If you’ve ever stood staring at a wall of supplements, wondering whether that bottle of fish oil, vitamin D, or saffron might lift your mood, you’re not alone.
Nutraceuticals and plant-based compounds are increasingly marketed as gentler, “natural” alternatives to antidepressants. And they may be less expensive and easier to obtain.
But how much evidence is there that they actually work to alleviate depression symptoms?
A new network meta-analysis offers a complicated answer: a few supplements may actually help with depression, but the evidence is nowhere near as solid as some of the research can make it seem.
Researchers analyzed 163 randomized controlled trials involving 15,757 adults diagnosed with major depressive disorder, covering 137 different nutrient-based supplements (nutraceuticals) or plant-based (phytoceutical) treatments.
The studies compared these compounds with either a placebo, or standard antidepressant treatment. Then they measured changes in depressive symptoms, treatment response, and whether participants stopped taking the treatment.
The researchers also did something a bit unusual – they went looking for reasons the results might be misleading.
They found plenty.
Across the studies, several treatments appeared to beat placebo, sometimes by a lot, but often the evidence was highly inconsistent.
Once the researchers filtered out studies with higher risk of bias, outliers, and other potential problems, only a handful of compounds continued to show evidence of an effect.
One of the most promising was eicosapentaenoic acid, or EPA, an omega-3 fatty acid. Twenty trials involving 8,483 people contributed to the analysis, making it one of the better-studied compounds in the review.
Vitamin D3 and a particular extract of St. John’s wort called ZE117 also appeared to reduce depressive symptoms compared with placebo.
But the evidence for vitamin D3 came from just three trials involving 344 people, while the ZE117 result came from three trials involving 207 people.
Those are small numbers. These compounds may or may not be effective, but more people would need to be studied to know either way, and those results replicated.
And some of the effects were almost too impressive. When they looked more closely at study quality, they found a telling pattern: the larger the reported benefit of the supplement, the lower the quality of the study tended to be.
The effect sizes for EPA, vitamin D3 and ZE117 in the researchers’ more carefully filtered analysis were larger than would typically be expected in a high-quality, double-blind, placebo-controlled trial of a depression treatment.
This drove some skepticism around the results, and they described them as “higher-than-expected” and ultimately considered them unrealistic.
That doesn’t mean the treatments don’t work. It means the way the study was designed makes it hard to trust the existing results.
Some other intriguing findings the analysis uncovered included other St. John’s wort extracts (ZE117 and WS5570) which were associated with higher depression-symptom remission rates than placebo.
Saffron showed a larger effect and curcumin showed medium-sized reductions in anxiety symptoms associated with depression. While these studies didn’t show many bias issues, these findings were also based on relatively small numbers of trials.
Still, the researchers acknowledge that there are real, known mechanisms behind this possible positive result, writing, “Saffron may upregulate brain-derived neurotrophic factor (BDNF) expression and enhance synaptic plasticity, which is often impaired in depression and anxiety.”
There are also gaps in what the trials tell us about safety.
The researchers found no nutraceutical or phytoceutical class that was significantly less tolerable than placebo, although citicoline (a supplement typically used to boost brain function) was associated with more dropouts.
But many original studies did not provide enough information to assess safety comprehensively – particularly long-term safety or the risk of suicidality.
After filtering the evidence, the authors conclude that only a few nutraceuticals and phytoceuticals show enough promise to warrant further, more rigorous trials. EPA, vitamin D3 and certain St. John’s wort extracts emerge as potential candidates for further investigation.
Related: Some Signs of Depression May Show Up in the Blood, Study Finds
The key word is potential. The researchers want to see much more robust studies on 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.”
With the overall confidence in the evidence rated low to very low, there’s still a considerable gap between “this might work” and “we know this works.”
The research has been published in Molecular Psychiatry.
This article was fact-checked by Fiona MacDonald and edited by Fiona MacDonald. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.
