Deadly Consequences of Pre-workout Supplements and the Lack of FDA Regulation

Seth Gemme, MD
Jason Hack MD
Brown University, Medical Toxicology

Nutrition supplements can be found in almost any grocery store, pharmacy, or nutrition specialty store. In 1994 there were only 4,000 nutrition supplements on the market. Today, Americans spend nearly 30 billion dollars on supplements and have a choice of over 85,000 products. Of these supplements, pre-workout energy powders have proven over and over again to have adverse effects and deadly consequences. Due to the Federal Drug Association’s (FDA) loose regulation of dietary supplements, these adverse effects are not readily apparent and often go unnoticed for years before coming under speculation.

Ultimate Orange was a pre-workout supplement first introduced in 1982 that gained popularity among those looking to increase stamina in the gym or on the field. The ingredient in the product responsible for this energy boosting effect is ephedra sinca, also known as má huáng. Ephedra sinca is a naturally occurring plant mainly found growing in the semi arid climates of Asia. It has been used for over 5,000 years to alleviate the symptoms of asthma, cough, and headache. It contains ephedrine and pseudoephedrine, which are similar structural analogs of methamphetamine. Acting as a sympathomimetic amine, ephedra acts to increase the release of norepinephrine and activate the postsynaptic alpha and beta-receptors on neurons. Ephedra sinca increases the athlete’s alertness, air entry into the lungs, and the metabolic rate, all while decreasing fatigue. Ephedra sinca also increases blood pressure, body temperature, and heart rate thus causing risk of dehydration, stroke, seizure, and adverse cardiac events.

Adverse events were not rare with ephedra containing supplements such as Ultimate Orange. A New England Journal of Medicine article from 2000 investigated 140 adverse events and found several that resulted in death or permanent disability. This reputable review of the adverse events as well as the death of Steve Belcher, a pitcher for the Baltimore Orioles, put pressure on the FDA. Therefore in 2004, the FDA banned all ephedra-containing supplements.

The FDA’s inconsistent response to harmful products is due to their inability to directly regulate the dietary supplement industry. An attempt was made for increased regulation by the Clinton administration by passing the Dietary Supplement Health and Education Act (DSHEA) of 1994, but this act still has loopholes. In order for a product to be sold as a dietary supplement, a manufacturer must prove it is naturally occurring, safe, and label the product as a “food” rather than a “drug”. All ingredients prior to 1994 were grandfathered as an old ingredient and do not need safety data. Neither old nor new ingredients need to have proven effectiveness. Due to the lack of resources and funding, the FDA does no formal testing on ingredients or supplement products prior to the release to the public. Once a product is on the market it is up to the manufacturer to report adverse events. The FDA then has the responsibility to prove it is unsafe if there are substantial reported adverse events.

A modern dietary supplement that illustrates the FDA’s loose regulation is a product made by USPlabs called Jack3d. Containing 1,3-Dimethylamylamine (DMAA), Jack3d was responsible for two well publicized deaths in the military in 2011. DMAA is similar to ephedra since they both are sympathomimetics. DMAA was first manufactured and introduced by Eli Lily as a nasal decongestant in the 1940’s; however after reports of headaches and tremors in users of the medication, it was voluntarily removed from the shelves in the 1970s.

DMAA regained attention in 2006 when an organic chemist for USPlabs, Patrick Arnold, synthesized it in the laboratory for use in Jack3d. The DSHEA of 1994 had specified that dietary supplements must contain naturally occurring ingredients in order to be sold to consumers; however, USPlabs relied on poor research to push the product to market and the FDA looked the other way. The poor quality research was a single small controversial Chinese study that found DMAA could be extracted from geranium. The methodology of the study was flawed and several subsequent studies could not produce the same result. The only study since to find DMAA in geranium plants found only nanograms in a single geranium plant. That means, in order to produce a single serving of Jack3d, one would need 50,000kg of geranium. It was clear that DMAA was synthesized and therefore did not meet the supplement standard put forth by the DSHEA, but the damage had already been done. The product had been on the market for over 5 years and was responsible for several deaths.

Similar to Ultimate Orange, Jack3d did not get the attention of the FDA until the product came under scrutiny by the media. On a summer day, while running in his battalion for only 10 minutes, Private Michael Sparling developed leg cramps followed by loss of consciousness and cardiac arrest. Once at the emergency department, he was found to have a temperature of 105.5 and despite multiple attempts at resuscitation including cooling, he died. He was found to have DMAA in his blood at autopsy. His as well as another soldier’s death caused the military to ban DMAA’s sale on bases and caught the eye of many media outlets.

The FDA’s tough road to banning DMAA began after the military deaths. Once the decision to ban the product was made, there were many legal and scientific steps the FDA had to complete. In the meantime, the FDA sent letters to several manufactures of products containing DMAA warning them about the harmful side effects. All manufactures except USPlabs took DMAA containing products off the shelves. The FDA even seized an USPlabs warehouse, destroying millions of dollars worth the product. It wasn’t until two years after the death that the FDA was successful in banning DMAA.

Despite the banning of ephedra and DMAA containing products, there continues to be pre-workout supplements on the market that contain dangerous sympathomimetic like compounds. The newest craze is a product made by Cellucor called C4 Extreme. The active ingredient is bitter orange, which contains Synephrine, a chemical similar in structure to ephedrine. There have already been reported adverse effects from this product.
It seems that once one product is banned a replacement is quickly marketed and adopted into daily use by athletes looking to get an extra edge. It is crucial for physician’s to ask patients about supplemental use, especially young athletes presenting with neurologic or cardiac symptoms. If an adverse event is identified, one can report it through the FDA Med Watch online reporting system. This is the only way the FDA under the current law can track adverse events of these loosely and sometimes deadly supplements.

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