Review reveals herbals show limited but “promising evidence” for depression

A review of over-the-counter (OTC) herbal medicinal products and dietary supplements identifies 64 products evaluated for depression, with differing levels of evidence for each. Products with promising but limited evidence include folic acid, lavender, zinc, tryptophan, rhodiola, and lemon balm. The authors urge that future research focus on these products and that trial safety reporting must be improved.

The team has identified a need to evaluate further how herbal medical products can supplement antidepressants and to explore potential benefits to combining these with psychological therapies for integrative support. 

Co-author Rachael Frost, Ph.D., a senior lecturer in Health and Social Care at Liverpool John Moores University, UK, tells Nutrition Insight that depression symptoms and diagnoses are increasing. Although talking therapies and antidepressants from the UK National Health Service provide “excellent support,” patients may experience delays in access or be reluctant to use medications. 

“We know from surveys that people with depression often try OTC products either alongside or while waiting for conventional treatment.”

“However, online information for people using these products is often confusing,” Frost cautions. “Sometimes, these products are made out to have no evidence, and sometimes a lab study with limited clinical relevance will be treated as though it means a product has groundbreaking effects.”

She adds that previous product reviews have been limited in focus, for example, only reviewing one ingredient or a few studies on a product range. 

Mapping the research landscape

For the paper published in Frontiers in Pharmacology, the authors reviewed 23,933 study records and 1,367 papers, identifying 209 clinical trials that assessed 64 OTC products for depression, where participants took the product for at least one week.

The team focused on clinical trials as the most rigorous way of evaluating products’ effectiveness and safety. The review includes studies in adults aged 18–60 with depression symptoms or a diagnosis. 

Several well-known products also had the most evidence: omega-3s (39 trials), St. John’s Wort (38), probiotics (18), saffron (18), and vitamin D (14). 

The authors reviewed 23,933 study records and 1,367 papers, identifying 209 clinical trials that assessed 64 OTC products for depression.Frost says she was surprised more trials were finding no effects on depression symptoms than positive evidence for omega-3s. St. John’s Wort and saffron trials showed beneficial effects compared to a placebo and prescription antidepressants. 

The review concludes that probiotics and vitamin D were more likely to rescue depression symptoms than a placebo. 

“I was surprised by the sheer number of products that had only a single trial available, which are helpful as a starting point, but the results need to be replicated,” Frost continues. “I was also surprised by how few teas have been evaluated, as these are a simple and accessible way that people often support their well-being.” 

Moreover, she notes that few trials compared OTC products to talking therapies or whether a combination would have additional benefits. These therapies are a “common first-line treatment for depression.” 

Promising products

Of the 64 OTC products studied, 41 had only one trial available, and 18 had emerging evidence. Of those 18, the review notes that folic acid, lavender, zinc, tryptophan, rhodiola, and lemon balm were “the most promising.” Frost adds that magnesium supplements also have promising evidence.

The team also found positive effects in two trials each for bitter orange, Persian lavender (Nepeta menthoides), and chamomile tea. 

Frost says that chamomile, lavender, and lemon balm, commonly used for mental health benefits, hold the most potential for further study.Frost believes that chamomile, lavender, and lemon balm hold the most potential for further study. “All three products have traditional uses for mental health and are fairly commonly taken.” 

“Our sister review of products for anxiety also found evidence that lavender may reduce anxiety symptoms and some limited evidence that chamomile may reduce anxiety symptoms. People with depression often experience some anxiety symptoms alongside this.”

The review found mixed effects on depression across clinical trials for several popular ingredients, including melatonin, magnesium, curcumin, cinnamon, echium, vitamin C, and a combination of vitamin D and calcium. Another trial combining prebiotics and s-adenosylmethionine (SAMe) did “not seem to be better than placebo,” says Frost. 

At the same time, Frost says other commonly used herbal medicines for depression symptoms, such as ginseng, ginkgo, lime flowers, orange blossom, and peppermint, have not been evaluated in trials.

Inconsistent safety reporting

The study authors call for a higher standard of safety reporting in clinical trials; 64, or 31%, of the trials did not sufficiently report side effects. 

Frost details: “Common problems we found were authors not including any information about side effects (aka adverse events) at all, not clearly reporting the type of side effects, or occasionally reporting types of effects but not the number.”  

The researchers generally found higher rates of mild side effects for products with more substantive evidence. In contrast, products with emerging data or single trials found no effects or did not report on side effects. 

The researchers urge OTC clinical trials to improve safety reporting, highlighting the number and types of adverse effects in each group.“When people make decisions about using these products, one of the concerns is often potential side effects or interactions with medications,” says Frost. “If we cannot be confident in evidence of benefits, we at least want to know if a product is likely to be safe.”  

She urges that clinical trials of OTC products need to be much clearer in their reporting, highlighting the number and types of adverse effects in each trial group and whether they can be linked to the product. 

“If no adverse events were found, this needs to be clearly stated,” she iterates. “This is particularly important where products are tested as an adjunct alongside antidepressants to detect any potential interactions. These recommendations are already on the Consolidated Standards of Reporting Trials checklist for reporting randomized trials, so this needs to be reinforced by journals before publication.” 

Clinical trial recommendations

Frost highlights three top priorities for clinical trials on OTC products for depression symptoms: 

• Trials evaluating whether these products can have additional benefits when taken alongside talking therapies. 
• Further evaluation of lavender, lemon balm, chamomile, folic acid, zinc, tryptophan, and magnesium. 
• Adding health economic analyses in trials of OTC products to determine if they can reduce the use of health service appointments, medication, or talking therapies, and if they provide a cost-effective way to support people with depressive symptoms. 

“As clinical trials are often expensive, there needs to be further funding to support evaluating these products,” she adds. “More industry-academia partnerships would also ensure high-quality clinical trials are being carried out.”

Frost says researchers should also be supported when navigating the regulatory hurdles involved in testing these OTC products. In the UK, these are regulated in the same way as conventional medical products that are under development as medications and are not currently available OTC for widespread consumption. 

“We can perhaps also better use large-scale remote data collection strategies (e.g., through apps) from those currently choosing to take these products to monitor safety, interactions, or lack thereof, and perceived effectiveness.” 

Last month, People Science’s co-CEO detailed how its decentralized clinical trial approach could save companies and researchers time and resources while improving research quality.