Updated July 31, 2023

Many people struggling with depression and anxiety look to vitamins and supplements as a natural alternative or complement to pharmaceutical antidepressants. But are they safe and effective? New clinical studies show the promising role of some vitamins and supplements in improving mood symptoms. However, research indicates that supplements alone cannot substitute medications for people with severe depression in terms of effectiveness. Further, natural products are not without side effects, and when used together with prescription medications, they may pose significant health risks. In this overview, we will discuss how supplements work as mood stabilizers for depression and anxiety, their potential side effects, and whether these can be taken along with antidepressants.
Supplements should not be taken lightly – an incorrect supplement or excessive use can worsen depression and affect the heart and digestive system. Pharmacists know about fundamental drug-food interactions, so consult your pharmacist before you decide if taking a supplement to improve your mood or treat depression is right for you.

Supplements with strong evidence of effectiveness

Vitamin B9

Vitamin B9, also known as folate, a type of folic acid, or L-methylfolate (LMF), can be an effective supplemental treatment for people with major depressive disorder (MDD) with higher body weight and positive inflammatory biomarkers in the blood. While it may help reduce depressive symptoms, vitamin B9 supplements alone are not sufficient and best used along with an antidepressant. No benefit was noted for lean people. There are many supplements containing various forms of folate. Vitamin B9 differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier, making it more effective. Vitamin B9 is also less affected by genetic variations in the MTHFR, MTR and MTRR genes mutation, which cause folate deficiencies. Vitamin B9 (LMF) is available as a prescription medical food and is approved for the treatment of depression. Other B group vitamins (B6 and B12) can also be used with B9.

Probiotics, Prebiotics and Synbiotics

Probiotics are live bacteria naturally present in fermented foods and can provide a health benefit when consumed in adequate amounts in their live form. Prebiotics, such as cocoa flavonoids, fructans, galacto- and pectic oligosaccharides, support the growth of protective microbiota in the gut. Synbiotics are a combination of probiotics and prebiotics. The healthy gut-brain connection is a known paradigm. A healthy diet improves depression and pain symptoms. The use of prebiotics can substantially enhance gut health and counteract the gastrointestinal symptoms of some medications. However, selecting the correct antidepressants based on your DNA and GI symptoms is a critical first step.

Potentially beneficial supplements

SAM-e

S-adenosyl methionine (SAM-e) is a natural substance produced in the body. Synthetic SAM-e is an over-the-counter supplement in North America but is a prescription drug in Europe. SAM-e is used to treat depression and pain. SAM-e works similarly to folate. Folate deficiency affects the synthesis of important neurotransmitters dopamine, serotonin, and acetylcholine. Folate deficiency may be one of the causes of depression. The benefit of SAM-e is that it is not impacted by genes that regulate folate metabolism, such as MTHFR. People with folate deficiency have lower levels of SAM-e. Therefore, SAM-e supplements may improve the synthesis of serotonin and dopamine, producing an antidepressant effect.

Some studies have found that SAM-e is just as effective as NSAIDs like ibuprofen and celecoxib and helps people with osteoarthritis and fibromyalgia. SAM-e also has fewer side effects than NSAIDs. SAM-e is considered safe and can be combined with TCAs, SSRIs, and SNRIs. SAM-e side effects can include insomnia, sweating, loss of appetite, constipation, nausea, dry mouth, dizziness, and anxiety. However, SAM-e is not recommended for people with bipolar disorder because it can induce manic episodes. Please consult your physician or pharmacist to see if SAM-e supplements are appropriate for your treatment.

Rhodiola

Rhodiola rosea root extract is considered an adaptogen – i.e., it alleviates physical and mental stress. Rhodiola has been studied extensively in Russia and Scandinavia. Controlled clinical trials support rhodiola’s efficacy for depression and anxiety. Rhodiola has several chemicals, including rosavin, tyrosols, and flavonoids. Like St. John’s Wort, rhodiola affects monoamine oxidase activity and produces an anti-anxiety and mood-stabilizing effect. It may also induce vivid dreams and thus can interfere with sleep. Rhodiola should be taken on an empty stomach at least 30 minutes before food to improve absorption and is considered safe. Rhodiola can be combined with tricyclic antidepressants. A mild serotonin syndrome reaction can occur when rhodiola is combined with paroxetine and other SSRIs. Consult your healthcare provider if you want to supplement your treatment with rhodiola rosea.

Omega-3

Omega-3s are widely recommended by naturopathic doctors and physicians based on claims that these fatty acids significantly improve cardiovascular and mental health. However, recent studies questioned some of these claims. Other studies demonstrated that the ratio of omega-6 to omega-3 correlates with depression. If a person has too little omega 3 versus other fatty acids, they may be more likely to be depressed. In contrast, the ratio of omega 6 to other fatty acids is unrelated to the risk of depression or anxiety. Some omega-3s, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found primarily in fish oil and certain types of algae. Another type of omega-3, alpha-linolenic acid (ALA), is found in flaxseed oil and some other vegetable oils. The omega-6 fatty acids are primarily found in vegetable oils.

Studies suggest that omega-3 essential fatty acids can help in treating depression. Omega-3s are thought to be quite safe at usual doses (up to 3 grams per day) and are mainly used as a supplement for the medical treatment of depression. Omega-3s alone are not sufficient as a depression treatment and are best used in combination with an antidepressant. In people with bipolar disorder, mania may occur when high doses (6 -10 grams a day) are used. High doses of omega-3 can also increase the risk of GI bleeding or excessive bleeding from cuts/surgery, which may be life-threatening, particularly for patients taking anticoagulants or antiplatelets for managing the risk of heart disease or NSAIDs (like Advil and naproxen) for chronic pain. Because it is a fat-soluble substance, omega-3 can accumulate in the body if taken at high doses for long periods and cause permanent kidney and liver damage.

Supplements to avoid

St. John’s Wort

Herbal supplement St. John’s Wort is one of the most commonly known natural products recommended for depression. Its effectiveness was studied in multiple clinical studies, which have not produced strong supporting evidence. Hence this supplement should not be used for treating depression. St. John’s Wort can affect specific liver enzymes involved in metabolizing many medications, making the medicine less effective than it should be or causing side effects. St. John’s Wort is also known to block the effectiveness of drugs known as MAOs (similar to MAOI antidepressants). MOA-A and MOA-B inhibitors are used to treat panic disorder, social phobias, treatment-resistant depression and atypical depression, as well as Parkinson’s disease. However, MOA inhibitors and St. John’s Wort cannot be combined with popular antidepressants, including SSRIs and SNRIs or other antidepressants, as such combinations can lead to serotonin syndrome, which can be fatal. Common side effects of St. John’s Wort include upset stomach and diarrhea, fatigue, restlessness, elevated blood pressure, and increased sensitivity to the sun. In patients with bipolar disorder, St. John’s Wort may also induce mania. People suffering from depression and taking antidepressants should not attempt to substitute medications or supplement treatment with St. John’s Wort.

Summary

• Some supplements, including vitamin B9, pro- and prebiotics, omega-3, rhodiola rosea, and SAM-e, can support the treatment of anxiety and depression. However, these supplements alone are insufficient to manage anxiety and depression.
• Your response to antidepressants is impacted by genetic variations in drug-metabolizing genes, which can also be adversely affected by supplements such as St. John’s Wort.
• Pharmacogenetic tests, such as Pillcheck, explain how your body metabolizes antidepressants and can assist your healthcare providers in selecting an appropriate drug and dose. Our clinical pharmacists can advise which supplements and nutrition may help your treatment.

References

Zhang Q et al., Effect of prebiotics, probiotics, synbiotics on depression: results from a meta-analysis BMC Psychiatry (2023) 23:477

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Maher, A. R., Hempel, S., Apaydin, E., Shanman, R. M., Booth, M., Miles, J. N., & Sorbero, M. E. (2016). St. John’s Wort for Major Depressive Disorder: A Systematic Review. Rand health quarterly, 5(4).

Sharma, A., Gerbarg, P., Bottiglieri, T., Massoumi, L., Carpenter, L. L., Lavretsky, H., … & Mischoulon, D. (2017). S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. The Journal of clinical psychiatry, 78(6), e656.

Tayama, J., et. al. (2018). Omega-3 polyunsaturated fatty acids and psychological intervention for workers with mild to moderate depression: a double-blind randomized controlled trial. Journal of Affective Disorders, 245.

Thesing CS et al. (2018) Omega-3 and omega-6 fatty acid levels in depressive and anxiety disorders. Psychoneuroendocrinology. Jan;87:53-62.

Wang, L.S., et. al. (2013). The influence of St. John’s Wort on CYP2C19 activity with respect to the genotype. Journal of Clinical Pharmacology, 44(6).