10 Mar 2019

Purported miracle medicines have always been with us. In the 1800s, traveling salesmen hawked cure-all elixirs. Nowadays, companies peddle myriad supplements on the internet, often with spurious claims that they are “scientifically” proven to treat this or that chronic ailment. Some promise to boost cognition, lower the risk of dementia, and even treat Alzheimer’s disease. However, these substances are not approved by the Food and Drug Administration for these indications, and data to support their claims are lacking. Researchers who spoke with Alzforum believe such supplements offer false hope while shrinking the wallets of people worried about cognitive decline and dementia.

The FDA warned 17 companies to stop advertising their dietary supplements as treatments for AD.

All but one quickly complied.

The move is part of an FDA initiative to better regulate the supplement industry.

It appears the FDA has had enough. On February 11, the agency mailed letters to 17 companies it accused of illegally marketing dietary supplements as dementia treatments (see FDA press release). In response, most companies removed the language in question. The supplements included vitamins, minerals, and herbal products. They also include compounds that were previously investigated as AD treatments but showed no efficacy against dementia in large trials. Lindsay Haake at the FDA press office told Alzforum that the agency’s goal is to “help consumers easily differentiate high-quality, compliant supplements from those that have not been manufactured or distributed in accordance with the law.”

Across the board, Alzheimer’s researchers and clinicians applauded the move. “The actions by the FDA are necessary and long overdue,” Jose Luchsinger at Columbia University, New York, wrote to Alzforum (see full comment below). Caleb (Tuck) Finch at the University of Southern California, Los Angeles, agreed, “As a basic researcher, I fully agree with the FDA initiatives.” In a statement, the Alzheimer’s Association wrote, “It is vital that federal agencies charged with consumer protection act quickly and decisively against dishonest businesses preying on individuals affected by this devastating disease.”

However, these FDA warnings by themselves may do little to stem the tide of deceptive advertising. With internet vendors and sites multiplying, new products and false claims continue to crop up faster than the agency can find them. In a February 12 JAMA editorial, Joanna Hellmuth at the University of California, San Francisco, wrote “More needs to be done on a national level to limit the claims of benefit for interventions that lack proven efficacy.”

The FDA agrees. Also on February 11, commissioner Scott Gottlieb outlined a number of steps the agency will take to improve regulation of dietary supplements. “We are announcing a new plan for policy advancements with the goal of implementing one of the most significant modernizations of dietary supplement regulation and oversight in more than 25 years,” Gottlieb wrote. This includes more efficient enforcement, alerting the public more quickly to unsafe or ineffective products, and working with industry to improve the safety of supplements. It is unclear what effect Gottlieb’s resignation, announced March 5, will have on this initiative.

Internet Hosts Modern-Day Traveling Medicine Show

The dietary supplement market has exploded with the commercialization of the internet and global marketing. The FDA estimates that supplement sales have expanded 10-fold in the last 25 years, and amount to a $40 billion industry in the U.S. alone, with as many as 80,000 products. Worldwide, the market has ballooned to $160 billion. Brain health supplements make up more than $3 billion of the global market, and are predicted to reach $5.8 billion by 2023 (see industry forecast). The surge in sales is driven by fear of cognitive decline and dementia, as well as a desire to enhance cognitive performance at work and school.

The supplement market expanded because regulations for these products are much looser than for drugs. Under the 1994 Dietary Supplement Health and Education Act (DSHEA), products are reasonably expected to be safe and labels to be truthful and not misleading, but unlike drugs, companies are not required to test either the safety or efficacy of dietary supplements. This is because according to DSHEA and the FDA, they are considered foods, not drugs. Most supplements are naturally occurring compounds that can be found in plants, animals, or the human body. This does not mean they are healthy. Socrates, if he came back from the dead, would likely say he was killed by a cup of hemlock—an extract from a flowering herb. Furthermore, the FDA does not regulate the purity of supplements, which means they can harbor harmful ingredients or active pharmaceuticals that are not disclosed on the label, Haake wrote.

Compounding this free-for-all, companies have leeway in what they are allowed to say on labels. They can claim that dietary supplements reduce the risk of a disease or condition, or that they improve an aspect of human health, such as the immune system, without having to prove it. This is known as a structure/function claim. They may not state that supplements prevent, treat, or cure a specific disease, and product labels must include a disclaimer to that effect. Thus, a supplement could say that it improves memory or concentration, but not that it treats Alzheimer’s disease.

The regulations mean companies must walk a fine line in their advertising. Some step out of bounds. For example, Nutrition Coalition in Moorhead, Minnesota, boasted that its coenzyme Q formulation “fights off degenerative brain diseases like Alzheimer’s.” Even when companies follow the rules, their language may mislead consumers into believing the product has more efficacy than it does, such as the claim by Earth Turns LLC in Chesterfield, Missouri, that a green tea supplement “supports healthy cognitive function.” The same can be said of many foods. How is the public to distinguish between “supports healthy cognitive function” and “treats Alzheimer’s?” In an email to Alzforum, Hellmuth wrote, “You can see how it could be confusing for patients and caregivers to distinguish between these two kinds of claims, particularly considering most people with Alzheimer's disease want to improve memory and concentration.”

Ads bend the rules to their advantage in other ways, too. Absent scientific proof to back up claims, they lean on personal testimonials and anecdotes, and cite research in animal or cellular models as though it proved relevance for human disease. For example, Nutrition Coalition noted the ability of curcumin to inhibit amyloid aggregation in vitro, and concluded that the spice “helps fight off that horrible disease.” Ads exaggerate findings, and neglect to mention study limitations. Rachelle Doody at Roche in Basel, Switzerland, told Alzforum that when she was in clinical practice, patients would often bring in newspaper ads or printouts from the internet asking about the touted benefits of some supplement for cognitive function. “If the ad mentioned patients or research in any way, or referenced the comments of an M.D. or Ph.D., patients often did not realize that it was an advertisement and not a news item,” Doody wrote to Alzforum. Conversations to debunk a supplement claim then take up visit time that could be spend discussing more helpful measures, or available drug trials. Eric Siemers at Siemers Integration, who was formerly with Eli Lilly, noted, “People are very worried about AD, and companies play on those fears.”

All of this creates a hall of mirrors, where consumers struggle to distinguish supplements that might be helpful from those that are a waste of money, or harmful. As one example, Hellmuth noted that high doses of Vitamin E increase the risk of stroke and death (Miller et al., 2005; Schürks et al., 2010). Neuroscientists contacted by Alzforum believe most brain health supplements are ineffective. “It is very likely that all such remedies are useless, and some are potentially hazardous,” Paul Aisen at the University of Southern California, San Diego wrote (full comment below). The Alzheimer’s Association notes that even if a supplement is safe to take on its own, it may interact with prescription medicines or other supplements in unpredictable ways.

The financial damage can be considerable. “Many consumers of these supplements are on fixed incomes. Retired elderly may be spending an important portion of their income on these unproven therapies,” Luchsinger said. Belief in the efficacy of a supplement could dissuade people from pursuing approved AD treatments. “It would be a shame if somebody took fish oil for their Alzheimer’s and not Aricept,” Siemers said. Aricept is a cholinesterase inhibitor approved by the FDA to treat AD.

The Sheriff Rides In

The situation spurred the FDA to step up enforcement, Haake wrote to Alzforum. First, the agency scoured product pages, newsletters, and blogs to identify companies claiming, illegally, that their products treated dementia. On February 5, the FDA issued 12 warning letters jointly with the Federal Trade Commission, which polices deceptive or fraudulent advertising. Such letters give companies 15 days to correct regulatory violations, after which the FDA may enact penalties. Previously, in November 2018, the agency had issued five advisory letters to separate companies selling putative AD treatments. Advisory letters flag less serious violations and ask companies to voluntarily comply with regulations, but do not threaten action. Both types of letter are posted online to alert consumers to the issue.

Fourteen of the companies are in the U.S., one in Canada, one in India, and one in Malaysia. The FDA flagged multiple products from each company (see table). They span a wide range, from vitamins (particularly B, C, D, and E) and minerals such as selenium, to various herbal extracts such as echinacea root and milk thistle. The list also includes physiological compounds like melatonin and colostrum, antioxidants like glutathione, and non-essential amino acids such as L-carnitine and L-theanine, which is found in plants. Some of the products have been investigated in AD studies, including curcumin, green tea, ginkgo biloba, omega-3 fatty acids, and coenzyme Q (CoQ10). A number of companies market mixtures of these ingredients with suggestive names like Cognispark, Mind Ignite, and Memory Revitalizer.

The warning letters spell out illegal statements the FDA found on each website, including claims to treat cancer, infection, diabetes, arthritis, etc. The brain health advertising can be blatant. Sovereign Laboratories LLC in Sedona, Arizona, claimed: “Studies have shown proline-rich polypeptides [in colostrum] improve the cognitive functioning of patients with mild to moderate Alzheimer’s disease.” This statement appears to be based on a few small, short trials from Poland (Leszek et al., 1999; Leszek et al., 2002; Bilikiewicz and Gaus, 2004). The Canadian company BR Naturals, Innisfil, Ontario, asserted that, “A new study in the … Journal of Alzheimer’s Disease supports existing evidence that coconut oil may help alleviate the neurodegenerative effects of Alzheimer’s disease and Parkinson’s.” In actuality, the study reported that coconut oil helped preserve the health of cultured neurons exposed to Aβ (Nafar and Mearow, 2014). TEK Naturals in Mount Pleasant, South Carolina, claimed “Mind Ignite is a safe and highly effective alternative to Adderall. … Clinically shown to help diseases of the brain such as Alzheimer’s and even dementia,” while Gold Crown Natural Products in Miami went further when it wrote: “It is proved that melatonin supplements are used to cure Alzheimer’s disease.”

Alzheimer’s researchers and advocates are angered by the level of deception. “My take is that the extent of false claims made by many supplement or memory-enhancing drug manufacturers is criminal,” wrote David Knopman at the Mayo Clinic in Rochester, Minnesota.

How effective is the FDA intervention? In this instance, it seems to have sparked quick action to clean up product advertising by all but one of the companies. “The site has removed the links and commentary that offended the FDA. That was never a selling feature of the products,” Dennis Butts at Peak Nootropics LLC in Houston wrote to Alzforum. Alzforum requested comment from all the companies warned by the FDA bar two, for which no contact information could be found. Save for Peak Nootropics, none responded. However, their websites, accessed between February 25 and March 7, were scrubbed of the language the FDA had called out. Some websites appeared to have deleted newsletters, articles, and blog posts discussing purported medical benefits; in a few cases, the products themselves were no longer for sale. For example, The Alzheimer’s Store, which sells household items to aid caregivers of people with dementia, received an advisory letter admonishing it for advertising aromatherapy as a means to boost cognition and alertness in AD patients. No aromatherapy products now appear on the site. As of March 8, one company appears to have ignored the FDA censure. This Wonderful Life New Age Shop, based in Malaysia, continues to offer products such as Dementia/Alzheimer’s (Day) Synergy Oil, which claims to be “an effective non-pharmacological therapy for dementia.” The company received an advisory letter.

Another recent FDA action drew a similar response. On February 19, the FDA cautioned consumers and health care providers not to use plasma from young donors to treat diseases of aging. “Such treatments have no proven clinical benefits … and are potentially harmful,” the agency wrote, warning of “bad actors charging thousands of dollars for infusions.” Although the letter threatened no action, one such clinic, Ambrosia Health in Monterey, California, immediately stopped treating patients. They had been charging $8,000 for one liter of young plasma.

If past regulatory actions are any guide, advertising changes prompted by official warnings do no damage to companies’ bottom lines. In January 2016, the FTC fined Lumos Labs $2 million dollars for deceptive advertising of its Lumosity brain-training software, which claimed to protect against cognitive decline (Jan 2016 news). The company paid up, and the FTC doled out the money in the form of refunds to Lumos customers. Since then, Lumos Labs has changed its marketing to make more modest claims, but continues to maintain a customer base and offer new products (see 2016 Fortune article).

What Does the Science Say?

Could any of these brain health products actually help Alzheimer’s patients? Gregory Cole at the University of California, Los Angeles, noted that some supplements, such as resveratrol, curcumin, and vitamin D, have demonstrated efficacy against AD-like pathology in preclinical studies and small clinical trials. However, no supplement has ever produced a clear benefit for AD patients in pivotal trials. Ginkgo biloba, the omega-3 fatty acid docosahexanoic acid, B vitamins, vitamin E, selenium, and resveratrol have all fallen short (Nov 2008 news; Nov 2010 news; Nov 2014 news; Mar 2017 news; Zhu et al., 2018).

Some companies abandoned clinical development when trials failed, only to market the compounds as “medical foods” (Oct 2009 series). Medical foods contain ingredients shown to benefit a particular disease or condition, and usually require a prescription, but they do not undergo FDA efficacy review (Morgan and Baggott, 2006). “CoQ10 is a good example of a nutraceutical with lots of interesting biochemistry in vitro, but it’s been studied in Parkinson’s and Huntington’s and does not have clinical effects, even at doses that would cost ~$100/month at the health food store,” Siemers wrote to Alzforum (Mar 2014 news).

“There is zero evidence from any reasonably rigorous study that any supplement or dietary aid has any benefit on cognitive function or decline in late life,” Knopman noted. Other clinicians agreed, noting that the only time they prescribe supplements is when patients have a documented deficiency, such as for vitamin B12. A recent meta-analysis of vitamin and mineral supplements supports this position, finding no consistent cognitive benefit of supplementation for healthy adults across 28 studies (Rutjes et al., 2018).

In general, the researchers Alzforum contacted believe that the purported benefits of dietary supplements should be investigated more rigorously than current regulations demand. “Personally, I think that we owe it to the public to hold such potential treatments to the same standards of evidence that we do for pharmaceuticals when they advertise to the public directly,” Doody wrote.

Philip Scheltens at VU University, Amsterdam, cited clinical trials of the nutraceutical drink Souvenaid, which he has helped run, as an example of how this should be done. In a two-year study of 311 people with prodromal AD, Souvenaid missed its primary endpoint, but met two secondary endpoints (Nov 2017 news). “I do think this is the way to test all these products, exactly as we do with pharma products, to avoid unfounded claims,” he wrote (full comment below). Tobias Hartmann at Saarland University in Homburg, Germany, agreed. “Any health claim related to any intervention should be derived from an informative prospective clinical trial,” he said.

One drawback is patents. Cole noted that because most supplements are not patented, they are unlikely to attract enough funding for rigorous clinical evaluation. “We need another mechanism to evaluate supplements … I believe the government should set up an internet-based, curated, evidence-reporting system that patients and their doctors can submit data to,” he wrote to Alzforum (full comment below).

Bringing Order to the Wild West

What does the FDA think? While the agency has not proposed holding dietary supplements to the same standards as drugs, its recent statement outlines several steps it will take to modernize the regulation of this market. Gottlieb set up a Dietary Supplement Working Group that will develop better ways to enforce regulations, and will also create a “rapid-response tool” to inform consumers about deceptive advertising. The FDA established a public-private partnership, the Botanical Safety Consortium, to determine how best to evaluate the safety of dietary supplements. The agency plans to hold a public meeting this spring to discuss ways to foster innovation in the supplement field while maintaining safety. Finally, the FDA expressed openness to updating the DSHEA.

“It is appropriate for the FDA to continue to evolve its regulatory framework to best serve both consumers and a rapidly changing industry,” Haake wrote. The agency would not make Gottlieb or other administrators available for an interview with Alzforum.

Some researchers believe revising the DSHEA is imperative. “I question the realistic impact these FDA actions can have when the DSHEA continues to allow manufacturers to make ambiguous claims of efficacy without supportive evidence … Stronger federal legislation is needed around supplements,” Hellmuth wrote to Alzforum.

One example of how the DSHEA opens the door to potential harm is the burgeoning market for nootropics, so-called “smart drugs” that are purported to enhance cognition. Under DSHEA regulations for “structure/function claims,” such supplements can be legally marketed as cognitive enhancers without clinical proof. One popular type is piracetam, a GABA derivative, and related racetam compounds. Others include plant extracts like forskolin, L-theanine, and bacopa monnieri. Under the DSHEA rules, even some prescription drugs fall into the nootropic category. These include modafinil and Adderall, which are prescribed for attention-deficit disorder. Websites and YouTube testimonials filmed by self-proclaimed “biohackers” promote the cognitive benefits of these supplements. In a June 2016 press release, the American Medical Association cautioned that the use of prescription stimulants to achieve a cognitive boost “is associated with a variety of adverse mental health conditions and patterns of substance misuse” while the benefits are “limited or modest at best in healthy individuals.” Moreover, safety and efficacy for non-prescription herbal nootropics are unknown, the association added.

Does the FDA have sufficient resources to police the growing supplement market? While the companies that were warned have cleaned up their acts while the FDA is looking at them, similar peddlers are likely to pop up in a game of regulatory whack-a-mole. The FDA has limited staff and funding to comb through websites. “I remain concerned that the FDA lacks the authority and resources to protect patients from entities promoting pseudomedicine for dementia and brain health,” Hellmuth noted. In a February 11 statement, the Council for Responsible Nutrition, the main trade association for the dietary supplement industry, based in Washington, D.C., called on Congress to appropriate more money to allow the FDA to regulate dietary supplements and “root out bad actors.”—Madolyn Bowman Rogers