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 Anthony Almada 
The Ephedra-Ephedrine Divide:
Presumed Equivalent Without Evidence
by Anthony Almada
Real World: Back in the mid to late 1980's, a supplement brand was gaining wide appeal among consumers and physique/physical-performance enthusiasts. It was Excel™, which promoted a line of encapsulated products delivering an extract of ephedra along with dottings of other ingredients (herbs and vitamins), following a product called Chi-Power™ (which was advertised in the original, small format Iron Man magazine. This, too, featured ephedra and had a spokesperson who was a martial artist/"Houdini" strong man who claimed he could physically break out of handcuffs. Forget the need for a key or picking a lock!
After Excel, a company called Pep® emerged, which also sported a suite of ephedra-centered products, including some that also added caffeine-rich herbal extracts. One of its leading offerings was Diet Pep®, a mixture of herbs enriched in ephedrine and its sister alkaloids (see below) and caffeine. This became a short-lived leader in the weight-loss/diet-pill category in health-food stores nationwide. Pep (the company), which also brought us other "memorable" products like Happy Camper™, later morphed into Natural Balance, Inc. (apparently needing to shed their ephedra-rich heritage). A product I co-created called Diet-Max® (KAL Nutritional Supplements, Woodland Hills, CA, now owned by Nutraceutical Corporation in Park City, UT), which was the first to use the term "thermogenic," bumped Diet Pep from the top of the charts for a few years. Notably, this was remarkably and relatively low in ephedrine alkaloids (5 mg per soft gel cap), yet it still became the category leader for a few years.
The success of these diet products ushered in the likes of Silver Sage's Thermogenics™ line (which for some time failed to accurately and clearly disclose it had real aspirin in it), TwinLab's Metabolift® and Ripped Fuel® products, Ultimate Orange®, and a host of other contenders. We even launched an ephedra-caffeine product while I was co-running EAS (Betadrine™), which was the first to use naringin as a presumed "extender" of caffeine's bioactivity, but we soon shelved it when the FDA began shooting their blowtorch at these types of products. (Plus it wasn't a big seller for us.)
While these products were scorching the shelves and aisles of vitamin stores and gyms, another player was mauling thousands of customers at shopping malls: Metabolife and their Metabolife 356® product. Enter the late-comers like Xenadrine RFA-1® and Hydroxycut®, and you have a very big punch bowl with lots of people helping themselves to multiple servings. Ephedra + herbal caffeine products became big business.
The Synthetic Ephedrine/Caffeine Combo Is Discovered
Medical/Research World: Back in the early 1970's, an anti-obesity drug concoction was serendipitously discovered by a Danish physician. It was called the "Elsinore Pill" because the good Dr. Erikson (its discoverer) had his practice in Elsinore, Denmark. While treating his asthmatic patients with a combo of synthetic ephedrine and caffeine, plus phenobarbital, he (and his patients) found unexpected (and much welcomed) weight loss. As weight-loss agents are worthy of National Enquirer front page status, the news of this new therapy spread like SARS in a crowded train station at rush hour. Within five years of his discovery, over 70,000 patients were taking the Elsinore Pill, with one Danish pharmaceutical company producing one million tablets per week.
The phenobarbital component was dropped, as it was the likely culprit of nasty skin rashes among some users. Unfortunately, this fostered the dumping of heaps of criticism, by both the media and medical communities, on good ol' Dr. Erikson—the true father of ephedrine + caffeine mixtures. To add insult to injury, his discovery was never captured and protected by a patent. Oh, how different the world is today.
The Elsinore Pill (EP, without phenobarbital) was shown to be superior to a prominent appetite suppressant drug of the era (diethylpropion—a cousin to the smoking-cessation and appetite-suppressing drug bupropion) and to a placebo in 132 subjects in a 12-week double-blind trial. EP (synthetic caffeine—100 mg—and synthetic ephedrine—40 mg—3 times daily) gave virtually identical weight loss to the drug (about 18 lbs) but was a leg ahead of the placebo weight loss of about 9 lbs. Although side effects (tremors and agitation) did occur more frequently in the EP users, they
were transient; i.e., not lasting. Moreover, the number of EP patients electing to withdraw from the study was equal to that of the diethylpropion group. There was no increase in blood pressure, pulse rate, or laboratory parameters. To this date, synthetic E+C combinations are still the biggest selling prescription weight-loss medications in Denmark. A brand name of prominence in this category is Letigen®, manufactured and marketed by Nycomed DAK Pharmaceutical Company in Roskilde.
Side Effects with the Synthetics
In the post-EP era, two notable findings transpired: 1) the development of evidence to support a ratio of synthetic ephedrine and caffeine (synthetic E+C) and 2) attribution of the majority of the weight loss to reduced eating (anorexigenic effect), NOT to thermogenesis. In a now classic study, different ratios of synthetic E+C were compared to synthetic E or C alone in relation to elevating metabolic rate (thermogenic response) and physiological markers influenced by the nervous system/cardiovascular/metabolic up-tick from the combo. A synthetic E+C combo of 20 mg E and 200 mg C fanned the metabolic flames greater than the sum of each of these 2 agents when given separately. It is important to recall that all of the acute synthetic E+C doses used in this study bumped systolic blood pressure, pulse rate, blood glucose, and insulin release.
The concern over the long-term effectiveness of synthetic E+C had arisen. A 24-week study in 180 obese subjects on a low-calorie diet regimen found synthetic E+C (20/200 three times/day) to be superior to synthetic E alone (20 mg three times/day), synthetic alone (200 mg three times/day), or placebo, with the combo synthetic E+C group losing over 17% of their starting bodyweight. Ephedrine or caffeine alone proved no different than a placebo. Within 8 weeks into the study, the occurrence of the "hummingbird syndrome" of side effects—tremors, insomnia, and dizziness associated with E+C use—was no different than placebo, with blood pressure falling to equivalent magnitudes in all of the groups.
However, two weeks after this trial ended, reports of tiredness and headaches appeared with a greater frequency in the synthetic E+C group. After this two-week post-trial period, all of the subjects in the study were offered the chance to enroll in another study, this time with ALL of the subjects receiving the synthetic E+C cocktail. The subjects who were in the original synthetic E+C group and continued on it did not regain weight through 50 weeks of use. Of the weight loss observed in this and other studies, 60 to 75% has been calculated to be due to the anorexigenic (appetite-suppressing) effects, with the balance due to thermogenic effects. One has to wonder where people get different information, including the long marketed but wholly erroneous claim that E+C turns on "brown fat" thermogenesis in adults. (Adults have only traces of brown adipose tissue, and ephedrine is thermogenic primarily in skeletal muscle in adult humans.)
Data Pirates: Synthetic Claims Applied to Herbal Products
As the Mt. Everest of synthetic E+C data began to arise out of laboratories across Europe and the U.S., use of this data began to find its way onto dietary supplement labels and brochures, health and bodybuilding magazines, and a slew of seminars catering to both consumers and retail employees. The divide was created: E+C derived from herbal sources (herbal E+C) was presumed to be equivalent to synthetic E+C, despite the obvious differences.
First off, synthetic E+C is comprised of only two pure chemicals, ephedrine (close relative of phenylpropanolamine/norephedrine, cousin of d-amphetamine, and a single chemical, despite what some may otherwise believe), and caffeine. In contrast, herbal E+C contains hundreds of different chemicals in varying percentages and varying from brand to brand and batch to batch. The chemicals of interest in herbal E+C are ephedrine and caffeine but with the major plant source of herbal E, ephedra species, also known as ma huang, several other ephedrine relatives coexist.
Let's put this into perspective. Drug company PX shows that its combination of two distinct anabolic steroids, in specific amounts, was superior at increasing fat-free and bone mass in cancer and HIV patients, compared to different ratios or the two anabolics used individually. Drug company PY takes that exact combination and adds a kitchen sink of other agents: androgens, testosterone precursors, and even some anti-estrogens. They then assert that their cocktail is just as safe and effective as PX's product, despite NEVER comparing the two head to head. Likely outcome: Terry Tate of Reebok shoes fame would do a real live commercial in the corporate headquarters of PY, followed by PX's legal team serving them a lawsuit for false advertising claims. No need to mention that the FDA would have a "guns drawn" field day at PY's facility if this ever transpired.
So why in the heck does it happen in the magical world of dietary supplements? My bet: some companies are Kist too cheap (or fearful) to put their money where their mouth is and would rather try to fool the consumer that they have the same thing but it is "natural" and "synergistic."
I was in a media teleconference several months ago with a very large, soon-to-be transformed herbal E+C marketer. The famous lawyer for the company (who had previously represented a big U.S. politician), who was joined by the CEO, started spouting out science jargon and research sound bites, stating that "ephedrine is in over-the-counter allergy medications" (wrong—it's pseudoephedrine) and referring to "15 years of clinical trials supporting the safety of ephedra." I didn't go to law school, and I make no attempt to practice law, but this guy didn't go to biochemistry school and was practicing science and research.
I shot my mouth off, communicated that herbal "ephedrine" is different from synthetic ephedrine, and received a barrage of personal attacks from the CEO, ignorant of what I was trying to communicate (but then again, he was not trained as a scientist either). The famous lawyer surprisingly stayed silent.
Ephedrine and Ephedra Are NOT Equivalent!
At the date of this call, and still at this time of writing, no study has ever attempted to show any herbal E+C product (they are all different) to be as safe and effective as synthetic E+C. While it is all too common to call ephedra "ephedrine," they are notably different. The ephedra that is added to dietary supplements typically contains four to five (or more) different chemicals, lumped under the title of "ephedrine alkaloids" or "ephedrine group alkaloids." So if a product label states "15 mg ephedrine alkaloids," the consumer is not getting 15 mg of ephedrine. They are typically getting 15 mg of ephedrine, pseudoephedrine, norephedrine, methylephedrine, and norpseudoephedrine combined, with ephedrine being
prominent in variable amounts. Add in the other unnamed and unknown chemicals found in (or sometimes spiked in) ephedra, and the cornucopia of those found in the conventional sources of botanical caffeine: green, oolong, or black tea, guarana, and/or cola nut, and you have the makings for a witches and warlock's brew.
Wait. Don't stop there. Add in all of the other esoteric and exotic ingredients, with presumed but unknown biological effects, which comprise the ubiquitous "proprietary blend." We now have a street legal cocktail that could be more flammable than racing fuel. How could anyone ever consider synthetic E+C to be bioequivalent to herbal E+C from a rational, logical basis?
Evidence on Ephedra?
We do have some evidence that a few herbal E+C are effective and variably safe, but only for up to a few months—and the herbal E+C product with 6 months of safety and efficacy data doesn't even exist!
The first herbal E+C study was done on Xenadrine RFA-1 and showed both safety and efficacy over a short term. RFA-1 enjoys more clinical safety and efficacy data than any other herbal E+C product on the market. Indeed, a recent study led by Doug Kalman, MS, RD, and associates, arguably the Earl of herbal E+C science, showed a ramped dosing schedule (half dose twice daily for 7 days, then full dose twice daily for 7 days) of RFA-1 to be without any cardiovascular side effects in healthy overweight subjects taking the product for two weeks. RFA-1 claims 20 mg of total ephedrine alkaloids (ephedra), 200 mg of caffeine (guarana), and 5 mg of synephrine (bitter orange) per dose. Despite this, Cytodyne and RFA-1 has also been the subject of a number of personal injury suits, presumably playing a part in compelling Cytodyne to introduce its ephedra-free product, Xenadrine EFX™.
Surprisingly, the platform of this product is all thermogenic, yet NO studies presented or published to date have shown weight and/or fat loss that was statistically superior to placebo. Don't consumers take weight-loss products to ultimately lose weight? Who wants to take a product that produces short-term elevations in metabolism if it doesn't produce any weight loss?!)
One of the most talked about studies on herbal E+C is the Metabolife 356® study, published in 2001. This 8-week study took moderately obese subjects, asked them to follow a lower fat (less than 30% of calories) diet and walk for 30 minutes 3x/week, and take either a placebo or 356 (2 tablets 3x/day, providing approximately 24 mg of total ephedrine alkaloids (from ephedra) and 80 mg of caffeine (from guarana)/dose). Here we saw notable drops in bodyfat (7.7 lbs vs. 1.54 lbs in placebo group) and weight (8.8 lbs vs. 1.76 lbs) after 8 weeks, but 8 of the 35 subjects that started the study on 356 dropped out or withdrew due to adverse effects (palpitations, chest pain, elevated blood pressure). This finding seems to be unknown by many.
In contrast to synthetic E+C studies, the percentage of subjects dropping out and withdrawing was substantially greater. Also and still puzzlingly, the placebo product was found to have small amounts of ephedrine and caffeine—so much for quality control. Notably, 356 sports a ratio of 12 mg total ephedrine alkaloids to 40 mg of caffeine, or 3:10—far off from the 1:10 of synthetic E+C shown to be maximally thermogenic and tolerable. If we assume that only half of the total ephedrine alkaloids is comprised of ephedrine, i.e., 6 mg, we come up with a 1.5:10 ratio. To date, this is the only placebo-controlled clinical trial done on Metabolife 356 that has been published in a scientific journal.
The biggest study to be published on herbal E+C involved a combo of only ephedra and kola nut, a blend made specifically for this study and which is not commercially marketed. (It doesn't have the "proprietary blend" and thus marketers would be inclined to think it isn't distinctive enough.) Many of the same researchers from the Metabolife study performed this study in 167 moderately obese subjects (given diet and activity recommendations similar to those in the Metabolife 356 study) over a 6-month supplementation period. This generic herbal E+C mix provided 30 mg of total ephedrine alkaloids (ephedra) and 64 mg of caffeine (kola nut) per dose, which was taken three times per day. After 6 months, a similar number of dropouts and side effects were seen in both the herbal E+C group and the placebo group. Weight loss was 11.66 lbs with the herbal E+C and 5.72 on the placebo, while fat loss was 9.46 lbs and 5.94 lbs, respectively. The numbers aren't as compelling for a 6-month supplementation period compared to the 2-month 356 study, but the absence of an exodus of subjects due to 356-associated side effects is.
The limited data that exists to support the safety and efficacy of herbal E+C products is dwarfed by the amount of data on synthetic E+C. Moreover, only a handful of the herbal E+C products have ANY data published in science journals, begging the question: what is the long-term safety and efficacy of all those other products out there? Herbal E+C products have been out on the market for almost 15 years, but there still is no long-term (6 months or greater) study on any of them. Because they are all chemically different by virtue of what exotic ingredients, both amounts and sources, are added to each different product, one cannot logically argue that they all biologically and toxicologically behave the same.
There do not appear to be floods of adverse reaction reports hailing from Denmark among the tens of thousands of users of synthetic E+C products. The published studies on synthetic E+C do not describe the magnitude of side effects that were seen in the 356 study. Most importantly, despite what herbal E+C product labels claim, they often do not match what is actually found in the capsules or tablets. One intriguing recent study found almost 31% of 35 different herbal E+C products tested to have over 110% of the total ephedrine alkaloids claimed on the label. They also found one product to contain 98% ephedrine (do you think it was spiked?) and another with 10% norpseudoephedrine, a more potent stimulant than ephedrine and a Schedule IV drug.
The onslaught of personal injury and class action lawsuits that have descended upon the herbal E+C marketers is in some ways a fitting ending. Electing not to do the long-term safety and efficacy studies, despite the 1 billion plus in consumer dollars spent on these products in the U.S. this past decade left them wide open for attack. Failing to invest in a head-to-head comparison of any herbal E+C product to a synthetic E+C composition reinforced the assumption that these herbal E+C concoctions, claimed to "protect the adrenals" and "safer than synthetic ephedrine and caffeine," were deluded by their own BS and looking at a scientific mirage. It is apparent that the herbal E+C era has ended. Let us hope that the moral of the story is learned and embraced: smart, intelligent product-specific science is the only bridge between dietary supplements and consumer/medical community confidence.
For complete references for this article, please email us at Editors@RealSOLUTIONSmag.com, and we'll email them to you directly. (They simply wouldn't fit.)
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