What is the recommended dose and ratio of DHA (docosahexaenoic acid) to EPA (eicosapentaenoic acid) for omega-3 fatty acid supplementation?

DHA and EPA Dosing and Ratio Recommendations

For general cardiovascular health and disease prevention, consume 1000-1500 mg/day of combined EPA+DHA (approximately 2:1 EPA:DHA ratio) for at least 12 weeks, achievable through two servings weekly of fatty fish or triglyceride-form supplements. 1, 2

Dosing by Clinical Indication

General Cardiovascular Health and Primary Prevention

• Minimum effective dose: 400-500 mg/day EPA+DHA reduces CHD death risk by 37% 3
• Optimal dose: 1000-1500 mg/day EPA+DHA as triglycerides for ≥12 weeks to achieve omega-3 index ≥8%, associated with 90% reduction in sudden cardiac death 2, 4
• Dietary approach: Two servings weekly of fatty fish (salmon, mackerel, herring, sardines, albacore tuna) provides approximately 400-500 mg/day 1, 3

Documented Coronary Heart Disease (Secondary Prevention)

• Recommended dose: 850-1000 mg/day EPA+DHA combined 1, 4
• This dose demonstrated 45% reduction in sudden death and 15% reduction in total death, nonfatal MI, and nonfatal stroke in post-MI patients 1
• Formulation note: LOVAZA (FDA-approved) contains approximately 465 mg EPA and 375 mg DHA per 1-gram capsule, providing an EPA:DHA ratio of approximately 1.2:1 5

Hypertriglyceridemia

• Moderate hypertriglyceridemia (200-499 mg/dL): 2-4 grams/day EPA+DHA 1, 6
• Severe hypertriglyceridemia (≥500 mg/dL): 4 grams/day EPA+DHA reduces triglycerides by ≥30% 6
• Doses ≥2 grams/day required for significant triglyceride reduction; optimal doses are 3-4 grams/day with reductions of 25-45% 7
• Important: Doses >3 grams/day require physician supervision due to potential bleeding risk 1

Cognitive Health and Alzheimer's Prevention

• Standard dose: 1500-2000 mg/day EPA+DHA for individuals with genetic risk factors (APOE e4/e4) 8
• Preferred ratio: EPA:DHA ratio of approximately 2:1 for better cognitive outcomes 8, 9
• Fish intake up to 2 portions (250g) weekly associated with 30% reduction in Alzheimer's disease risk 10
• Dose-response relationship exists between omega-3 index achieved and improvement in executive function 10, 8

EPA:DHA Ratio Considerations

Ratio Variations in Clinical Studies

The evidence shows considerable variation in EPA:DHA ratios used across different conditions:

• Cognitive function studies: Ratios ranged from 1:2 (krill oil: 193 mg EPA/92 mg DHA) to 2.1:1 (EPA 1700 mg/DHA 800 mg) 10
• Cardiovascular studies: Most effective formulations used approximately 1.2:1 to 2:1 ratios 5
• General recommendation: EPA:DHA ratio ≥2:1 appears more effective for biological outcomes including cognitive and fertility benefits 8, 9

Formulation-Specific Ratios

• LOVAZA (FDA-approved): 465 mg EPA/375 mg DHA = 1.2:1 ratio 5
• Cognitive health protocols: 2:1 EPA:DHA ratio preferred 8, 9
• Triglyceride lowering: Both EPA-only and EPA+DHA formulations effective; EPA-only does not raise LDL-C in very high triglycerides 6

Bioavailability and Formulation

Triglyceride-form supplements are more bioavailable and effective than ethyl ester formulations 2

• Ethyl ester formulations (like LOVAZA) show dose-dependent increases in serum phospholipid EPA, but DHA increases are less marked and not dose-dependent 5
• For achieving omega-3 index ≥8%, triglyceride formulations require lower doses and shorter duration than ethyl esters 2

Safety Thresholds and Monitoring

Established Safety Limits

• Up to 5 grams/day: Combined EPA+DHA considered safe for long-term supplementation without increased bleeding risk 1
• EPA alone up to 1.8 grams/day: Specifically evaluated and deemed safe 1
• Monitoring required: Doses >3 grams/day require physician supervision 1

Common Side Effects

• Mild gastrointestinal symptoms (fishy taste, belching, nausea) are most common but do not represent safety concerns 1
• No increased bleeding risk observed with doses up to 4 grams/day, even with concurrent antiplatelet or anticoagulant therapy 1

Special Populations

Pregnancy and Lactation

• Omega-3 fatty acids (EPA and DHA) are detected in human milk; supplementation increases levels 5
• Pregnant/nursing women should limit fish consumption to 2 servings weekly due to mercury concerns; purified supplements are safer for higher intakes 9
• Animal studies show no teratogenic effects at clinically relevant exposures 5

Elderly Patients

• Safety and efficacy in patients >60 years does not differ from younger patients 5
• For established cardiovascular disease in elderly: at least 850-1000 mg EPA+DHA daily 1

Sex Differences

• Females have greater uptake of EPA into serum phospholipids than males, though clinical significance is unknown 5
• Men with higher n-3 PUFA levels show better executive functioning and processing speed, while women show better verbal and nonverbal episodic memory 10

Practical Implementation Algorithm

1. Determine clinical indication:

   • General health/primary prevention → 1000-1500 mg/day EPA+DHA 1, 2
   • Documented CHD → 850-1000 mg/day EPA+DHA 1, 4
   • Hypertriglyceridemia → 2-4 grams/day EPA+DHA 1, 6
   • Cognitive health/APOE e4 → 1500-2000 mg/day EPA+DHA 8

2. Select formulation:

   • Prefer triglyceride form over ethyl ester for better bioavailability 2
   • Choose EPA:DHA ratio ≥2:1 for cognitive benefits 8, 9
   • Standard formulations (1.2:1 ratio) acceptable for cardiovascular indications 5

3. Duration of treatment:

   • Minimum 12 weeks to achieve omega-3 index ≥8% 2
   • Longer duration (6-18 months) may be needed for cognitive outcomes 10

4. Monitoring:

   • Doses ≤3 grams/day: routine monitoring not required 1
   • Doses >3 grams/day: physician supervision with consideration of bleeding time checks 1
   • Consider omega-3 index testing to confirm achievement of ≥8% target 4, 2