Depression is twice as common in women as it is in men. The highest rate of first time depression occurs in adolescents and young adults aged 12 to 24.^10832,10833 Depression is the leading cause of death and disability for people aged 18 to 44. Depression commonly occurs along with conditions such as heart disease. In fact, patients with both heart disease AND depression are 4.5 times more likely to have a heart attack than non-depressed cardiac patients.^10833,10835 Depression can also be fatal by itself...about 15% of depressed patients commit suicide.¹⁰⁸³⁴

Depression is thought to be due to altered neurochemistry. Three major neurotransmitters play a central role... norepinephrine, serotonin, and dopamine. Norepinephrine affects vigilance, motivation, and overall energy levels. In concert with serotonin, norepinephrine affects anxiety and irritability. Serotonin seems to control impulsivity. Serotonin, along with dopamine, regulates appetite, sex, and aggression.¹⁰⁸³³

Major depression is subclassified as mild, moderate, or severe depression. This division is based on the intensity of depressive symptoms and how impaired patients are by their depression.^10831,10833 Dysthymia is a chronic, less severe form of depression. Dysthymia is defined by milder depressive symptoms that persist for 2 or more years.¹⁰⁸³¹

*Note: Many natural products are tried for depression, but very few have reliable evidence that they work. Inclusion in this list does NOT imply that these products are effective for depression.
 

Many natural products also seem to affect neurotransmitters and brain biochemistry and are therefore tried for depression. Lots of depressed patients turn to natural products.^10841,10842 Over 50% try a natural product. Only HALF tell their physician.¹⁰⁸⁴²

St. John's wort (Hypericum perforatum) is the most common supplement tried for depression. It works similarly to conventional antidepressants. St. John's wort inhibits the reuptake of serotonin, norepinephrine, and dopamine. It also appears to affect other neurochemicals...adenosine, benzodiazepine, and gamma-aminobutyric acid (GABA). It may even act as a weak monoamine oxidase inhibitor. The exact mechanism of St. John's wort for treating depression is unknown.^{763,4521,8936}

Many St. John's wort products are standardized to the component hypericin. But now researchers think the antidepressant activity is most likely due to other components ...hyperforin and adhyperforin.^763,4521

For MILD and MODERATE depression, most studies show St. John's wort is superior to placebo.^{4899,6428,9592} St. John's wort doesn't seem to help SEVERE depression.^5096,10843 St. John's wort also appears to be as effective as low-dose TCAs for mild to moderate depression.^{3548,3549,3551,6434} And possibly as effective as the SSRIs fluoxetine (Prozac) and sertraline (Zoloft).^{3550,4897,6400} However, recently in two large trials, St. John's wort was no better than placebo.^5096,10843 These trials were performed in psychiatry centers. Many St. John's wort trials are in primary care settings. Patient characteristics can be different in primary care settings versus psychiatric clinics. ¹¹¹⁵⁴

Tell patients St. John's wort may help mild to moderate depression. The daily dose most commonly used is 300 mg three times daily.⁴⁸⁹⁹ The incidence of adverse effects in patients treated with St. John's wort is similar to placebo and less than conventional antidepressants.^4899,10845 Sexual dysfunction is less frequent with St. John's wort than with SSRIs.¹⁰⁸⁴³

Serotonin syndrome can occur with St. John's wort alone or when it's taken with other drugs that increase serotonin levels.^542,6201 Hypertensive crisis has been reported in a patient taking St. John's wort and eating tyramine-containing food and red wine.⁷⁸¹² Tell patients not to combine St. John's wort with other antidepressants.

St. John's wort is a potent inducer of cytochrome P450 3A4 (CYP3A4). St. John's wort also induces P-glycoprotein, a cellular pump that protects the body against foreign substances. P-glycoprotein can pump drug molecules out of a cell...reducing absorption.^1340,7810 St. John's wort is also thought to induce CYP1A2 and CYP2C9.^1292,3556 St. John's wort probably has little effect on CYP2D6.^{3599,4835,10830,10847,10848}

St. John's wort shows efficacy similar to conventional drugs for mild to moderate depression. But it can have a lot more drug interactions than many conventional antidepressants. Emphasize to patients the importance of telling ALL healthcare providers about their use of St. John's wort. Although St. John's wort might help, there are significant drug interactions and in most cases a conventional antidepressant is preferred.

S-adenosylmethionine (SAMe) is an amino acid derivative synthesized in the body. SAMe is also available from protein sources, like meat. SAMe is used for both depression and osteoarthritis. SAMe works differently than most conventional antidepressants. It seems to increase dopamine and norepinephrine levels.^{5196,5232,9110}

SAMe appears to be about as effective as TCAs for treating depression.^{5189,5192,5193,5195,5200,9108,9109} There's no reliable evidence that SAMe treats depression faster than conventional antidepressants. SAMe is generally well-tolerated. It's been taken safely for up to 24 months.^9108,9113

SAMe may have an additive effect on drugs that increase serotonin levels.^5231,5232 Serotonin syndrome has been reported with concurrent use of SAMe and the TCA clomipramine (Anafranil).³⁵²¹ Tell patients not to combine SAMe with other antidepressants.

Chemically, SAMe is notoriously unstable. Several oral salt forms of SAMe are available...sulfate, sulfate-p-toluenesulfonate (also labeled as tosylate), and butanedisulfonate.^5231,5444 Tell patients to look for the butanedisulfonate salt...it's the most bioavailable and seems to be the most stable.^5446,9110

SAMe is expensive. It can cost more than $150 per month for doses commonly used to treat depression... 800 mg BID.⁵¹⁸⁹ This is more than the cost of newer antidepressants. Tell patients SAMe might help depression, but it's extremely expensive.

Inositol is a naturally occurring isomer of glucose. Inositol is sometimes called vitamin B8, but it's NOT actually a vitamin. Inositol works differently than other antidepressants. Rather than increase neurotransmitter levels as most antidepressants do, inositol plays a supporting role in cellular communication. It relays messages from serotonin, norepinephrine, and cholinergic receptors.¹⁰⁸⁵⁰

There's preliminary evidence that taking high-dose inositol 12 grams per day for 4 weeks might help depression.²¹⁸⁵ But this benefit goes away rapidly when it's stopped.²⁰²⁶ Inositol is well-tolerated. But there's not enough evidence yet to recommend it.

Phenylalanine is an amino acid precursor of tyrosine, which is a precursor to the neurotransmitters dopamine and norepinephrine. Tyrosine increases neurotransmitter levels.⁹⁹³¹ This may contribute to an antidepressant effect. A phenylalanine/tyrosine free diet elicits symptoms of depression in non-depressed patients.¹⁰⁸⁵²

Limited clinical research suggests phenylalanine might be useful for depression.^2468,2469 Tyrosine doesn't seem to have any effect on MODERATE depression.⁷²⁰⁸ There's interesting research about phenylalanine for treating depression, but it's too soon to recommend it.

Phenylalanine should be avoided in people with inherited disorders of phenylalanine metabolism, such as phenylketonuria and alkaptonuria.^2084,10754 Phenylalanine in patients with schizophrenia or taking neuroleptics can exacerbate tardive dyskinesia.^2457,2458 Phenylalanine and levodopa can exacerbate tremor, rigidity, and the "on-off" syndrome in patients with Parkinson's disease.^3291,3294 Tell patients with these conditions not to use phenylalanine.

L-tryptophan and 5-hydroxytryptophan (5-HTP) are precursors of serotonin. Taking these supplements might help for depression. But there are concerns about safety.

The largest safety concern for L-tryptophan and 5-HTP is potentially fatal eosinophilia-myalgia syndrome (EMS). In 1989, more than 1500 cases of EMS and 37 deaths were associated with L-tryptophan use in the U.S. Ninety-five percent of all EMS cases were traced to a single international manufacturer. In 1990, FDA limited the importation of all over-the-counter L-tryptophan products.⁷⁰⁶⁷ L-tryptophan has not been proven to be the cause of EMS. EMS may have been caused by one of several impurities.^8051,10289 Similar impurities have been isolated in 5-HTP products.¹⁰⁰⁸⁴ The long-term safety of L-tryptophan and 5-HTP is unknown.

Tryptophans, especially 5-HTP, might improve depressive symptoms. But the optimal dose is unknown.^10857,10858 Information on long term safety is also lacking. Until the questions of EMS and long-term safety are resolved, tell patients not to use L-tryptophan or 5-HTP for depression.

Some research suggests phosphatidylserine and acetyl-L-carnitine might relieve depressive symptoms in elderly patients.^{3603,3604,7113} Preclinical research suggests phosphatidylserine increases norepinephrine and dopamine levels. But this does not appear to occur in humans.⁷¹¹³ Preliminary research suggests that acetyl-L-carnitine may enhance synaptic transmission.¹⁰³⁹⁵ But it's too soon to recommend either phosphatidylserine or acetyl-L-carnitine for depression.

The omega-3 fatty acids, docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA), are essential polyunsaturated fatty acids (PUFAs). DHA is the predominant omega-3 fatty acid in the brain. DHA is required for optimal neuronal function.¹⁰⁸⁶⁶

Researchers theorize that omega-3s might normalize membrane structure in the brain. Omega-3s might also improve neurotransmitter uptake.^10870,10871 Low omega-3 levels in plasma and red blood cells are associated with depression.^{10859,10860,10866}

DHA alone doesn't seem to have any significant effect on depression.¹⁰⁸⁶⁹ But omega-3 fatty acids might have a role as ADJUNCT agents in depression. Several studies suggest that either combination DHA/EPA supplements or EPA alone can reduce depressive symptoms in patients already using conventional antidepressants.^{10866,10871,10872}

Doses of greater than 3 grams per day of omega-3s are often used for adjunctive treatment of depression. These doses can inhibit platelet aggregation, cause bleeding, and potentially increase the risk for hemorrhagic stroke.^{1313,7603,8699} Theoretically, omega-3 supplements might have an additive effect with anticoagulant drugs. However, some research suggests that doses of 3 to 6 grams per day might not have a significant effect on coagulation in patients taking warfarin (Coumadin).⁸⁸⁰¹

Tell patients taking conventional antidepressants that omega-3 fatty acids might help. Remind patients to inform ALL healthcare providers that they are taking omega-3 fatty acids. It's important to be aware of the increased bleeding risk.

Dehydroepiandrosterone (DHEA) is an endogenous steroid hormone. DHEA is metabolized to androstenedione, the major precursor to androgens and estrogens. DHEA levels are higher in men than in women, and naturally decline with age in both sexes.⁸⁵⁹⁷

Theories about how DHEA might work for depression are vague. DHEA levels in depressed patients can be higher, lower, or the same as non-depressed patients.^{10874,10875,10876,10877} Elderly people with depression seem to have lower levels of DHEA following successful treatment of depression.

DHEA is possibly safe to use short-term, but the safety of long-term or high dose DHEA is unknown. Relatively low doses (50-100 mg per day) can cause DHEA to rise above physiological levels.⁴²⁵¹ DHEA is a potent estrogen agonist. It causes the growth of estrogen-receptor positive breast cancer cells. DHEA can overcome the estrogen receptor antagonist action of conventional medications like fulvestrant (Faslodex).¹⁰³⁷⁰ People at risk for hormone-sensitive cancer and other hormone-sensitive conditions should avoid DHEA.

There's evidence DHEA helps depression in some patients.^3270,4233 But there isn't enough evidence to recommend it. There are also concerns about its safety. Tell patients not to use DHEA for depression.

Other endogenous hormones such as pregnenolone and progesterone are sometimes suggested for treatment of depression. But there's no reliable research to support their use.

Depression is sometimes blamed on vitamin deficiency. There's no evidence that multivitamins or vitamin C are useful for treating depression. Some very preliminary research suggests varying efficacy of B vitamins. But it's too early to recommend vitamin supplements for treating depression.^10888,10889

Folic acid is required for the production of neurotransmitters including serotonin.^10884,10885 Folic acid deficiency is common among patients with depression.^{10879,10880,10881} People with low folate status or lower dietary folate intake have a higher risk for depression.^10882,10883 Lower folate levels also link to poor response rates for patients taking antidepressants.^6239,10880

Limited clinical research suggests that folic acid is NOT effective as a replacement for conventional antidepressant therapy.¹⁰⁸⁸⁶ But commonly used folic acid doses of 500 mcg per day might be effective when used in addition to conventional antidepressants, especially in women.^{3657,10884,10887}

At doses less than 1000 mcg per day, folic acid is associated with few side effects. Folic acid therapy can mask vitamin B12 deficiency and allow progression of neurological damage. Check patients' vitamin B12 status before starting folic acid therapy.⁶²⁴³

There's no evidence that taking folic acid prevents depression. If patients ask about folate supplementation, suggest foods high in folates...citrus fruits, dark leafy vegetables, and folate-fortified cereals and grains. It's too early to recommend folate for treating depression.

Other natural products such as damiana, ginkgo, glutamine, lavender, turmeric, and yohimbe are sometimes tried for depression. But research is too preliminary to recommend them.

St. John's wort has been extensively studied for its effects on depression. Compared with other natural products, it is extremely well-researched in terms of pharmacology. St. John's wort appears to be effective for MILD and MODERATE depression with relatively few adverse effects.

For patients not taking interacting medications, St. John's wort may be a reasonable choice for MILD and MODERATE depression. Refer patients with SEVERE depression to a mental health specialist. St. John's wort is not effective for SEVERE depression.

S-adenosylmethionine (SAMe) is not as well studied as St. John's wort...but it seems safer in terms of drug interactions. SAMe is extremely expensive when taken in antidepressant doses. Tell patients to wait for more definitive studies and lower cost formulations.

The serotonin precursors L-tryptophan and 5-HTP might be useful as add-ons to conventional antidepressant therapy. But until the issue of eosinophilia-myalgia causing impurities is resolved, these supplements should be avoided.

Omega-3 fatty acids show promise as adjunctive treatments with conventional antidepressants. Explain the increased risk of bleeding to patients and the importance of telling all healthcare providers about omega-3 use.

Steer patients away from dehydroepiandrosterone (DHEA). The evidence for antidepressant effect is weak and the long-term risks are unknown.

Supplemental folic acid looks promising as an additive to conventional antidepressants in patients likely to be folate deficient. Taking a folic acid-containing multivitamin and/or increasing dietary intake of folate may be helpful.

Emphasize to patients the importance of telling ALL healthcare providers about the natural products they're taking. Many natural products (e.g., St. John's wort, SAMe, L-tryptophan) can have an additive effect on drugs with serotonin or monamine oxidase activity. Serotonin syndrome and hypertensive crisis can result.