Supplements for Depression May Help, but Evidence Remains Uncertain

If you have ever found yourself looking at a shelf packed with supplements and asking whether fish oil, vitamin D or saffron could improve your mood, you are far from the only one.

Nutraceuticals and plant-derived compounds are being promoted ever more often as milder, "natural" substitutes for antidepressants. They can also be cheaper and more readily available.

Yet how strong is the evidence that they can genuinely ease symptoms of depression?

A recent network meta-analysis gives a nuanced response: some supplements could be helpful for depression, but the supporting evidence is far less secure than parts of the research might suggest.

Researchers examined 163 randomised controlled trials, involving 15,757 adults with major depressive disorder. The review covered 137 nutrient-based supplements, known as nutraceuticals, and plant-based treatments, known as phytoceuticals.

These studies compared the compounds against either a placebo or conventional antidepressant treatment. Researchers then assessed shifts in depressive symptoms, treatment response and whether participants discontinued treatment.

Nutraceuticals and phytoceuticals for depression

The team also took the somewhat unusual step of actively searching for factors that could distort the findings.

They found no shortage of them.

Several treatments seemed to outperform placebo across the trials, at times by substantial margins, although the evidence was frequently very inconsistent.

After excluding studies with a greater risk of bias, outliers and other possible issues, only a small number of compounds still had evidence indicating an effect.

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, was among the most encouraging options. It was one of the more thoroughly investigated compounds in the review, with 20 trials involving 8,483 people contributing to the analysis.

Vitamin D3 and ZE117, a specific extract of St. John's wort, also appeared to lessen depressive symptoms relative to placebo.

However, the evidence for vitamin D3 was drawn from only three trials with 344 participants, while the ZE117 finding came from three trials involving 207 people.

Those totals are limited. These compounds may be effective or they may not, but studies involving more participants, with replicated results, are needed to establish this either way.

Why the supplement findings require caution

Some reported effects were nearly too striking. A closer examination of study quality revealed a notable trend: the bigger the claimed supplement benefit, the more likely the study was to be of lower quality.

In the researchers' more stringently filtered analysis, the effect sizes for EPA, vitamin D3 and ZE117 exceeded what would normally be anticipated from a high-quality, double-blind, placebo-controlled trial of a depression treatment.

This prompted scepticism about the findings. The researchers called them "higher-than-expected" and ultimately judged them unrealistic.

That does not show that the treatments are ineffective. Rather, the studies' design makes the currently available results difficult to rely on.

The analysis also identified several other notable findings. Other St. John's wort extracts, ZE117 and WS5570, were linked to higher rates of remission from depression symptoms than placebo.

Saffron produced a larger effect, while curcumin delivered medium-sized reductions in anxiety symptoms linked with depression. Although these studies showed few indications of bias, the findings were likewise based on comparatively few trials.

Even so, the researchers recognise that plausible, established mechanisms could underpin this possible benefit. They write, "Saffron may upregulate brain-derived neurotrophic factor (BDNF) expression and enhance synaptic plasticity, which is often impaired in depression and anxiety."

Safety evidence and future trials

The trials also leave important unanswered questions about safety.

No class of nutraceutical or phytoceutical was found to be significantly less tolerable than placebo. However, citicoline - a supplement generally used to enhance brain function - was associated with a higher number of dropouts.

Many of the original studies, though, did not report enough detail for safety to be evaluated fully, especially regarding long-term safety and the risk of suicidality.

Having filtered the evidence, the authors conclude that only a limited number of nutraceuticals and phytoceuticals appear sufficiently promising to justify further, more rigorous trials. EPA, vitamin D3 and particular St. John's wort extracts stand out as possible candidates for additional investigation.

The crucial word is potential. The researchers call for far more robust research into these supplements, writing that their work is "underscoring that more high-quality studies are needed and that the results of this NMA should be interpreted with caution."

As overall confidence in the evidence was rated from low to very low, a substantial divide remains between "this might work" and "we know this works."

The research was published in Molecular Psychiatry.

This article was fact-checked and edited by Fiona MacDonald. Although we take pride in our process, we are only human. If you notice an error, please let us know.