Written by justis berg
28 March 2011
 

Ephedrine/Caffeine Combo:
New Study Says “Not Guilty”

In this fast-paced world, where printed news media is losing audience because it is too slow in reporting when compared to television outlets, and absolutely stagnant in comparison to instantaneous release on the Web, headline-grabbing controversies appear and disappear in days, even hours. The urgency of more current problems tends to displace yesterday’s crises in the minds of the public (and programming of the media). Thus, it is of little surprise that people have forgotten the prominence of ephedrine/caffeine-based weight-loss products and the hotly debated allegations of harm that preceded the ban on ephedrine, pseudoephedrine and ephedra (ma huang) from the market.  The following is a somewhat brief and superficial review of the events that defined that time, acknowledging that a few sentences do not adequately convey the entirety of related issues. Ephedrine-based, over-the-counter (OTC) products including herbal ephedra-based products were being purchased in record amounts, as weight-conscious consumers found the products to be effective in curbing appetite, boosting energy and burning calories.1 Numerous peer-reviewed studies and reviews confirmed the efficacy of the ephedrine/caffeine combination in causing weight loss, increasing resting energy expenditure (metabolism) and reducing appetite.2-8 The beta-adrenergic-stimulating nature of the products also provided a performance boost to athletes, increasing its appeal and expanding its market to normal-weight, active individuals.9 Unfortunately, the stimulating effect also appealed to young adults and adolescents for fighting fatigue and as a party drug.10 Sales of ephedrine-containing products established the ingredient as the keystone of the top-selling products in the highly lucrative weight-loss category. Estimates of use are inherently inaccurate, but it is not unreasonable to accept that 33 percent of young adults had some exposure to such products, given that overweight and obesity was affecting more than 50 percent of the nation at that time.11


However, obesity was just being identified as a significant condition poised to dramatically affect public health and the financial welfare of the nation; certain companies were violating the spirit of DSHEA (Dietary Supplement Health and Education Act) by adulterating supplements with pharmaceutical drugs; unscrupulous advertising was tainting the industry’s reputation; and certain companies were marketing ephedra-based products as a party drug to high-risk youth and young adults. Ephedrine was already a regulated drug within sports organizations, being placed on the banned substance list by the NCAA in 1997 and prior to that by the IOC/WADA (1994) for its stimulant-based ergogenic properties. Though relatively few well-known athletes were sanctioned, a small number were banned from competition. It was during this time that the topic of adulteration (intentional or unintentional) in OTC and supplement production was raised as an element in the athletes’ (largely unsuccessful) appeals of the bans.12 As ephedrine and ephedra use became increasingly prevalent, and its use/abuse was associated with mood, behavior and health problems, watch groups became rightfully anxious about its presence as an unregulated stimulant accessible to minors. Further, the potential threat of cardiovascular harm or death was raised by concerned individuals and health professionals.11 Beta-adrenergic stimulants are capable of inducing dangerous elevations in blood pressure or irregular heart rhythms in sensitive individuals or when dosed/consumed in excess of the therapeutic range. As often happens, once public awareness was raised, numerous reports were registered in the media and public forums. Public health watch agencies released statements calling for a ban of ephedrine-containing products in the interest of the public’s welfare.13 The well-publicized deaths of users of ephedra-containing products fortified public support for withdrawing the products from retail shelves.14 The level of attention and implied risk in ephedra-containing products, along with the punitive damages awarded in civil litigation, caused insurers to raise premiums such that scrupulous manufacturers withdrew ephedra-containing products from their product line prior to the formal ban handed down from the U.S. Food & Drug Administration (FDA) in 2004.15

In the FDA’s statement, available on their website, are two quotes that would be contested by many who followed the research and reports of ephedrine-related weight-loss products. “There is strong scientific evidence of harm associated with the use of ephedra products” and “The agency found that supplements containing ephedra show little evidence of effectiveness, except for short-term weight loss.”15 A following comment, “These reactions have been linked to serious health problems, including heart ailments and strokes,” serves as the primary reason for the passage of the 2004 rule that removed ephedra-containing products from the retail market. Finally, "This final rule will protect consumers by ensuring that these dangerous products are removed from the market and never sold," says FDA Commissioner Mark B. McClellan, MD, PhD. Clearly, the FDA is certain that ephedrine and ephedra-alkaloids are inherently dangerous chemicals that should not be placed within reach of consumers. Of course, this does not take into account ephedrine and pseudoephedrine contained within over-the-counter medicines that treat asthma, nasal congestion and minor eye irritation. However, as those products are regulated in most states to be dispensed only from “behind the pharmacy counter” and only in amounts less than a defined threshold, the risk of adulteration or abuse are lessened considerably.
Thus, the existence of ephedrine-containing and pseudoephedrine-containing weight-loss products were relegated to history. Previously (2001), phenylpropanolamine (PPA) experienced a similarly rapid and controversial withdrawal from the market, despite the long-standing success of Dexatrim® and like products.16 A study published in The New England Journal of Medicine concluded that PPA was associated with an increased risk of hemorrhagic stroke in women, causing the FDA to recommend the withdrawal of all PPA-containing products from the retail market.17 This move was vigorously debated, as many scientific experts contested the conclusion and study design of this and a related PPA review.18 Interestingly, the same issue of the NEJM contained a preliminary report of 140 cases of adverse events related to ephedrine.11

Witch-Hunt Mentality?
The door closed on PPA, ephedrine and pseudoephedrine during that brief period. Yet, in the rush to defend the safety of the public (a noble and justified cause), were these drugs being subjected to a “witch-hunt” mentality? Were they deemed to be dangerous without conclusive evidence? The counter-argument can also be made that they were proclaimed safe without conclusive evidence. Is it possible that in the interest of securing the nation against all harm that the FDA erred on the side of caution? Is it possible there were other influences beyond the pharmaceutical effects of these drugs that increased the urgency of federal agencies to act? A recent study published in the American Journal of Epidemiology provided what is perhaps the most extensive examination of any association between the use of Letigen (a prescribed weight-loss drug containing 20mg of ephedrine and 200mg of caffeine) and adverse cardiovascular events.19 This review is literally awe-inspiring in the completeness of its data, reaching a degree that would be literally unobtainable in the U.S. A brief description of the study design will reveal why it is appropriate to state that its findings are conclusive. Denmark is a relatively small country located in the Scandinavian region of Europe, with a population of less than 6 million (in comparison, New York City has over 8 million residents). In addition to its acclaim as the happiest country in the world and least corrupt, Denmark has a well-organized health care system and governmental records that allowed researchers to track the use, users and health care system utilization relating to Letigen.19 The tracking and release of such data in the U.S. is inconceivable due to the privacy protection regulations, potential civil rights issues, and liability. Statistics Denmark provided access to records from the Danish National Registry of Patients, the Prescription Database of the Danish Medicines Agency, the Danish Registry of Death, and the Danish Person Registry. With the collective information, researchers were able to fully account for all prescriptions for Letigen during the study period (1995-2001), medical diagnoses and surgical procedures for all Danish citizens, death reports and migrating habits.19  Of the 5.4 million Danes residing in Denmark during that period, nearly 300,000 filled prescriptions for Letigen (298,848). The records for those people were extracted, and additional prescription information was obtained… seeking evidence of drugs or other appetite suppressants that might interact with Letigen, including those used in the treatment of cardiovascular disease, clotting disorders, diabetes, arthritis or asthma.

Two different comparisons were made— the first being the familiar use of matched controls (people of the same age and general health). In addition to directly comparing the subjects to controls, the researchers compared the subjects’ health prior to being prescribed Letigen to the period of exposure to the drug (case-crossover design). Subjects had to be at least 18, filled his/her first Letigen prescription during the study period and remained in Denmark for at least 18 months after being dispensed Letigen. Endpoints included any case-defining event (heart attack, stroke), death, emigration, age of 70, cancer, or the end of the study period. After excluding people who did not meet their criteria, there still remained 257,364 subjects contributing over 1,000,000 person years of observational data. In that large cohort, 2,316 “case-defining events” occurred during the seven-year study period, meaning a subject had a heart attack (839), stroke (946) or died of natural causes outside of a hospital (531).19 This is obviously the group of interest, representing the dangers so passionately spoken of in the FDA’s statement. Though the numbers seem alarming on first glance, this actually represents a low incidence rate. By comparison, the U.S. has an annual incidence rate of heart attack of 0.46 percent.20 Subjects who experienced an adverse event were more likely to be older and have pre-existing cardiovascular risks, as determined by prescriptions for cardiovascular, anti-clotting and diabetes drugs. When the relationship between Letigen use and the adverse event was analyzed, it was discovered that there was no greater risk during current Letigen use (within the previous 90 days) as compared to being “off” the drug. In fact, Letigen use actually had a lower risk of adverse event in a) deaths outside the hospital, b) women, and c) statin users (a class of cholesterol-lowering drugs).19  Interestingly, the greatest risk with Letigen use appeared to arise within the first 10 days of use (days zero to 10 following first prescription).19 With longer use, the prevalence of adverse events decreased steadily. This suggests that during the study period, one or more contraindications (medical reasons not to prescribe a drug) to Letigen use were not detected during the physician’s exam prior to prescribing the drug. This does not imply incompetence on the part of the Danish physicians, as many conditions are not evident during screening exams, such as aneurysms (weak, bulged areas in blood vessels that predispose a person to hemorrhagic stroke); thrombotic disorders (abnormal clotting); and conduction abnormalities (irregular heartbeats). Even during the introductory phase of Letigen use, there was no significant increase in risk relating to any of the study’s endpoints.

 

No “Substantially Increased Risk”
The conclusion of the study, following approximately a quarter-million people for greater than 1,000,000 person-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.”19 It is interesting that the conclusion was stated in that manner, 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 statistically 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-existing 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 prescribed 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 conclusive 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 prescribed by a physician, dispensed from a pharmacy, manufactured using the Danish equivalent of good manufacturing 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 findings in the Danish study and the furor raised about ephedra products in the U.S.? As mentioned above, ephedrine exposure 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 considered 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.21 Obviously, 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 exemplified 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 feeling. Sadly, consumers sought these products out, as they mistakenly believed they were more effective than appropriately 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 centers stated that ephedrine-related complaints were more common than other OTC products, but recall that these products were much more popular than other OTC products.11,15 Further, the toxicity of ephedrine/caffeine is immediate 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 be faced in the cough and cold products that are still available 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 pundits 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 concern 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 theories— 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 without the expense, inconvenience and risk (as has been shown with fen-phen, rimonabant and other pharmaceutical 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 legislation or physician resistance; allegations of bribes, inappropriate influence with the FDA, and numerous FDA-approved drugs causing harm or death have eroded public confidence in the pharmaceutical industry. Yet, it is clear that any pharmaceutical company that could produce a cost-effective 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 blockbuster brand Dexatrim® (PPA) and the many ephedrine/caffeine products which were providing consumers 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 dramatically. Sadly, such a product has not been introduced since that time.


Another possibility spoken of more quietly in nonscientific 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 society. 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 individuals 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 distribution was going to be more difficult to control, as it could be synthesized in crude “bathtub” labs and the intermediate 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).22 It is suggested that the real danger involving OTC ephedrine had little to do with ephedrine-based drug reactions, 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.23,24 However, 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 effective 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 production, 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 spontaneous reports, and does not withstand scientific scrutiny.

Much like eyewitness testimony that condemns an innocent man, whose innocence is later proven through DNA analysis of the evidence, this study calls for a re-assessment 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:

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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.

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8.   Breum L, Pedersen JK, et al. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity. A double-blind multi-centre trial in general practice. Int J Obes Relat Metab Disord, 1994 Feb;18(2):99-103.

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14. Chass M. BASEBALL; Pitcher's Autopsy Lists Ephedra as One Factor. The New York Times, March 14, 2003.

15. Rados C. Ephedra Ban: No Shortage of Reasons. FDA Consumer Magazine 2004 March-April. Available at http://www.fda.gov/FDAC/features/2004/204_ephedra.html, accessed November 13, 2008.

16. Center for Drug Evaluation and Research. FDA Letter to Manufacturers of Drug Products Containing Phenylpropanolamine (PPA). U.S. Food and Drug Administration • Center for Drug Evaluation and Research. Available at http://www.fda.gov/cder/drug/infopage/ppa/ppaltr.htm, accessed November 13, 2008.

17. Kernan WM, Viscoli CM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med, 2000 Dec 21;343(25):1826-32.

18. Stier BG, Hennekens CH. Phenylpropanolamine and hemorrhagic stroke in the Hemorrhagic Stroke Project: a reappraisal in the context of science, the Food and Drug Administration, and the law. Ann Epidemiol, 2006 Jan;16(1):49-52.

19. Hallas J, Bjerrum L, et al. Use of a prescribed ephedrine/caffeine combination and the risk of serious cardiovascular events: a registry-based case-crossover study. Am J Epidemiol, 2008 Oct 15;168(8):966-73.

20. American Heart Association. Heart Attack and Angina Statistics. Available at http://www.americanheart.org/presenter.jhtml?identifier=4591, accessed November 13, 2008.

21. Haller CA, Duan M, et al. Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements. J Anal Toxicol, 2004 Apr;28(3):145-51.

22. Cunningham JK, Liu LM. Impacts of federal precursor chemical regulations on methamphetamine arrests. Addiction, 2005 Apr;100(4):479-88.

23. Eccles R. Substitution of phenylephrine for pseudoephedrine as a nasal decongestant. An illogical way to control methamphetamine abuse. Br J Clin Pharmacol, 2007 Jan;63(1):10-4.

24. Cunningham JK, Liu LM. Impact of methamphetamine precursor chemical legislation, a suppression policy, on the demand for drug treatment. Soc Sci Med, 2008 Apr;66(7):1463-73.

25. Topolski JM. Epidemiology of methamphetamine abuse in Missouri. Mo Med, 2007 Jan-Feb;104(1):82-8.