245 5th Avenue
3rd floor
NY, NY 10016

Evidence-based Guide to Supplements for Depression

by | December 1, 2020

Evidence-based Guide to Supplements for Depression

With the world changing at a faster rate than ever, it’s easy to feel as if things are out of control. Keeping up with work and social demands, parenting, and living in uncertainty, fear, and isolation due to Covid-19 are triggers for anxiety and depression. This is particularly true for individuals who are already prone to depression. If you are dealing with depression, I want to offer hope that there are things you can do to effectively cope with depression, and not let it control you. Most importantly, it is imperative that you work with a qualified primary care physician, therapist, and/or psychiatrist, to determine the optimal modalities of treatment for you. 

Understanding What Depression Is

Did you know that major depression is one of the most common mental health disorders in the US? Over 17 million adults in the US have had at least 1 major depressive episode. This mood disorder that leaves people feeling sad and uninterested in activities can also include the following symptoms:

  • Feeling hopeless
  • Increased sleep or insomnia
  • Difficulty concentrating
  • Decrease in energy
  • Lack of appetite or excessive appetite resulting in weight loss or gain
  • Moving and/or speaking slowly
  • Feelings of guilt and worthlessness
  • Thoughts of death and self-harm
  • Restlessness
  • Anger or irritability
  • At times, it can be accompanied by unexplained physical symptoms

How is Depression Diagnosed? 

Major depression can be diagnosed by your primary care doctor after speaking with you and asking screening questions, and/or administering a questionnaire. A common form for this used in medical practices is the PHQ-9 questionnaire. Depression symptoms need to be present for at least two weeks and are severe enough to be significantly impacting social, occupational, and other areas of functioning. 

Doctors will also work to rule medical conditions (e.g., hypothyroidism), nutrient deficiencies that can contribute to depression (e.g., vitamin D or iron deficiency), other psychiatric disorders, and substance use which may present with depression as one of the symptoms. 

It’s also important to mention that major depression is different from sadness and grief. While grief can lead to depression, with sadness or grief, feelings come in waves, and self-esteem is generally maintained. With depression, however, a low mood typically occurs for a more prolonged period of time and is accompanied by self-loathing as well as loss of interest in things. Depression can also lead to suicidal thoughts. The good news is that with a team of healthcare professionals, and evidence-based tools, depression is a treatable mental health condition.

What Causes Major Depression?

While we still do not have a precise answer to this question, research has elucidated a number of contributing factors and mechanisms that contribute to developing this mental health condition:

  • Genetic make up
  • Stressful life events such as the loss of a loved one
  • Trauma 
  • Burnout
  • Chemical imbalances in the brain
  • Suboptimal ability of the brain to regulate mood
  • Medical conditions such as hypothyroidism, nutrient deficiencies, chronic infections
  • Medications 
  • Lifestyle (e.g., screen time, sedentary lifestyle, poor nutrition) 
  • Isolation and lack of social support

How is Major Depression Treated?

Evidence reveals that combination of psychotherapy (cognitive behavioral therapy) and medications (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or another class of antidepressants) is more effective than either treatment alone for depression. The optimal therapies for each individual dealing with depression depend on the severity of depression, other medical conditions the patient has, medications the patient is on, the support system, patient preference, frequency of follow-up, and other factors.

Successfully coping with depression symptoms may include several additional practices. 

An analysis of 11 clinical trials found that relaxation techniques are more effective than no treatment for reducing self-reported symptoms of depression but less effective than therapy. Progressive muscle relaxation is an excellent practice that can be done daily to support mood and help build stress-resiliency. Regular aerobic exercise and physical activity can also help support mood and reduce symptoms of depression. As long as you don’t have any contraindications, put those sneakers on and go for a run, or start dancing!

Mindfulness-based stress reduction (MBSR) has been found to be effective in reducing symptoms of depression, anxiety, and suicidal thoughts in veterans. Another study comparing MBSR and aerobic exercise found that both were effective in reducing symptoms of anxiety and depression and anxiety and increase in subjective well-being.

Loneliness has been correlated to depressive symptoms. Having a close community of loved ones, building a support system, and addressing loneliness are crucial. 

While medications and supplements can be extremely helpful treatments (and necessary in some cases) in ameliorating symptoms of depression, a multimodality approach that promotes a healthy lifestyle, social connectivity, stress management, addresses triggers, and promotes self-efficacy and self-confidence is equally important in achieving long term results. While the above are all important factors to address, the focus of this article is going to be on supplements. 

As an integrative medicine physician, I often get asked about supplements that can be supportive for mood symptoms. Some individuals prefer to try supplements rather than medications, but before doing so, it is important to do research and talk to your doctor about whether supplemental support is appropriate for you.

Fish Oil

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 fatty acids found in fish oil. Another omega-3, alpha-linolenic acid (ALA), is present in plant oils including flaxseed, soybean, and canola oils. While ALA can be converted to EPA, then DHA in the body, this conversion is inefficient (less than 15%). This is why it is important to consume EPA and DHA directly. Omega-3 fatty acids play an important role in the body – they are incorporated into the cell membranes, provide energy for the body, have anti-inflammatory properties, and are involved in multiple systems. While omega-3 fatty acids EPA and DHA, have benefits for cardiovascular health and other health conditions, they’ve also been found to help with depression symptoms. 

A review of 10 clinical trials concluded that omega-3 fatty acid supplementation for 4 weeks or more was more effective at reducing symptoms of depression than placebo in people with depression and bipolar disorder. An analysis of observational studies including 255,076 individuals and over 20,000 cases of depression found a correlation between dietary omega-3 fatty acid intake and a lower risk of depression. The maximum effect was achieved when the intake of omega-3 fatty acids was 1.8g/day. The authors reported, however, that the limitations of this review included study design and confounding factors. 

The American Psychiatric Association generally recommends omega 3 fatty acids such as fish oil be added to treatment for mood disorders. Dosage typically starts at 1g/day, however, any dose greater than 3g/day should be monitored by a physician, as higher doses may be associated with an increased risk of bleeding. You should always consult your doctor before starting dietary supplements. 

B Vitamins

B vitamins, including B6, B9 (folate), and B12, play a role in how the brain functions. More specifically, they are involved in chemical reactions that regulate levels of neurotransmitters like serotonin and norepinephrine. Vitamin B6, B12, and folate also act as cofactors for enzymatic reactions in the methionine and folate cycles. Deficiency in one or more of these vitamins can lead to the accumulation of amino acid homocysteine. There is a correlation between high homocysteine and low mood, therefore, having a deficiency in these vitamins can have a negative effect on mental health. Interestingly, correcting homocysteine has not been shown to improve mood symptoms, so while it may be a marker of low mood (just as it is a marker of cardiovascular disease), correcting it may not correlate with improvement in mood. This review article argues that individuals who may suffer from insufficiency or deficiency in B vitamins should consume a vitamin B complex that includes the entire vitamin B group.

A study where participants were either given a vitamin B complex (Max Stress B supplement) or placebo, found that vitamin B complex improved depression, anxiety, and mental health quality of life of adults with depression more than placebo did. The intervention in this study lasted 60 days.

A review of 18 scientific papers that studied the effect of at least 4 weeks of vitamin B complex on mood, found that 11 of these articles reported that vitamin B supplementation had a positive effect on mood, and performed better than placebo. Its benefit for depression symptoms did not reach statistical significance, however, and no benefit was found with respect to anxiety. They did find that vitamin B vitamin supplementation benefited the healthy and at-risk populations with respect to stress and that it may also benefit those who have poor nutrient status. This is why, in certain situations, it may be helpful to test the B vitamins, especially prior to considering supplementation. 

American Psychiatric Association recommends folate as a reasonable addition to the treatment of major depressive disorder but reports that data don’t support that it be used alone.

In the context of the discussion relating to nutrients and mood, it is important to emphasize that whenever possible, in a healthy individual, healthy nutrition should be the source of most nutrients (assuming that an individual does not have low levels of nutrients, has access, ability, and desire to consume a healthy, whole-food plant-based diet, and does not have any medical conditions that impair absorption of nutrients). Mediterranean diet is an excellent source of B vitamins. Specifically, B vitamins can be found in dark, leafy vegetables, nuts, and seeds, legumes, fruit, whole grains, eggs, dairy, fish, and meat. 

For those who do need dietary supplements, dosing for these vitamins should be discussed with your doctor and you shouldn’t exceed their recommendations. High levels of certain vitamins can lead to harmful effects (e.g., excess vitamin B6 can cause nerve damage; excess folate has been associated with increased risk of colorectal cancer and skin cancer). 


Iron deficiency, especially in premenopausal women, is not uncommon and can have an impact on mental health and quality of life. Poor concentration, fatigue, apathy, and an altering of neurotransmitter production in the brain, can all result from iron deficiency.

A randomized, placebo-controlled trial found that iron supplementation in mothers with post-partum depression improved their iron stores and improved their depressive symptoms (whereas placebo did not) after 6 weeks of treatment.

Aside from not getting enough iron in the diet, some of the causes of iron deficiency include heavy periods, Celiac disease, autoimmune gastritis, H. pylori infection, blood loss from the gastrointestinal tract (e.g., due to colorectal cancer), and gastric bypass procedure. Consult with your doctor to determine if your iron levels need to be checked.


Zinc is an essential trace mineral found in high amounts in the brain. Lower levels of zinc have been linked to depression in patients on hemodialysis. Supplementation with zinc has been found to be a helpful additional treatment for depression.

While it is recommended that non-pregnant women take 8mg of zinc per day and men take 11mg per day, higher doses have been studied in depression. One study found that when 25 mg of zinc daily is added to an SSRI (medication for depression), depressive symptoms are significantly more reduced than when a placebo is added to an SSRI.

Though zinc supplementation can be beneficial for individuals with major depression, it should be noted that a high amount of zinc intake can limit the absorption of copper, leading to copper deficiency. It may therefore be necessary to take a low dose of the copper supplement in addition to zinc supplementation, and measure levels of both periodically. When starting a new supplement or changing a dose, always talk to your qualified healthcare provider.

It is also wise to incorporate zinc-containing foods into the diet. Plant-based sources of zinc include baked beans, pumpkin seeds, cashews, chickpeas, oatmeal, almonds, kidney beans, and peas. Other sources include oysters, beef, crab, lobster, pork chop, chicken, yogurt, and cheese.

Vitamin D

We know that vitamin D helps the body absorb calcium and keeps bones strong, but there have been mixed studies about the relationship between vitamin D and depression. Vitamin D plays a key role in regulating neurotransmitters, neurotrophic factors (a family of molecules that support the growth, survival, and maturation of neurons), the communication between the nervous system and the immune system, and the production of antioxidants. Given the multiple roles of vitamin D within the nervous system, it is no surprise that it has been studied in the context the treatment of depression. 

Vitamin D deficiency has been linked to depression, dementia, diabetes, autism, and schizophrenia. 

A study of nearly 13,000 participants found that higher vitamin D levels were associated with a significantly reduced risk of current depression in individuals with a previous history of depression, but not associated with risk of current depression in individuals with no prior history of depression. This points to the fact that vitamin D is likely one of the factors that may predispose to depression, but that there are other factors involved that may affect the impact of low vitamin D. 

Interestingly, studies on vitamin D supplementation for depression have yielded mixed results. A review of research studies reported that one randomized controlled trial found positive results when vitamin D was added to an antidepressant in patients with major depressive disorder. Another study found that in overweight and obese individuals who are vitamin D deficient and do not have clinical depression, vitamin D supplementation did not significantly change their depressive symptoms compared to placebo. A study that included patients with depression found no difference in symptoms after vitamin D supplementation vs. placebo after 3 months. Less than 1/3 of these patients were deficient in vitamin D at the start of the study, therefore no definitive conclusions can be drawn for patients with depression and a vitamin D deficiency. Another study in patients with major depressive disorder found that supplementation with vitamin D led to a non-significant trend towards lower depression scores after 8 weeks, compared to placebo. It is clear that more studies are needed to elucidate the relationship between vitamin D and depression. Until then, it is important to keep vitamin D levels within the expected range.

Vitamin D levels can be boosted through exposure to sunlight, food (e.g., seafood, mushrooms), and supplementation. The suggested dosage of Vitamin D is between 600-800 IU, or higher doses for a limited period of time, depending on the level of deficiency. In my practice, I have found that different individuals respond to vitamin D doses differently and that it is important to repeat vitamin D levels after starting supplementation. Consult your doctor to have your vitamin D measured and determine if supplementation is appropriate. Note that vitamin D supplements can interact with medications and should only be taken under a doctor’s supervision.


SAM-e, or S-adenosyl methionine, is a compound found naturally in the body. It has several important functions, including maintaining cell membranes and the production of serotonin, dopamine, and norepinephrine. It requires vitamins B6 and B12 to be used efficiently. When taken as a supplement, SAM-e has been found to have antidepressant effects – both when taken alone or as augmentation to antidepressant medication. 

SAM-e has been studied since the 1970’s. A review of studies concluded that SAM-e is a promising treatment for depression, but that there is limited evidence available with respect to its efficacy and safety.

Effective doses of this compound for depression typically range from 400mg twice daily to 800mg twice daily with a typical starting dose of 200mg twice daily. As SAM-e works in conjunction with B12 and folate, it is important that levels of these not be low. SAM-e has been observed to cause mania and hypomania, therefore individuals with bipolar disorder should not take it unless they are on a mood-stabilizing medication and their psychiatrist feels that it is safe. Additionally, if one is on a selective serotonin reuptake inhibitor (SSRI) or St. John’s wort for depression and taking SAM-e, there is a risk of a serious condition called serotonin syndrome. Therefore, SAM-e should only be taken upon a doctor’s recommendation and with the doctor’s supervision.

St. John’s Wort (SJW)

St. John’s wort is the most commonly used natural depression treatment in Europe and the US.

A large review of 35 studies and almost 7000 patients with mild to moderate depression found that St. John’s wort is better than placebo and comparable to antidepressant medications in efficacy. Interestingly, the authors also found that subjects taking St. John’s wort were less likely to experience side effects, compared to individuals who took antidepressant medications. That being said, there were concerns about the quality of assessments for side effects, so this should be taken with a grain of salt. It should also be noted that there is a lack of research on severe depression and St. John’s wort. A meta-analysis of studies that were published the following year (2017) confirmed the efficacy of St. John’s wort for mild to moderate depression. They also pointed out that the long-term safety and efficacy of St. John’s wort isn’t known as the herb was studied for no more than 12 weeks in these trials. A 2016 review paper concluded that for patients with mild-moderate depression who prefer not to use conventional antidepressants, SJW is a reasonable first-line option.

St. John’s wort can interact with medications and it is important to take it only under the guidance and supervision of a physician who is knowledgeable in the use of it. Use of St. John’s wort with an antidepressant or SAM-e can lead to the serious condition known as serotonin syndrome. Moreover, it can lead to hypomanic and manic episodes and is, therefore, contraindicated in individuals with bipolar disorder.


Rhodiola is grown in the cold, mountainous regions of Europe and Asia. It is considered to be an adaptogen and it stimulates the body’s stress response to support stress resiliency. A study showed that Rhodiola administered daily for 6 weeks at 340-680mg/day improved symptoms of depression. Rhodiola also reduces stress-related fatigue and improves mental performance when administered at 576mg extract/day. 

When compared to an antidepressant, sertraline, Rhodiola was not as effective, however, it had a better side effect profile and was better tolerated. The authors, therefore, suggested that it may be appropriate for some individuals with mild to moderate depression. The combination of Rhodiola and sertraline have been found to be more effective at alleviating symptoms of depression than sertraline and placebo in patients with depression.

Though most will tolerate this herb well, some have experienced dizziness, dry mouth, agitation, and irritability. Bleeding or bruising can occur if used at high doses (600-900mg/day). It can also interfere with some medications; therefore, always consult your doctor before taking it.

Considering Your Options

Depression not only comes with devastating symptoms for many, but it can also lead to confusion, frustration, and loss of hope for the person experiencing it and their loved ones. The good news is, however, that there are many options for treatment. 

If you believe you may be experiencing symptoms of depression, consider taking the next step to work with your doctor and discuss the possible triggers for your depression, as well as strategies and treatment options that will support you, identify and address the root causes, and improve your symptoms. These strategies can include cognitive behavioral therapy, exercise, mindfulness, meditation, yoga, lifestyle habits (nutrition, sleep, movement, community, and support), support group, medications, supplements, neurofeedback, and others.

If you are considering dietary supplements as a natural treatment for depression, I recommend talking to your physician first, as the risk/benefit ratio of taking a supplement must be considered. Supplements and botanical remedies are not without side effects, and many interact with medications and other supplements. It is therefore important to understand the level of evidence supporting supplement use, possible side effects, as well as contraindications. For instance, some supplements for depression may exacerbate mania in individuals with bipolar disorder. One needs to be under the supervision of a physician when considering supplement use.

If you work with an integrative medicine physician, or an integrative psychiatrist, they can do the appropriate testing and recommend supplements that may support your wellbeing.

If you are struggling with thoughts of self-harm, call the Suicide Hotline at 800-273-8255 or visit the National Suicide Prevention Lifeline, or SAMHSA

Additional and related resources:


Nothing stated or posted in this article is intended or should be taken to be the practice of medical or counseling care. The information made available in this article, including, but not limited to, interviews, text, graphics, images, links to other articles, websites, and other material contained in this article, is strictly for informational and entertainment purposes only. The information in this article is NOT (and should not be used as) a substitute for professional psychiatry, psychology, medical, nursing, or professional healthcare advice or services, nor is it designed to suggest any specific diagnosis or treatment. Please always seek medical advice from your physician or a qualified health care provider regarding any medical questions, conditions or treatment, before making any changes to your health care regimen, medications or lifestyle habits. None of the information in this article is a representation or warranty that any particular drug or treatment is safe, appropriate or effective for you, or that any particular healthcare provider is appropriate for you. Never disregard professional medical advice or delay seeking help from a health care provider due to something you have read or seen in this article. Your reading/use of this article does not create in any way a physician-patient relationship, any sort of confidential, fiduciary or professional relationship, or any other special relationship that would give rise to any duties. This article does not recommend or endorse any specific tests, healthcare providers, procedures, or treatments, and if you rely on any of the information provided by this article, you do so solely at your own risk.

Interested in becoming a patient?

Contact us for a complimentary discovery call with Dr. Bojana

Grab your FREE MEDITATION GUIDE when you sign up for my Thrive in Health and Life newsletter!

You'll receive my tips, tools and resources (including delicious, EASY recipes!) for living your healthiest, most vibrant life!

Upon registering, you will receive my guide on how to create your own unique meditation practice.

About the Author

Bojana Jankovic Weatherly, MD

Bojana Jankovic Weatherly, MD

Dr. Bojana (Boy•ana) Jankovic Weatherly is an award winning physician, double board certified in internal and integrative medicine. After completing internal medicine residency, she did a fellowship in integrative medicine, trained in functional medicine, nutrition and mindfulness. Her approach is rooted in evidence-based medicine that is personalized to each individual she works with.


Submit a Comment

Your email address will not be published. Required fields are marked *

Pin It on Pinterest

Share This
Call Now Button
Get Your FREE Meditation Guide

Click for more information