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Ephedrine: Banned by the FDA 2004

Kelly Roseberry

 

Date: 11/16/2005 

 

 

 

What is ephedrine?

 

Ephedrine (also known as Ma-huang or ephedra) is an alkaloid compound derived from active chemicals found naturally in a number of plants.  Until its recent ban in the USA by the FDA, ephedrine had been a popular dietary supplement in the United States primarily used for weight loss and energy enhancement.  Additionally, it has been used for thousands of years in Chinese medicine to treat a variety of illnesses including asthma, colds and flu, fever, chills, headaches, edema, hyperhydrosis, nasal congestion, bone pains, coughing, and wheezing.

 

General description of ephedrine and its products (M.G. Soni et al.)

 

 

Image

Synthesis of ephedrine and related alkaloids (M.G. Soni et al.)

 

 

Before it was taken off the market, ephedrine was an active ingredient found in at least 200 over-the-counter products, and it had been estimated that as many as two to three billion doses were consumed every year in the United States.

 

Some common ephedrine-containing products are:

 

Text Box:  Text Box:  Metabolife 356 (Metabolife International)
Ripped Fuel (TwinLab Laboratories)
Extreme Ripped Force (American Bodybuilding)
Diet Fuel (Twin Laboratories)
GH Fuel (TwinLab Laboratories)
Herbal Fuel (TwinLab Laboratories)
MetaboLift (TwinLab Laboratories)
ThermiCare (Met-Rx USA)                           
ETA Stack (Nutra Sport)
Xenadrine RFA-1 (Cytodyne Technologies)
Ultimate Orange (Next Nutrition, Inc)
Text Box:  UltraCuts (BioPlex)
Vasopro (Mega Pro International) 
Adipokinex (Syntrax Innovations, Inc)
ThermoPlex (Bioplex)

Thermogenic Power (Nature's Herbs)
 Chinese Ephedrine (Frontiers, Inc.)
MetaCuts (Metaform)
Chinese Ma Huang (Gaia Herbs, Inc)
Lipokinetix (Syntrax Innovations, Inc)
Clenbutrx (Vital Pharm, Inc)
BetaLean HP (EAS)
Diet Pep (Natural Balance, Inc)
      Dirulean (ISS Research)
Dyma-Burn Xtreme (Dymatize Nutrition)

 

 

How does ephedrine work?

 

Ephedrine is usually taken orally.  Although the gastrointestinal tract completely absorbs it within 2-2.5 hours, effects are generally evident within an hour of ingestion.  Ephedrine works, like amphetamines, as a central nervous stimulant. It releases norepinephrine and dopamine from neuronal storage sites in the sympathetic nervous system on effector organs.  Through this process, ephedrine indirectly stimulates adrenergic receptors (the same receptors targeted by adrenaline) thereby increasing the heart rate, cardiac output and blood pressure, decreasing appetite, and making the user feel more energetic. 

 

 

Side effects of ephedrine

 

Due to its nature as a stimulant, ephedrine-containing supplements have been associated with increased risk of adverse side effects, including:

 

Text Box:  Text Box:  Headache

Hypertension

Insomnia

Irritability

Motor Restlessness

Tachycardia

Urinary Retention

Cardiac Arrhythmias

Myocardial Infarction

Psychosis

Seizures

Stroke

And even Death

 

 

The role of the FDA

 

Products that are classified as “dietary supplements,” including those containing ephedrine, do not need pre-market approval from the FDA.  Once a dietary supplement is marketed, the FDA must demonstrate that the supplement is unsafe before thy can remove it from the marketplace.  Because ephedrine-containing dietary supplements are readily available to the public in grocery stores, health food stores, pharmacies, and on the internet, the FDA and other government agencies have taken steps to evaluate the safety and efficacy of ephedrine. 

 


Date



Event



July 1993

FDA issued first public warning about possible safety issues

October 1995

FDA convened the Special Working Group on Food Products Containing Ephedrine Alkaloids and concluded there was sufficient evidence to suggest adverse effects associated with use

August 1996

FDA convened Food Advisory Committee to discuss safety of ephedrine; unable to reach consensus

June 1997

FDA published a proposed rule on dosage, duration limits, and product labeling

July 1999

US General Accounting Office released Dietary Supplement Uncertainties in the Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids; concluded insufficient evidence to support dosage and duration limits

April 2000

FDA withdrew much of its proposed rule

August 2000

Office of Women's Health of the US Department of Health and Human Services convened a public meeting to discuss safety

September 2000

Office of Women's Health recommended additional research be conducted

June 2002

US Department of Health and Human Services commissioned the RAND Corporation to evaluate safety and efficacy

February 2003

RAND Corporation released Ephedrine and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects

February 2003

FDA published white paper presenting the evidence on ephedrine's safety and effectiveness

March 2003

FDA announced proposed rules to establish manufacturing and labeling standards for all dietary supplements

December 2003

FDA announced plan to prohibit sales of dietary supplements containing ephedrine

February 2004


FDA published Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk in the Federal Register


Major regulatory events concerning ephedrine (M.L. Chavez)

 

On February 11, 2004, the FDA released its final rule declaring dietary supplements containing ephedrine alkaloids to be adulterated under the Federal Food, Drug, and Cosmetic Act.  The ruling, which prohibited the sale of ephedrine-containing dietary supplements because they present an unreasonable risk of illness or injury, went into effect on April 12, 2004.  As a result, ephedrine-containing products have been removed from the market, and many companies have reformulated their products to contain ephedrine alternatives.  FDA Commissioner Mark B. McClellan, M.D., Ph.D., affirms that “this final rule will protect consumers by ensuring that these dangerous products are removed from the market and never sold.” 

 

 

See the FDA’s full final report from the Federal Register here

 

 

Research

 

Pittler and Ernst (2004) conducted a systematic review of existing scientific literature concerning the effectiveness of ephedrine as a dietary supplement for body-weight reduction.  In five double-blind trials, it was concluded that the combination of ephedrine and caffeine was effective for promoting a modest short-term weight loss of ~0.9kg/month more than placebo.  However, the intake of ephedrine-containing supplements was shown to be associated with a 2.2-3.6 –fold increase in odds of psychiatric, autonomic, or gastrointestinal symptoms and heart palpitations.  The authors concluded the evidence for ephedrine as an aid in reducing body weight was not convincing, and ephedrine could not be recommended for over-the-counter use.

 

 

Haller and Benowitz (2000) reviewed 140 adverse event reports (AERs) related to the use of dietary supplements containing ephedrine that were submitted to the FDA between 1997 and 1999. The investigators concluded that 31% of the reports were "definitely" or "probably" related to the use of supplements containing ephedrine and another 31% were deemed to be "possibly" related. Among the adverse events that were deemed "definitely," "probably," or "possibly" related to the use of supplements containing ephedrine, 47% involved the cardiovascular system and 18% involved the central nervous system. The adverse events included hypertension (17 reports), palpitations, tachycardia or both (13), stroke (10), and seizures (7). Ten events resulted in death, and 13 events produced permanent disability. The authors concluded that the use of dietary supplements containing ephedrine might pose a health risk to some individuals.

 

 

Samenuk et al. (2002) assessed AERs filed with the FDA from 1995 to 1997. During this period, 926 cases of possible ephedrine-related toxicity were reported to the FDA. These investigators identified 37 serious cardiovascular events. In these cases, use of ephedrine was temporally related to stroke (16 reports), myocardial infarction (10), or sudden death (11). In 36 of the 37 patients, use of ephedrine was reported to be within the manufacturers’ dosing guidelines. The authors concluded ephedrine use is temporally related to stroke, myocardial infarction and sudden death, underlying heart or vascular disease is not a prerequisite for ephedrine-related adverse events, and the cardiovascular toxic effects associated with ephedrine were not limited to massive doses.

 

 

In 2002, the Council of Responsible Nutrition also studied the AERs filed with the FDA. A total of 1173 AERs were studied and 69 AERs were identified reporting death following ephedrine use. Of the 1173 reports, 121 were selected for further evaluation. Of these 121, 47 were considered to contain serious adverse events, including stroke and stroke-like symptoms (15 reports), seizures (13), cardiac arrest (15) and two individuals who collapsed. From the selected 121 cases, there were an additional 8 reports of death: six were cardiovascular (one occurred in an automobile accident and one was a spontaneous abortion). Among the six cardiovascular-related deaths, five were males and one was female. All five males that died from cardiovascular problems were using dietary supplements containing ephedrine as an athletic performance enhancer. Additionally, four of the five were simultaneously using other performance enhancing products such as caffeine; therefore, their deaths cannot be directly attributed to the use of ephedrine. The report concluded that after extensive examination of these AERs, it was not possible to conclusively determine if there were any unexpected toxicological effects due to the ephedrine contained in the dietary supplements based solely on the information presented.

 

 

In addition to the above described adverse event reports filed with the FDA, during 1993 and 1995 the Texas Department of Health received reports of approximately 500 adverse events, including seven deaths due to myocardial infarction or stroke in patients who used ephedrine-containing supplements (CDC, 1996). Recently, the nation’s largest maker of ephedrine-containing weight loss supplements has turned over nearly 1500 consumer complaints to the FDA.  Fourteen of these alleged serious adverse events, including strokes (10 reports), heart attacks (2), and seizures (2).

 

 

Conclusions and Recommendations

 

It is difficult to interpret whether the adverse events reported in conjunction with use of ephedrine are actually the result of ephedrine use alone, or the result of other factors such as the amount consumed, underlying sensitivity, simultaneous use of other stimulants, contaminants, inconsistent potency, or a combination of these factors.  None of the AERs or human case reports on ephedrine establish a direct causal relationship between intake of ephedrine and the reported injuries.  However, the FDA found that there were sufficient grounds for removing ephedrine-containing drugs from the marketplace because they presented “unreasonable risk of illness or injury.”  The ban of ephedrine is the first time the FDA has gone through the difficult steps required by the Dietary Supplement Health and Education Act to ban a dietary supplement.  Therefore, I strongly urge against any use of ephedrine-containing dietary supplements because of the potential serious health hazards they pose to consumers.

 

 

Resources

 

Centers for Disease Control and Prevention, (CDC). (1996). Adverse

events associated with ephedrine-containing products, Texas, December 1993–September 1995. Journal of the American Medical Association, 276, 1711–1712.

 

Chavez, M.L.  (2004). More evidence supporting the ban of ephedra

dietary supplements.  The Annals of Pharmacotherapy, 38, 895-897.

 

Council of Responsible Nutrition. (2000). Safety assessment and

determination of a tolerable upper limit for ephedra. Cantox Health Sciences International, 1–169.

 

Food and Drug Administration, (FDA).  (2004). Final Rule Declaring

Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk.  Federal Register, 69, 6787-6854.

 

Pittler, M.H., & Ernst, E.  (2004). Dietary supplements for body-weight

reduction: A systematic review.  American Journal for Clinical Nutrition, 79, 529-536.

 

Rados, C.  (2004). Ephedra ban: no shortage of reasons.  FDA

Consumer Magazine, 38. 

<http:// www.fda.gov/fdac/features/2004/204_ephedra.html>

 

Samenuk D., Link, M.S., Homoud, M.K., Contreras, R., Theohardes,

T.C., Wang, P.J., & Estes III, N.A.M.  (2002). Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine.  Mayo Clinic Proceedings, 77, 12-16.  

 

Soni, M.G., Carabin, I.G., Griffiths, J.C., & Burdock, G.A.  (2004).

Safety of ephedra: Lessons learned.  Toxicology Letters, 150, 97-110.

 

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