our findings in many species. This fall in long chain polyunsaturate levels then has adverse consequences for organ function and may lead, in particular, to liver and brain pathology. Dietary impact of these fats is variable in the alcoholic population and may be protective for alcohol-induced organ pathology; this may help to explain why some alcoholics develop liver disease or organic brain syndrome and others do not.
In human infants in the first week of life, our results indicate a general capacity to perform 18- carbon EFA metabolism to 20 and 22-carbon end products for both the n-3 and n-6 pathways. There was a surprising inverse relationship between gestational age and metabolic capacity that was strongest for docosahexaenoic acid (DHA). This is consistent with the rapid formation of neural membranes for which DHA is an important structural constituent during the brain growth spurt in the third trimester of human development. The rate of conversion in these infants is slow and appears inadequate to support the amount of DHA required for optimal brain and other organ development. We concluded, therefore, that infant formula must have preformed DHA added to support optimal nervous system growth and function; formulas in North America have only recently become available with DHA supplements. A requirement for preformed DHA was supported by studies of rat brain development with low n-3 fatty acid content in the diet. It was demonstrated that docosapentaenoic acid (22:5n6) was unable to completely replace brain DHA in this case, especially in rapidly growing brain areas like the cerebellum as well as in the retina. This effect was maximized during rapid brain growth at 10-20 postnatal days.
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1. Adverse neurodevelopmental outcomes associated with inadequate seafood consumption during pregnancy (Hibbeln et al. 2008).
In 2004, the Environmental Protection Agency and FDA advised limiting seafood intake during pregnancy in order to reduce fetal exposure to methyl-mercury (MeHg). However, compliance (<340 g/w) also restricts intake of nutrients essential for optimal neuronal development, in particular DHA. Deficiencies during early development can potentially increase risk of childhood pathological outcomes in verbal functioning and disruptive behavioral problems. Here the study population was mother and infant pairs (n=1 1,875) enrolled in the UK Avon Longitudinal Study of Parents and Children (ALSPAC). This cohort is a representative sample (>85%) of pregnancies in the Avon region near Bristol, UK. Mothers completed a food frequency questionnaire assessing seafood consumption at 32 w gestation. Consumption of seafood, eicosapentaenoic acid (EPA), DHA, and MeHg were estimated based on typical consumption patterns. Groups reporting no seafood consumption to some (up to 340 g/w) or exceeding 340 g/w were compared in multivariate logistic regression models including 29 variables. Outcomes were assessed among children (n=8,946) at 6, 18, 30 and 42 m (Denver Developmental Screening Test-DDST) and 8y (Strengths and Difficulties Questionnaire-SDQ) and the Wechsler Intelligence Scale for Children-III. Maternal depression was assessed by the Edinburgh Postnatal Scale of Depression (EPSD) at 18 w and 32 w gestation plus 8 w and 32 w postnatal. Findings. Maternal compliance (consuming <340 g/w) increased risks of their children scoring in the lowest quartile for verbal IQ (none: odds ratio 1.42, 95% confidence interval, 1.12-1.81, p<0.004) (some: odds ratio 1.09, 95% confidence interval, 0.92-1.29, ns) (overall model, p<0.02), compared to mothers exceeding the recommendation, after adjustment for potential confounding variables. Maternal compliance also increased risks for pathological scores in fine motor, communication and social subscales of the DDST and in peer problems and prosocial subscales of the SDQ. Risk of maternal depression increased during and after pregnancy. Conclusions. The toxicological risks and nutritional benefits were aggregated by evaluating seafood intake as a whole in a western population. Consumption of less than 340 g/w of seafood during pregnancy increased risks for pathological outcomes in the neurodevelopmental domains where protection was intended by the 2004 advisory. Limitation of fish consumption was also associated with increased risks for pathological prosocial and peer problems at 8 years of age and increased risk of maternal depression during and after pregnancy. This study stimulated the US Food and Drug Administration to conduct a scientific quantitative reevaluation modeling the potential topological risks from trace methyl-mercury and the nutritional benefits from seafood in the US population. This draft report, which modeled all relevant available published data, confirmed the findings of this study. This FDA evaluation may constitute the scientific basis for a revision of the 2004 advisory.
2. Development of high throughput quantitative assessments of omega-3 fatty acid status. A major impediment to the translation of the assessment of omega-3 fatty acid deficiencies on population scale has been the lack of low cost high throughput analytically accurate methods to assess omega-3 fatty acid status. We have developed a robotic high throughput methodology to quantitatively assess essential fatty acids in human plasma in low volumes at low cost. We are currently applying this method among approximately 9,000 mother infant pairs who are enrolled in the ALSPAC cohort to assess their long chain omega-3 status at birth and it nine years of age. These data will be used to assess neuropsychiatric and neurodevelopmental endpoints. In addition we have developed an active collaboration with the Center for Disease Control and developed methods for the quantitative analysis of trace metals including methyl-mercury, selenium, iron, cadmium and zinc in this well-characterized population (Robert Jones, PhD CDC). The measures will be utilized in risk benefit models to predict neurodevelopmental outcomes. This project has been co-funded by the National Oceanic and Atmospheric Administration (NOAA).
3. Metabolic studies on alcohol in long chain omega-3 turnover.
An intractable and long-standing problem in the field of EFA biology has been the relative efficacy of interconversion of 18- and 20-carbon precursors to longer chain, more unsaturated products. This problem can be addressed by dosing an animal with multiple stable isotope labels within a given pathway. These isotopes must be chosen so that they are distinguishable isotopomers when metabolized. We have been able to simultaneously give oral doses of two n-3 precursors and two n-6 precursors simultaneously and measure the conversion of each isotope independently to AA or DHA. This novel technique has been named MultiplE Simultaneous Stable Isotopes (MESSI). Our results in rats and human infants indicate that the 20-carbon intermediates are more efficiently converted to DHA than the 18-carbon intermediates when expressed on a per dose basis.
Over the past two decades the Section of Nutritional Neurochemistry has established that chronic alcohol use lowers brain composition of docosahexaenoic acid (DHA) in a series of clinical and animal models. Metabolic studies were conducted in the section utilizing deuterium labeled precursors. These were the first clinical studies performed in human adults assessing the effects of diets low in preformed EPA and DHA on the increased formation of EPA and DHA from precursors (linoleic acid and linolenic acid), their transportation and the effects of smoking and chronic alcohol use on this metabolism. Nonalcoholic smokers have an increased degradation of DHA and exhibit an increased compensatory production of DHA from precursors. Similarly, alcoholics exhibit increased degradation of DHA, and compensatory production. However, when the intensity of the alcohol challenge is too great, supplementation of DHA in the form of tablets cannot keep pace with its increase catabolism and tissue levels fall, consistent with our findings with chronic alcohol exposure in various experimental models. This fall in tissue levels of long chain polyunsaturated fatty acids then has adverse consequences to organ function, in particular hepatic steatosis and risk of fibrosis and brain apoptosis. Increasing the dietary intake of omega- 3 fatty acids in an alcoholic population may be protective for alcohol induced organ pathology. This variable may help to explain why some alcoholics develop hepatic steatosis and fibrosis and others don't. The alcohol-induced decline in brain DHA levels may contribute to the increased risk of major depression and aggressive disorders among alcoholics.
4. Long chain omega-3 fatty acid supplementation of alcoholics.
This randomized placebo-controlled intervention trial among aggressive alcoholics was designed to determine if supplementation in early abstinence reduced aggressive behaviors, reduced depressive symptoms, and altered cerebral spinal fluid levels of neurotransmitter metabolites. Subjects were randomized to receive either 2 g per day of EPA plus DHA or placebo oil. Subjects were followed as outpatients for 12 weeks monitoring relapse to alcohol and substance use and changes in craving, mood and aggression. 165 lumbar punctures were performed to obtain baseline and final measures on each subject. Unfortunately compliance by subjects was poor and the projected changes in tissue composition of omega-3 fatty acids were achieved in only 25% of the active agent randomized group. Thus, we were not able to evaluate efficacy in reducing relapse. However, in the study population as a whole, low CSF DHA content was correlated with smaller brain volume at baseline, indicating that low DHA status increased vulnerability to the adverse effects of alcohol on brain development. Lower CSF DHA content was also correlated with lower levels of metabolites of serotonin and dopamine in the CSF.
5. Suicide and inadequate long chain omega-3 fatty acid status
Epidemiologic data indicate that low fish consumption is a risk factor, but certainly not a sole determinant for suicide mortality. We examined 1,767 subjects in northern Finland and reported that frequent fish consumption (twice per week or more) significantly reduced the risk of reporting depressive symptoms (odds ratio = 0.63, p<0.03) and of reporting suicidal thinking (odds ratio = 0.57, p<0.04) after adjustment for confounding variables (Tanskanen et al., 2000). Lower fish consumption was associated with a doubling of the risk of suicidal thinking by mothers during pregnancy, after control for 29 confounding variables in a longitudinal cohort study enrolling 14,541 pregnancies (Golding, et al, in press 2009). These epidemiological observations are consistent with the assessment of omega-3 long chain fatty acid (LCFA) body compositions directly among patients. Among suicide att empters without depression as a primary diagnosis, low concentrations of plasma EPA alone were robustly correlated with greater psychopathology on rating scales of impulsivity, guilt, future suicide risk, and most subscales of the Comprehensive Psychopathological Rating Scale (Hibbeln et al., 2000). Low DHA status predicted greater risk of a new suicide attempt in a follow up study of more than 800 days, 5% of subjects above the median split had new attempts compared to 50% having new attempts among those below the median split (Sublette et al 2006). Resting PET scans of these subjects quantifying regional glucose uptake showed that future suicide attempters had greater activity in the anterior cingulate and limbic forebrain, consistent with the suspected pathophysiology of severe depression and PTSD. Low DHA in plasma phospholipid robustly predicted this regional hyperactivity (r = - 0.86, p<0.0001) indicating that low DHA status may increase limbic system mediated anxiety (Sublette et al, 2008). In a randomized blinded placebo controlled trial, we have reported a 45 % reduction in suicidal thinking and a 30% reduction in depression among patients with recurrent self harm recruited from an emergency room (Hallahan et al. 2007). This intervention used 2 g/d of omega-3 LCFAs in a 12 week trial of n = 49 subjects. Subjects also reported a reduced perception of daily stresses and anxiety which is likely relevant to reduction of risk of the development of PTSD.
6. Deficiencies in long chain omega-3 fatty acids and major depressive symptoms. One long-term effort of the Section on Nutritional Neurochemistry has been to evaluate the efficacy of seafood consumption or long chain omega-3 fatty acids in the treatment of major depressive symptoms and their application in other psychiatric disorders. In 2006 the section was instrumental in developing treatment recommendations issued by the American Psychiatric Association (Freeman et al 2006). This statement included a meta-analysis of randomized placebo-controlled intervention trials and indicated that the treatment effect size of long chain omega-3 fatty acids was equal to or greater than second-generation antidepressants.
7. Docosahexaenoic acid metabolism assessed by Positron Emission Tomography (PET) Docosahexaenoic acid (DHA, 22:6n-3) is a critical constituent of brain, but its metabolism has not been measured in the human brain in vivo. In monkeys, using positron emission tomography (PET), we first showed that intravenously injected [1-11C]DHA mostly entered non-brain organs, with approximately 0.5% entering brain. Then, using PET and intravenous [1-11C]DHA in 14 healthy adult humans, we quantitatively imaged regional rates of incorporation (K*) of DHA. We also imaged cerebral blood flow (rCBF) using PET and intravenous [15O]water. Values of K* for DHA were higher in gray than white matter regions and correlated significantly with values of rCBF in 12 of 14 subjects despite evidence that rCBF does not directly influence K*. For the entire human brain, the net DHA incorporation rate Jin, the product of K* and the unesterified plasma DHA concentration, equaled 3.8 ± 1.7 mg/day. This net rate is equivalent to the net rate of DHA consumption by brain and, considering the reported amount of DHA in brain, indicates that the half-life of DHA in the human brain approximates two and a half years. Thus, PET with [1-11C] DHA can be used to quantify regional and global human brain DHA metabolism in relation to health and disease (Umhau et al. 2009, in press).
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- Search PubMed for publications by Hibbeln JR.
 N. Parletta, R.V. Gow, J.R. Hibbeln, Current evidence and future directions for research with omega-3 fatty acids and attention deficit hyperactivity disorder (in press), Cur Opin Clin Nutr Metabolic Care, (2014).http://www.ncbi.nlm.nih.gov/pubmed/25581035
 T. Hamazaki, H. Colleran, K. Hamazaki, Y. Matsuoka, M. Itomura, J. Hibbeln, The safety of fish oils for those whose risk of injury is high, Mil Med, 179 (2014) 134-137.http://www.ncbi.nlm.nih.gov/pubmed/25373097
 J. Golding, S. Gregory, Y. Iles-Caven, R. Lingam, J.M. Davis, P. Emmett, C.D. Steer, J.R. Hibbeln, Parental, prenatal, and neonatal associations with ball skills at age 8 using an exposome approach, Journal of child neurology, 29 (2014) 1390-1398.http://www.ncbi.nlm.nih.gov/pubmed/24828115
 J.R. Hibbeln, R.V. Gow, The potential for military diets to reduce depression, suicide, and impulsive aggression: a review of current evidence for omega-3 and omega-6 Fatty acids, Military medicine, 179 (2014) 117-128.http://www.ncbi.nlm.nih.gov/pubmed/25373095
 B.P. Marriott, K. Yu, S. Majchrzak-Hong, J. Johnson, J.R. Hibbeln, Understanding diet and modeling changes in the omega-3 and omega-6 Fatty Acid composition of u.s. Garrison foods for active duty personnel, Military medicine, 179 (2014) 168-175.http://www.ncbi.nlm.nih.gov/pubmed/25373102
 A.Y. Taha, Y. Cheon, K.F. Faurot, B. Macintosh, S.F. Majchrzak-Hong, J.D. Mann, J.R. Hibbeln, A. Ringel, C.E. Ramsden, Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools, Prostaglandins, leukotrienes, and essential fatty acids, 90 (2014) 151-157.http://www.ncbi.nlm.nih.gov/pubmed/24675168
 J. Golding, C.D. Steer, T. Lowery, R. Jones, J.R. Hibbeln, Fish consumption and blood mercury levels: Golding et al. respond, Environmental health perspectives, 122 (2014) A120-121.http://www.ncbi.nlm.nih.gov/pubmed/24787643
 M.E. Sublette, H.C. Galfalvy, J.R. Hibbeln, J.G. Keilp, K.M. Malone, M.A. Oquendo, J.J. Mann, Polyunsaturated fatty acid associations with dopaminergic indices in major depressive disorder, The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum, 17 (2014) 383-391.http://www.ncbi.nlm.nih.gov/pubmed/24300434
 R.V. Gow, J.R. Hibbeln, Omega-3 fatty acid and nutrient deficits in adverse neurodevelopment and childhood behaviors, Child and adolescent psychiatric clinics of North America, 23 (2014) 555-590.http://www.ncbi.nlm.nih.gov/pubmed/24975625
 A.R. Alvheim, B.E. Torstensen, Y.H. Lin, H.H. Lillefosse, E.J. Lock, L. Madsen, L. Froyland, J.R. Hibbeln, M.K. Malde, Dietary linoleic acid elevates the endocannabinoids 2-AG and anandamide and promotes weight gain in mice fed a low fat diet, Lipids, 49 (2014) 59-69.http://www.ncbi.nlm.nih.gov/pubmed/24081493
 J.S. Vaz, G. Kac, A.E. Nardi, J.R. Hibbeln, Omega-6 fatty acids and greater likelihood of suicide risk and major depression in early pregnancy, Journal of affective disorders, 152-154 (2014) 76-82.http://www.ncbi.nlm.nih.gov/pubmed/23726775
 J. Golding, C.D. Steer, T. Lowery, J.R. Hibbeln, ALSPAC mercury study and fish consumers: Golding et al. respond, Environmental health perspectives, 122 (2014) A38-39.http://www.ncbi.nlm.nih.gov/pubmed/24486699
 A. Raine, J. Portnoy, J. Liu, T. Mahoomed, J.R. Hibbeln, Reduction in behavior problems with omega-3 supplementation in children aged 8-16 years: a randomized, double-blind, placebo-controlled, stratified, parallel-group trial, Journal of child psychology and psychiatry, and allied disciplines, (2014).http://www.ncbi.nlm.nih.gov/pubmed/25146492
 E.M. Wells, A. Navas-Acien, B.J. Apelberg, J.B. Herbstman, J.M. Jarrett, Y.H. Lin, C.P. Verdon, C. Ward, K.L. Caldwell, J.R. Hibbeln, R.U. Halden, F.R. Witter, L.R. Goldman, Association of selenium and copper with lipids in umbilical cord blood, Journal of developmental origins of health and disease, 5 (2014) 281-287.http://www.ncbi.nlm.nih.gov/pubmed/24965134
 Y.H. Lin, J.A. Hanson, S.E. Strandjord, N.M. Salem, M.N. Dretsch, M.D. Haub, J.R. Hibbeln, Fast transmethylation of total lipids in dried blood by microwave irradiation and its application to a population study, Lipids, 49 (2014) 839-851.http://www.ncbi.nlm.nih.gov/pubmed/24986160
 J.T. Brenna, G.C. Burdge, M.A. Crawford, P. Clayton, S.C. Cunnane, R. Gow, J.R. Hibbeln, A.J. Sinclair, J. Stein, P. Willatts, RE: Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial, Journal of the National Cancer Institute, 106 (2014) dju015.http://www.ncbi.nlm.nih.gov/pubmed/24685922
 J. Golding, C.D. Steer, J.R. Hibbeln, P.M. Emmett, T. Lowery, R. Jones, Dietary predictors of maternal prenatal blood mercury levels in the ALSPAC birth cohort study, Environmental health perspectives, 121 (2013) 1214-1218.http://www.ncbi.nlm.nih.gov/pubmed/23811414
 M.A. Beydoun, M.T. Fanelli Kuczmarski, H.A. Beydoun, J.R. Hibbeln, M.K. Evans, A.B. Zonderman, omega-3 fatty acid intakes are inversely related to elevated depressive symptoms among United States women, The Journal of nutrition, 143 (2013) 1743-1752.http://www.ncbi.nlm.nih.gov/pubmed/24005610
 C.E. Ramsden, K.R. Faurot, D. Zamora, C.M. Suchindran, B.A. Macintosh, S. Gaylord, A. Ringel, J.R. Hibbeln, A.E. Feldstein, T.A. Mori, A. Barden, C. Lynch, R. Coble, E. Mas, O. Palsson, D.A. Barrow, J.D. Mann, Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial, Pain, 154 (2013) 2441-2451.http://www.ncbi.nlm.nih.gov/pubmed/23886520
 R.V. Gow, F. Vallee-Tourangeau, M.A. Crawford, E. Taylor, K. Ghebremeskel, A.A. Bueno, J.R. Hibbeln, A. Sumich, K. Rubia, Omega-3 fatty acids are inversely related to callous and unemotional traits in adolescent boys with attention deficit hyperactivity disorder, Prostaglandins, leukotrienes, and essential fatty acids, 88 (2013) 411-418.http://www.ncbi.nlm.nih.gov/pubmed/23664595
 R.V. Gow, A. Sumich, F. Vallee-Tourangeau, M.A. Crawford, K. Ghebremeskel, A.A. Bueno, J.R. Hibbeln, E. Taylor, D.A. Wilson, K. Rubia, Omega-3 fatty acids are related to abnormal emotion processing in adolescent boys with attention deficit hyperactivity disorder, Prostaglandins, leukotrienes, and essential fatty acids, 88 (2013) 419-429.http://www.ncbi.nlm.nih.gov/pubmed/23660373
 C.D. Steer, E. Lattka, B. Koletzko, J. Golding, J.R. Hibbeln, Maternal fatty acids in pregnancy, FADS polymorphisms, and child intelligence quotient at 8 y of age, The American journal of clinical nutrition, 98 (2013) 1575-1582.http://www.ncbi.nlm.nih.gov/pubmed/24067669
 B.A. MacIntosh, C.E. Ramsden, K.R. Faurot, D. Zamora, M. Mangan, J.R. Hibbeln, J.D. Mann, Low-n-6 and low-n-6 plus high-n-3 diets for use in clinical research, The British journal of nutrition, 110 (2013) 559-568.http://www.ncbi.nlm.nih.gov/pubmed/23328113
 A.R. Alvheim, B.E. Torstensen, Y.H. Lin, H.H. Lillefosse, E.J. Lock, L. Madsen, J.R. Hibbeln, M.K. Malde, Dietary linoleic acid elevates endogenous 2-arachidonoylglycerol and anandamide in Atlantic salmon (Salmo salar L.) and mice, and induces weight gain and inflammation in mice, The British journal of nutrition, 109 (2013) 1508-1517.http://www.ncbi.nlm.nih.gov/pubmed/22883314
 E. Lattka, B. Koletzko, S. Zeilinger, J.R. Hibbeln, N. Klopp, S.M. Ring, C.D. Steer, Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC), The British journal of nutrition, 109 (2013) 1196-1210.http://www.ncbi.nlm.nih.gov/pubmed/22877655
 J.C. Umhau, W. Zhou, S. Thada, J. Demar, N. Hussein, A.K. Bhattacharjee, K. Ma, S. Majchrzak-Hong, P. Herscovitch, N. Salem, Jr., A. Urish, J.R. Hibbeln, S.C. Cunnane, S.I. Rapoport, J. Hirvonen, Brain docosahexaenoic acid [DHA] incorporation and blood flow are increased in chronic alcoholics: a positron emission tomography study corrected for cerebral atrophy, PloS one, 8 (2013) e75333.http://www.ncbi.nlm.nih.gov/pubmed/24098376
 J.C. Umhau, D.T. George, R.P. Heaney, M.D. Lewis, R.J. Ursano, M. Heilig, J.R. Hibbeln, M.L. Schwandt, Low vitamin D status and suicide: a case-control study of active duty military service members, PloS one, 8 (2013) e51543.http://www.ncbi.nlm.nih.gov/pubmed/23308099
 C.E. Ramsden, D. Zamora, B. Leelarthaepin, S.F. Majchrzak-Hong, K.R. Faurot, C.M. Suchindran, A. Ringel, J.M. Davis, J.R. Hibbeln, Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis, Bmj, 346 (2013) e8707.http://www.ncbi.nlm.nih.gov/pubmed/23386268
 S. Vaz Jdos, G. Kac, P. Emmett, J.M. Davis, J. Golding, J.R. Hibbeln, Dietary patterns, n-3 fatty acids intake from seafood and high levels of anxiety symptoms during pregnancy: findings from the Avon Longitudinal Study of Parents and Children, PloS one, 8 (2013) e67671.http://www.ncbi.nlm.nih.gov/pubmed/23874437
 C.E. Ramsden, A. Ringel, A.E. Feldstein, A.Y. Taha, B.A. MacIntosh, J.R. Hibbeln, S.F. Majchrzak-Hong, K.R. Faurot, S.I. Rapoport, Y. Cheon, Y.M. Chung, M. Berk, J.D. Mann, Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans, Prostaglandins, leukotrienes, and essential fatty acids, 87 (2012) 135-141.http://www.ncbi.nlm.nih.gov/pubmed/22959954
 A.R. Alvheim, M.K. Malde, D. Osei-Hyiaman, Y.H. Lin, R.J. Pawlosky, L. Madsen, K. Kristiansen, L. Froyland, J.R. Hibbeln, Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity, Obesity, 20 (2012) 1984-1994.http://www.ncbi.nlm.nih.gov/pubmed/22334255
 Y.H. Lin, J.D. Loewke, D.Y. Hyun, J. Leazer, J.R. Hibbeln, Fast transmethylation of serum lipids using microwave irradiation, Lipids, 47 (2012) 1109-1117.http://www.ncbi.nlm.nih.gov/pubmed/23015312
 Y.H. Lin, N. Salem, Jr., E.M. Wells, W. Zhou, J.D. Loewke, J.A. Brown, W.E. Lands, L.R. Goldman, J.R. Hibbeln, Automated high-throughput fatty acid analysis of umbilical cord serum and application to an epidemiological study, Lipids, 47 (2012) 527-539.http://www.ncbi.nlm.nih.gov/pubmed/22430941
 C.D. Steer, J.R. Hibbeln, J. Golding, G. Davey Smith, Polyunsaturated fatty acid levels in blood during pregnancy, at birth and at 7 years: their associations with two common FADS2 polymorphisms, Human molecular genetics, 21 (2012) 1504-1512.http://www.ncbi.nlm.nih.gov/pubmed/22194195
 J. Golding, K. Northstone, P. Emmett, C. Steer, J.R. Hibbeln, Do omega-3 or other fatty acids influence the development of 'growing pains'? A prebirth cohort study, BMJ open, 2 (2012).http://www.ncbi.nlm.nih.gov/pubmed/22923631
 M.A. Schuckit, T.L. Smith, J. Heron, M. Hickman, J. Macleod, G. Lewis, J.M. Davis, J.R. Hibbeln, S. Brown, L. Zuccolo, L.L. Miller, G. Davey-Smith, Testing a level of response to alcohol-based model of heavy drinking and alcohol problems in 1,905 17-year-olds, Alcoholism, clinical and experimental research, 35 (2011) 1897-1904.http://www.ncbi.nlm.nih.gov/pubmed/21762180
 T.L. Blasbalg, J.R. Hibbeln, C.E. Ramsden, S.F. Majchrzak, R.R. Rawlings, Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century, The American journal of clinical nutrition, 93 (2011) 950-962.http://www.ncbi.nlm.nih.gov/pubmed/21367944
 K.N. Harper, J.R. Hibbeln, R. Deckelbaum, C.P. Quesenberry, Jr., C.A. Schaefer, A.S. Brown, Maternal serum docosahexaenoic acid and schizophrenia spectrum disorders in adult offspring, Schizophrenia research, 128 (2011) 30-36.http://www.ncbi.nlm.nih.gov/pubmed/21324652
 M.P. Freeman, J.R. Hibbeln, M. Silver, A.M. Hirschberg, B. Wang, A.M. Yule, L.F. Petrillo, E. Pascuillo, N.I. Economou, H. Joffe, L.S. Cohen, Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: a preliminary open trial, Menopause, 18 (2011) 279-284.http://www.ncbi.nlm.nih.gov/pubmed/21037490
 M.D. Lewis, J.R. Hibbeln, J.E. Johnson, Y.H. Lin, D.Y. Hyun, J.D. Loewke, Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison, The Journal of clinical psychiatry, 72 (2011) 1585-1590.http://www.ncbi.nlm.nih.gov/pubmed/21903029
 L. Buydens-Branchey, M. Branchey, J.R. Hibbeln, Higher n-3 fatty acids are associated with more intense fenfluramine-induced ACTH and cortisol responses among cocaine-abusing men, Psychiatry research, 188 (2011) 422-427.http://www.ncbi.nlm.nih.gov/pubmed/21658782
 E.M. Wells, J.M. Jarrett, Y.H. Lin, K.L. Caldwell, J.R. Hibbeln, B.J. Apelberg, J. Herbstman, R.U. Halden, F.R. Witter, L.R. Goldman, Body burdens of mercury, lead, selenium and copper among Baltimore newborns, Environmental research, 111 (2011) 411-417.http://www.ncbi.nlm.nih.gov/pubmed/21277575
 C.E. Ramsden, J.R. Hibbeln, S.F. Majchrzak-Hong, All PUFAs are not created equal: absence of CHD benefit specific to linoleic acid in randomized controlled trials and prospective observational cohorts, World review of nutrition and dietetics, 102 (2011) 30-43.http://www.ncbi.nlm.nih.gov/pubmed/21865817
 C.E. Ramsden, J.D. Mann, K.R. Faurot, C. Lynch, S.T. Imam, B.A. MacIntosh, J.R. Hibbeln, J. Loewke, S. Smith, R. Coble, C. Suchindran, S.A. Gaylord, Low omega-6 vs. low omega-6 plus high omega-3 dietary intervention for chronic daily headache: protocol for a randomized clinical trial, Trials, 12 (2011) 97.http://www.ncbi.nlm.nih.gov/pubmed/21496264
 B.L. Gracious, M.C. Chirieac, S. Costescu, T.L. Finucane, E.A. Youngstrom, J.R. Hibbeln, Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder, Bipolar disorders, 12 (2010) 142-154.http://www.ncbi.nlm.nih.gov/pubmed/20402707
 C.E. Ramsden, J.R. Hibbeln, S.F. Majchrzak, J.M. Davis, n-6 fatty acid-specific and mixed polyunsaturate dietary interventions have different effects on CHD risk: a meta-analysis of randomised controlled trials, The British journal of nutrition, 104 (2010) 1586-1600.http://www.ncbi.nlm.nih.gov/pubmed/21118617
 C.D. Steer, G. Davey Smith, P.M. Emmett, J.R. Hibbeln, J. Golding, FADS2 polymorphisms modify the effect of breastfeeding on child IQ, PloS one, 5 (2010) e11570.http://www.ncbi.nlm.nih.gov/pubmed/20644632
 A.M. Brownawell, W.S. Harris, J.R. Hibbeln, D.M. Klurfeld, I. Newton, A. Yates, Assessing the environment for regulatory change for eicosapentaenoic acid and docosahexaenoic acid nutrition labeling, Nutrition reviews, 67 (2009) 391-397.http://www.ncbi.nlm.nih.gov/pubmed/19566599
 J. Golding, C. Steer, P. Emmett, J.M. Davis, J.R. Hibbeln, High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish, Epidemiology, 20 (2009) 598-603.http://www.ncbi.nlm.nih.gov/pubmed/19289957
 L. Buydens-Branchey, M. Branchey, J.R. Hibbeln, Low plasma levels of docosahexaenoic acid are associated with an increased relapse vulnerability in substance abusers, The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions, 18 (2009) 73-80.http://www.ncbi.nlm.nih.gov/pubmed/19219668
 R.J. Pawlosky, J.R. Hibbeln, D. Herion, D.E. Kleiner, N. Salem, Jr., Compartmental analysis of plasma and liver n-3 essential fatty acids in alcohol-dependent men during withdrawal, Journal of lipid research, 50 (2009) 154-161.http://www.ncbi.nlm.nih.gov/pubmed/18723835
 C.E. Ramsden, J.R. Hibbeln, W.E. Lands, Letter to the Editor re: Linoleic acid and coronary heart disease. Prostaglandins Leukot. Essent. Fatty Acids (2008), by W.S. Harris, Prostaglandins, leukotrienes, and essential fatty acids, 80 (2009) 77; author reply 77-78.http://www.ncbi.nlm.nih.gov/pubmed/19147338
 M.E. Sublette, M.S. Milak, J.R. Hibbeln, P.J. Freed, M.A. Oquendo, K.M. Malone, R.V. Parsey, J.J. Mann, Plasma polyunsaturated fatty acids and regional cerebral glucose metabolism in major depression, Prostaglandins, leukotrienes, and essential fatty acids, 80 (2009) 57-64.http://www.ncbi.nlm.nih.gov/pubmed/19128951
 J.R. Hibbeln, J.M. Davis, Considerations regarding neuropsychiatric nutritional requirements for intakes of omega-3 highly unsaturated fatty acids, Prostaglandins, leukotrienes, and essential fatty acids, 81 (2009) 179-186.http://www.ncbi.nlm.nih.gov/pubmed/19619995
 D.B. Allison, J.W. Newcomer, A.L. Dunn, J.A. Blumenthal, A.N. Fabricatore, G.L. Daumit, M.B. Cope, W.T. Riley, B. Vreeland, J.R. Hibbeln, J.E. Alpert, Obesity among those with mental disorders: a National Institute of Mental Health meeting report, American journal of preventive medicine, 36 (2009) 341-350.http://www.ncbi.nlm.nih.gov/pubmed/19285199
 J.R. Hibbeln, Depression, suicide and deficiencies of omega-3 essential fatty acids in modern diets, World review of nutrition and dietetics, 99 (2009) 17-30.http://www.ncbi.nlm.nih.gov/pubmed/19136836
 I. Hanbauer, I. Rivero-Covelo, E. Maloku, A. Baca, Q. Hu, J.R. Hibbeln, J.M. Davis, The Decrease of n-3 Fatty Acid Energy Percentage in an Equicaloric Diet Fed to B6C3Fe Mice for Three Generations Elicits Obesity, Cardiovascular psychiatry and neurology, 2009 (2009) 867041.http://www.ncbi.nlm.nih.gov/pubmed/20029635
 M.P. Freeman, M. Davis, P. Sinha, K.L. Wisner, J.R. Hibbeln, A.J. Gelenberg, Omega-3 fatty acids and supportive psychotherapy for perinatal depression: a randomized placebo-controlled study, Journal of affective disorders, 110 (2008) 142-148.http://www.ncbi.nlm.nih.gov/pubmed/18206247
 M.A. Schuckit, T.L. Smith, R. Trim, J. Heron, J. Horwood, J.M. Davis, J.R. Hibbeln, A.S. Team, The performance of elements of a 'level of response to alcohol'-based model of drinking behaviors in 13-year-olds, Addiction, 103 (2008) 1786-1792.http://www.ncbi.nlm.nih.gov/pubmed/18778389
 L. Buydens-Branchey, M. Branchey, J.R. Hibbeln, Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers, Progress in neuro-psychopharmacology & biological psychiatry, 32 (2008) 568-575.http://www.ncbi.nlm.nih.gov/pubmed/18060675
 S.M. Conklin, J.I. Harris, S.B. Manuck, J.K. Yao, J.R. Hibbeln, M.F. Muldoon, Serum omega-3 fatty acids are associated with variation in mood, personality and behavior in hypercholesterolemic community volunteers, Psychiatry research, 152 (2007) 1-10.http://www.ncbi.nlm.nih.gov/pubmed/17383013
 J.R. Hibbeln, J.M. Davis, C. Steer, P. Emmett, I. Rogers, C. Williams, J. Golding, Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study, Lancet, 369 (2007) 578-585.http://www.ncbi.nlm.nih.gov/pubmed/17307104
 B. Hallahan, J.R. Hibbeln, J.M. Davis, M.R. Garland, Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial, The British journal of psychiatry : the journal of mental science, 190 (2007) 118-122.http://www.ncbi.nlm.nih.gov/pubmed/17267927
 M.R. Garland, B. Hallahan, M. McNamara, P.A. Carney, H. Grimes, J.R. Hibbeln, A. Harkin, R.M. Conroy, Lipids and essential fatty acids in patients presenting with self-harm, The British journal of psychiatry : the journal of mental science, 190 (2007) 112-117.http://www.ncbi.nlm.nih.gov/pubmed/17267926
 S.M. Conklin, S.B. Manuck, J.K. Yao, J.D. Flory, J.R. Hibbeln, M.F. Muldoon, High omega-6 and low omega-3 fatty acids are associated with depressive symptoms and neuroticism, Psychosomatic medicine, 69 (2007) 932-934.http://www.ncbi.nlm.nih.gov/pubmed/17991818
 R.J. Pawlosky, J.R. Hibbeln, N. Salem, Jr., Compartmental analyses of plasma n-3 essential fatty acids among male and female smokers and nonsmokers, Journal of lipid research, 48 (2007) 935-943.http://www.ncbi.nlm.nih.gov/pubmed/17234605
 J.R. Hibbeln, From homicide to happiness--a commentary on omega-3 fatty acids in human society. Cleave Award Lecture, Nutrition and health, 19 (2007) 9-19.http://www.ncbi.nlm.nih.gov/pubmed/18309762
 L.C. Reis, J.R. Hibbeln, Cultural symbolism of fish and the psychotropic properties of omega-3 fatty acids, Prostaglandins, leukotrienes, and essential fatty acids, 75 (2006) 227-236.http://www.ncbi.nlm.nih.gov/pubmed/16962306
 L.R. Nieminen, K.K. Makino, N. Mehta, M. Virkkunen, H.Y. Kim, J.R. Hibbeln, Relationship between omega-3 fatty acids and plasma neuroactive steroids in alcoholism, depression and controls, Prostaglandins, leukotrienes, and essential fatty acids, 75 (2006) 309-314.http://www.ncbi.nlm.nih.gov/pubmed/16959481
 M.A. Schuckit, T.L. Smith, A. Waylen, J. Horwood, G.P. Danko, J.R. Hibbeln, J.M. Davis, J. Pierson, An evaluation of the performance of the self-rating of the effects of alcohol questionnaire in 12- and 35-year-old subjects, Journal of studies on alcohol, 67 (2006) 841-850.http://www.ncbi.nlm.nih.gov/pubmed/17061001
 J.C. Umhau, K.M. Dauphinais, S.H. Patel, D.A. Nahrwold, J.R. Hibbeln, R.R. Rawlings, D.T. George, The relationship between folate and docosahexaenoic acid in men, European journal of clinical nutrition, 60 (2006) 352-357.http://www.ncbi.nlm.nih.gov/pubmed/16278690
 M.E. Sublette, J.R. Hibbeln, H. Galfalvy, M.A. Oquendo, J.J. Mann, Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk, The American journal of psychiatry, 163 (2006) 1100-1102.http://www.ncbi.nlm.nih.gov/pubmed/16741213
 J.R. Hibbeln, L.R. Nieminen, T.L. Blasbalg, J.A. Riggs, W.E. Lands, Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity, The American journal of clinical nutrition, 83 (2006) 1483S-1493S.http://www.ncbi.nlm.nih.gov/pubmed/16841858
 M.P. Freeman, J.R. Hibbeln, K.L. Wisner, B.H. Brumbach, M. Watchman, A.J. Gelenberg, Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression, Acta psychiatrica Scandinavica, 113 (2006) 31-35.http://www.ncbi.nlm.nih.gov/pubmed/16390366
 M.P. Freeman, J.R. Hibbeln, K.L. Wisner, J.M. Davis, D. Mischoulon, M. Peet, P.E. Keck, Jr., L.B. Marangell, A.J. Richardson, J. Lake, A.L. Stoll, Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry, The Journal of clinical psychiatry, 67 (2006) 1954-1967.http://www.ncbi.nlm.nih.gov/pubmed/17194275
 J.R. Hibbeln, T.A. Ferguson, T.L. Blasbalg, Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention, International review of psychiatry, 18 (2006) 107-118.http://www.ncbi.nlm.nih.gov/pubmed/16777665
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