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A combined DHA-rich fish oil and cocoa flavanols intervention does not improve cognition or brain structure in older adults with memory complaints: results from the CANN randomized, controlled parallel-design study.
Vauzour, D, Scholey, A, White, DJ, Cohen, NJ, Cassidy, A, Gillings, R, Irvine, MA, Kay, CD, Kim, M, King, R, et al
The American journal of clinical nutrition. 2023;118(2):369-381
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At a population level, interventions that delay the onset of dementia by 2 years are predicted to reduce the number of dementia patients by 20%. Prospective cohort studies have consistently reported cognitive and neurophysiological benefits of the fish-derived omega-3 long-chain polyunsaturated fatty acids (PUFAs), EPA, and DHA and plant-derived flavanols (FLAVs). This study hypothesised that 12-month administration of a combination of 500 mg cocoa FLAVs with 1.5g omega-3 long-chain PUFAs would improve cognitive function in a mixed subjective cognitive impairment and mild cognitive impairment cohort. This study is based on the results of the CANN randomised controlled trial. A total of 258 participants were recruited and randomised to control or test intervention. Following baseline measurements, 125 participants were randomised into the active OM3FLAV intervention group and 121 into the control group. Results showed that the 1-year intervention with EPA and DHA and cocoa FLAVs did not improve cognition or protect the brain against atrophy in older adults with evidence of memory deficits. Authors concluded that given the complexity of neuropathological processes underpinning cognitive decline and dementia risk, multidomain, multinutrient, or whole diet approaches may be needed to positively impact the cognitive trajectory in the medium term (months to 3 years).
Abstract
BACKGROUND There is evidence that both omega-3 long-chain polyunsaturated fatty acids (PUFAs) (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and cocoa flavanols can improve cognitive performance in both healthy individuals and in those with memory complaints. However, their combined effect is unknown. OBJECTIVES To investigate the combined effect of EPA/DHA and cocoa flavanols (OM3FLAV) on cognitive performance and brain structures in older adults with memory complaints. METHODS A randomized placebo-controlled trial of DHA-rich fish oil (providing 1.1 g/d DHA and 0.4 g/d EPA) and a flavanol-rich dark chocolate (providing 500 mg/d flavan-3-ols) was conducted in 259 older adults with either subjective cognitive impairment or mild cognitive impairment. Participants underwent assessment at baseline, 3 mo, and 12 mo. The primary outcome was the number of false-positives on a picture recognition task from the Cognitive Drug Research computerized assessment battery. Secondary outcomes included other cognition and mood outcomes, plasma lipids, brain-derived neurotrophic factor (BDNF), and glucose levels. A subset of 110 participants underwent structural neuroimaging at baseline and at 12 mo. RESULTS 197 participants completed the study. The combined intervention had no significant effect on any cognitive outcomes, with the exception of reaction time variability (P = 0.007), alertness (P < 0.001), and executive function (P < 0.001), with a decline in function observed in the OM3FLAV group (118.6 [SD 25.3] at baseline versus 113.3 [SD 25.4] at 12 mo for executive function) relative to the control, and an associated decrease in cortical volume (P = 0.039). Compared with the control group, OM3FLAV increased plasma HDL, total cholesterol ratio (P < 0.001), and glucose (P = 0.008) and reduced TG concentrations (P < 0.001) by 3 mo, which were sustained to 12 mo, with no effect on BDNF. Changes in plasma EPA and DHA and urinary flavonoid metabolite concentrations confirmed compliance to the intervention. CONCLUSIONS These results suggest that cosupplementation with ω-3 PUFAs and cocoa flavanols for 12 mo does not improve cognitive outcomes in those with cognitive impairment. This trial was registered at clinicaltrials.gov as NCT02525198.
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Docosahexaenoic acid (DHA) intake estimated from a 7-question survey identifies pregnancies most likely to benefit from high-dose DHA supplementation.
Christifano, DN, Crawford, SA, Lee, G, Brown, AR, Camargo, JT, Kerling, EH, Gajewski, BJ, Valentine, CJ, Gustafson, KM, DeFranco, EA, et al
Clinical nutrition ESPEN. 2023;53:93-99
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Preterm birth (PTB) is the primary cause of infant mortality worldwide; and infants who survive have a higher risk of child disability. A recent Cochrane Review concluded that there is strong evidence that omega-3 fatty acids, especially docosahexaenoic acid (DHA), reduce early PTB (EPTB, <34 weeks gestation) and PTB (<37 weeks gestation) by 42% and 11%, respectively. The aim of this study was to investigate whether DHA intake at baseline alone could identify pregnancies for which high dose DHA supplementation lowered risk of EPTB and PTB. This study used the results from two randomised clinical trials of DHA supplementation during pregnancy in which participants completed the DHA-Food Frequency Questionnaire (FFQ) before randomisation to 200mg/day or high dose DHA, i.e., 800mg/day or 1000mg/day. A total of 1400 participants were enrolled in the two trials. Results show that the DHA-FFQ predicted participants whose risk of EPTB and PTB was reduced by consuming a DHA supplement of 800mg/day or 1000mg/day compared to 200mg/day. In fact, participants who started the study with an average daily DHA intake of <150mg had a 64% lower rate of EPTB and a 24% lower rate of PTB if they were assigned to 800mg/day or 1000mg/day compared to 200mg/day DHA. Authors conclude that the DHA-FFQ identifies women who could benefit from high dose DHA supplementation at least as effectively as a blood measure of DHA but with far fewer barriers for clinical implementation.
Abstract
BACKGROUND Two randomized trials found women with low blood docosahexaenoic acid (DHA; an omega 3 fatty acid) had fewer early preterm births (<34 weeks gestation) if they were assigned to high dose DHA supplementation, however, there is currently no capacity for clinicians who care for pregnancies to obtain a blood assessment of DHA. Determining a way to identify women with low DHA intake whose risk could be lowered by high dose DHA supplementation is desired. OBJECTIVE To determine if assessing DHA intake can identify pregnancies that benefit from high dose DHA supplementation. STUDY DESIGN This secondary analysis used birth data from 1310 pregnant women who completed a 7-question food frequency questionnaire (DHA-FFQ) at 16.8 ± 2.5 weeks gestation that is validated to assess DHA status. They were then randomly assigned to a standard (200 mg/day) or high dose (800 or 1000 mg/day) DHA supplement for the remainder of pregnancy. Bayesian logistic regressions were fitted for early preterm birth and preterm birth as a function of DHA intake and assigned DHA dose. RESULTS Participants who consumed less than 150 mg/day DHA prior to 20 weeks' gestation (n = 810/1310, 58.1%) had a lower Bayesian posterior probability (pp) of early preterm birth if they were assigned to high dose DHA supplementation (1.4% vs 3.9%, pp = 0.99). The effect on preterm birth (<37 weeks) was also significant (11.3% vs 14.8%, pp = 0.97). CONCLUSION The DHA-FFQ can identify pregnancies that will benefit most from high dose DHA supplementation and reduce the risk of preterm birth. The DHA-FFQ is low burden to providers and patients and could be easily implemented in obstetrical practice.
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Effect of Docosahexaenoic Acid and Eicosapentaenoic Acid Supplementation on Sleep Quality in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Trial.
Yokoi-Shimizu, K, Yanagimoto, K, Hayamizu, K
Nutrients. 2022;14(19)
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Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are unsaturated Omega-3 fatty acids, primarily found in fish and seafood. The fatty acids fulfil many vital roles in the body, such as creating cell membranes, supporting brain functions and being associated with many disease-protective benefits. These fatty acids also influence sleep in children and young adults, but less is known about their effect in older people. Hence, this Japanese study investigated the impact of EPA and DHA on sleep quality in people above the age of ≥ 45. 66 males and females with poor sleep participated in this randomized, placebo-controlled, double-blinded, parallel-grouped study. They either received 860 mg of combined DHA/EPA per day (576 mg DHA/284 mg EPA) or a placebo of corn oil for 12 weeks. The outcome was assessed subjectively via sleep quality and mood questionnaires, as well as objectively with a sleep scanner and blood samples. Blood samples and blood pressure where also monitored as a safety measure. Upon completion of the study there was a subjective improvement, which was backed-up by the results of the sleep scanner. This study confirmed that DHA/EPA improves sleep quality in the middle aged and older population and does so at doses lower than those administered in previous studies. The authors had set the daily minimum intake of DHA/EPA at 860 mg/day for this trial, as previous research showed no effects at lower doses. They also noted that poor responders tended to be people with pre-existing conditions or those who were pregnant. This population may require higher dosages of DHA/EPA than healthy patients. Overall, the intervention was well tolerated. Ensuring adequate DHA and EPA levels and intake could be part of nutritional strategies for sleep support.
Abstract
Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)-omega-3 fatty acids with various functions-influence sleep in children and young adults. However, only limited studies on their effects on sleep in middle- and old-aged adults have been reported. Therefore, we investigated the effects of DHA and EPA on sleep quality in subjects aged ≥ 45 years. We performed a randomized, placebo-controlled, double-blinded, parallel-grouped study, in which we randomly assigned 66 healthy Japanese males and females. Each individual received six 480 mg capsules containing 576 mg DHA and 284 mg EPA per day (DHA/EPA group, n = 33), or corn oil (placebo group, n = 33), for 12 weeks. Before and after the intervention, the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA) and the sleep state test were conducted. In the DHA/EPA group, factor III (frequent dreaming) scores among the OSA-MA scores were significantly improved compared to the placebo group. Additionally, sleep state tests revealed that sleep efficiency improved in the DHA/EPA group. To our knowledge, this study is the first to report that DHA/EPA improves sleep quality in middle- and old-aged individuals, even at doses lower than those administered in previous studies.
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Impulsiveness in children with attention-deficit/hyperactivity disorder after an 8-week intervention with the Mediterranean diet and/or omega-3 fatty acids: a randomised clinical trial.
San Mauro Martin, I, Sanz Rojo, S, González Cosano, L, Conty de la Campa, R, Garicano Vilar, E, Blumenfeld Olivares, JA
Neurologia. 2022;37(7):513-523
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From a clinical perspective, impulsiveness is an important diagnostic characteristic of several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). ADHD is a neurodevelopmental disorder characterised by a persistent pattern of lack of attention and/or hyperactivity and impulsiveness. Dietary approaches to the treatment of ADHD include fatty acid supplementation, particularly with omega-3 polyunsaturated fatty acids (n-3 PUFA) The aim of this study was to analyse changes in the Barratt Impulsiveness Scale (BIS-11c) scores in children with ADHD after an 8-week intervention with the Mediterranean diet, omega-3 fatty acid supplementation, or Mediterranean diet plus omega-3 fatty acid supplementation, as compared to a control group. This study is a cross-sectional, observational cohort study of an 8-week dietary intervention in children with ADHD. Participants (n= 60) were divided into 4 groups, with a control group and 3 intervention groups. Results show that participants with ADHD taking n-3 PUFA supplements (550 mg EPA and 225 mg DHA daily) showed significantly lower levels of impulsiveness than those adopting a Mediterranean diet and controls. These participants also scored lower on all subscales of the BIS (cognitive, motor, and lack of planning). However, there weren’t any differences in impulsive behaviour between patients taking n-3 PUFA supplements and those taking supplements and adhering to the Mediterranean diet. Authors conclude that omega-3 rich (EPA/DHA) supplements should be considered for paediatric patients with ADHD, particularly those with the predominantly hyperactive-impulsive subtype.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The results from this study show no statistically significant differences between groups, except for the group of children receiving omega-3 supplementation.
- Patients with ADHD receiving omega 3 fatty acids (550 mg eicosatetraenoic acid [EPA] and 225 mg docosahexaenoic acid [DHA]) daily presented with less impulsive behaviour than controls with ADHD and patients who adopted a Mediterranean diet.
- EPA/DHA supplements may be considered for paediatric patients with ADHD, particularly those with the predominantly hyperactive-impulsive subtype.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
A randomized, cross-sectional study was conducted to investigate the effects of a Mediterranean diet and Omega-3 supplementation on the impulsiveness in children with attention-deficit/hyperactivity disorder (ADHD).
Methods
76 Children ages 6-16 years of either sex, with a diagnosis of ADHD, were divided into 4 groups, with a control group and 3 intervention groups. Group 1 (controls) followed their usual diet. Group 2 (Mediterranean diet) adopted a Mediterranean diet according to a series of recommendations. Group 3 (omega-3) received omega-3 fatty acid supplements. Group 4 (Mediterranean diet + omega-3) adopted the same diet as group 2 and also received omega 3 fatty acid supplements.
Dieticians provided a tailored Mediterranean diet for each participant. The Omega-3 supplement comprised of 550mg EPA and 225mg of DHA sourced from deep-sea sardines and anchovies.
The Barratt Impulsiveness Scale (BIS-11c) was administered to every child individually to evaluate impulsiveness. The KIDMED questionnaire was administered to evaluate the participant’s adherence to the Mediterranean diet. The study was conducted over 8 weeks. At the endpoint, 60/76 subjects completed the study.
Results
Primary clinical outcomes were:
- Children in the omega-3 supplement group showed a significant drop in the Barratt Impulsiveness Scale score after the intervention (from 49 to 45.10; p =.049).
- Children in the Mediterranean diet and supplement group showed higher cognitive scores (from 2.758 to 2.631).
Limitation
There was a statistically significant difference between groups for the KIDMED score (a measure of adherence to a Mediterranean diet), reflecting a higher adherence to the Mediterranean diet by the control group.
Clinical practice applications:
- Approximately 20%-40% of patients with ADHD do not respond to pharmacological treatment therefore there is a need for alternative options.
- Based on these findings, a practitioner could therefore consider recommending 550mg of eicosatetraenoic acid (EPA) and 225mg of docosahexaenoic acid (DHA) sourced from deep-sea sardines and anchovies for at least 8 weeks to help reduce impulsiveness and improve cognitive function in patients with a hyperactive-impulsive subtype of ADHD.
Considerations for future research:
- This study included combined types of ADHD therefore further investigations are needed on each type of ADHD using different interventions to establish which intervention works best.
- Assessment of diet and omega status before intervention was not conducted, which may have affected outcomes in this study. Further research could consider gathering this data at baseline.
- Larger studies are also needed to determine the relationship between BIS scores and treatments to deepen our understanding of this topic.
- Conflict of interest statement: This study was fully funded by the manufacturer of the provided Omega 3 supplement.
Abstract
INTRODUCTION The Barratt Impulsiveness Scale (BIS) is a self-administered instrument designed to assess the personality/behavioural construct of impulsiveness. Impulsiveness has been associated with several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). This study assesses the progression of impulsive behaviour in children with ADHD after an 8-week dietary intervention with the Mediterranean diet and/or omega-3 fatty acid supplementation, by using a version of the 11-item BIS adapted for children (BIS-11c). METHODS This cross-sectional study includes 60 children with ADHD from the region of Madrid, Spain. Participants were divided into 4 groups, with one control group and 3 intervention groups (Mediterranean diet; omega-3 supplementation; and Mediterranean diet plus omega-3 supplementation). A personalised Mediterranean diet was designed for members of groups 2 and 4. The BIS-11c was administered to determine the level of impulsiveness, and the KIDMED test was used to assess adherence to the Mediterranean diet. RESULTS The supplementation group showed a fairly significant decrease in the total BIS-11c (P = .049). Total cognitive score slightly decreased in the diet and supplementation groups. Only the control group showed a considerable decrease in the total motor score. Total nonplanning scores were lower in all groups after the intervention. Baseline and final BIS-11c scores were positively correlated with treatments (r > 0.9). CONCLUSION An intake of 550 mg EPA fatty acid and 225 mg DHA fatty acid per day for 8 weeks is associated with less marked impulsive behaviour in children with ADHD. A Mediterranean diet may improve BIS scores, although our results are not conclusive in this population.
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Type 2 diabetes preventive effects with a 12-months sardine-enriched diet in elderly population with prediabetes: An interventional, randomized and controlled trial.
Díaz-Rizzolo, DA, Serra, A, Colungo, C, Sala-Vila, A, Sisó-Almirall, A, Gomis, R
Clinical nutrition (Edinburgh, Scotland). 2021;40(5):2587-2598
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Older people have a higher risk of developing Type 2 diabetes (T2D) due to the possibility of β-cell dysfunction due to ageing. Sardines are believed to be protective against the development of T2D. Therefore, this randomised controlled trial evaluated the preventative effects of a sardine-rich diet in elderly prediabetic patients. For one year, both the sardine group (SG) and control group (CG) followed a T2D prevention diet, with the SG consuming 200 g of sardines each week. Both groups improved body weight, BMI, waist and hip circumference, and body composition. Taurine, EPA, DHA, omega-3 fatty acid, calcium, iodine, zinc, phosphorous and fluoride, vitamin B12 and D, and lycopene and tocopherols were found to be higher in the SG than the CG, indicating the sardines were protective against T2D. In SG, HDL cholesterol and adiponectin levels were significantly increased, and blood pressure and triglycerides were decreased, signalling a reduced risk of T2D and cardiovascular disease. In addition, SG showed a reduction in HOMA-IR and an Omega-3 fatty acid was substituted for Omega-6 fatty acids in the erythrocyte membrane, suggesting a reduced risk of T2D. Further robust research is required to confirm the protective effect of a sardine-enriched diet against T2D. It may be useful to healthcare providers to comprehend how a sardine-enriched diet could improve obesity, T2D and CVD markers in pre-diabetic elderly patients.
Abstract
BACKGROUND Fish could play a role in preventing type 2 diabetes (T2D) but there has been little specification about the type of fish and the preventive mechanism involved in its health claim. The sardine is a source of omega-3 and taurine that, in isolation or in synergy, would produce T2D-delaying through different molecular mechanism. HYPOTHESIS The consumption of twice a week of sardine, during one year would reduce T2D-developing risk in a population with prediabetes (preDM) and old age. DESIGN 152 subjects with fasting glucose between 100-124 mg/dL aged ≥65 yo were recruited from three primary care centers in Barcelona and were randomly distributed among two interventional groups: control group (CG) and sardine group (SG). Both groups received same T2D-prevention nutritional during a year but only SG had to add 200 g of sardine per week. All variables were collected before to start and at the end of the diet. (ClinicalTrials.gov: NCT03557541). RESULTS 152 people were randomized into CG (n=77) and SG (n=75) with 18 and 12 drop outs respectively. Subjects in SG, significantly compared to CG, decreased percentage classified-individuals in a very high risk group to develop T2D according to FINDRISC (p=0.035). In addition to increasing HDL-cholesterol and adiponectin and decreasing triglycerides (p<0.05) and blood pressure (<0.05), SG showed a lower HOMA-IR (p=0.032). The consumption of sardine characteristics nutrients as omega-3, EPA and DHA, vitamin D, fluorine and taurine were higher for SG (p<0.05). These results agreed with the increased of taurine, fatty acid (FA) omega-3 and bile acids circulating metabolites (p<0.05). Changes erythrocyte membrane FA were detected only in SG with a decrease of 5 omega-6 FA (p<0.001) and an increase of 3 omega-3 FA types (p<0.001). CONCLUSION We conclude that a year T2D-prevention diet with sardine supplementation has a greater protective effect against developing T2D and CV events.
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Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial.
Ramsden, CE, Zamora, D, Faurot, KR, MacIntosh, B, Horowitz, M, Keyes, GS, Yuan, ZX, Miller, V, Lynch, C, Honvoh, G, et al
BMJ (Clinical research ed.). 2021;374:n1448
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This study could be of interest to practitioners who are interested in dietary interventions that may decrease the incidence or severity of headaches in women. Omega 3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are believed to be precursors for molecules that may have pain reducing properties. Whereas omega 6 fatty acids such as linoleic acid are believed to be precursors for molecules that may have pain promoting effects. The objective of this 3 armed randomised, double blinded controlled trial was to determine whether increasing dietary intake of omega 3 EPA and DHA, whilst either maintaining or decreasing omega 6 linoleic acid, may lead to a decrease in headache frequency and severity. 182 participants were assigned into one of 3 treatment groups, the first, H3 diet, increasing EPA and DHA to 1.5g/day and maintaining linoleic acid, the second, H3-L6 diet, increasing EPA and DHA to 1.5g/day whilst decreasing linoleic acid and the control group maintaining EPA, DHA and linoleic acid. Both the H3 and H3-L6 diets increased the levels of the molecule believed to be involved in reducing pain to a statistically significant level. This was found to be consistent with the results reported by the patients both in headache hours per day and days with headache in the month. The authors conclude that increasing levels of omega 3 fatty acids in the diet whilst decreasing levels of omega 6 fatty acids in the diet may decrease the frequency and severity of headaches. This study was for 16 weeks and predominantly women with a mean age of 38, further studies for longer and on other populations such as men, children and older populations, would be required to see if the same results could be obtained.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Important from a public health perspective
- Increasing n-3 levels and decreasing n-6 levels could be modified by dietary change and appear to reduce the frequency and duration of headaches in migraine sufferers
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Background
Circulating lipid mediators have been implicated in headache pathogenesis.
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.
Study Design
Three arm, parallel group, randomized, modified double blind, controlled trial.
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 total energy intake
- H3-L6 diet (n=61)—increase n-3 EPA+DHA to 1.5 g/day and decrease linoleic acid to ≤1.8% of total energy intake
- Control diet (n=60)—maintain EPA+DHA at <150 mg/day and linoleic acid at around 7% of total energy intake
All participants received foods accounting for two thirds of daily food energy and 1/3rd from foods not provided by the Research Kitchen. For these foods participants rely on their training by the dietitian and website diet guides for shopping and choosing foods in restaurants. Participants were encouraged to continue seeing their headache physician and continue usual care.
Results
In intention-to-treat analyses (n=182) at 16 weeks
- The H3-L6 and H3 diets increased circulating 17-HDHA 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 (quality of life) 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, suggesting additional benefit from lowering dietary linoleic acid (−2.0, −3.2 to −0.8).
- 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.
Clinical practice applications:
These findings might be useful for Nutritional Therapists and Clinical Practitioners:
- To inform practitioners of the benefits of assessing n-3 and n-6 fatty acids in migraine patients.
- Inform practitioners of the potential benefits to reducing n-6 as well as increasing n-3 levels in migraine patients
- Inform practitioners of the potential lack of correlation between headache duration and frequency and quality of life measures
Considerations for future research:
- Trialing larger doses of n-3
- Longer term follow up whilst maintaining these diets
- Attempting to validate an optimal serum level of 17-HDHA for these patients that could be used in clinical practice
Abstract
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.
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Association between cognitive function and supplementation with omega-3 PUFAs and other nutrients in ≥ 75 years old patients: A randomized multicenter study.
Baleztena, J, Ruiz-Canela, M, Sayon-Orea, C, Pardo, M, Añorbe, T, Gost, JI, Gomez, C, Ilarregui, B, Bes-Rastrollo, M
PloS one. 2018;13(3):e0193568
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Nutrition may play an important role in the prevention of dementia. The aim of this study was to evaluate the effect of a multinutrient supplementation rich in omega-3 fatty acids on the cognitive function of adults aged 75 years and over with either no, or mild, cognitive impairment. Participants were given either a multinutrient capsule (each containing DHA 250 mg, EPA 40 mg, vitamin E 5 mg, phosphatidylserine 15 mg, tryptophan 95 mg, vitamin B 12 5 μg, folate 250 μg and ginkgo biloba 60 mg) or a placebo, three times a day for one year. Supplementation with the multinutrient did not improve overall cognitive function in the group. However, it did result in an improvement in memory in a sub-group of older people who were previously well nourished, but not in those with worse nutritional status.
Abstract
A few studies have assessed the association between omega-3 polyunsaturated fatty acids (n-3 PUFA) and cognitive impairment (CI) in very old adults. The aim of this study was to evaluate the effect of a multinutrient supplementation rich in n-3 PUFA on the cognitive function in an institutionalized ≥75-year-old population without CI or with mild cognitive impairment (MCI). A multicenter placebo-controlled double-blind randomized trial was conducted between 2012 and 2013. Cognitive function was assessed at baseline and after one year using 4 neuropsychological tests. Nutritional status was assessed using Mini Nutritional Assessment (MNA). Interaction between Mini-Mental State Examination (MMSE) score and nutritional status were analyzed using linear regression models. A total of 99 participants were randomized to receive placebo or pills rich in n-3 PUFA. After 1-year follow-up, both groups decreased their MMSE score (-1.18, SD:0. 53 and -0.82, SD:0. 63, p = 0.67 for the control and the intervention group respectively). The memory subscale of the MMSE showed an improvement (+0.26, SD:0.18) in the intervention group against a worsening in the control group (-0.11, SD: 0.14; p = 0.09 for differences between groups). Patients at intervention group with normal nutritional status (MNA ≥24) showed an improvement in the MMSE (+1.03, p = 0.025 for differences between 1-y and baseline measurements) against a worsening in the group with malnutrition (MNA<24) (-0.4, p = 0.886 for differences between 1-y and baseline; p of interaction p = 0.05). Supplementation with n-3 PUFA did not show an improvement in the global cognitive function in institutionalized elderly people without CI or with MCI. They only suggest an apparent improvement in memory loss if previously they were well nourished.
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Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.
Rapaport, MH, Nierenberg, AA, Schettler, PJ, Kinkead, B, Cardoos, A, Walker, R, Mischoulon, D
Molecular psychiatry. 2016;21(1):71-9
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This study investigated whether Omega 3 (n-3) fatty acids had a clinical effect on five inflammatory biomarkers on individuals diagnosed with Major Depressive Disorder (MDD). Individuals were randomised into 3 groups, each of which took 8 weeks of double blind treatment with either eicosapentaenoic acid enriched n-3 fatty acids (EPA), docosahexaenoic acid enriched n-3 fatty acids (DHA), or placebo. There were no significant differences in the outcomes of the groups. However, it was noted that individuals with higher levels of inflammatory markers who took EPA improved more than those on placebo, and less on DHA than placebo. he larger the number of high inflammatory markers, the wider the gap between the improvements of the EPA versus placebo. Individuals with high hs-CRP, IL-6 or leptin responded less well to placebo than those with lower levels of these biomarkers. EPA was less effective than placebo or DHA if subjects had low levels of all 5 biomarkers. The five biomarkers were strongly influenced by gender and weight. The majority of obese women and men had at least one high marker of inflammation, and many of these had 2 high markers. There was no difference in treatment patterns for men and women. This is consistent with literature that suggests that inflammation is associated with obesity. Results suggest that it is important to look at more than one marker of inflammation, and that subjects with a specific combination inflammation markers were more likely to respond to EPA treatment. The authors concluded that anti-inflammation therapy was only beneficial for those with inflammation related MDD, and not helpful and possibly harmful for those with physiologically derived MDD.
Abstract
This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾ 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.
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Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment.
Oulhaj, A, Jernerén, F, Refsum, H, Smith, AD, de Jager, CA
Journal of Alzheimer's disease : JAD. 2016;50(2):547-57
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Many studies are exploring preventative measures to delay or prevent mild cognitive impairment (MCI) and Alzheimer’s disease. A recent trial (VITACOG) demonstrated that omega-3 fatty acid status enhances the protective effects of B-vitamins on brain atrophy. The present study uses the VITACOG data to investigate whether there is an association on cognitive function. This study revealed that a higher baseline omega-3 fatty acid status enhances the beneficial effects of B vitamins on both brain atrophy and cognitive decline. The authors conclude that this interaction may slow down the disease process in MCI and warrants further clinical trials investigating this relationship.
Abstract
A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.
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Supplementation with B vitamins or n-3 fatty acids and depressive symptoms in cardiovascular disease survivors: ancillary findings from the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) randomized trial.
Andreeva, VA, Galan, P, Torrès, M, Julia, C, Hercberg, S, Kesse-Guyot, E
The American journal of clinical nutrition. 2012;96(1):208-14
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Depression is associated with poorer outcomes in people with heart disease. Substantial evidence suggests a link between dietary factors and mental health. The objective of this study was to examine the effects of supplementation with B vitamins or omega-3 (n-3) fatty acids on depressive symptoms in people with heart disease. Adults aged 45-80 years with cardiovascular disease were randomly assigned to receive 0.56mg folate (as 5-methyl-tetrahydrofolate), 3mg vitamin B6 and 0.02mg vitamin B12 ; 600mg EPA and DHA (in a 2:1 ratio); B vitamins plus n-3 fatty acids; or a placebo. Depressive symptoms were measured at years 3 and 5 using the Geriatric Depression Scale. There was no association between supplementation with B vitamins and depressive symptoms. However, men who took n-3 fatty acid supplements had a 28% higher risk of experiencing symptoms of depression. There was no such association observed in women. The authors concluded that the results of the study do not support the use of B vitamin or n-3 supplements for the prevention of depression in CVD survivors.
Abstract
BACKGROUND Dietary factors might affect depressive symptoms. OBJECTIVE In secondary data analyses, we examined effects of supplementation with B vitamins or n-3 (omega-3) fatty acids on depressive symptoms in cardiovascular disease survivors. DESIGN The SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) trial was a secondary prevention trial (2003-2009; n = 2501) in which individuals aged 45-80 y were randomly assigned, by using a 2 × 2 factorial design, to receive 0.56 mg 5-methyl-tetrahydrofolate and vitamins B-6 (3 mg) and B-12 (0.02 mg); EPA and DHA (600 mg) in a 2:1 ratio; B vitamins and n-3 fatty acids; or a placebo. Depressive symptoms were evaluated at years 3 and 5 with the 30-item Geriatric Depression Scale (GDS). Overall and sex-specific ORs and 95% CIs were estimated in 2000 participants by using factorial logistic regression. RESULTS After a median of 4.7 y of supplementation, there was no association between allocation to receive B vitamins and depressive symptoms. However, the allocation to receive n-3 fatty acids was positively associated with depressive symptoms (GDS >10) in men (adjusted OR: 1.28; 95% CI: 1.03, 1.61) but not in women. CONCLUSIONS We showed no beneficial effects of a long-term, low-dose supplementation with B vitamins or n-3 fatty acids on depressive symptoms in cardiovascular disease survivors. The adverse effects of n-3 fatty acids in men merit confirmation.