Half of the US population regularly takes dietary supplements, but ensuring they are safe has proven difficult and contentious since the Dietary Supplement Health and Education Act of 1994 (DSHEA) became law⁽ Reference Kantor, Rehm and Du ^{1 –} Reference Denham ^{3 )}. This law significantly reduced regulatory oversight of dietary supplements. As a consequence, it led to a rapid increase in dietary supplement availability and consumption, in part because manufacturers were not required to demonstrate the safety and efficacy of their products. Currently, over 85 000 dietary supplements are on the market and an estimated $US 41·1 billion of them were sold in a recent year⁽ Reference Cohen ^{4 , 5 )}.

Surveillance systems available to determine whether dietary supplements present a risk to the population are inadequate and numerous severe injuries and deaths have occurred from dietary supplement consumption^{( 6 )}. The Food and Drug Administration (FDA) regularly recalls dietary supplements because of safety concerns and adulteration, including unintentional contamination. It was recently reported that approximately 23 000 emergency room visits each year in the USA are attributable to adverse events associated with dietary supplement use⁽ Reference Geller, Shehab and Weidle ^{7 )}. Most information the FDA receives on potentially dangerous dietary supplements is obtained as anecdotal information submitted by clinicians, consumers or manufacturers using the FDA’s adverse event reporting system and an occasionally pertinent scientific publication. Only about one in 100 adverse events that occur due to dietary supplement use is reported to the FDA and many reports lack sufficient information to be useful^{( 6 )}.

From 2006 to 2011 we conducted anonymous, voluntary surveys of dietary supplement use of over 4000 active duty US Armed Forces personnel including reports of the adverse events they experienced. Over half (53–82 %) of service members reported regularly using dietary supplements and service members were much more likely to use purported performance-enhancing dietary supplements than civilians⁽ Reference Lieberman, Stavinoha and McGraw ^{8 –} Reference Austin, McLellan and Farina ^{11 )}. As we conducted these surveys, a dietary supplement, 1,3-dimethylamylamine (DMAA), was aggressively marketed for physical performance-enhancement and weight loss, purportedly by increasing intensity of workouts and effectiveness of weight training⁽ Reference Cohen ^{12 )}. This ingredient, DMAA, was marketed as a dietary ingredient based on apparently false claims it occurred naturally in geraniums (spp. Geraniaceae). One of the regulatory requirements of DSHEA is that any product sold as a dietary supplement be a naturally occurring substance⁽ Reference Cohen ^{12 ,} Reference Zhang, Woods and Breitbach ^{13 )}. Surprisingly, nearly 50 years ago, DMAA was marketed as an FDA-approved inhaled nasal decongestant by Eli Lilly and Company under the tradename Forthane™. Like many drugs for this and other indications, it is a sympathomimetic compound similar in structure to phenylephrine, amphetamine and ephedra⁽ Reference Cohen ^{12 –} Reference Austin, Travis and Pace ^{14 )}. According to the FDA and several peer-reviewed reports, adverse effects reported as a consequence of DMAA use include cardiac arrest, haemorrhagic stroke and death⁽ Reference Karnatovskaia, Leoni and Freeman ^{15 –} Reference Gee, Tallon and Long ^{17 )}. In one recent case report, cardiac arrest was reported to have occurred after consumption of a product that contained DMAA but was not labelled as such⁽ Reference Karnatovskaia, Leoni and Freeman ^{15 )}. Furthermore, consumption of several DMAA-containing supplements has been reported to be associated with severe liver injury, in several instances requiring a liver transplant⁽ Reference Foley, Butlin and Shields ^{18 )}.

Several animal studies have been conducted to examine various effects of DMAA⁽ Reference Zovico, Curty and Leal ^{19 ,} Reference Dolan and Gatch ^{20 )}. In one rodent study, acute administration of a DMAA-containing supplement increased running time and distance⁽ Reference Zovico, Curty and Leal ^{19 )}. However, chronic administration (4 weeks) of the supplement impaired exercise performance. The authors concluded the supplement had acute stimulant-like effects on rodents consistent with the pharmacological profile of DMAA and its reported acute effects in man⁽ Reference Zovico, Curty and Leal ^{19 )}. In another rodent study, DMAA produced effects on behaviour similar to those produced by cocaine and to a lesser extent methamphetamine⁽ Reference Dolan and Gatch ^{20 )}.

Several years ago, ephedra was marketed as a dietary supplement for purported performance-enhancement and weight loss like DMAA, and over three billion doses were consumed a year before it was banned in 2004 after nearly 15 000 adverse events associated with its use, including multiple deaths, were reported⁽ Reference Cohen ^{12 ,} Reference Haller and Benowitz ^{21 )}. It appears DMAA was introduced and marketed as a replacement for ephedra, given ephedra’s widespread popularity. It is not surprising that since they have common mechanisms of action and potency, the safety issues and regulatory history of ephedra repeated itself with DMAA⁽ Reference Cohen ^{12 ,} Reference Fabricant ^{22 )}. In 2013, the FDA issued warning letters to manufacturers of DMAA-containing products to cease its manufacturing and sale after receiving over 100 reports of illness, including six deaths, in both the general population and military service members⁽ Reference Fabricant ^{22 )}. However, due in part to the failure of existing surveillance systems, it took over 16 months for the FDA to take definitive action on DMAA-containing products. Recently, dietary supplement manufacturers have marketed other products that may be dangerous, appear structurally similar to DMAA and are sympathomimetics, such as 1,3-dimethylbutylamine⁽ Reference Cohen, Travis and Venhuis ^{23 )}. Therefore, the objective of the current cross-sectional study was to determine whether there was an association between use of dietary supplements containing DMAA and self-reported adverse events among armed forces personnel.

Results

The mean age of the population sampled was 28·5 (sd 7·4) years. Eighty per cent were males, 75 % had at least some college education and 11 % were deployed to a combat theatre. Individuals surveyed were serving in the Air Force (39 %), Army (37 %) or Coast Guard (24 %). On average, personnel spent 5 h/week (297 (sd 221) min) engaged in aerobic exercise, much more than the general civilian population^{( 25 )}. Overall, 11 % of those surveyed used dietary supplements labelled as containing DMAA at least once weekly.

Service members using DMAA reported experiencing significantly more adverse events than non-users in crude and adjusted models (Table 1). In the fully adjusted model (Model 3), which included adjustment for use of other dietary supplements, as well as multiple demographic factors, DMAA users relative to non-users were over two times more likely to report tachycardia (OR=2·37; 95 % CI 1·75, 3·20), dizziness (OR=2·17; 95 % CI 1·42, 3·33) and tremors (OR=2·32; 95 % CI 1·67, 3·22), and over three times more likely to report numbness/tingling (OR=3·36; 95 % CI 2·21, 5·12; Table 1). Both tachycardia and tremors are classic side-effects of sympathomimetics like ephedrine, and other adverse events significantly associated with DMAA-containing supplements, such as dizziness, have also been associated with consumption of sympathomimetics⁽ Reference Cohen ^{12 ,} Reference Haller and Benowitz ^{21 )}. Adjusting for other dietary supplements used by service members somewhat attenuated the magnitude of the relationship between DMAA use and adverse events (Model 2), as might be expected. When demographic variables were also included (Model 3), they had only a relatively small effect on the extent of the relationship between DMAA use and specific side-effects (Table 1).

Table 1 Associations between self-reported 1,3-dimethylamylamine (DMAA) use and adverse events among US Armed Forces personnel (n 4374), 2010–2011. OR and 95 % CI were derived from logistic regression models; users are defined as those consuming DMAA at least one or more times per week

* Model 1=crude, unadjusted model.

† Model 2=adjusted for total number of dietary supplements used.

‡ Model 3=adjusted for total number of dietary supplements used, age, gender, education, aerobic exercise, BMI and military branch.

§ Statistical significance of Wald χ ² test.

The nature of the adverse events reported by the service members taking DMAA is consistent with a recent report by authors from the Centers for Disease Control and Prevention and the FDA that documented symptoms observed in emergency departments that were attributed to dietary supplements, particularly those such as weight-loss and energy-increasing products that frequently contain various stimulants⁽ Reference Geller, Shehab and Weidle ^{7 )}. Adverse effects observed in that study included palpitations, chest pain, tachycardia, headache and dizziness and were frequently present in individuals 20–34 years old and associated with consumption of weight-loss and energy supplements⁽ Reference Geller, Shehab and Weidle ^{7 )}. It should be noted side-effects experienced by consumers using sympathomimetic or other cardiostimulatory dietary supplements may account in part for their popularity. Perceptible physiological changes may convince users the products are working since most dietary supplements do not produce readily noticeable effects. This may encourage manufacturers to include higher doses of stimulants, as well as multiple stimulants, in their products.