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Cohen PA, Zakharevich I, Gerona R. Presence of Piracetam in Cognitive Enhancement Dietary Supplements. JAMA Intern Med. 2020;180(3):458–459. doi:10.1001/jamainternmed.2019.5507
The US Food and Drug Administration (FDA) recently warned that cognitive enhancement supplements “may be ineffective, unsafe, and could prevent a person from seeking an appropriate diagnosis and treatment.”1 Brain enhancement supplements or “nootropics” have become increasingly popular, with US sales exceeding $640 million in 2015 alone. Despite their popularity, the risks of these products are poorly understood. In this study, we analyzed dietary supplements for the presence of the nootropic drug piracetam.
In many European countries, piracetam is prescribed for cognitive impairment, dementia, and other disorders. A Cochrane review,2 however, found that despite widespread use of piracetam for dementia and cognitive impairment, the evidence for its efficacy is poor in quality and quantity. In the United States, piracetam has no FDA-approved use and the only drug in its class approved for use by the FDA is levetiracetam, an antiepileptic. The FDA has determined that piracetam is not permitted to be sold as a dietary supplement,3 but enforcement is limited, and piracetam supplements remain available for sale.
Supplements were identified by the Google search engine using the terms “piracetam” and “dietary supplement.” All products were purchased online and were analyzed if the actual label contained both terms. One sample of each brand was purchased in October 2018 and a second sample in November 2018.
An adaptation of our previous method was used to prepare and analyze samples.4 Powder from dietary supplement capsules was reconstituted in methanol to make a 100-mg powder/mL mixture. The samples were vortexed and centrifuged, then the supernate serially diluted to 100 ng/mL in 10% acetonitrile before analysis by liquid chromatography-quadrupole time-of-flight mass spectrometry using our previously described method (eMethods in the Supplement).
Fourteen brands were identified, 2 were unavailable for purchase, and 7 did not include “dietary supplement” on the actual label. Therefore, 10 samples from 5 brands of supplements were analyzed. Eight samples from 4 brands contained piracetam (Table). The quantity of piracetam ranged from 831 mg to 1542 mg per recommended serving size and varied from 85% to 118% of the labeled amount. Following the manufacturers’ recommendations on the labels, consumers could be exposed to quantities ranging from 831 mg to 11 283 mg of piracetam per day, depending on the brand consumed.
Consumers of cognitive enhancement supplements may be exposed to high dosages of a prohibited drug. In Europe, prescription piracetam is commonly formulated in 800- and 1200-mg tablets with a usual daily dose for cognitive disorders of 2400 to 4800 mg, with dosing adjusted based on renal function. In this study, we found supplements with individual doses of piracetam exceeding 1500 mg, and daily doses greater than 11 000 mg. Adverse effects of piracetam at pharmaceutical dosages include anxiety, insomnia, agitation, depression, drowsiness, and weight gain.5 The risks of piracetam in over-the-counter supplements at supratherapeutic dosages, particularly in elderly consumers with renal insufficiency, are unknown.
This study has several limitations. The sample size was small and the quantitative findings may not be representative of all piracetam products because we only analyzed those products marketed as dietary supplements. Furthermore, quantities might vary within individual brands over longer periods of time.
Our findings demonstrate that even after the FDA rejected an application to market piracetam as a new supplement ingredient,3 the drug was nevertheless introduced into the marketplace. Despite FDA warning letters,6 the products remain on the market. Until the law governing supplements is reformed such that products adulterated with drugs can be effectively removed from the market, clinicians should advise patients that supplements marketed as cognitive enhancers may contain prohibited drugs at supratherapeutic doses.
Corresponding Author: Pieter A. Cohen, MD, Somerville Hospital Primary Care, 236 Highland Ave, Somerville, MA 02143 (firstname.lastname@example.org).
Accepted for Publication: September 24, 2019.
Published Online: November 25, 2019. doi:10.1001/jamainternmed.2019.5507
Author Contributions: Drs Cohen and Gerona had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Cohen, Gerona.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Cohen.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Zakharevich, Gerona.
Administrative, technical, or material support: Gerona.
Study supervision: Cohen, Gerona.
Conflict of Interest Disclosures: Dr Cohen has collaborated in research with NSF International and received research support from Consumers Union. No other conflicts are reported.
Additional Contributions: The authors thank Paul Bain, PhD, of Harvard Medical School for his expert assistance in obtaining references and Xizhao Chen, BS, of University of Virginia for assistance in identifying the supplements.