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Compound-specific isotope analysis reveals no retroconversion of DHA to EPA but substantial conversion of EPA to DHA following supplementation: a randomized control trial

Metherel AH, Irfan M, Klingel SL, Mutch DM, Bazinet RP (2019) Am J Clin Nutr.  110(4) 823–831,, Epub June 17 

Web URL: Read this and related abstracts on PubMed here



It has long been believed that DHA supplementation increases plasma EPA via the retroconversion pathway in mammals. However, in rodents this increase in EPA is likely due to a slower metabolism of EPA, but this has never been tested directly in humans.


The aim of this study was to use the natural variations in 13C:12C ratio (carbon-13 isotopic abundance [δ13C]) of n-3 PUFA supplements to assess n-3 PUFA metabolism following DHA or EPA supplementation in humans.


Participants (aged 21.6 ± 2.2 y) were randomly assigned into 1 of 3 supplement groups for 12 wk: 1) olive oil control, 2) ∼3 g/d DHA, or 3) ∼3 g/d EPA. Blood was collected before and after the supplementation period, and concentrations and δ13C of plasma n-3 PUFA were determined.


DHA supplementation increased (P < 0.05) plasma EPA concentrations by 130% but did not affect plasma δ13C-EPA(-31.0 ± 0.30 to -30.8 ± 0.19, milliUrey ± SEM, P > 0.05). In addition, EPA supplementation did not change plasma DHA concentrations (P > 0.05) but did increase plasma δ13C-DHA (-27.9 ± 0.2 to -25.6 ± 0.1, P < 0.05) toward δ13C-EPA of the supplement (-23.5 ± 0.22). EPAsupplementation increased plasma concentrations of EPA and docosapentaenoic acid (DPAn-3) by 880% and 200%, respectively, and increased plasma δ13C-EPA (-31.5 ± 0.2 to -25.7 ± 0.2) and δ13C-DPAn-3 (-28.9 ± 0.3 to -25.0 ± 0.1) toward δ13C-EPA of the supplement.


In this study, we show that the increase in plasma EPA following DHA supplementation in humans does not occur via retroconversion, but instead from a slowed metabolism and/or accumulation of plasma EPA. Furthermore, substantial amounts of supplemental EPA can be converted into DHA. δ13C of n-3 PUFA in humans is a powerful and underutilized tool that can track dietary n-3 PUFA and elucidate complex metabolic questions.


Both of the main long-chain omega-3 fatty acids found in fish and seafood - EPA and DHA - are needed for brain health, and ideally, would be provided directly by the diet.

Shorter-chain omega-3 fats such as ALA - found in some plant and seed oils - do NOT have the same health benefits. And although some conversion of ALA to longer-chain omega-3 is possible within the body, this conversion process is not reliable - especially for DHA. For this reason, the scientific consensus is that omega-3 DHA should be considered an essential nutrient.(Brenna et al 2009)

This innovative study made use of a novel tracing technique to assess the origin of different omega-3 within the body, using blood samples from humans supplemented with EPA, DHA or an olive oil placebo in a randomised controlled trial. 

Results showed that:
1) if EPA alone is supplemented, blood EPA levels rise, and some EPA is converted to DHA (even though blood DHA levels do not change significantly)
2) if DHA alone is supplemented, blood DHA levels rise, but conversion of DHA to EPA does NOT happen (even though blood levels of EPA do increase, this appears to be simply because some EPA is spared from conversion into DHA).

These latest findings indicate that a direct dietary source of both EPA and DHA would be the most efficient way to ensure adequate blood and tissue levels of both these key omega-3.

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