From the abstract of a 2003 article titled “A Double-Blind, Placebo-Controlled Study of the Omega-3 Fatty Acid Docosahexaenoic Acid in the Treatment of Major Depression”:

Thirty-six depressed patients were randomly assigned to receive DHA, 2 g/day, or placebo for 6 weeks. Response was defined a priori as a >=50% reduction in the score on the Montgomery-Åsberg Depression Rating Scale. Thirty-five participants were evaluable; 18 received DHA, and 17 received placebo. RESULTS: Response rates were 27.8% in the DHA group and 23.5% in the placebo group. The difference in response rates between groups did not reach statistical significance. CONCLUSIONS: This trial failed to show a significant effect of DHA monotherapy in subjects with major depression.

This study is unusual in that it used DHA rather than EPA. EPA studies have been more successful. Excerpt from an overview:

One meta-analysis combined all the studies involving adults with unipolar or bipolar depression reported above, in which omega-3 fatty acids were used to augment existing treatments or as monotherapy. Best-case and worst-case analyses were carried out, and omega-3 fatty acids were found to produce a statistical improvement compared to placebo under both scenarios (best-case p = 0.02, worst-case p = 0.03). A second review including the same data has also suggested a benefit of omega-3 fatty acids in major depression. However, as the authors of both reviews point out, there is significant heterogeneity among the included trials, and this undermines the reliability of the combined results.

Here is the conclusion from another review article:

Trial evidence that examines the effects of n–3 PUFAs on depressed mood is limited and is difficult to summarize and evaluate because of considerable heterogeneity. The evidence available provides little support for the use of n–3 PUFAs to improve depressed mood.

A weak effect, in other words. I would be surprised if omega-3s helped a lot with depression. My self-experimentation pointed to a different cause of depression — seeing faces too little in the morning and/or too much at night.

Dr. Jorn Dyerberg was one of two Danish doctors who discovered that Eskimos in Greenland, with low rates of heart disease, have much more omega-3 in their blood than Danes in Greenland, with normal rates of heart disease. This was the beginning of the great interest in omega-3s. Here is an interview with Dr. Dyberg. Among his comments:

As for ALA, an omega-3 from plants that is converted in the body to EPA and subsequently DHA, he was unconvinced. In terms of biological effects of DHA and EPA, Dr. Dyerberg said there are many. “We don’t know of any specific biological effects of ALA,” he said.

“Tissue experiments give you an ALA concentration of zero. This omega-3 is either burnt or converted,” he said. “And the conversion is low.”

“If we want the benefits of omega-3, we have to eat them as long chain,” he said, referring to EPA and DHA.

My research — revealing very clear benefits of flaxseed oil, no doubt because of its ALA — shows this is quite wrong.

Thanks to Dave Lull.

I was surprised to see a chapter in Fish, Omega-3 and Human Health devoted to hypertension. Isn’t high blood pressure caused by too much salt and too much weight? Well, yes, but a special strain of rats used as an animal model of hypertension turned out to have a defect in their immune system. Perhaps high blood pressure is also caused by immune-system over-reaction.

A 1993 meta-analysis of studies of the effect of fish oil on blood pressure concluded:

Diet supplementation with a relatively high dose of omega-3 PUFA, generally more than 3 g/d, can lead to clinically relevant BP reductions in individuals with untreated hypertension.

The sizes of the blood pressure changes:

Weighted, pooled estimates of SBP [systolic blood pressure] and DBP [diastolic blood pressure] change (mm Hg) with 95% confidence intervals were -1.0 (-2.0 to 0.0) and -0.5 (-1.2 to +0.2) in the trials of normotensives, and -5.5 (-8.1 to -2.9) and -3.5 (-5.0 to -2.1) in the trials of untreated hypertensives.

A different meta-analysis reached essentially the same conclusion.

Note the use of fish oil. Fish oil has long-chain omega-3 fats, while flaxseed oil — which I have used in my self-experimentation — has only the short-chain omega-3 fat, which is converted to long-chain omega-3 after you eat it. Fish oil is often considered better because the omega-3s don’t need to be converted. But this way of thinking misses something. Because the omega-3s in flaxseed oil are converted to long-chain omega-3s by enzymes, the amount of long-chain omega-3 in the body rises more slowly (and thus lasts longer) than if you take fish oil supplying the same amount of long-chain omega-3. Flaxseed oil supplies a kind of time-release long-chain omega-3. A long low dose could easily be more potent than a short high dose.

Thanks to Dave Lull.

I ordered Fish, Omega-3 and Human Health (2005, 2nd ed.) by William Lands from Amazon in March. It came a few days ago. It is published by the AOCS Press. AOCS = American Oil Chemists’ Society.

A jewel of a book. Like a research monograph, it has lots of data, graphs, and references; unlike a research monograph, it tries to reach any scientifically literate reader, not just specialists. It has much more about mechanism than other books on the subject. “Health” in the title mainly means circulatory system health (heart disease, strokes); there is also a chapter on the immune system and a chapter on cancer. Almost nothing about mental illness or the brain. Nothing about gum disease.

I read the first edition a year ago. It is a sign of changes in my thinking that I didn’t notice a comparison of epilepsy rates in Eskimos (high omega-3 diet) and Danes (low omega-3 diet) living in Greenland. The Eskimos have twice as much epilepsy. It is the only big negative effect of the Eskimo diet. The epilepsy difference fits something I think now but didn’t think a year ago: omega-3 makes neurons more easily excited. Three observations led me to this: (a) In my choice reaction-time experiments, flaxseed oil caused an increase in anticipation errors. To reduce them, I changed from a two-choice task to a four-choice task. (b) A friend said I have become more talkative, apparently due to consuming much more flaxseed oil/day. (c) I found that flaxseed oil reduces simple RT — latency to press a button when something happens.

The two-to-one epilepsy ratio is the only case where the Eskimos are clearly worse off. The ratios in the other direction are much larger. The Danes had 20 times more psoriasis than the Eskimos (as I noted earlier), and 25 times more bronchial asthma.

…My sister said that — curious from reading this blog — she increased her daily dose of flaxseed oil from one capsule (10 calories) to 1 Tablespoon (110 calories) per day. She noticed three positive effects. One is that the skin around her fingernails improved. It cracked less often. (I’d say the same — hadn’t realized it until she mentioned it.) Another, first noticed by her dentist (”I didn’t say anything”), is that her gums were in better shape. The third, more subtle than the first two, is more energy. She has noticed no negative effects.

Anonymous wrote again, with new data:

I started taking two tablespoons of flax seed oil about a month after reading this post by you [about Tyler Cowen’s dental experience] (sometime around the beginning of August, I think). I decided to try it because I have had bleeding gums for about as long as I can remember. This has always confused me, because I don’t have any cavities and have otherwise good dental health. I would always ask my dentists about this, and they would always tell me I didn’t floss enough, but even when I would floss regularly, the bleeding wouldn’t totally stop. After about a week or so of two tablespoons of flax seed oil a day, I had virtually no gum bleeding. I didn’t change anything else.

Then, about two weeks ago, my girlfriend pointed something out to me: I was not taking pain relievers anymore. I train in amateur mixed martial arts (MMA), which is a very intense, full contact combat sport that combines boxing, muay thai, brazilian jiu-jitsu, and wrestling. For as long as I’ve been training in it, I have had to deal with muscle soreness and pain in my joints, and to deal with it, I would take 4-6 ibuprofen before training. But, for about the past three months, I wasn’t in enough pain to need it. I didn’t really think about it at first, just chalking it up to getting tougher. But that doesn’t make sense–I’ve been training in MMA for well over a year, and the only thing I have done differently in the past three months is start taking flax seed oil. I wasn’t 100% sure that the flax seed oil was making the difference, but considering the effect it has on inflammation–which is what ibuprofen is for–it made sense.

That was when I sent you the emails you posted. One of your commenters accused me of falling victim to the placebo effect, so I decided to test it. I stopped taking flaxseed oil on November 5th. At the time, my gums were not bleeding, I had no joint pain or soreness of any significance, and I felt great overall.

As I write this it’s November 15th. My gums have bled heavily when I brushed this week, especially the past few days, and I have intense pain in both shoulders, soreness in my left elbow, and my knees are throbbing. I had intended to go two weeks without taking any flaxseed oil, but I am stopping the experiment now because this is all the proof I need.

One more interesting fact: I took four tablespoons a few hours ago, instead of the regular two, thinking that maybe I could load up and it might help me get back to normal quickly. The pain is pretty much the same, and I just brushed and my gums bled, so obviously the flaxseed oil takes more than a few hours to affect those problems. But–and I haven’t measured this with reaction tests like you do–I feel considerably more mentally alert right now. I don’t know if I felt like this before, and maybe I didn’t notice it because it came on slowly, or maybe I need four tablespoons at once to see a difference, but I really do feel the difference.