Should Ephedrine Be Banned in Weight-Loss Products?

Shari Lieberman, Ph.D., C.N.S., F.A.C.N.

T here has long been scientific interest in ephedrine as aweight-loss agent. Since the mid-1980s the ephedrine–caf-feine (EC) combination was being developed as an

antiobesity drug and this development followed the “gold stan-dard” of pharmacologic research. EC had been used by millionsof people in the United States and there are conflicting reportsabout adverse events (mostly unconfirmed) associated with ECuse, ranging from several dozen to 500, and including, possibly, 8deaths.1 The vast majority of these reports have been connectedwith abuse and misuse, rather than the appropriate use ofephedrine.

In addition, ma huang or ephedra (Ephedra sinica) has beenused in Traditional Chinese Medicine (TCM) for thousands ofyears as one of the most potent and safe bronchodialators anddecongestants. Ephedra contains several alkaloids includingephedrine, pseudoephedrine, and norephedrine, which are nat-urally present when the whole herb is used. This herb is soimportant that pseudoephedrine (now commercially synthe-sized) is included in most cold, flu, and sinus over-the counter(OTC) medications.

Yet, over the past 18 months, several states have banned thesales of ephedrine and ephedra but not pseudoephedrine. Andon February 11, 2004, the Food and Drug Administration(FDA) published its final ruling in the Federal Register thatephedrine alkaloids are to be banned in all dietary supple-ments.2 The ban takes effect on April 12, 2004. However, thereis an exemption for the ephedra used in TCM. This Op-Ed arti-cle considers whether or not the ban on ephedrine for weightloss supplements is appropriate and backed by scientific evi-dence.

Obesity is chronic, requires chronic treatment, has an increas-ing incidence, and has few effective treatments. The benefits ofcaffeine and ephedrine in treating obesity appear to outweigh

the small associated risks. Restriction of dietary herbal supple-ments containing EC, often with other ingredients, should bebased on controlled clinical trials of these products.

What the Research Shows

More than 30 human clinical studies exist on the ephedra–caf-feine combination, demonstrating that it is safe and effectivewhen used as directed.3–10 This article examines more recentstudies that have been published.*

A review of the literature in MEDLINE,® on using EC to treatobesity concluded that the combination is effective for causingweight loss.3 EC produces an equivalent weight loss to that pro-duced by diethylpropion and superior weight loss compared todexfenfluramine. EC has a long history of safe nonprescriptionuse. The adverse events accompanying acute dosing are mildand transient. Adverse events produced by EC reach and remainat placebo levels after 4–12 weeks of continuous treatment.Available data are from randomized trials that have lasted up to6 months, which should surely show this phenomenon.

Ephedra A 6-month randomized, double-blind placebo controlled trial4

was conducted with a total of 167 subjects (with a body–massindex [BMI] of 31.8 ± 4.1 kg/m2) who were randomized to place-bo (n = 84) or herbal treatment (n = 83) at two outpatient weight-control research units.

According to a last-observation-carried-forward analysis,herbal versus placebo treatment decreased body weight (–5.3 kg± 5.0 kg versus –2.6 kg ± 3.2 kg, P<0.001), body fat (–4.3 kg ± 3.3kg versus –2.7 kg ± 2.8 kg, P = 0.020), and low-density lipoproteincholesterol (–8 mg/dL ± 20 mg/dL versus 0 mg/dL ± 17 mg/dL,P = 0.013), and increased high-density lipoprotein cholesterol(+2.7 mg/dL ± 5.7 mg/dL versus –0.3 mg/dL ± 6.7 mg/dL, P =0.004). Herbal treatment also produced small changes in blood-pressure variables (+3 mmHg to –5 mmHg, P ≤0.05 mmHg) andincreased heart rate (4 bpm ± 9 bpm versus –3 bpm ± 9 bpm,P<0.001), but did not increase cardiac arrhythmias (P>0.05).

According to the subjects’ self-reports, dry mouth (P<0.01),heartburn (P<0.05), and insomnia (P<0.01) were increased anddiarrhea was decreased (P<0.05). Irritability, nausea, chest pain,

59

Op-Ed

Should Ephedrine Be Banned in Weight-Loss Products?

*Most of the earlier work was published by A. Astrup and can be easilyaccessed on MEDLINE® (www.ncbi.nlm.nih.gov/entrez/query.fcgi) sim-ply by searching for papers under his name.

and palpitations did not differ between treatment and controlsubjects, nor did the numbers of subjects who withdrew. In this6-month placebo-controlled trial, herbal ephedra–caffeine(90/192 mg per day) promoted reduction of body weight andbody fat and improved blood lipid levels without producing sig-nificant adverse events.

EC and Aspirin Combination Without ExerciseThe relative efficacy of EC and aspirin (ECA) mixtures for

addressing weight loss have been previously reported.11 Thisstudy evaluated the use of EC and aspirin to enhance positivebody-composition changes in people with BMIs of >27.5 Two

groups of patients were recruited (n = 20, all males) for interven-tion versus placebo conditions. Patients were excluded if theyhad histories of hypertension, prostate disease, depression, orthyroid disease.

Ten (10) patients received 20 mg of ephedrine, 200 of mg caf-feine, and 325 mg of aspirin, 3 times per day, with each meal(group 1), and 10 subjects were assigned to a placebo group(group 2). The study subjects were instructed not to engage inany new activities or change their eating habits over the 6-weekperiod.

Weight loss over the 6-week period was 6 times greater for thetreatment group compared to that in the placebo group (9.9 lbsversus 1.5 lbs). Diet analysis revealed an average intake of 1800calories for both groups. Initial body-composition studies hadrevealed a significant loss of body fat in the ECA-treated groupcompared to the placebo group. Group 1 lost 6 lbs of body fatand ~3 lbs of total body water. ECA is known to have milddiuretic affects, which may have accounted for these increasedwater losses.

The weight loss in the treatment group was a significant per-centage (5.5 percent) of body-weight loss compared to that inplacebo group (P<0.05). Complaints of dry mouth were reportedduring the first few weeks in the treatment group but were notconsidered to be serious. ECA was demonstrated to be a safe andeffective intervention for promoting weight loss and positivebody composition changes during a 6-week period in nonexercis-ing or calorie-controlled conditions.

Diet + EC, +Ephedrine, or + CaffeineThe sympathomimetic agent ephedrine has shown potent

thermogenic and antiobesity properties in rodents. The effect ismarkedly enhanced by caffeine, while caffeine alone has noeffect. In a randomized, placebo-controlled double-blindedstudy with humans, 180 obese patients were treated with diet(4.2 megajoules[MJ]/day) plus an EC combination (20 mg/200mg), plus ephedrine (20 mg), plus caffeine (200 mg), or plusplacebo, 3 times per day, for 24 weeks.6 Withdrawals were dis-tributed equally in the four groups, and 141 patients completedthe trial. Mean weight loss was significantly greater with thecombination than with placebo from week 8 to week 24 (EC, 16.6kg ± 6.8 kg versus placebo, 13.2 kg ± 6.6 kg [mean ± standarddeviation], P = 0.0015). Weight loss in both the ephedrine-treat-ed and the caffeine-treated groups was similar to that of theplacebo group. Side-effects (tremors, insomnia, and dizziness)were transient and, after 8 weeks of treatment, the effects hadreached placebo levels. Systolic and diastolic blood pressure fellsimilarly in all four groups. The authors concluded that, analo-gous to animal studies, the EC combination is effective, whilecaffeine, and ephedrine separately are ineffective for treatinghuman obesity.

Beta-2 AgonistsTreatment with beta 2-agonists promotes fat loss and muscle

growth in numerous species, but human studies had been lack-ing. In a recent study, the effect of a compound with beta 2-ago-nistic properties (ephedrine 20 mg/caffeine 200 mg) was

60 ALTERNATIVE & COMPLEMENTARY THERAPIES—APRIL 2004

Should Botanicals be Marketed for Weight-Loss Products?

Comments by Eric Yarnell, N.D., R.H., and Kathy Abascal, B.S., J.D.

We found Dr. Shari Lieberman’s article highly informative, and weagree with her opinion that the Food and Drug Administration(FDA) should approach its regulatory duties evenhandedly. It shoulddefinitely protect the public by regulating compounds that causesignificant damage before taking action on compounds such asephedrine that have evidence of efficacy and are not associated withsignificant adverse instances.

The FDA’s willingness to permit acetaminophen, pseudoephedrine,and cigarettes to remain over the counter while banning the herbephedra (Ephedra sinica) and other herbs containing ephedrine all toostrongly indicates that “money talks.” Ephedra may remain available inChinese patent formulas, although this legal point is not entirely clear,but similar American or European herbal formulas are no longerallowed—another case of lack of fairness and logic on the part of theFDA.

However, as botanical practitioners we are most concerned withthe appropriate use of herbs. In all but rare cases, this means thatherbs should be used as they have been for centuries or millennia.Ephedra has a long history of use in allergic rhinitis and asthma. Itwas not used traditionally as a weight-loss product. Ephedra has nohistory of use to increase the endurance or metabolism of athletes.Our great sorrow lies in losing the use of an herb that has done, andcould do, so much good for so many of our clients because this herband its isolated constituents were marketed and touted for the noveluse as an unsupervised weight-loss agent.

We live in a society that worships thinness but markets giganticservings of high fat fast foods. We live in a society that advertises to thegullible that weight loss can be accomplished quickly by simply takingpills. Given the advertising and marketing of weight loss, abuse of dietagents may be too tempting for the public and perhaps their use shouldalways be monitored by professionals.

It is our opinion that—if the FDA was going to act—it should havelimited its regulation to the use of ephedra and each of its isolatedconstituents in weight-loss products rather than in all dietarysupplements because there is no traditional basis for such use, littlemodern research basis for such use, and because the potential forharm with medically unsupervised weight-loss products is very high.That type of regulation would be much preferable to the present lawthat bans an herb that is highly beneficial and quite safe when used inaccordance with tradition. And certainly clinical research should beencouraged to fully investigate the validity of the traditional uses ofephedra.

Dr. Yarnell and Ms. Abascal are regular contributors on botanical topics in the journal.

evaluated. Fourteen (14) obese women were treated with a 4.2-MJper day diet and either EC or placebo, 3 times per day, for 8weeks in a double-blinded study.7

Weight loss was not different in the groups, but the EC–treatedgroup lost 4.5 kg more body fat and 2.8 kg less fat-free mass(FFM). The decrease in 24-hour energy expenditure (EE) seen inthe placebo group was 10 percent on day 1 and 13 percent on day56, but was only 7 percent and 8 percent in the treated group (P =0.044). The higher EE in the EC group was entirely covered by fatoxidation. These findings provided evidence that promotion offat loss and preservation of FFM during weight reduction mayalso be achieved pharmacologically in humans.

Ephedrine–CaffeineA 24-week open follow-up trial was conducted with obese

patients who had experienced some weight reduction in a priorstudy. For the new study, the subjects received an EC combination(20 mg/200 mg), 3 times per day.8 The new study was a continua-tion of a previous 24-week, double-blinded, placebo-controlledstudy in which the EC mixture had shown superior weight-reduc-ing properties compared to either ephedrine alone (20 mg) or caf-feine alone (200 mg), 3 times per day. The medication was stoppedbetween weeks 24 and 26 to evaluate withdrawal symptoms. Thefollow-up period was from weeks 26 to 50.

Of 127 patients in the study, 99 completed the follow-up treat-ment, which resulted in an additional weight loss of 1.1 kg (P =0.02). Adverse drug reactions were all minor and temporary.The authors concluded that the EC combination is safe and effec-tive in long-term treatment in improving and maintainingweight loss. No clinically relevant withdrawal symptoms wereobserved.

ECA with Unrestricted Energy IntakeThe safety and efficacy of a mixture of ephedrine (75–150 mg),

caffeine (150 mg), and aspirin (330 mg), in divided premeal doses,were investigated in 24 obese humans (mean BMI 37.0) in a ran-domized, double-blinded placebo-controlled trial.9 Energy intakewas not restricted. Overall weight loss over 8 weeks was 2.2 kgfor ECA-treated subjects versus 0.7 kg for those on placebo(P<0.05).

Eight (8) of 13 placebo subjects returned 5 months later andreceived ECA in an unblinded crossover trial. After 8 weeks,mean weight loss with ECA was 3.2 kg versus 1.3 kg for placebo(P = 0.036). Six (6) subjects continued on ECA for 7–26 months.After 5 months on ECA, the average weight loss in 5 of thesesubjects was 5.2 kg compared to 0.03 kg gained during 5months between studies with no intervention (P = 0.03). Thesixth subject lost 66 kg over 13 months via self-imposed caloricrestriction.

In both studies, there were no significant changes in heart rate,blood pressure, blood glucose, insulin, and cholesterol levels,and no differences in the frequency of side-effects. ECA in thesedoses was thus well-tolerated in otherwise healthy obese subjectsand supported modest, sustained weight loss even without pre-scribed caloric restriction and may be more effective in conjunc-tion with restriction of energy intake.

Diet + EC for AdolescentsThirty-two (32) (male/female ratio = 16/16) obese adolescents

were treated by diet (using a calculated daily energy requirementminus 500 kcal) and either EC or placebo for 20 weeks in a random-ized, double-blinded placebo-controlled trial.10 Adolescents whoweighed <80 kg took 1 tablet, 3 times per day (100 mg/10 mg),whereas adolescents who weighed >80 kg took 2 tablets, 3 timesper day. There were three dropouts (girls) from the placebo group.

The age, weight, and BMI values (mean range) of the placeboand EC-treated groups were, respectively, 16.0 years old(14.3–17.6 years old) and 16.0 years old (14.2–17.7 years old),103.0 kg (77.2–126.4 kg) and 104.8 kg (69.8–150.2 kg) kg, 35.2kg/m2 (28.3–42.3 kg kg/m2), and 36.5 kg/m2 (31.3–51.8 kg/m2).

The decrease in relative body weight, BMI, and body fat(measured by bioelectric impedance) was significantly (P <0.05)greater in the EC-treated group (mean ± standard deviation;14.4 ± 10.5 percent, 2.9 ± 1.9 kg/m2, 6.6 ± 6.0 kg) than in theplacebo group (2.2 ± 5.8 percent, 0.5 ± 1.6 kg/m2, 0.5 ± 2.7 kg).Relative body weight decreased by more than 5 percent in 81percent of the EC-treated group but only in 31 percent of theplacebo group.

Adverse events were negligible and did not differ between theEC-treated and placebo groups. Withdrawal symptoms weremild and transient and their frequency and severity were not dif-ferent between the treatment and placebo groups. This pilotstudy showed that EC can be a safe and effective compound fortreating obesity in adolescents.

Summary of the ResearchThe vast majority of the published research3–10 consists of dou-

ble-blinded and placebo-controlled studies. What is interesting inall these published studies is the apparent lack of serious side-effects associated with EC supplementation used as an antiobesi-

ALTERNATIVE & COMPLEMENTARY THERAPIES—APRIL 2004 61

Ephedra (Ephedra sinica). Photograph ©2002 by Holly Shul Vogel,Green Farmacy Garden, Fulton, Maryland; reprinted with permissionfrom Yarnell E, Abascal K, Hooper CG. Clinical Botanical Medicine.Larchmont, NY: Mary Ann Liebert, Inc., 2003:210.

ty drug at specific dosages. Furthermore, prior work had demon-strated that ephedrine alone or caffeine alone were not signifi-cantly effective for inducing weight loss—hence the interest inthe EC combination.

All studies reviewed concluded that the EC combination is safeand effective for treating very overweight or obese individualsthat are otherwise healthy. The study on adolescents is particu-larly interesting because the EC combination was deemed to besafe and effective for this population.10

There are no well-documented serious adverse effects reportedfor EC used at appropriate levels in very overweight or obeseotherwise healthy individuals.3–10 As noted above, there is evena double-blind, placebo-controlled trial that used EC to treatobese adolescents with an excellent outcome and negligibleadverse effects that did not differ between the placebo and treat-ment groups.10 Many researchers concluded that ephedrine orEC combinations are safe and effective for inducing weightloss.3–10 So what is the problem?

The Pseudoephedrine Problem

Pseudoephedrine has been studied as a weight-loss agent andis apparently ineffective as noted in the papers covering theabovementioned research.3–10 There are no studies combiningthe effects of pseudoephedrine and caffeine. One must remember

that ephedrine alone was not shown to be as effective for induc-ing weight loss unless ephedrine was combined with caf-feine.3–10

The side-effects reported for EC are not unlike those reportedwith OTC cold, sinus, and flu remedies, which contain pseu-doephedrine. Yet, unlike some the prescription drugs used forinducing weight loss, EC does not appear to pose any seriousside-effects when used as directed according to the studies Ireviewed.3–10

Confusing Pseudoephedrine with EphedraIn Natural Business, a headline in May 2001 read: “More

Ephedra Lawsuits Likely, Experts Say.”12 The article was about alawsuit filed by a woman who reportedly suffered from a strokecaused by a weight-loss product that reportedly containedephedra. She was awarded millions of dollars in punitive andcompensatory damages. On closer inspection and upon analysisof the supplement, it was discovered that the product she tookactually contained added unlabeled pseudoephedrine.

However, despite the scary headline, the writer of the articlestated that “ephedrine and its relationship to heart attack andstroke have shown that ephedrine is safe when used at the rec-ommended dosage of 25 mg or less.” Because the amount ofpseudoephedrine added to the product was beyond that natural-ly occurring in ephedra, the writer concluded that it was the


Ephedra in the Lay PressWhat Are Patients Being Told?

One of the more measured articles in the lay media on ephedra (Ephedra sinica), published in a recent issue of The New York Times, offeredreaders a somewhat more balanced perspective but still lacked some essential coverage.

Noting that ephedra can use will still be permitted for acupuncturists, herbalists, and practitioners of Oriental medicine, the article highlightedthe fact that the ban only applies to dietary supplements, raising some interesting but unanswered questions.

While stating that the supplements were “linked to heart attack, stroke, and sudden death because of their ability to raise blood pressure,increase heart rate and speed up brain activity,” the article did not state exactly what the “links” were to the serious diseases cited. Were theylinked this way in the popular press? By politicians? By a few lawsuits? By misidentification? Readers were not told.

The author did include observations by practitioners who are skilled in the use of ephedra, including:• Use of a specific antidote (white tiger decoction) to counteract side-effects• Use of ephedra to treat asthma and coughs• Use of ephedra with a complex of other herbs that moderate its effects• Awareness of contraindications for patients who have high blood pressure or those who are pregnant.Interestingly, the herbalists written about in the article said that they would not choose it as a weight-loss agent although the FDA ban would

not exclude this possibility.The ephedra–caffeine combination was noted but little was said about it.The article noted that companies that made the weight-loss supplements have been faced with lawsuits regarding ephedra and had insurance

premiums raised for all their products, making the companies more likely to stop making the ephedra products. However, the article did notprovide information about what the findings were in the lawsuits, for example, if perhaps, the problems stemmed from misuse of the products orfrom use of products with pseudoephedrine. Nor did the author state how many companies were involved; thus, readers did not learn how“widespread” the problem actually is.

Although it was noted that unavailability of the products may cause some consumers to purchase and misuse over-the-counter (OTC) asthmamedications that contain ephedrine, the article did not suggest who these consumers might be. No mention was made of the fact that there is anobesity epidemic, causing more people to have concerns about how much they or their spouses and children weigh. Were more women likely tobe affected perhaps, being that women are usually under more pressure socially to lose weight? What would the effect be on children? Finally,the article did not make note of the fact that the OTC products that might be used to replace ephedra-based products have worse adverse-effect profiles than ephedra does.

While mildly questioning the appropriateness of the ban, the article did not really provide readers with enough usable scientific information tomake a reasoned judgment about the ban.

Duenwald M. Despite F.D.A. Ban, ephedra won’t go away. The New York Times, February 17, 2004:F5.

unlabeled added pseudoephedrine that may have been responsi-ble for this serious-side effect. Indeed, the cause of the stroke inthis particular patient was later believed to be from unlabeledpseudoephedrine.

While the title of this article mentioned “Ephedra,” the lawsuithad virtually nothing to do with this well-known plant and hadeverything to do with the product being laced with pseu-doephedrine.

Pseudoephedrine is an OTC drug, cannot be added to anydietary supplement, and has no place in treating weight loss.Any dietary supplement company that laces its product withpseudoephedrine is violating the Dietary Supplement Health andEducation Act.

Adverse Events Associated With PseudoephedrineSome adverse-event data on pseudoephedrine has been report-

ed but it is not easy to find articles on the FDA’s Web site1,2 notethat pseudoephedrine is associated with fewer cardiovascularand central-nervous-system effects than ephedrine. However,upon closer inspection of some of the documents.2,13 it becomesclear that even proper use of pseudoephedrine can result in sig-nificant side-effects and that inappropriate use can result indeath.

A case report13 that also reviewed the scientific literature foradverse events reported for pseudoephedrine stated: “Althought h i s d r u g c o m b i n a t i o n ( d e x t r o m e t h o r p h a n a n d p s e u -doephedrine) is generally considered quite safe when it utilizedin recommended doses, overmedication can result in seriousneurologic and cardiovascular abnormalities that occasionallycan be life-threatening.”13 This particular report highlighted acase of a 2-year-old child who developed hyperirritability, psy-chosis, and ataxia after being overmedicated.

This report13 also reviewed the literature for other adverseevents and highlighted the fact that more than 170 OTC prepara-t ions contain sympathomimetic agents such as phenyl-propanolamine and pseudoephedrine and, yet, the medicalliterature has few reports of adverse events although such eventshave been reported to agencies and emergency rooms.

Another case report described a pregnant woman who tookrelatively high doses of two OTC cold remedies and devel-oped ventricular arrhythmia and presyncope. This paperreviewed the literature for adverse events associated withpseudoephedrine, confirmed that there are safety issues con-cerning pseudoephedrine, and noted that underreporting is aproblem.

Along with some of the approval data2 on the FDA’s Web sitefor cold and flu remedies that contain pseudoephedrine andibuprofen, data are presented on poisoning in children. Ibupro-fen poisoning more than doubled from 1994 to 1999 and pseu-doephedrine poisoning increased 30 percent from 1555 exposuresin 1994 to 1508 exposures in 1999. There was one death reportedin 1994 and another in 1997.

In the same article, adverse events reported for a study exam-ining pseudoephedrine versus ibuprofen/pseudoephedrine com-bination effects in children were included. There was no placebo.The results revealed that 50 percent of the subjects in the pseu-doephedrine-alone group reported asthesia, pain, abdominalpain, increased appetite, rash, and hypertension. Similar adverseevents were reported in the ibuprofen/pseudoephedrine groupand were rated as mild in severity, yet, there were no data indi-cating that the events were, in fact, milder.

In addition, in the drug combination group, 27.3 percent ofsubjects reported adverse events, including chills, rhinitis, andotitis media. The writers of the report concluded that there is “lit-tle abuse potential” for these OTC drugs and stated: “Except forrhinitis and asthenia, all adverse experiences were considerednot to be related to [the] study medication.”

As a scientist I was shocked to find this conclusion when therewas no placebo group. Apparently the researchers were morethan just researchers—they were also clairvoyant! Moreover,these adverse events statistics were considered to be perfectlyacceptable for children. It was also reported on the FDA Web site,in these same documents, that pseudoephedrine may cause birthdefects.† This is quite startling, to say the least.

Nonephedrine OTC Drugs AcceptedDespite Poorer Safety Profiles

In light of this ban on ephedra, it is instructive to consideradverse events associated with other common OTC products thathave been sold for years.

AcetaminophenThere are numerous reports of acetaminophen toxicity.14,15

Acetaminophen gained widespread popularity in the 1960s as aless-toxic, analgesic antipyretic agent than aspirin.16 Ironically,acetaminophen is now the second leading cause of toxic drugingestion in the United States. Acetaminophen toxicity is thus areal burden on our health care system and hepatotoxicity thatresults from acetaminophen overdose has become an importantproblem.

Researchers identified 93 consecutive patients, hospitalized foracetaminophen toxicity over a 52-month period from 1996 to1999 in an urban county hospital. A retrospective case-controlanalysis was conducted, using the data obtained from the hospi-tal’s medical records. Acetaminophen accounted for 7.5 percentof all cases of poisoning admitted during this period.

Of the 93 patients, 80 were classified as suicidal and 13 hadaccidentally poisoned themselves in attempts to relieve pain. Theratio of females to males was found to be 2:1. Of the 93 patientsstudied, 88 were admitted to the hospital’s intensive care unit foran initial 24–48 hours of monitoring.

Peak acetaminophen levels were higher in the suicidal over-dose group (mean 121.7 mg/L ± 97.0 mg/L versus 64.5 mg/L ±61.8 mg/L, P <0.05) than in the accidental-use group. In spite ofthis, peak aminotransferase levels >1000 IU/L were more oftenseen in the latter group (39 percent versus 12%, P <0.05). Hepaticcoma and death were seen more often in the accidental overdose


†To access these documents on the FDA Web s i te , v is i t www.fed.gov/cder

group (15 percent versus 0 percent, P <0.05). Interestingly, chron-ic alcohol abuse was also more frequent in the accidental-over-dose category (39 percent versus 18 percent, P = 0.05).

These statistics from just one urban county hospital demon-strate clearly the abuse potential for acetaminophen and the writ-ers of this paper acknowledged the agent as the second leadingcause of toxic drug ingestion in the United States.

Overdoses of acetaminophen are, indeed, an increasingly com-mon cause of acute liver failure.16 A study on this study exam-ined knowledge about acetaminophen therapeutic usage andtoxicity among emergency department visitors. Adult visitors inan urban/suburban emergency department hospital waitingroom were surveyed via a questionnaire; 103/138 (75 percent) ofthe patients who were approached completed the questionnaire.Eighteen (18) percent of the subjects reported that they believedthe maximum daily acetaminophen dose is ≥5 g. When asked toidentify acetaminophen-containing products, only 13 percentchose Percocet and 6 percent chose Vicodin. Motrin was the med-ication respondents most frequently believed to containacetaminophen. Tylenol was another product that tended to berecognized by patients.

Fifty-two (52) percent of the respondents did not knowacetaminophen toxicity causes liver damage. No statistically sig-nificant differences existed with regard to gender, race and age;more female subjects routinely inform doctors about theiracetaminophen use compared to males (64 percent versus 30 per-cent). Some study subjects had very limited knowledge regard-ing therapeutic use of acetaminophen and its toxicity.

Other Nonsteroidal Anti-Imflammatory DrugsIn reviewing the data on nonsteroidal anti-inflammatory drugs

(NSAIDs) a review paper15 noted that, each year, approximately107,000 individuals are hospitalized for gastrointestinal (GI) com-plications derived from NSAID use and that, among patientswith arthritis alone, at least 16,500 die as a consequence ofNSAID use. These are conservative estimates because they nottake into account GI complications occurring in patients whotake OTC NSAIDs. If one considers that, every year, in the Unit-ed States, there are more than 70 million prescriptions written forNSAIDs and more than 30 billion tablets are sold OTC, the num-ber of injuries and death caused by only one type of adverseevent related to NSAID use—GI complications—reaches stagger-ing figures.

Cough and Cold MedicinesAccording to a paper on the use of OTC cough and cold medi-

cations in children,17 these preparations are marketed widely forrelief of common cold symptoms and, yet, studies have failed todemonstrate the benefit of these medications for young children.In addition, OTC medications can be associated with significantmorbidity and even mortality in either acute overdoses or whenadministered in correct doses chronically.

Physicians often do not inquire about OTC medication use andparents (or other caregivers) often do not perceive OTCs as medi-cations. The authors of this study presented 3 cases of adverseoutcomes over a 13-month period, including 1 death, as a resultof OTC cough and cold medication use. The authored exploredthe toxicities of OTC cough and cold medications, discussedmechanisms of dosing errors, and suggested that physiciansshould be more vigilant in inquiring specifically about use OTCswhen evaluating an ill child.

Ibuprofen, Aspirin, and ParacetamolA PAIN [Paracetamol, Aspirin, Ibuprofen New tolerability]

study18 was a blinded, randomized comparison of the tolerabili-ty of OTC analgesics for treating common types of acute painencountered in a community. The authors of this review com-pared the toxicity of aspirin, paracetamol, and ibuprofen.18

A total of 8677 adults were randomized to treatment withibuprofen 1200 mg per day, paracetamol 3 g per day, or aspirin 3g per day for 1–7 days. The most common indications for treat-ment were musculoskeletal conditions (31–33 percent), colds orflu (19–20 percent), backache (15–17 percent), sore throat (11–12percent), and headache (10–11 percent). Significant adverse eventswere more common with aspirin (10.1 percent) than ibuprofen(7.0 percent) (P<0.001) or paracetamol (7.8 percent). Significant GIevents were less frequent with ibuprofen (4.0%) than with aspirin(7.1 percent, P<0.001) or paracetamol (5.3 percent) (P = 0.025). Forevery 100 patients treated, 5 more will experience significantadverse events if they are taking aspirin rather than ibuprofen,and four more than if they were taking paracetamol.

The authors concluded that low-dose ibuprofen is as effectiveas aspirin and paracetamol for the indications normally treatedwith OTC medications and ibuprofen is associated with the low-est risk of GI toxicity of any NSAID. By contrast, the researchersnoted that even low-dose aspirin is associated with an apprecia-ble risk of GI toxicity. The researchers also said that paracetamolis well-tolerated and effective for treating mild-to-moderate painbut observed that there is growing concern about a possible riskof GI toxicity and a possible link with asthma in children.

Conclusions

In reviewing many double-blind placebo controlled studies it isclear that EC combinations are safe when used as directed in veryoverweight and obese adults and adolescents when used as direct-ed (200–600 mg of caffeine and 20–60 mg of ephedrine) withoutadverse effects.3–10 The studies were conducted on healthy indi-viduals who did not have hypertension, liver dysfunction, or othermedical conditions that could preclude them from taking EC.

Some of the prescription weight-loss drugs such as phenflu-ramine have been removed from the market as a result of unac-ceptable risk–benefit profiles, while other agents, such as orlistat,have mixed reports of effectiveness and tolerability in the scien-tific literature.‡

Most of these studies on ephedrine or ephedrine-containingproducts have been conducted over a 6-month period. But mostprescription weight-loss drugs, with the exception of sibutramine


‡For an excellent review of prescription weight-loss drugs, visitwww.weight-loss-i.com/obesity-drug-treatment-weight-loss.htm

and orlistat, are not intended for use of more than a 6-monthperiod. Some drugs are known to lose their effectiveness after 6months and are not recommended for past this time period.

Longer than 6 months of use should also monitored very cau-tiously when using EC, or, perhaps, individuals should beencouraged to reduce the dose as their weight decreases. EC cer-tainly has the potential for abuse with the “more is better” atti-tude of the American public and therein lies the danger.

Ephedrine may not be safe for everyone—nor are many OTCdrugs. Responsible companies have put warning labels on theirweight-loss supplements containing EC. Individuals who havehypertension or liver conditions should be told to check withtheir physicians before taking the products.

Ephedrine abuse (as occurs with many OTC products) caninduce serious and even fatal side-effects. But, even given thispossibility, the statistics about abuse of EC, and resulting death,become infinitesimal 14–16 compared to those for aspirin, ibupro-fen, and paracetamol. Furthermore, acetaminophen is the secondleading cause of toxic drug ingestion in the United States and isone of the major causes of liver transplants.13,14 Clearly, none ofthese OTC products have been removed from the marketplacedespite staggering statistics on abuse, toxicity, and death—partic-ularly when compared to EC.

And some physicians practice off-label uses of other drugs,such as antidepressants, which are not approved for that pur-pose.

There has been no political or media promotion of the potentialtoxicity of these products despite the staggering statistics aboutthe dangers involved with their use. No dietary supplementshould ever be removed from the market as a result of politics orpressure from special interests.

It is interesting that, to date, there is no truly safe and effectiveprescription weight-loss drug. And gastric bypass is being pro-moted by celebrities as a viable option for treating obesitydespite the serious consequences of this surgery, including therisk of death.

If one calls FDA, there is a prompt on the phone loop forephedrine adverse events and then all other products are justlumped into another category of drug adverse events.

The media has highlighted ephedrine constantly so this agentis now a highly recognized substance. One may even surmisethat the media and politicians have produced mass hysteria.

It is clear that the warning labels on OTC products are not get-ting the point across to the public either, and I agree that thewarning labels on EC products were inadequate. In 1997, anexpert panel convened by the FDA came to the conclusion thatthe ephedrine issue can be handled via better warning labels onproducts that contain ephedrine —not by removal from the mar-ketplace.

An excellent review in HerbalGram19 eloquently disputed theadverse-reaction reports that the FDA relied upon when makingthe decision to ban ephedrine. This review showed that there wasmisinterpretation of the data.

I would strongly urge that interested parties read this paperwritten by experts from the American Botanical Council, AustinTexas. The best solution would have been to require an insert in

all weight-loss products that contain EC: The insert could explainclearly ephedra’s risk–benefit profile and potential adverseeffects and put this information, together with other warnings, inprint that is legible. This insert could also include wording thatsuggests that the product is best used according to professionaladvice.

Many potentially dangerous OTC products have labels that arenot readable because the print is so small. Because I do not useany ephedrine containing products in my practice for weightmanagement, I would not be personally affected by the ban. Ithas been estimated that obese people have, on average, nearlytwice the average risk of health problems as normal-weight indi-viduals and more chronic health problems than smokers, heavydrinkers, or people who are poor.20 Therefore, denying EC com-binations to these patients, for whom the combinations hold littleto no risk if used appropriately, is simply a travesty of science. Iam also personally concerned about the future of dietary supple-ments that can assist in weight management along with diet andexercise, such as green tea (Camellia sinensis), bitter orange (Citrusaurantium), and 5-hydroxytryptophan. It appears that weight-management supplements are a particular target of politiciansand government agencies. ■

References1. U.S. Food and Drug Administration Center For Food Safety andApplied Nutrition, MMWR Report from the Centers For Disease Controland Prevention. Adverse Events Associated with Ephedrine-ContainingProducts—Texas, December 1993–September 1995. August 16, 1996.Online document at: www.cfsan.fda.gov/~dms/ds/ds-ephe2.htmlNovember 16, 2000. 2. U.S. Food and Drug Administration, Center For Drug Evaluation andResearch, Application 21-373. www.fda.gov/cder search word “pseudoephedrine.” Online documents at: www.fda.gov//cder/nda/200221373_Ibuprofen%Pseudoephedrine_biopharmr.pdf November 20, 2002;and www.fda.gov/cdr/foi/nda/2002/21/273_Ibuprofen%Pseudoephedrine_mdr.pdf November 20, 2002.3. Greenway FL. The safety and efficacy of pharmaceutical and herbalcaffeine and ephedrine use as a weight loss agent. Obesity Rev2001;2:199–211.4. Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Nasser JA,Strauss R, Meredith T. Herbal ephedra/caffeine for weight loss: A 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Dis-ord 2002;26:593–604.5. Colker CM, Kalman DS, Minsch A. Ephedrine, caffeine and aspirinenhance fat loss under non-exercising conditions. J Am Coll Nutr1997;16:a116.6. Astrup A, Breum L, Toubro S, Hein P, Quaade F. The effect and safetyof an ephedrine/caffeine compound compared to ephedrine, caffeine andplacebo in obese subjects on an energy restricted diet: A double blindtrial. Int J Obes Relat Metab Disord 1992;16:269–277.7. Astrup A, Buemann B, Christensen NJ, Toubro S, Thorbek G, Victor OJ,Quaade F. The effect of ephedrine/caffeine mixture on energy expenditureand body composition in obese women. Metabolism 1992;41:686–688.8. Toubro S, Astrup A, Breum L, Quaade F. The acute and chronic effects ofephedrine/caffeine mixtures on energy expenditure and glucosemetabol i sm in humans . In t J Obes Re la t Metab Disord . 1993 ;17(suppl.3):S73–S77;discussion S82.9. Daly PA, Krieger DR, Dulloo AG, Young JB, Landsberg L. Ephedrine,caffeine and aspirin: Safety and efficacy for treatment of human obesity.Int J Obes Relat Metab Disord 1993; 17(suppl.1):S73–S78.10. Molnar D, Torok K, Erhardt E, Jeges S. Safety and efficacy of treat-ment with an ephedrine/caffeine mixture: The first double-blind placebo-


controlled pilot study in adolescents Int J Obes Relat Metab Disord2000;24:1573–1578.11. Toubro S, Astrup AV, Breum L, Quaade F. Safety and efficacy of long-term treatment with ephedrine caffeine and ephedrine/caffeine mixture.Int J Obes Relate Metab Disord 1993;17(suppl.1):S69–S62.12. More ephedra lawsuits likely. Natural Business, May 2001. 13. Roberge RJ, Hirani KH, Rowland PL, Berkeley R, Krenzelok EP. Dex-tromethorphan and pseudoephedrine-induced agitated psychosis andataxia: Case report. J Emerg Med 1999;17:285–288.14. Singh G. Recent considerations in nonsteroidal anti-inflammatorydrug gastropathy. Am J Med 1998;105(1B):31S–38S.15. Gyamlani GG, Parikh CR. Acetaminophen toxicity: Suicidal vs. acci-dental. Crit Care 2002;6:155–159.16. Chen L, Schneider S, Wax P. Knowledge about acetaminophen toxici-ty among emergency department visitors. Vet Hum Toxicol 2002Dec;44(6):370-3. 17. Gunn VL, Taha SH, Liebelt EL, Serwint JR. Toxicity of over-the-counter cough and cold medications. Pediatrics 2001;108:E52. 18. Moore N. Forty years of ibuprofen use. Int J Clin Pract Suppl2003;135:28–31.19. Kingston R, Blumenthal M. A rational perspective on adverse events

reports on herbs: Misinterpretation of adverse reactions tabulated in theTESS annual report of the American Association of Poison Control Cen-ters as they related to ephedra dietary products . HerbalGram2003;60:48–53.20. Lieberman S. Natural methods for accelerating weight loss. AlternComplement Ther 2003;9:307–311.

Shari Lieberman, Ph.D., C.N.S., F.A.C.N., is a research scientist andindustry consultant based in New York City and Hillsboro, Florida.

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Should Ephedrine Be Banned in Weight-Loss Products?