Krill Oil 500 mg by Fortify

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults over 40 years of age with mild forgetfulness shows that taking a specific combination supplement (BGG Japan Co.) containing astaxanthin 9 mg and tocotrienols 50 mg daily for 12 weeks might improve composite and verbal memory when compared with placebo (105099). This study was funded by the supplement manufacturer.
• Age-related macular degeneration (AMD). Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with non-advanced AMD shows that a specific combination product (Azyr, Sifi S.p.A.) containing astaxanthin 4 mg, lutein, zeaxanthin, vitamin E, vitamin C, zinc, and copper, taken daily for 12 months, improves selective dysfunction in the central retina, but does not improve dysfunction in the peripheral retinal areas, when compared with baseline (19196). The validity of this finding is limited by the lack of a comparator group.
• Aging skin. Small studies suggest that oral and topical astaxanthin may be beneficial in aging skin; however, there is conflicting evidence regarding its effects on wrinkles. Details: Small studies in middle-aged adults show that taking astaxanthin (Astavita Astaxanthin, Astavita; AstaReal Oil 50F, Fuji Chemical Industry Co., Ltd.) 2-3 mg orally twice daily for 6-8 weeks improves elasticity, fine lines, wrinkles, and skin moisture when compared with placebo (19561,91734). However, a meta-analysis of small clinical studies in healthy adults shows that taking oral astaxanthin 2-12 mg daily for 4-16 weeks modestly improves moisture content and skin elasticity, but has no effect on wrinkle depth, when compared with placebo (107961). The validity of this meta-analysis is limited due to the population heterogeneity and variety of astaxanthin formulations utilized. In addition to oral astaxanthin, one study also used topical astaxanthin 0.094% (AstaTROL-Hp, Fuij Chemical Industry Co., Ltd.) 1 mL applied twice daily (91734). A systematic review of two very small, nonblinded studies in healthy adults suggests that topical application, either in combination with oral astaxanthin or alone, might have anti-aging skin effects when used for 2-3 weeks (107961).
• Alzheimer disease. Although there is interest in using oral astaxanthin for Alzheimer disease, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Athletic performance. Small studies suggest that oral astaxanthin may improve some aspects of athletic performance. Details: Two small studies in trained cyclists show that taking astaxanthin (Fuji Health Science, Inc. or AstaReal) 4-12 mg daily for 1 or 4 weeks decreases the time to complete a 20-40 km cycling trial by about 50-100 seconds when compared with placebo (91735,105096). However, a larger study in trained cyclists shows that taking astaxanthin (BioReal) 20 mg, vitamin C 300 mg, and vitamin E 50 mg daily for 4 weeks does not decrease time needed to complete a predetermined amount of cycling work (a timed trial) when compared with placebo (91738). Reasons for the discrepancies are not clear but may relate to the fitness level of the athletes in the studies or the differences in timed trial protocols used in the studies.
• Carpal tunnel syndrome. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of astaxanthin 4 mg, lutein, beta-carotene, and vitamin E (BioAstin, Cyanotech) orally 3 times daily for 8 weeks does not reduce the rate or duration of pain due to carpal tunnel syndrome when compared with placebo (19164).
• Diabetes. It is unclear if oral astaxanthin is beneficial for diabetes. Details: A small clinical trial in adults with diabetes shows that taking astaxanthin (Nature Vision) 8 mg daily for 8 weeks does not reduce levels of cholesterol or fasting blood glucose or reduce diastolic blood pressure when compared with placebo. However, there were some modest beneficial effects on visceral fat, triglyceride level, and systolic blood pressure (109778).
• Dry eye. It is unclear if oral astaxanthin is beneficial for dry eye syndrome. Details: A clinical study in adults and elderly patients with mild to moderate dry eye syndrome shows that taking oral astaxanthin 6 mg twice daily for 30 days improves symptom severity, tear break-up time, fluorescein break-up time, and meibomian gland dysfunction, but not visual acuity or intraocular pressure, when compared with baseline (107962). The validity of these findings is limited by the lack of a comparator group.
• Dyspepsia. It is unclear if oral astaxanthin improves symptoms of dyspepsia. Details: One clinical study in adults with functional dyspepsia with or without Helicobacter pylori infection shows that taking astaxanthin (AstaCarox, AstaReal AB) 16 mg or 40 mg daily for 4 weeks does not reduce indigestion, pain, or H. pylori counts when compared with placebo. However, astaxanthin 40 mg daily may reduce reflux in H. pylori-positive patients (19165).
• Exercise-induced muscle damage. Small clinical studies in trained athletes suggest that oral astaxanthin may not improve markers of muscle damage from exercise. Details: A small study in professional male soccer players shows that taking astaxanthin 4 mg daily for 90 days does not seem to reduce exercised-induced biomarkers of muscle damage, such as creatinine kinase, when compared with placebo (91739). Taking a combination of astaxanthin 4 mg and lutein 480 mg (BioAstin, Cyanotech) daily for 3 weeks also did not reduce creatinine kinase levels after exercise in trained athletes when compared with placebo (safflower oil) (19199).
• Exercise-induced muscle soreness. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in resistance trained athletes shows that taking a combination of astaxanthin 4 mg and lutein 480 mg (BioAstin, Cyanotech) daily for 3 weeks does not reduce muscle soreness or improve muscle performance 96 hours after exercise when compared with placebo (safflower oil) (19199).
• Fatigue. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy patients shows that taking a specific combination product (ASTOTS, Fujifilm Co.) containing astaxanthin 6 mg and sesamin 10 mg after breakfast daily for 4 weeks does not improve overall fatigue after completion of mental and physical tasks when compared with placebo (98769).
• Heart failure. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with heart failure with reduced left ventricular ejection fraction (LVEF) shows that taking a specific supplement containing astaxanthin 12 mg, tocotrienol 40 mg, and L-ascorbic acid 2-glucoside 30 mg (AstaReal ACT, AstaReal Co., Ltd.) daily for 3 months may increase LVEF from 34% to 38% and modestly increase exercise tolerance as measured by the six-minute walk test when compared with baseline (105097). The validity of these findings is limited by the lack of a comparator group. Furthermore, this study was funded by the supplement manufacturer.
• Hyperlipidemia. Small clinical studies suggest that oral astaxanthin is not beneficial for reducing cholesterol levels. Details: One small clinical study in adults with mild hyperlipidemia shows that taking astaxanthin (AstaReal Astaxanthin, Fuji Chemical Industry) 12 mg or 18 mg daily for 12 weeks reduces triglyceride levels, while taking 6 mg or 12 mg daily increases high-density lipoprotein (HDL) cholesterol levels, when compared with placebo. However, total cholesterol and low-density lipoprotein (LDL) cholesterol levels were not affected (19167). Meta-analyses of small clinical studies mostly in adults without hyperlipidemia have also been conducted. One shows that taking astaxanthin 4-18 mg daily for up to 12 weeks does not reduce total or LDL cholesterol levels, but may increase HDL cholesterol levels, when compared with control (105100). A more recent analysis shows that taking astaxanthin 4-20 mg daily for up to 6 months has no beneficial effects on blood lipid levels and might actually increase levels of LDL cholesterol (109776).
• Hypertension. It is unclear if oral astaxanthin reduces blood pressure. Details:A meta-analysis of four small clinical trials shows that taking astaxanthin does not have a clinically beneficial effect on systolic or diastolic blood pressure (109776). However, none of the trials were conducted in patients with hypertension.
• Impaired glucose tolerance (prediabetes). It is unclear if oral astaxanthin is beneficial in patients with prediabetes. Details: A small clinical study in healthy adults and adults with prediabetes shows that taking oral astaxanthin 12 mg daily for 12 weeks improves glycated hemoglobin (HbA1c) when compared with baseline, but not when compared with placebo. Insulin sensitivity and postprandial glucose levels were also improved when compared with baseline, but no statistical comparison to the placebo group was conducted (107965). The validity of this study is limited due to unclear reporting.
• Infertility. It is unclear if oral astaxanthin improves reproductive outcomes in patients with infertility due to endometriosis or polycystic ovary syndrome (PCOS). Details: A small clinical study in adults with infertility secondary to moderate or severe endometriosis undergoing assisted reproductive therapy in Iran shows that taking astaxanthin (AstaReal, AstaReal Co.) 6 mg daily for 12 weeks improves the numbers of oocytes retrieved, mature oocytes, and high-quality embryos but not the quantity of immature oocytes, fertilization rate, number of transferred embryos, or clinical pregnancy rate when compared with placebo (112434). Similarly, a small clinical study also conducted in Iran in patients with infertility due to PCOS undergoing assisted reproductive therapy shows that taking astaxanthin (Algalife Pure astaxanthin) 8 mg daily for 40 days prior to egg retrieval modestly improves the high-quality embryo rate, but not the total number of embryos or the clinical pregnancy rate, when compared with placebo (109775).
• Male infertility. It is unclear if oral astaxanthin improves male infertility. Details: A small low-quality clinical study in males with infertility who are participating in intra-uterine insemination shows that taking astaxanthin (AstaCarox, AstaReal AB) 16 mg daily for 3 months does not seem to increase sperm count and quality, but might result in a higher total pregnancy rate of 23% compared with a 3.6% rate in the placebo group (19197). The validity of this finding is limited by poor study methodology and differences between treatment groups. Another small clinical study in males with infertility and oligospermia shows that taking astaxanthin (Astasan, Sensilab) 16 mg daily does not increase sperm concentration or sperm motility when compared with placebo (105098).
• Menopausal symptoms. Although there is interest in using oral astaxanthin for menopausal symptoms, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
• Metabolic syndrome. Although there is interest in using oral astaxanthin for metabolic syndrome, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Nonalcoholic fatty liver disease (NAFLD). Although there is interest in using oral astaxanthin for NAFLD, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Osteoarthritis. Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with mild knee or hip osteoarthritis shows that taking a combination product containing astaxanthin 2 mg, krill oil, and hyaluronic acid daily for 12 weeks (FlexPro MD, Valensa) reduces joint pain and stiffness and improves objective and subjective measures of joint function but does not improve overall physical function when compared with placebo (112432). It is unclear if these effects are due to astaxanthin, other ingredients, or the combination.
• Obesity. Although there is interest in using oral astaxanthin for weight loss, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
• Parkinson disease. Although there is interest in using oral astaxanthin for Parkinson disease, there is insufficient reliable information about the clinical effects of astaxanthin for this condition.
• Physical performance. It is unclear if oral astaxanthin improves physical performance in older adults. Details: A small clinical trial in healthy nursing home residents shows that taking astaxanthin (AstaReal) 12 mg twice daily for 16 weeks, in combination with vitamin E 40 mg and vitamin C 30 mg daily, increases the 6-minute walking distance by about 38 meters, a significant increase when compared with placebo containing vitamin E and vitamin C. However, there was no effect on muscle strength (109777). Another small clinical trial in healthy, older adults (aged 65-85 years) undergoing exercise endurance testing shows that a specific combination product (AstaReal; Fuji Health Science, Inc) containing astaxanthin 12 mg, tocotrienol 10 mg, and zinc 6 mg, taken as 2 capsules daily for 12 weeks, reduces the respiratory exchange ratio, but does not improve leg muscle endurance or perceived exertion, when compared with placebo. In a subgroup analysis of males, but not females, those taking astaxanthin had a greater total exercise efficiency when compared with placebo (107963).
• Rheumatoid arthritis (RA). Oral astaxanthin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with RA shows that taking a supplement containing astaxanthin 4 mg, lutein 40 mcg, vitamin A 65 IU, vitamin E 50 IU, and safflower oil 460 mg (BioAstin, Cyanotech) three times daily for 8 weeks reduces pain and improves satisfaction by approximately 40% when compared with placebo (94125).
• Stroke. Although there is interest in using oral astaxanthin for recovery from stroke, there is insufficient reliable information about the clinical effects of astaxanthin for this purpose.
• Sunburn. It is unclear if oral astaxanthin might help to prevent sunburn. Details: A very small clinical study in Japanese adults shows that taking astaxanthin (Astots, Fujifilm Corporation) 4 mg daily for 9 weeks might increase skin tolerance to ultraviolet (UV) light when compared with placebo (96884). It is unclear if this translates to a lower risk of sunburn. More evidence is needed to rate astaxanthin for these uses.

(Read more about ASTAXANTHIN)

POSSIBLY EFFECTIVE

• Dry eye. Taking oral krill oil seems to reduce dry eye symptoms. Details: Clinical research shows that taking krill oil (Nutra-Life OceanClean red krill oil) providing eicosapentaenoic acid (EPA) 945 mg and docosahexaenoic acid (DHA) 510 mg daily for 90 days improves overall symptoms of dry eye disease by 77% when compared with placebo. Taking krill oil also appears to improve tear film stability and eye redness (96114).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral krill oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking capsules containing krill oil, zinc, vitamin D, sea buckthorn berry oil, cacao bean extract, hyaluronic acid, and red clover isoflavones (GliSODin Skin Nutrients Advanced Anti-Aging Formula, Isocell North America Inc.) 780 mg three times daily along with applying tazarotene cream 0.1% nightly for about 12 weeks improves fine wrinkles, overall sun damage, skin moisture, and skin elasticity when compared with tazarotene cream alone. It is not clear if these benefits are due to krill oil, other ingredients, or the combination (91778).
• Alzheimer disease. Although there has been interest in using oral krill oil for Alzheimer disease, there is insufficient reliable information about the clinical effects of krill oil for this condition.
• Cancer. Although there has been interest in using oral krill oil for cancer prevention, there is insufficient reliable information about the clinical effects of krill oil for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral krill oil for CVD, there is insufficient reliable information about the clinical effects of krill oil for this condition.
• Cognitive function. It is unclear if oral krill oil is beneficial for improving cognitive function in children. Details: A clinical trial shows that taking krill oil 4 grams daily, providing eicosapentaenoic acid (EPA) 520 mg and docosahexaenoic acid (DHA) 280 mg, usually for 12 months does not improve measures of cognitive function compared with placebo in school children (110372,110374). Some of the children took krill oil 2 grams daily for 3 months before changing to 4 grams for the remaining 9 months. In addition, despite the relatively large number of children included in the study, conclusions are limited due to high drop-out and low adherence rates. The effect of krill oil on cognitive function in adults is not clear.
• Depression. It is unclear if oral krill oil is beneficial for depression in adolescents. Details: In adolescents with depressive feelings, preliminary clinical research shows that taking 4 capsules daily of krill oil for 3 months, and then 8 capsules daily for another 9 months, does not reduce self-reported depressive feelings or improve self-esteem when compared with placebo (104571). However, compliance was low. The krill oil product used provided eicosapentaenoic acid 65 mg and docosahexaenoic acid 35 mg per capsule. The effect of krill oil on clinical depression or in adults with depression is not clear.
• Diabetes. It is unclear if oral krill oil is beneficial for glycemic control. Details: In patients with type 2 diabetes, preliminary clinical research shows that taking two krill oil capsules daily providing omega-3 fatty acids 1000 mg for 4-21 weeks does not improve most glycemic indices when compared to olive oil. However, there was a small improvement in levels of high-density lipoprotein (HDL) cholesterol after 21 weeks (104572). Most patients in this study were also using oral hypoglycemic drugs.
• Dysmenorrhea. It is unclear if oral krill oil is beneficial for reducing pain or analgesic use. Details: Preliminary clinical research shows that taking a specific krill oil product (Neptune Krill Oil, Neptune Technologies & Bioresources, Inc.) 2 grams daily reduces the need for analgesics in females with dysmenorrhea by up to 50% from baseline (15754). The validity of this finding is limited by the lack of a control group.
• Exercise-induced muscle damage. It is unclear if oral krill oil is beneficial for reducing exercise-induced muscle damage. Details: A small clinical trial in resistance-trained males shows that taking krill oil 3 grams daily for 3 days before a bout of muscle-damaging resistance exercise modestly reduces levels of serum creatine kinase 24 and 48 hours later compared with taking placebo. There were also modest improvements in agility in the first 24 hours and muscle strength over 72 hours. The krill oil provided eicosapentaenoic acid (EPA) 360 mg and docosahexaenoic acid (DHA) 210 mg daily, as well as 2590 mcg daily astaxanthin. There were no effects of taking krill oil on levels of lactate dehydrogenase or on recovery for sprint time (110373). Preliminary clinical research in untrained males shows that taking a specific blend of krill oil and New Zealand green-lipped mussel lipid extract (ESPO-572, Pharmalink), at a dosage of 200 mg daily for 30 days, starting 26 days before a downhill run and following 72 hours post-exercise, reduces plasma creatine kinase and tumor necrosis factor-alpha levels, and improves joint range of motion, when compared with placebo. However, this combination was similarly effective to a lipid extract of New Zealand green-lipped mussel (PCSO-524; Pharmalink), suggesting that any benefits may be due to New Zealand green-lipped mussel, as opposed to krill oil (105509).
• Hyperlipidemia. Evidence for the use of oral krill oil for hyperlipidemia is conflicting. Details: A meta-analysis of clinical research shows that taking krill oil reduces levels of low-density lipoprotein (LDL) cholesterol by about 16 mg/dL in patients with hypercholesterolemia, hypertriglyceridemia, or normal lipid levels (96162). However, a sensitivity analysis reveals that this benefit is related to the inclusion of a single preliminary clinical trial. This trial shows that taking a specific krill oil product (Neptune Krill Oil, Neptune Technologies & Bioresources, Inc.) 1-3 grams daily for 12 weeks reduces LDL cholesterol, total cholesterol, and triglycerides, and increases high-density lipoprotein (HDL) cholesterol, when compared with both fish oil and placebo in patients with hyperlipidemia (15753). When this study was removed from the meta-analysis, krill oil showed no significant benefit on LDL cholesterol levels (96162). However, the available clinical research has involved a range of doses, durations, and populations (15753,19374,96162). Another meta-analysis of clinical research in healthy volunteers or people with dyslipidemia, diabetes, metabolic syndrome, or cardiovascular disease shows that krill oil and fish oil similarly lower LDL cholesterol, total cholesterol, and triglycerides, and increase HDL cholesterol (104110).
• Hypertension. Although there has been interest in using oral krill oil for hypertension, there is insufficient reliable information about the clinical effects of krill oil for this condition.
• Hypertriglyceridemia. It is unclear if oral krill oil is beneficial for hypertriglyceridemia. Details: A meta-analysis of clinical research shows that taking krill oil reduces triglyceride levels by about 14 mg/dL in patients with hypercholesterolemia, hypertriglyceridemia, or normal lipid levels (96162). Another meta-analysis of two randomized, controlled trials in patients with severe hypertriglyceridemia shows that taking krill oil 4 grams daily for 12 weeks reduces triglyceride levels by 26%, compared with a 15% reduction in the placebo group (107474). Also, a small clinical study in patients with hypertriglyceridemia shows that taking a specific krill oil product (Superba Krill Oil, Aker BioMarine ASA) 0.5-4 grams in two divided doses daily for 12 weeks lowers triglyceride levels by 10% when compared with baseline. The effect does not appear to be dose-dependent, and there is significant variability in the triglyceride level changes. Krill oil did not affect levels of total, LDL, or HDL cholesterol (91600).
• Obesity. It is unclear if oral krill oil is beneficial for weight loss. Details: A small clinical trial in females with a body mass index (BMI) over 25 kg/m2 shows that taking krill oil (Pholias, Anapolis, Goias) 1.5 grams twice daily for 8 weeks, providing eicosapentaenoic acid (EPA) 500 mg daily, does not affect anthropometric measures, including waist and abdominal circumference and BMI, compared with placebo (110371).
• Osteoarthritis. It is unclear if oral krill oil is beneficial for osteoarthritis. Details: Clinical research in patients with knee osteoarthritis shows that taking krill oil (Superba BOOST, Aker BioMarine) 4 grams daily for 6 months, providing eicosapentaenoic acid (EPA) 0.6 grams, docosahexaenoic acid (DHA) 0.28 grams, and astaxanthin 0.45 mg daily, modestly improves knee pain, stiffness, and function, compared with taking placebo. However, it is unclear if any benefits are clinically significant and there was no effect on the estimated use of NSAIDs (110370). Also, preliminary clinical research shows that among patients with cardiovascular disease and either rheumatoid arthritis or osteoarthritis, taking a specific krill oil product (Neptune Krill Oil, Neptune Technologies & Bioresources, Inc.) 300 mg daily for 30 days improves pain by 38%, stiffness by 39%, and functionality by 36% when compared with baseline. These improvements are significantly greater than those seen with placebo (15760). The effects of krill oil specifically in patients with osteoarthritis is unclear from this study.
• Parkinson disease. Although there has been interest in using oral krill oil for Parkinson disease, there is insufficient reliable information about the clinical effects of krill oil for this condition.
• Premenstrual syndrome (PMS). It is unclear if oral krill oil is beneficial for reducing symptoms of PMS. Details: Preliminary clinical research shows that taking a specific krill oil product (Neptune Krill Oil, Neptune Technologies & Bioresources, Inc.) 2 grams daily reduces self-reported symptoms of PMS (15754). However, the validity of these findings is limited by concerns with the study methodology. Other preliminary clinical research shows that taking a specific combination product containing krill oil 350 mg, thiamine 1.4 mg, riboflavin 1.6 mg, vitamin B6 2 mg, soy isoflavones 50 mg, and rosemary extract 50 mg (Cleanmarine for Women, Novabrands Ltd. Co) two capsules daily for 3 months reduces anxiety, mood swings, breast tenderness, food cravings, bloating, skin outbreaks, forgetfulness, fatigue and insomnia, and headaches when compared with baseline. However, it is unclear if these improvements are due to krill oil, other ingredients, or the combination, and the validity of these findings is limited by the lack of a comparator group (91604).
• Rheumatoid arthritis (RA). It is unclear if oral krill oil is beneficial for RA. Details: Preliminary clinical research shows that among patients with cardiovascular disease and either rheumatoid arthritis or osteoarthritis, taking a specific krill oil product (Neptune Krill Oil, Neptune Technologies & Bioresources, Inc.) 300 mg daily for 30 days improves pain by 38%, stiffness by 39%, and functionality by 36% when compared with baseline. These improvements are significantly greater than those seen with placebo (15760).
• Sarcopenia. It is unclear if oral krill oil is beneficial for improving muscle loss or strength in older adults. Details: Clinical research in inactive adults over age 65 years shows that taking krill oil (Superba BOOST, Aker BioMarine) 2 grams twice daily, providing eicosapentaenoic acid (EPA) 772 mg, docosahexaenoic acid (DHA) 384 mg, and choline 316 mg, for 6 months modestly increases knee and grip strength, and muscle thickness, compared with taking placebo. Knee and grip strength increased by 7.1% and 8.8%, respectively, over baseline. Both improvements were statistically significant compared with placebo. However, there was no effect on general physical performance (110369).
• Stroke. Although there has been interest in using oral krill oil for stroke, there is insufficient reliable information about the clinical effects of krill oil for this condition. More evidence is needed to rate krill oil for these uses.

(Read more about KRILL OIL)

POSSIBLY INEFFECTIVE

• Cardiovascular disease (CVD). Most research suggests that increasing dietary intake of omega-6 fatty acids does not reduce the risk of CVD. Details: A meta-analysis including 19 low-quality randomized controlled trials that followed patients for 1-8 years shows that higher intake of omega-6 fatty acids for at least 12 months does not reduce the risk of primary or secondary CVD events, coronary heart disease (CHD) events, stroke, or all-cause or CVD mortality when compared with a lower intake. The intake of omega-6 fatty acids ranged from 0.8% to 20.6% of energy (99973). Population research conducted over about 7.3 years has also found that baseline red blood cell omega-6 fatty acid levels are not associated with CVD events, CHD events, ischemic strokes, CVD deaths, or all-cause mortality (99974), and red blood cell omega-6 fatty acid levels do not differ between people with or without coronary artery disease in patients hospitalized for coronary angiography (96918). However, some research suggests that individual omega-6 fatty acids may have differing effects in the body. One population study has found that increased levels of shorter chain omega-6 fatty acids in red blood cells, including linoleic acid, gamma linolenic acid, and dihomo-gamma linolenic acid, are associated with a reduced risk of CVD mortality. Higher levels of the longer chain omega-6 fatty acids adrenic acid and docosapentaenoic acid are associated with a moderately increased risk of overall mortality in these patients (96918). Higher quality studies are needed to confirm these findings.
• Child development. Most research suggests that supplementing infant formula with arachidonic acid, an omega-6 fatty acid, and docosahexaenoic acid (DHA), an omega-3 fatty acid, does not improve infant or child development. Details: Meta-analyses of clinical research show that inclusion of arachidonic acid in infant formula at levels of up to 0.84% of fatty acids, in addition to DHA, for 2-12 months does not improve visual or neurodevelopmental outcomes in preterm or full-term infants up to 18 months of age (96919,96920). Also, giving infants DHA- and arachidonic acid-supplemented formula during infancy does not appear to improve neurodevelopment by the age of 6 years (92503).
• Hyperlipidemia. Increasing dietary intake of omega-6 fatty acids does not seem to lower plasma cholesterol or triglyceride levels. Details: A meta-analysis of clinical research shows that increasing intake of omega-6 fatty acids, specifically linoleic acid or gamma-linolenic acid, by replacing dietary saturated or monounsaturated fatty acids modestly reduces levels of total cholesterol. However, the clinical significance is unclear. Also, increasing intake of omega-6 fatty acids does not seem to affect levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, or triglycerides (99973).
• Multiple sclerosis (MS). Most research suggests that taking omega-6 fatty acids is not beneficial for MS. Details: A meta-analysis of the available literature shows that taking omega-6 fatty acids, mainly as linoleic acid, does not seem to prevent disease progression in relapsing-remitting MS patients or chronic progressive MS patients at 24 months (107318).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if increased dietary omega-6 fatty acid intake is beneficial for preventing age-related cognitive decline. Details: Population research has found that the highest blood levels of omega-6 fatty acids during middle age are associated with the best overall cognitive functioning 13 years later when compared with lower intakes (99979). In addition, the highest tertile of omega-6 fatty acid intake in older adults, at least 8.8 mg per kcal daily, is inversely associated with having low cognitive performance. However, the same pattern was observed for the highest tertile of omega-3 fatty acids, and the omega-6 to omega-3 fatty acid ratio in the diet had no overall association with cognitive performance (103308).
• Attention deficit-hyperactivity disorder (ADHD). Oral omega-6 fatty acids have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of omega-3 and omega-6 fatty acids twice daily for 3-6 months does not improve symptoms of ADHD in most children when compared with placebo, although it may improve ADHD symptoms in a subgroup of children with ADHD inattentive subtype plus comorbid neurodevelopmental disorders (65864).
• Blepharitis. It is unclear if oral omega-6 fatty acids are beneficial for blepharitis. Details: One preliminary clinical study in patients with Meibomian gland dysfunction shows that taking a specific product (Medilar, Fidia Oftal Bausch & Lomb Pharmaceuticals), which contains the omega-6 fatty acids linoleic acid 28.5 mg and gamma-linolenic acid 15 mg, once daily for 180 days in combination with eyelid hygiene can improve cloudiness from eye secretions and gland obstruction when compared with baseline (66665). However, the lack of a control group limits the validity of these results. Population research involving postmenopausal adults has also found that moderate dietary intake of omega-6 fatty acids is associated with a reduced risk of developing Meibomian gland dysfunction. However, high intake was not associated with a reduced risk in these patients, and the protective effect of omega-6 fatty acids, if any, in the general population is unclear (99978). Higher quality research is needed to confirm these results.
• Cancer. It is unclear if increased dietary intake of omega-6 fatty acids is beneficial for cancer prevention. Details: In a meta-analysis of clinical research, increasing intake of dietary omega-6 fatty acids does not seem to reduce cancer risk or mortality. However, the included research is of low quality (107005). Also, a meta-analysis of population research has found that dietary intake of omega-6 fatty acids is not associated with cancer risk. However, high blood levels of omega-6 fatty acids were associated with an 8% reduced risk of cancer when compared to low blood levels, with breast cancer carrying the strongest association. Each 5% increase in blood levels of omega-6 fatty acids was associated with a 2% decreased cancer risk (107006). These results should be interpreted with caution, since factors other than omega-6 fatty acid intake, such as alcohol intake or overall diet, may affect blood levels of omega-6 fatty acids (100516).
• Developmental coordination disorder (DCD). Oral omega-6 fatty acids have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of omega-6 and omega-3 fatty acids for 3 months can improve reading, spelling, and behavior, but not motor skills, when compared with placebo in children with DCD (13748).
• Diabetes. It is unclear if higher dietary or supplemental intake of omega-6 fatty acids is associated with a reduced risk of diabetes. Details: Population research has found that the highest blood levels of the omega-6 fatty acid linoleic acid are associated with a 43% reduced risk of developing diabetes over a period of 5-42 years when compared with the lowest blood levels. Blood levels of another omega-6 fatty acid, arachidonic acid, do not seem to be linked to diabetes risk (96914). These results should be interpreted with caution, since factors other than omega-6 fatty acid intake, such as alcohol intake or overall diet, may affect blood levels of omega-6 fatty acids (100516). In addition, a meta-analysis of low-quality clinical research does not support any benefit of omega-6 fatty acids in the prevention or treatment of type 2 diabetes (101504).
• Diarrhea. It is unclear if formula supplemented with arachidonic acid is beneficial for diarrhea prevention in infancy. Details: Preliminary clinical research shows that infant formula supplemented with arachidonic acid 34 mg/100 kcal and docosahexaenoic (DHA) acid, an omega-3 fatty acid, 17 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) can reduce the incidence of diarrhea in the first year of life when compared with non-supplemented infant formula (92505).
• Dry eye. It is unclear if dietary intake of omega-6 fatty acids is beneficial for dry eye prevention. Details: Population research has found that higher intake of dietary omega-6 fatty acids is not associated with a reduced risk of dry eye after menopause (99978).
• Hypertension. It is unclear if dietary intake of omega-6 fatty acids is beneficial for blood pressure reduction. Details: Population research has found that higher dietary intake of omega-6 fatty acids, especially linoleic acid, is inversely associated with the odds of hypertension in non-diabetic individuals. However, in patients with diabetes, higher intake of omega-6 fatty acids is associated with an increased odds of hypertension (99975).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if dietary intake of omega-6 fatty acids is beneficial for NAFLD prevention. Details: Cross-sectional population research is mixed with respect to dietary intake of omega-6 fatty acids in patients with NAFLD when compared with healthy controls. One large cross-sectional study based on data from the National Health and Nutrition Examination Survey (NHANES) between 2007-2014 has found that consuming omega-6 fatty acids at a dose of at least 250 mg/kg daily is associated with an 82% reduced risk of having NAFLD when compared with consuming less than 121.3 mg/kg daily (107002).
• Obesity. It is unclear if oral omega-6 fatty acids are beneficial for reducing cholesterol or triglyceride levels in adults with obesity. Details: In individuals with abdominal obesity, a small clinical trial shows that taking linoleic acid 15 grams (females) or 20 grams (males) (Pharmatech AS) daily for 7 weeks from safflower oil has modest beneficial effects on levels of low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-, and total cholesterol when compared with baseline or taking fish oil. However, there was no effect on triglyceride levels (107003).
• Photoreactive keratectomy. Oral omega-6 fatty acids have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: Preliminary clinical research in patients who have undergone photoreactive keratectomy shows that taking a tablet containing the omega-6 fatty acids linoleic acid and gamma-linolenic acid, as well as beta-carotene, B vitamins, and trace minerals, daily for 30 days can improve tear production and eye healing when compared with a control group (66679).
• Respiratory tract infections. It is unclear if supplementing infant formula with arachidonic acid is beneficial for preventing respiratory tract infections. Details: Preliminary clinical research shows that infant formula supplemented with arachidonic acid 34 mg/100 kcal and docosahexaenoic acid (an omega-3 fatty acid) 17 mg/100 kcal (Enfamil Premium 1 and Enfamil Premium 2, Mead Johnson Nutrition) can reduce the incidence of respiratory illness in the first year of life when compared with non-supplemented infant formula (92505). More evidence is needed to rate omega-6 fatty acids for these uses.

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LIKELY SAFE ...when used in amounts found in foods. Astaxanthin has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when taken orally and appropriately. Astaxanthin 4-18 mg daily has been used with apparent safety for up to 12 weeks. Doses of 40 mg daily have been used with apparent safety for up to 4 weeks (19165,19167,19197,32621,96884,105100).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in amounts greater than those typically found in foods.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Krill oil has been used safely at doses of up to 4 grams daily in clinical trials lasting for up to 6 months (15753,15754,15760,19374,91600,96114,96162,107474,110370).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately (110372,110374). In children 14 years of age, krill oil 4 grams daily, providing doses of eicosapentaenoic acid (EPA) 520 mg and docosahexaenoic acid (DHA) 280 mg daily, has been used with apparent safety for up to 12 months (110372,110374).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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LIKELY SAFE ...when used orally in amounts found in foods. Dietary intake in amounts of 5% to 10% of daily calories are appropriate according to the Dietary Reference Intake (DRI) Acceptable Macronutrient Distribution Range (AMDR) (23723). There is insufficient reliable information available about the safety of omega-6 fatty acids when used orally in medicinal amounts.

CHILDREN: LIKELY SAFE
when consumed by children over the age of 12 months as part of the diet in amounts between 5% to 10% of daily calories according to the Dietary Reference Intake (DRI) Acceptable Macronutrient Distribution Range (AMDR) (23723).

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed as part of the diet in amounts between 5% and 10% of daily calories according to the Dietary Reference Intake (DRI) Acceptable Macronutrient Distribution Range (AMDR) (23723).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when high amounts of omega-6 fatty acids are consumed in the diet. Population research suggests that the highest maternal intakes of omega-6 fatty acids (15.2-47.6 grams or 137-428 kcal daily) during pregnancy is associated with a 2.4-times greater odds of giving birth to an infant below the 10th percentile for birth weight when compared with the lowest maternal intakes (0.4-5.7 grams daily) (96913). In addition, population research in women with a history of atopy suggests that the highest blood levels of omega-6 fatty acids during the second trimester is associated with an increased odds of having a child develop atopic dermatitis by age 4-6 years when compared with the lowest intakes (103309). There is insufficient reliable information available about supplemental omega-6 fatty acids; avoid using.

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CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, astaxanthin may decrease levels of drugs metabolized by CYP2B6.  Details In vitro research shows that astaxanthin induces cytochrome CYP2B6 enzyme activity in human hepatocytes (32613). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, astaxanthin may decrease levels of drugs metabolized by CYP3A4.  Details In vitro research shows that astaxanthin induces CYP3A4 enzyme activity in human hepatocytes (32613). This effect has not been reported in humans.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, krill oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Taking high doses of omega-3 fatty acids from fish oil can modestly decrease platelet aggregation (8671,8679,8696,19375). Since krill oil also contains these fatty acids, taking high doses of krill oil might also inhibit platelet aggregation. Theoretically, taking high doses of krill oil with antiplatelet or anticoagulant drugs might increase the risk of bleeding. However, the omega-3 content of krill oil is much lower than that of fish oil.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking krill oil with antidiabetes drugs might increase the risk of hypoglycemia.  Details Some research in animals and humans shows that krill oil might lower blood glucose levels (15753,19376). However, a small study shows that taking krill oil does not reduce blood glucose levels in patients with type 2 diabetes, most of whom were taking antidiabetes drugs (104572).

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General ...Orally, astaxanthin seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, red fecal color.

Gastrointestinal ...Orally, astaxanthin 6 mg daily has caused two cases of increased bowel movements and two cases of red fecal color (91736). A higher dose of astaxanthin (AstaCarox, AstaReal AB) 40 mg daily has caused severe stomach/abdominal pain in two patients (19165).

Ocular/Otic ...Canthaxanthin, another carotenoid substance that is chemically related to astaxanthin, has caused crystals in the retina and loss of visual acuity in one patient (8455). This effect has not been observed with astaxanthin, but patients who have visual changes while taking astaxanthin should stop taking it immediately.

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General ...Orally, krill oil seems to be well tolerated when used in doses up to 4 grams daily.
Most Common Adverse Effects:
Orally: Bloating, decreased appetite, diarrhea, fishy burps, flatulence, heartburn, nausea, and stomach discomfort.

Cardiovascular ...Orally, krill oil may cause hypertension, but this effect has only been observed for one patient in one clinical trial (91600).

Dermatologic ...Orally, krill oil may cause minor facial skin rash, skin oiliness, or localized pimples (15754,91599,110372,110374).

Gastrointestinal ...Orally, krill oil may cause gastrointestinal side effects including stomach discomfort or upset, decreased appetite, taste change, heartburn, fishy burps, bloating, flatulence, diarrhea, vomiting, and nausea (57836,91599,91600,110372,110374). However, these effects seem to be less severe or occur less often with krill oil compared to fish oil (15754).

Neurologic/CNS ...When taken orally, headache, tiredness, and dizziness have been reported rarely in clinical research (110372,110374).

Pulmonary/Respiratory ...When taken orally, sore throat has been reported rarely in clinical research (110372,110374).

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General ...Orally, consuming omega-6 fatty acids in amounts found in foods is well tolerated.

Cardiovascular ...Dietary intake of the omega-6 fatty acid linoleic acid in amounts of 5% to 10% of daily calories is appropriate according to the Dietary Reference Intake (DRI) Acceptable Macronutrient Distribution Range (AMDR) (23723). However, higher intake levels, especially when compared with omega-3 fatty acid intake, might be detrimental. For example, a higher ratio of dietary omega-6 to omega-3 fatty acids is thought to increase the risk of cardiovascular disease compared to a lower ratio (66678). However, the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism, the Council on Cardiovascular Nursing, and the Council on Epidemiology and Prevention, suggest that reduction of omega-6 fatty acids in the diet is unlikely to be beneficial for the cardiovascular system if replaced with saturated or trans-fatty acids (66692). Population research has found that higher intake of omega-6 fatty acids might be associated with hypertension and increased levels of plasma homocysteine, a risk factor for cardiovascular disease and atherosclerosis (65498,66640,66642).

Musculoskeletal ...In epidemiological research, increased intake of omega-6 fatty acids was associated with elevated risk of fracture in the elderly (66662).

Neurologic/CNS ...In epidemiological research, an increased dietary ratio of omega-6 fatty acids to omega-3 fatty acids has been associated with an elevated risk of having a sleep disorder (107001).

Oncologic ...Some population research has found that high omega-6 fatty acid intake or blood levels are associated with an increased risk for cancer, including breast cancer and prostate cancer (3508,7824,66660,66664,66729).

Psychiatric ...In epidemiological research, adolescents with attention-deficit hyperactivity disorder (ADHD) had higher levels of omega-6 and lower levels of omega-3 fatty acids in red blood cells (48200). The role of omega-6 fatty acids in ADHD is unclear; it is possible that the low levels of omega-3 fatty acids and essential fatty acids in general may be playing a role. Also, higher levels of some omega-6 fatty acids in the body are associated with greater depressive symptomology and neuroticism (65815,66659). Higher concentrations of some omega-6 fatty acids in red blood cells of patients with schizophrenia are correlated with positive schizotypal trait measures in healthy adults (66635). This may be related to increased intake of omega-6 fatty acids in the diet of patients with schizophrenia (96916).

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