A recent paper that highlighted quality issues with galantamine supplements was “deeply embarrassing” for the industry, according to Peter Lurie, a medical doctor who heads up the nonprofit Center for Science in the Public Interest (CSPI) in the nation’s capital.

The research published in the Journal of the American Medical Association (JAMA) analyzed both dietary supplements and generic drugs containing galantamine, finding the supplements failed to meet label claims but the drugs were accurately labeled and free of contaminants.

Physician Pieter Cohen of Harvard Medical School and Cambridge Health Alliance authored the research letter, along with three researchers from Belgium. The researchers purchased the galantamine supplements on Amazon, which didn’t respond to a request for comment for this story.

Researchers found the quantity of galantamine in the supplements ranged from less than 2% to 110% of the labeled amount, with three products contaminated with genes associated with diarrheal illness.

“It’s not just that in previous Pieter Cohen papers [researchers] find erratic quantities of the advertised [supplement] ingredient to say nothing of contaminants, it’s that you have a comparison group to a product that is clearly being made well as a drug,” said Lurie, president and executive director of CSPI. “And that really is a profound black eye.”

Related:9 of 10 Amazon galantamine memory supplements failed to meet label claim

Now, it’s come to light that galantamine shouldn’t even be sold as a dietary supplement, according to the Food and Drug Administration.

FDA galantamine warning letter

In late February, the Council for Responsible Nutrition (CRN) shared with FDA a 2002 warning letter from FDA’s Center for Drug Evaluation and Research (CDER). In the letter to Life Enhancement Inc., FDA concluded galantamine is excluded from the definition of a dietary supplement under section 201(ff)(3) of the Federal Food, Drug and Cosmetic Act (FDCA) and was authorized for investigation as a new drug before being marketed in supplements.

“Promotional literature for your product announced that it was introduced in October 2000. However, the authorization of galantamine for investigation as a new drug had already been disclosed in 1997 by several disclosures in ‘The Pink Sheet’ that made public the clinical trials being done by Janssen Pharmaceutics Products, whose product, Reminyl, is now the subject of an approved NDA,” David Horowitz, an FDA official who oversaw CDER’s Office of Compliance, wrote in the warning letter to Life Enhancement.

An NDA is a new drug application. Since 1938, every new drug has been subject to an NDA before U.S. commercialization, according to FDA.

“Your article ‘Fight Alzheimer’s Disease,’ also mentions galantamine being used in clinical trials in 1985,” Horowitz added in the 2002 warning letter. “FDA has found no information indicating that galantamine was marketed as a food or dietary supplement before its authorization for investigation as a new drug. If, as appears to be the case, galantamine had already been investigated in clinical trials and those trials made public before October 2000, and galantamine was not marketed as a food or dietary supplement before its authorization for investigation as a new drug, your product would not be eligible for treatment as a ‘dietary supplement.’”

FDA has approved galantamine as a prescription medication for the treatment of mild to moderate dementia from Alzheimer’s disease, according to Cohen and his research colleagues. They added the ingredient is marketed as a supplement for myriad cognitive conditions including memory enhancement.

FDA approved galantamine hydrobromide as a drug in December 2004 for “Razadyne,” formerly Reminyl, according to a “Drug Approval Package” on FDA’s website. The sponsor of the NDA was Johnson & Johnson Pharmaceutical Research Inc.

CRN had been aware of the 2002 warning letter and retrieved it recently through a Google search, Craig Muckle, a spokesman for the Washington, D.C.-based trade group, said.

On Feb. 26, FDA updated its directory (on supplement ingredients and other substances) with galantamine, which includes a link to the 2002 warning letter, an FDA spokesperson confirmed. FDA had no additional comment on the 2002 warning letter.

The directory includes a “category” tab that elucidates the regulatory status of an ingredient. Galantamine is associated with category 3: “Ingredient is not a ‘dietary ingredient’ under section 201(ff)(1)” of the FDCA.

In 2019 comments filed with FDA in a proceeding related to a public meeting about “Responsible Innovation in Dietary Supplements,” a group known as the Biotechnology Innovation Organization raised regulatory issues regarding supplements containing galantamine.

Among other observations, BIO argued “galantamine hydrobromide does not occur in natural products,” is synthesized in labs and doesn’t qualify as a dietary ingredient.

“Yet, galantamine hydrobromide is sold in multiple dietary supplements in similar dosage strengths to FDA-approved drugs — to preserve and support memory function and increase and induce lucid dreaming,” John Murphy III, a lawyer for BIO, wrote to FDA. “Many of the products are marketed without warnings and precautions equivalent to the FDA-approved drugs (e.g., warnings/precautions regarding serious skin reactions, gastrointestinal bleeding, and potential fetal harm).”

BIO did not respond to a request for comment for this story.

“These are not legitimate supplements, and yet people like Pieter Cohen can keep finding them, and they sully the reputable industry because he gets to write these stories that say these products shouldn’t be out there,” CRN President and CEO Steve Mister said in an interview. “And he’s right. They’re not dietary supplements.”

Reaction to FDA ‘inaction’

Several sources contacted for this article found FDA’s position curious since galantamine is widely sold as a dietary supplement. The researchers in the JAMA paper tested 10 brands of galantamine supplements and 11 brands of generic galantamine medications.

“It's very hard to square the FDA's position with its actions,” Harvard’s Cohen said in an email to Natural Products Insider, when asked about FDA’s 2002 determination that galantamine is excluded from the definition of a dietary supplement. “FDA has been aware of galantamine supplement sales for more than 20 years but has not taken any effective enforcement actions to remove them from the marketplace. The agency's inaction raises profound issues about its dedication to ensuring that unlawfully marketed supplements are removed from the marketplace."

CSPI’s Lurie supported FDA moving against ingredients like galantamine that the agency has determined are excluded from being marketed in supplements due to their approval or investigation as a new drug.

Lurie, who previously served as associate commissioner for public health strategy and analysis at FDA, said the agency typically uses few provisions in the law when targeting supplement companies.

“It’s almost always the same thing. It’s either, there’s a contaminant with an active drug. That’s category 1. Category 2 is a disease claim,” Lurie said. “Interestingly enough, both of those are really drug authorities.”

He described as a “very useful” third target FDA moving against supplements that have already been approved as a drug.

“The evidentiary requirements are not significant. And it seems to me like a case [FDA officials] could win,” he opined. “If they’re not going after them, it’s either because there’s no will or because there’s no resources — most likely the latter.”

Piecing together the evidence

In the case of galantamine, it’s unclear how the 2002 warning letter to Life Enhancement was resolved. The same product targeted in the FDA letter called “GalantaMind” is still being sold today and is marketed as a “memory optimizer.” According to the Supplement Facts panel on Life Enhancement’s website, the product contains 8 milligrams of galantamine hydrobromide.

The product has 33 ratings on Amazon, with an average of 4.5 out of 5 stars.

One of the top (five-star) reviews said, “It works!!! Have tried many brain vitality boosters. This is first one that works.”

Another “top review” with one star commented, “This product made me extremely nauseous. I followed the instructions carefully on how to take it and each time after consuming it with food at breakfast I was so sick I could not go to work. Also it cost $111 and [cannot] be returned.”

Natural Products Insider could not confirm whether Cohen and his research colleagues tested GalantaMind since they did not disclose the identity of the supplement brands that were studied.

Life Enhancement did not respond to multiple requests for comment.

“I have no idea what transpired between FDA and the firm back in 2002,” Natural Products Association (NPA) President and CEO Daniel Fabricant, Ph.D., said in an interview when asked to comment on the galantamine warning letter.

Fabricant, who oversaw FDA’s Division (now an Office) of Dietary Supplement Programs during the Obama administration, described the administrative record on galantamine as “an absolute wreck because you’re dealing with 22 years after the fact.”

“And also, if you got in front of the judge with this, what does FDA plead?” he asked. “Well, ‘Hey, we’ve been asleep for 22 years. Sorry, we just woke up, Your Honor.’ The whole thing [is] not good for anybody.”

Cara Welch, Ph.D., who oversees the FDA Office of Dietary Supplement Programs (ODSP), told Natural Products Insider that the directory (with galantamine and other supplement ingredients and substances) is intended to provide “current and accurate information.”

While confirming the information about ingredients in the directory represents FDA’s most current information, Welch added, “We always welcome feedback and information regarding these ingredients; and if firms have information that calls FDA’s views into question, we … invite them to submit that information to the FDA because we want it to be an accurate reflection of our actions and communications regarding the listed ingredient.”

One of the challenges related to drug preclusion is that supplement firms rarely are in a position to sue the agency over administrative determinations like the one involving galantamine, according to legal experts. FDA has determined that multiple ingredients widely available to U.S. consumers are excluded from dietary supplement products due to being either first approved or studied as drugs, including CBD (cannabidiol) and NMN (nicotinamide mononucleotide), among others.

“FDA can very successfully cast a shadow over an ingredient by simply raising this possibility of drug preclusion. It is unfortunately not a situation that can really be litigated because it doesn’t constitute what the attorneys call a ‘final agency action,’” CRN’s Mister, who is a lawyer, observed. “And you can’t go to court and sue the agency until something has reached that stage of being a final action.”