April 2021 Issue
Cognitive Health: Cognitive Health Supplements — Behind the Hype
By Carrie Dennett, MPH, RDN, CD
Vol. 23, No. 4, P. 12
The science around “memory boosters” is shaky, but could they be harmful to health, too?
Between baby boomers wanting to stay as sharp for as long as possible and millennials wanting to boost productivity, the market for cognitive health supplements is booming. We’ve come a long way from ginseng and ginkgo biloba—two herbal supplements touted for brain health benefits until science found that the claims greatly exceeded the hype.1,2 Today, nootropics—natural or synthetic substances that may positively affect mental skills—are increasingly popular, with annual sales surpassing $640 million in 2015.3 But are they safe and effective? Often, the answer is “no.”
For example, in early 2019, the FDA warned that many companies touting supplements that prevent, treat, or cure Alzheimer’s disease and dementia use unproven claims in their marketing. Many of these products are sold online via websites or social media platforms.4 The FDA issued warning letters, but that hasn’t prevented these products from being sold. Some supplements promoted for memory or cognitive clarity contain drugs that haven’t been approved by the FDA and aren’t allowed to be sold as dietary supplements, yet they’re easy to purchase online. Some popular supplements advertised on TV claim to be “clinically” proven but in fact are not. Some are still in the “maybe” category, with only a few small studies to back them up. The following are four popular supplements.
A synthetically produced compound sometimes referred to on product labels as Vinca minor extract, lesser periwinkle extract, or common periwinkle extract, vinpocetine is an ingredient in many supplements marketed for enhanced memory, focus, or mental acuity. Despite being widely available in the United States, vinpocetine isn’t FDA approved for any use, although in some countries it’s regulated as a prescription drug.5 In June 2019, the FDA issued a consumer warning that vinpocetine can cause miscarriage or harm fetal development if used during pregnancy.6
Despite not being FDA approved for any use, piracetam is openly available for sale in the United States. Piracetam belongs to the racetams class of drugs, which includes the FDA-approved anticonvulsant levetiracetam, used in epilepsy treatment. Piracetam is available by prescription in some countries, but a 2001 Cochrane review concluded there wasn’t enough evidence to support use of piracetam for dementia or other cognitive problems.7
Pieter Cohen, MD, an associate professor at Harvard Medical School and an internist at Cambridge Health Alliance, has published numerous papers examining adulteration in dietary supplements and calling to reform the Dietary Supplement Health and Education Act of 1994, the law that governs supplements. One of these papers is a 2020 analysis of dietary supplements containing piracetam published in JAMA Internal Medicine. His team found that the amount contained in the manufacturer-recommended daily doses ranged from 831 to 11,283 mg. The upper end is significantly higher than prescription doses of 2,400 to 4,800 mg (adjusted based on renal function) administered in Europe, where prescription piracetam is used for cognitive disorders.8
Cohen’s team conducted another 2020 analysis that examined 10 supplements listing analogs of piracetam—omberacetam (Noopept), aniracetam, oxiracetam, or phenylpiracetam—as an ingredient in either the Natural Medicines Database or the National Institutes of Health’s Dietary Supplement Label Database, and on the product label. None of those drugs is approved in the United States, but Cohen’s team also found three additional unapproved drugs—vinpocetine, phenibut, and picamilon—in their samples. In the two products containing phenibut and picamilon, these drugs weren’t listed on the product label or in supplement databases.9
Cohen says he has two big concerns about these findings, both related to known side effects of these unapproved drugs: “Older consumers [could be] trying to use these products to help with forgetfulness or early dementia but then suffering from adverse effects such as lowered blood pressure and falls that could lead to serious harm,” he says. “For all consumers, I am most concerned about one of the drugs we found called phenibut. This drug has addictive potential and has led to dozens of hospitalizations and even some patients requiring mechanical ventilation.”10
The popular supplement Neuriva claims to improve focus, accuracy, memory, learning, and concentration. Neuriva contains an extract of coffee cherry—coffee beans are the seeds of the coffee cherry, or coffee fruit—along with soy-based phosphatidylserine, a type of phospholipid found in the human brain.
The claims are that coffee cherry extract can increase the body’s levels of brain-derived neurotrophic factor (BDNF), a neuroprotein essential for neurogenesis. However, while this has been shown to increase levels of BDNF in the brains of rats—although that increase doesn’t always translate to improved performance in mazes—blood levels of BDNF don’t affect brain levels in humans because it can’t cross the blood-brain barrier.11 A 2020 randomized controlled double-blinded trial of 71 adults with mild cognitive decline observed reductions in reaction time in the first week of taking coffee cherry extract, compared with placebo, that persisted throughout the remainder of the 28-day study period.12 The study is one of several funded and conducted by a manufacturer of coffee fruit extract.
Claims are that Prevagen improves memory and supports healthy brain function, including a “sharper mind” and “clearer thinking.” Prevagen allegedly maintains the balance of calcium in the brain and enhances the effectiveness of other brain proteins. However, the main ingredient, apoaequorin, a calcium-binding protein isolated from the Aequorea victoria jellyfish, has no known role in memory or cognitive function, and there are no studies showing that it can cross the blood-brain barrier. In fact, a 2014 safety assessment shows that apoaequorin is mostly broken down during digestion.13 A 2016 independent review by the Alzheimer’s Drug Development Foundation says it was unlikely to have any benefits for brain health,14 noting that the one company-sponsored randomized controlled trial didn’t show that apoaequorin worked better than placebo.15
The maker of Prevagen, Quincy Bioscience, is embroiled in an ongoing legal battle with the Federal Trade Commission and the New York State Attorney General, facing charges that it has made false and unsubstantiated claims.16 In 2012, the FDA sent Quincy a letter warning that the company was violating federal law, alleging that the active ingredient was a synthetic copy of apoaequorin that never had been part of the human diet or sold in supplements. The agency also documented 1,000 “adverse events” between 2008 and 2011, including chest pain, vertigo, and seizures.17
“It would be great if the brain supplements advertised worked to improve cognition, keep memories sharp, and enhance our brains as we age, but unfortunately, the claims are overblown,” says Chris Rosenbloom, PhD, RDN, FAND, coauthor of Food & Fitness After 50 and a nutrition professor emerita at Georgia State University in Atlanta. She emphasizes that some supplements tout “clinical trials” to prove they work. But some of those studies are done by an in-house firm without sufficient controls, such as a placebo group. “If you take a supplement and then [are] asked if you feel better, you might say ‘yes,’ but that is hardly proof that it works for everyone,” she says.
Rosenbloom says this serves as a good reminder for health professionals that while dietary supplements are regulated, they aren’t as regulated as some would like. “The FDA is not authorized to review supplements for safety or effectiveness before they’re sold to consumers, so it’s the consumer’s responsibility to evaluate the claims. And that’s hard to do because the advertising is slick.”
So what should a dietitian do when clients are taking “cognitive health” supplements? Rosenbloom suggests asking clients why they take the supplement, what other medications they take, and how much money they’re spending on the supplement, and then evaluate the risks vs benefits. Overall, she doesn’t see any evidence that supplements have major benefits beyond what can be achieved through diet and lifestyle. “The things we do for our heart are also really good for our brain,” she says.
Because of the possibility of adulteration, even conscientious consumers of cognitive health supplements may run the risk of consuming a potentially dangerous substance. Cohen has this advice: “I don’t recommend my patients use any supplement promoted as a cognitive enhancer, but if they’re going to use them despite my advice, I recommend they only use supplements listing a single ingredient and that the product is certified by a high-quality third-party certification program such as USP or NSF International,” he says. (Note: Cohen collaborates in research with NSF International). “These high-quality programs would not certify a supplement that contains an unapproved drug.”
— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times, owner of Nutrition by Carrie, and author of Healthy for Your Life: A Holistic Guide to Optimal Wellness.
1. Geng J, Dong J, Ni H, et al. Ginseng for cognition. Cochrane Database Syst Rev. 2010;(12):CD007769.
2. Snitz BE, O’Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA. 2009;302(24):2663-2670.
3. U.S. Government Accountability Office. Memory supplements: results of testing for selected supplements. https://www.gao.gov/assets/700/695049.pdf. Published October 18, 2018.
4. FDA takes action against 17 companies for illegally selling products claiming to treat Alzheimer’s disease. FDA website. https://www.fda.gov/news-events/press-announcements/fda-takes-action-against-17-companies-illegally-selling-products-claiming-treat-alzheimers-disease. Published February 11, 2019.
5. Vinpocetine in dietary supplements. FDA website. https://www.fda.gov/food/dietary-supplement-products-ingredients/vinpocetine-dietary-supplements. Updated June 3, 2019.
6. Statement on warning for women of childbearing age about possible safety risks of dietary supplements containing vinpocetine. FDA website. https://www.fda.gov/news-events/press-announcements/statement-warning-women-childbearing-age-about-possible-safety-risks-dietary-supplements-containing. Updated June 3, 2019.
7. Flicker L, Grimley Evans J. Piracetam for dementia or cognitive impairment. Cochrane Database Syst Rev. 2001;(2):CD001011.
8. Cohen PA, Zakharevich I, Gerona R. Presence of piracetam in cognitive enhancement dietary supplements. JAMA Intern Med. 2020;180(3):458-459.
9. Cohen PA, Avula B, Wang YH, Zakharevich I, Khan I. Five unapproved drugs found in cognitive enhancement supplements. [published online September 23, 2020]. Neurol Clin Pract. doi: 10.1212/CPJ.0000000000000960.
10. Graves JM, Dilley J, Kubsad S, Liebelt E. Notes from the field: phenibut exposures reported to poison centers — United States, 2009–2019. MMWR Morb Mortal Wkly Rep. 2020;69(35):1227-1228.
11. Xing Y, Wen CY, Li ST, Xia ZX. Non-viral liposome-mediated transfer of brain-derived neurotrophic factor across the blood-brain barrier. Neural Regen Res. 2016;11(4):617-622.
12. Robinson JL, Hunter JM, Reyes-Izquierdo T, et al. Cognitive short- and long-term effects of coffee cherry extract in older adults with mild cognitive decline. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2020;27(6):918-934.
13. Moran DL, Tetteh AO, Goodman RE, Underwood MY. Safety assessment of the calcium-binding protein, apoaequorin, expressed by Escherichia coli. Regul Toxicol Pharmacol. 2014;69(2):243-249.
14. Alzheimer's Drug Discovery Foundation. Apoaequorin. https://www.alzdiscovery.org/uploads/addf_access/addf-apoaequorin-full-report.pdf. Updated June 13, 2016.
15. Moran DL, Underwood MY, Gabourie TA, Lerner KC. Effects of a supplement containing apoaequorin on verbal learning in older adults in the community. Adv Mind Body Med. 2016;30(1):4-11.
16. Quincy Bioscience Holding Company. Federal Trade Commission website. https://www.ftc.gov/enforcement/cases-proceedings/152-3206/quincy-bioscience-holding-company. Updated March 10, 2020.
17. FDA warning letter to Quincy Bioscience. Casewatch website. https://quackwatch.org/cases/fdawarning/prod/fda-warning-letters-about-products-2012/quincy/. Published October 29, 2012.