Evidence-Based Supplements for Depression

Research funding is often harder to come by when it comes to dietary supplements, so by default there tends to be limited high quality, rigorous scientific evidence to support their use in chronic health conditions. However, there are a number of supplements that do have research support for their use in depression, and here is a brief overview.

Omega-3 fatty acids

Omega-3 fatty acids are popular for use in a variety of different conditions, including depression. Polyunsaturated fatty acids like omega-3’s are a component of neuron cell membranes, and low levels of omega-3’s have been found in the serum and red blood cell membranes of individuals with major depressive disorder.

A 2007 systematic review by Lin and Su1 evaluated the research literature on omega-3’s. They identified 94 studies, of which they selected 7 that met rigorous criteria for inclusion in their review. While differences in the studies limited comparability, they found that omega-3’s did improve depressive symptoms in individuals with major depressive disorder and bipolar depression.

S-Adenosyl Methionine (SAMe)

S-adenosyl methionine, commonly referred to as SAMe, acts as a donor of single-carbon methyl groups in the production of neurotransmitters and other substances in the body. Supplementing with SAMe may boost synthesis of the neurotransmitters involved in depression and affect how neuron membranes interact with neurotransmitters.

A 2012 review by Papakostas et al.2 found that SAMe 1600 mg/day improved symptoms of depression when used alone or as an adjunct to antidepressant therapy. There were a number of limitations in the existing research, including many of the studies using injectable rather than oral SAMe and a lack of direct comparisons to newer antidepressants.


L-methylfolate is an activated form of folic acid that is a precursor to SAMe. Several studies have found a correlation between low levels of methylfolate and major depressive disorder, particularly depression that is less responsive to antidepressant treatment. A genetic variation commonly seen in individuals with depression can impair the body’s ability to produce the activated methylfolate form.

A 2012 review by Papastokas et al.2 found that L-methylfolate 15 mg/day improved depressive symptoms when used alone or as an adjunct to antidepressant therapy. Another 2012 study by Papastokas et al.3 found that adding L-methylfolate improved depressive symptoms in individuals who had only a partial response to SSRI antidepressants. L-methylfolate may play an even more significant role in individuals who are obese or who have elevated levels of C-reactive protein, an inflammatory marker found in the blood.


Creatine is involved in the formation of the creatine kinase enzyme in the brain, which plays a role in creating an energy supply to meet increased demand. High levels of certain chemicals related to creatine have been associated with a better response to treatment with SSRI antidepressants and augmentation with the thyroid hormone triiodothyronine.

A 2012 study by Lyoo et al.4 found that initiating SSRI antidepressant therapy along with creatine supplementation (3 g/day for one week then 5 g/day for 7 weeks) resulted in a more rapid improvement in depressive symptoms compared to SSRI plus placebo. This may be related to effects on enzymatic activity in the brain that allow the SSRI to take effect more quickly. This study was only conducted in females, since animal models showed that males did not demonstrate a response to creatine. Lyoo suggested that this may be related to differences in cerebral metabolism and the effects of estrogen.


N-acetylcysteine (NAC) is used in IV form in hospital settings to prevent damage to the liver related to acetaminophen toxicity. It works by increasing production of a substance called glutathione, which decreases inflammatory stress. There are indications of a link between inflammation and depression, which may explain why the antidepressant effect that has been observed with NAC. NAC also enhances neurogenesis (brain cell growth) and affects the activity of glutamate, a major neurotransmitter.

A 2014 study by Birk et al.5 added NAC 1000 mg twice a day to the usual treatment regimens of individuals with major depressive disorder and found improved remission and response rates as well as improved overall functioning scores, but only after 16 weeks. A small 2011 study by Magalbaes6 found that NAC 1000 mg twice a day was also effective as an adjunct in the treatment of bipolar depression.

Vitamin B12

A number of studies have found a correlation between depression and vitamin B12 deficiency, and studies have also shown a relationship between vitamin B12, folate, and homocysteine, which are also implicated in depression. A small 2013 study by Syed et al.7 examined individuals with major depressive disorder and vitamin B12 levels at the low end of the normal range. They found that combining injectable vitamin B12 1000 mcg weekly for 6 weeks with an SSRI or tricyclic antidepressant produced a greater improvement in depressive symptoms than the combination of antidepressant plus placebo. Vitamin B12 is also available in oral form, although some people may have problems with absorption via this route.

Any time you’re considering making changes to your treatment regimen it’s a good idea to consult your doctor, naturopath, or other healthcare providers. Often supplements are the most useful when added to conventional depression treatment, and they offer a natural way to boost the effectiveness of your existing depression treatment plan.



Photo by Leti Kugler on Unsplash