Omega-3 Fatty Acids

(including Fish Oil)

(updated 12/2014)

Bottom line: the research is clear. This stuff works. Not very powerfully, and it takes a while to get in there. If you’re going to really do it, do it right: buy a version that is

  1. highly concentrated so you can get to 1,000 mg (1 gram) of EPA per day in 2 or 3 pills  per day
  2. at least 60% EPA. This means math, people, right there in the grocery store…

Introduction

Omega-3 fatty acids, given in the form of fish oil tablets, were shown in a 1999 controlled trialStoll to maintain mood stability far better than an olive oil placebo. This was a very exciting result, especially as the trial was inspired by “bench chemistry” — omega-3 fatty acids were recognized to have intracellular effects similar to lithium and valproate.

There are two “omega-3” fatty acids in fish oil: EPA (eicosapentaenoic) and DHA (docusahexaenoic). Some studies in people with depression or bipolar disorder have used EPA alone, including one of the most recent with the strongest positive results; but one of the larger earlier studies using EPA alone showed no benefit. Many of the other studies shown below, including the first one from Harvard, used fish oil tablets which provided both EPA and DHA. For now it seems safe to conclude that having both does not interfere with the antidepressant and mood stabilizing actions; and that EPA alone might be sufficient.

You may have heard of omega-3’s or fish oil as having some benefit in reducing heart disease as well. That research is a little farther along than the mood research. I have not followed it closely but it seems that the focus there is more on DHA than EPA. This means that if you want both benefits, you may need to stick with a source that has both EPA and DHA. Luckily, it turns out that the cheapest version has both, and has been lowest in the tests of mercury (undetectable levels).

Do they work?

Here’s a summary of many of the early fish oil studies regarding use in mood disorders.  Just notice a few things and go on:

  1.  there are a lot of them, it’s amazing;
  2.  omega-3’s have shown benefit in both bipolar and “unipolar” depression, and in bipolar prevention (mood stabilizer effect); and
  3. the doses are all over the place, so we needed a follow-up analysis (linked below) to establish what dose is sufficient.

In all the bipolar studies, and several of the depression studies, the omega-3 fatty acid dose was added to prior medications. These data should not be interpreted to indicate that O-3’s alone are a treatment for mood disorders.

Author / Link Condition Studied total # of patients; placebo control? EPA / DHA / fish oil (grams) Outcome
Stoll, 1999 Bipolar, recently in remission 80/placebo 9.6 grams of fish oil Relapse rate sharply reduced in O-3 group
Keck, 2006 Bipolar Depression 120/placebo 6 grams EPA No difference from placebo
Frangou, 2006 Bipolar Depression
(rather mild)
75 divided into three groups, incl. placebo; added to ongoing medications 1 gram EPA versus
2 grams EPA
EPA sig­nificant­ly better than placebo; 1 gram no better than 2; no increase in mania scores on EPA
Sagduyu, 2005 Bipolar 37/ no placebo 0.5 to 6 grams; mostly 1-2 grams less irritability
Osher, 2005 Bipolar Depression 12/no placebo 1-2 grams EPA 8 of 10 res­pon­ded; no mania increase
Zanarini, 2003 “Borderline” 30/placebo 1 gram EPA Decreased aggression, depression (if use particular statistical tweaking)
Jazaveri, 2008 Depressed 60/placebo 1 gram EPA or fluoxe­tine (Prozac) or both EPA equivalent to fluoxe­tine, com­bina­tion better than either alone
Nemets, 2002 Depressed 20/placebo 2 grams EPA Highly significant benefits by week 3
Peet, 2002 Depressed 70/placebo 1, 2, and 4 grams EPA only 1-gram group did best; 2 gms did not improve, 4 gms trended better
Marangell, 2003 Depressed 35/placebo 2 grams DHA At 6 weeks, a trend but not significant benefit
Silver, 2005 Depressed 77/placebo 8 grams of fish oil No benefit; used “in addition to usual therapy”, however
Su, 2003 Depressed 28/placebo (esti­mated) 4.4 grams EPA / 2.2 grams DHA Significant benefits versus placebo by week 4, bigger yet by week 8
Chiu, 2003 Depressed, pregnant case report 4 grams EPA/ 2 grams DHA Improve­ment by week 4, better yet by week 6
Su, 2008 Depressed, preg­nant 36/placebo 2.2 grams of EPA and 1.2 grams of DHA 62% responded, versus 27% on placebo; and remission, 38% vs. 18% on placebo.
Puri, 2001 Depressed, 7 yrs of rx not working Case report 4 grams of fish oil “structural brain changes” reported (smaller ventricles, which theoreti­cal­ly is consistent with brain growth)
Amminger et al. Schizo­phrenia prevention 41 “sub­threshold psycho­sis”/ 40 placebo 1.2 grams / day of omega – 3’s total 2 out of 41 taking fish oil developed psycho­sis; vs. 11 of 40 in the control group

What dose should I take?

A recent analysis suggests that 1 gram of EPA per day may be the best standard dose to shoot for. As much as 2 grams of EPA is okay but not clearly better. More than 2 grams might actually produce less benefit (not to mention how many pills that would require, and their cost).

How many pills do you need to get 1 gram of EPA? That depends on how concentrated the pill is, and how much EPA per pill. Cheaper means less concentrated, which means more pills per day to reach this target dose. Pay more, you might be able to take fewer pills.

But you also need a pill that’s at least 60% EPA. This means more math. See my Dose page for details on why you need that and how to do the math if you need some help.  My details page (Fish Stories) has some examples of the cheapest way to do this.

Risks (not mercury, not prostate cancer)

There are basically no known risks with fish oil. [Update August 2013: there are new concerns about prostate cancer risk. Men should see my separate page about omega-3’s and prostate cancer.] Three which have been discussed can be nearly dismissed, as shown here. This does not mean there are no risks; it means there are no significant known risks. Notice the difference. On the other hand, one cannot say anything as nearly reassuring about any of our regular medications. Here are four risks which have been discussed:  mercury / heavy metals  (really long section); hypomania; and bleeding; and prostate cancer.

1. Mercury. One of the cheapest fish oils, shown in the following table, has “undetectable levels” so you could stop worrying about it right there. But being reassured like that doesn’t work for a lot of people, so here are more details if you like. Otherwise, skip forward to the next risk)

Some would not entirely trust the United States Food and Drug Administration (FDA) for advice, but this at least gives you a yardstick of some kind. In 2014 the FDA updated their recommendations to pregnant women regarding fish consumption; but I like their earlier more explicit guidelines:

  • Do not eat Shark, Swordfish, King Mackerel, or Tilefish because they contain high levels of mercury.
  • Eat up to 12 ounces (2 average meals) a week of a variety of fish and shellfish that are lower in mercury.
    • Five of the most commonly eaten fish that are low in mercury are shrimp, canned light tuna, salmon, pollock, and catfish.
    • Another commonly eaten fish, albacore (“white”) tuna has more mercury than canned light tuna. So, when choosing your two meals of fish and shellfish, you may eat up to 6 ounces (one average meal) of albacore tuna per week.
  • Check local advisories about the safety of fish caught by family and friends in your local lakes, rivers, and coastal areas. If no advice is available, eat up to 6 ounces (one average meal) per week of fish you catch from local waters, but don’t consume any other fish during that week.

The table below gives mercury in a different unit, making comparison with the above yardstick difficult. A review article on fish oil for the American Heart Journal in March of 2006DeFillipis summarized this issue by noting that the FDA believes 10 mcg/L, which is found in some fish oils (see table below) is “negligible”. Less than 6 mcg/L, as with the Kirkland brand, means “undetectable” using these laboratory tests.

Brand Name Mercury level
(mcg/liter)
CVS 10
Kirkland <6
Nordic Ultimate <6
Omega-Brite 12
Sundown <6

Update 2014: an outfit called LabDoor has analyzed a large number of individual fish oil products. On their site you can pick yours and see their report which includes mercury. All products tested fell well below the amount below a suggested safe maximum (10 parts per billion; the highest was 3 parts per billion). But that limit was set by an industry group. Surfing through the 30 fish oils tested there, it looks like almost all fall between 2 and 4 parts per billion.  One product had 6 ppb, and the little Nordic Natural Fishies (like gummi-fish) had only 1 ppb, but that’s because so little of the product is actually fish oil!

Two recommendations emerge from all this:

  1. Since at least in theory there may still be some risk from heavy metal exposure if you’re taking high doses, you ought to be quite certain that taking it really make the difference, that it really helps you.
  2. If you are going to use it for a long time, you should probably use a version of fish oil which has the lowest levels of heavy metals you can find. Check yours on LabDoor. (I have no $ connection there)

2. Hypomania. Notice the emphasis in the research studies on depression, versus bipolar disorder. There is a report of hypomania developing while on omega-3’sKinrys (and in the Harvard study as wellStoll), although whether the fatty acids were the “cause” of this episode is of course not certain. I’m watching for more such reports (update 2011: no more reports, no patients of mine ever showing such signs I could associate with the fish oil…).

3. Blood clotting. Fish oil has a mild anti-blood-clotting effect, at least in some people.2007 This is thought to contribute to a possible reduction in heart problems (because heart attacks and strokes often involve a blot clot where it shouldn’t be clotting).  But it can have some effect on  blood coagulation if you taking aspirin or coumadin/warfarin Buckley , so you should let your doctors know you’re taking it.

4. Prostate cancer.  Bottom line, in my view: this is a non-issue. But it’s really complicated. I don’t think I’m missing something, but if you want to have a look at the data, here’s my introduction to the issue.

Fish burps

Although a few people may experience loose, fatty stool, the main side effect problem for fish oil is fish burps (“When I burp I feel like a seal”). This is usually managed by taking the pills with meals. If that isn’t sufficient to stop the problem, put the pills in the refrigerator, or freezer, between meals. This makes them sort of an “extended release” capsule. Watch out for condensation inside the bottle if you do this and live in a moist climate. You could just keep a week’s supply or so in a separate bottle that you open every day.

Conclusions

  • the evidence is now clear that omega-3 fatty acids do something, at least in some people;
  • make sure your pill has at least 60% EPA if you’re going to bother to do this at all;
  • the risks seem minimal, and there may actually be additional benefits (on cholesterol, perhaps arthritis);
  • for the lowest cost, it takes several large pills per day at least to get 1 gram of EPA (spend more, fewer pills);
  • fish burps can be managed easily
  • it’s not clear how long you have to wait to see benefits, but especially with the smaller doses they may take 1-2 months to show up, so if you take them, prepare yourself for a period of taking pills with no clear benefits.

Do I recommend them to my patients? Yes, rather commonly, especially when we’re looking for all possible anti-depression tools to use, rather than have to use a typical antidepressant. I still have yet to see a clear-cut stunning improvement like those case reports in the table above, but because the risk appears to be so minimal, in many cases it seems like it’s worth a try. One fellow wrote a strong testimonial about being able to go off lithium with fish oil, but he made some other big changes too: testimonial.

Other fishy stories: