New research gives us cause to be wary of supplements that claim to improve mental focus and memory. These products can contain unapproved pharmaceutical compounds in doses and combinations that can be dangerous to users, according to a new paper.

An analysis performed by a team at the Harvard Medical School in Boston, Massachusetts, found five drugs that have not been deemed safe or approved for human use in over-the-counter supplements known as “nootropics”,”smart drugs”, or “cognitive enhancers”. The findings highlight the need for tighter regulation of such products, the team argues.

Brainboosters, brainbusters

“Over-the-counter cognitive supplements are popular because they promise a sharper mind, but they are not as closely regulated as pharmaceutical drugs,” said study author Pieter A. Cohen, M.D., of Harvard Medical School in Boston, Mass.

“Use of these supplements poses potentially serious health risks. Not only did we detect five unapproved drugs in these products, we also detected several drugs that were not mentioned on the labels, and we found doses of unapproved drugs that were as much as four times higher than what would be considered a typical dose.”

Current laws in the U.S. do not require dietary supplements to be tested for safety or effectiveness by the Food and Drug Administration (FDA) before hitting the shelves, unlike pharmaceutical drugs. The FDA only intervenes if such supplements reach the market with misleading or incomplete labels, or if they contain unapproved substances.

The team searched the National Institutes of Health Dietary Supplement Label Database and the Natural Medicines Database looking for supplements that contain piracetam analogues. Piracetam is a drug that is not approved in the U.S. but has previously been included in supplements. An analogue is a substance with a chemical structure that is similar to but slightly different from another compound, and they are often used as loopholes around safety laws (since they tend to have the same effect but aren’t, strictly speaking, the same substance).

They identified a total of 10 supplements from the list. Eight of them promised to increase mental ability, one was sold as “workout explosives”, and the last is described as having the words “outlast, endure, overcome” printed on the label. In total, these products contained five unapproved drugs, they explain. Two of these were piracetam analogues (omberacetam and aniracetam), and the other three were vinpocetine, phenibut, and picamilon.

Known side-effects of these compounds can include increased and decreased blood pressure, agitation, or sedation, and the FDA has warned that vinpocetine should not be consumed by women of childbearing age as it “may cause a miscarriage or harm fetal development”. All the supplements contained oberacetam, which is prescribed as a medicine for traumatic brain injury and mood disorders in Russia but at a typical dose of 10 milligrams (mg); the recommended dosage of these supplements contained 40 mg each, or four times that dosage.

The team also warns that some supplements contained more than one unapproved substance, with one of them combining four unapproved drugs. Furthermore, most of the quantities listed on the labels were inaccurate.

Researchers also found that for those products with drug quantities provided on the labels, a majority of the declared quantities were inaccurate.

“With as many as four unapproved drugs in individual products, and in combinations never tested in humans, people who use these cognitive enhancement supplements could be exposing themselves to potentially serious health risks,” said Cohen. “The effects of consuming untested combinations of unapproved drugs at unpredictable dosages are simply unknown and people taking these supplements should be warned.”

“The fact that these supplements are listed in official databases does not mean the labeling is accurate or the dosage levels of ingredients in these supplements are safe,” he adds. “Our study also raises concerns regarding the quality and legality of supplements listed in supplement databases.”

These supplements could be particularly harmful in combination with prescription drugs, the team adds, as the compounds can interact in unknown ways. One particularly troubling possibility is that consumers of such supplements may experience side-effects and treat those side-effects with prescription medicine, placing themselves at risk.

The study didn’t look at all unapproved substances marketed in cognitive supplements, but their results don’t paint an encouraging picture.

The findings have been presented at the 2021 American Academy of Neurology Annual Meeting.