Many complementary and alternative therapies, including various dietary supplements, are readily accessible and commonly used for the treatment of depression. In this article, I will first describe how dietary supplements are defined by the U.S. Food and Drug Administration (FDA) and then briefly review five products that have been used in the treatment of depression.
What Is a Dietary Supplement?
The term dietary supplement was defined by Congress in the Dietary Supplement Health and Education Act (DSHEA) of 1994 (FDA, 2012a). A dietary supplement is an orally ingested product containing a “dietary ingredient” intended to supplement the diet. The dietary ingredient in these products may include vitamins, minerals, herbs or other botanicals, amino acids, and other physiological substances such as enzymes, organ tissues, glandulars, and metabolites. Unlike drugs, dietary supplements are not intended to treat, diagnose, prevent, or cure disease.
By law, the FDA regulates dietary supplement ingredients and products according to regulations that are different than those covering conventional prescription and over-the-counter drug products. Under the DSHEA, the dietary supplement manufacturer is responsible for ensuring that a dietary supplement or ingredient is safe before it is marketed. Manufacturers do not need to register such products with the FDA or obtain FDA approval before producing or selling them, but they must comply with the Dietary Supplement Current Good Manufacturing Practices (FDA, 2007) for quality control. Manufacturers are required to ensure that product label information is truthful and not misleading, which generally means that no claims can be made for the therapeutic use or effectiveness of a product. Since 2007, manufacturers have also been required to submit to the FDA all serious adverse event reports associated with use of dietary supplements in the United States. The FDA can take action against dietary supplement manufacturers for products only after they are marketed, primarily if the product is found to be unsafe or, less often, if false or misleading claims are made about the product.
Dietary Supplements for Depression
L-methylfolate (Deplin®) is designated by the FDA as a medical food. A medical food is defined as “a food which is formulated to be consumed or administered enterally [or orally] under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation” (FDA, 2012b, para. 1). Medical foods are exempt from FDA labeling requirements for health claims and nutrient content, and they are not reviewed or approved by the FDA. They must comply with good manufacturing practice regulations and labeling practices for protection against food allergens.
L-methylfolate is marketed for adjunctive use in treating depression in patients with suboptimal folate levels (Pamlab, LLC, 2011). It is available only by prescription. The putative mechanism of action claimed for L-methylfolate in depression is that it aids in the synthesis of the neurotransmitters serotonin, norepinephrine, and dopamine. Low folate levels have been associated with a poor response to antidepressant medications (Coppen & Bolander-Gouaille, 2005). Two open-label studies in mixed patient populations (depressed older adults and depressed patients with alcoholism) suggested some antidepressant benefit for methylfolate monotherapy (Di Palma, Urani, Agricola, Giorgetti, & Dalla Verde, 1994; Guaraldi, Fava, Mazzi, & la Greca, 1993). One open-label study suggested that adding folinic acid improved depression in patients with a partial or non-response to a serotonin reuptake inhibitor (SRI) antidepressant drug or the antidepressant agent venlafaxine (Effexor®) (Alpert et al., 2002).
Several controlled trials have been conducted, but the quality and methodology of these studies have been criticized (Taylor, Carney, Goodwin, & Geddes, 2004). A randomized double-blind trial was conducted in 41 folate-deficient patients with schizophrenia or depression (Godfrey et al., 1990). Among the 24 depressed patients, whose concurrent antidepressant therapy was not clearly characterized, adjunctive treatment with L-methylfolate was modestly but significantly superior to placebo in improving mood symptoms. A randomized double-blind study in depressed older adult patients with dementia found no difference in outcome between L-methylfolate plus placebo versus low-dose trazodone (Desyrel®) (Passeri et al., 1993). A study that randomized patients with major depression to fluoxetine (Prozac®) plus folate or to fluoxetine plus placebo found that folate augmentation was modestly but significantly effective only among the female participants (Coppen & Bailey, 2000). A similar study that randomized patients with major depression to fluoxetine plus folate or fluoxetine plus placebo found that folate augmentation was modestly but significantly effective (Resler et al., 2008).
The recommended dosage for L-methylfolate is 7.5 to 15 mg per day. Although generally well tolerated, its use can potentially mask the hematologic (anemia) or neurologic (neuropathy) effects of vitamin B12 deficiency.
S-adenosyl-L-methionine (SAM-e) is a naturally occurring amino acid molecule present in all living cells. It is a major methyl group donor in the human body, which is important for neurotransmitter synthesis and cellular second-messenger system function. Systematic reviews and meta-analyses of controlled trials in outpatients with depression have found that, when administered intravenously or intramuscularly, SAM-e is more effective than placebo and as effective as tricyclic antidepressant drugs (Papakostas, 2009), but it has not been compared to newer-generation antidepressant drugs and it has not been well studied in more severe depression. Less evidence supports the use of oral SAM-e, although some trials have demonstrated its efficacy as well. In addition, there is a paucity of evidence examining whether oral forms of SAM-e can be safe, well tolerated, and efficacious when used as adjunctive treatment for those who do not respond to antidepressant agents. Only one such study has been conducted, which found SAM-e more effective than placebo when added to SRI treatment non-responders (Papakostas Mischoulon, Shyu, Alpert, & Fava, 2010).
The dosage range for SAM-e in clinical studies has been 200 to 1600 mg per day. Possible side effects include insomnia, anxiety, decreased appetite, sweating, dizziness, dry mouth, constipation, and nausea.
Omega-3 Fatty Acids
Omega-3 fatty acids are a group of polyunsaturated fatty acids. They are considered essential because they cannot be synthesized in the body but have important physiological effects throughout the body. They are found mainly in fatty fish and vegetable oils but are also available as dietary supplements. Based on the known role of omega-3 fatty acids in central nervous function—and the epidemiological association between low fish intake and depression—omega-3 fatty acids have been investigated for the treatment of depression (Parker et al., 2006).
The most important omega-3 fatty acids that have been studied for their health benefits, including cardiovascular disease and depression, are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Meta-analyses of placebo-controlled trials have demonstrated significant antidepressant efficacy in bipolar depression (Sarris, Mischoulon, & Schweitzer, 2012) and unipolar depression (Martins, Bentsen, & Puri, 2012), although the methodology and quality of the studies are variable. In most of the clinical studies, omega-3 fatty acids were used together with antidepressant medication. There has been interest in omega-3 fatty acids for treating postpartum depression, but the only placebo-controlled trial found no benefit (Levant, 2011).
The dosage range for omega-3 fatty acids in clinical studies has been 1,000 to 9,000 mg per day, although 1,000 mg per day appears to be effective in most studies. The effectiveness of EPA alone, or the combination of EPA plus DHA, has been better established than that of DHA alone. Possible side effects include gastrointestinal discomfort. Although bleeding is a theoretical concern, this has not been noted in depression or cardiovascular studies.
The amino acid molecule L-tryptophan is converted to 5-hydroxytryptophan, which is then converted to the neurotransmitter serotonin. The hormone melatonin, important for sleep regulation, is synthesized from serotonin in the pineal gland. Based on this synthetic pathway, L-tryptophan and 5-hydroxytryptophan have each been advocated as treatments for depressive disorders and insomnia (Soh & Walter, 2011). When used for treating depression, they are typically added to an antidepressant drug. For treating insomnia, they are generally used alone. Neither molecule has been proven effective for depression or insomnia in controlled studies.
The most common dosages for either molecule are 150 to 300 mg per day, although higher doses have been used in clinical studies of depression. Possible side effects include nausea, diarrhea, headache, and sedation. More serious serotonergic side effects, including serotonin syndrome, are possible if they are combined with strongly serotonergic antidepressant drugs. In 1989, an epidemic of a newly identified illness called eosinophilia-myalgia syndrome (EMS, characterized by peripheral eosinophilia with scleroderma-like features) was associated with the use of tryptophan products. More than 30 individuals died. This syndrome was later linked to a chemical impurity generated during the production process of tryptophan from a particular manufacturer. Tryptophan products were withdrawn from the market by the FDA but were allowed to be reintroduced in 2005. A case report of EMS associated with L-tryptophan was recently published, so vigilance is still required (Allen et al., 2011).
Although most psychotropic drugs have direct effects on neurotransmitter reuptake sites or neurotransmitter receptors, they may also have direct or indirect effects on second-messenger signal transduction systems, which ultimately mediate the synthesis of various protein products that lead to their therapeutic benefit. Inositol, a precursor of the phosphatidyl-inositol second-messenger system, has not been clearly shown to be effective in a small number of controlled studies of unipolar and bipolar depression (Taylor, Wilder, Bhagwagar, & Geddes, 2004). Usual dosages in clinical trials were 6 to 12 grams per day. Possible side effects are nausea, flatus, diarrhea, and sedation.