Ingredient review —Omega-3 fatty acids (EPA/DHA)
What is it?
Description
Omega-3 fatty acids are polyunsaturated fatty acids that possess lipid-mediating and anti-inflammatory properties, and are essential for human health. (158) Two of the most important omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA found in supplements are most commonly derived from the livers of lean fish such as cod, and in the tissue of oily fish, including herring, mackerel, salmon, sardines, and tuna. (54) However, EPA and DHA are actually synthesized by the algae that are consumed by fish, not the fish themselves. A variety of supplements now exist, providing EPA and DHA from fish, algal, and other sources, though fish oils are predominantly used. (158)
General daily recommendations for omega-3s include the consumption of at least 1,000 mg total per day, providing a minimum combined sum of 250 mg of EPA and DHA. (139)(400) Most Americans do not typically meet current general dietary guidelines, even with supplementation. (278) EPA and DHA are believed to provide broad cardiovascular and neurological benefits, though their positive effects for clinical improvement in various conditions remain controversial. (351)
Not be confused with: Alpha-linolenic acid (a separate omega-3 fatty acid found in plant-foods)
Main uses
Cardiometabolic disorders
Cognitive function and maintenance
Inflammatory/pain disorders
Neurological disorders
Prenatal and offspring health/development
Prevention of cardiovascular surgical complications
Psychological disorders
Renal disorders
Formulations
EPA/DHA source
Characteristics & bioavailability
Algal oil
Krill oil
Natural fish oils
Processed fish oils
Fish oils manufactured to EPA/DHA concentrates, either as ethyl ester-bound fish oils or re-esterified TGs (73)
Ethyl ester-bound fish oils bind ethanol to the free fatty acids of fish oils by removing their glycerol backbone (73)
Re-esterified TGs reconnect free fatty acids back to glycerol after ethyl esterification to re-promote absorption/metabolism (73)
Relative order of highest to lowest bioavailability
Dosing & administration
Allergic disease development (prenatal)
General outcomes from A-level evidence
cord blood IL-13, and the risk/severity of atopic dermatitis, hay fever, asthma, and food allergies (e.g., egg or peanut) in infants during the first year of life, with possible extension to adolescence when consumed during pregnancy (45)(146)(200)(207)(246)(357)
Note: some evidence conflicts with regards to the use of omega-3s for the primary prevention of allergic disease or sensitization (17)
Dosing & administration
4,000 mg (with ~ 1,100-1,600 mg EPA/ 920-2,250 mg DHA) per day from 20-25 weeks gestation until delivery to pregnant women with optional continuation for 3-4 months during breastfeeding
Outcomes
prevalence/odds of food allergy by one year of age, severity of atopic dermatitis, IgE-associated disease by the age of two, risk of asthma by the age of 16, probability of needing prescription medications for asthma or allergic rhinitis by the age of 18, neonatal Th2:Th1 ratio, IL-10 response to cats, neutrophil LTB4 production (with lower IL-6 and IL-10 response), prostaglandin E2, & oxidative stress (F2-isoprostanes)
Class of evidence
b
Dosing & administration
1,500 mg (with 100-1,060 mg EPA/ 275-800 mg DHA) per day from 12-21 weeks gestation until delivery to pregnant women
Outcomes
relative risk of developing atopic dermatitis or sensitization to egg (~39%) within the first year of life, and for house dust mite (33%) by the age of six
Class of evidence
b
Alzheimer’s disease (AD)
Dosing & administration
4,000 mg (with 600 mg EPA/ 1,600 mg DHA) per day for six months to older adults
Outcomes
rate of decline in Mini-Mental State Examination score in Px with very mild cognitive dysfunction, and agitation & depression scores in Px with APOE-⍵4 genotype
global DNA hypomethylation
Class of evidence
b
Angioplasty
General outcomes from A-level evidence
Dosing & administration
6,000-15,000 mg (with 2,700-3,000 mg EPA/ 1,800-2,100 mg DHA as ethyl esters) in three divided doses per day for 3-4 weeks before and after coronary angioplasty with conventional antiplatelet regimen, with a 50% reduction in dose for six months post-intervention
Class of evidence
b
Dosing & administration
1,000 mg (with 460 mg EPA/ 380 mg DHA as ethyl esters) per day for one month after coronary angiography during standard therapy
Outcomes
flow-mediated dilation, asymmetric dimethylarginine, pores in the fibrin network, & susceptibility to fibrinolysis
Class of evidence
b
Dosing & administration
3,200 mg (EPA) per day for one week before coronary angioplasty with conventional antiplatelet regimen, and for six months post-angioplasty
Outcomes
rate of restenosis per vessel & per patient by ~20-27% (92)
Class of evidence
c
Asthma
Dosing & administration
4,000 mg (with 1,280 mg EPA/ 920 mg DHA as Pikasol™) per day from 30 weeks gestation until delivery to pregnant women
Outcomes
Class of evidence
b
Dosing & administration
4,000 mg (with 1,320 mg EPA/ 888 mg DHA bound to TGs as Incromega™ TG3322) per day from 24 weeks gestation until 1 week post-delivery to pregnant women
Outcomes
rate of persistent wheeze or asthma in offspring (31%), risk of lower respiratory tract infections (25%) by the age of 3 (48)
Class of evidence
b
Dosing & administration
1,000 mg (as EPA/DHA) per day for nine months to adults with asthma
Outcomes
FEV1 by 23% (104)
Class of evidence
c
Dosing & administration
20,000 mg (with 3,200 mg EPA/ 2,000 mg DHA bound to TGs) per day for three weeks to patients (Px) with bronchial asthma
Outcomes
pulmonary function, & LTB5
LTC4-LTE4, PGD2, IL-1β, TNF-ɑ, LTB4, & need for bronchodilators (243)
Class of evidence
c
Dosing & administration
1,800-3,600 mg (with 504-1,008 mg EPA/ 216-532 mg DHA; dosages of EPA and DHA were 17.0-26.8 and 7.3-11.5 mg.kg of bodyweight, respectively) per day for 10 months to children with bronchial asthma
Outcomes
asthma symptom scores and reactivity to acetylcholine (264)
Class of evidence
c
Athletic performance
General outcomes from A-level evidence
Some evidence exists for benefits on reaction time, mood, cardiovascular effects (in cyclists), muscle recovery, post-exercise nitric oxide responses, and TNF-α; however, there is inconsistent evidence for endurance performance, pulmonary function, muscle performance, and training adaptation (218)
Dosing & administration
1,800-2,400 mg (with 600 mg EPA/ 260 mg DHA) per day for eight weeks prior to exercise and one-week post exercise to healthy untrained adults
Outcomes
Class of evidence
b
Dosing & administration
2,000-8,000 mg (with 140-3,000 mg EPA/ 560-2,400 mg DHA) per day for eight weeks to cyclists
Outcomes
Class of evidence
b
Dosing & administration
1,546 mg (with 551 mg EPA/ 551 mg DHA) in protein supplement per day for five weeks during pre-season training to professional rugby athletes
Outcomes
muscle soreness & fatigue, providing improved maintenance of muscular power (49)
Class of evidence
c
Dosing & administration
5,000-9,000 mg (with 3,500-6,300 mg EPA/ 1,000-1,800 mg DHA) per day for one month to competitive soccer players
Outcomes
Improves anaerobic endurance capacity (142)
Class of evidence
c
Atrial fibrillation (AF), postoperative
General outcomes from A-level evidence
Dosing & administration
>1,000 mg DHA (in ratios of <1.2 for EPA:DHA) per day
Outcomes
relative risk of postoperative AF (37%) (387)
Class of evidence
a
Dosing & administration
2,000 mg (with 600 mg EPA/ 400 mg DHA) per day for five days prior to surgery in addition to standard care
Outcomes
duration of AF, time in the ICU, & total time in hospital (361)
Class of evidence
b
Dosing & administration
2,000 mg (with ~850 mg EPA/DHA bound to ethyl esters) per day for five days prior to surgery and until hospital discharge, postoperatively
Class of evidence
c
Dosing & administration
4,000 mg (with ~2,000 mg EPA/ 1,300 mg DHA) per day for 6-12 months post-surgery adjunct to antithrombotic treatment
Outcomes
Class of evidence
c
Dosing & administration
6,000 mg (with 300 mg EPA/ 1,500 mg DHA) per day for 1-2 months before pulmonary vein isolation to Px with paroxysmal AF
Outcomes
pulmonary venous effective refractory periods (ERP), & left atrial ERPs
dispersion of pulmonary venous ERP, incidence of AF, & AF cycle length (210)
Class of evidence
c
Attention deficit hyperactivity disorder (ADHD)
General outcomes from A-level evidence
Dosing & administration
> 500 mg (as EPA) per day to children and adolescents
Outcomes
inattention with doses lower than 500 mg of EPA (which may also contain DHA), but >500 mg of EPA is required to reduce hyperactivity (65)
Class of evidence
a
Dosing & administration
~600-2,400 mg (with ~80-550 mg EPA/ 40-175 mg DHA bound to phospholipids or TGs in fish oil) per day for 3-4 months to children
Outcomes
Improves attention score (test of variables of attention; TOVA), CPRS subscores for cognitive problems/inattention, Conners ADHD index, Conners global index (restlessness-impulsivity), DSM-IV symptom subscores (inattentive and hyperactive-impulsivity), oppositional behavior, perfectionism, social problem subscales, & parent emotional-impact score (148)(231)(326)(358)
Class of evidence
b
Dosing & administration
2,000 mg (containing either 1,100 mg EPA/ 100 mg DHA, or 265 mg EPA/ 1,030 mg DHA) per day for four months to children
Outcomes
Class of evidence
c
Dosing & administration
1,300 mg (with 650 mg EPA/ 650 mg DHA) per day for 16 weeks to children and adolescents using or not using methylphenidate
Outcomes
Improves parent-rated attention (51)
Class of evidence
c
Autism spectrum disorder (ASD)
Dosing & administration
750 mg (with 200-722 mg DHA) per day for 6-12 months to children with optional combination with 2000 IU vitamin D
Outcomes
Class of evidence
b
Dosing & administration
1,500 mg (with 840 mg EPA/ 700 mg DHA) per day for six weeks to children or adolescents
Outcomes
Improves hyperactivity & stereotypy (13)
Class of evidence
c
Bipolar disorder
General outcomes from A-level evidence
Dosing & administration
500-1,000 mg (as EPA bound to ethyl esters) twice per day to adults for three months
Outcomes
Class of evidence
b
Dosing & administration
1,000 mg (with 700 mg EPA/ 100 mg DHA as OmegaBrite®) twice per day with or without psychoeducational psychotherapy for three months to children and adolescents
Outcomes
Class of evidence
c
Dosing & administration
4,800-5,650 mg (as 2,500-3,100 mg EPA/ 1,500-1,700 mg DHA) twice per day added to current psychotherapy/medication treatments for 1-4 months to adults
Outcomes
Class of evidence
c
Cachexia
Dosing & administration
2,000-2,200 mg (as EPA) per day for 6-12 weeks during a polymeric diet with or without concomitant meloxicam to cancer patients
Outcomes
Class of evidence
c
Dosing & administration
2,000 mg (with 360 mg EPA/ 240 mg DHA) three times per day with or without concomitant celecoxib for six weeks to adults with advanced lung cancer
Outcomes
muscle strength & body weight
CRP compared with fish oil alone (64)
Class of evidence
c
Cardiovascular disease (CVD)
General outcomes from A-level evidence
risk of myocardial infarction, coronary heart disease (CHD) death, total CHD, CVD death, and total CVD, (1)(173) particularly in Px with high baseline TGs (≥ 150 mg/dL) or LDL-C (≥130 mg/dL) (229)
Note: outcomes in CVD have been extremely controversial with regards to the primary and secondary prevention of CVD and related events but given their safety profile, fish oils may be recommended for cardiovascular health; (204) doses >3,000 mg may be required for therapeutic benefit on CVD risk factors including the reduction of TGs (~15%), and improvement in SBP, DBP, heart rate, CRP, and HDL-C, with increases in LDL-C; (1)(7) older evidence shows no relationship between supplementation and reducing risk of CVD (26)(303)
Dosing & administration
<1,000-1,800 mg (as EPA/DHA) per day, ongoing
Outcomes
risk of myocardial infarction (8%), coronary heart disease (CHD) death (14%), total CHD (5%), CVD death (7%), total CVD (3%), & cardiac death (8%)
Class of evidence
a
Dosing & administration
> 3,000 mg (as EPA/DHA) per day, ongoing
Outcomes
TGs in particular, with possible improvements in SBP, DBP, heart rate, CRP, & HDL-C, and increases in LDL-C (7)
Class of evidence
a
Dosing & administration
700-3,000 mg (as DHA from algal oil - 1,680 mg as a median dose) per day
Outcomes
TGs
HDL-C & LDL-C (44)
Class of evidence
a
Coronary artery/heart disease (CAD/CHD)
General outcomes from A-level evidence
incidence of cardiac mortality (8-39% with a dose-response relationship) particularly in high-risk populations, total CHD (7%), atherosclerotic progression, and platelet aggregation (10)(132)(173)(180)(215)(322)(401)
flow-mediated dilation (~2.3%) (373)
Note: other evidence shows no effect on preventing atherosclerotic plaque accumulation, or reducing CHD-related events; (26)(189) fish oil administration increased the risk for sudden cardiac death in Px with angina, providing possible evidence for contraindication in CHD in the presence of angina (401)
Dosing & administration
> 1,800-3,000 mg (as EPA/DHA) per day for > 2-6 months to adults
Outcomes
Class of evidence
a
Cognitive function
Dosing & administration
> 1,000 mg (as EPA/DHA, containing >580 mg DHA) per day to adults with mild memory complaints
Outcomes
episodic memory (396)
Class of evidence
a
Dosing & administration
400-1,800 mg (as EPA/DHA) per day for a minimum of six months to older adults
Outcomes
rate of cognitive decline, particularly in ages >70 (397)
Class of evidence
a
Dosing & administration
1,500 mg (with 600 mg DHA from algal oil) per day for 16 weeks to children aged 7-12
Outcomes
reading and behavior (301)
Class of evidence
b
Dosing & administration
1,000 mg (with 772 mg EPA/ 368 mg DHA) twice per day for 12 weeks to older adults
Outcomes
cerebral cortex oxyhemoglobin (measuring neural activation)
P300 latency (measuring quicker rate of information processing) (203)
Class of evidence
c
Cyclosporine-induced hypertension or nephrotoxicity
General outcomes from A-level evidence
serum creatinine (measure of nephrotoxicity) & DBP, but overall, evidence is insufficient to recommend fish oil to improve adverse effects of cyclosporine (220)
Dosing & administration
3,000-4,000 mg (with 1,860 mg EPA/ 1,512 mg DHA) per day during cyclosporine therapy starting four days postoperatively for 6-12 months to heart transplant recipients
Outcomes
Class of evidence
b
Dosing & administration
6,000-12,000 mg (with 1,800-2,160 mg EPA/ 1,200-1,440 mg DHA bound to ethyl esters) per day for 1-3 months to liver or kidney transplant recipients, or Px with psoriasis
Outcomes
Class of evidence
c
Cystic fibrosis
General outcomes from A-level evidence
Limited evidence indicates that omega-3s may provide some benefit, but current evidence remains insufficient (376)
Dosing & administration
5,000 mg (with 3,200 mg DHA) per day for two months to adults
Outcomes
arachidonic acid:DHA ratio in erythrocytes by one month, and expression of human leukocyte elastase complexes & IL-6 in blood (256)
Class of evidence
c
Dosing & administration
60 mg/kg body weight (EPA/DHA) per day adjunct to azithromycin for 12 months
Outcomes
number of pulmonary exacerbations & duration of antibiotic therapy (153)
Class of evidence
c
Depression
General outcomes from A-level evidence
symptoms of depression in clinical depression, depressive mood disorders or with depressive symptoms with greater effect using EPA than DHA, where formulations should contain >50-60% EPA (29)(30)(145)(151)(205)(219)(221)(235)(340)
Dosing & administration
>1,000-1,500 mg (EPA/DHA with >60% EPA) per day to adults or older adults with depressive disorder or bipolar depression
Outcomes
Improves depression scores in Px with mild-moderate depression, and inconsistently provides benefit to individuals with depressive symptoms at higher range doses
Class of evidence
a
Dosing & administration
<1,000 mg (as EPA in formulations containing >60% EPA) per day to Px with depression or depressive symptoms
Outcomes
Improves depression scores compared with lower concentrations (<60% EPA), or compared with formulations containing high DHA proportions, or pure DHA (which were ineffective) (219)
Class of evidence
a
Dry eye
Dosing & administration
~1,500 mg (as 1,000 mg EPA/ 500 mg DHA as fish or krill oil) per day for three months
Outcomes
Class of evidence
b
Dosing & administration
2,240 mg (as 1,680 mg EPA/ 560 mg DHA in re-esterified TG form) per day for 12 weeks to Px with meibomian gland dysfunction
Outcomes
disease severity score, tear osmolarity, & MMP-9
Improves tear breakup time (115)
Class of evidence
b
Dosing & administration
2,400 mg (as 1,440 mg EPA/ 960 mg DHA) per day to users of visual terminal displays
Outcomes
Improves dry eye symptom scores, tear breakup time, & conjunctival cytology (47)
Class of evidence
b
Dysmenorrhea
General outcomes from A-level evidence
pain scores (290)
Dosing & administration
< 1,350 mg (as EPA) per day for up to three months
Outcomes
pain with low dose protocols compared with protocols with higher doses or longer durations (290)
Class of evidence
a
Dosing & administration
300-1,800 mg (as 180-1,080 mg EPA/ 120-720 mg DHA) per day with or without vitamin B1, or vitamin E for 1-12 weeks
Outcomes
Class of evidence
b
Dosing & administration
2,000 mg (as Neptune Krill Oil™) per day for three months to women with premenstrual syndrome
Outcomes
dysmenorrhea & emotional symptoms of PMS to a similar extent to fish oil, but is more efficacious in reducing the need for other analgesics (314)
Class of evidence
c
Dosing & administration
15 mL (with 550 mg EPA/ 205 mg DHA) per day for three months
Outcomes
Visual analogue scale, low back pain, & abdominal pain (253)
Class of evidence
c
Epilepsy
General outcomes from A-level evidence
Note: evidence is currently too limited to make clinical recommendations at a high level (316)
Dosing & administration
1,200-1,700 mg (with 360-1,000 mg EPA/ 240-700 mg DHA) per day for 12-16 weeks to children or adults
Outcomes
Class of evidence
b
Dosing & administration
Daily administration of 937 mg (as 50.8 mg EPA/ 417.8 mg DHA) or 934 mg (as 385.6 mg EPA/ 81.2 mg DHA) to children (aged 5-10), 1874 mg (as 101.6 mg EPA/ 835.6 mg DHA) or 1,867 mg (as 771.2 mg EPA/ 162.4 mg DHA) to adolescents (aged 11-16), or 2,811 mg (as 152.4 mg EPA/ 1,253 mg DHA) or 2,802 mg (as 1,156.8 mg EPA/ 243 mg DHA) to adults (aged 17-50) with drug-resistant epilepsy adjunct to anticonvulsants for one year
Outcomes
incidence of seizures by 42% by EPA-heavy formulations or by 39% with DHA-heavy formulations with no statistical difference between the two (176)
Class of evidence
b
Heart failure
General outcomes from A-level evidence
risk of heart failure by 15% with higher intakes of dietary fish oils, (99) brain natriuretic peptides, serum norepinephrine, TNF-ɑ, IL-1, (371)(385) and left ventricular end-systolic volume
left ventricular ejection fraction
Improves functional capacity and peak oxygen consumption, particularly in non-ischaemic heart failure (386)
Note: may not reduce the risk of sudden cardiac death in heart failure (9)
Hemodialysis graft dysfunction
General outcomes from A-level evidence
relative risk of graft failure (19-29%), risk for cardiovascular events by 69%, depression scores, serum iPTH, CRP, and TGs in Px on maintenance hemodialysis or with arteriovenous fistula (161)(365)
Note: other evidence does not support the use of omega-3s to improve vascular access in hemodialysis (344)
Hypertension
Dosing & administration
> 500-2,000 mg (EPA/DHA) per day to adults for a minimum of eight weeks
Outcomes
Class of evidence
a
Hypertriglyceridemia (HTG)
General outcomes from A-level evidence
Triglycerides (TG), total cholesterol, VLDL, & apolipoprotein C-III (with EPA ethyl esters) (217)(312) including in type II diabetes, (157)(255)(299) and HIV/AIDs (272)(339)(366)
Note: prescription omega-3 products are generally recommended for hypertriglyceridemia as they contain much higher concentrations of EPA, DHA, or both than supplements, making them much more practical; Px may need to consume more than 11 capsules from dietary supplements per day to match prescription fish oil efficacy; (27) for every 1,000 mg, a reduction of ~8 mg/dL in TGs may be expected, while a greater reduction of ~19 mg/dL may be observed in Px with higher baseline TGs (>294 mg/dL) (181)
Dosing & administration
1,000-3,250 mg (as fish oil or krill oil, containing high proportions of TG or phospholipid-bound EPA/DHA, respectively), ongoing
Class of evidence
a
Dosing & administration
1,000-3,000 mg (as EPA/DHA) per day, for a minimum of 4-8 weeks to patients with HIV/AIDS using stable antiretroviral therapy
Class of evidence
a
Dosing & administration
> 2,000 mg (as EPA ethyl esters) per day, ongoing
Outcomes
Apolipoprotein C-III compared with supplements containing EPA + DHA, or DHA only (312)
Class of evidence
a
Dosing & administration
2,000-4,000 mg (as EPA/DHA as fish oil or algal oil) per day for 4-24 weeks to adults, though doses up to 15,000 mg may be used safely
Outcomes
Class of evidence
b
Dosing & administration
7,500 mg (with 3,000 mg DHA from algal oil) per day for three months to adults
Outcomes
TGs (24%), large VLDL (92%) & VLDL particle diameter (11nm), small LDL particles (22%), intermediate-density lipoprotein (53%), nonesterified fatty acids (13%), TG:HDL-C ratio (34%), number of circulating neutrophils (10-12%), CRP (15%), IL-6 (23%), & granulocyte monocyte-colony stimulating factor (21%);
Class of evidence
b
Dosing & administration
1,500 mg (as 1,000 mg EPA/ 500 mg DHA in Omega Rx® by Dr. Sears Zone ®) twice per day for 12 weeks to obese children and adolescents
Outcomes
TGs by 39% (94)
Class of evidence
b
Dosing & administration
500-3,000 mg (with 67-268 mg EPA & 33-132 mg DHA in Superba™ krill oil or as Neptune Krill Oil™) once or twice per day for 12 weeks to adults
Outcomes
Class of evidence
b
Dosing & administration
1,800 mg (as EPA) per day for three months to adults
Outcomes
TGs (31%)
endothelial function & VLDL oxidation (271)
Class of evidence
c
Dosing & administration
1,250 mg (as DHA in TG form) per day for six weeks to adults
Outcomes
TGs (17-21%)
HDL-C (6%) (89)
Class of evidence
c
Dosing & administration
6,000 mg (with 2,000 mg EPA/ 1,000 mg DHA in HiMega®) per day for six weeks with pravastatin to adults
Outcomes
TG, total cholesterol, VLDL, & intermediate-density lipoprotein to a greater extent than fish oil or atorvastatin alone (77)
Class of evidence
c
IgA nephropathy
General outcomes from A-level evidence
relative risk (~19%) of >50% increase in serum creatinine and end-stage renal disease (ESRD), but generally, high-level evidence does not support the use of fish oil in IgA nephropathy (222)
Dosing & administration
6,000 mg (840-935 mg EPA/ 485-680 mg DHA) once or twice per day for 2-4 years to adults
Outcomes
incidence of >50% reductions in glomerular filtration rate (GFR) after four years, incidence of >50% increases in creatinine, slows the rate of GFR reduction, slows the rate of creatinine increases after 2-4 years, & cumulative percent of patients developing ESRD or who died after 4-6.4 years (11)(100)(101)
Class of evidence
b
Dosing & administration
1,800 mg (as EPA) per day for 1 year to adults using ACE inhibitors, angiotensin II receptor blockers or corticosteroids
Outcomes
estimated creatinine clearance rate (354)
Class of evidence
c
Infant cognitive, psychomotor, and visual development
Dosing & administration
400-600 mg (as DHA from algal oil) per day from 14-22 weeks of pregnancy until delivery to pregnant women
Outcomes
Class of evidence
b
Dosing & administration
300 mg (as 180 mg EPA/ 120 mg DHA) per day from 20 weeks gestation until 1 month post-partum to pregnant women
Outcomes
communication score at 4th month of age (276)
Class of evidence
b
Dosing & administration
200 mg (as DHA from algal oil) per day to lactating mothers for four months post-delivery
Outcomes
Bayley Psychomotor Development Index in infants 30 months old (185)
Class of evidence
b
Dosing & administration
Formula containing EPA (0.06%) and DHA (0.2%) from 3rd day of life until two months after their expected term to preterm birth infants
Outcomes
visual acuity after two months, but not beyond (63)
Class of evidence
c
Inflammatory bowel disease
Dosing & administration
500 mg (as EPA) twice per day adjunct to standard therapy for six months to Px with ulcerative colitis
Outcomes
fecal calprotectin
Improves odds of maintaining clinical remission compared with standard therapy alone (319)
Class of evidence
b
Dosing & administration
1,500 mg (with 600 mg EPA/ 300 mg DHA bound to free fatty acids) three times per day for 12 months to Px with Crohn’s disease
Outcomes
Improves odds of maintenance of clinical remission by 12 months (39)
Class of evidence
c
Menopausal symptoms
Dosing & administration
1,500 mg (with 1,050 mg EPA/ 150 mg DHA bound to ethyl esters) per day for eight weeks to middle-aged women
Outcomes
Class of evidence
b
Migraine
General outcomes from A-level evidence
duration of migraines by 3.44 hours but no effect on frequency or intensity (227)
Dosing & administration
2,500 mg (1,200 mg EPA/ 600 mg DHA) per day for two months to Px with episodic migraines with optional addition of curcumin
Outcomes
Class of evidence
b
Dosing & administration
750 mg (as 400 mg EPA/ 350 mg DHA) twice per day for two months with amitriptyline to Px with chronic migraine
Outcomes
number of days with headache compared with amitriptyline alone (332)
Class of evidence
b
Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH)
General outcomes from A-level evidence
fatty liver, steatosis score, ALT, AST, GGT, TG, total cholesterol, LDL-C, HOMA-IR, and glucose
Dosing & administration
>250 mg (as DHA) to children, or >3,000 mg (as EPA/DHA) to adults per day for a minimum of six months
Outcomes
Class of evidence
a
Obesity/overweight
Dosing & administration
400-2,040 mg (as 180-600 mg EPA/ 120-1,620 mg DHA) 1-3 times per day for 4-12 weeks to overweight/obese subjects with or without a lifestyle intervention
Outcomes
waist circumference, body fat percentage, BMI, abdominal skin thickness, weight, weight regain post-intervention, depression scores (in px with depression), & VO2max compared with lifestyle intervention alone, and mean caloric/macronutrient intake in Px not on lifestyle intervention
Class of evidence
b
Dosing & administration
2,300-4,000 mg (with ~1,200 mg EPA/ ~800 mg DHA) per day for 12 weeks to obese adults with concurrent metabolic risk factors on a calorie-restricted diet
Class of evidence
b
Dosing & administration
3,000 mg (as 2,700 mg EPA or 2,700 mg DHA in re-esterified TG form) per day for 10 weeks to obese adults with low-grade inflammation
Outcomes
Class of evidence
c
Dosing & administration
250-500 mg (as DHA) per day for six months to obese Px on an isocaloric diet
Outcomes
anti-inflammatory fatty acid index
AA/EPA & AA/DHA ratios in erythrocytes (90)
Class of evidence
c
Oral mucositis
General outcomes from A-level evidence
No data currently available.
Dosing & administration
2,000 mg (with 360 mg EPA/ 240 mg DHA bound to ethyl esters) per day during chemotherapy over three weeks
Outcomes
duration and pain/irritation severity of mucositis within 1-2 weeks, & eliminated mucositis after two weeks
Improved Px ability to speak, & eat or swallow food (159)
Class of evidence
b
Osteoarthritis (OA)
General outcomes from A-level evidence
Note: marine oils may not reduce pain in OA (323)
Dosing & administration
300 mg (with 51 mg EPA/ 30 mg DHA as Neptune Krill Oil™) per day for one month to adults
Outcomes
WOMAC pain, stiffness and functional impairment scores within seven days, & CRP in seven days with further reductions after 2-4 weeks (97)
Class of evidence
b
Dosing & administration
2,000 mg (with 240 mg EPA/ 110 mg DHA as Superba™ krill oil) per day for one month in Px with mild knee pain
Outcomes
Improves pain/stiffness in sleeping & standing positions, and range of motion (342)
Class of evidence
b
Dosing & administration
15 ml equivalent to 1,500 mg (with 450 mg EPA/DHA) per day for two years to adults with knee OA
Outcomes
WOMAC pain score to a greater extent than high dose (164)
Class of evidence
c
Osteoporosis
General outcomes from A-level evidence
serum osteocalcin but not bone-specific alkaline phosphatase or collagen type I cross-linked C-telopeptide (324)
Dosing & administration
1,200 mg (with 720 mg EPA/ 480 mg DHA) per day for six months to postmenopausal women on standard calcium + vitamin D regimens
Outcomes
bone-specific alkaline phosphatase & osteocalcin, but this may be primarily driven by calcium/vitamin D
EPA/DHA:arachidonic acid ratio (102)
Class of evidence
b
Dosing & administration
4,000 mg (with 2,520 mg EPA/ 1,680 mg DHA) per day for three months to postmenopausal breast cancer survivors on aromatase inhibitor therapy
Outcomes
bone resorption, & omega-6:omega-3 ratio (175)
Class of evidence
c
Dosing & administration
4,000 mg (with 640 mg EPA/ 440 mg DHA) per day for four months to osteoporotic patients
Outcomes
osteocalcin, procollagen, serum calcium, & urinary calcium clearance (360)
Class of evidence
c
Periodontitis
General outcomes from A-level evidence
clinical attachment loss and probing depth when used as adjunct therapy for three months, compared with standard therapy alone (208)
Dosing & administration
3,000 mg (with 450-900 mg EPA/ 900 mg DHA) or 2,000 mg (as DHA), per day for 3-6 months with aspirin and standard periodontitis therapy to adults
Outcomes
Class of evidence
b
Dosing & administration
500-2,000 mg (with 180-600 mg EPA/ 120-400 mg DHA) per day for 1-6 months to adults receiving periodontal therapy
Outcomes
Class of evidence
b
Peripheral arterial disease
General outcomes from A-level evidence
Dosing & administration
2,200 mg (with 1,300 mg EPA/ 900 mg DHA in Pro-Omega™ by Nordic Naturals) twice per day for 1-3 months to adults
Outcomes
Class of evidence
b
Dosing & administration
5,000 mg (with 900 mg EPA/ 600 mg DHA) twice per day for seven weeks to adults
Outcomes
TGs (382)
Class of evidence
c
Preterm birth prevention
General outcomes from A-level evidence
relative risk for early preterm birth of < 34 weeks (22-68%), preterm birth of < 37 weeks (10-39%), low birth weight (10-23%), perinatal death (25%), and rate of neonatal care admission (8%)
infantile birth weight (~50-122g), birth length (0.28 cm), head circumference (0.09 cm), gestational age (~5-14 days), but also prolonged gestation > 42 weeks (61%), and large for gestational age (15%) (67)(177)(192)(244)(313)
Note: there may not be an effect on reducing risk of recurrent preterm birth (308)
Dosing & administration
200-1,000 mg (emphasizing DHA) during pregnancy
Outcomes
relative risk for early preterm birth of < 34 weeks (42%), preterm birth of < 37 weeks (11%), low birth weight (10%), perinatal death (25%), & rate of neonatal care admission (8%)
prolonged gestation > 42 weeks (61%), large for gestational age (15%)
Class of evidence
a
Dosing & administration
600 mg (as DHA from algal oil) per day from 14.5 weeks gestation to delivery to pregnant women
Outcomes
preterm delivery, & duration of hospital stay
gestation duration (2.9 days), birth weight (172 g), birth length (0.7 cm), & head circumference (0.5 cm) (62)
Class of evidence
b
Dosing & administration
1,000 mg (with 180 mg EPA/ 120 mg DHA) from 20 weeks gestation to birth to pregnant women
Outcomes
odd of preterm labor (26%), & frequency of low birth weight (275)
Class of evidence
b
Psoriasis
Dosing & administration
>1,800 mg (as EPA/DHA) per day for up to eight weeks to adults
Outcomes
psoriasis area and severity index (PASI) score, erythema, scaling, & itching
Note: lower doses and longer durations may still provide benefit, but greatest improvements observed with higher doses over shorter durations (75)
Class of evidence
a
Dosing & administration
6,000 mg (3,060 mg EPA/ 1,920 mg DHA bound to ethyl esters) per day for four months
Outcomes
CD25+ lymphocyte percentage (335)
Class of evidence
c
Dosing & administration
1,800 mg (as EPA bound to ethyl esters) per day for 12 weeks concomitant to low dose etretinate
Outcomes
Improves clinical response to etretinate and reduces time to 50% reduction severity scores (87)
Class of evidence
c
Psychosis
General outcomes from A-level evidence
No data currently available.
Dosing & administration
1,200 mg (700-740 mg EPA/ 400-480 mg DHA) per day for 3-4 months to adolescents and young adults with subthreshold psychosis, or with adjunct risperidone to adolescents and adults with recent-onset psychosis
Outcomes
functioning scores
TGs, risk for transition to psychotic disorder (~23%, with reduced risk by 6.7-year follow-up), positive and negative syndrome scale (PANSS), general symptoms scores within first 1-3 months, and by 12-month follow-up in subthreshold psychosis
Class of evidence
b
Dosing & administration
1,000 mg (as EPA bound to ethyl esters) twice per day for three months to Px with first-episode psychosis
Outcomes
Class of evidence
b
Renal disease
General outcomes from A-level evidence
relative risk (61-70%) of developing end-stage renal disease (ESKD) in Px with chronic kidney disease (CKD) not receiving renal replacement therapy via reduced risk of proteinuria (55%), relative risk of CVD mortality in Px on hemodialysis, TGs, LDL, & CRP in end-stage renal disease with omega-3s (172)(311)(388)
Dosing & administration
2,000 mg (with 920 mg EPA/ 760 mg DHA) twice per day for two months to Px with chronic kidney disease
Outcomes
Class of evidence
b
Dosing & administration
1,000 mg (180 mg EPA/ 120 mg DHA) three times per day for 3-6 months to Px on hemodialysis with or without ESRD
Outcomes
Class of evidence
b
Dosing & administration
1,000-1,250 mg (with 600 mg EPA/ 300 mg DHA) per day to Px on chronic hemodialysis for 3-4 months
Outcomes
Class of evidence
b
Rheumatoid arthritis
Dosing & administration
< 1,350 mg (as EPA) or > 2,700-3,000 mg (as EPA/DHA in a >1.5 EPA/DHA ratio) per day for minimum 3-4 months as adjunct therapy
Outcomes
Class of evidence
a
Sarcopenia
General outcomes from A-level evidence
No data currently available.
Dosing & administration
3,000-4,000 mg (with 1,860-2,100 mg EPA/ 600-1,500 mg DHA) per day for 8-26 weeks to older adults on a resistance training program
Outcomes
Class of evidence
b
Schizophrenia
General outcomes from A-level evidence
psychotic symptom severity and conversion rates to first-episode psychosis in Px in the prodromal phase, non-psychotic symptoms with improved response rate to antipsychotics in Px with first-episode schizophrenia, but has inconsistent effects in chronic schizophrenia (66)
Note: older studies indicate that evidence is inconclusive (190)
Dosing & administration
2,200 mg (as 1,320 mg EPA/ 880 mg DHA) per day adjunct to benzodiazepines, nonbenzodiazepine ‘Z-drugs’, injectable forms of antipsychotics, antidepressants, mood stabilizers, or anticholinergics, if clinically indicated, for six months to drug-naive or early-treated first episode Px with schizophrenia
Outcomes
frequency of 50% improvement in total PANSS score, which was associated with improvements in general psychopathology, depressive symptoms, level of functioning, clinical global impression, BDNF, PBMC telomerase, & total antioxidative capacity (inversely correlated with depressive symptoms)
8-isoprostane F2α
Class of evidence
b
Dosing & administration
2,000-3,000 mg (as EPA bound to ethyl esters) per day adjunct to antipsychotics for three months to chronic schizophrenic patients
Class of evidence
b
Dosing & administration
1,000-1,140 mg (as 740 mg EPA/ 400 mg DHA) per day for 2-4 months in addition to antipsychotics with recent onset schizophrenia or documented schizophrenia
Outcomes
Class of evidence
c
Sickle cell disease
General outcomes from A-level evidence
No data currently available.
Dosing & administration
~320 mg (as ~40 mg EPA/ 280 mg DHA) per day to children aged 2-4, 640 mg (as 80 mg EPA/ 560 mg DHA) per day to children aged 5-10, or 960 mg (120 mg EPA/ 840 mg DHA) per day to adolescents aged 11-16, or 1,280 mg (320 mg EPA/ 1,120 mg DHA) per day to young adults aged 17-24 with sickle cell disease for 6-12 months
Outcomes
Class of evidence
b
Dosing & administration
100 mg/kg (as 12 mg per kg EPA/ 18 mg per kg DHA) three times per day for 12 months to adults with sickle cell disease
Outcomes
frequency of pain episodes requiring hospitalization by ~50%, plasma prothrombin fragment 1.2, D-dimer, & plasmin:antiplasmin complex (348)
Class of evidence
c
Systemic lupus erythematosus (SLE)
General outcomes from A-level evidence
No data currently available.
Dosing & administration
3,000 mg (with 540 mg EPA/ 360 mg DHA) per day for six months weeks to adults
Outcomes
Class of evidence
b
Dosing & administration
4,500 mg (as 2,250 mg EPA/ 2,250 mg DHA from Metagenics®) per day for six months to adults
Outcomes
Class of evidence
b
Dosing & administration
1,280 mg (as 1,080 mg EPA/ 200 mg DHA) per day for 12 weeks to women with low activity SLE
Outcomes
CRP, total cholesterol, & LDL-C (82)
Class of evidence
c
Type II diabetes
General outcomes from A-level evidence
Triglycerides
Note: while fish oils consistently reduce TGs and increase LDL across meta-analyses, inconsistent results on total cholesterol, VLDL and HDL exists between evidence; evidence consistently demonstrates no relationship between supplementation and fasting glucose, HBA1C, insulin, insulin resistance, or the incidence of type 2 diabetes (52)(68)(124)(131)(157)(255)(299)(384)
Adverse effects
It has been suggested that fish oil supplements increase the risk of bleeding due to their anti-thrombotic properties. (37) However, systematic reviews have not found this theory to be substantiated. (38)(365)(387) Another concern is the possible increased exposure to environmental toxins, such as mercury, polychlorinated biphenyls, or other organochlorines, though this may also be unsubstantiated. (242)(331) Higher incidence of gastrointestinal adverse effects may occur when combined with statins, (72) but not placebo, and are typically limited to mild-moderate severity. (367) Fishy tasting eructation is commonly reported with fish oil supplementation. (19)
Pharmacokinetics
Absorption
- EPA and DHA bound to triglycerides require emulsification and hydrolysis via lingual, gastric, and pancreatic lipases into free fatty acids and mono-glycerols prior to incorporation into micelles and subsequent absorption in the small intestine
- EPA/DHA bound to phospholipids are only hydrolyzed in the small intestine and may spontaneously form micelles for absorption
- Triglycerides are resynthesized from free fatty acids, mono-glycerols, and phospholipids in enterocytes and packaged into chylomicrons for transport in the lymphatic system to the liver for redistribution within lipoprotein molecules (e.g., LDL or HDL) or as plasma phospholipids (178)(261)
Distribution
- Widely distributed to phospholipid membranes, but particularly distributed to neural, retinal, heart, and brain tissues
- Can be stored as triglycerides in adipose tissue
- Highest distribution concentrations dose-dependently begin to plateau with one gram per day within approximately two weeks (23)(237)
Metabolism
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