Friday, August 12, 2011

Omega 3, Inflammation, and Anxiety in Medical Students

During all the fist-pumping, bright, sparkly eye-admiring, and general back-slapping of the inaugural Ancestral Health Symposium last weekend, the world of academia rolled on, and some cool evolutionary psychiatry-type papers were published.  Today's entry reviews a neat paper from my favorite journal, Brain, Behavior, and Immunity.  Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial.  Somehow I missed it in all the pre-conference hoopla, but as usual Jamie was Johnny-on-the-spot and emailed me the link.  And he thinks I'm the nerd.  :-)

This paper combines a lot of positives - a randomized controlled trial, using actual blood metrics (plasma 6:3 ratios and PBMC 6:3 ratios along with measurements of inflammatory cytokines.)  And they weren't completely stupid with the placebo (so many RCTs of omega 3 supplementation in mental health use soybean oil or olive oil placebos - both of which can throw a huge question mark into the results, as both may have their own mental health effects).

Let's begin with the interesting stuff from the introduction.  Inflammation is related to all sorts of bad mojo like heart disease, autoimmune disease, stroke, and mental illness.  Populations that eat more fish tend to suffer less from these diseases, and it is felt that the omega-3 PUFAs in fish may be protective against inflammation.  Epidemiological data and observational studies have shown higher fish or DHA and EPA intake is associated with lower incidence of depressive disorders, both in non-psychiatrically ill and psychiatrically ill populations.  The randomized controlled trials of omega 3 supplementation have had mixed results, with an overall trend for improving clinical depression, but not necessarily sub-clinical depressed mood.  The data for anxiety disorders is less robust - lower omega-3 plasma levels are found in folks with social anxiety, but two small RCTs of supplementation in anxiety also had mixed results.  It is important to know that both anxiety and depression are associated with an increase in pro-inflammatory cytokines - most commonly measured ones are IL-6 and TNFalpha.

Very roughly (for more info, visit Anastasia's latest post), omega 3 fatty acids become anti-inflammatory cytokines, and omega 6 fatty acids become inflammatory cytokines (as always in biochemistry that is not the whole story, but it will work for our purposes today).  Therefore, increasing omega 3s will help reduce inflammation, or so goes the theory.  My favorite grumpy Belgian Dr. Maes had a cool paper out in 2000 showing that medical students with worse (ie higher) serum 6:3 ratios had higher increases in inflammatory markers (LPS and TNFalpha) during exam times.  Interesting.  Let's see what happens in the medical students from today's paper.

Over the course of a few years, several cohorts of a total of 68 medical students, aged 21-29, 38 men and 30 women, were randomized to either an omega 3 supplement of 2085mg EPA and 348 mg DHA (I think this is the OmegaBrite supplement sold by a Harvard psychiatrist, Andy Stoll - I think he led a grand rounds for us, but I don't know him personally) or placebo.  The placebo was a mixture of palm, olive, soybean, canola, and coco butter oils meant to mimic standard fatty acid ratios consumed by adults in the US.  The placebo also had a fish flavoring added to keep the experiment blinded.   The supplementation went on for about 12 weeks total, and data was collected before, during (critically, the day before major exams) and several months after supplementation was discontinued.

The fatty acid ratios were studied in an interesting way - first straight-up plasma levels were measured, then levels were measured from inflammation-stimulated cultures of peripheral blood mononuclear cells (PBMCs, like lymphocytes).  Que?  Well,  the reservoir of active omega 6 and omega 3 precursors to our inflammatory or anti-inflammatory response is housed on our cell membranes - so when you stimulate these immune T or B cells with an inflammatory signal (typically LPS is used), they start spitting out cytokines in response, the level of inflammatory response depending upon what raw omega 3 or omega 6 materials they have.  So in this experiment, not only was the straight-up omega 6 to omega 3 ratio in the blood measured, so was the simulated omega 6 and omega 3 inflammatory/anti-inflammatory immune response itself.  Kinda neat.  All right.

Results!  An impressive 67 of the 68 students completed the trial (med students are dutiful).  Any "habitual fish-eaters" and anyone on omega-3 supplementation or other inflammation-modulating medication or supplement regimen was excluded, along with anyone with any health problems or any smokers.  At the beginning, levels of the omega 3s DHA and EPA were about the same across all groups - by the third blood draw, plasma levels of EPA and DHA were 6-fold and 1/2-fold higher in the experimental group than in controls.  The levels in the PMBCs were 3 fold and 1/3 fold higher than in controls.

As for the inflammatory response and anxiety levels in the students, supplementation reduced the levels of IL-6 and TNFalpha by 14% in the experimental group, and anxiety scores (which were low across all groups at all measured times) were also decreased by 20% in the experimental group.  There was no change in the amount of inflammation at exam-time, unlike in the previous Maes study.

The researchers found these results to be pretty exciting - especially as this was a young, healthy population.  The average 6:3 ratio at baseline was 10.82, which is quite a bit lower than the population averages of 15-17:1 (though markedly higher than Cordain's estimates of 3:1 in hunter-gatherers).  Baseline levels of IL-6 and TNFalpha for all the medical students were lower than the population average and baseline intake of EPA+DHA in these students was 70% higher than their national age peers.  So even though these medical students had better ratios and less simmering inflammation than the general population and were perhaps a poor choice for this particular study, the OmegaBrite intervention significantly decreased the inflammatory response, and the changes might have been more marked in a more typical American population.  And, indeed, previous randomized controlled trials of omega 3 PUFA supplementation have rather consistently produced decreased inflammation in the elderly, diabetics, and folks with high triglycerides.

This study is the first one to show anxiolytic effects of omega 3 supplementation in a population without baseline anxiety.  Depression scores (like the anxiety scores, low at baseline) were not affected - which is in concordance with the large body of evidence showing omega-3 PUFA supplementation can be effective for clinical but not sub-clinical depression.

The paper ends with an interesting discussion of the safety of omega-3 fatty acid supplementation - at these low amounts, there is not an increase in hemorrhagic stroke or bleeding time, even in combination with aspirin.  Epidemiologic studies show decreased risk of dying from pneumonia, reduction in post-surgical infections, and much lower risk of thrombotic stroke in folks who eat more fish.  The FDA deems that doses up to 3 grams per day of marine PUFAs are "generally recognized as safe."

So - medical students - 2.5g daily of EPA/DHA equals 20% less anxiety and 14% less inflammation.  Everyone else might benefit even more.  Since we know by taste that fish aren't rotten (I hope), I think it is safest to get fish oil from fish (wild-caught and sourced carefully to avoid PCBs and heavy metals), and safer still to limit all easily oxidized PUFAs (6 and 3) in the diet to the minimal requirements we need.

* My big omega 3 post can be found here:  Your Brain on Omega 3
* Biochem nerds will want to check out this paper by Omega 3 Heavy Hitter Artemis Simopoulos


  1. Nice find! I happened to buy 6 tins of smoked oysters and 4 of sardines (packed in olive oil) this morning. Ate one of each today chased down with bone broth so good, it was solid jello when I pulled it out of the fridge. This kind of eating leaves me calm and clear headed. Now if I could only get my neurotic 6-year old to partake....

  2. I would have loved to see then also measure pre and post testing HDL levels and LDL levels with the fishoil consumption. Everyone goes on and on about how they lower TG's but their bigger longterm affect is on raising HDL because they decrease IL-6 and TNF alpha which are the main stimulants to raising acute phase reactants. As HDL rises endotoxin clearance increases greatly in the portal circulation. Another lesser known effect is sleep improves as anxiety drops because of the rise in DHEA that occurs as IL-6 drops in the brain. This improves sleep and glutathione and SAMe in neurons. All cool stuff. Everyone should get O6/O3 ratios before they make a dietary change. Nice blog. Dr. Kruse

  3. Spectacular stuff. I knew I learned all of this gobbledygook for a reason. Excellent methodology, and so it looks like hard evidence that our ability to cope with inflammation is a factor in our ability to cope with anxiety. Makes sense to me.

    Dr. Kruse up there also seems to have answered my question about how this all influenced endotoxemia. Superb.


  4. The full paper seems to be available at,%202011.pdf

    I wonder how long it took blood level metrics to rise? The first blood test after supplementation began was apparently 3 weeks in.

  5. With all that anxiety about my own exam I seem to have missed this post. Maybe I needed a bit of EPA/DHA myself.

    I am quite interested in timelines like the previous commenter, gwern. I was under impression that you needed higher doses of bioavailable omega-3 to change the cellular membrane ratio in such a short period of time (3 weeks only). If omega-6 intake remains similar and displacement is the primary mechanism used I thought it takes much longer to force the ratio change. Interesting.

    Also how long term are the anti-inflammatory effects of such supplementation? Would be curious to retest blood levels 12 weeks after and see. I understand that desaturases/elongases have naturally a higher affinity to omega-3. Would it make the effect of "good diet" last longer? So many questions, so little time!

    Like your last paragraph. Totally agree: maximum benefit with minimal damage.
    Great article, thanks.

  6. Emily, I currently take Carlson's Finest lemon fish liquid. I take a whole tablespoon (instead of the suggested teaspoon) which gives me a total of 4800mg Omega 3's - 2400 EPA,1500 DHA and 900 other acids. What do you think? Carlson's makes a Medomega with one teaspoon giving you 2800mg Omega 3s - 1200 EPA and DHA, 400 other. Since I take a tablespoon I'm getting even more and I still save money as MedOmega is much more expensive... Thank you, Michael