Supplements for depression and anxiety: Are they safe and effective?
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Many people with depression or anxiety look to vitamins, herbs and other supplements, either instead of or alongside prescription medications. Some supplements do have evidence of benefit, especially for mild depression, but the effects are usually modest, product quality varies, and some can interact dangerously with medications. This article summarizes what Canadian guidelines and recent research say, and how to use supplements safely. Always talk to your doctor or pharmacist before starting a supplement, especially if you take other medications.
What do Canadian guidelines say about supplements for depression?
The 2023 Canadian CANMAT depression guidelines rank complementary treatments by the strength of evidence. They recommend considering a supplement on its own only for mild depression. For moderate depression, supplements may be added to standard treatment, and severe depression needs standard medical treatment.
| Supplement | CANMAT 2023 recommendation for depression |
|---|---|
| St. John's wort | First-line for mild depression; second-line for moderate depression |
| L-methylfolate | Second-line (small benefit) |
| SAM-e | Third-line (mixed results) |
| Omega-3 fatty acids | Third-line (uncertain evidence) |
| Saffron, lavender, rhodiola (roseroot) | Third-line for mild depression (modest evidence) |
| Probiotics | Mixed evidence |
St. John's wort: effective, but with serious interactions
St. John's wort has the best evidence of any herbal treatment for mild depression. However, it causes many dangerous interactions:
- It strongly speeds up the liver enzyme CYP3A4 (and also CYP2C19), which can make other medications less effective, including birth control pills, warfarin, some heart and HIV medications, transplant drugs and some cancer treatments.
- Combined with antidepressants such as SSRIs and SNRIs, or with MAO inhibitors, it may cause serotonin syndrome, a potentially serious reaction.
- It can cause sensitivity to sunlight, stomach upset and restlessness, and may trigger mania in people with bipolar disorder.
Never combine St. John's wort with an antidepressant or start it while taking other prescription medications without talking to your doctor or pharmacist.
Which other supplements have some evidence?
L-methylfolate (active folate)
L-methylfolate is the active form of folate, a B vitamin. Meta-analyses suggest it can modestly improve depression, mainly when added to an antidepressant. Some studies suggest a greater benefit in people with higher body weight or signs of inflammation. Folic acid, the synthetic form found in most multivitamins, is not recommended as a depression treatment. Variants in the MTHFR gene affect how the body converts folic acid, but L-methylfolate does not need this conversion.
SAM-e
S-adenosylmethionine (SAM-e) is a natural substance involved in making brain chemicals such as serotonin and dopamine. Some studies found benefit when added to antidepressants, but recent trials were mixed, so CANMAT now ranks it as third-line. SAM-e can cause nausea, insomnia and anxiety, and may trigger mania in people with bipolar disorder.
Omega-3 fatty acids
Omega-3s from fish oil (EPA and DHA) are widely used. A 2021 Cochrane review found a small effect on depressive symptoms that was unlikely to be clinically meaningful, based on low-certainty evidence. Omega-3s are generally safe at usual doses but can slightly increase bleeding risk at high doses, especially with blood thinners or anti-inflammatory painkillers.
Saffron, lavender and rhodiola
Saffron extract has reduced depressive symptoms in several small trials, both alone and added to antidepressants. Oral lavender oil has some evidence for anxiety and depression. Rhodiola (roseroot) has limited and mixed evidence. All three are third-line options for mild depression, and product quality can vary.
Probiotics
The gut-brain connection is an active area of research. A 2023 meta-analysis and an international clinician taskforce found some benefit for probiotics added to antidepressants, but CANMAT considers the evidence too uncertain to recommend them. A healthy diet supports both mood and pain management, and choosing antidepressants based on your DNA and gut symptoms can help when digestive side effects are a problem.
What about supplements for anxiety?
Evidence for anxiety is more limited. The WFSBP and CANMAT taskforce found modest support for ashwagandha and lavender oil in anxiety disorders, and did not recommend kava for generalized anxiety disorder; kava has also been linked to liver injury. For proven treatments, read What are the best medications for anxiety?
How can you use supplements safely?
- Tell your doctor and pharmacist about every supplement you take.
- Do not use supplements instead of treatment for moderate or severe depression, or if you have thoughts of suicide.
- Avoid St. John's wort with antidepressants and many other medications.
- People with bipolar disorder should be cautious with St. John's wort and SAM-e, which can trigger mania.
- Check with your health care provider before using supplements during pregnancy or breastfeeding.
- Choose products from reputable manufacturers. In Canada, look for a Natural Product Number (NPN) on the label.
How do genes fit in?
Your genes affect how you respond to the antidepressants that supplements are often combined with. CYP2C19, CYP2D6 and CYP2B6 influence many SSRIs and SNRIs, and St. John's wort speeds up CYP3A4 and CYP2C19, which can change your drug levels further. Pillcheck reports these genes and 355 medications in total. A Pillcheck pharmacist reviews your results, your medications and your supplements, and can advise your prescriber on safe combinations.
Summary
- St. John's wort is effective for mild depression but interacts with many medications, including antidepressants.
- L-methylfolate has modest evidence as an add-on treatment; SAM-e, omega-3, saffron, lavender and rhodiola have weaker evidence.
- The evidence for probiotics is still uncertain.
- Supplements are not a substitute for treatment of moderate or severe depression.
- Always tell your prescriber and pharmacist about supplements, and consider how your genes affect your medications.
Frequently asked questions
What is the best supplement for depression?
St. John's wort has the strongest evidence for mild depression, but it interacts with many medications. L-methylfolate has modest evidence as an add-on to antidepressants.
Can I take St. John's wort with my antidepressant?
No, not without medical advice. The combination may cause serotonin syndrome, and St. John's wort can lower the levels of many other medications.
Does fish oil help depression?
The evidence is uncertain. A Cochrane review found only a small effect that is unlikely to be clinically meaningful.
Are supplements safe for anxiety?
Some, such as lavender oil and ashwagandha, have modest evidence. Kava is not recommended for generalized anxiety and has been linked to liver injury. Talk to your health care provider before using any supplement.
Can a pharmacist help me choose supplements?
Yes. A pharmacist can check for interactions with your medications, and a pharmacogenetic test can show how your body handles antidepressants.
References
Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Can J Psychiatry. 2024;69(9):641-687.
Sarris J, Ravindran A, Yatham LN, et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J Biol Psychiatry. 2022;23(6):424-455.
Appleton KM, Voyias PD, Sallis HM, et al. Omega-3 fatty acids for depression in adults. Cochrane Database Syst Rev. 2021;11:CD004692.
Zhang Q, et al. Effect of prebiotics, probiotics, synbiotics on depression: results from a meta-analysis. BMC Psychiatry. 2023;23:477.
Wang LS, Zhu B, Abd El-Aty AM, et al. The influence of St John's Wort on CYP2C19 activity with respect to genotype. J Clin Pharmacol. 2004;44(6):577-581.
Sharma A, Gerbarg P, Bottiglieri T, et al. S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656-e667.
