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The effects of low-ratio n-6/n-3 PUFA on biomarkers of inflammation: a systematic review and meta-analysis.
Wei, Y, Meng, Y, Li, N, Wang, Q, Chen, L
Food & function. 2021;(1):30-40
Abstract
OBJECTIVE The purpose of the systematic review and meta-analysis was to determine if low-ratio n-6/n-3 long-chain polyunsaturated fatty acid (PUFA) supplementation affects serum inflammation markers based on the current studies. METHODS PubMed, Embase and The Cochrane library databases were systematically searched to find randomized controlled trials (RCTs) on the effect of low-ratio n-6/n-3 PUFA intervention on inflammation markers up to July 2020. Data were pooled using standardized mean difference (SMD) and 95% confidence intervals (95% CI), with P value ≦ 0.05 as statistical significance. RESULTS Thirty-one RCTs were included in the meta-analysis. The analysis indicated that increasing low-ratio n-6/n-3 PUFA supplementation decreased the level of tumor necrosis factor-α (TNF-α) (SMD = -0.270; 95% CI: -0.433, -0.106; P = 0.001) and interleukin 6 (IL-6) (SMD = -0.153; 95% CI: -0.260, -0.045; P = 0.005). There were no significant effects on C-reactive protein (CRP) (SMD = -0.027; 95% CI: -0.189: 0.135; P = 0.741). Subgroup analysis indicated that there was a significant reduction in TNF-α serum concentration in subjects from Asia (SMD: -0.367; 95% CI: -0.579, -0.155; P = 0.001) and in subjects with diseases (SMD: -0.281; 95% CI: -0.436, -0.127; P < 0.001). In the subgroup of the n-6/n-3 ratio ≦5, low-ratio n-6/n-3 PUFA supplementation could decrease the level of TNF-α (SMD: -0.335; 95% CI: -0.552, -0.119; P = 0.002). Serum IL-6 decreased significantly in patients from the Europe subgroup (SMD: -0.451; 95% CI: -0.688, -0.214; P < 0.001), but not in Asia (SMD: -0.034; 95% CI: -0.226, 0.157; P = 0.724), North America (SMD: -0.115; 95% CI: -0.274, 0.044; P = 0.157) and Oceania (SMD: 0.142; 95% CI: -0.557, 0.842; P = 0.690). CONCLUSION Low-ratio n-6/n-3 PUFA supplementation could decrease significantly the concentration of serum TNF-α and IL-6, but not decrease CRP concentration.
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Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomised trials.
Hanson, S, Thorpe, G, Winstanley, L, Abdelhamid, AS, Hooper, L, ,
British journal of cancer. 2020;(8):1260-1270
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BACKGROUND The relationship between long-chain omega-3 (LCn3), alpha-linolenic acid (ALA), omega-6 and total polyunsaturated fatty acid (PUFA) intakes and cancer risk is unclear. METHODS We searched Medline, Embase, CENTRAL and trials registries for RCTs comparing higher with lower LCn3, ALA, omega-6 and/or total PUFA, that assessed cancers over ≥12 months. Random-effects meta-analyses, sensitivity analyses, subgrouping, risk of bias and GRADE were used. RESULTS We included 47 RCTs (108,194 participants). Increasing LCn3 has little or no effect on cancer diagnosis (RR1.02, 95% CI 0.98-1.07), cancer death (RR0.97, 95% CI 0.90-1.06) or breast cancer diagnosis (RR1.03, 95% CI 0.89-1.20); increasing ALA has little or no effect on cancer death (all high/moderate-quality evidence). Increasing LCn3 (NNTH 334, RR1.10, 95% CI 0.97-1.24) and ALA (NNTH 334, RR1.30, 95% CI 0.72-2.32) may slightly increase prostate cancer risk; increasing total PUFA may slightly increase risk of cancer diagnosis (NNTH 125, RR1.19, 95% CI 0.99-1.42) and cancer death (NNTH 500, RR1.10, 95% CI 0.48-2.49) but total PUFA doses were very high in some trials. CONCLUSIONS The most extensive systematic review to assess the effects of increasing PUFAs on cancer risk found increasing total PUFA may very slightly increase cancer risk, offset by small protective effects on cardiovascular diseases.
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Intake of polyunsaturated fatty acids and risk of preclinical and clinical type 1 diabetes in children-a systematic review and meta-analysis.
Liu, X, Zhang, Y, Wu, H, Zhu, P, Mo, X, Ma, X, Ying, J
European journal of clinical nutrition. 2019;(1):1-8
Abstract
BACKGROUND/OBJECTIVES The association between the intake of polyunsaturated fatty acids (PUFAs) and the risk of preclinical and clinical type 1 diabetes (T1D) in children has generated conflicting results. Thus, we aimed to evaluate the definite effects of PUFAs on the risk of preclinical and clinical T1D. SUBJECTS/METHODS Three databases were systematically searched up to July 18, 2017 to identify relevant observational studies, without language restriction. Any study included should report the risk of preclinical or clinical T1D in children with PUFAs supplementation compared with the controls, and report relative risks (RRs) or odds ratios (ORs) or provide data for estimation. Pooled RRs (or ORs) with 95% confidence intervals (CI) were calculated using random-effects models irrespective of statistical heterogeneity assessed by I2 statistic. RESULTS We identified seven studies (three prospective cohort studies and four case-control studies) on PUFAs intake during pregnancy or during early life in children. The pooled RR between the risk of preclinical T1D and n-3 PUFAs supplementation against controls was 0.98 (95%CI, 0.85-1.13), with no heterogeneity. The results were similar after the intake during pregnancy, but not during early life in children (pooled RR, 0.45; 95%CI, 0.21-0.96; P = 0.039). N-3 PUFAs supplementation was not associated with a significant reduction in the risk of clinical T1D in children (pooled RR, 0.87; 95%CI, 0.71-1.08), with substantial heterogeneity(I2 = 64.7%). No association was also found between n-6 PUFAs intake and the risk of preclinical (1.07; 0.97-1.017) or clinical T1D (1.05; 0.92-1.20) in children. CONCLUSIONS The result of the meta-analysis does not support that n-3 or n-6 PUFAs supplementation in children affects the overall risk of preclinical or clinical T1D. However, n-3 PUFAs intake in early life might reduce the risk of preclinical T1D. Therefore, this finding should be verified by more and well-designed prospective research in the future.
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The Relationship Between Omega-3, Omega-6 and Total Polyunsaturated Fat and Musculoskeletal Health and Functional Status in Adults: A Systematic Review and Meta-analysis of RCTs.
Abdelhamid, A, Hooper, L, Sivakaran, R, Hayhoe, RPG, Welch, A, ,
Calcified tissue international. 2019;(4):353-372
Abstract
We conducted a systematic review and meta-analysis to assess the effects of increasing dietary omega-3, omega-6 and mixed polyunsaturated fatty acids (PUFA) on musculoskeletal health, functional status, sarcopenia and risk of fractures. We searched Medline, Embase, The Cochrane library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) databases for Randomised Controlled Trials (RCTs) of adults evaluating the effects of higher versus lower oral omega-3, omega-6 or mixed PUFA for ≥ 6 months on musculoskeletal and functional outcomes. We included 28 RCTs (7288 participants, 31 comparisons), 23 reported effects of omega-3, one of omega-6 and four of mixed total PUFA. Participants and doses were heterogeneous. Six omega-3 trials were judged at low summary risk of bias. We found low-quality evidence that increasing omega-3 increased lumbar spine BMD by 2.6% (0.03 g/cm2, 95% CI - 0.02 to 0.07, 463 participants). There was also the suggestion of an increase in femoral neck BMD (of 4.1%), but the evidence was of very low quality. There may be little or no effect of omega-3 on functional outcomes and bone mass; effects on other outcomes were unclear. Only one study reported on effects of omega-6 with very limited data. Increasing total PUFA had little or no effect on BMD or indices of fat-free (skeletal) muscle mass (low-quality evidence); no data were available on fractures, BMD or functional status and data on bone turnover markers were limited. Trials assessing effects of increasing omega-3, omega-6 and total PUFA on functional status, bone and skeletal muscle strength are limited with data lacking or of low quality. Whilst there is an indication that omega-3 may improve BMD, high-quality RCTs are needed to confirm this and effects on other musculoskeletal outcomes.
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Association of Dietary Intake Ratio of n-3/n-6 Polyunsaturated Fatty Acids with Breast Cancer Risk in Western and Asian Countries: A Meta-Analysis.
Nindrea, RD, Aryandono, T, Lazuardi, L, Dwiprahasto, I
Asian Pacific journal of cancer prevention : APJCP. 2019;(5):1321-1327
Abstract
Objective: This systematic review and meta-analysis were performed to determine association of dietary intake ratio of n-3/n-6 polyunsaturated fatty acids with breast cancer risk in Western and Asian countries. Methods: The authors conducted a meta-analysis of published research articles on association of dietary intake ratio of n-3/n-6 polyunsaturated fatty acids (PUFAs) with breast cancer risk in Western and Asian countries published between January 2000 and February 2019 in online article databases of PubMed, ProQuest and EBSCO. Pooled risk ratios (RR) were calculated using fixed and random-effect models. Publication bias was visually evaluated by performing funnel plots and statistically assessed by Egger’s and Begg’s tests. Data were processed by using Stata version 14.2 (Stata Corporation). Results: This study reviewed 913 articles. There were 13 studies included in systematic review continued by meta-analysis of relevant data with total number of samples: 275,264 patients. The results showed dietary intake ratio of n-3/n-6 PUFAs with breast cancer risk in Western and Asian countries (RR = 0.99; 95% CI: 0.92-1.07). Dietary intake ratio of n-3/n-6 PUFAs with breast cancer risk in Western countries reached (RR = 0.98; 95% CI: 0.91-1.06) and there was any significant publication bias for studies included. Dietary intake ratio of n-3/n-6 PUFAs with breast cancer risk in Asian countries reached (RR = 1.18; 95% CI: 0.94-1.47) and there was not any significant publication bias for studies included. Conclusion: This analysis confirmed association of dietary intake ratio of n-3/n-6 PUFAs with breast cancer risk in Western and Asian countries. Higher dietary intake ratio is associated with lower risk of breast cancer in Asian countries rather than Western countries. This study suggests increasing dietary intake ratio n-3/n-6 PUFAs will provide benefit for breast cancer prevention.
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Omega-6 fats for the primary and secondary prevention of cardiovascular disease.
Hooper, L, Al-Khudairy, L, Abdelhamid, AS, Rees, K, Brainard, JS, Brown, TJ, Ajabnoor, SM, O'Brien, AT, Winstanley, LE, Donaldson, DH, et al
The Cochrane database of systematic reviews. 2018;(11):CD011094
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BACKGROUND Omega-6 fats are polyunsaturated fats vital for many physiological functions, but their effect on cardiovascular disease (CVD) risk is debated. OBJECTIVES To assess effects of increasing omega-6 fats (linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA)) on CVD and all-cause mortality. SEARCH METHODS We searched CENTRAL, MEDLINE and Embase to May 2017 and clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to September 2016, without language restrictions. We checked trials included in relevant systematic reviews. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing higher versus lower omega-6 fat intake in adults with or without CVD, assessing effects over at least 12 months. We included full texts, abstracts, trials registry entries and unpublished studies. Outcomes were all-cause mortality, CVD mortality, CVD events, risk factors (blood lipids, adiposity, blood pressure), and potential adverse events. We excluded trials where we could not separate omega-6 fat effects from those of other dietary, lifestyle or medication interventions. DATA COLLECTION AND ANALYSIS Two authors independently screened titles/abstracts, assessed trials for inclusion, extracted data, and assessed risk of bias of included trials. We wrote to authors of included studies. Meta-analyses used random-effects analysis, while sensitivity analyses used fixed-effects and limited analyses to trials at low summary risk of bias. We assessed GRADE quality of evidence for 'Summary of findings' tables. MAIN RESULTS We included 19 RCTs in 6461 participants who were followed for one to eight years. Seven trials assessed the effects of supplemental GLA and 12 of LA, none DGLA or AA; the omega-6 fats usually displaced dietary saturated or monounsaturated fats. We assessed three RCTs as being at low summary risk of bias.Primary outcomes: we found low-quality evidence that increased intake of omega-6 fats may make little or no difference to all-cause mortality (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.12, 740 deaths, 4506 randomised, 10 trials) or CVD events (RR 0.97, 95% CI 0.81 to 1.15, 1404 people experienced events of 4962 randomised, 7 trials). We are uncertain whether increasing omega-6 fats affects CVD mortality (RR 1.09, 95% CI 0.76 to 1.55, 472 deaths, 4019 randomised, 7 trials), coronary heart disease events (RR 0.88, 95% CI 0.66 to 1.17, 1059 people with events of 3997 randomised, 7 trials), major adverse cardiac and cerebrovascular events (RR 0.84, 95% CI 0.59 to 1.20, 817 events, 2879 participants, 2 trials) or stroke (RR 1.36, 95% CI 0.45 to 4.11, 54 events, 3730 participants, 4 trials), as we assessed the evidence as being of very low quality. We found no evidence of dose-response or duration effects for any primary outcome, but there was a suggestion of greater protection in participants with lower baseline omega-6 intake across outcomes.Additional key outcomes: we found increased intake of omega-6 fats may reduce myocardial infarction (MI) risk (RR 0.88, 95% CI 0.76 to 1.02, 609 events, 4606 participants, 7 trials, low-quality evidence). High-quality evidence suggests increasing omega-6 fats reduces total serum cholesterol a little in the long term (mean difference (MD) -0.33 mmol/L, 95% CI -0.50 to -0.16, I2 = 81%; heterogeneity partially explained by dose, 4280 participants, 10 trials). Increasing omega-6 fats probably has little or no effect on adiposity (body mass index (BMI) MD -0.20 kg/m2, 95% CI -0.56 to 0.16, 371 participants, 1 trial, moderate-quality evidence). It may make little or no difference to serum triglycerides (MD -0.01 mmol/L, 95% CI -0.23 to 0.21, 834 participants, 5 trials), HDL (MD -0.01 mmol/L, 95% CI -0.03 to 0.02, 1995 participants, 4 trials) or low-density lipoprotein (MD -0.04 mmol/L, 95% CI -0.21 to 0.14, 244 participants, 2 trials, low-quality evidence). AUTHORS' CONCLUSIONS This is the most extensive systematic assessment of effects of omega-6 fats on cardiovascular health, mortality, lipids and adiposity to date, using previously unpublished data. We found no evidence that increasing omega-6 fats reduces cardiovascular outcomes other than MI, where 53 people may need to increase omega-6 fat intake to prevent 1 person from experiencing MI. Although benefits of omega-6 fats remain to be proven, increasing omega-6 fats may be of benefit in people at high risk of MI. Increased omega-6 fats reduce serum total cholesterol but not other blood fat fractions or adiposity.
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Omega-6 fatty acid biomarkers and incident type 2 diabetes: pooled analysis of individual-level data for 39 740 adults from 20 prospective cohort studies.
Wu, JHY, Marklund, M, Imamura, F, Tintle, N, Ardisson Korat, AV, de Goede, J, Zhou, X, Yang, WS, de Oliveira Otto, MC, Kröger, J, et al
The lancet. Diabetes & endocrinology. 2017;(12):965-974
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BACKGROUND The metabolic effects of omega-6 polyunsaturated fatty acids (PUFAs) remain contentious, and little evidence is available regarding their potential role in primary prevention of type 2 diabetes. We aimed to assess the associations of linoleic acid and arachidonic acid biomarkers with incident type 2 diabetes. METHODS We did a pooled analysis of new, harmonised, individual-level analyses for the biomarkers linoleic acid and its metabolite arachidonic acid and incident type 2 diabetes. We analysed data from 20 prospective cohort studies from ten countries (Iceland, the Netherlands, the USA, Taiwan, the UK, Germany, Finland, Australia, Sweden, and France), with biomarkers sampled between 1970 and 2010. Participants included in the analyses were aged 18 years or older and had data available for linoleic acid and arachidonic acid biomarkers at baseline. We excluded participants with type 2 diabetes at baseline. The main outcome was the association between omega-6 PUFA biomarkers and incident type 2 diabetes. We assessed the relative risk of type 2 diabetes prospectively for each cohort and lipid compartment separately using a prespecified analytic plan for exposures, covariates, effect modifiers, and analysis, and the findings were then pooled using inverse-variance weighted meta-analysis. FINDINGS Participants were 39 740 adults, aged (range of cohort means) 49-76 years with a BMI (range of cohort means) of 23·3-28·4 kg/m2, who did not have type 2 diabetes at baseline. During a follow-up of 366 073 person-years, we identified 4347 cases of incident type 2 diabetes. In multivariable-adjusted pooled analyses, higher proportions of linoleic acid biomarkers as percentages of total fatty acid were associated with a lower risk of type 2 diabetes overall (risk ratio [RR] per interquintile range 0·65, 95% CI 0·60-0·72, p<0·0001; I2=53·9%, pheterogeneity=0·002). The associations between linoleic acid biomarkers and type 2 diabetes were generally similar in different lipid compartments, including phospholipids, plasma, cholesterol esters, and adipose tissue. Levels of arachidonic acid biomarker were not significantly associated with type 2 diabetes risk overall (RR per interquintile range 0·96, 95% CI 0·88-1·05; p=0·38; I2=63·0%, pheterogeneity<0·0001). The associations between linoleic acid and arachidonic acid biomarkers and the risk of type 2 diabetes were not significantly modified by any prespecified potential sources of heterogeneity (ie, age, BMI, sex, race, aspirin use, omega-3 PUFA levels, or variants of the FADS gene; all pheterogeneity≥0·13). INTERPRETATION Findings suggest that linoleic acid has long-term benefits for the prevention of type 2 diabetes and that arachidonic acid is not harmful. FUNDING Funders are shown in the appendix.
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Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.
Guan, W, Steffen, BT, Lemaitre, RN, Wu, JHY, Tanaka, T, Manichaikul, A, Foy, M, Rich, SS, Wang, L, Nettleton, JA, et al
Circulation. Cardiovascular genetics. 2014;(3):321-331
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BACKGROUND Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs. METHODS AND RESULTS To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1×10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2×10(-15), 5.0×10(-11), 7.6×10(-65), and 2.4×10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1×10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3×10(-72), 2.6×10(-151), and 6.3×10(-140), respectively). CONCLUSIONS Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.
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Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial.
Brasky, TM, Darke, AK, Song, X, Tangen, CM, Goodman, PJ, Thompson, IM, Meyskens, FL, Goodman, GE, Minasian, LM, Parnes, HL, et al
Journal of the National Cancer Institute. 2013;(15):1132-41
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BACKGROUND Studies of dietary ω-3 fatty acid intake and prostate cancer risk are inconsistent; however, recent large prospective studies have found increased risk of prostate cancer among men with high blood concentrations of long-chain ω-3 polyunsaturated fatty acids ([LCω-3PUFA] 20:5ω3; 22:5ω3; 22:6ω3]. This case-cohort study examines associations between plasma phospholipid fatty acids and prostate cancer risk among participants in the Selenium and Vitamin E Cancer Prevention Trial. METHODS Case subjects were 834 men diagnosed with prostate cancer, of which 156 had high-grade cancer. The subcohort consisted of 1393 men selected randomly at baseline and from within strata frequency matched to case subjects on age and race. Proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for associations between fatty acids and prostate cancer risk overall and by grade. All statistical tests were two-sided. RESULTS Compared with men in the lowest quartiles of LCω-3PUFA, men in the highest quartile had increased risks for low-grade (HR = 1.44, 95% CI = 1.08 to 1.93), high-grade (HR = 1.71, 95% CI = 1.00 to 2.94), and total prostate cancer (HR = 1.43, 95% CI = 1.09 to 1.88). Associations were similar for individual long-chain ω-3 fatty acids. Higher linoleic acid (ω-6) was associated with reduced risks of low-grade (HR = 0.75, 95% CI = 0.56 to 0.99) and total prostate cancer (HR = 0.77, 95% CI = 0.59 to 1.01); however, there was no dose response. CONCLUSIONS This study confirms previous reports of increased prostate cancer risk among men with high blood concentrations of LCω-3PUFA. The consistency of these findings suggests that these fatty acids are involved in prostate tumorigenesis. Recommendations to increase LCω-3PUFA intake should consider its potential risks.
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Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents.
Gillies, D, Sinn, JKh, Lad, SS, Leach, MJ, Ross, MJ
The Cochrane database of systematic reviews. 2012;(7):CD007986
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BACKGROUND Attention deficit hyperactivity disorder (ADHD) is a major problem in children and adolescents, characterised by age-inappropriate levels of inattention, hyperactivity and impulsivity, and is associated with long-term social, academic and mental health problems. The stimulant medications methylphenidate and amphetamine are the most frequently used treatments for ADHD, but these are not always effective and can be associated with side effects. Clinical and biochemical evidence suggests that deficiencies of polyunsaturated fatty acids (PUFA) could be related to ADHD. Children and adolescents with ADHD have been shown to have significantly lower plasma and blood concentrations of PUFA and, in particular, lower levels of omega-3 PUFA. These findings suggest that PUFA supplementation may reduce the attention and behaviour problems associated with ADHD. OBJECTIVES To compare the efficacy of PUFA to other forms of treatment or placebo in treating the symptoms of ADHD in children and adolescents. SEARCH METHODS We searched the following databases in August 2011: CENTRAL (The Cochrane Library 2011, Issue 2), MEDLINE (1948 to July Week 3, 2011), EMBASE (1980 to 2011 Week 29), PsycINFO (1806 to current), CINAHL (1937 to current), BIOSIS (1969 to 30 July 2011), Science Citation Index (1970 to 30 July 2011), Social Science Citation Index (1970 to 30 July 2011), Conference Proceedings Citation Index - Science (1990 to 30 July 2011), Conference Proceedings Citation Index - Social Science and Humanities (1990 to 30 July 2011), Cochrane Database of Systematic Reviews (2011, Issue 7), DARE (2011 Issue 2), Dissertation Abstracts (via Dissertation Express) and the metaRegister of Controlled Trials (mRCT). In addition, we searched the following repositories for theses on 2 August 2011: DART, NTLTD and TROVE. We also checked reference lists of relevant studies and reviews for additional references. SELECTION CRITERIA Two review authors independently assessed the results of the database searches. We resolved any disagreements regarding the selection of studies through consensus or, if necessary, by consultation with a third member of the review team. DATA COLLECTION AND ANALYSIS Two members of the review team independently extracted details of participants and setting, interventions, methodology and outcome data. If differences were identified, we resolved them by consensus or referral to a third member of the team. We made all reasonable attempts to contact the authors where further clarification or missing data were needed. MAIN RESULTS We included 13 trials with 1011 participants in the review. After screening 366 references, we considered 23 relevant and obtained the full text for consideration. We excluded five papers and included 18 papers describing the 13 trials. Eight of the included trials had a parallel design: five compared an omega-3 PUFA supplement to placebo; two compared a combined omega-3 and omega-6 supplement to placebo, and one compared an omega-3 PUFA to a dietary supplement. Five of the included trials had a cross-over design: two compared combined omega-3/6 PUFA to placebo; two compared omega-6 PUFA with placebo; one compared omega-3 to omega-6 PUFA, and one compared omega-6 PUFA to dexamphetamine. Supplements were given for a period of between four and 16 weeks.There was a significantly higher likelihood of improvement in the group receiving omega-3/6 PUFA compared to placebo (two trials, 97 participants; risk ratio (RR) 2.19, 95% confidence interval (CI) 1.04 to 4.62). However, there were no statistically significant differences in parent-rated ADHD symptoms (five trials, 413 participants; standardised mean difference (SMD) -0.17, 95% CI -0.38 to 0.03); inattention (six trials, 469 participants; SMD -0.04, 95% CI -0.29 to 0.21) or hyperactivity/impulsivity (five trials, 416 participants; SMD -0.04, 95% CI -0.25 to 0.16) when all participants receiving PUFA supplements were compared to those receiving placebo.There were no statistically significant differences in teacher ratings of overall ADHD symptoms (four trials, 324 participants; SMD 0.05, 95% CI -0.18 to 0.27); inattention (three trials, 260 participants; SMD 0.26, 95% CI -0.22 to 0.74) or hyperactivity/impulsivity (three trials, 259 participants; SMD 0.10, 95% CI -0.16 to 0.35).There were also no differences between groups in behaviour, side effects or loss to follow-up.Overall, there were no other differences between groups for any other comparison. AUTHORS' CONCLUSIONS Overall, there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents. The majority of data showed no benefit of PUFA supplementation, although there were some limited data that did show an improvement with combined omega-3 and omega-6 supplementation.It is important that future research addresses current weaknesses in this area, which include small sample sizes, variability of selection criteria, variability of the type and dosage of supplementation, short follow-up times and other methodological weaknesses.