By Trevor Butterworth, Forbes
A recent NPR segment summed up the stakes in the emerging controversy over DMAA, a dietary stimulant used to boost focus and performance in sports, and as an ingredient in some weight loss products: In 2011, DMAA enjoyed a $100 million market in the US alone.
But after two soldiers, one of whom “had a history of mild obesity and sickle cell trait,” died on training exercises, and the US military issued two case reports in which DMAA was found in their blood, alarm bells began to ring. NPR quoted a Harvard doctor, Pieter Cohen, saying DMAA was “the most dangerous ingredient sold today in supplements in the United States,” and if you were to follow the subsequent media coverage the public has been snookered once again by the Wild West regulation of dietary supplements that allowed the “amphetamine-like” substance to be sold. Enact the bans, call the trial lawyers, launch the lawsuits.
But while there are many troubling aspects to the way dietary supplements are regulated in the US, there are equally troubling aspects to DMAA becoming the poster supplement for regulatory negligence. Take the seemingly devastating comment by Harvard’s Cohen: How could anyone know that DMAA is “the most dangerous ingredient” in supplements when the overwhelming majority of those supplements have never been subjected to a human trial of any sort? After all, the Chinese herb Aristolochia, which through its component aristolochic acid – is surprisingly adept at causing kidney failure and cancer, is still available over the Internet?
Indeed, what distinguishes DMAA from most supplements is that there is a clinical and pharmacological safety database. Moreover, given its recent popularity, and given that DMAA was used in a nasal decongestant for over 40 years, one can reasonably and conservatively infer hundreds of millions of doses taken since the 1940s. Surely if DMAA was as dangerous as it has been made out to be in the media coverage, there would be a confluence of evidence from the risks identified in clinical studies and a substantial body of case reports tying those risks to adverse and fatal outcomes?
The problem is that the clinical evidence shows nothing that could account for the handful of deaths, assuming those who died weren’t abusing the supplement by taking far more of it than the recommended dose, or using it in a manner the warning label warns against. In the death of a marathon runner, which a UK court attributed to DMAA, there is some question as to whether the runner had an irregular heartbeat – which is something identified on the warning label as a reason to avoid the supplement.
The scientific case against DMAA being guilty as charged, begins with the claim that it is similar to amphetamine. “There is a slight chemical similarity,” said Joseph Rodricks, a founding principal of the global environmental health consulting firm Environ, “but it[DMAA] is a much simpler molecule.” The key structural feature in amphetamines that produces central nervous system effects is completely missing, he explained. “It’s just unfair to compare the two.”
Environ specializes in toxicological analysis with the aim of reducing health risks and environmental contamination and ensuring compliance with regulatory goals. The company was hired, for example, by National Geographic to see how it could improve its environmental impact, and won an award for helping set new standards on pollution and sustainable growth for the Port of Los Angeles.
Rodricks spent 15 years as a scientist at the FDA, and held the post of Associate Commissioner for Health Affairs. Notably, he was also a reviewer of a study, “The Use of Dietary Supplements by Military Personnel, which the US Army commissioned from the Institute of Medicine. He is also the author of the chapter on exposure assessment for the National Academies of Science Reference Manual on Scientific Evidence. In short, he is a recognized authority on toxicology.
About a year ago, USPLabs asked him to conduct a review all the clinical evidence on the supplement, which is present in two of its products, Jack3D and Oxyelite Pro. he “There are seven clinical trials of recent origin that form the core data upon which our safety assessment was done,” he said, stressing that “these are clinical trials; they’re not observational studies and they’re not case reports. The measurements have been very carefully made, the designs are all strong, the numbers – at least in the earlier studies – were fairly small, but they grew over time.”
When you add all these studies together, he says, the most striking thing is the consistency of the results: mild and transient effects on blood pressure. Even when DMAA and caffeine were combined in one study and the subjects went on a 10km run, the researchers found no increase in heart rate during the run, compared to the runners given a placebo. In the other studies, there was no evidence of adverse effects on kidney and liver function, no reports of light-headedness or loss of consciousness, no evidence of fluid or electrolyte loss that might contribute to heat stroke.
“There’s nothing unusual appearing anywhere,” said Rodicks. “On the whole, for dietary supplements, this is a substantial database.” He also noted that there wasn’t anything in the pharmacological database (when DMAA was used in a nasal decongestant) that suggests a problem. There is also no difference in results between the two independent and industry-funded studies – and specifically with regards to the acute increase in blood pressure.
One of the researchers who conducted several of these clinical trials is Richard Bloomer, Professor and Chair of the Department of Health and Sport Sciences at The University of Memphis. When we gave people a single 25mg dose, he said, “their blood pressure barely moved from baseline.” When we gave them single 50mg and 75mg doses, blood pressure increased and did so in a dose dependent manner (meaning that the more you take the more it goes up). As a consequence, people who are hypertensive – that is people who have high blood pressure, should avoid DMAA – which, again, is something that the warning label on USPLabs’ Jack3D points out. But then, said Bloomer, “people who are hypertensive shouldn’t be using stimulants of any sort.”
As to prolonged use, “what we see is that with heart rate, blood pressure and a variety of different parameters that can be measured in blood, there is negligible change across time, whether using DMAA-based supplements for 2 weeks, 8 weeks, 12 weeks. Granted people are going to come back and say, ‘you only had 10, 12, 15 individuals per group, and we would like to see 100 individuals per group.” Well, he says, so would he, but the cost of conducting such a large study would be staggering.
At the same time, the consistency of mild effects in all the studies leaves us without a scientific rationale for DMAA being problematic, outside of an acute increase in systolic blood pressure for people who are either hypertensive to begin with, or who are hypersensitive to stimulants, or who are, in effect, abusing the product by taking huge doses and possibly combining it with other synergistic substances. This may well have been what happened in three cases of non-fatal cerebral hemorrhage in New Zealand, who either consumed DMAA in products sold as party pills or in a powder mixed in a drink.
According to Bloomer, if you look at the blood DMAA data presented in the New Zealand case reports (Gee et al. 2012) in light of a recent lab investigation that directly measured blood DMAA following a single 25mg dose, the victims may have taken “15 to 25 times the dosage used in the laboratory study.” All three also appear to have been drinking alcohol – something that Jack3D, for example, warns against doing when taking DMAA as a sports supplement; one also had traces of cannabis in their urine. Still, all made a full recovery.
Given that many Americans drink two to three cups of coffee per day, totaling about 300mg of caffeine, “if you used 20 times that amount – 6,000mg – I’d bet you’d run into some problems,” said Bloomer. There are also people who are extremely tolerant or intolerant to stimulants; some are able to tolerate 500mg of caffeine without any problems while that dosage would induce anxiety and jitters in others.
At the same time, the problem with case reports is that they are considered the lowest form of evidence in medicine. They are detailed descriptive accounts not systematic, controlled analyses – and while they often point to unusual and potentially important issues, they can say nothing about cause and effect.
As the authors of the case reports on DMAA published in Military Medicine note, “no causal relationship between the supplement ingredients and deaths can be confirmed.” Their speculation as to why DMAA could have contributed to these deaths is at odds with the findings in the clinical literature. The degree to which heat stress and exertional heat stroke may have played a role in these deaths is also unclear. The army subsequently conducted a much more detailed investigation, but the results have not yet been made public.
At the same time, Rodricks pointed to new evidence on the pharmacokinetics of DMAA – how the chemical passes through the body and the body’s effect on it – which will be published shortly, filling in another key piece of evidence. While he did not want to comment on data that were unpublished, he did not indicate that this data would cause a rethink on risk.
Bloomer readily acknowledged the concerns many clinicians have about the state of the dietary ingredient market in terms of research and regulation. “The fact that there are studies on stimulants like caffeine and DMAA is somewhat unique in the dietary supplement industry,” he said, “because, frankly, a lot of companies come to market without doing any research and really don’t have any desire or any plans to conduct the research, and yet the products are still sold with the idea that they’re not only safe, but effective.” Indeed, he said, in some cases, the only thing effective about the product is the marketing, which leads to a placebo effect.
And that, in the end, is the real challenge with DMAA: how do you reconcile claims that it could have so powerful an effect on the body as to have killed a handful of people with the clinical data that shows it results in a mild and transient increase in systolic blood pressure when used at the recommended doses?