Each review contains information about the ingredient’s clinical applications, formulations, dosing & administration, adverse effects, and pharmacokinetics. Learn more about our critical appraisal research or contact us for initial guidance and more information.

Omega-3 fatty acids (EPA/DHA)

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/developmentPrevention of cardiovascular surgical complications
Psychological disorders
Renal disorders

Formulations

EPA/DHA source	Characteristics & bioavailability
Algal oil	Vegetarian/vegan source of EPA/DHA, with supplements typically high in DHA (211) More environmentally friendly, sustainable, and may possess lower contaminant risk than fish oil (158)(186) Relatively little research conducted on clinical efficacy to date
Krill oil	Predominantly phospholipid-bound (73)(380) Relatively little research conducted on clinical efficacy to date
Natural fish oils	40 minutes; higher achievable Cmax than oral tablets
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) Relatively expensive to produce compared with processed ethyl ester forms, but may have greater stability (341)
Relative order of highest to lowest bioavailability	1. Krill oil: phospholipid-bound (78)(202)(213)(296)(320) 2. Processed fish oil: re-esterified TG-bound (108)(320) 3. Natural fish oil/algal oil: natural TG-bound (108)211)(307) 4. Natural fish oil/algal oil: free fatty acid-bound (88)(211)(270)(307) 5. Processed fish oil: ethyl ester-bound (88)(108)(213)(270)(320)

Dosing & administration

Allergic disease development (prenatal)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3-6 mg per day, one hour before bedtime for 4-6 weeks in children
Outcomes	SCORAD index, and sleep onset latency IgE levels at higher doses (8)(86)
Class of evidence	B

Alzheimer’s disease (AD)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2.5 mg adjunct to atenolol 25-100 mg/day) or metoprolol (50-100 mg/day) 1 hour before bedtime for 3 weeks in adults
Outcomes	total sleep time, sleep efficiency, and Stage 2 sleep; sleep onset latency which persists upon discontinuation (72)
Class of evidence	C

Angioplasty
General outcomes from A-level evidence	No data currently available.
Dosing & administration	10 mg per day, 1 hour before bedtime until entrainment achieved and taper-reduced to 0.5 mg over 3 months in adults
Outcomes	sleep duration time awake after 1st sleep onset, and day-time napping (31)(67)
Class of evidence	C
Dosing & administration	5 mg (slow-release) per day 1-2 hours before bedtime for 3-6 weeks in adults
Outcomes	sleep duration to a clinically relevant degree, but with no statistical significance (66)(68)
Class of evidence	C

Asthma
General outcomes from A-level evidence	No data currently available.
Dosing & administration	10 mg per day in the evening for 2 weeks
Outcomes	cluster headache frequency within 3-5 days Headaches may resume upon discontinuation (45)
Class of evidence	C

Athletic performance
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5 mg per day, 3-4 hours before bedtime for 2-4 weeks in adults
Outcomes	sleep onset latency, wake time and total sleep time, reports of sleepiness and fatigue, and nocturnal melatonin profile onset by ~1.5 hours (12)(41)(55)
Class of evidence	C
Dosing & administration	5 mg per day in the evening for 4 weeks in adults with depressive symptoms
Outcomes	CES-D and Hamilton Depression Rating Scale-17 depression scores, and sleep discontinuity (65)
Class of evidence	C
Dosing & administration	0.3-3 mg (slow- release) per day, 1.5-6.5 hours before dimming of light for 4 weeks in adults
Outcomes	time to melatonin production from circadian phase, with greater efficacy the earlier the administration before dim light (54)
Class of evidence	C

Atrial fibrillation (AF), postoperative
General outcomes from A-level evidence	No data currently available.
Dosing & administration	10 mg per day at bedtime for 8 weeks in adults
Outcomes	sleep quality pain and dysmenorrhea by ~40%, risk of use of other analgesics by 80%, and BNDF levels (75)
Class of evidence	C

Attention deficit hyperactivity disorder (ADHD)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3 mg per day, 30 minutes before bedtime adjunct to AEDs for 3 months in children
Outcomes	seizure frequency especially at night sleep efficiency and continuity (61)(88)
Class of evidence	C
Dosing & administration	6 mg (<30 kg; 30 kg; >age of 9)(fast- or slow-release) as add-on therapy to AEDs within 1 hour of bedtime for 4-8 weeks in children
Outcomes	GSH-Px and GSSG-Rd activities Improves attention, memory, language subscale scores in measures of QoL (29)(30)
Class of evidence	C

Autism spectrum disorder (ASD)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3-5 mg alone or combined with fluoxetine, or 10 mg alone or combined with amitriptyline per day for 6-8 weeks in adults
Outcomes	pain, and Fibromyalgia Impact Score (FIQ) scores inhibitory action of the endogenous pain-modulating system (14)(37)
Class of evidence	B

Bipolar disorder
General outcomes from A-level evidence	No data currently available.
Dosing & administration	0.05-0.15 mg/kg, or 5 mg per day, 1-2 hours before dim-light onset for 1-4 weeks in children
Outcomes	time to ‘lights-off’, sleep onset and melatonin onset, sleep offset, and sleep latency sleep duration, general health scores, and function status scores; Sleep onset, onset latency and dim-light melatonin onset increases with earlier circadian time of administration (80)(81)(90)
Class of evidence	B
Dosing & administration	0.3-2 mg (slow- release) per day, 1-2 hours before bedtime after the evening meal for 3-weeks to 6 months in the elderly with melatonin deficiency
Outcomes	sleep quality/efficiency, maintenance, morning alertness, QoL, and Clinical Global Impression (CGI) scores sleep latency, sleep initiation time, and wake-time after sleep onset May improve daytime psychomotor performance. No withdrawal upon discontinuation, or build up of tolerance (18)(32)(44)(52)(92)(93)(95)(100)
Class of evidence	B

Cachexia
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3-5 mg per day at bedtime for 2-8 weeks in adults
Outcomes	abdominal pain, bloating and constipation rectal pain threshold Improves overall IBS, extracolonic IBS, and QoL scores (9)(51)(69)(82)
Class of evidence	B

Cardiovascular disease (CVD)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	0.5-5mg (fast-release) close to bedtime at the destination of travel for 3 days prior to flight and 3-5 days post-flight in adults
Outcomes	jet lag symptoms including compromised sleep quality, greater time to sleep onset, fatigue and daytime sleepiness, and days to normalize sleep patterns rate of jet lag prevention; most effective when travelling east and over 5 time zones (36)(62)(63)(83)(84)
Class of evidence	A
Dosing & administration	2 mg (slow-release) at night at the destination of travel for 4 days after arrival in adults
Outcomes	time to fall asleep, number of awakenings and time spent awake after sleep onset sleep duration and quality to the same extent as zopiclone May not be as effective as fast-release formulations (60)(84)
Class of evidence	C

Coronary artery/heart disease (CAD/CHD)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3 mg (fast-release) or 4 mg (slow-release) for < 3 months in adults
Outcomes	migraine prophylaxis with similar efficacy to amitriptyline (6)(20)(50)
Class of evidence	A

Cognitive function
General outcomes from A-level evidence	No data currently available.
Dosing & administration	25 mg per day, 1 hour before bedtime for 6 months in adults
Outcomes	serum pro-inflammatory cytokines and markers of oxidative stress (71)
Class of evidence	C

Cyclosporine-induced hypertension or nephrotoxicity
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2-3 mg (slow- release) per day, 1-2 hours before bedtime for 3-4 weeks in adults
Outcomes	SBP and DBP (7)(25)(73)
Class of evidence	A
Dosing & administration	1.5-2 mg per day, 1-2 hours before bedtime for 2-4 weeks in the elderly
Outcomes	SBP and DBP (26)(27)
Class of evidence	C

Cystic fibrosis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	10 mg per day, 1 hour before bedtime for 12 weeks in adults
Outcomes	sleep quality, insulin sensitivity, and PPAR-γ and LDL-R expression anxiety and depression scores, insulin, HOMA-IR, total cholesterol, and LDL-C (77)
Class of evidence	B

Depression
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3-10 mg, 60-100 minutes prior to standard anesthetic administration in adults
Outcomes	anxiety, sedation; most effective in combination with alprazolam; no cognitive/psychomotor impairment as seen with midazolam anxiety as effectively as gabapentin anxiety before, during, and after surgery, perioperative pain, fentanyl requirements, and with higher doses intraocular pressure in cataract surgery (1)(38)(43)(56)(64)
Class of evidence	B
Dosing & administration	0.1-0.5 mg/kg with/without acetaminophen or paracetamol 45 minutes before anaesthetic administration in children
Outcomes	pre-operative anxiety as effectively as midazolam, dose of propofol needed for anaesthesia compared with midazolam, post-operative agitation as effectively as dexmedetomidine and midazolam, post-operative excitement and sleep disturbance 2 weeks post-surgery; as effective as midazolam to induce sedation (19)(59)(70)
Class of evidence	B

Dry eye
General outcomes from A-level evidence	No data currently available.
Dosing & administration	20 mg per day at night starting 7 days prior to and adjunct with radiotherapy and chemotherapy
Outcomes	risk of asthenia, cachexia, fatigue, hypotension leukopenia, nausea/vomiting, myelosuppression, neurotoxicity, thrombocytopenia (47)(48)(49)(76)(96)
Class of evidence	A

Dysmenorrhea
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3 mg per day 30 minutes before bedtime for 4 weeks in adults
Outcomes	number of 30‐s REM sleep epochs without muscle atonia CGI score (42)
Class of evidence	C

Epilepsy
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2 mg (slow- release) per day, 1-2 hours before bedtime for 24 weeks with standard therapy in the elderly
Outcomes	sleep efficiency, cognitive performance measured by Instrumental Activities of Daily Living (IADL), and Mini-Mental State Examination (MMSE) scores (94)
Class of evidence	B
Dosing & administration	3-6 mg (fast- release) per day, 30 minutes to 2 hours before bedtime for 10 days in the elderly with mild cognitive impairment or Alzheimer’s type dementia
Outcomes	rest-activity rhythm, sleep quality, and duration sleep onset latency, and nocturnal activity; May improve ADAS cognition and non-cognition scores (4)(40)
Class of evidence	C

Heart failure
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3 mg (40kg) (fast-release) per day in the evening for 4 weeks in children
Outcomes	time to sleep onset, and dim light melatonin onset sleep duration (9)
Class of evidence	B

Hemodialysis graft dysfunction
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2-5 mg (slow- release) per day for 10 days and titrated up to 15 mg (if unresponsive) 20-30 minutes before bedtime for up to 3-4 months in children
Outcomes	sleep latency by ~30 minutes sleep duration, sleep efficiency with higher doses, clinician and parent impressions of improvement May improve externalizing behaviors (11)(24)(74)(97)(98)
Class of evidence	B

Hypertension
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3 mg per day, 2 hours before bedtime for 3 weeks in children and young adults
Outcomes	sleep efficiency exhaled breath condensate nitrite (13)
Class of evidence	C

Hypertriglyceridemia (HTG)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5-10 mg (slow- release) per day at night for 4 weeks adjunct to fluoxetine in adults
Outcomes	sleep quality (15)
Class of evidence	C

IgA nephropathy
General outcomes from A-level evidence	No data currently available.
Dosing & administration	6 mg (<30 kg; 30 kg; >age of 9)(fast- or slow-release) as add-on therapy to AEDs within 1 hour of bedtime for 4-8 weeks in children
Outcomes	sleep latency and wakefulness after sleep onset, REM sleep duration, parasomnias score, and total sleep score slow-wave sleep duration and REM latency (28)(39)
Class of evidence	C

Infant cognitive, psychomotor, and visual development
General outcomes from A-level evidence	No data currently available.
Dosing & administration	0.5 mg (fast- release) titrated up to 12 mg over 4 weeks if unresponsive, 45 minutes before bedtime for 12 weeks in children
Outcomes	sleep duration sleep onset latency, but may wake up earlier (3)(23)(97)
Class of evidence	B

Inflammatory bowel disease
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3-5 mg per day, within 1 hour before bedtime for 1 for 2-4 weeks in adults
Outcomes	sleep quality and quantity sleep disturbance, and daytime sleepiness (16)(53)
Class of evidence	C
Dosing & administration	50 mg per day, 30 minutes before bedtime for 2 weeks in adults
Outcomes	sleep duration (16)
Class of evidence	C
Dosing & administration	25 mg twice per day for 1 year in adults
Outcomes	COX-2 activity, levels of nitrates/nitrites and lipoperoxides (58)
Class of evidence	C

Menopausal symptoms
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2-3 mg (slow- release) for 2-3 weeks
Outcomes	sleep efficiency/quality, depth and duration, morning alertness, mood, and daytime functioning awakenings, and sleep onset latency (78)(85)
Class of evidence	C

Migraine
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2 mg (slow- release) per day, 2 hours before bedtime for 4 weeks in adults
Outcomes	sleep quality, efficiency, and scores for vitality and mental health scores for anxiety, depression and fatigue (22)
Class of evidence	C

Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5-10 mg per day, 20 minutes before bedtime for 2 weeks in children
Outcomes	sleep duration Normalizes melatonin patterns in responders and higher doses may continue to improve sleep latency, duration and fragmentation (33)(34)(57)
Class of evidence	C

Obesity/overweight
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5 mg per day at bedtime for 4 weeks in adults
Outcomes	pain scores, and use of other analgesics pain threshold (91)
Class of evidence	C

Oral mucositis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5 mg per day at bedtime for 4 weeks in adults
Outcomes	pain scores, and use of other analgesics pain threshold (91)
Class of evidence	C

Osteoarthritis (OA)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5 mg per day at bedtime for 4 weeks in adults
Outcomes	pain scores, and use of other analgesics pain threshold (91)
Class of evidence	C

Osteoporosis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5 mg per day at bedtime for 4 weeks in adults
Outcomes	pain scores, and use of other analgesics pain threshold (91)
Class of evidence	C

Periodontitis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	5 mg per day at bedtime for 4 weeks in adults
Outcomes	pain scores, and use of other analgesics pain threshold (91)
Class of evidence	C

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

May be β-oxidized (energy production), incorporated into phospholipid membranes of cells, consumed in the synthesis of eicosanoids (signaling molecules in inflammation, and cardiovascular regulation) or other lipid-inflammatory mediators such as resolvins or protectins (73)(345)

Excretion

Half-lives of plasma EPA and DHA are 37 and 48 hours, respectively (73)
Half-lives of EPA and DHA in platelet and mononuclear cell membranes are one to two months, providing better indication of long-term bioavailability than plasma (73)(237)