Drug Profile

Background

The plant species ephedra (also known as ma huang, Chinese ephedra, or epitonin) contains a number of related chemical compounds known collectively as ephedrine alkaloids. The principal active ingredient is known as ephedrine, a compound used in the 1920s as a central nervous system stimulant and as a treatment for nasal congestion and asthma. Use declined as more effective therapies for these conditions were identified.[1]

Ephedra is very closely related to the drug amphetamine as well as phenylpropanolamine (DEXATRIM), a drug that was removed from the market due to its association with stroke.[2] All these compounds are called sympathomimetics: they increase metabolic rate, heart rate and blood pressure. The “high” produced by these drugs makes them candidates for recreational abuse.

Claimed uses and mislabeling

Besides recreational drug use, an indication not recognized by the medical profession, the primary uses of ephedra recently have been for weight loss and enhanced athletic performance. The latter is also not a medical indication (to say nothing of the ethics of drug-enhanced athletic competition). In any event, no randomized trials have studied use of ephedra to enhance athletic performance. A meta-analysis of randomized, controlled trials concluded that “the effect of ephedra or ephedrine as it is used to promote enhanced athletic performance is unknown.”[3]

For weight loss, there is not a single randomized trial that lasted longer than six months. There is, therefore, no evidence for the long-term efficacy of the ephedra alkaloids. Combining studies of ephedra and ephedrine (and including those in which caffeine, another sympathomimetic, was also administered), the weight loss due to the ephedra alkaloids was estimated at two pounds per month, a trivial amount for an obese person.[3]

As with many dietary supplements, the labels for many ephedra-containing supplements have not always accurately reflected the contents. Measured amounts of ephedra in one study ranged from 25 to 105 percent of the labeled amount. Many products contained other ephedra alkaloids, and there was significant lot-to-lot variation in content.[4] Public Citizen identified nine manufacturers producing 10 dietary supplements that openly advertised their products as containing synthetic ephedrine alkaloids, even though dietary supplements are not allowed to contain synthetic versions of the supplement.[5]

Side effects

The primary safety concerns with respect to ephedra have related to the cardiovascular and central nervous systems. It is no surprise that ephedra would affect the cardiovascular system. Clinical experiments have associated the supplement with heart rhythm abnormalities,[6] increased blood pressure[7] and prolongation of the QTc interval in the electrocardiogram (ECG or EKG).[8] Prolongation of this interval is associated with increased risk for life-threatening arrhythmias. The Food and Drug Administration (FDA) has removed drugs from the market for QTc prolongations less severe than those described for ephedra.[8]

Ephedra has also been associated with case reports of stroke.[9] A more formal study of the risks of ephedra suggested a risk for a particular type of stroke at higher doses of ephedra, but this finding did not reach statistical significance.[10] Psychiatric effects associated with ephedra include bizarre behavior, hallucinations, paranoia, agitation, anxiety, mania and nightmares.[11]

Additional concerns have included ephedra-induced hearing loss[12] and unrelieved, painful erections (priapism).[13] The Government Accountability Office, an investigative branch of the U.S. Congress, lists the following adverse effects associated with ephedra, in addition to those mentioned above: appetite loss, nausea, vomiting, urinary disturbances, sweating, insomnia, dizziness, shortness of breath, fever, tremor, muscle injury, nerve damage, severe headaches, memory loss, seizures and dependency.[14]

In addition to the clinical reports of adverse effects and the inadequate manufacturing standards, several studies systematically examined the FDA’s adverse event monitoring system for cases of serious harm related to ephedra. (It is widely acknowledged that this system collects a small fraction of all events that occur, particularly for dietary supplements, because supplement manufacturers are not even required to report adverse events to the FDA.) Two nonoverlapping reports covering the period from 1995 to early 1999, before the prime of ephedra use, identified 21 deaths related to ephedra.[15],[16]

These reports and others led Public Citizen to call for the banning of ephedra-containing dietary supplements in September 2001. It was not until December 2003 that the FDA finally acted to do so. By then, over 155 deaths associated with the drug had been reported to the FDA, most due to heart attacks and strokes.[17] All indications are that ephedra has been by far the most injurious of all dietary supplements marketed in the U.S. In FDA data from 1993 through 2001, ephedrine alkaloids accounted for 42 percent of all reports of and 59 percent of all deaths from dietary supplements.[18] In another study that adjusted for the relative use of dietary supplements, ephedra was associated with a 220-fold increase in the probability of having an adverse event compared to all other dietary supplements combined.[1]

Interactions with other drugs

In published medical journal articles and FDA documents, the following drugs were identified as having interactions with ephedra: tramadol (ULTRAM, ULTRACET),[19] monoamine oxidase (MAO) inhibitors (e.g., phenelzine)[20] stimulants (e.g., caffeine, decongestants).[21] The 2003 edition of Evaluations of Drug Interactions lists metformin (GLUCOPHAGE, GLUCOVANCE, METAGLIP) and reserpine (SERPALAN) as having either “highly clinically significant” or “clinically significant” interactions with ephedrine.

Regulatory actions surrounding ephedra and ephedrine

2001: Public Citizen petitions the FDA to ban ephedra.

2003: Years after the dangers of ephedra were recognized, the FDA finally removed the supplement from the market.[22] Nonetheless, some stores may still have it in inventory.[23] We recommend you not use this product and discard any pills you may have in your possession.

2008: In 2008 the regulatory agency in Canada, Health Canada, issued an advisory to consumers warning them not to use ephedrine or ephedra alone or in combination with caffeine or other stimulants for weight loss, increased energy or body building, due to the possibility of serious and possibly fatal adverse side effects. [24]

Although this drug is no longer officially marketed in the U.S., either because it was withdrawn for safety reasons or its manufacturer discontinued its production, we continue to provide information about it because people may have supplies in their homes that they may otherwise continue to use or they may obtain these drugs via the Internet.