Fish oil
Omega-3/Drug Interactions:
GeneralGeneral: In human research, increased levels of docosahexaenoic acid (DHA) in the blood were associated with a decreased risk of relapsing to substance abuse (22). Antiallergic agentsAntiallergic agents: In human research, fish or omega-3 fatty acid intake was associated with a prevention of childhood eczema (430), infant atopic or allergic outcomes (355), and childhood asthma (136). AntiandrogensAntiandrogens: Clinical evidence suggests that dietary supplementation with PUFAs increases the efficacy of antiandrogen therapy in the treatment of prostate cancer (431). AntiarrhythmicsAntiarrhythmics: There is conflicting clinical evidence regarding the antiarrhythmic effects of fish oil (432; 433; 434; 155; 435). Eicosapentaenoic acid (EPA) may block fast voltage-dependent sodium channels via specific binding, which results in prolongation of the inactivated states of these channels (436; 437). Fish oil may have a protective against arrhythmias; however, the exact mechanism is not understood, nor are the effects with antiarrhythmic agents. AntiasthmaticsAntiasthmatics: There is conflicting evidence regarding the effect of fish oil on asthma (442; 140; 443; 444; 445; 446; 142; 331; 447; 448; 449; 450; 451), and its effects with antiasthma drugs are not well understood. In one clinical study, a decreased use of short-term bronchodilators was reported (178). However, exacerbation of asthma has also been reported (117; 371; 126; 259). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: There are case reports of increased bleeding and elevated international normalized ratios (INR) in patients taking warfarin or aspirin with fish oil (97; 98; 320). Diets containing salmon oil, mackerel, or cod liver oil have been reported to prolong bleeding times in healthy volunteers (374; 452; 453; 454; 455). This effect may be due to fish oil-induced suppression of thromboxane A2 synthesis. In human research, the addition of omega-3 ethyl esters to a combination of aspirin and clopidogrel increased the platelet response to clopidogrel after percutaneous coronary intervention (456). In patients who are aspirin-resistant, addition of omega-3 fatty acids to aspirin improved the response to aspirin and reduced platelet reactivity (457). Some clinical evidence suggests that fish oil does not affect coagulation, even when taken with anticoagulant or antiplatelet agents like aspirin (458; 377). Recent reviews report a lack of evidence for significant bleeding risk with fish oil consumption (378; 49; 459). Antidepressants: SSRIsAntidepressants: SSRIs: In human research, addition of omega-3 fatty acids to sertraline treatment did not increase the antidepressant effects of this agent (460). AntidiabeticsAntidiabetics: Although slight increases in fasting blood glucose levels have been noted in patients with type 2 ("adult-onset") diabetes, the available scientific evidence suggests that long-term effects of fish oil are lacking in patients with diabetes, including a lack of change in hemoglobin A1C levels (99; 100; 88; 249; 70). There are limited reports from the 1980s that increased insulin needs in diabetic patients taking long-term fish oils may be related to other dietary changes or weight gain (101; 102). A clear relationship between fish oil and antidiabetic agents is lacking. Selected abstracts from the British Dietetic Association Conference in 2008 on the impact of fish oil supplements on insulin sensitivity have been published (461); however, further details are lacking. AntiestrogensAntiestrogens: Laboratory evidence indicates a decreased estrogen receptor production with fish oil supplementation (114). Antigout agentsAntigout agents
: According to secondary sources, antigout agents may interact with fish oil supplementation.AntihypertensivesAntihypertensives: Multiple human trials report small reductions in blood pressure with intake of omega-3 fatty acids (103; 104; 105; 106; 107; 108; 109; 462; 463; 88; 70). Reductions of 2-5mmHg have been observed, and effects appear to be dose responsive (higher doses have greater effects) (104). DHA may have greater effects than EPA (464). According to a systematic review, treatment with omega-3 reduced mean arterial blood pressure when used in combination with diuretics and beta-blockers vs. diuretics and beta-blockers alone, and omega-3 reduced mean arterial blood pressure when used in combination with enalapril or ACE, calcium antagonist, beta-blockers, and diuretics (323). Anti-inflammatoriesAnti-inflammatories: Reduction of inflammation has been observed in various animal models (465; 466; 467; 468; 469; 470; 471) and in humans (472). In a clinical trial, two participants receiving omega-3 fatty acids experienced adverse reactions to aspirin or nonsteroidal anti-inflammatory agents (141). In patients with rheumatoid arthritis, treatment with fish oil capsules reduced the need for nonsteroidal anti-inflammatory drug use (70). Also, fish oil treatment increased the inhibitory activity of paracetamol by cyclooxygenase (70). In patients with neck or back pain, fish oil treatment resulted in reduced need for ibuprofen and reduced back and abdominal pain (473). In patients with rheumatoid arthritis, treatment with fish oil capsules reduced the need for nonsteroidal anti-inflammatory drug (NSAID) use and increased the inhibitory activity of paracetamol by cyclooxygenase (474; 475). AntilipemicsAntilipemics: In animal and human models, omega-3 fatty acids lowered triglyceride levels (476; 477; 88; 123; 130; 128; 70; 249) and increased HDL cholesterol levels (88; 123; 70; 249); they may increase (worsen), decrease (improve), or have no effect on low-density lipoprotein (LDL; "bad") cholesterol levels (123; 130; 70; 249). In human research, addition of omega-3 fatty acids to simvastatin increased LDL cholesterol levels; however, this increase was confined predominantly to those with low LDL cholesterol levels (478). Addition of simvastatin and omega-3 fatty acids had greater beneficial effects on plasma lipids over simvastatin alone (479; 382). In atorvastatin-treated patients, reduced non-high-density lipoprotein (HDL) cholesterol levels over atorvastatin alone (480). Total cholesterol, triglyceride, and very-low-density lipoprotein cholesterol levels were reduced, and HDL cholesterol levels increased, to a significantly greater extent than placebo plus atorvastatin. In rosuvastatin-treated patients, omega-3 improved endothelial-dependent vasodilation (481). Addition of the omega-3 fatty acids also further improved the lipid profile. The addition of EPA to statins increased the prevention of primary and secondary major coronary events (482). AntineoplasticsAntineoplastics: Epidemiologic evidence suggests that fish oil may reduce the risk of developing breast, colon, or prostate cancer (483; 484; 485; 486; 487; 488; 489). AntipsychoticsAntipsychotics: Preliminary evidence suggests that some psychiatric conditions, including depression and hyperactivity, are associated with low EPA and DHA levels (490; 491; 492; 213; 493; 494; 495; 496), and fish oil has been demonstrated to be beneficial in reducing symptoms of bipolar disorder in humans (146). In patients taking clozapine, omaga-3 fatty acids reduced triglyceride levels; total and LDL cholesterol levels increased (110). AntiretroviralsAntiretrovirals: In patients on antiretroviral therapy, omega-3 fatty acids reduced triglyceride levels (163; 497; 128). The potential effects of different doses of omega-3 PUFAs on hypertriglyceridemia, compared with fibrates, in patients with HIV on combination antiretroviral therapy has also been discussed (498); however, further details are lacking. AspirinAspirin: In a clinical trial, two participants receiving omega-3 fatty acids experienced adverse reactions to aspirin or nonsteroidal anti-inflammatory agents (141). In human research, use of fish oils in combination with aspirin increased bleeding (320). Bone agentsBone agents: Omega-3 fatty acids in combination with other agents had mixed effects on bone density in human research (499; 500; 501; 249). In a systematic review (502) of a single clinical trial of EPA plus DHA in women with osteoporosis (503), levels of osteocalcin and procollagen increased, and serum and urinary levels of calcium increased. The authors suggested that this may indicate an improvement in calcium absorption and osteoblastic activity. Cardiovascular agentsCardiovascular agents: In a meta-analysis, fish oil reduced heart rate, especially in patients with higher baseline heart rates or in those undergoing longer treatment duration (504). Increases (worsening) in low-density lipoprotein (LDL; "bad") cholesterol levels by 5-10% have been observed with intake of omega-3 fatty acids (357). In patients with ventricular tachycardia at study entry, there was worse outcome at two years in omega-3-supplemented patients in a study included in a meta-analysis (115). In elderly patients, 2g of fish oil daily for six months increased heart rate variability (358). CyclosporineCyclosporine: According to a systematic review, omega-3 lacked a statistically significant effect on cyclosporine levels following a kidney or heart transplant (323). Dermatologic agentsDermatologic agents: Skin rashes, itching, and skin irritation have been reported (221; 354; 123; 204; 141). Pruritus caused the withdrawal of one subject in a clinical trial (117). In a clinical trial, omega-3 fatty acid infusion caused a local skin reaction (330). DexamethasoneDexamethasone: In humans treated with omega-3 fatty acids, area under the curve of plasma insulin response was reduced following induction of insulin resistance by dexamethasone (505). Gastrointestinal agentsGastrointestinal agents: Gastrointestinal upset is common with the use of fish oil supplements, occurring in up to 5% of patients in clinical trials, with nausea in up to 1.5% of patients (312; 106; 221; 354; 362; 234; 179; 208; 180; 363; 364; 178; 365; 366; 330; 122; 151; 150; 260; 251; 141; 249). Diarrhea and loose stools may also occur (22; 193; 330; 151; 150; 126; 204; 259; 260; 261; 249; 134), with potentially severe diarrhea at very high doses (367; 116; 266; 178; 368). There are also reports of increased burping (221; 365; 366; 330; 127; 268; 122; 150; 251; 204; 134), acid reflux, heartburn, indigestion (369; 366; 259; 260; 261), abdominal bloating (362; 260), abdominal or gastrointestinal pain or discomfort (370; 160; 126; 204), anorexia (149), flatulence (150; 204), constipation (266), vomiting (360; 151; 150; 260; 141), steatorrhea (368; 371; 150; 126), fishy hiccups (141), metallic taste (141), and a fishy breath odor and aftertaste (110; 362; 221; 266; 364; 118; 365; 330; 127; 151; 150; 259; 260; 261; 251; 70; 141; 134). HepatotoxinsHepatotoxins: Mild elevations in liver function tests (alanine aminotransferase; ALT) have been reported rarely (119). However, in human research, omega-3 fatty acids were also found to improve levels of ALT and aspartate aminotransferase (AST) (263; 8). A parenteral lipid emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil decreased liver enzymes (AST, ALT, and alpha-glutathione S-transferase) vs. the control emulsion in postoperative patients (506). Hormonal agentsHormonal agents: Clinical evidence suggests that dietary supplementation with PUFAs increases the efficacy of antiandrogen therapy in the treatment of prostate cancer (431). There is laboratory evidence of decreased estrogen receptor production with fish oil supplementation (114). HypoglycemicsHypoglycemics: Although slight increases in fasting blood glucose levels have been noted in patients with type 2 diabetes, the available scientific evidence suggests that long-term effects of fish oil are lacking in patients with diabetes, including a lack of change in hemoglobin A1C levels (99; 100; 88; 249; 70). There are limited reports from the 1980s that increased insulin needs in diabetic patients taking long-term fish oils may be related to other dietary changes or weight gain (101; 102). A clear relationship between fish oil and antidiabetic agents is lacking. Selected abstracts from the British Dietetic Association Conference in 2008 on the impact of fish oil supplements on insulin sensitivity have been published (461); however, further details are lacking. HypotensivesHypotensives: Multiple human trials report small reductions in blood pressure with intake of omega-3 fatty acids (103; 104; 105; 106; 107; 108; 109; 462; 463; 88; 70). Reductions of 2-5mmHg have been observed, and effects appear to be dose responsive (higher doses have greater effects) (104). DHA may have greater effects than EPA (464). ImmunosuppressantsImmunosuppressants: In renal transplant patients, fish oil did not significantly alter immunosuppressant drug toxicity (specifically calcineurin inhibitor toxicity) (507). Neurologic agentsNeurologic agents: Restlessness and formication (the sensation of ants crawling on the skin) have also been reported (354). A short-term decline in memory was noted in some subjects (179). Headache, dizziness, depression, inability to sleep, and comorbid somatic disorders have been reported in clinical trials (361; 330; 251; 249; 134). Tiredness (significance vs. control was lacking) (151) and other psychiatric side effects (unspecified) have been reported (118). Fainting occurred in pregnant women at delivery, although differences vs. control were lacking (251). In a study reported in a systematic review, severe paresthesia and central nervous system toxicity occurred in one trial participant each (150). Ophthalmic agentsOphthalmic agents: Blurred vision has been reported (204). PaclitaxelPaclitaxel: The maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly DHA-paclitaxel (taxane fatty acid conjugate) were determined (508). The use of DHA allowed for the slow release of paclitaxel. Omega-3/Herb/Supplement Interactions:
Antiallergic agentsAntiallergic agents: In human research, fish or omega-3 fatty acid intake was associated with a prevention of childhood eczema (430), infant atopic or allergic outcomes (355), and childhood asthma (136). AntiandrogenicsAntiandrogenics: Clinical evidence suggests that dietary supplementation with PUFAs increases the efficacy of antiandrogen therapy in the treatment of prostate cancer (431). AntiarrhythmicsAntiarrhythmics: There is conflicting clinical evidence regarding the antiarrhythmic effects of fish oil (432; 433; 434; 155; 435). EPA may block fast voltage-dependent sodium channels via specific binding, which results in prolongation of the inactivated states of these channels (436; 437). Fish oil may have a protective against arrhythmias; however, the exact mechanism is not understood nor are its effects with antiarrhythmic agents. AntiasthmaticsAntiasthmatics: There is conflicting evidence regarding the effect of fish oil on asthma (442; 140; 443; 444; 445; 446; 142; 331; 447; 448; 449; 450; 451). In one clinical study, a decreased use of short-term bronchodilators was reported (178); however, exacerbation of asthma has also been reported (117; 371; 126; 259). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: There are case reports of increased bleeding and elevated international normalized ratios (INR) in patients taking warfarin with fish oil (97; 98). Diets containing salmon oil, mackerel, or cod liver oil have been reported to prolong bleeding times in healthy volunteers (374; 452; 453; 454; 455). This effect may be due to fish oil-induced suppression of thromboxane A2 synthesis or higher prostacyclin I3 levels. However, there is clinical evidence that suggests fish oil does not affect coagulation, even when taken with anticoagulant or antiplatelet agents like aspirin (458; 377). Recent reviews report a lack of evidence for significant bleeding risk with fish oil consumption (378; 49; 459). Antidepressants: SSRIsAntidepressants: SSRIs: In human research, addition of omega-3 fatty acids to sertraline treatment did not increase the antidepressant effects of this agent (460). AntidiabeticsAntidiabetics: Although slight increases in fasting blood glucose levels have been noted in patients with type 2 ("adult-onset") diabetes, the available scientific evidence suggests that long-term effects of fish oil are lacking in patients with diabetes, including a lack of change in hemoglobin A1C levels (99; 100; 88; 249; 70). There are limited reports from the 1980s that increased insulin needs in diabetic patients taking long-term fish oils may be related to other dietary changes or weight gain (101; 102). A clear relationship between fish oil and antidiabetic agents is lacking. Selected abstracts from the British Dietetic Association Conference in 2008 on the impact of fish oil supplements on insulin sensitivity have been published (461); however, further details are lacking. AntiestrogensAntiestrogens: Laboratory evidence indicates decreased estrogen receptor production with fish oil supplementation (114). Anti-inflammatoriesAnti-inflammatories: Reduction of inflammation has been observed in various animal models (465; 466; 467; 468; 469; 470; 471) and in humans (472). AntilipemicsAntilipemics: In animal and human models, omega-3 fatty acids lowered triglyceride levels (476; 477; 88; 123; 130; 128; 70; 249) and increased HDL cholesterol levels (88; 123; 70; 249); they may increase (worsen), decrease (improve), or have no effect on low-density lipoprotein (LDL; "bad") cholesterol levels (123; 130; 70; 249). AntineoplasticsAntineoplastics: Epidemiologic evidence suggests that fish oil may reduce the risk of developing breast, colon, or prostate cancer (483; 484; 485; 486; 487; 488; 489). AntioxidantsAntioxidants: In human research, a combination of EPA, gamma-linolenic acid (GLA), and antioxidants improved respiratory symptoms and decreased mortality in septic patients (509). In fish oil-supplemented mothers, a decreased antioxidant status was lacking (429). In humans exposed to particulate matter, supplementation with fish oil increased Cu/Zn superoxide dismutase activity and glutathione levels (7). In vitro, DHA decreased oxidative stress in human fibroblasts (510). GSH content increased and was associated with elevated catalytic activities of gamma-glutamyl-cysteinyl ligase, glutathione reductase, and glutathione S-transferase. AntipsychoticsAntipsychotics: Preliminary evidence suggests that some psychiatric conditions, including depression and hyperactivity, are associated with low EPA and DHA levels (490; 491; 492; 213; 493; 494; 495; 496), and fish oil has been demonstrated to be beneficial in reducing symptoms of bipolar disorder in humans (146). The effects of fish oil with antipsychotic agents are not well understood. Bone agentsBone agents: Omega-3 fatty acids in combination with other agents had mixed effects on bone density in human research (499; 500; 501; 249). In a systematic review (502) of a single clinical trial of EPA plus DHA in women with osteoporosis (503), levels of osteocalcin and procollagen increased, and serum and urinary levels of calcium increased. The authors suggested that this may indicate an improvement in calcium absorption and osteoblastic activity. Cardiovascular agentsCardiovascular agents: In a meta-analysis, fish oil reduced heart rate, especially in patients with higher baseline heart rates or in those undergoing longer treatment duration (504). Increases (worsening) in low-density lipoprotein (LDL; "bad") cholesterol levels by 5-10% have been observed with intake of omega-3 fatty acids (357). In patients with ventricular tachycardia at study entry, there was worse outcome at two years in omega-3-supplemented patients in a study included in a meta-analysis (115). In elderly patients, 2g of fish oil daily for six months increased heart rate variability (358). Conjugated linoleic acidConjugated linoleic acid: In human research, supplementation with CLA plus long-chain omega-3 fatty acids prevented increased abdominal fat mass and raised fat-free mass and adiponectin levels in younger obese individuals; insulin sensitivity was not negatively affected (511). In older obese men, the combination of omega-3 fatty acids and CLA increased fasting glucose (511). In human research, effects of CLA on DHA status were lacking, suggesting a lack of effect on synthesis of DHA from ALA (512). In intestinal cells in vitro, conversion of trans-vaccenic acid to CLA was affected by EPA (513). Dermatologic agentsDermatologic agents: Skin rashes, itching, and skin irritation have been reported (221; 354; 123; 204; 141). Pruritus caused the withdrawal of one subject in a clinical trial (117). In a clinical trial, omega-3 fatty acid infusion caused a local skin reaction (330). Evening primrose oilEvening primrose oil: In pregnant women, a combination of fish oil and evening primrose oil increased plasma gamma-linolenic acid (GLA), dihomo (D)-GLA, and DHA levels, without having a negative effect of arachidonic acid (514). Fat-soluble vitaminsFat-soluble vitamins: Reviewers noted that a theoretical interaction, although unproven clinically, exists between a fatty meal and an increase in lipid-soluble vitamin absorption (189). Also, fish liver oil contains the fat-soluble vitamins A and D, and therefore fish liver oil products (such as cod liver oil) may theoretically increase the risk of vitamin A or D toxicity. Vitamin D absorption from fish oil capsules vs. multivitamins was examined; differences were lacking (515). The effect of fish oil on vitamin D absorption has been examined (516); however, further details are lacking. FolateFolate: A combination of methyltetrahydrofolic acid and fish oil further increased fetal omega-3 status and attenuated depletion of maternal stores over fish oil alone in pregnant women (393). In human research, a combination of fish oil and 5-methyltetrahydrofolate (5-MTHF), during the second half of pregnancy, increased the level of proliferation cell nuclear antigen (PCNA) vs. placebo (517). Gamma-linolenic acidGamma-linolenic acid: In human research, a combination of EPA, gamma-linolenic acid (GLA), and antioxidants improved respiratory symptoms and decreased mortality in septic patients (509). According to a clinical trial, in patients with acute lung injury, a diet enriched with a combination of EPA and GLA was helpful for gas exchange, respiratory dynamics, and requirements for mechanical ventilation (518). Gastrointestinal agentsGastrointestinal agents: Gastrointestinal upset is common with the use of fish oil supplements, occurring in up to 5% of patients in clinical trials, with nausea in up to 1.5% of patients (312; 106; 221; 354; 362; 234; 179; 208; 180; 363; 364; 178; 365; 366; 330; 122; 151; 150; 260; 251; 141; 249). Diarrhea and loose stools may also occur (22; 193; 330; 151; 150; 126; 204; 259; 260; 261; 249; 134), with potentially severe diarrhea at very high doses (367; 116; 266; 178; 368). There are also reports of increased burping (221; 365; 366; 330; 127; 268; 122; 150; 251; 204; 134), acid reflux, heartburn, indigestion (369; 366; 259; 260; 261), abdominal bloating (362; 260), abdominal or gastrointestinal pain or discomfort (370; 160; 126; 204), anorexia (149), flatulence (150; 204), constipation (266), vomiting (360; 151; 150; 260; 141), steatorrhea (368; 371; 150; 126), fishy hiccups (141), metallic taste (141), and a fishy breath odor and aftertaste (110; 362; 221; 266; 364; 118; 365; 330; 127; 151; 150; 259; 260; 261; 251; 70; 141; 134). GlucosamineGlucosamine: In human research, a combination of omega-3 fatty acids and glucosamine was more beneficial than glucosamine alone for symptoms of osteoarthritis (519). HepatotoxinsHepatotoxins: Mild elevations in liver function tests (ALT) have been reported rarely (119). However, in human research, omega-3 fatty acids were also found to improve levels of ALT and AST) (263; 8). A parenteral lipid emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil decreased liver enzymes (AST, ALT, and alpha-glutathione S-transferase) vs. the control emulsion in postoperative patients (506). Hormonal agentsHormonal agents: Clinical evidence suggests that dietary supplementation with PUFAs increases the efficacy of antiandrogen therapy in the treatment of prostate cancer (431). There is laboratory evidence of decreased estrogen receptor production with fish oil supplementation (114). Hormone replacement therapyHormone replacement therapy: Decreased estrogen receptor production has been associated with fish oil supplementation (114). HypoglycemicsHypoglycemics: Although slight increases in fasting blood glucose levels have been noted in patients with type 2 diabetes, the available scientific evidence suggests that long-term effects of fish oil are lacking in patients with diabetes, including a lack of change in hemoglobin A1C levels (99; 100; 88; 249; 70). There are limited reports from the 1980s that increased insulin needs in diabetic patients taking long-term fish oils may be related to other dietary changes or weight gain (101; 102). A clear relationship between fish oil and antidiabetic agents is lacking. Selected abstracts from the British Dietetic Association Conference in 2008 on the impact of fish oil supplements on insulin sensitivity have been published (461); however, further details are lacking. HypotensivesHypotensives: Multiple human trials report small reductions in blood pressure with intake of omega-3 fatty acids (103; 104; 105; 106; 107; 108; 109; 462; 463; 88; 70). Reductions of 2-5mmHg have been observed, and effects appear to be dose responsive (higher doses have greater effects) (104). DHA may have greater effects than EPA (464). LycopeneLycopene: In vitro, lycopene and EPA synergistically inhibited the growth of human colon cancer HT-29 cells (520). ImmunosuppressantsImmunosuppressants: In renal transplant patients, fish oil did not significantly alter immunosuppressant drug toxicity (specifically calcineurin inhibitor toxicity) (507). Medium-chain triglyceridesMedium-chain triglycerides: In patients with severe hypertriglyceridemia, a formula containing omega-3 fatty acid medium-chain triglycerides resulted in a decrease in plasma triglycerides and cholesterol, and a slight reduction in glucose and uric acid (521). In men, following a bolus injection of 80% medium-chain triglycerides and 20% fish oil, omega-3 fatty acids increased in leukocytes and platelets within 60 minutes (522). Neurologic agentsNeurologic agents: Restlessness and formication (the sensation of ants crawling on the skin) have also been reported (354). A short-term decline in memory was noted in some subjects (179). Headache, dizziness, depression, inability to sleep, and comorbid somatic disorders have been reported in clinical trials (361; 330; 251; 249; 134). Tiredness (significance vs. control was lacking) (151) and other psychiatric side effects (unspecified) have been reported (118). Fainting occurred in pregnant women at delivery, although differences vs. control were lacking (251). In a study reported in a systematic review, severe paresthesia and central nervous system toxicity occurred in one trial participant each (150). PhosphatidylserinePhosphatidylserine: In a group of nondemented elderly with memory complaints, a novel preparation of phosphatidylserine with DHA attached improved cognitive performance vs. placebo (523). PhytosterolsPhytosterols: The combination of omega-3 fatty acids with phytosterols for decreased cardiovascular disease risk was the topic of a review (524). The authors discussed recent evidence suggesting that the combination of phytosterols and omega-3 fatty acids may reduce cardiovascular risk in a complementary and synergistic way. In human research in persons fed an olive oil-based diet, a supplement containing fish oil fatty acid esters of plant sterols reduced triglyceride levels more than sunflower oil esters of plant sterols (525). PolicosanolPolicosanol: The effects of a combination treatment with policosanol and omega-3 fatty acids on platelet aggregation have been studied in randomized, double-blind clinical research (526); however, further details are lacking.SeleniumSelenium: In humans, plasma selenium was positively correlated with fish consumption and omega-3 PUFAs in red blood cell PUFAs (527). Vitamin EVitamin E: Extended ingestion of fish oil may cause a deficiency of vitamin E (111; 112; 113). Omega-3/Food Interactions:
GeneralGeneral: The U.S. Food and Drug Administration (FDA) has ruled that the use of EPA and DHA, the primary omega-3 fatty acids found in fish, as dietary supplements is safe and lawful, provided that daily intakes of EPA and DHA omega-3 fatty acids do not exceed 3g per person from conventional food and dietary supplement sources.EggsEggs: In healthy volunteers, omega-3-enriched eggs (two eggs daily for six weeks) decreased triglyceride levels, as well as insulin and C-reactive protein (528).Ketogenic dietKetogenic diet: In animal research, an unrestricted ketogenic diet enriched with omega-3 fatty acids and medium-chain triglycerides delayed tumor growth (529). MilkMilk: In patients with metabolic syndrome, milk enriched with omega-3 and oleic acid fatty acids, folic acid, and vitamin E resulted in a reduction in serum triglycerides, as well as total and LDL cholesterol (530). Olive oilOlive oil: The addition of olive oil to patients supplemented with fish oil increased the beneficial effects of fish oil on rheumatoid arthritis symptoms (531). ProteinProtein: In cancer patients, a protein- and energy-dense EPA-containing nutritional supplement resulted in reduced weight loss and increased remission rate when compared with patients not receiving this supplement (532). Omega-3/Lab Interactions:
Adrenocorticotropic hormone (ACTH)Adrenocorticotropic hormone (ACTH): In human research, fish oil blunted ACTH levels in healthy humans submitted to intravenous lipopolysaccharide (321). AlbuminAlbumin: Decreased plasma albumin occurred in patients receiving omega-3 fatty acid supplementation (250). Alpha-tocopherolAlpha-tocopherol: In human research, omega-3 fatty acids increased alpha-tocopherol levels (326). Alzheimer's disease markersAlzheimer's disease markers: In patients with Alzheimer's disease (AD), dietary omega-3 fatty acids did not influence the AD markers tau-protein, hyperphosphorylated tau-protein, and beta-amyloid (Abeta(1-42)) in cerebrospinal fluid (533). Antioxidant statusAntioxidant status: In humans exposed to particulate matter, supplementation with fish oil increased Cu/Zn superoxide dismutase activity and glutathione levels (7). Arterial stiffness/flow-mediated dilationArterial stiffness/flow-mediated dilation: In human research, omega-3 fatty acids improved the capacitive arterial compliance and pulse wave velocity (137). In human research, omega-3 fatty acids increased flow-mediated dilation (168). Beta-hydroxybutyrateBeta-hydroxybutyrate: In healthy subjects, EPA decreased postprandial beta-hydroxybutyrate responses (534). Blood pressureBlood pressure: Multiple human trials have reported small reductions in blood pressure with intake of omega-3 fatty acids (103; 104; 105; 106; 107; 108; 109; 462; 463; 88; 70). Reductions of 2-5mmHg have been observed, and effects appear to be dose responsive (higher doses have greater effects) (104). DHA may have greater effects than EPA (464). Bone markersBone markers: Omega-3 fatty acids in combination with other agents had mixed effects on bone density in human research (499; 500; 501; 249). In a systematic review (502) of a single clinical trial of EPA plus DHA in women with osteoporosis (503), levels of osteocalcin and procollagen increased, and serum and urinary levels of calcium increased. C-reactive protein (CRP) levelsC-reactive protein (CRP) levels: The data on fish oils and CRP are mixed (535; 536; 537; 164; 538; 539; 261; 70; 191). While omega-3 fatty acids from both plants (ALA) and fish (EPA plus DHA) have been shown to reduce CRP in some studies, others have failed to show an effect or show an increase. CatecholaminesCatecholamines: In human research, fish oil blunted norepinephrine levels in healthy humans submitted to intravenous lipopolysaccharide (321). In human research, omega-3 fatty acids decreased plasma norepinephrine (540; 70). Coagulation panelCoagulation panel: There are case reports of increased bleeding and elevated international normalized ratios (INR) in patients taking warfarin with fish oil (97; 98). Diets containing salmon oil, mackerel, or cod liver oil have been reported to prolong bleeding times in healthy volunteers (374; 452; 453; 454; 455). In human research, fish oil reduced thromboxane B2 (70). In human research, oil from Schizochytrium spp. (high in omega-3 DHA and omega-6 DPA) increased factor VII coagulant activity (357). In human research, omega-3 consumption decreased platelet aggregation ex vivo (541; 8). CortisolCortisol: In human research, fish oil blunted plasma cortisol levels in healthy humans submitted to intravenous lipopolysaccharide (321). CreatineCreatine: In human research, omega-3 fatty acids consumption resulted in reduced serum creatine levels (165; 248). CreatinineCreatinine: In human research, omega-3 fatty acids increased serum creatinine (247). CytokinesCytokines: In Alzheimer's disease patients, fish oil rich in DHA reduced interleukin (IL)-6, IL-1beta, and granulocyte colony-stimulating factor secretion after stimulation of peripheral blood mononuclear cells with lipopolysaccharide (542). In general, the effects of fish oil on interleukins and tumor necrosis factor (TNF)-alpha are mixed (539; 126; 70; 542; 543; 164; 533; 544; 136; 545; 141; 145). Seafood consumption was associated with an influence on fasting levels of adipocytokines, including leptin, TNF-alpha, and adiponectin (88). Erythrocyte sedimentation rate (ESR)Erythrocyte sedimentation rate (ESR): In human research, EPA reduced ESR (126). In one study that assessed the effects of omega-3 fatty acids in patients with active ulcerative colitis, the treatment group had an increase in ESR despite the endoscopic score improving (261). FibrinogenFibrinogen: In human research, seal oil reduced fibrinogen levels (70). Glucose, insulin, and hemoglobin A1CGlucose, insulin, and hemoglobin A1C: Although slight increases in fasting blood glucose levels have been noted in patients with type 2 diabetes, the available scientific evidence suggests that long-term effects of fish oil are lacking in patients with diabetes, including a lack of change in hemoglobin A1C levels (99; 100; 88; 249; 70). There are limited reports from the 1980s that increased insulin needs in diabetic patients taking long-term fish oils may be related to other dietary changes or weight gain (101; 102). In human research, when the analysis was limited to only studies that assessed insulin sensitivity using HOMA scores, participants administered omega-3 fatty acids showed increased sensitivity (262). Heart rateHeart rate: In human research, habitual consumption of tuna or other fish and marine omega-3 was associated with specific heart rate variability components in older adults, including indices of vagal activity, baroreceptor responses, and sinoatrial node function (546). In human research, fish oil and omega-3 fatty acids decreased (547; 504; 5) or increased or lacked an effect on heart rate (191). HomocysteineHomocysteine: According to a meta-analysis, the effects of omega-3 fatty acids on homocysteine levels were mixed (169; 70). Inflammatory biomarkersInflammatory biomarkers: According to a systematic review, omega-3 fatty acid use is associated with changes in plasma biomarkers, reflecting reduced inflammation (548; 70). Intercellular adhesion molecule-1 (ICAM-1)Intercellular adhesion molecule-1 (ICAM-1): In hemodialysis patients, omega-3 fatty acids resulted in a decrease in serum sICAM-1 (164). According to a meta-analysis of human research, omega-3 fatty acid supplementation reduced levels of sICAM-1 (549; 539). Leukotrienes and prostaglandinsLeukotrienes and prostaglandins: In human research, omega-3 fatty acids increased synthesis of leukotriene B5 and suppression of leukotriene B4 synthesis, and increased synthesis of prostaglandin E2 (117; 550; 141; 70). In healthy subjects, DHA increased the leukotriene B5:leukotriene B4 ratio (551). In exercising subjects, omega-3 fatty acids decreased leukotriene E4, 9alpha,11beta-prostaglandin F2, and leukotriene B4 (145). Lipid profileLipid profile: In animal and human models, omega-3 fatty acids lowered triglyceride levels (476; 477; 88; 123; 130; 128; 70; 249) and increased HDL cholesterol levels (88; 123; 70; 249); they may increase (worsen), decrease (improve), or have no effect on low-density lipoprotein (LDL; "bad") cholesterol levels (123; 130; 70; 249). In human research, addition of omega-3 fatty acids to simvastatin increased LDL cholesterol levels; however, this increase was confined predominantly to those with low LDL cholesterol levels (478). In patients with metabolic syndrome, purified EPA decreased small, dense LDL cholesterol and remnant lipoprotein particles (538). In hypertriglyceridemic men, DHA decreased levels of triglyceride and small, dense LDL particles (238). In healthy men, fish oil in a single meal increased very-low-density lipoprotein (VLDL) concentration but reduced VLDL particle size vs. a reference meal (552). In healthy Japanese subjects with a high basal level of fish consumption, fish oil supplementation did not decrease plasma triglyceride, total cholesterol, LDL cholesterol, or whole-blood viscosity, and there were no changes in the fatty acid composition of plasma and erythrocyte phospholipids (553). In children with hyperlipidemia following a low-fat diet, DHA increased LDL subclass 1 and HDL subclass 2 (large and buoyant; less atherogenic particles) and decreased LDL subclass 3 (small and dense; more atherogenic particles) (554). In hypertriglyceridemic men, DHA decreased fasting plasma remnant-like particle-cholesterol (RLP-C) and improved the red blood cell omega-3 index, novel risk factors for cardiovascular disease (555). In type 2 diabetic patients, treatment with n-3 LC-PUFAs decreased the particle size of VLDL and increased the particle size of HDL (556). LipoproteinLipoprotein: In human research, pmega-3 fatty acids reduced lipoprotein (a) levels (218). Liver function testsLiver function tests: Mild elevations in liver function tests (ALT) have been reported rarely (119). However, in human research, omega-3 fatty acids were also found to improve levels of ALT and AST (263; 8; 557; 70). A parenteral lipid emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil decreased liver enzymes (AST, ALT, and alpha-glutathione S-transferase) vs. the control emulsion in postoperative patients (506). Lung function testsLung function tests: In human research, omega-3 fatty acids improved forced expiratory volume (142; 70). PlasmalogenPlasmalogen: In individuals with X-linked adrenoleukodystrophy, treatment with omega-3 fatty acids increased concentrations of plasmalogen in erythrocytes (8). Platelet countPlatelet count: In one study that assessed the effects of omega-3 fatty acid in patients with active ulcerative colitis, the treatment group had an increase in platelet count, despite the endoscopic score improving (261). Protein CProtein C: In human research, seal oil reduced protein C levels (70). Red blood cell omega-3 indexRed blood cell omega-3 index: In hypertriglyceridemic men, DHA decreased fasting plasma remnant-like particle-cholesterol (RLP-C) and improved the red blood cell omega-3 index, novel risk factors for cardiovascular disease (555). SelectinSelectin: According to human research, effects of omega-3 on e-selectin may be lacking or there may be slight increases (539). SeleniumSelenium: In humans, plasma selenium was positively correlated with fish consumption and omega-3 PUFAs in red blood cell PUFAs (527). ThrombomodulinThrombomodulin: In human research, omega-3 fatty acids decreased thrombomodulin levels (558). UreaUrea: In human research, krill oil decreased plasma levels of urea (70). Vascular adhesion molecule-1 (VCAM-1)Vascular adhesion molecule-1 (VCAM-1); According to systematic reviews, the effects on VCAM-1 are mixed, with increased, decreased, or no effects (549; 539). Very-long chain fatty acidsVery-long chain fatty acids: In individuals with X-linked adrenoleukodystrophy, treatment with omega-3 fatty acids reduced plasma concentrations of very-long-chain fatty acids (8). White blood cellsWhite blood cells: In healthy subjects, postoperative patients, and HIV patients, DHA increased the leukotriene B5:leukotriene B4 ratio (551; 163; 326).