Brain booster? Memory enhancer? Do they really exist? How safe are they?
Response by Thuy Ngan Vo, November 2017
Nowadays, more people are complaining how easily they forget things, and more people are asking about brain boosters and memory enhancers. To meet this increasing demand, a wide range of over-the-counter supplements have come on the market: Prevagen, Natrol Cognium®, Healthy Brain All-Day Focus, and many more. Do they really work? How safe are they? My investigation aims at providing some knowledge about the health benefits of products claiming to be “memory enhancers” or “brain boosters”.
Let’s start with Prevagen – a product by Quincy Bioscience. The manufacturer stated that Prevagen was “clinically shown to help with mild memory problems associated with aging.”[1] Prevagen contains apoaequorin – a calcium-binding protein. One hypothesis of age-related memory decline suggests that too much calcium in the brain is the cause of cell degeneration and cell death thus leading to impaired memory, declined focus or concentration. The purported mechanism of action of Prevagen is that apoaequorin binds to calcium; thus, preventing it from crossing the blood brain barrier[1]. To support the claim about the efficacy of Prevagen, Quincy Bioscience cited an animal study where apoaequorin infused directly into the brains of rats showed some neuroprotective effects against ischemic cell death induced by cerebral ischemic events. However, the study was solely funded by Quincy Bioscience and the study did not address memory at all[2]. Though the manufacturer website cited much clinical testing, peer review clinical research is nonexistent. Details of the methodology of the study funded by Quincy Bioscience or any study using apoaequorin have not been posted on Moreover, since apoaequorin is a protein, orally taking Prevagen will subject apoaequorin to digestive enzymes in the stomach and intestine, making it unlikely to survive intact in the gastrointestinal tract. In addition, most proteins cannot easily cross the gastrointestinal epithelial barrier due to high molecular weight, low lipophilicity, and charged functional groups[2]. Owing to poor oral absorption, a protein drug, such as insulin must be given parenterally. Apoaequorin with a molecular weight of 22,000 Da is unlikely to cross the blood brain barrier. Though a peptide metabolite of apoaequorin could possibly cross the blood brain barrier, no published reports of the pharmacokinetics of apoaequorin or its metabolites are available[2].
Natrol Cognium® – a supplement by Natrol which features Cera-Q®, a silk protein hydrolysate.  The manufacturer website claims that “imaging studies show the silk protein increases blood flow and glucose to the areas of the brain responsible for memory and cognition.  It also acts like an antioxidant for the brain, protecting it from free radicals and oxidation that cause aging.”[3] “When degraded by enzymes, silk proteins yield specific sizes or compositions of silk peptides (SPs) and silk amino acids (SAAs; composed of 19 amino acids) obtained from full degradation of silk proteins via acidic (HCl) hydrolysis. Both SPs and SAAs show anti-diabetic, hypocholesterolemic, and antioxidative actions. SAA preserves dopaminergic nerves in the Parkinson disease (PD) model animals whereas SP improved cognitive function of rats with aging brain facilitated by D-galactose.”[4] The isolated active compound was identified as tyrosine-glycine (C11H14N2O4) with a molecular weight of 238.10 Da, which is expected to easily cross the blood brain barrier to manifest its activity[5]. However, only two of the nine clinical trials claimed on the manufacturer website can be retrieved from PubMed database. These two trials tested on rats not humans. The first trial performed by Kim K et al published in 2009 article in J. Med Food is not convincing. Like Robert Speth mentioned in his comments about the validity of this manuscript: “the trial stated that the placebo treated groups consistently showed improvements in double-blind studies.”[6] However, “in the only comparison of the Natrol Cognium® ingredient-treated group and the placebo group, the Natrol Cognium® ingredient-treated group performed slightly worse in the CTT-2 test: 74.8 (30.6) versus 74.5 (20.1) seconds, respectively, after a 4-week treatment!”[6] In addition, the statistical analyses in the paper is questionable. The paper claimed “a 1.7% improvement in CTT-1 time after taking Natrol Cognium® for 4 weeks with p<0.05. Given the large error variances 41 and 36% of the mean values before and after Natrol Cognium® ingredient-treatment, respectively, (the variance of the mean of the individual before and after difference for a paired comparison analysis is not provided in the manuscript), it’s hard to believe that a 1.7% improvement would be statistically significant or clinically meaningful.”[6] Therefore, this report does not support the advertising claims of Natrol Cognium®. The other manuscript published in 2013 by Kang YK et al has been retracted from JMB for misconduct of the authors due to data fabrication and falsification[7]. Kang YK was the co-author of 6 out of 9 clinical trials cited on Natrol website. This casts suspicion over the validity of the 6 trials. In addition, after Kang YK’s paper was retracted, there are no more studies on silk protein available. Healthy Brain All-Day Focus – a product by Applied Nutrition – contains vitamin D3, vitamin B12 as Cyanocobalamin and a botanical blend composed of the extracts of Rhodiola Rosea root, Ginkgo, Turmeric, Curcuminoids, Clubmoss, DMAE, L-Theanine, Alpha Lipoic Acid, Phosphatidylcholine and Phosphatidylserine. The manufacturer claims that this formula works by supplying antioxidants aimed at preventing memory loss associated with aging. Contrary to what people believe, research shows that Ginkgo doesn’t improve or preserve memory. In one landmark trial, published in the Journal of the American Medical Association in 2008, 1500 participants aged 75 and older taking 120mg Ginkgo twice a day for 6 years did not decrease the incidence of Alzheimer’s disease or dementia compared to the placebo group[8]. Vitamin B12, on the contrary, may slow the age-related brain atrophy[9]. Rhodiola Rosea extract might exhibit some neuroprotective effects[10]. A systemic review of RCTs performed in 2011 confirms the beneficial effects of Rhodiola Rosea on physical performance, mental performance, and certain mental health conditions[11]. However, the review also admits “a lack of independent replications of the single different studies and suggests more research to confirm the neuroprotective effect of the herb.”[12] On the other hand, taking Rhodiola Rosea supplement should be done with caution due to a negative result of a RCT to compare the efficacy of Rhodiola Rosea with placebo for reducing fatigue in nursing students on shift work. “A total of 48 of 18 to 55-year-old students from the Nursing Faculty of the University of Alberta were randomized to 364mg of Rhodiola Rosea (n = 24) or placebo (n = 24) in clinical rotations between January 2011 and September 2011.”[13] This study indicates that the group treated with Rhodiola Rosea for a 42-day shift work showed worsened fatigue compared with placebo [13]. So, what should we do instead? “In 1990, a small study of 22 Alzheimer’s patients reported they had high concentrations of homocysteine in their blood”[9]. Homocysteine is an amino acid and breakdown product of protein metabolism that, at high concentration in the blood stream, has been linked to an increased risk of heart attacks and strokes. In addition, recent research proves homocysteine as “a strong, independent risk factor for the development of dementia and Alzheimer’s disease. In the Framingham Study, they estimated that 1 in 6 Alzheimer’s cases may be attributable to elevated homocysteine in the blood[9]. High plasma homocysteine is now thought to play a role in brain damage, and cognitive and memory decline[14][16]. “Homocysteine is a breakdown product of methionine, which comes mostly from animal protein. Thus, decreased methionine intake on a diet low in animal products and low in diary may be a factor contributing to lower homocysteine levels.”[9] “A double-blind RCT found that homocysteine-lowering by B vitamins can slow the rate of brain atrophy in people with mild cognitive impairment.”[9][17] “A 24-month RCT involving 168 participants was performed in 2010. The participants over 70 years old with mild cognitive impairment were given high dose folic acid, vitamins B6 and B12. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63-0.90] in the active treatment group and 1.08% [0.94-1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test score.”[18] Though our body can detoxify homocysteine using folate, vitamin B12, and vitamin B6, most people don’t get enough of these vitamins through their diet.

In summary, a simple and safe treatment that targets homocysteine can slow down the rate of brain atrophy due to aging. Be active, get enough sleep, maintain a healthy life style and follow a diet low in animal protein and diary. Eat your green leafy vegetable and take a vitamin B12 supplement regardless of whether you are a meat eater or vegetarian or vegan. If you insist on taking some “brain booster” or “memory enhancer”, don’t waste your money on Prevagen or Natrol Cognium®. Choose Healthy Brain All-Day Focus – at least it has vitamin B12 and possibly other ingredients that may in the future prove beneficial. In the US, dietary supplements including vitamins, minerals, herbs, amino acids, and substances such as enzymes, organ tissues and metabolites are classified by the FDA as food. They are not regulated as strictly as drugs. Proof of safety, effectiveness, post-marketing surveillance are not required for dietary supplements. Disease treatment claims are not allowed for dietary supplements. Many tests have raised questions about the quality and safety of dietary supplements. Therefore, remember to read the fine print on all the labels of dietary supplements before you buy them and, if possible, purchase natural products with USP Verified symbol.

Quincy Bioscience 2017. Prevagen improves memory. Retrieved from
Gayle Nicholas Scott. Does Prevagen help memory loss? Medscape. 2018 March. Retrieved from
Natrol 2017. Cognium Clinical Studies. Retrieved from
Yeseul Cha, Sang Hoon Lee, Su KilJang et al. A silk peptide fraction restores cognitive function in AF64A-induced Alzheimer disease model rats by increasing expression of choline acetyltransferase genee. Toxical Appl Pharmacol. 2017 Jan 1; 314:48-64.
Kim K, Park S, Yoo HK, Lee JY, Jung HY, Kim DH, Lee HJ, Kim JY, Young C, Marshall MR, Kim SS, Jeong Y. Brain Factor-7 Extracted from Bombyx mori Enhances Cognition and Attention in Normal Children. J. Med Food. 2009c; 12(3):643-648
Robert Speth. Brain factor-7 extracted from Bombyx mori enhances cognition and attention in normal children. Comments. PubMed. 2017 July. Retrieved from
Kang YK et al. Retraction to Memory-enhancing effects of silk fibroin-derived peptides in scopolamine-treated mice. J Microbiol Biotechnol. 2016 Dec 28;26(12):2228.
Lauren Cooper. The Truth about Memory Supplements. Consumer Reports. 2016 August. Retrieved from
Michael Greger. Preventing Brain Loss with B Vitamins? Nutrition Facts. Retrieved from
Juřica J, Koupá T. Rhodiola rosea and its neuropsychotropic effects. Ceska Slov Farm. 2016 Summer;65(3):87-93.
Nabavi, Seyed Fazel. Rhodiola rosea L. and Alzheimer’s Disease: From Farm to Pharmacy. Phytotherapy research. 2016 Apr;30(4):532-9.
Hung SK, Perry R, Ernst E. The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials. Phytomedicine. 2011 Feb 15;18(4):235-44.
Punja S, Shamseer L, Olson K et al. Rhodiola rosea for mental and physical fatigue in nursing students: a randomized controlled trial. PLoS One. 2014 Sep 30;9(9):e108416.
Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006 May 29;580(13):2994-3005. Epub 2006 May 6.
Seshadri S, Beiser A, Selhub J, Jacques PF et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002 Feb 14;346(7):476-83.
Zhuo JM, Wang H, Praticò D. Is hyperhomocysteinemia an Alzheimer’s disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci. 2011 Sep;32(9):562-71.
Smith AD, Smith SM, de Jager CA et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010 Sep 8;5(9):e12244.
Douaud G, Refsum H, de Jager CA et al. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9523-8.
Prepared on 10/29/2017 by Thuy Ngan (Tina) Vo