Supplements for depression: What the research reveals


Struggling with the black dog of depression? The supplement aisle abounds with options for people seeking a non-medicinal remedy — but figuring out what works and what doesn’t can be a challenge for consumers and experts alike.

That’s because the data are generally poor, says Dr. Charles Raison, associate professor of psychiatry in the College of Medicine at the University of Arizona in Tucson.

There are some exceptions. Hundreds of studies have investigated the effects of omega-3 fatty acids and St. John’s wort. Researchers have been studying a compound known as SAM-e for decades. And, more recently, evidence on the effectiveness of folate compounds has been piling up.


Even though all of these compounds are available over the counter in one form or another, there are precautions you should take if you choose to self-medicate, to avoid potential drug interactions and make sure you’re getting adequate mental health care.

“We always recommend that patients take these natural supplements under the care of a doctor and not independently,” says Dr. George Papakostas, an associate professor of psychiatry at Harvard Medical School.

Here’s a look at what the latest studies have shown.

Omega-3 fatty acids

Omega-3s already have a solid reputation as heart-healthy supplements. Researchers are now trying to figure whether the fatty acids, particularly the ones found in seaweed and oily fish such as salmon, might have a role in treating depression.

For more than a decade, studies have pointed to an association between fish consumption and depression: Across the globe, rates of depression are lower in populations that eat more fish, particularly omega-3 rich fish such as salmon, tuna, sardines and mackerel. Studies have also shown that omega-3 levels are lower in people with depression than in people without.

These findings, in turn, have prompted hundreds of studies to determine whether omega-3 supplements can help treat depression. Two recent reviews analyzed the data from dozens of the most well-designed of these studies, and they came to a similar conclusion: Omega-3s appear most likely to help people with severe depression but are unlikely to help those with minor depression or who are simply in a bad mood.


One of the reviews, published in the journal of the American College of Nutrition in 2009, found that there may be important differences depending on the type of omega-3 supplement. Fish oil contains two types: DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid). Studies that used pure DHA or more than 50% DHA reported no effect on depression. Studies using pure EPA or more than 50% EPA found that symptoms improved.

But the authors of both reviews agreed that drawing conclusions from the existing body of evidence was a challenge. Even the most well-designed studies were small and brief. Many included patients with a wide range of symptoms and different types and severity of depression. And few used the same treatment regimens: Some gave participants omega-3s alone, some gave omega-3s along with other drugs, and doses varied widely.

Though the usefulness of omega-3s in depression is still fuzzy, one thing is clear: Studies haven’t turned up evidence of harmful side effects, just “fishy, burpy breath,” says Mary Fristad, professor of psychiatry, psychology and human nutrition at Ohio State University Medical Center in Columbus.

Because they’re so safe, researchers are now beginning to study whether omega-3s might help treat depression in children. A couple of recent, small studies — one in Israel, one in Australia — showed a 40% to 50% improvement of depressive symptoms in children given omega-3s. (This is a new area of investigation, and the findings are very preliminary, stresses Fristad, who is doing research in this area.)

Other scientists are looking at whether omega-3s might help conditions related to depression, such as anxiety. In a study published earlier this year, medical students who took a daily omega-3 supplement containing 2,085 milligrams of EPA and 348 mg DHA for 12 weeks had a 20% reduction in anxiety compared with students who took a placebo.

Despite such findings, “it’s too soon to say omega-3s can combat stress,” says study lead author Janice Kiecolt-Glaser, professor of psychiatry and psychology at Ohio State University College of Medicine. But in terms of general health, it’s a good idea to make sure you’re getting enough of them in your diet, she says.



Folate, a B vitamin found in leafy greens, beans and eggs, is a nutrient that’s essential for good health. Though its effects on depression haven’t been studied as extensively as omega-3s, existing studies have shown consistently positive results, says Dr. David Mischoulon, an associate professor of psychiatry at Harvard Medical School, who has researched the vitamin.

As with omega-3s, the first clue that folate might help treat depression came from population studies showing an association between folate deficiencies and depression. Scientists began to ask whether administering the vitamin to patients would help treat the condition.

Studies have focused on three forms of the vitamin: folic acid, the synthetic version used in supplements and fortified foods; 5-methylene tetrahydrofolate, also known as 5-MTHF, methylfolate or L-methylfolate, which is a breakdown product of folic acid and folate; and folinic acid, a synthetic compound that gets broken down into 5-MTHF.

As in the case of omega-3s, existing studies on the folate compounds have looked at patients with a variety of diagnoses, including major depressive disorder, alcoholism plus depression, dementia with depressive symptoms, bipolar depression and schizophrenia. Most studies examined the compounds’ effects when given in conjunction with another drug, such as the antidepressant fluoxetine (Prozac) or lithium. In several studies, the folate compounds appeared to improve the effectiveness of the prescription drugs and in some cases to reduce unwanted side effects.

Mischoulon says many researchers are now focusing on 5-MTHF, or L-methylfolate. Folate is needed to make the brain chemicals dopamine, serotonin and norepinephrine, and L-methylfolate is the only form of folate that can cross the blood-brain barrier. That means a smaller dose of L-methylfolate may be able to exert the same effect as a much larger dose of folate. (Mischoulon is conducting a clinical trial of a commercial form of L-methylfolate called Deplin; the trial is supported by Pamlab, Deplin’s maker.)


Last year, the American Psychiatric Assn.’s Task Force on Complementary and Alternative Medicine reviewed the body of evidence on folate and depression and concluded that the folate compounds appeared to be “a low-risk and reasonable part of a treatment plan” for major depression when added to prescription antidepressants. Much more research, they concluded, is needed to determine how useful folate may be on its own.


S-adenosyl-L-methionine, or SAM-e, has a close relationship with folate: the body needs 5-MTHF in order to make SAM-e. SAM-e, in turn, is needed to make key messenger chemicals in the brain.

European scientists first noted SAM-e’s antidepressant effects in the 1970s, and the compound has been used as a depression treatment on that continent ever since. In the U.S., SAM-e wasn’t commercially available until the 1990s.

Intrigued by reports from Europe, in 2002 the U.S. Agency for Healthcare Research and Quality conducted a review of the evidence on SAM-e and depression, and concluded that the compound was better than a placebo and equivalent to standard antidepressants in improving mood.

But most of the studies reviewed by the agency dated from the 1970s and 1980s and used an intravenous or intramuscular form of SAM-e (a SAM-e shot, that is, instead of a pill). Researchers who studied oral SAM-e in the 1990s noted that the molecule was very unstable and subject to rapid disintegration.


A newer, more stable version of oral SAM-e is now available. But despite this, there have been few recent studies on SAM-e and depression.

One small trial published in 2004 found that oral SAM-e quickly reduced symptoms of depression in a small population of people infected with HIV. Another 2004 study reported that SAM-e improved symptoms in patients with major depression who were taking prescription antidepressants but had experienced little to no relief from the drugs.

Last year, Harvard researchers reported a larger trial in the American Journal of Psychiatry in which 73 patients with major depression whose prescription antidepressants weren’t helping received either SAM-e pills or a placebo as an “add-on” treatment. After six weeks, patients who took SAM-e had a greater improvement in symptoms.

Like the majority of studies on omega-3s and folate, SAM-e studies also, on the whole, have tended to focus on a small number of patients for a short time. The American Psychiatric Assn. Task Force’s 2010 report called the published studies on SAM-e “promising” but noted that “definitive studies are still required.”

Those studies may be a long way off because, as a naturally occurring compound, SAM-e can’t be patented, says Papakostas, who was lead author of the Harvard study. For that reason, he says, “research is moving very slowly.”

St. John’s wort


St. John’s wort is one of the most well-studied natural supplements for depression, but opinions on the supplement are split among the psychiatrists who research alternative therapies for depression.

Study results are similarly mixed. Some well-designed studies have shown that St. John’s wort relieves depression better than a placebo; others show it doesn’t. Ditto for studies comparing St. John’s wort with prescription drugs.

And to top it all off, studies have revealed that St. John’s sort interferes with a long list of prescription drugs, including oral contraceptives, hormone replacement therapy, blood thinners, immune-suppressing drugs, antiretrovirals and several prescription antidepressants.

Opinions on the plant are generally more favorable in Europe, where St. John’s wort has a longer history of use as an antidepressant. A review of 29 trials published in 2008 by the nonprofit Cochrane Collaboration concluded that for patients with major depression, St. John’s wort was better than a placebo and equivalent to standard antidepressants, but with fewer side effects.

But St. John’s wort looks much less impressive when you take only the largest, most rigorously designed studies into account, says Dr. Richard Shelton, professor of psychiatry at the Vanderbilt University Medical Center in Nashville. And so far, there have been only a few of these.

In a 2001 study published in the Journal of the American Medical Assn., Shelton and colleagues randomly assigned 200 patients with major depression to take either 900 milligrams of St. John’s wort or a placebo daily for eight weeks. The supplement was no more effective than the placebo and was more likely to cause headaches.


A similarly designed study published in the same journal in 2002 compared St. John’s wort with a placebo and the prescription antidepressant sertraline in 340 patients. Those who received St. John’s wort fared no better than patients who received the placebo — but then again, the same was true of patients who received sertraline.

Finally, a 2005 study in the Journal of Clinical Psychopharmacology found that of 135 patients, those randomly assigned to take St. John’s wort experienced more relief than those given a placebo or the prescription antidepressant fluoxetine.

Taken as a whole, however, the body of evidence on St. John’s wort suggests that it’s little better than a placebo, Shelton says.

“If it helps at all, it probably has only a very minor effect on depression,” he says. “It seemed promising on basis of early studies, but these just weren’t well-designed.”