Presence of Piracetam in Cognitive Enhancement Dietary Supplements | Complementary and Alternative Medicine | JAMA Internal Medicine | JAMA Network
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Table.  Information Provided on the Label Compared With Measured Quantity of Piracetam in Nootropic Dietary Supplementsa
Information Provided on the Label Compared With Measured Quantity of Piracetam in Nootropic Dietary Supplementsa
1.
US Food and Drug Administration. FDA takes action against 17 companies for illegally selling products claiming to treat Alzheimer’s disease. February 11, 2019. https://www.fda.gov/news-events/press-announcements/fda-takes-action-against-17-companies-illegally-selling-products-claiming-treat-alzheimers-disease. Accessed October 23, 2019.
2.
Flicker  L, Grimley Evans  J.  Piracetam for dementia or cognitive impairment.  Cochrane Database Syst Rev. 2001;(2):CD001011.PubMedGoogle Scholar
3.
Walker  SJ. 75-day premarket notification of new dietary ingredients: piracetam. Office of Nutritional Products, Labeling and Dietary Supplements, US Food and Drug Administration. Mar 3 2004; NDI 215. https://www.regulations.gov/document?D=FDA-2004-S-0571-0127. Accessed October 23, 2019.
4.
Cohen  PA, Bloszies  C, Yee  C, Gerona  R.  An amphetamine isomer whose efficacy and safety in humans has never been studied, β-methylphenylethylamine (BMPEA), is found in multiple dietary supplements.  Drug Test Anal. 2016;8(3-4):328-333. doi:10.1002/dta.1793PubMedGoogle ScholarCrossref
5.
Brayfield  A.  Martindale: The Complete Drug Reference. 39th ed. London, UK: PhP, Pharmaceutical Press; 2017:399.
6.
US Food and Drug Administration. Evol Nutrition Associates, Inc. 7/10/12 Warning Letter (12-ATL-14). July 10, 2012. https://www.fdalabelcompliance.com/letters/ucm312672. Accessed October 23, 2019.
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    1 Comment for this article
    Patient-friendly resource?
    Catherine Davis, PhD, Clin. Health Psychol | Georgia Prevention Institute, Medicine, Medical College of Georgia, Augusta University
    Thank you for this important report. Can you suggest a patient-friendly factsheet or other resource that will help convince supplement-enthusiasts to be more cautious in their selection of supplements? Supplement advertising can be much more appealing than medical advice, so a degree of charm is needed.
    CONFLICT OF INTEREST: None Reported
    Views 5,632
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    Research Letter
    November 25, 2019

    Presence of Piracetam in Cognitive Enhancement Dietary Supplements

    Author Affiliations
    • 1Department of Medicine, Cambridge Health Alliance, Somerville, Massachusetts
    • 2Harvard Medical School, Boston, Massachusetts
    • 3Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco, San Francisco, California
    • 4Now at Department of Biochemistry and Molecular Genetics, Anschutz Medical Campus, University of Colorado, Denver, Aurora, Colorado
    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.

    Methods

    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).

    Results

    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.

    Discussion

    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.

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    Article Information

    Corresponding Author: Pieter A. Cohen, MD, Somerville Hospital Primary Care, 236 Highland Ave, Somerville, MA 02143 (pcohen@challiance.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.

    References
    1.
    US Food and Drug Administration. FDA takes action against 17 companies for illegally selling products claiming to treat Alzheimer’s disease. February 11, 2019. https://www.fda.gov/news-events/press-announcements/fda-takes-action-against-17-companies-illegally-selling-products-claiming-treat-alzheimers-disease. Accessed October 23, 2019.
    2.
    Flicker  L, Grimley Evans  J.  Piracetam for dementia or cognitive impairment.  Cochrane Database Syst Rev. 2001;(2):CD001011.PubMedGoogle Scholar
    3.
    Walker  SJ. 75-day premarket notification of new dietary ingredients: piracetam. Office of Nutritional Products, Labeling and Dietary Supplements, US Food and Drug Administration. Mar 3 2004; NDI 215. https://www.regulations.gov/document?D=FDA-2004-S-0571-0127. Accessed October 23, 2019.
    4.
    Cohen  PA, Bloszies  C, Yee  C, Gerona  R.  An amphetamine isomer whose efficacy and safety in humans has never been studied, β-methylphenylethylamine (BMPEA), is found in multiple dietary supplements.  Drug Test Anal. 2016;8(3-4):328-333. doi:10.1002/dta.1793PubMedGoogle ScholarCrossref
    5.
    Brayfield  A.  Martindale: The Complete Drug Reference. 39th ed. London, UK: PhP, Pharmaceutical Press; 2017:399.
    6.
    US Food and Drug Administration. Evol Nutrition Associates, Inc. 7/10/12 Warning Letter (12-ATL-14). July 10, 2012. https://www.fdalabelcompliance.com/letters/ucm312672. Accessed October 23, 2019.
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