Question
Can a dietary supplement whose main ingredient was originally discovered in jellyfish improve memory problems?
 | Gayle Nicholas Scott, PharmD Assistant Professor, Eastern Virginia Medical School, Norfolk, Virginia |
Aequorea victoria, also known as the crystal jellyfish, is native to the Pacific Northwest.[1] In 2008, Osamu Shimomura shared the Nobel Prize for Chemistry for the discovery that this jellyfish emits green light through a chemical process involving the binding of calcium with the protein aequorin.[2] Apoaequorin, which is a part of aequorin, has since been synthesized using recombinant DNA and is used for tagging otherwise invisible proteins in biomedical research.[1,3]
Prevagen® (Quincy Bioscience; Madison, Wisconsin) is a widely advertised dietary supplement that is labeled to contain synthetically produced apoaequorin. Its advertising claims that the product promotes "healthy brain function," a "sharper mind," "better memory," and "clearer thinking."[4] Yet, all of these claims are followed by an asterisk and the disclaimer (in small print), "These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease."
As a dietary supplement, so-called structure and function claims can be included for Prevagen, with no requirement for evidence of efficacy. If a medical claim, such as "treats mild cognitive impairment" or "treats Alzheimer disease," were made, clinical trials supporting these claims would be required.
What's the Evidence?
The calcium-binding property of apoaequorin seems to be the basis for suggesting usefulness in age-related memory loss and dementia. Maintenance of cerebral calcium hom*oeostasis is fundamental to the survival and function of neurons; calcium is a principal intracellular messenger. One hypothesis of age-related memory decline suggests that control of intracellular calcium concentrations becomes impaired, leading to neuronal dysfunction.[5]
The manufacturer's explanation of the mechanism of action of Prevagen is vague: "Laboratory research has demonstrated that Prevagen has powerful cell supporting activity by providing a protein originally found in jellyfish. In aging, these proteins are depleted leaving brain cells vulnerable to damage."[4]
No peer-reviewed research is available on the purported mechanism of action of apoaequorin on memory in animals or humans. In an animal study funded by Quincy Bioscience, apoaequorin infused directly into the brains of rats protected neurons against ischemic cell death when administered before induced cerebral ischemic events, but the study did not address memory.[6]
Despite claims of clinical testing in advertising and on the manufacturer's website, peer-reviewed clinical research on apoaequorin is nonexistent.[4]
An abstract of a manufacturer-sponsored study was published in 2011[7]; however, a full report of the study has not been published in the peer-reviewed literature. The abstract reports a double-blind, placebo-controlled, 3-month study of apoaequorin in 222 healthy adults with self-reported memory problems. The apoaequorin group showed more improvements in verbal and visual learning, memory, and delayed recall than in the placebo group, according to the manufacturer's website.
Details of the methodology of this manufacturer-sponsored study (or any study using apoaequorin) have not been posted on ClinicalTrials.gov.
Is Prevagen Safe?
Reports of adverse effects of apoaequorin have not been published. Safety was not mentioned in the published abstract.[7]
In a warning letter to the manufacturer, the US Food and Drug Administration cited failure to report more than 1000 adverse events, such as seizures, strokes, and worsening symptoms of multiple sclerosis, some of which resulted in hospitalization.[8]
The manufacturer's website does not mention these adverse effects but cites the product's safety in two animal studies,[9,10] which the manufacturer used to obtain "generally regarded as safe" (GRAS) status for the use of apoaequorin as a food additive.[11]
According to the GRAS documentation, as of January 2014, the manufacturer had received 2281 reports of adverse events.[11] The top 10 adverse effects were:
Headache: 428 events (18.76%);
Dizziness: 172 events (7.54%);
Nausea: 155 events (6.80%);
Hypertension: 84 events (3.68%);
Diarrhea: 74 events (3.24%);
Memory impairment: 74 events (3.24%);
Insomnia: 63 events (2.76%);
Anxiety: 54 events (2.37%);
Stomach pain: 51 events (2.24%); and
Confusion: 46 events (2.02%).
The manufacturer deemed 26 reports of serious effects, including chest pain, seizures, and tremors, to be unrelated to apoaequorin. Allergic-type reactions, such as itching and rash, also have been reported.
Is Prevagen Bioavailable?
Bioavailability and dose-ranging studies that are required for drugs are not required for dietary supplements. Apoaequorin is a protein. Proteins are metabolized by such enzymes as pepsin and hydrolysis in the acidic environment in the stomach, and in the intestine by proteases and peptidases. Unpublished in vitro data indicate that apoaequorin is metabolized by pepsin,[11] making it unlikely that apoaequorin survives intact in the gastrointestinal tract.
In addition, most proteins are characterized by high molecular weight, low lipophilicity, and charged functional groups that impede absorption across the gastrointestinal epithelial barrier.[12] Owing to poor oral absorption, protein drugs, such as insulin, etanercept, and erythropoietin, are given parenterally. The oral bioavailability of apoaequorin is unknown, but unlikely.
The design of drugs for diseases involving the brain is challenged by the blood/brain barrier. Apoaequorin is unlikely to cross the blood/brain barrier (with the large leap of faith that it could reach the bloodstream from the intestine). Drugs that penetrate the blood/brain barrier are small molecules (molecular weight < 400 to 500 Da) and are highly lipid soluble.[13] Apoaequorin has a molecular weight of 22,000 Da and, as a protein, is poorly lipophilic. In theory, a peptide metabolite of apoaequorin could cross the blood/brain barrier, but no published reports of the pharmaco*kinetics of apoaequorin or its metabolites are available.
This presents the question: If apoaequorin is poorly absorbed and does not cross the blood/brain barrier, how can it cause adverse effects? In theory, an apoaequorin metabolite could cause adverse effects. Another possible cause could be unlabeled ingredients in the product. The presence of prescription drugs and other adulterants has been reported in a variety of dietary supplements.[14,15,16]
Summary
Only about one fourth of adults with memory problems discuss them with their healthcare provider.[17] Given the frequency of advertisem*nts for Prevagen, patients who are concerned about memory loss may consider trying this product instead of seeking medical care. Patients should be advised that contrary to advertising claims, reliable research on the efficacy and safety of Prevagen is not available. Patients should also be aware that clinical trials of dietary supplements, such as vitamin E, have not found any individual micronutrient to be beneficial in cognitive health.[18] It is important for patients to understand that memory loss has multiple causes and should be assessed by a healthcare provider.
Some research suggests that exercise; an active lifestyle; and a heart-healthy diet, such as the Mediterranean diet, may diminish memory decline. Such factors as controlling blood pressure and not smoking also are advantageous. The less-advertised lifestyle approach to preventing and treating age-related memory loss is a better recommendation to patients, vs a magical jellyfish protein.
