Most Promising OTC Products for Depression Flagged

Among over-the-counter (OTC) products for depression, St. John’s wort, saffron, probiotics, and vitamin D have the strongest evidence of efficacy, new research showed.

However, folic acid and lavender also show promise and should be prioritized in future research, the investigators noted.

As more patients turn to OTC products to manage depressive symptoms, it’s important to answer questions about the state of the related research, study investigator Rachael Frost, PhD, Senior Lecturer in Health and Social Care, School of Public and Allied Health, Liverpool John Moores University, Liverpool, England, who is herbal practitioner, told Medscape Medical News.

Frost said her team aimed to map the current evidence base for OTC products for depression — asking whether research has focused too narrowly on a few supplements, whether other promising options are being overlooked, and how future studies and consumer guidance could be better directed.

The findings were published online on July 15 in Frontiers in Pharmacology.

Mapping the Research

The prevalence of major depressive disorder (MDD) ranges from 2% to 21%, depending on the country and the measures used, and rates continue to rise — prompting some experts to describe depression as a growing epidemic.

Many patients are reluctant to take antidepressants and face long wait times for psychological therapies, said Frost. “There’s a strong drive for people to self-manage, particularly if they have mild or moderate symptoms of depression,” she noted.

Part of a larger project summarizing existing evidence on OTC products — including herbal medicinal products (HMPs), vitamins and minerals, and homeopathic preparations — for depression, anxiety, and insomnia, the goal of the current review was to “map” the full research landscape on OTC products for depression in adults aged 18-60 and identify gaps where further study is needed, said Frost.

The review included 209 trials assessing 64 different products. Most studies were conducted in Iran, followed by Germany, the US, Australia, the UK, and China.

Double-blind designs were the most common. Sample sizes varied widely, with a median of 62 participants per study.

All trials used depression rating scales as either primary or secondary outcomes. The most frequently used were the Hamilton Depression Rating Scale, the Montgomery-Aberg Depression Rating Scale, and the Clinical Global Impression Scale.

Dietary supplements were evaluated in 114 trials, HMPs in 94 trials, and one trial — outside these categories — investigated aspirin.

Evidence Gaps

In the HMP category, most studies focused on products in capsule form. Frost found this somewhat surprising given the popularity, affordability, and ease of incorporating herbal teas into daily life. She suggested the lack of research on teas may be due to practical challenges — such as the difficulty of creating a placebo tea for controlled trials.

Notably, none of the studies evaluated homeopathic products for depression.

“Homeopathic trials just focused on well–being, rather than looking at people who had symptoms or a diagnosis of depression,”saidFrost.

Few studies examined multivitamins, which can be challenging to evaluate due to varying combinations of vitamins, minerals, and sometimes added herbal extracts or probiotics, Frost explained.

Dietary supplements were more often compared to placebo (86%) than HMPs (67%), whereas HMPs were more frequently compared to prescription drugs (32%) than dietary supplements (5%). Additionally, supplements were more likely to be tested as adjuncts to other depression treatments, most commonly antidepressants — compared to HMPs.

Very few studies evaluated OTC products vs psychotherapy. This, said Frost, is despite psychological therapies being “quite popular” and often a first–line treatment for depression.

“Whether psychological therapies are better than OTC products or if there would be additive effects if people take both at the same time, is a question that needs answering,” she said.

Products With Potential

Products supported by evidence from more than 10 trials included St. John’s wort, saffron, probiotics, and vitamin D. Within these categories, a variety of products, extracts, and dosages were tested.

Most studies on St. John’s wort favored its use compared with placebo and showed effects comparable to or better than prescription antidepressants. While the evidence for St. John’s wort is strong, caution is advised due to potential interactions with antidepressants, contraceptive pills, and other medications, said Frost.

Saffron products also showed generally positive effects compared with placebo. When evaluated alongside antidepressants, saffron demonstrated similar benefits and could be a promising new option to recommend, said Frost.

Results for both probiotics and vitamin D favored the intervention compared with placebo.

“Given that probiotics and vitamin D also might provide benefits for things like the gut, bone health, and immunity, they are probably worth recommending,” Frost noted.

Potential mechanisms by which these OTC products may alleviate depressive symptoms include reducing inflammation, mitigating oxidative stress, modulating the microbiota-gut-brain axis, suppressing hyperactivity of the hypothalamic-pituitary-adrenal axis, and regulating neurotransmitter activity.

The review included several trials on omega-3 supplements, most comparing them to placebo. Frost noted that these studies were more likely to report null findings, indicating that omega-3 may not be a strong recommendation for depression.

Among products with emerging evidence (two to nine trials), the review identified folic acid, lavender, zinc, tryptophan, rhodiola, and lemon balm as the most promising. Bitter orange, Persian lavender (Nepeta menthoides), and chamomile each showed positive results in two trials.

These promising products, Frost said, warrant further evaluation to better understand their potential benefits.

While some emerging OTC products show promise, Frost cautions that their effectiveness is not guaranteed. She stresses the importance of doctors having open, honest discussions with patients to ensure any supplements do not interfere with existing health conditions or medications.

The study on aspirin showed no evidence of efficacy for depression.

Many trials lacked sufficient safety data; however, among those that reported safety outcomes, most products demonstrated a favorable safety profile, Frost noted.

Experts Weigh In 

Commenting on the research for Medscape Medical News, Jonathan Burgess, MD, clinical assistant professor at Lifestyle Psychiatry Clinic, Stanford University, in Stanford, California, said the review gives him “quite a bit of homework,” as he plans to examine several of the original studies.

However, he pointed out that the review did not differentiate between eicosapentaenoic acid (EPA)-predominant and docosahexaenoic acid-predominant omega-3 formulations.

Contrary to the review’s suggestion that omega-3s are ineffective for depression, Burgess noted that multiple meta-analyses have shown that EPA-predominant formulas are convincingly effective for depression.

He said that beyond advising a healthy diet, regular exercise, and good sleep hygiene, EPA-predominant omega-3s, St. John’s wort, saffron, and probiotics are his “go-to’s” for patients with depression who want to try OTC treatments.

Burgess agreed that lavender and folate show considerable promise but cautioned that, like any effective treatment, they can have side effects. He cited cases where patients overused lavender and experienced suicidal thoughts, warned that excessive zinc intake can disrupt copper balance, and highlighted the risk of serotonin syndrome—a potentially life-threatening condition — in patients taking tryptophan alongside St. John’s wort.

Also commenting for Medscape Medical News was David Mischoulon, MD, PhD, director of the Depression Clinical and Research Program at Massachusetts General Hospital and professor of Psychiatry at Harvard Medical School, both in Boston, who has extensively researched natural remedies.

He said the review offers a useful snapshot of the current state of the field and aligns with his overall understanding of the evidence base.

However, he questioned why the review included so few studies on S-adenosyl-methionine (SAMe), a compound involved in the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine. The review cited only two parallel randomized controlled trials on SAMe, one of which he coauthored.

“I’m surprised because it’s one of the better studied natural products. The review seems to underestimate how much has been done with regard to that particular product,” said Mischoulon.

Mischoulon said he is “a lot more comfortable” recommending SAMe for patients with depression than many other OTC products, largely due to its strong safety profile. Aside from occasional nausea or indigestion at higher doses, SAMe is generally well tolerated. Unlike St. John’s wort — which can interact with immunosuppressants, antiretrovirals, cancer therapies, antidepressants, and hormonal contraceptives — SAMe does not interact with other medications, he noted.

In addition to SAMe, Mischoulon also considers omega-3 supplements a viable OTC option for depression.

However, he emphasized the importance of directing future research toward emerging products. He noted that well-studied options like St. John’s wort and omega-3s have already been thoroughly reviewed and suggested that greater attention should be given to lesser-known supplements such as lavender and folic acid.

Frost and Burgess reported no relevant disclosures. Mischoulon reported receiving research support from Nordic Naturals and Heckel Medizintechnik GmbH. He works with the MGH Clinical Trials Network and Institute, which has received research funding from multiple pharmaceutical companies.