According to the European Food Safety Authority (EFSA), consumption of omega-3 fatty acids at observed intake levels has not been associated with adverse effects in healthy children or adults (303). Long-term supplemental intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) combined up to about 5 g/day do not appear to increase the risk of spontaneous bleeding episodes or bleeding complications, or affect glucose homeostasis immune function or lipid peroxidation, provided the oxidative stability of the fatty acids is guaranteed. Supplemental intakes of EPA and DHA combined at doses of 2–6 g/day, and just DHA at doses of 2–4 g/day, induce an increase in LDL-cholesterol concentrations of about 3%, which may not have an adverse effect on cardiovascular disease risk possibly due to ApoE genotype (340) or LDL particle size, whereas EPA at doses up to 4 g/day has no significant effect on LDL-cholesterol.
Supplemental intakes of EPA and DHA combined at doses up to 5 g/day, and supplemental intakes of EPA alone up to 1.8 g/day, do not raise safety concerns for adults. Supplemental intakes of DHA alone up to about 1 g/day do not raise safety concerns for the general population. No data are available for DPA when consumed alone.
Gamma-linolenic acid (18:3n-6)
Supplemental gamma-linolenic acid is generally well-tolerated and serious adverse side effects have not been observed at doses up to 2.8 g/day for 12 months (218).
High doses of borage seed oil, evening primrose oil, or black currant seed oil may cause gastrointestinal upset, loose stools, or diarrhea (216).
People with a history of seizures or seizure disorder are generally advised to avoid evening primrose oil and other gamma-linolenic acid-rich oils (216) and may prolong bleeding time (341).
Alpha-linolenic acid (18:3n-3)
Although flaxseed oil is generally well-tolerated, high doses may cause loose stools or diarrhea (219).
Allergic and anaphylactic reactions have been reported with flaxseed and flaxseed oil ingestion (220).
Potential for increased macular degeneration risk:
While some studies have shown that certain omega-3 fatty acids such as DHA may reduce the risk of developing macular degeneration other studies of shorter-chain omega-3 fatty acids suggest that, high doses of ALA may increase the risk of developing this disorder.
Clearly, more research is needed to evaluate a potential risk.
Potential for increased prostate cancer risk:
Some studies have shown that long-chain omega-3 fatty acids may reduce the risk of developing some cancers.
In contrast, a meta-analysis has suggested that consumption of high doses of shorter-chain omega-3 fatty acidssuch as ALA may increase the risk of prostate cancer and promote growth in late stage colon cancer (100).
However, a systematic review and meta-analysis examining more recent studies that were specifically designed to look for prostate cancer risk factors in humans and a systematic review found no such link (101).
Eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)
Serious adverse events have been reported rarely in those subjects using fish oil or other EPA and DHA supplements. U.S. health authorities have acknowledged that up to 3 g/day of long-chain omega-3 fatty acids (EPA and DHA) intake is Generally Recognized As Safe (GRAS) (2). The most common adverse effect of fish oil or EPA and DHA supplements is a fishy aftertaste. Belching and heartburn have also been reported. Additionally, higher doses may cause nausea and loose stools.
Potential for excessive bleeding:
The potential for high omega-3 fatty acid intakes, especially EPA and DHA, to prolong bleeding times has been well-studied, and may play a role in the heart-protective effects of omega-3 fatty acids. Although excessively long bleeding times and increased incidence of stroke have been observed with very high intakes of EPA + DHA (6.5 g/day), it is not known whether high intakes of EPA and DHA are the only factor responsible for these observations(1).
Although the Institute of Medicine did not establish a tolerable upper level of intake (UL) for omega-3 fatty acids, caution was advised with the use of supplemental EPA and DHA, especially for those who are at increased risk of excessive bleeding (1).
Potential for immune system suppression:
Although the suppression of inflammatory responses resulting from increased omega-3 fatty acid intakes may benefit individuals with inflammatory or autoimmune diseases, anti-inflammatory doses of omega-3 fatty acids could decrease the potential of the immune system to destroy disease-causing agents (e.g., virus or bacteria)(221,339).
Although it is not clear if measured immunosuppressive effects translate to impaired immune responses in vivo, caution should be observed when considering omega-3 fatty acid supplementation in individuals with compromised immune systems (1).
Linoleic acid (18:2n-6)
Potential for increased prostate cancer risk:
Animal studies have shown that omega-6 fatty acids (linoleic acid and arachidonic acid), such as the fat found in corn oil, promote the growth of prostate tumor cells. More research is needed to evaluate potential cancer-promoting effects in humans.
Randomized controlled trials have not found any adverse effects on growth in infants fed formulas enriched with AA and DHA for up to one year (17, 18).
In early studies of DHA-enriched infant formula, EPA- and DHA-rich fish oil was used as a source of DHA. However, some preterm infants receiving fish oil-enriched formula had decreased plasma AA concentrations, which were associated with decreased growth (222). This effect was attributed to the potential for high concentrations of EPA to interfere with the synthesis of AA, which is essential for normal growth. Consequently, EPA content was decreased and AA was added to DHA-enriched formula. Most currently available infant formulas contain only AA and DHA derived from fungal and algal sources, respectively, or fish oils with a DHA/EPA ratio above 3.
The safety of supplemental omega-3 and omega-6 fatty acids, including borage seed oil, evening primrose oil, black currant seed oil, and flaxseed oil, has not been established in pregnant or breast-feeding (‘lactating’) women (216). Studies of fish oil supplementation during pregnancy and lactation have not reported any serious adverse effects.
Some species of fish – especially larger predatory fish (e.g., swordfish) – may contain significant levels of environmental contaminants, such as methylmercury, polychlorinated biphenyls (PCBs), or others (44). Excessive exposure to these toxic substances can cause brain and kidney damage. Developing fetuses, infants, and young children are especially vulnerable to the toxic effects of mercury on the brain.
While removing the skin, fat, and internal organs of the fish prior to cooking and allowing the fat to drain from the fish while it cooks decreases exposure to a number of fat-soluble pollutants, such as PCBs (223), methylmercury is found throughout the muscle of the fish, so these cooking precautions will not reduce exposure to methylmercury.
In order to limit the exposure of the developing fetus, infants, and young children to methylmercury, health authorities have made the following recommendations for women who may become pregnant, pregnant women, and breast-feeding women (147,342):
Several independent laboratory analyses in the U.S. have found commercially available omega-3 fatty acid supplements to be free of methylmercury, PCBs, and dioxins (224, 225, 226). In general, fish body oils contain lower levels of PCBs and other fat-soluble contaminants than fish liver oils, and the absence of methylmercury in omega-3 fatty acid supplements can be explained by the fact that mercury accumulates in the muscle, rather than the fat of fish (2). Additionally, fish oils that have been more highly refined also contain lower levels of PCBs (227).
DHA algal oil supplements are contaminant-free, vegetarian, and sustainable sources of DHA manufactured under Good Manufacturing Practices (GMP) conditions from microalgae. The DHA algal oil is not from a genetically modified organism and is both kosher and halal.
As pyrrolizidine alkaloids, potentially liver-toxic and cancer-promoting compounds, can be found in various parts of the borage plant, people who take borage oil supplements should use products that are certified free of pyrrolizidine alkaloids (216).
Because of the potential for interactions, dietary supplements should not be taken with medication without first talking to an experienced healthcare provider.
Fat-soluble antioxidants, such as vitamin E, play an important role in preventing the oxidation of polyunsaturated fatty acids (PUFA). It has been suggested that the amount of vitamin E required to prevent the damaging effects of free radicals on PUFA (‘lipid peroxidation’) increases with the amount of PUFA consumed (1, 228).
One widely used intake recommendation is 0.6 mg vitamin E (alpha-tocopherol) per gram of dietary PUFA.
Authored by Dr Peter Engel in 2010, reviewed and revised by Karin Yurko-Mauro on 30.06.2017.