There are a number of natural products on the market that have been fairly well studied for the treatment of depression. Probably the best characterized of them is St. John’s Wort, which is an herbal antidepressant that has been studied quite extensively. There is probably something in the neighborhood of 40 clinical trials that have been published on it. By and large, most of the studies suggest that St. John’s Wort is more effective than placebo and probably as effective as low-dose tricyclic antidepressants. With regard to the newer agents such as SSRIs, there is less evidence because fewer studies have been carried out. Unfortunately, a lot of the studies comparing St. John’s Wort against an SSRI and against placebo have actually yielded fairly equivocal results. In some cases, neither St. John’s Wort nor the established antidepressant were able to separate from placebo, so the question of efficacy versus the SSRI still remains unclear. More work needs to be done in that area.

But by and large, if the body of work as a whole is considered – and a number of meta-analyses have been done in this regard – the data suggest that St. John’s Wort is effective and certainly a very reasonable choice for people with depression. St. John’s Wort also seems to be pretty safe, although there are a number cautions that need to be exercised with it. For example, it should not be combined with SSRIs because there’s a risk of serotonin syndrome as a result of an interaction between the two. There are other drug-drug interactions that can occur with St John’s Wort and certain anti-HIV drugs, birth control pills, and anticancer drugs as well as immunosuppressive drugs. Also, there are certain side effects that are idiosyncratic to St. John’s Wort. One example is phototoxicity: people who take St. John’s Wort are, in theory, at a greater risk of getting sunburned if they have long exposures to the sun. Those people should be very careful; if they’re going to the beach, they should wear plenty of sunscreen and protect themselves.


David Mischoulon, MD
Director of Research
Depression Clinical and Research Program a
Massachusetts General Hospital
Assistant Professor of Psychiatry
Harvard Medical School

I have been using folic acid with some of my female patients along with their SSRI when there is augmentation needed or the SSRI is not quite enough.Any experiences in this area?

Several studies have shown an association between folate deficiency and depression. Research also suggests that folate supplementation may augment antidepressant efficacy in patients with folate deficiency and, possibly, in patients with normal folate levels.

Available forms of folate supplementation include:

• Folic acid - found in most over the counter folate supplements.
• Dihydrofolate - the dietary form of folate found in foods such as spinach, orange juice and eggs.
• Folinic acid - also known as leucovorin, an adjuvant chemotherapy agent.

These forms of folate are enzymatically converted to L-methylfolate, which crosses the blood-brain barrier and is involved in the brain’s synthesis of dopamine, serotonin and norepinephrine. While most people receive adequate dietary folate, it is possible that, in some cases, reduced enzyme function results in low levels of L-methylfolate and, therefore, impaired production of dopamine, serotonin and norepinephrine in the brain. The FDA recently approved an oral formulation of L-methylfolate for adjunctive use in patients who have partially responded to antidepressant treatment. This form of L-methylfolate (trade name, Deplin) is classified as a “medical food” and is available by prescription only.


Further Reading:
Farah A. The Role of L-Methylfolate in Depressive Disorders. CNS Spectrums 2009; 14:1[suppl 2]: 2-7

Fava M, Mischoulon D. Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues. J Clin Psychiatry 2009; 70[suppl 5]: 12-17


Michael Hirsch, MD
MGH Academy Staff Psychiatrist
Massachusetts General Hospital

What about SAM-e ?

S-adenosyl-l-methionine (SAM-e) has been used as in antidepressant in Europe since the 1970s and has been available in the United States as a dietary supplement since 1999. SAM-e is naturally produced in the body and is involved in many biochemical pathways, including donating methyl groups necessary for the synthesis of serotonin, norepinephrine and dopamine.

Several studies have suggested that SAM-e is effective as a primary treatment for major depression, with an effect size comparable to tricyclic antidepressants and with superior tolerability. However, only two studies have examined SAM-e as an adjunct to standard antidepressant treatment. The first, a double-blind placebo controlled study of 81 patients taking imipramine, suggested that adjunctive SAM-e may accelerate improvement of depressive symptoms. In the second study, an open-label trial involving 30 patients who had inadequate response to SSRI or venlafaxine treatment, 43% of patients remitted after four weeks of adjunctive treatment with SAM-e.

Of note, most of these studies used intravenous or intramuscular formulations of SAM-e. Although more studies of oral SAM-e are needed, evidence suggests that it does cross the blood-brain barrier and has comparable effects to the parenterally administered forms. In studies using oral SAM-e, the typical dose was 800mg to 1600mg daily.

SAM-e appears to be well tolerated, with possible side effects including mild insomnia, decreased appetite, nausea, dry mouth, sweating and jitteriness.


Recommended Reading:

Hardy M, Coulter I, Morton SC, et al. S-adenosyl-l-methionine for treatment of depression, osteoarthritis, and liver disease. Evidence Report/Technology Assessment Number 64. AHRQ Publication No. 02-E034. Prepared by Southern California Evidence-based Practice Center under Contract No. 290-97-0001. Rockville, MD: Agency for Healthcare Research and Quality: 2002. http://www.ncbi.nlm.nih.gov/books/bv.fc ... ction.2161.

Papakostas GI. Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. J Clin Psychiatry. 2009;70 Suppl 5:18-22.



Michael Hirsch, MD
MGH Academy Staff Psychiatrist
Massachusetts General Hospital