Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4-year DHAX trial

Invest Ophthalmol Vis Sci. 2014 Jul 11;55(8):4958-66. doi: 10.1167/iovs.14-14437.


Purpose: Docosahexaenoic acid (DHA) continues to be evaluated and recommended as treatment and prophylaxis for various diseases. We recently assessed efficacy of high-dose DHA supplementation to slow vision loss in patients with X-linked retinitis pigmentosa (XLRP) in a randomized clinical trial. Because DHA is a highly unsaturated fatty acid, it could serve as a target for free-radical induced oxidation, resulting in increased oxidative stress. Biosafety was monitored during the 4-year trial to determine whether DHA supplementation was associated with identifiable risks.

Methods: Males (n = 78; 7-31 years) meeting entry criteria were enrolled. The modified intent-to-treat cohort (DHA = 33; placebo = 27) adhered to the protocol ≥ 1 year. Participants were randomized to an oral dose of 30 mg/kg/d DHA or placebo plus a daily multivitamin. Comprehensive metabolic analyses were assessed for group differences. Treatment-emergent adverse events including blood chemistry metabolites were recorded.

Results: By year 4, supplementation elevated plasma and red blood cell-DHA 4.4- and 3.6-fold, respectively, compared with the placebo group (P < 0.00001). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A, vitamin E, platelet aggregation, antioxidant activity, lipoprotein cholesterol, or oxidized LDL levels (all P > 0.14). Adverse events were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations). One participant was unable to tolerate persistent GI discomfort.

Conclusions: Long-term, high-dose DHA supplementation to patients with XLRP was associated with limited safety risks in this 4-year trial. Nevertheless, GI symptoms should be monitored in all patients taking high dose DHA especially those with personal or family history of GI disturbances. ( number, NCT00100230.).

Keywords: adverse events; biosafety; fatty acids.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Child
  • Chromatography, High Pressure Liquid
  • Dietary Supplements
  • Docosahexaenoic Acids / administration & dosage*
  • Docosahexaenoic Acids / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Electroretinography
  • Follow-Up Studies
  • Genetic Diseases, X-Linked / drug therapy*
  • Genetic Diseases, X-Linked / genetics
  • Genetic Diseases, X-Linked / metabolism
  • Humans
  • Male
  • Oxidative Stress / drug effects*
  • Retinitis Pigmentosa / drug therapy*
  • Retinitis Pigmentosa / genetics
  • Retinitis Pigmentosa / metabolism
  • Time Factors
  • Treatment Outcome
  • Young Adult


  • Docosahexaenoic Acids

Supplementary concepts

  • Retinitis Pigmentosa 6

Associated data