Omega-3 fatty acids found in fish oil, particularly DHA, are needed for normal nervous system function. Depressed people have been reported to have lower omega-3 fatty acid levels (e.g., DHA) than people who are not depressed.^{26 , 27 , 28 , 29} Low levels of the other omega-3 fatty acid from fish, EPA, have correlated with increased severity of depression.³⁰ In some double-blind trials, supplementation with various amounts of fish oil was beneficial for the treatment of depression in both children³¹ and adults,³² but fish oil was ineffective in other double blind trials.^{33 , 34}

EPA alone has also been reported to be beneficial. There is one case report of a man with a long history of severe depression who showed clear improvement within one month of starting a purified EPA supplement (4 grams per day of the ethyl ester of eicosapentaenoic acid [E-EPA]).³⁵ In a double-blind study, supplementation with E-EPA for 12 weeks was significantly more effective than a placebo at relieving symptoms of depression.³⁶ E-EPA was beneficial, even though the participants in the study had failed to respond adequately to conventional antidepressant drugs. The conventional medications were continued during treatment with E-EPA or placebo. An effective level of intake was 1 gram per day, whereas larger amounts of E-EPA resulted in little or no benefit. The authors of the study suggested that taking too much E-EPA might cause an imbalance with other essential fatty acids, which could reduce the effectiveness of the treatment.

A deficiency of the B vitamin folic acid can also disturb mood. A large percentage of depressed people have low folic acid levels.³⁷ Folic acid supplements appear to improve the effects of lithium in treating manic-depressives.³⁸ Depressed alcoholics report feeling better with large amounts of a modified form of folic acid.³⁹ Anyone suffering from chronic depression should be evaluated for possible folic acid deficiency by a doctor. Those with abnormally low levels of folic acid are sometimes given short-term, high amounts of folic acid (10 mg per day).

Iron deficiency is known to affect mood and can exacerbate depression, but it can only be diagnosed and treated by a doctor. While iron deficiency is easy to fix with iron supplements, people who have not been diagnosed with iron deficiency should not supplement iron.

Deficiency of vitamin B12 can create disturbances in mood that respond to B12 supplementation.⁴⁰ Significant vitamin B12 deficiency is associated with a doubled risk of severe depression, according to a study of physically disabled older women.⁴¹ Depression caused by vitamin B12 deficiency can occur even if there is no B12 deficiency-related anemia.⁴²

Mood has been reported to sometimes improve with high amounts of vitamin B12 (given by injection), even in the absence of a B12 deficiency.⁴³ Supplying the body with high amounts of vitamin B12 can only be done by injection. However, in the case of overcoming a diagnosed B12 deficiency, one can follow an initial injection with oral maintenance supplementation (1 mg per day), even when the cause of the deficiency is a malabsorption problem such as pernicious anemia.

Oral contraceptives can deplete the body of vitamin B6, a nutrient needed for maintenance of normal mental functioning. Double-blind research shows that women who are depressed and who have become depleted of vitamin B6 while taking oral contraceptives typically respond to vitamin B6 supplementation.⁴⁴ In one trial, 20 mg of vitamin B6 were taken twice per day. Some evidence suggests that people who are depressed—even when not taking the oral contraceptive—are still more likely to be B6 deficient than people who are not depressed.⁴⁵

Several clinical trials also indicate that vitamin B6 supplementation helps alleviate depression associated with premenstrual syndrome (PMS),⁴⁶ although the research remains inconsistent.⁴⁷ Many doctors suggest that women who have depression associated with PMS take 100–300 mg of vitamin B6 per day—a level of intake that requires supervision by a doctor.

Disruptions in emotional well-being, including depression, have been linked to serotonin imbalances in the brain.⁴⁸ Supplementation with 5-HTP (5-hydroxytryptophan) may increase serotonin synthesis. Researchers are studying the possibility that 5-HTP might help people with depression. Some trials using 5-HTP with people suffering from depression have shown sign of efficacy.^{49 , 50 , 51 , 52 , 53} However, much of the research was either uncontrolled or used 5-HTP in combination with antidepressant drugs. Depressed people interested in considering this hormone precursor should consult a doctor.

Omega-3 fatty acids found in fish oil, particularly DHA, are needed for normal nervous system function. Depressed people have been reported to have lower omega-3 fatty acid levels (for example, DHA) than people who are not depressed.^{55 , 56 , 57 , 58} Low levels of the other omega-3 fatty acid from fish, EPA, have correlated with increased severity of depression.⁵⁹ In some double-blind trials, supplementation with various amounts of fish oil was beneficial for the treatment of depression in both children and adults,^{60 , 61} but fish oil was ineffective in other double blind trials.^{62 , 63}

EPA alone has also been reported to be beneficial. There is one case report of a man with a long history of severe depression who showed clear improvement within one month of starting a purified EPA supplement (4 grams per day of the ethyl ester of eicosapentaenoic acid [E-EPA]).⁶⁴ In a double-blind study, supplementation with E-EPA for 12 weeks was significantly more effective than a placebo at relieving symptoms of depression.⁶⁵ E-EPA was beneficial, even though the participants in the study had failed to respond adequately to conventional antidepressant drugs. The conventional medications were continued during treatment with E-EPA or placebo. An effective level of intake was 1 gram per day, whereas larger amounts of E-EPA resulted in little or no benefit. The authors of the study suggested that taking too much E-EPA might cause an imbalance with other essential fatty acids, which could reduce the effectiveness of the treatment.

Ginkgo biloba (240 mg per day) may alleviate depression in depressed elderly people not responding to antidepressant drugs.⁶⁶ It is unknown if ginkgo could alleviate depression in other age groups. A small, preliminary trial has shown that ginkgo can reduce sexual problems caused by antidepressants like fluoxetine (Prozac), bupropion (Wellbutrin), venlafaxine (Effexor), and nefazodone (Serzone) in men and women.⁶⁷ Double-blind trials are now needed to determine whether ginkgo is truly effective for this purpose.

Preliminary evidence indicates that people with depression may have lower levels of inositol.⁶⁸ Supplementation with large amounts of inositol can increase the body’s stores by as much as 70%.⁶⁹ In a double-blind trial, depressed people who received 12 grams of inositol per day for four weeks had a significant improvement in symptoms compared to those who took placebo.⁷⁰ In a double-blind follow-up to this trial, the antidepressant effects of inositol were replicated. Half of those who responded to inositol supplementation relapsed rapidly when inositol was discontinued.⁷¹

Disruptions in emotional well-being, including depression, have been linked to serotonin imbalances in the brain.⁷² L-Tryptophan is the precursor to serotonin, and low body levels of L-tryptophan are associated with depression symptoms.⁷³ Furthermore, L-tryptophan supplements have been shown to increase serotonin levels.⁷⁴  Many uncontrolled studies report that 3 to 6 grams per day of L-tryptophan helps improve mood in depressed people.^{75 , 76} Several controlled trials found that 3 to 6 grams per day of L-tryptophan were equally as effective as antidepressant medications.^{77 , 78} Some,^{79 , 80 , 81} though not all,^{82 , 83} double blind studies reported that similar amounts of L-tryptophan were superior to a placebo for improving depression symptoms. Trials using amounts above 6 grams per day of L-tryptophan have often found no benefit for depression, suggesting that 3 to 6 grams per day is optimum.⁸⁴ 5-Hydroxytryptophan (5-HTP), a breakdown product of L-tryptophan and a serotonin precursor, has also been studied as a treatment for depression. Some trials using 200 to 300 mg per day of 5-HTP with people suffering from depression have shown signs of efficacy.^{85 , 86 , 87 , 88 , 89 , 90} However, much of the research was either uncontrolled or used 5-HTP in combination with antidepressant drugs. Depressed people interested in considering 5-HTP should consult a doctor.

The amino acid L-tyrosine can be converted into norepinephrine, a neurotransmitter that affects mood. Women taking oral contraceptives have lower levels of tyrosine, and some researchers think this might be related to depression caused by birth control pills.⁹¹ L-tyrosine metabolism may also be abnormal in other depressed people⁹² and preliminary research suggests supplementation might help.^{93 , 94} Several doctors recommend a 12-week trial of L-tyrosine supplementation for people who are depressed. Published research has used a very high amount—100 mg per 2.2 pounds of body weight (or about 7 grams per day for an average adult). It is not known whether such high amounts are necessary to produce an antidepressant effect.

Melatonin might help some people suffering from depression. Preliminary double-blind research suggests that supplementation with small amounts of melatonin (0.125 mg taken twice per day) may reduce winter depression.⁹⁵ People with major depressive disorders sometimes have sleep disturbances. A timed-release preparation of melatonin (5–10 mg per day for four weeks) was shown to be effective at improving the quality of sleep in people with major depression who were taking fluoxetine (Prozac), but melatonin did not enhance its antidepressant effect.⁹⁶ There is a possibility that melatonin could exacerbate depression, so it should only be used for this purpose under a doctor’s supervision.

L-phenylalanine is another amino acid that converts to mood-affecting substances (including phenylethylamine and norepinephrine). Preliminary research reported that L-phenylalanine improved mood in most of the depressed people studied.⁹⁷DLPA is a mixture of the essential amino acid L-phenylalanine and its synthetic mirror image, D-phenylalanine. DLPA (or the D- or L- form alone) reduced depression in 31 of 40 people in a preliminary trial.⁹⁸ Some doctors suggest a one-month trial with 3–4 grams per day of phenylalanine for people with depression, although some researchers have found that even very low amounts—75–200 mg per day—were helpful in preliminary trials.⁹⁹ In one double-blind trial, depressed people given 150–200 mg of DLPA per day experienced results comparable to that produced by an antidepressant drug.¹⁰⁰

SAMe (S-adenosyl methionine) is a substance synthesized in the body that has recently been made available as a supplement. SAMe appears to raise levels of dopamine, an important neurotransmitter in mood regulation. Higher SAMe levels in the brain are associated with successful drug treatment of depression, and oral SAMe has been demonstrated to be an effective treatment for depression in most,^{102, 103, 104} but not all,¹⁰⁵ clinical trials. SAMe has been found to be effective both when used by itself and when used as add-on treatment to antidepressant medication.¹⁰⁶ Most trials used 1,600 mg of SAMe per day. While it does not seem to be as powerful as full applications of antidepressant medications¹⁰⁷ or St. John’s wort, SAMe’s effects are felt more rapidly, often within one week.¹⁰⁸

Less than optimal intake of selenium may have adverse effects on psychological function, even in the absence of signs of frank selenium deficiency. In a preliminary trial of healthy young men, consumption of a high-selenium diet (226.5 mcg selenium per day) was associated with improved mood (i.e., decreased confusion, depression, anxiety, and uncertainty), compared to consumption of a low-selenium diet (62.6 mcg selenium per day.)¹⁰⁹ In a double-blind trial, people who had a low selenium intake experienced greater improvement in depression symptoms after selenium supplementation (100 mcg per day) than did people with adequate selenium intake, suggesting that low-level selenium deficiency may contribute to depression.¹¹⁰

Caution: It is likely that there are many drug interactions with St. John's wort that have not yet been identified. St. John's wort stimulates a drug-metabolizing enzyme (cytochrome P450 3A4) that metabolizes at least 50% of the drugs on the market.¹¹¹ Therefore, it could potentially cause a number of drug interactions that have not yet been reported. People taking any medication should consult with a doctor or pharmacist before taking St. John's wort.

St. John’s wort extract has been compared to the prescription tricyclic antidepressants imipramine (Tofranil),^{115 , 116 , 117} amitriptyline (Elavil),¹¹⁸ fluoxetine (Prozac®),¹¹⁹ and maprotiline (Ludiomil).¹²⁰ The improvement in symptoms of mild to moderate depression was similar, with notably fewer side effects, in people taking St. John’s wort.

In a double-blind trial using standard amounts of fluoxetine (Prozac)—20 mg per day—St. John’s wort extract in the amount of 400 mg twice daily was equally effective at relieving depression in people aged 60–80 years.¹²¹ Another trial found that 250 mg of St. John’s wort extract two times per day was also as effective as 20 mg of fluoxetine in treating adults with mild to moderate depression.¹²² In both trials comparing St. John’s wort to fluoxetine, there were far fewer side effects reported by people taking St. John’s wort.

One clinical trial compared a higher amount of the St. John’s wort extract LI 160 (1,800 mg per day) with a higher amount of imipramine (150 mg per day) in more severely depressed people.¹²³ Again, the improvement was virtually the same for both groups with far fewer side effects for the St. John’s wort group. While this may point to St. John’s wort as a possible treatment for more severe cases of depression, this treatment should only be pursued under the guidance of a healthcare professional.

Two well-publicized double-blind studies published in the Journal of the American Medical Association (JAMA) concluded that St. John's wort is not an effective treatment for depression. However, each of these studies had potential flaws. In the first study,¹²⁴ 900–1,200 mg of St. John's wort per day was slightly more effective than a placebo, as assessed by the Hamilton Rating Scale for Depression. However, the difference was not statistically significant. Although the remission rate was significantly greater with St. John's wort than with placebo, only 14.3% of the patients who received the herb went into remission, causing the authors of the report to question St. John's wort's efficacy. However, the 4.9% remission rate in the placebo group was far below the placebo response rate seen in other studies of depression. That finding suggests that many of the patients recruited for this study would have been unlikely to respond to any treatment.

In the second JAMA study, depressed patients were given one of three treatments: St. John's wort, placebo, or an antidepressant medication with proven efficacy (e.g., sertraline; Zoloft). Although St. John's wort was no more effective than the placebo, by many measures neither was sertraline.¹²⁵ The relatively poor outcome with sertraline makes one wonder whether the design of the study, or the criteria used to select participants, may have somehow skewed the results to make St. John's wort appear less effective than it really is.

Despite these two negative studies, the bulk of the scientific evidence indicates that St. John's wort is an effective treatment for mild to moderate depression.

Recent European trials have successfully treated mild to moderate depression using 500 to 1,050 mg of St. John’s wort per day. As an antidepressant, St. John’s wort should be taken for four to six weeks before judging its effectiveness.

Oral contraceptives can deplete the body of vitamin B6, a nutrient needed for maintenance of normal mental functioning. Double-blind research shows that women who are depressed and who have become depleted of vitamin B6 while taking oral contraceptives typically respond to vitamin B6 supplementation.¹²⁶ In one trial, 20 mg of vitamin B6 were taken twice per day. Some evidence suggests that people who are depressed—even when not taking the oral contraceptive—are still more likely to be B6 deficient than people who are not depressed.¹²⁷

Several clinical trials also indicate that vitamin B6 supplementation helps alleviate depression associated with premenstrual syndrome (PMS),¹²⁸ although the research remains inconsistent.¹²⁹ Many doctors suggest that women who have depression associated with PMS take 100–300 mg of vitamin B6 per day—a level of intake that requires supervision by a doctor.

Blood levels of vitamin D (measured as 25-hydroxyvitamin D) have been found to be significantly lower in people with depression than in healthy people.¹³⁰ Vitamin D supplementation may be associated with elevations in mood. In a double-blind trial, healthy people were given 400–800 IU per day of vitamin D3, or no vitamin D3, for five days during late winter. Results showed that vitamin D3 significantly enhanced positive mood and there was some evidence of a reduction in negative mood compared to a placebo.¹³¹ In another double-blind trial, people without depression took 600 IU of vitamin D along with 1,000 mg of calcium, or a placebo, twice daily for four weeks.¹³² Compared to the placebo, combined vitamin D and calcium supplementation produced significant elevations in mood that persisted at least one week after supplementation was discontinued.

Caution: Calcium supplements should be avoided by prostate cancer patients.   

In one double-blind trial, people without depression took 600 IU of vitamin D along with 1,000 mg of calcium, or a placebo, twice daily for four weeks.¹³³ Compared to the placebo, combined vitamin D and calcium supplementation produced significant elevations in mood that persisted at least one week after supplementation was discontinued.

There have been five case reports of chromium supplementation (200–400 mcg per day) significantly improving mood in people with a type of depression called dysthymic disorder who were also taking the antidepressant drug sertraline (Zoloft).¹³⁴ These case reports, while clearly limited and preliminary in scope, warrant further research to better understand the benefits, if any, of chromium supplementation in people with depression.

Damiana has traditionally been used to treat people with depression. Yohimbine (the active component of the herb yohimbe) inhibits monoamine oxidase (MAO) and therefore may be beneficial in depressive disorders. However, clinical research has not been conducted for its use in treating depression.

An isolated preliminary trial suggests the supplement NADH may help people with depression.¹³⁵ Controlled trials are needed, however, before any conclusions can be drawn.

Phosphatidylserine (PS), a natural substance derived from the amino acid serine, affects the levels of neurotransmitters in the brain related to mood. In a preliminary trial, elderly women suffering from depression who were given 300 mg of PS per day for 30 days experienced, on average, a 70% reduction in the severity of their depression.¹³⁶ Most research has been conducted with PS derived from bovine (cow) brain tissue. Due to concerns about the possibility of humans contracting infectious diseases (such as Creutzfeld-Jakob or “mad cow” disease), bovine PS is not available in the United States. The soy- and bovine-derived PS, are not structurally identical, and there is evidence that soy-derived PS may not have the same beneficial effects as bovine PS.¹³⁷

Pumpkin seeds contain L-tryptophan, and for this reason have been suggested to help remedy depression.¹³⁸ However, research is needed before pumpkin seeds can be considered for this purpose. It is unlikely the level of L-tryptophan in pumpkin seeds would be sufficient to relieve depression.

Vervain is a traditional herb for depression; however, there is no research to validate this use.

Damiana has traditionally been used to treat people with depression. Yohimbine (the active component of the herb yohimbe) inhibits monoamine oxidase (MAO) and therefore may be beneficial in depressive disorders. However, clinical research has not been conducted for its use in treating depression.