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NCCIH Clinical Digest

for health professionals

Depression and Complementary Health Approaches: What the Science Says

December 2021

Clinical Guidelines, Scientific Literature, Info for Patients: 
Depression and Complementary Health Approaches


Omega-3 Fatty Acid Supplementation

At present, it’s uncertain whether omega-3 fatty acid supplementation may be useful for depression. Some studies have shown small effects in adjunctive therapy in patients with a diagnosis of major depressive disorder (MDD) and on depressive patients without a diagnosis of MDD; however, most trials have been adjunctive studies. Controlled trials of omega-3 fatty acids as monotherapy are inconclusive compared to standard antidepressant medicines, and it remains unclear that a mechanism is present to suggest that a pharmacologic or biologic antidepressant effect exists.

What Does the Research Show?

  • A 2021 Cochrane review of 35 randomized controlled trials (34 studies involving a total of 1924 participants investigated the impact of omega-3 PUFA (polyunsaturated fatty acid) supplementation compared to placebo, and one study involving 40 participants investigated the impact of omega-3 PUFA supplementation compared to antidepressant treatment) evaluated the effect of omega-3 PUFAs on MDD. For the placebo comparison, omega-3 PUFA supplementation resulted in a small-to-modest benefit for depressive symptomology compared to placebo. The reviewers noted that this effect is unlikely to be clinically meaningful. The reviewers concluded that currently we do not have sufficient high-certainty evidence to determine the effects of omega-3 PUFAs as a treatment for MDD.
  • 2021 systematic review and meta-analysis of 31 trials involving 41,470 participants assessed the effects of long-chain omega-3s and found that increasing long-chain omega-3 probably has little or no effect on the risk of depression symptoms (median dose 0.95 g/d, duration 12 months) or anxiety symptoms (median dose 1.1 g/d, duration 6 months).
  • 2020 network meta-analysis involving 910 participants with MDD in 10 trials with 3 adjuvant therapy strategies (high-dose omega-3 PUFAs, low-dose omega-3 PUFAs, and placebo) concluded that high-dose omega-3 PUFA supplementation might be more superior than low-dose in the early therapy period for MDD. However, the reviewers noted that more head-to-head clinical trials need to be carried out to provide more direct comparison and enhance the evidence of the efficacy of omega-3 PUFAs for this disorder.
  • 2020 meta-analysis of 18 randomized controlled trials involving a total of 4,052 pregnant women or postpartum women concluded that omega-3 PUFAs had an overall significant but small beneficial effect on perinatal depression. The reviewers advised against prescribing omega-3 PUFAs for the treatment or prevention of depressive symptoms during pregnancy, given a lack of effect with low heterogeneity. In contrast, the reviewers noted that omega-3 PUFA supplementation may be a promising adjuvant treatment for postpartum depression.


  • Omega-3 fatty acid supplements are generally safe and well-tolerated. When side effects do occur, they typically consist of minor gastrointestinal symptoms and fishy aftertaste.
  • There is some concern that omega-3 supplements may extend bleeding time. The risk appears to be minimal and should never be used in patients who take drugs that affect platelet function. It is important to discuss any potential herb-drug interactions with patients if they are considering using omega-3 fatty acids.
  • It is uncertain whether people with fish or shellfish allergies can safely consume fish oil supplements and should not be used in such patients.

St. John’s Wort (Hypericum perforatum)

Results of some studies suggest that St. John’s wort (Hypericum perforatum) may have an effect on mild-to-moderate major depressive disorder (MDD) for a limited number of patients, similar to standard antidepressants, but the evidence is far from definitive. Although some studies have demonstrated a slight efficacy over placebo, others contradict these findings.

The significant herb-drug interactions of St. John’s wort (Hypericum perforatum) are important safety considerations.

What Does the Research Show?

  • A 2016 systematic review of 35 studies involving 6,993 participants found that St. John’s wort monotherapy for mild and moderate depression is superior to placebo in improving depression symptoms and not significantly different from antidepressant medication. However, evidence of heterogeneity and a lack of research on severe depression reduce the quality of the evidence.
  • 2015 systematic review and network meta-analysis of 66 studies involving 15,161 patients examined whether antidepressants and other agents, including St. John’s wort (Hypericum perforatum), may be more effective than placebo in the primary care setting. The reviewers found that St. John’s wort (Hypericum perforatum), as well as some other agents, showed some positive results, but because the current evidence is limited, conclusions about their place in clinical practice cannot be drawn.
  • The 2010 American Psychiatric Association Task Force on Complementary and Alternative Medicine report states that St. John’s wort (Hypericum perforatum) may eventually become a reasonable treatment for mild-to-moderate MDD for a limited number of individuals, although not all recent studies for the treatment of MDD demonstrated efficacy over placebo. The report also indicates any potential efficacy is only a greater consensus and support from studies in mild-to-moderate MDD.
  • In a 2011 randomized controlled trial examining the treatment of minor depression with St. John’s wort (Hypericum perforatum) or citalopram over the course of 12 weeks, neither St. John’s wort nor citalopram showed any benefit over placebo.
  • 2012 study examined longer-term efficacy of St. John’s wort (Hypericum perforatum) versus sertraline and placebo in patients with MDD and found that St. John’s wort, sertraline, and placebo produced similar treatment effects over the course of 26 weeks.


  • Drug interactions with St. John’s wort (Hypericum perforatum) limit use and are important safety considerations.
  • Combining St. John’s wort (Hypericum perforatum) and certain antidepressants can lead to serotonin syndrome, with dangerous symptoms ranging from tremor and diarrhea to very dangerous confusion, muscle stiffness, drop in body temperature, and even death.
  • Other side effects of St. John’s wort (Hypericum perforatum) are usually minor and uncommon and may include upset stomach and sensitivity to sunlight. Also, St. John’s wort may worsen feelings of anxiety in some people.
  • A rare, but possible side effect of taking St. John’s wort (Hypericum perforatum) is psychosis. Those with certain mental health disorders, such as bipolar disorder, are at risk of experiencing this rare side effect. Therefore, it is important to discuss this potential side effect with patients who are considering using St. John’s wort and encourage discontinuation of the herb if they experience a worsening of symptoms.
  • Taking St. John’s wort (Hypericum perforatum) increases the activity of cytochrome P450 3A4 (CYP3A4) enzyme and reduces plasma concentrations and can weaken many prescription medicines, such as:
    • Antidepressants
    • Oral contraceptives
    • Cyclosporine
    • Digoxin
    • Some HIV drugs including indinavir
    • Some chemotherapeutic agents including irinotecan
    • Warfarin and other anticoagulants


Current scientific research does not support the use of SAMe (S-adenosyl-L-methionine) for the treatment of depression.

What Does the Research Show?

  • 2016 Cochrane review of 8 randomized controlled trials involving 934 adults concluded that there isn’t enough high-quality evidence nor the ability to draw firm conclusions based on that evidence about the effects of SAMe for the treatment of depression.
  • 2020 randomized, double blind, placebo-controlled trial involving 90 participants evaluated the effects of the combination of SAMe 200 mg and Lactobacillus plantarum (L. plantarum) HEAL9 for the overall symptomatology of mild-to-moderate depression over a 6-week period. A greater reduction in depressive symptoms for the combination of SAMe and L. plantarum compared to placebo was seen at treatment week 6.
  • Preliminary results from a 2014 randomized controlled trial in a subsample of 144 participants with major depressive disorder (MDD) who received SAMe, escitalopram, or placebo for 12 weeks provided some evidence for the use of SAMe in the treatment of MDD. However, in the parent study, SAMe failed to demonstrate any advantage over placebo for MDD.


  • 2009 review of evidence for SAMe for the treatment of MDD concluded that there is insufficient evidence examining whether the oral preparations of SAMe can be safe or efficacious when used as adjunctive treatment for patients with MDD who are unresponsive to antidepressants.
  • Information on the long-term safety of SAMe is limited and inconclusive. However, in one study of alcohol-related liver disease in which participants took SAMe for 2 years, no serious side effects were reported.
  • SAMe may decrease the effects of levodopa. It is also possible that SAMe might interact with drugs and dietary supplements that increase levels of serotonin, including some antidepressants, L-tryptophan, and St. John’s wort, but the evidence for such interactions is very limited.
  • SAMe promotes the growth of Pneumocystis, a fungus that can cause pneumonia in people with suppressed immune systems. It is possible that taking SAMe might increase the likelihood or severity of Pneumocystis infection in people who are HIV positive and should never be used in these patients.
  • Side effects of SAMe appear to be uncommon, and when they do occur they are usually problems such as nausea or digestive upsets.


Data from current scientific research do not support the use of inositol for the treatment of depression.

What Does the Research Show?

  • A 2016 systematic review and meta-analysis of several adjunctive nutraceuticals for depression found no significant benefit over placebo for inositol.
  • A 2014 meta-analysis of seven randomized controlled trials (two bipolar studies, one bipolar and major depressive disorder (MDD) study, two MDD studies, and two premenstrual dysphoric disorder (PMDD) studies) involving 242 participants found no significant treatment effect of inositol for depressed patients. However, inositol showed a trend of efficacy of depressive symptoms over placebo in patients with PMDD.


  • There is a paucity of data on the safety and side effects of inositol. A 2014 meta-analysis of inositol for depression and anxiety disorders found that inositol marginally caused gastrointestinal upset compared with placebo. A 2011 European review on the safety of inositol had similar findings in that inositol induced gastrointestinal side effects such as nausea, flatus, and diarrhea.


There is some evidence that suggests acupuncture may provide a modest reduction in symptoms of depression, particularly when compared with no treatment or a control.

What Does the Research Show?

  • A 2018 Cochrane review of 64 studies involving a total of 7,104 participants concluded that acupuncture may result in a moderate reduction in the severity of depression when compared with treatment as usual/no treatment, and the use of acupuncture may lead to a small reduction in the severity of depression when compared with a control. Reviewers also concluded that the effects of acupuncture compared with medication and psychological therapy are uncertain because of the low quality of evidence.
  • A 2019 meta-analysis of seven trials compared the effectiveness of acupuncture therapy in patients with post-stroke depression and found evidence to support the use of acupuncture for this condition. Subgroup analyses also showed that acupuncture alone resulted in better outcomes than drug therapy in improving depressive symptoms.
  • A 2019 systematic review and meta-analysis of 29 studies involving 2,268 participants (22 trials were conducted in China and 7 conducted outside of China) concluded that acupuncture may be a suitable adjunct to usual care and standard antidepressant medication. However, most of the trials included in the review and meta-analysis were at a high risk of bias.


  • Relatively few complications from using acupuncture have been reported. Still, complications have resulted from the use of nonsterile needles and improper delivery of treatments.
  • When not delivered properly, acupuncture can cause serious adverse effects, including skin infections, punctured organs, pneumothoraces, and injury to the central nervous system.

Music Therapy

There is some evidence that music therapy may provide short-term benefits for people with depression.

What Does the Research Show?

  • A 2020 meta-analysis of 55 randomized controlled trials found that music therapy exhibited a significant reduction in depressive symptoms compared with the control group, and music medicine (i.e., music as therapy that is not managed by a music therapist, and does not involve a therapeutic relationship) exhibited a stronger effect in reducing depressive symptoms. Among the specific music therapy methods, recreative music therapy, guided imagery and music, music-assisted relaxation, music and imagery, improvisational music therapy, and therapeutic music listening exhibited a different effect, respectively.
  • A 2017 Cochrane review of 9 studies involving a total of 421 participants (411 of whom were included in the meta-analysis that investigated short-term effects of music therapy for depression) concluded that music therapy provides short-term beneficial effects for people with depression. Reviewers also found that music therapy shows efficacy in decreasing anxiety levels and improving functioning of depressed individuals.


  • There are no adverse effects associated with music therapy.


There is some evidence that yoga may be helpful in reducing depressive symptoms.

What Does the Research Show?

  • A 2017 Cochrane review of 23 studies (involving 1,272 participants) in people with depressive symptoms (although not necessarily diagnosed with depression) found that yoga was helpful in reducing symptoms in 14 of the studies.
  • A 2017 systematic review of 7 studies (involving 240 participants) found some evidence of beneficial effects of yoga for major depressive disorder (MDD); however, the reviewers judged the evidence to be insufficient to justify recommending yoga for people with this condition. Problems included the small number of people studied and an inability to compare benefits with risks because of inadequate information on safety.
  • A 2020 systematic review of 27 studies evaluated yoga as an intervention for reducing anxiety and depression in children and adolescents. The reviewers concluded that yoga generally leads to some reductions in anxiety and depression in youth; however, the methodological quality of evidence included in the review was weak to moderate.


  • Yoga is generally considered a safe form of physical activity for healthy people when performed properly, under the guidance of a qualified instructor. However, as with other types of physical activity, injuries can occur. The most common injuries are sprains and strains. Serious injuries are rare.
  • People with health conditions, older adults, and pregnant women may need to avoid or modify some yoga poses and practices.


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