By now you've heard the disappointing news that TREND-HD, the phase III clinical trial testing ethyl-EPA for Huntington's has failed. The facts are pretty clear, EPA was no better than placebo, and in the following weeks, the HD community took a deep breath and accepted that this was the end of the omega-3 story. But should it be? In this article Dr. Goodman suggests a second look-- and wonders if the wrong omega-3 was tested.

EPA and DHA Background: EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are essential fatty acids that are vital to brain health. While both molecules are important for many functions, DHA is by far the most abundant (many thousand-fold), and is the principle omega-3 in brain. EPA, though it may be more important in other tissues, is thought to play only a supporting role in brain [Freemantle E 2006]. Studies show that low blood levels of DHA (but not EPA) are correlated with greater risk of developing Alzheimer's [Schaefer EJ 2006] and neuropsychiatric disorders [Young G 2005].

Early pilot trials using ethyl-EPA gave no benefit in Alzheimers [Boston PF 2004], while an omega-3 combination containing almost 2 grams of DHA suggested benefit for those with early disease [Freund-Levi Y 2006]. DHA is the omega-3 selected by experts for Alzheimer Center Consortium Trials. The DHA dose for this trial is 2 grams per day (1 gram twice daily). Alzheimer's scientists believe that high doses of DHA is the drug to test for brain disorders, and that EPA may be far inferior (private communication with University of California researcher Dr. Greg Cole).

Why no DHA in Trend-HD? Company scientists assumed that DHA was not needed. They believed that a significant portion of Miraxion EPA would be converted to DHA in the human body, but it is unclear if this was measured. However, scientific reports in late 2006 and early 2007 (after TREND-HD began) suggested that this assumption was not correct. Martek Biosciences, the drug company whose DHA is being used in Alzheimers, report that EPA is not converted at significant levels to DHA in blood [Arterburn LM 2006]. In fact pure EPA may have detrimental effects by displacing the more important DHA from membranes [Portolesi R 2007].

These findings suggest that EPA may have been the wrong omega-3 to study. TREND-HD may tell us nothing about the effect of DHA in Huntington's.

Should we stop taking DHA omega-3 supplements? The real answer is that we still don't know. Decisions for using DHA can be based only on evidence from preclinical studies and clinical trials in other brain diseases.

In hindsight it is regrettable that EPA was tested alone. But the much more profound downside is not that EPA gave negative results, but that we are likely to never know whether DHA is useful. There aren't many drug companies willing to take the multi-million dollar chance to test another omega-3 in Huntington's. Results from the DHA Alzheimer's trial may be the best evidence we ever get.

What to do next? Because the clinical trial answer is still unknown for DHA, omega-3 supplements containing DHA will remain on the HDDW favorites list. If you decide to take an omega-3 supplement, make sure it contains plenty of DHA, and is free of contaminants. Though 1 gram twice daily is being used in clinical trials, "best" DHA dosage is not known. It is also unclear that combinations of EPA and DHA would be better than DHA alone.

HDDW has used OmegaBrite in Huntington's Disease Drug Work trials. However, based on present research, I believe this preparation contains too little DHA and is not the best choice for HD.

Dr. Goodman's "new" favorite: On my review of available omega-3 supplements, the one that stands out is OmegaLife-3. It has passed high level pharmaceutical grade testing at Covance and contains 400 grams of DHA per tablet. This is higher DHA dosage per pill than any approved by Consumer Lab, but would require 10 tablets per day to equal the dose used in Alzheimer's clinical trials. Because this product contains high doses of EPA as well, the high dose of combined omega-3's will cause diarrhea. Instead, I recommend slowly increasing to the dose that does not cause side effects.

There's another good reason to use this product. Alan and Sandy McDonald have established the St. Louis Huntington's Disease Foundation, and partnered with Unicity, the manufacturer of OmegaLife-3. Through this foundation, Unicity "gives back" a portion of proceeds to support HD organizations of the purchaser's choice. This is a great way to do business.

References

Freemantle E, Vandal M, Tremblay-Mercier J, Tremblay S, Blachère JC, Bégin ME, Brenna JT, Windust A, Cunnane SC. Omega-3 fatty acids, energy substrates, and brain function during aging. Prostaglandins Leukot Essent Fatty Acids. 2006 Sep;75(3):213-20. Epub 2006 Jul 7. PubMed abstract

Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006 Nov;63(11):1545-50. PubMed abstract

Young G, Conquer J. Omega-3 fatty acids and neuropsychiatric disorders. Reprod Nutr Dev. 2005 Jan-Feb;45(1):1-28. PubMed abstract

Boston PF, Bennett A, Horrobin DF, Bennett CN. Ethyl-EPA in Alzheimer's disease--a pilot study. Prostaglandins Leukot Essent Fatty Acids. 2004 Nov;71(5):341-6. PubMed abstract

Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. PubMed abstract

Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1467S-1476S. PubMed abstract

Portolesi R, Powell BC, Gibson RA. Competition between 24:5n-3 and ALA for Delta 6 desaturase may limit the accumulation of DHA in HepG2 cell membranes. J Lipid Res. 2007 Jul;48(7):1592-8. Epub 2007 Apr 4. PubMed abstract