The conclusion of the study, following approximately a quarter-million people for greater than 1,000,000 per- son-years, was that the use of Letigen (20mg ephedrine + 200mg caffeine) as prescribed (one to four times daily), “was not associated with a substantially increased risk of adverse cardiovascular outcomes in this study.”19It is interesting that the conclusion was stated in that man- ner, by stating that there was no “substantially increased risk.” This suggests there may be a hidden risk, but in fact, if any effect was suggested by the data in the study, it was that Letigen may actually have provided a statisti-
cally protective effect. Of course, the authors rightly
noted that the findings are not evidence that Letigen was protective. As Letigen patients were being treated for weight-management issues and screened for pre-exist- ing health conditions, they may have been healthier as a group than the controls. This is called “confounding by contraindication.” Obviously, those with evident heart disease, cancer or other conditions would not be pre- scribed a stimulant-based weight-loss drug.
This study is impressive due to the comprehensive recording of details, immense number of subjects, follow- up and completeness. Its findings can be considered con- clusive within the limitations of the study. As noted earlier, Denmark is a small country in terms of population and geography. The findings may not apply to other races or
cultures. The ephedrine and caffeine combination was pre- scribed by a physician, dispensed from a pharmacy, manu- factured using the Danish equivalent of good manufactur- ing practices and administered to a population that was screened for health problems prior to exposure. In contrast, the U.S. experience involved herbal products sold in an unsupervised fashion in the retail market.
Why then is there such a discrepancy between the find- ings in the Danish study and the furor raised about ephedra products in the U.S.? As mentioned above, ephedrine expo- sure in the U.S. was very undisciplined and often occurred in herbal products standardized for ephedrine content. Though many companies were scrupulous in verifying the raw material and manufacturing process to guarantee the amount of ephedrine present per serving, others took the low road, concerned only about cost/profit and marketed a loosely controlled product. Herbal ephedra was often con- sidered to be equivalent to ephedrine, but in fact it is much different. Ma huang, the herbal source, contains a variety of alkaloids (a chemical class that includes ephedrine as well as pseudoephedrine, synephrine and other bioactives). It is entirely possible that failing to account for the additional stimulant effect of the chaperone alkaloids could have exposed consumers to a greater amount of beta-adrenergic stimulation than was anticipated.21Obviously, if a different herb adulterated the product or the capsules were “spiked” with ephedrine, then the situation becomes even more complex. Another factor is the American lifestyle…the use of numerous drugs and supplements makes the possibility of a drug interaction likely, and the general health of Americans is poor in comparison to the Danes, as exempli- fied by the American obesity epidemic.
Recall as well, that nearly every product on the market included caffeine and other ingredients in addition to the ephedrine content. This introduced the possibility of an adverse interaction or misdosing each ingredient. Further, as caffeine is a cheap additive, it was simple to “spike” products with caffeine to give the consumer a jittery feel- ing. Sadly, consumers sought these products out, as they mistakenly believed they were more effective than appro- priately dosed products. The inclusion of less well-studied additives, and their effect on ephedrine/caffeine action or clearance, increased the potential for an adverse effect.
Yet, despite the extremely liberal use of these products, reports of adverse effects were relatively rare. Health cen- ters stated that ephedrine-related complaints were more common than other OTC products, but recall that these products were much more popular than other OTC prod- ucts.11,15Further, the toxicity of ephedrine/caffeine is immedi- ate and easily sensed (nervousness, rapid heart rate, tremor, sleep or mood disturbance). Obviously, a properly dosed pharmaceutical alternative, similar to Letigen, would alleviate many of these problems.
It is interesting that ephedrine, pseudoephedrine and PPA have been labeled as being high-risk drugs due to their cardiovascular effects, and the chronic (long-term) use forms have been pulled from the shelves. However, the greatest risk reported in the Danish study occurs during acute use, in naïve subjects. This is the scenario that would
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be faced in the cough and cold products that are still avail- able on the market. Add on the sudden increase in blood pressure that occurs during coughing or sneezing, and it makes it more alarming to see those products remain, as opposed to chronic-use products.
Science does not appear to agree with the political pun- dits who have judged ephedrine/caffeine and found it to be guilty of causing public harm. It is the nature of American politics to react rather than respond, and when public con- cern was adequately raised, the verdict was decided. Is it possible, though, that ephedrine/caffeine was a “fall guy?” Many people have pointed fingers at conspiratorial theo- ries— some with merit, others being more dubious.
A maxim used in criminal investigation is cui bono (who benefits). Who would benefit from removing a safe and effective weight-loss product from the market? It is certainly not the overweight individual seeking to lose weight with- out the expense, inconvenience and risk (as has been shown with fen-phen, rimonabant and other pharmaceuti- cal drugs) of needing to visit a physician’s clinic and obtain a prescription. It is certainly not the athlete (not competing in an organization that bans ephedrine) looking for a (assumably) safe and effective ergogenic. It is certainly not society who bears the financial burden of treating obesity and obesity-related conditions.
Who then? Accusing fingers point at big pharma. The pharmaceutical industry takes the brunt of much of America’s ire…necessary drug therapy is often prohibitively expensive, especially for noninsured people; quality-of-life drugs are not developed or are restricted either by legisla- tion or physician resistance; allegations of bribes, inappro- priate influence with the FDA, and numerous FDA-approved drugs causing harm or death have eroded public confi- dence in the pharmaceutical industry. Yet, it is clear that any pharmaceutical company that could produce a cost-effec- tive weight-management drug or drug combination would make billions of dollars. The only barrier to herding the American obese to questionably effective and marginally tolerated drugs such as alli®was the presence of the block-
buster brand Dexatrim®(PPA) and the many
ephedrine/caffeine products which were providing con- sumers with subjective benefit and measurable weight loss. When ephedrine and PPA were removed from the market, the marketing potential for any effective OTC weight-loss product or prescription product escalated dra- matically. Sadly, such a product has not been introduced since that time.
Another possibility spoken of more quietly in nonscien tific circles is a serious social issue. Methamphetamine is a stimulant-class drug. Historically, it was trafficked by biker gangs and other elements that operate on the fringe of soci- ety. Though similar in effect to cocaine, it was much cheaper and referred to as “trailer park coke,” in addition to other slang terms (meth, crystal, crank, etc.), as most users were white and lower income. However, as enforcement against cocaine gained some degree of success, drug-seeking indi- viduals discovered methamphetamine whose supplies were initially unhampered. As the numbers of methamphetamine users rose and its effects touched “middle-class America,”
enforcement turned its eye on that problem.
It was quickly discovered that methamphetamine distri- bution was going to be more difficult to control, as it could be synthesized in crude “bathtub” labs and the intermedi- ate used in production was easily obtained at the local health store, truck stop, pharmacy or over the Internet. That intermediate is ephedrine (pseudoephedrine can also be used).22It is suggested that the real danger involving OTC ephedrine had little to do with ephedrine-based drug reac- tions, but rather with its use in the cottage-industry meth labs hidden in garages, sheds, trailers and basements throughout America. Unfortunately, the easy answer for enforcement agencies appears to have been to close access (legitimate and illegitimate) to ephedrine.23,24However, as people living in rural areas know, methamphetamine use continues to be a problem; much of the ephedrine used by larger, better organized gangs in production crosses the border illegally from Mexico.25
The Danish study uncovers new evidence that demands an appeal of the status of ephedrine/caffeine for weight loss. The need for an affordable, convenient, safe and effec- tive weight-loss product remains as the current options are all lacking. Perhaps the Danish model would be best, to make a Letigen-like drug, available only by prescription to minimize the risks of diversion to methamphetamine pro- duction, abuse and use by people with clinically evident contraindications. Further, educating the consumer to be aware of signs of toxicity or adverse effects, particularly during the first month of use, is critical to minimize the potential for harm.
Ephedrine/caffeine has been tried and found guilty of harm by a zealous FDA in the court of public opinion. One
very important comment from the Danish study deserves to be boldly acknowledged. As suggested by
the Danish authors in their published study, most “evidence” of adverse effects associated with
ephedrine/caffeine use appears to be based on sponta- neous reports, and does not withstand scientific scrutiny.
Much like eyewitness testimony that condemns an inno- cent man, whose innocence is later proven through DNA analysis of the evidence, this study calls for a re-assess- ment of ephedrine/caffeine for weight management. Case reports involving hundreds, even thousands of ephedrine users are statistically (not emotionally) meaningless due to the huge number of users in the U.S. and abroad. The new evidence uncovered by a “Dream Team” of scientists, and data in the country of Denmark, suggests that an innocent sits on death row. Hopefully, some avenue of appeal will be made available to reevaluate this case.
References:
1. Blanck HM, Khan LK, et al. Use of nonprescription weight loss prod- ucts: results from a multistate survey. JAMA, 2001 Aug 22-29;286(8):930-5. 2. Malchow-Moller A, Larsen S, et al. Ephedrine as an anorectic: the story of the ‘Elsinore pill’. Int J Obes, 1981;5(2):183-7.
3. Dulloo AG, Miller DS. Ephedrine, caffeine and aspirin: “over-the- counter” drugs that interact to stimulate thermogenesis in the obese.
Nutrition, 1989 Jan-Feb;5(1):7-9.
4. Krieger DR, Daly PA, et al. Ephedrine, caffeine and aspirin promote weight loss in obese subjects. Trans Assoc Am Physicians, 1990;103:307- 12.