Earlier this week, New York Times journalist Anahad O'Connor continued reporting on his investigation of the dietary supplement industry, this time calling into question the FDA's apparent silence on a harmful amphetamine derivative in herbal products for weight loss, athletic performance, and mental concentration.
The two major themes of O'Connor's piece are that 1) the FDA has been unresponsive to researcher and physician warnings about BMPEA, a poorly-studied chemical closely related to amphetamine, and 2) the FDA's dietary supplement regulators may have been compromised by their former relationships with the industry. In this piece, we'll focus on the first topic. In a subsequent post, we'll discuss the skill set needed to effectively lead FDA's supplement regulatory efforts.
BMPEA: Unrelated to herbals having no herbs
First, some background. The BMPEA story is very different from the recent attention by the New York State Attorney General to herbal products that are allegedly devoid of the plant or plants listed on the label. The NYAG's investigation of store brands of seven herbals at GNC, Walmart, Walgreens, and Target revealed that the majority of products lacked DNA corresponding to the herbal source. The results have been disputed because DNA analysis is the wrong test for products made from concentrated extracts of plant materials.
The BMPEA story is instead one of economically-motivated adulteration – where the products contain more than what is advertised. Supplements billed as weight loss aids, stimulants, or thermogenic fat-burners have a long history of containing additional chemicals unrelated to any natural extracts. Most commonly, these are synthetic drugs that were formerly used for similar purposes. For example, the FDA routinely finds weight loss supplements contaminated with sibutramine, the weight loss drug once sold as Meridia, that was withdrawn from the market because it increased the risk of heart attacks in people with preexisting heart disease.
The current flap is from a newly-published study that follows up on FDA's discovery in 2013 that other supplements contain BMPEA, another substance with the potential for cardiovascular reactions. The supplements claim to have extracts of blackbrush, a plant found in southern Texas and northern Mexico whose botanical name is Acacia rigidula.
The 50 or so plants of the Acacia genus contain one or more chemicals called biogenic amines, including amphetamine. These chemicals are sometimes called phenethylamines and are relatives of our own neurotransmitters, norepinephrine and epinephrine (adrenaline).
The fact that plants would also make similar chemicals is no surprise, really. Another desert plant, Ephedra sinica, or Mormon tea, contain ephedrine and pseudoephedrine, stimulants that we also use as nasal decongestants. All the chemicals described here begin with the amino acids phenylalanine or tyrosine – nature is crafty in using readily available building blocks to make all manner of chemicals.
The problem for BMPEA as a dietary supplement component is that it doesn't occur naturally in the plant. FDA's analytical chemists tested for BMPEA in four batches of Acacia rigidula leaves, twigs, and bark. They found some phenethylamines, but not BMPEA. Nevertheless, FDA scientists found BMPEA in nine of the 21 products they tested and none of the other amines from the actual plant in almost all of the samples. The main component, phenethylamine, is found both in plants and almost all of the supplements. But the supplements contained thousands and ten thousands more phenethylamine than in the actual plant.
BMPEA was first made in 1931 by researchers at Sharp & Dohme Laboratories in Baltimore in trying to figure out how to make drugs that affected blood pressure. These researchers not only found that BMPEA could increase blood pressure but that it was active when given orally to rats and rabbits. But even today, the compound hasn't been fully evaluated in humans. For example, we don't know what dose causes an unsafe rise in blood pressure or whether it triggers heart rhythm disturbances. And because it's ever-so-close to the structure of amphetamine – BMPEA is called a positional isomer of amphetamine – we don't know if it causes a high that might cause it to be addictive.
Surely the FDA must've taken these off the market, right?
Pieter A. Cohen, MD, an assistant professor at Harvard Medical School and internist at the Cambridge Health Alliance, wondered what the FDA was doing about the problem since Acacia rigidula-containing products were still being sold online and in retail stores. Together with colleagues at the University of California, San Francisco, and Haverford College, Cohen analyzed 21 brands of supplements listed as containing Acacia rigidula plant or extract, including three that still listed BMPEA on their ingredient labels. They found that 11 of the products still contained BMPEA, at amounts ranging for 6.5 to 93 mg per recommended supplement dose. And unlike the FDA's published study, Cohen and colleagues listed the specific names of the products tested.
Regarding the first concern of lagging regulatory responsiveness, I'd argue that the blame may be misplaced: The FDA must assemble a considerable analytical chemistry and legal case to withdraw supplements with a naturally-occurring but potentially-harmful chemical in the absence of adverse reaction reports. And the reason for these restrictions are legislative. The Dietary Supplement Health and Education Act of 1994 (DSHEA) allows supplements to be sold without testing for safety or efficacy, and they can only be withdrawn if there are enough reports of adverse reactions to establish a causal relationship with the supplement. So, crudely speaking, one must accumulate a body count before the FDA is allowed to step in on safety grounds.
We should be reminded that the FDA only has the authority over that which is charged by Congress. Back when tobacco-wrangling FDA Commissioner David Kestler planned in the early 1990s to turn his attention next to the Wild West of the dietary supplement industry, the potential plan was met with a massive protest letter campaign from health food advocates and other industry boosters. Opponents to any sort of regulation screamed that Congress wanted to take away our vitamins and leave us at the whims of the pharmaceutical industry and their paid-for FDA supporters. Of course, the dietary supplement makers have their own trade organizations and lobbyists that aim to protect their interests.
The result was the passage of Sens. Orrin Hatch and Tom Harkin-sponsored but watered-down bill – in the wee hours of the morning of the last Senate session of the 103rd Congress. So while the FDA is a convenient scapegoat, we're reaping what was sown 20 years ago to relieve supplement makers of the same stringent requirements required of pharmaceutical companies.
On one hand, FDA has done an admirable job given the limits of its authority. My email queue of FDA announcement of adulterated supplements has grown so long that I don't report on most of them. They tend to be these types of weight loss supplements adulterated with sibutramine and other old drugs or permutations of erectile dysfunction supplements adulterated with the the active ingredients of Viagra or Cialis, or their chemical relatives.
In these cases, FDA has invoked the offense that those manufacturers are selling "unapproved drugs." Unfortunately, this violation can't be used in the BMPEA case since it was never sold as a drug. However, the FDA should be able to order product recalls because the chemical is not present in the plant and because the plant does not appear to have been used as a traditional folk medicine, another criteria for allowing an untested herbal medicine to be sold under DSHEA.
Cohen and colleagues argue that the FDA should've done just that once they identified BMPEA in supplements in 2013, a finding that the FDA itself listed as one of its major accomplishments of that year. At present, the FDA has not issued a statement on the BMPEA issue. So we don't know what's behind the holdup.