Dietary fatty acids improve perceived sleep quality, stress, and health in migraine: a secondary analysis of a randomized controlled trial.

Background: Migraine is a prevalent disabling condition often associated with comorbid physical and psychological symptoms that contribute to impaired quality of life and disability. Studies suggest that increasing dietary omega-3 fatty acid is associated with headache reduction, but less is known about the effects on quality of life in migraine. Methods: After a 4-week run-in, 182 adults with 5-20 migraine days per month were randomized to one of the 3 arms for sixteen weeks. Dietary arms included: H3L6 (a high omega-3, low omega-6 diet), H3 (a high omega-3, an average omega-6 diet), or a control diet (average intakes of omega-3 and omega-6 fatty acids). Prespecified secondary endpoints included daily diary measures (stress perception, sleep quality, and perceived health), Patient-Reported Outcome Measurement Information System Version 1.0 ([PROMIS©) measures and the Migraine Disability Assessment (MIDAS). Analyses used linear mixed effects models to control for repeated measures. Results: The H3L6 diet was associated with significant improvements in stress perception [adjusted mean difference (aMD): -1.5 (95% confidence interval: -1.7 to -1.2)], sleep quality [aMD: 0.2 (95% CI:0.1-0.2)], and perceived health [aMD: 0.2 (0.2-0.3)] compared to the control. Similarly, the H3 diet was associated with significant improvements in stress perception [aMD: -0.8 (-1.1 to -0.5)], sleep quality [aMD: 0.2 (0.1, 0.3)], and perceived health [aMD: 0.3 (0.2, 0.3)] compared to the control. MIDAS scores improved substantially in the intervention groups compared with the control (H3L6 aMD: -11.8 [-25.1, 1.5] and H3 aMD: -10.7 [-24.0, 2.7]). Among the PROMIS-29 assessments, the biggest impact was on pain interference [H3L6 MD: -1.8 (-4.4, 0.7) and H3 aMD: -3.2 (-5.9, -0.5)] and pain intensity [H3L6 MD: -0.6 (-1.3, 0.1) and H3 aMD: -0.6 (-1.4, 0.1)]. Discussion: The diary measures, with their increased power, supported our hypothesis that symptoms associated with migraine attacks could be responsive to specific dietary fatty acid manipulations. Changes in the PROMIS© measures reflected improvements in non-headache pain as well as physical and psychological function, largely in the expected directions. These findings suggest that increasing omega-3 with or without decreasing omega-6 in the diet may represent a reasonable adjunctive approach to reducing symptoms associated with migraine attacks. Trial Registration: ClinicalTrials.gov NCT02012790.

Analysis of omega-3 and omega-6 polyunsaturated fatty acid metabolism by compound-specific isotope analysis in humans.

Natural variations in the 13C:12C ratio (carbon-13 isotopic abundance [δ13C]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δ13C signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m2) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δ13C were determined. The H6 intervention exhibited increases in plasma LNA δ13C signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δ13C or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δ13C-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δ13C.

Associations between Plasma Lipid Mediators and Chronic Daily Headache Outcomes in Patients Randomized to a Low Linoleic Acid Diet with or without Added Omega-3 Fatty Acids.

A previous report showed that 12-week lowering of dietary omega-6 linoleic acid (LA) coupled with increased omega-3 polyunsaturated fatty acid (PUFA) intake (H3-L6 diet) reduced headache frequency and improved quality of life in patients with chronic daily headaches (CDHs) compared to dietary LA reduction alone (L6 diet). The trial also showed that targeted dietary manipulation alters PUFA-derived lipid mediators and endocannabinoids. However, several additional classes of lipid mediators associated with pain in preclinical models were not measured. The current secondary analysis investigated whether the clinical benefits of the H3-L6 diet were related to changes in plasma unesterified PUFA-derived lipid mediators known to be involved in nociception, including prostanoids. Lipid mediators were measured by ultra-high-pressure liquid chromatography coupled with tandem mass-spectrometry. Compared to baseline, dietary LA lowering with or without added omega-3 fatty acids did not alter unesterified n-6 PUFA-derived lipid mediators, although several species derived from LA, di-homo-gamma-linolenic acid, and arachidonic acid were positively associated with headache frequency and intensity, as well as mental health burden. Alpha-linolenic acid (ALA)-derived metabolites were also associated with increased headache frequency and intensity, although they did not change from the baseline in either dietary group. Compared to baseline, docosahexaenoic acid (DHA)-derived epoxides were more elevated in the H3-L6 group compared to the L6 group. Diet-induced elevations in plasma DHA-epoxides were associated with reduced headache frequency, better physical and mental health, and improved quality of life (p < 0.05). Prostanoids were not detected, except for PGF2-alpha, which was not associated with any outcomes. This study demonstrates that diet-induced changes in DHA-epoxides were associated with pain reduction in patients with chronic headaches, whereas n-6 PUFA and ALA metabolites were associated with nociception. Lipid mediator associations with mental health and quality of life paralleled pain management outcomes in this population. The findings point to a network of multiple diet-modifiable lipid mediator targets for pain management in individuals with CDHs.

Targeted dietary interventions to reduce pain in persistent post-traumatic headache among service members: Protocol for a randomized, controlled parallel-group trial.

INTRODUCTION: Post-traumatic headache (PTH) is common after traumatic brain injury (TBI), especially among active-duty service members (SMs), affecting up to 35% of patients with chronic TBI. Persistent PTH is disabling and frequently unresponsive to treatment and is often migrainous. Here, we describe a trial assessing whether dietary modifications to increase n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and reduce n-6 linoleic acid (LA), will alter nociceptive lipid mediators and result in clinical improvements in persistent PTH. METHODS: This prospective, randomized, controlled trial tests the efficacy, safety, and biochemical effects of targeted, controlled alterations in dietary n-3 and n-6 fatty acids in 122 adult SMs and military healthcare beneficiaries with diagnosed TBI associated with actively managed persistent frequent (>8 /month) PTH with migraine. Following a 4-week baseline, participants are randomized to one of two equally intensive dietary regimens for 12 additional weeks: 1) increased n-3 EPA + DHA with low n-6 LA (H3L6); 2) usual US dietary content of n-3 and n-6 fatty acids (Control). During the intervention, participants receive diet arm-specific study oils and foods sufficient for 75% of caloric needs and comprehensive dietary counseling. Participants complete daily headache diaries throughout the intervention. Clinical outcomes, including the Headache Impact Test (HIT-6), headache hours per day, circulating blood fatty acid levels, and bioactive metabolites, are measured pre-randomization and at 6 and 12 weeks. Planned primary analyses include pre-post comparisons of treatment groups on clinical measures using ANCOVA and mixed-effects models. Similar approaches to explore biochemical and exploratory clinical outcomes are planned. CLINICALTRIALS: gov registration: NCT03272399.

Adjunctive dietary intervention for bipolar disorder: a randomized, controlled, parallel-group, modified double-blinded trial of a high n-3 plus low n-6 diet.

OBJECTIVE: To investigate the preliminary efficacy of a high n-3 plus low n-6 (H3-L6) dietary intervention in improving mood stability in Bipolar Disorder (BD) when compared to dietary intervention with usual U.S. levels of n-6 and n-3 polyunsaturated fatty acid (PUFA) intakes (control diet, CD). METHODS: This 2-arm, parallel-group, randomized, modified double-blind, controlled 48-week study of 12-week intensive diet intervention in subjects with BD was conducted at a single suburban-rural site in the mid-Atlantic region. Participants with DSM-IV TR BD I or II with hypomanic or depressive symptoms were randomized, stratified on gender (N = 82). The intervention included the provision of group-specific study foods and dietary counseling. Variability of mood symptoms was measured by a twice-daily, 12-week ecological momentary analysis (EMA) paradigm, and group differences were analyzed using multilevel models. Circulating n-3 and n-6 fatty acids were measured at baseline and after 4, 8, and 12 weeks of diet exposure. RESULTS: All 82 randomized participants were included in biochemical analyses. Seventy participants completed at least 2 EMA surveys and were included in primary EMA analyses. Variability in mood, energy, irritability, and pain as measured using EMA was reduced in the H3-L6 group compared to the CD group. No significant differences in mean ratings of mood symptoms, or any other symptom measures, were detected. The dietary intervention effect on target PUFAs significantly differed by the group over time. CONCLUSIONS: A dietary intervention adjunctive to usual care showed preliminary efficacy in improving variability in mood symptoms in participants with BD. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02272010.

Implementation of malnutrition quality improvement reveals opportunities for better nutrition care delivery for hospitalized patients.

BACKGROUND: Gaps in hospital-based nutrition care practices and opportunities to improve care of patients at risk of malnutrition or malnourished have been demonstrated by several US hospitals implementing quality improvement (QI) projects. This study examined the impact of nutrition care process improvements focused on better documentation of identification and diagnosis of malnutrition in 5 hospital services and differences between nutritionally targeted vs nontargeted services. METHODS: Data on malnutrition risk screening, nutrition assessment, malnutrition diagnosis, and nutrition care plan delivery were collected from 32,723 hospital encounters for patients admitted to the intensive care unit, pulmonology, oncology, urology, and general medicine services (targeted) as well as the rest of the nontargeted hospital services between 2017 and 2019. RESULTS: Higher rates of morbidity in targeted service patients compared with those in the patient population admitted in the nontargeted services were observed, including higher rates of malnutrition risk (37.43% vs 19.16%, P < .001), higher rates of moderate and severe malnutrition first identified by a registered dietitian nutritionist (20.27% vs 9.67%, P < .001), and malnutrition diagnosis confirmed by an admitting physician (16.72% vs 6.74%, P < .001). CONCLUSIONS: The findings suggest sustained improvements in confirmed rates of malnutrition identification and diagnosis are achievable. Targeting malnutrition QI efforts to hospital services with higher patient morbidity is an effective method for improving malnutrition diagnosis, in particular in hospitals with limited resources, which in turn can result in improved nutrition care delivery.

Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial.

OBJECTIVE: To determine whether dietary interventions that increase n-3 fatty acids with and without reduction in n-6 linoleic acid can alter circulating lipid mediators implicated in headache pathogenesis, and decrease headache in adults with migraine. DESIGN: Three arm, parallel group, randomized, modified double blind, controlled trial. SETTING: Ambulatory, academic medical center in the United States over 16 weeks. PARTICIPANTS: 182 participants (88% women, mean age 38 years) with migraines on 5-20 days per month (67% met criteria for chronic migraine). INTERVENTIONS: Three diets designed with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and linoleic acid altered as controlled variables: H3 diet (n=61)-increase EPA+DHA to 1.5 g/day and maintain linoleic acid at around 7% of energy; H3-L6 diet (n=61)-increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of energy; control diet (n=60)-maintain EPA+DHA at <150 mg/day and linoleic acid at around 7% of energy. All participants received foods accounting for two thirds of daily food energy and continued usual care. MAIN OUTCOME MEASURES: The primary endpoints (week 16) were the antinociceptive mediator 17-hydroxydocosahexaenoic acid (17-HDHA) in blood and the headache impact test (HIT-6), a six item questionnaire assessing headache impact on quality of life. Headache frequency was assessed daily with an electronic diary. RESULTS: In intention-to-treat analyses (n=182), the H3-L6 and H3 diets increased circulating 17-HDHA (log ng/mL) compared with the control diet (baseline-adjusted mean difference 0.6, 95% confidence interval 0.2 to 0.9; 0.7, 0.4 to 1.1, respectively). The observed improvement in HIT-6 scores in the H3-L6 and H3 groups was not statistically significant (-1.6, -4.2 to 1.0, and -1.5, -4.2 to 1.2, respectively). Compared with the control diet, the H3-L6 and H3 diets decreased total headache hours per day (-1.7, -2.5 to -0.9, and -1.3, -2.1 to -0.5, respectively), moderate to severe headache hours per day (-0.8, -1.2 to -0.4, and -0.7, -1.1 to -0.3, respectively), and headache days per month (-4.0, -5.2 to -2.7, and -2.0, -3.3 to -0.7, respectively). The H3-L6 diet decreased headache days per month more than the H3 diet (-2.0, -3.2 to -0.8), suggesting additional benefit from lowering dietary linoleic acid. The H3-L6 and H3 diets altered n-3 and n-6 fatty acids and several of their nociceptive oxylipin derivatives in plasma, serum, erythrocytes or immune cells, but did not alter classic headache mediators calcitonin gene related peptide and prostaglandin E2. CONCLUSIONS: The H3-L6 and H3 interventions altered bioactive mediators implicated in headache pathogenesis and decreased frequency and severity of headaches, but did not significantly improve quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT02012790.

Methodology for altering omega-3 EPA+DHA and omega-6 linoleic acid as controlled variables in a dietary trial.

BACKGROUND & AIMS: Increasing dietary intake of n-3 EPA+DHA and lowering dietary n-6 LA is under investigation as a therapeutic diet for improving chronic pain syndromes as well as other health outcomes. Herein we describe the diet methodology used to modulate intake of n-3 and n-6 PUFA in a free living migraine headache population and report on nutrient intake, BMI and diet acceptability achieved at week 16 of the intensive diet intervention and week 22 follow-up time-point. METHODS: A total of 178 participants were randomized and began one of three diet interventions: 1) a high n-3 PUFA, average n-6 PUFA (H3) diet targeting 1500 mg EPA+DHA/day and 7% of energy (en%) from n-6 linoleic acid (LA), 2) a high-n-3 PUFA, low-n-6 PUFA (H3L6) targeting 1500 mg EPA+DHA/day and <1.8 en% n-6 LA or 3) a Control diet with typical American intakes of both EPA+DHA (<150 mg/day) and 7 en% from n-6 LA. Methods used to achieve diet change to week 16 include diet education, diet counseling, supply of specially prepared foods, self-monitoring and access to online diet materials. Only study oils and website materials were provided for the follow-up week 16 to week 22 periods. Diet adherence was assessed by multiple 24 h recalls administered throughout the trial. Diet acceptability was assessed in a subset of participants at 4 time points by questionnaire. RESULTS: At week 16 H3 and H3L6 diet groups significantly increased median n-3 EPA+DHA intake from 48 mg/2000 kcals at baseline to 1484 mg/2000 kcals (p < 0.0001) and from 44 mg/2000 kcals to 1341 mg/2000 kcals (p < 0.0001), respectively. In the Control group, EPA+DHA intake remained below the typical American intake with baseline median at 60 mg/2000 kcals and 80 mg/2000 kcals (p = 0.6) at week 16. As desired, LA intake was maintained in the H3 and Control group with baseline median of 6.5 en% to 7.1 en% (p = 0.4) at week 16 and from 6.5 en% to 6.8 en% (p = 1.0) at week 16, respectively. In the H3L6 group, n-6 LA decreased from 6.3 en% at baseline to 3.2 en% (p < 0.0001) at week 16. There were no significant changes in BMI or diet acceptability throughout the trial or between diet groups. CONCLUSIONS: We find this diet method to be acceptable to research participants and successful in altering dietary n-3 EPA+DHA with and without concurrent decreases in n-6 LA. If n-6 LA of less than 3 en% is desired, additional techniques to limit LA may need to be employed.

Comparing prospective headache diary and retrospective four-week headache questionnaire over 20 weeks: Secondary data analysis from a randomized controlled trial.

BACKGROUND: Headache diaries and recall questionnaires are frequently used to assess headache frequency and severity in clinical and research settings. METHODS: Using 20 weeks of data from an intervention trial with 182 participants, we evaluated concordance between an electronic headache diary administered on a daily basis and designed to capture the presence and severity of headaches on an hourly basis (the headache diary) and a recall questionnaire, with retrospective estimation of the number of headache days assessed on a monthly basis. We further examined whether the duration or severity of headaches assessed by the electronic diary impacted concordance between these two measures. RESULTS: Over the course of four 28-day periods, people with migraine participating in a dietary intervention reported an average of 13.7 and 11.1 headache days in the headache diary and recall questionnaire, respectively. CONCLUSION: Over time, the concordance between headache days reported in these two measures tended to increase; however, the recall questionnaire headache estimates were lower than the diary measures in all four periods. When analysis was restricted to headaches lasting 8 hours or more, the number of headache days was more closely aligned with days reported in the recall questionnaire, indicating that the accuracy of recall estimates is likely to be influenced by headache duration. Restriction of analyses to moderate-to-severe headaches did not change results as much as headache duration. The findings indicate that recall questionnaires administered on a monthly basis may underestimate headache frequency and therefore should not be used interchangeably with headache diaries.Clinical Trials.gov Identifier: NCT02012790.

Metabonomics reveals altered metabolites related to inflammation and energy utilization at recovery of cystic fibrosis lung exacerbation.

BACKGROUND: Cystic fibrosis lung disease is characterized by chronic bacterial infections in the setting of mucus abnormalities. Patients experience periodic exacerbations that manifest with increased respiratory symptoms that require intensification of therapy with enhanced airway clearance and intravenous (IV) antibiotics. OBJECTIVES: In an observational study we tested if the profile of metabolites in serum distinguished the pre-from post-exacerbation state and which systemically measurable pathways were affected during the process to recovery. METHODS: Serum collected within 48 h of start and completion, respectively of IV antibiotics was collected from people with CF ages 6-30 years. Three day food records were collected prior to each sample. To reduce variation between subjects only subjects who had pancreatic insufficiency, had similar CF mutations, and did not have CF liver disease or diabetes were included. Metabolomic profiling was conducted by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy with metabolites being identified based on retention time/index, mass to charge ratio and comparison to known compounds. Biostatistical analyses used paired t-test with correction for multiple comparisons and orthogonal partial least square discriminant analysis. RESULTS: Thirty subjects (20 male) with a mean ±â€¯SEM age of 15.3 ±â€¯1.2 years participated, 17 of whom had matched food-records. Lung function was significantly improved post-therapy compared to pre-therapy, (mean ±â€¯SEM) 75 ±â€¯4% vs. 68 ±â€¯4% predicted (n = 26). Serum metabonomics showed distinction of the pre-vs. post-therapy groups with 123 compounds contributing to the differentiation pre-versus post-antibiotics by multiple biostatistical analyses. Compounds and pathways affected included bile acids and microbial derived amino acid metabolites, increases in lipid classes of the glycerophospholipid, glycerolipids, cholesterol, phopsholipids, and most pronounced, the class of sphingolipids. Changes in n6/n3 fatty acids, decreased polyamines but increased metabolites in the nitric oxide pathway, and changes in the tryptophan-kynurenine pathway indicated decreased inflammation at resolution of exacerbation. CONCLUSIONS: Changes in serum metabolites that distinguished CF pulmonary exacerbation vs. resolution of symptoms showed evidence of decreased inflammation and improvement from a catabolic state.

A sixteen-week three-armed, randomized, controlled trial investigating clinical and biochemical effects of targeted alterations in dietary linoleic acid and n-3 EPA+DHA in adults with episodic migraine: Study protocol.

Migraine is a prevalent neurological disorder, affecting over 16% of adult women and 7% of adult men in the U.S., causing significant pain, disability, and medical expense, with incomplete benefits from conventional medical management. Migraine, as a chronic pain syndrome, provides a practical model for investigating the impact of dietary modifications in omega-3 (n-3) and omega-6 (n-6) fatty acids. This paper reports the protocol of a trial to assess whether targeted dietary modifications designed to increase n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with or without concurrent reduction in n-6 linoleic acid (LA), will alter nociceptive lipid mediators and mediate decreases in frequency and severity of migraine. This prospective, randomized, controlled trial in 153 male and female adult subjects, ages 18-99, with diagnosed and actively managed episodic migraine tests the efficacy, safety, and biochemical effects of targeted, controlled alterations in dietary omega-3 and omega-6 fatty acids. Participants are masked to diet hypotheses and all assessors are masked to treatment assignment. Following a four-week baseline period, participants with migraine headache frequency of 5-20 per month are randomized to one of three intensive dietary regimens for 16 additional weeks followed by a less intensive observation period. Dietary intervention arms include: 1) increased n-3 EPA+DHA with low n-6 linoleic acid (H3 L6); 2) increased n-3 EPA+DHA with usual US dietary intake of n-6 linoleic acid (H3 H6); and 3) usual US dietary content of n-3 and n-6 fatty acids (L3 H6). During the actual intervention, subjects receive content-specific study oils and foods sufficient for two meals and two snacks per day, as well as dietary counseling. Biochemical and clinical outcome measures are performed at intervals throughout this period. This randomized controlled trial is designed to determine whether targeted alterations in dietary n-3 and n-6 fatty acids can alter nociceptive lipid mediators in a manner that decreases headache pain and enhances quality of life and function in adults with frequent migraines. TRIAL REGISTRATION: NCT02012790.

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

UNLABELLED: 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: 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.

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.

Omega-3 and omega-6 fatty acids are precursors of bioactive lipid mediators posited to modulate both physical pain and psychological distress. In a randomized trial of 67 subjects with severe headaches, we recently 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. Additionally, we examined the effect of the interventions on the number of cases with substantial physical or mental impairments as defined by cutoff values in the Brief Symptom Inventory (BSI-18), Medical Outcomes Study Short Forms 12 (SF-12), Headache Impact Test (HIT-6), and the number of headache days per month. In the intention-to-treat analysis, participants in the H3-L6 group experienced statistically significant reductions in psychological distress (BSI-18 mean difference: -6.56; 95% confidence interval [CI]: -11.43 to -1.69) and improvements in SF-12 mental (mean difference: 6.01; 95% CI: 0.57 to 11.45) and physical (mean difference: 6.65; 95% CI: 2.14 to 11.16) health summary scores. At 12 weeks, the proportion of subjects experiencing substantial impairment according to cutoff values in the BSI-18, SF-12 physical, HIT-6, and headache days per month was significantly lower in the H3-L6 group. Dietary manipulation of n-3 and n-6 fatty acids, previously shown to produce major improvements in headache, was found to also reduce psychological distress and improve HRQOL and function.

Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools.

BACKGROUND: Dietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations. OBJECTIVE: To evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. DESIGN: Secondary analysis of a randomized trial. 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. RESULTS: Compared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3-L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations. CONCLUSION: 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 alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial.

Omega-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single-blinded, parallel-group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n-3 and n-6 fatty acids for treatment of chronic headaches. After a 4-week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food-based 12-week dietary interventions: a high n-3 plus low n-6 (H3-L6) intervention, or a low n-6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT-6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n-6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n-3 and n-6 derivatives. Fifty-six of 67 patients completed the intervention. Both groups achieved targeted intakes of n-3 and n-6 fatty acids. In intention-to-treat analysis, the H3-L6 intervention produced significantly greater improvement in the HIT-6 score (-7.5 vs -2.1; P<0.001) and the number of Headache Days per month (-8.8 vs -4.0; P=0.02), compared to the L6 group. The H3-L6 intervention also produced significantly greater reductions in Headache Hours per day (-4.6 vs -1.2; P=0.01) and the n-6 in HUFA score (-21.0 vs -4.0%; P<0.001), and greater increases in antinociceptive n-3 pathway markers 18-hydroxy-eicosapentaenoic acid (+118.4 vs +61.1%; P<0.001) and 17-hydroxy-docosahexaenoic acid (+170.2 vs +27.2; P<0.001). A dietary intervention increasing n-3 and reducing n-6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality-of-life in this population.

Low-n-6 and low-n-6 plus high-n-3 diets for use in clinical research.

Few trials have evaluated the metabolic effects and health outcomes of lowering dietary n-6 PUFA. The objectives of the present paper were (1) to report the methods employed to lower dietary n-6 PUFA, while either increasing or maintaining n-3 PUFA intake and (2) to validate our methods with 24 h recalls and erythrocyte fatty acid analyses. A total of sixty-seven subjects were randomised to either (1) an average-n-3 PUFA, low-n-6 PUFA (L6) intervention designed to lower linoleic acid (LA; #2·5% of energy (en%)) and arachidonic acid (#60 mg/d), while maintaining an average US intake of n-3 PUFA or (2) a high-n-3 PUFA, low-n-6 PUFA (H3-L6) intervention designed to lower n-6 LA, while increasing the n-3 PUFA a-linolenic acid (ALA; $1·5 en%) and EPA þ DHA ($1000 mg/d). Pre- and intraintervention nutrient intakes were estimated with six 24 h dietary recalls per subject. Both groups achieved the targeted reductions in dietary LA to #2·5 en% (median LA 2·45 (2·1, 3·1); P,0·001). Intakes of n-3 PUFA did not change for the L6 group. Target increases in n-3 ALA (median 1·6 en%, (1·3, 2·0), P,0·001) and EPA þ DHA (1482 mg, (374, 2558), P,0·001) were achieved in the H3-L6 group. Dietary changes were validated by corresponding changes in erythrocyte n-6 and n-3 fatty acid composition. Dietary LA can be lowered to #2·5 en%, with or without concurrent increases in dietary n-3 PUFA, in an outpatient clinical trial setting using this integrated diet method.

Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans.

Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in human diets, a major component of human tissues, and the direct precursor to the bioactive oxidized LA metabolites (OXLAMs), 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). These four OXLAMs have been mechanistically linked to pathological conditions ranging from cardiovascular disease to chronic pain. Plasma OXLAMs, which are elevated in Alzheimer's dementia and non-alcoholic steatohepatitis, have been proposed as biomarkers useful for indicating the presence and severity of both conditions. Because mammals lack the enzymatic machinery needed for de novo LA synthesis, the abundance of LA and OXLAMs in mammalian tissues may be modifiable via diet. To examine this issue in humans, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced the abundance of plasma OXLAMs, and reduced the LA content of multiple circulating lipid fractions that may serve as precursor pools for endogenous OXLAM synthesis. These results show that lowering dietary LA can reduce the synthesis and/or accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions. Future studies evaluating the clinical implications of diet-induced OXLAM reductions are warranted.

Low-glycemic load decreases postprandial insulin and glucose and increases postprandial ghrelin in white but not black women.

Alterations in appetite hormones favoring increased postprandial satiety have been implicated in both the glycemic control and potential weight-loss benefits of a low-glycemic diet. Racial differences exist in dietary glycemic load and appetite hormone concentrations. This study examined the impact of glycemic load on appetite hormones in 20 black women [10 normal weight, BMI = 22.8 ± 1.42 (mean ± SD); 10 obese, BMI = 35.1 ± 2.77] and 20 white women (10 normal weight, BMI = 22.9 ± 1.45; 10 obese, BMI = 34.3 ± 2.77). Each woman completed two 4.5-d weight-maintenance, mixed-macronutrient, high-glycemic vs. low-glycemic load diets that concluded with a test meal of identical composition. Blood samples collected before and serially for 3 h after each test meal were assayed for plasma ghrelin and serum insulin and glucose concentrations. Compared with the high-glycemic load meal, the low-glycemic load meal was associated with lower insulin(AUC) (P = 0.02), glucose(AUC) (P = 0.01), and urge to eat ratings (P = 0.05) but with higher ghrelin(AUC) (P = 0.008). These results suggest the satiating effect of a low-glycemic load meal is not directly linked to enhanced postprandial suppression of ghrelin. Notably, these effects were significant among white but not black women, suggesting that black women may be less sensitive than white women to the glucoregulatory effects of a low-glycemic load. These findings add to a growing literature demonstrating racial differences in postprandial appetite hormone responses. If reproducible, these findings have implications for individualized diet prescription for the purposes of glucose or weight control in women.

Inhibition of fried meat-induced colorectal DNA damage and altered systemic genotoxicity in humans by crucifera, chlorophyllin, and yogurt.

UNLABELLED: Dietary exposures implicated as reducing or causing risk for colorectal cancer may reduce or cause DNA damage in colon tissue; however, no one has assessed this hypothesis directly in humans. Thus, we enrolled 16 healthy volunteers in a 4-week controlled feeding study where 8 subjects were randomly assigned to dietary regimens containing meat cooked at either low (100°C) or high temperature (250°C), each for 2 weeks in a crossover design. The other 8 subjects were randomly assigned to dietary regimens containing the high-temperature meat diet alone or in combination with 3 putative mutagen inhibitors: cruciferous vegetables, yogurt, and chlorophyllin tablets, also in a crossover design. Subjects were nonsmokers, at least 18 years old, and not currently taking prescription drugs or antibiotics. We used the Salmonella assay to analyze the meat, urine, and feces for mutagenicity, and the comet assay to analyze rectal biopsies and peripheral blood lymphocytes for DNA damage. Low-temperature meat had undetectable levels of heterocyclic amines (HCAs) and was not mutagenic, whereas high-temperature meat had high HCA levels and was highly mutagenic. The high-temperature meat diet increased the mutagenicity of hydrolyzed urine and feces compared to the low-temperature meat diet. The mutagenicity of hydrolyzed urine was increased nearly twofold by the inhibitor diet, indicating that the inhibitors enhanced conjugation. Inhibitors decreased significantly the mutagenicity of un-hydrolyzed and hydrolyzed feces. The diets did not alter the levels of DNA damage in non-target white blood cells, but the inhibitor diet decreased nearly twofold the DNA damage in target colorectal cells. To our knowledge, this is the first demonstration that dietary factors can reduce DNA damage in the target tissue of fried-meat associated carcinogenesis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00340743.

Low omega-6 vs. low omega-6 plus high omega-3 dietary intervention for chronic daily headache: protocol for a randomized clinical trial.

BACKGROUND: Targeted analgesic dietary interventions are a promising strategy for alleviating pain and improving quality of life in patients with persistent pain syndromes, such as chronic daily headache (CDH). High intakes of the omega-6 (n-6) polyunsaturated fatty acids (PUFAs), linoleic acid (LA) and arachidonic acid (AA) may promote physical pain by increasing the abundance, and subsequent metabolism, of LA and AA in immune and nervous system tissues. Here we describe methodology for an ongoing randomized clinical trial comparing the metabolic and clinical effects of a low n-6, average n-3 PUFA diet, to the effects of a low n-6 plus high n-3 PUFA diet, in patients with CDH. Our primary aim is to determine if: A) both diets reduce n-6 PUFAs in plasma and erythrocyte lipid pools, compared to baseline; and B) the low n-6 plus high n-3 diet produces a greater decline in n-6 PUFAs, compared to the low n-6 diet alone. Secondary clinical outcomes include headache-specific quality-of-life, and headache frequency and intensity. METHODS: Adults meeting the International Classification of Headache Disorders criteria for CDH are included. After a 6-week baseline phase, participants are randomized to a low n-6 diet, or a low n-6 plus high n-3 diet, for 12 weeks. Foods meeting nutrient intake targets are provided for 2 meals and 2 snacks per day. A research dietitian provides intensive dietary counseling at 2-week intervals. Web-based intervention materials complement dietitian advice. Blood and clinical outcome data are collected every 4 weeks. RESULTS: Subject recruitment and retention has been excellent; 35 of 40 randomized participants completed the 12-week intervention. Preliminary blinded analysis of composite data from the first 20 participants found significant reductions in erythrocyte n-6 LA, AA and %n-6 in HUFA, and increases in n-3 EPA, DHA and the omega-3 index, indicating adherence. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01157208).