A little-known and somewhat scrappy shrub native to Texas and Mexico is at the heart of one of the more recent controversies surrounding dietary supplements with botanical ingredients. Acacia rigidula (Fabaceae), sometimes used in weight-loss and sports performance products, was implicated in a study from Harvard University Medical School, which found that products listing A. rigidula on the label contained beta-methylphenylethylamine (BMPEA), a synthetic isomer of amphetamine.1 After three weeks of swirling publicity that included criticism of the US Food and Drug Administration’s (FDA’s) alleged inaction on regulating products containing synthetic and unapproved stimulant ingredients, alleged conflicts of interest between FDA and industry, and statements from three US senators calling for FDA to remove BMPEA-containing products from the market, the agency sent warning letters to five companies and banned the sale of BMPEA, noting potential health issues.2,3

(In a related development, FDA later took action on April 24, sending warning letters to companies selling DMBA, a different unapproved stimulant, after the ingredient was found in supplements tested in a 2014 study from Harvard.4,5)

Though this might have been a fairly standard procedural event in which FDA dealt with marketers’ not filing a New Dietary Ingredient (NDI) notification, or citing companies for use of a banned substance, it followed on the heels of the New York Attorney General’s investigation into private-label herbal dietary supplement products that reportedly failed DNA barcode tests for identity at four major retailers in New York state.6,7 As a result, the BMPEA/A. rigidula issue has become the latest log on a fire that is fueling the increasingly negative consumer perception of dietary supplements in general, and herbal supplements in particular. It has some industry experts concerned that these ongoing controversies and misinformation in the media are increasing the “vulnerability” of supplement companies and may even generate a “national referendum” on the Dietary Supplement Health and Education Act of 1994 (DSHEA).

While FDA’s announcement banning the sale of BMPEA was not unexpected and was supported by several industry groups, many say the current atmosphere remains dynamic. Lead author of the Harvard study on BMPEA and A. rigidula, Pieter Cohen, MD, who has been both an outspoken critic of supplements and FDA’s enforcement of DSHEA, called FDA’s action a step in the right direction, albeit a small one. “This only addresses those products that openly listed BMPEA on the label – a clear violation of DSHEA,” he wrote (e-mail, April 27, 2015). “What is much more insidious are the products that list only Acacia rigidula or other botanical ingredients, but are actually spiked with drugs like BMPEA.”

What FDA did not deal with in this latest action is the legal status of A. rigidula. The wording of the FDA letters calling the products “misbranded” rather than adulterated, which would be more typical in this type of scenario, was interesting, according to industry veteran Loren Israelsen, president of United Natural Products Alliance, an industry trade group. “It is clear that FDA is responding to external pressure. They moved quickly to get the letters out, and as far as I am concerned, they are doing their job. But it is an interesting dynamic,” he wrote (e-mail, April 25, 2015).

“I think the action is significant and appropriate,” said Daniel Fabricant, PhD, CEO of the Natural Products Association, an industry trade association (oral communication, April 29, 2015). “The agency has to be very thoughtful and metered when they do these things. Their experts have to be court-ready. So the language they use would depend on their evidence. If it is a labeling issue, then that is likely the legal theory they would advance. That doesn’t mean they can’t tack on an adulteration charge after further testing.”

Regarding the legal standing of A. rigidula, Fabricant added that the herb could qualify as a dietary ingredient, but what is in question is whether the stimulant compound BMPEA is a constituent of acacia. “The science in general probably does not support inclusion of this ingredient as an extract of the plant,” Fabricant said.

A Tale of Two Compounds

To understand how A. rigidula became linked with an amphetamine-like stimulant requires a quick review of the history of the plant’s use as a supplement. The current A. rigidula/BMPEA issue began with the release of the Harvard study in early April, noting that 11 of 21 products tested that claimed to contain A. rigidula on their labels contained BMPEA, a compound that was first synthesized in 1931 as a potential replacement for amphetamine but never approved for human consumption. BMPEA has not been studied for safety and efficacy in humans and was known primarily as a research chemical, according to Dr. Cohen’s paper in Drug Testing and Analysis.1

It has, however, been used in some products sold as dietary supplements since 2010.8 The Harvard researchers also revealed that a 2012 study by FDA, published in the Journal of Pharmaceutical and Biomedical Analysis in 2014, had similar findings, yet the agency failed to act or warn consumers about supplements that contained the compound.9

Following three weeks of discourse, the agency sent warning letters to five companies: Hi-Tech Pharmaceuticals, Inc.; Tribravus Enterprises, LLC; Train Naked Labs, LLC; Better Body Sports, LLC; and Human Evolution Supplements, Inc.10 (One of those companies, Hi-Tech Pharmaceuticals, of Norcross, Georgia, has filed a libel and slander suit against the Harvard team, seeking both punitive and compensatory damages.11 The company is also involved in a legal battle with FDA over products containing another stimulant, 1,3-dimethylamylamine [DMAA], that is also banned in dietary supplements.12)

The first association between A. rigidula and BMPEA, however, likely dates back to research in the 1960s, and then the 1990s, which recorded large amounts of compounds, including methamphetamine, mescaline, and others that would become classified as controlled substances, in A. rigidula.13,14 According to James Neal-Kababick, director of Flora Research Laboratories, LLC in Grants Pass, Oregon, aggressive extraction technology, coupled with old analytical technologies, likely led to misidentification of compounds in these early papers, which may have informed some use of the plant in supplement products. More recent studies, including the 2012 analysis by FDA, used more advanced analytical techniques and researchers were able to conduct characterizations of botanical materials. “The later results suggest some fairly significant errors in the earlier work,” said Neal-Kababick (oral communication, April 23, 2015).

FDA’s study found that “many of the ingredients noted in the earlier papers did not show up in A. rigidula, or were at such low levels it would take tons of raw materials to make one product run,” added Neal-Kababick. “It doesn’t add up. And you can’t spend 10 or 20 times as much on a product as you can sell it for. It doesn’t calculate economically.”

Further, Neal-Kababick noted that it is unlikely that such a common plant in the Southwestern United States would contain an “armada of Schedule 1 controlled substances” without attracting more attention (email, May 18, 2015). “If methamphetamine and mescaline were really in those leaves at any appreciable level to render them a source of those substances, the DEA would have an army of agents spraying herbicides or ripping out plants.”

There also may have been poor quality peer review of the earlier papers, he added. “Reviewers have to have enough depth to catch things of concern, and, a lot of times, they are not able to dive in, or [they] have limited understanding and accept certain things as fact.” At the time of some of these publications, he continued, there was a peer-review desert that still exists somewhat today. Due to time constraints, many scientists are very limited in what they can fact-check. “Journals had a hard time getting reviewers, and reviewers often did not dive in too far. This resulted in a lot of erroneous or inadequate papers in the 1990s and early 2000s.”

History aside, the Harvard study on BMPEA triggered a second round of negative publicity about dietary supplements and the industry that produces them. Such media coverage followed ongoing headlines regarding the separate New York AG investigation, and included calls from Senators Charles Schumer (D-NY), Dick Durbin (D-IL), and Richard Blumenthal (D-CT) urging FDA to ban BMPEA2,3, and a New York Times editorial15 alleging industry conflicts of interest at FDA, as well as multiple other media reports on the poor quality and inadequate regulation of supplements. And then, on May 12, Cohen and his team released a new case report noting that a hemorrhagic stroke in a 53-year old woman was likely caused by exercise in combination with the use of a BMPEA-containing supplement.16

Although the timing of these developments may be coincidental, the recent issues have at least some industry stakeholders questioning motivations of key players in the overall drama. This is the same argument and the same players that have criticized DSHEA from the beginning, Israelsen noted (e-mail, April 20, 2015). “There are some people who would say that the New York AG investigation, and continuance of non-GMP compliance [by some companies], all point to the same thing — an underlying fault in the law. Change the law and the problem goes away.”

Dr. Cohen calls his latest research nothing more than a continuation of his ongoing work to push FDA to enforce DSHEA. “In my recent paper on BMPEA, I emphasize two main themes: the presence of this new stimulant in supplements and the FDA inaction. I do not venture a guess as to why FDA has been so slow to move against the ingredient, which has no role in dietary supplements and poses potential health risks,” he said (e-mail, April 22, 2015).

Although Dr. Cohen has argued for aggressive enforcement of DSHEA and sees the law as an excellent framework for the sales of vitamins and minerals, he does note that it is less appropriate for other ingredients, like botanicals, probiotics, and glandular extracts. “Many physician-critics of the supplement industry believe we should regulate botanicals like drugs. I disagree,” he stated. “I think there is a compromise solution, in which regulations should be tailored to the special challenges of providing access and high-quality botanical supplements to consumers.” Some of the changes he would consider recommending would be to require disclosure of known adverse events on the label, make reports of these events publicly available, and create a more robust system to detect adverse effects from supplements.

The FDA Dilemma

Regulatory experts believe that DSHEA provides FDA with adequate tools, but the agency may be hampered by too many priorities and limited resources. The problem, Israelsen added, is that FDA continues to struggle with the job of taking effective leadership with dietary supplements. And that issue is not likely to improve, considering the current lack of resources and expertise at FDA. “It is hard to see at the moment how FDA can be a clearly focused regulator that industry can work with. But that is the way it is at the moment,” said Israelsen.

Neal-Kababick noted that one FDA agent told him that for every criminal case the agency pursues, there are many more that they do not go after due to limitations of budget and resources. “I personally feel from my some two decades of interaction with FDA that if they are properly funded to enforce the cGMP regulations, then we would see the rogue products nipped in the bud and companies with deficiencies would more quickly be brought to compliance,” he said.

“I can’t answer the question about FDA’s lack of action other than it is a resource priority,” said Dr. Fabricant. “We know that one of every four dollars is spent on some kind of packaged good [that comes under the FDA regulatory purview]. So it is a tall path they have to follow, and I understand the issue legally. But I think there was not really a public health hook [with BMPEA], so there has not been a great need to act immediately.”

What may be more concerning is that the New York AG situation has made the industry much more vulnerable to reports like the one on BMPEA and A. rigidula, noted Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), an industry trade association (oral communication, April 18, 2015). “It makes this seem like a mainstream problem, but the [BMPEA] issue is very limited in terms of products with Acacia rigidula. However, coming on the heels of the New York investigation and the focus on retail, it makes this seem like a much more widespread issue.”

Mister added that in CRN’s conversations with members of New York AG Eric Schneiderman’s staff, he seems to be taking the position that even if the DNA tests that prompted all of this are erroneous, they know there is activity taking place in the industry that shouldn’t occur. “Maybe they pointed their finger in the wrong direction, but they got consumers concerned and that is good enough,” Mister said.

Regardless, Dr. Fabricant pointed out that “the industry has a perception challenge right now and needs to meet that challenge, such that we are not always in reactive mode. We need to be more proactive and start painting organizations and industry in a good light.”

Mister believes that FDA is smart enough to see the difficulty of what is happening, but he also reiterated that it is a pivotal time for the industry. “Companies will need to be much more careful in addressing their critics and the media, in light of these recent actions. Retailers need to know what is on their store shelves, and they need to step up and be smart about the vendors they are dealing with,” he said.

These issues have definitely been taken out of proportion and perspective, Neal-Kababick agreed. He added: “Companies that are doing the right thing have to unfairly compete with those who are not doing things right. If FDA doesn’t stop them, it will be very hard for good companies to compete.”

“Too many companies,” Neal-Kababick continued, “are doing high production, without the heart of traditional pharmacognosy in their organization, and they don’t have botanical practitioners involved in designing their products. It’s a big issue.”

Beyond the negative media, these issues are creating new problems and unrealistic expectations of industry. As an example, Neal-Kababick noted GNC’s settlement with the New York AG following their citation by the office after some of their products reportedly failed the DNA barcode tests. The settlement, he said, was perceived as if the Attorney General was whipping GNC into shape, when the company actually admitted no wrongdoing but did agree to use DNA testing on raw materials.17 “I know it was an economic decision for their shareholders, but it doesn’t benefit industry. Many small companies are not able to mandate such requirements to their suppliers of botanical extracts who are often middle brokers and not the manufacturers. Even if [the companies] could, how can they confirm the data is from the actual product being purchased after changing hands?” he questioned. “This is where chromatographic techniques and microscopy become extremely critical as they must test what they use.”

The Upside of Controversy

While some people in the natural products industry have had a tendency to point fingers at others in the wake of these problems, Dr. Fabricant believes that companies also need to shoulder some of the blame for the current status quo. “It is never a bad idea to hold up a mirror and get your house in order, and this is providing that opportunity,” he said. “As an industry we have become too apathetic politically. We need to get people more involved and that means joining associations, giving to PACs [political action committees], and sending letters to Congress saying ‘I am an industry member, I vote, I provide jobs, and this situation seems motivated by political agendas rather than scientific fact.’”

CRN’s Steve Mister says these problems should be a wake-up call for industry, starting with companies in the high-risk categories of weight-loss, sports performance, and sexual enhancement. “They should be doing appropriate tests and not spiking their products with things that should not be there.”

This is also a reminder that the New Dietary Ingredient process is not optional just because the industry is waiting on the next draft of the guidance, said Mister, referring to the NDI requirement in Section 8 of DSHEA, which stipulates that a company notify FDA 75 days prior to marketing any “new” ingredient in a dietary supplement that was not sold in the United States prior to October 15, 1994, provide safety data for that ingredient, and obtain FDA consent for the marketing of the ingredient. The FDA has not yet issued final guidance on this process or the criteria for having to file the notices.

“It is a fundamental requirement that companies with New Dietary Ingredients must give FDA a 75-day notice, and that goes back to 1994,” Mister said. “So even though we are still arguing about the nuances of the process, the process still needs to be followed, and that was not done in the case of BMPEA.”

While the world as dietary supplement companies know it may be somewhat altered, the situation may not be as dire as some believe it to be. As witnessed by its April 23 announcement, FDA does have procedures to keep unsafe products off store shelves. And although some critics have urged Congress to enact sweeping changes to DSHEA, Israelsen sees no real clues that this kind of scenario is imminent. “Although you can never be certain, it appears now that given the schedule and issues facing Congress, we are not seeing the conditions necessary for a successful attempt to amend DSHEA.”

That said, he noted that things feel different than before, with the change in industry’s historic leadership and its unique political legacy, along with the current willingness of the national press to be a bull horn to communicate accusations against dietary supplements. The debate to come, Israelsen added, may be to “consider a middle ground that is both practical and doable to achieve the jointly held view of quality products with compliant research, and yet preserve broad access for US consumers.”

But first, he continued, “we need to square up to and answer questions about how to do this by addressing proper enforcement of DHSEA. Until we see what a fully engaged and enforced DSHEA looks like, it is premature to change the law.… We can only do so much. FDA has to do the rest.”

References

1.         Cohen PA, Bloszies C, Yee C, Gerona R. An amphetamine isomer whose efficacy and safety in humans has never been studied, B-methylphenylethylamine (BMPEA) is found in multiple dietary supplements. Drug Testing and Analysis. Published online April 7, 2015. doi:10.1002/dta.1793.

2.         Daniells S. NY Senator calls for BMPEA to be banned, but such a move would be ‘wasteful’, says FDA. NutraIngredients-USA.com. April 13, 2015. Available at: www.nutraingredients-usa.com/Regulation/NY-Senator-calls-for-BMPEA-to-be-banned-but-such-a-move-would-be-wasteful-says-NPA. Accessed April 30, 2015.

3.         Schultz H. Durbin, Blumenthal urge FDA to take action against BMPEA. NutraIngredients-USA.com. April 15, 2015. Available at: www.nutraingredients-usa.com/Regulation/Durbin-Blumenthal-urge-FDA-to-take-action-against-BMPEA. Accessed April 30, 2015.

4.         US Food and Drug Administration. FDA warning letters on DMBA: Available at: www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/default.htm. Accessed April 30, 2015.

5.         Cohen PA, Travis JC, Venhuis BJ. A Synthetic stimulant never tested in humans, 1,3-dimethylbutylamine (DMBA), is identified in multiple dietary supplements. Drug Testing and Analysis. Published online October 8, 2014. DOI: 10.1002/dta.1735.

6.         A.G. Schneiderman Asks Major Retailers To Halt Sales Of Certain Herbal Supplements As DNA Tests Fail To Detect Plant Materials Listed On Majority Of Products Tested [press release]. New York, NY: Office of the New York Attorney General. May 6, 2015. Available at: www.ag.ny.gov/press-release/ag-schneiderman-asks-major-retailers-halt-sales-certain-herbal-supplements-dna-tests. Accessed May 19, 2015.

7.         O’Connor A. Herbal Supplements Are Not Often What They Seem. The New York Times. February 3, 2015. Available at: www.nytimes.com/2013/11/05/science/herbal-supplements-are-often-not-what-they-seem.html. Accessed May 6, 2015.

8.         Cohen P. “Clinicians’ Perspective on the Dietary Supplement Health and Education Act of 1994’s (DSHEA) Ability to Ensure the Safety of Dietary Supplements.” Presentation at the 15th Annual Oxford International Conference on the Science of Botanicals at the National Center for Natural Product Research, University of Mississippi. April 14, 2015.

9.         Pawar RS, Grundel E, Fardin-Kia AR, Rader JI. Determination of selected biogenic amines in Acacia rigidula plant materials and dietary supplements using LC-MS/MS methods. J Pharm Biomed Anal. 2014;88:457-466.

10.         US Food and Drug Administration. FDA warning letters on BMPEA. Available at: www.fda.gov/Food/DietarySupplements/QADietarySupplements/ucm443790.htm. Accessed April 30, 2015.

11.         Hi-Tech Pharmaceuticals Sues Self-Professed Weight Loss Expert – Harvard professor Pieter A. Cohen for $50 million in Compensatory Damages and $150 Million in Punitive Damages for Libel and Slander [press release]. Norcross, GA: Hi-Tech Pharmaceuticals, Inc.; April 29, 2015. Available at: www.bizjournals.com/prnewswire/press_releases/2015/04/29/CL93423. Accessed April 30, 2015.

12.         Long J. FDA, Hi-Tech Embroiled in DMAA legal battle. Natural Products Insider. April 25, 2015. Available at: www.naturalproductsinsider.com/blogs/supplement-law/2015/04/fda-hi-tech-remain-embroiled-in-dmaa-legal-battle.aspx. Accessed May 1, 2015.

13.         Clement BA, Goff CM, Forbes TDA. Toxic Amines and Alkaloids from Berlandieri. Phytochemistry.1997;46:2249-2254.

14.         Camp BJ, Norvell MJ. The phenylethylamine alkaloids of native range plants. Econ Bot. 1966; 20(3):274-278.

15.         New York Times Editorial Board. Conflicts of Interest at the F.D.A. The New York Times. April 13, 2015. Available at: www.nytimes.com/2015/04/13/opinion/conflicts-of-interest-at-the-fda.html?_r=0. Accessed April 30, 2015.

16.         Cohen PA et al. Hemorrhagic Stroke Probably Caused by Exercise Combined with a Sports Supplement Containing β-Methylphenylethylamine (BMPEA): A Case Report. Annals of Intern Med. May 12, 2015.

17.         Morell A. GNC, NY AG Deal: Herbal Supplements Were In Compliance But New Testing Requirements Instated. Forbes. March, 31, 2015. Available at: www.forbes.com/sites/alexmorrell/2015/03/31/gnc-ny-ag-deal-herbal-supplements-were-in-compliance-but-new-testing-requirements-instated/. Accessed May 6, 2015.

18.         Pawar RS et al. Determination of biogenic amines in A. rigidula and in dietary supplements using LC-MS/MS methods. Presented in session titled “Recent Advances in Analytical Methods to Ensure Food Safety” at the 245th Annual Meeting of American Chemical Society. New Orleans, LA. April 8, 2013.

Acacia rigidula Herb Profile

Commonly known as blackbrush, blackbrush acacia, chaparro prieta, catclaw or gavia, Acacia rigidula is a spiny, thicket-forming shrub with stiff branches that is native to the Rio Grande plain in Texas and northern Mexico. The perennial tree grows  3-15 feet tall and has aromatic pale white to golden yellow flowers that bloom from March to June. The bark of the shrub is a whitish color and its leaves are dark green, glossy, and crowded¹. A member of the Fabaceae family, A. rigidula produces a legume-type fruit. Its native habitat is prairie, plains, meadows, pastures, savannahs, and chaparral and brush country.² The plant grows on limestone hillsides, is adaptable to a variety of soil types, drought tolerant, and hardy to 20º F (-6.7º C).³

While it is known that Native Americans and Hispanic peoples made numerous therapeutic preparations from North American acacias,⁴ there is little information about indigenous uses of A. rigidula and few reports of its use as a traditional medicine. That said, there is some record that the people of the Mexican Kickapoo tribe drank a decoction of A. rigidula leaves, or a combination of A. rigidula and A. farnesiana roots, for treatment of severe diarrhea with blood in the stool.⁴ Other species of Acacia, notably A. farnesiana, are more often mentioned in literature as being used in traditional treatments for ailments, ranging from headache and respiratory disorders to rheumatism and a treatment for conjuntivitus.⁴

In current times, A. rigidula or its extracts are often listed as ingredients in weight-loss supplements that claim to provide stimulant and appetite-suppressing properties.⁵ These products frequently contain other botanical extracts such as hoodia (Hoodia gordonii, Apocynaceae) and bitter orange (Citrus aurantium, Rutaceae). Although no serious problems have been documented regarding the consumption of Acacia legumes, there are some reported cases of sheep and goat poisonings related to consumption of A. berlandieri and A. rigidula foliage and fruit.⁶ Consumption of the plants by these animals was associated with development of locomotor ataxia, also known as “limber leg,” in which the animals develop a wobbling in the hind legs that leads to stumbling, falling, and prostration, and sometimes causes death.^4,6 The condition is attributed to the appreciable levels of toxic alkaloids in the plant, which can be a significant part of the diet for these grazing animals in times of drought. The overconsumption of A. rigidula and A. berlandieri also has been linked to poor reproductive health in cattle.^6,7 

More than 50 species of the Acacia genus have been reported to contain various amines and alkaloids.⁵ In studies looking specifically at A. rigidula, researchers in the 1960s reported that the plant contained the phenethylamine-type compounds N-methyl-β-phenethylamine, N-methylphenethylamine (N-MePEA), and N-methyltyramine (N-MeTYR).⁸ In the 1990s, a study of acacia plant material gathered in spring and late season, reported trace amounts of compounds that reserachers identified as amphetamine and methamphetamine, especially in plant material from the fall.^6,7 Later research by Pawar et al. has noted that amphetamine is a synthetic compound and the only time it has been reported naturally was from the papers noted above.⁵ The research concluded that, in contrast to the earlier reports, they found only fairly low amine levels in authenticated A. rigidula materials. The study also demonstrated that β-methylphenethylamine (B-MePEA), a synthetic compound apparently added to A. rigidula extracts, can be misidentified as amphetamine when using LC-MS methods. They suggested that particular care must be taken to separate isomers chromatographically when using these methods.⁵

—Karen Raterman