The Ultimate Diet Pill


Community Veteran
By Stephen Schmitz, MD, MPH
and Bruce Kneller, BSN-RN

Let us warn you. This is not your typical, easy-reading, elementary science article. It contains some challenging stuff. We strongly recommend you read it, though, especially if the idea of pharmaceutically aided fat loss appeals to you on any level. Researchers Schmitz and Kneller have taken the now-famous ephedrine/caffeine/aspirin stack and put it under the microscope. Although the stack is undeniably effective, they have some strong reservations regarding its safety. Don't worry, though. They think they've found something far safer, far better, and quite legal. (Hey, we wouldn't ask you to read through complicated stuff if we weren't sure you were going to hit paydirt at the end of the article.)

The Ephedrine/Caffeine/Aspirin "stack" (ECA) has been utilized for over three years by various members of the bodybuilding and fitness community as a fairly effective tool to increase thermogenesis/lipolysis in order to reduce body adipose content. One of the components of ECA, ephedrine, is also found as the active ingredient in many over-the-counter (OTC) recreational drugs (e.g. Herbal Ecstasy®). Additionally, ephedrine has been directly implicated in the deaths of at least 13 people over the last 18 months as well as a substantial number of other Serious Adverse Events (SAE) requiring direct intervention by medical teams in hospital emergency departments across the country.

The sale of raw, bulk ephedrine powder to individuals has also been tightly controlled as this compound can be converted to amphetamine / methamphetamine by those with even a cursory knowledge of chemical synthesis. Recently, the Food and Drug Administration (FDA) has launched an exhaustive investigation regarding the safety of ephedrine and many states have elected to outright ban the OTC sale of it. Additionally, the World Health Organization (WHO) decided that it will recommend that countries change the status of ephedrine from OTC to prescription-only because of safety concerns. It is expected that the WHO will notify the US government of their intentions later this year, which will give the US enough time to take up a position before the United Nations Commission on Narcotic Drugs' annual meeting in 1999. It is the opinion of the authors that ephedrine will no longer be an OTC compound by the year 2000.

Through a review of contemporary literature we elected to ascertain if a suitable replacement for ephedrine or ECA could be found. In evaluating the data, we elected to pursue compounds that fell under certain parameters.

Compound(s) must be:

• legal to possess without a prescription from a health care provider
• fairly inexpensive
• readily obtainable in all US states and territories
• safer for humans than ephedrine
• naturally occurring and not prohibited by law from being sold as food supplements
• thermogenic and/or lipolytic in humans or acceptable mammalian models

Initially, we expected to find chemical entities with some thermogenic/lipolytic potential that approached—but did not equal/exceed—that of ephedrine or ECA. However, after a thorough review of studies in peer-reviewed medical journals, we have identified a common and oft overlooked compound that meets all of the criteria above and in fact, exceeds ephedrine's potential as a thermogenic and lipolytic slimming agent in humans. We have also concluded, based on our review of literature, that complete revision of ECA potentially yields a safer and more efficacious "stack". Before we enter into our discussion of our newly formulated "stack", we feel it necessary to discuss why we feel that ephedrine is an unsuitable compound based on it's relatively poor safety performance.


Ephedrine's {alpha-[1-(methylamino)ethyl]benzene-methanol} role as one of the key components of lipolytic agents sold OTC stems from it's mechanism of action and physiological effects. Ephedrine falls into a class of drugs called "sympathomimetic amines" which exhibit some of the stimulant properties of epinephrine and norepinephrine (Adrenalin and Noradrenaline). Ephedrine imparts a number of physiological effects after oral administration. It stimulates heart rate, contractility and cardiac output; increases blood pressure; increases the resistance to outflow of urine from the bladder; promotes dilation of the bronchioles; and is a potent central nervous system (CNS) stimulant.

These physiological effects account for both ephedrine's effectiveness as a "fat burner" and also for the unacceptably high number of SAEs recorded. A recent query of the Special Nutritionals Adverse Event Monitoring System at the FDA revealed that since 1996 there have been 13 deaths, one transient ischemic attack (stroke like event), three hypertensive crises, three episodes of syncope (passing out) and 5 life-threatening cardiac anomalies. An SAE can be defined as "any adverse drug experience occurring at any dose that results in any of the following outcomes: death or life threatening; persistent or significant disability/incapacity; requires or prolongs hospitalization; imparts a congenital anomaly; or other important events which may jeopardize the subject and may require medical or surgical intervention to prevent one of the above outcomes.

Although it is difficult to "prove" that a drug or medicinal product caused a particular symptom (this is a point the tobacco industry has relied on and abused for years), the close relationship between the known physiological effects and the adverse effects makes a convincing case for ephedrine as the cause in many or most cases of the described SAEs.

Ephedrine is rarely ingested as a pure drug. In the majority of the "stacks" and ephedrine products available in the fitness/weight loss market, a combination of ephedrine alkaloids is present.3 These alkaloids are also naturally-occurring chemical stimulants (e.g. methylephedrine). Although the proportions of these various alkaloids varies in commercial preparations, the most common alkaloid is indeed ephedrine. The source of the alkaloid can vary from a raw botanical; to powdered plant material; to concentrated extract (the majority of preparations).3

In addition to the unstandardized mix of ephedrine alkaloids in any given preparation, most of these supplements contain between 6 and 20 other bioactive ingredients. Some of these other ingredients have known or suspected physiological and pharmacological properties and have potential for interacting with ephedrine alkaloids to increase both the physiologal effects and significantly increase adverse reactions. One of these (caffeine) has been shown to increase the stimulant effect of ephedrine.4 It is well known that for both prescription and OTC medications, that the greater the number of substances, the greater the chance for known and unknown drug interactions.

Substances that have similar mechanisms of action such as ephedrine and caffeine (both CNS and cardiovascular stimulants), taken simultaneously , can have an additive (1 + 1 = 2) or synergistic (1 + 1 = 3) effect. The "buzz" or "rush" that recreational users sometimes get—which might be perceived by an increased heart rate or hyper-alertness—may actually be more of an adverse event. There is often a very narrow therapeutic range between a desired drug effect and an undesired adverse event. Factors known to increase the sensitivity of an individual to sympathomimetic amines (like ephedrine) are shown below.

Factors Influencing Sensitivity to Sympathomimetic Amines

Factor: Age
Example: Children, elderly

Factor: Genetics
Example: Altered metabolism

Factor: Physiologic states
Example: Exercise, underweight

Factor: Dieting practices
Example: Severe caloric or fluid restriction

Factor: Medications and food
Example: Certain antihypertensive medications, monoamine oxidase inhibitors, caffeine or other stimulants

Factor: Diseases
Example: Heart, thyroid or seizsure disorder, high blood pressure, depression, psychiatric conditions, prostate enlargement

The adverse effects associated with ephedrine alkaloids are troublesome for a number of reasons. First, they affect a variety of organ systems (cardiovascular, CNS, gastrointestinal) and have considerable toxicity (see list below). Secondly and perhaps most striking is that the SAEs associated with ephedrine occur in people who are usually quite healthy (see list below). The "typical" person (at least regarding other drugs) in whom adverse events occur are often elderly; infants or young children; male or female; who have known or yet unknown underlying medical problems and who take multiple prescription medications. The typical person experiencing an adverse event related to ephedrine is young, healthy, mostly female, takes no prescription medication and has no underlying medical condition.

It's not too surprising when a 65-year-old man with a known history of severe cardiovascular disease has a heart attack while shoveling the snow from his driveway, but when a 30-year-old woman experiences a massive heart attack, it's noteworthy because we don't expect a healthy 30-year-old to have any of the known risk factors for a heart attack, let alone actually experience a heart attack.

Since 1993, The FDA has received more than 800 reports of illness and injuries associated with the use of more than 100 different dietary supplements that contained—or were thought to contain—ephedrine alkaloids. As previously mentioned, at least 13 deaths associated with ephedrine use have been reported since 1996, mostly in young, otherwise-healthy individuals. Because of concern about the popularity and easy availability of ephedrine alkaloids, and because of the perceived public safety issue, the FDA has called for significant changes in dose, labeling, information to consumers, and duration of use with regards to ephedrine alkaloids. These changes include:

A) Limiting to an 8 mg dose per serving of ephedrine alkaloids.
B) Clearly indicating the potential health hazards on an easily seen label.
C) Limiting the duration of use to seven consecutive days.

An expert panel of physicians, scientists and public health specialists at the FDA, after careful considerations, believe that the above steps are necessary to alert the public and protect the public from potential SAEs associated with regular and chronic ephedrine use.

Serious Adverse Events Associated With Ephedrine Alkaloids

Organ System: Cardiovascular
Signs / Symptoms: Cardiac arrest and DEATH, severe hypertension, heart rhythm disturbances, myocardial infarction, stroke

Organ System: Nervous
Signs / Symptoms: Seizures, psychosis, SUICIDE or suicidal ideation, altered or loss of consciousness

Organ System: Gastrointestinal
Signs / Symptoms: Hepatitis (increased liver enzymes such as transaminases)

Characteristics of SAE's Associated With Ephedrine5

• Cardiovascular and nervous system most commonly affected
• Patterns of symptoms consistent across different populations
• Occurred both in healthy individuals and those with underlying disease
• Majority of events (>75%) occurred in females
• Many signs and symptoms occurred in young adults who are normally at low risk for the described events (e.g. heart attack and stroke)
• 84% of cases reported in people <49 years of age
• 59% of SAEs occurred within 4 weeks of starting; 14% on the first day
• 92% of SAEs occurred in people trying to lose weight or increase energy; 5% for athletic enhancement; 2% for recreational euphoria


Aspirin {salicyclic acid acetate} and it's naturally occurring methyl ester (methyl salicylate)—found in the leaves of Gaultheria procumbrens and on the bark of Betula lenta—have long been used as analgesics, anti-inflammatories, antipyretics and recently as anti-coagulants. The "A" portion of ECA, aspirin has been thought of potentiating the thermogenic and lipolytic properties of both ephedrine and caffeine. Recent research seems to contradict this however. At a study at The University of London's Department of Nutrition and Dietetics, 40 women (20 non-obese and 20 obese) were given either ephedrine and caffeine (30 mg and 100 mg) or ephedrine, caffeine and aspirin (30 mg, 100 mg, and 300 mg) post prandially (1050 kJ liquid meal). Using indirect calorimetry, observations were made in all groups every 30 minutes for 160 minutes. There was no significant differences between the groups that received aspirin and the groups that did not. We conclude that aspirin does not potentiate the acute thermic effect of ephedrine and caffeine.6

In another study conducted at King's College in London, it was demonstrated that aspirin does not potentiate the thermogenic response to ephedrine in lean women and only slightly so in obese women.7 The increase seen in this study represented a 1.2 kcal per hour increase in metabolism for lean women and a 2.4 kcal per hour increase in metabolism in obese women over use of ephedrine alone, which over an entire week, would represent less than one ounce of bodyweight. We feel that this is insignificant.7

Based on these two studies, we feel that aspirin and its analogs do not play a substantial role in inducing or increasing thermogenesis and/or lipolysis but they do have the potential to induce SAEs when consumed over long periods of time (e.g. ulceration of the stomach and increases in bleeding times). Therefore, we feel that aspirin and it's analogs should not be used in any thermogenic/lipolytic stack.

Yohimbine {(16a, 17a)-17-Hydroxyyohimban-16-carboxylic acid methyl ester} is a naturally-occurring indole alkaloid with alpha2-adrenergic blocking activity. Yohimbine is found in the Coryanthe johimbe and related trees as well as in the herb Rauwolfia serpenta. Yohimbine, as a hydrochloride salt, has been used for years as a mydriatic and alpha2-adrenergic blocker. It has also been used as a prescription aphrodisiac (e.g. Yocon, Aphrodyne) with each tablet containing 5.4 mg of yohimbine HCl.

Yohimbe Bark Extract has been used for many years by bodybuilders—and rightly so—as there is mounting evidence that this compound (alone or stacked with others) acts as a fairly effective slimming agent, especially in women placed on calorie-restricted diets. In one study conducted at The Silesian School of Medicine in Poland, twenty obese female outpatients were subjected to a three-week low-energy diet and according to a double-blind protocol, randomized to receive one of two treatments of yohimbine. Ten subjects received 5 mg of oral yohimbine four times per day and ten subjects received a placebo. The study protocol provided that each subject "take their medication" and adhere to a 1,000 Kcal /diet for a total of three weeks. The oral yohimbine subject lost, on average, 107% more bodyweight that the placebo subject.8

Yohimbine has also demonstrated increased lipolysis as evidenced by increased plasma free fatty acids. In a study conducted as Laboratorie de Pharmacologie Medicale et Clinique in France, oral yohimbine at dosages of 0.25 mg/kg significantly increased non-esterified plasma fatty acids over a four-hour period, as well as increased oxygen consumption and carbon dioxide and heat production within 30 minutes after administration. This clearly illustrates an increase in metabolic rate. In addition, oral yohimbine increased sympathetic nervous system activity as indicated by increases in plasma norepinephrine.9

Another study at the same institution also yielded promising results. Oral yohimbine administration (0.2 mg/kg) induced lipid mobilization in fasting, non-obese women (body mass index = 20.2 +/- 0.5, age 35.5 years +/- 2.7 years) without significant action on plasma glucose, insulin levels, heart rate or blood pressure during the time-course experiment. Plasma norepinephrine levels increased by 100% after oral yohimbine administration. In obese women (body mass index = 36.4 +/- 2.1, age 37.0 years +/- 3.6 years), the effects were nearly identical with regards to lipolysis, plasma norepinephrine levels, etc. Oral administration of the beta-blocker propanolol dramatically reduced the lipid mobilizing effect of yohimbine.

This is exceptionally interesting because it was previously thought by many bodybuilding "gurus" that the fat mobilizing effects of yohimbine in women were probably due to an abundance of alpha2 adrenoreceptors around the fatty areas of the thighs and buttocks. We disagree. It appears that the lipid-mobilizing effects of oral yohimbine in women are mainly attributable to the increase in synaptic norepinephrine with a resultant increment in lipolysis by beta adrenergic agonism. The alpha2 adrenoreceptors seem to be a very minor component of the lipomobilizing effects of yohimbine.

Morever, when tested on non-obese women, the lipomobilizing effects of yohimbine is not enhanced when compared to obese women (those thought to have the abundance of alpha2 adrenoreceptors).10 This is something we would certainly expect to see if the alpha2 adrenoreceptors were involved to any great degree. We feel that yohimbine is relatively safe and certainly belongs in any thermogenic/lipolytic stack. A prescription drug in single doses above 3 mg, yohimbine can be sold without a prescription if the single dose amount is less than or equal to 2.9 mg.


L-Tyrosine is a common, non-essential amino acid that can be synthesized in-vivo from the amino acid phenylalanine. In several studies conducted at The Massachusetts College of Pharmacy and Allied Health Sciences, L-Tyrosine potentiated the anorectic effect of various mixed-acting sympathomimetics (including ephedrine, amphetamine and phenylpropanolamine). Because these aformentioned mixed-acting sympathomimetics are known to increase blood pressure to varying degrees, these studies were conducted to examine the effects of L-Tyrosine's ability to influence the pressor response to these compounds. No potentiation was observed with the addition of L-Tyrosine. Thus, the anorectic potentiating effects that L-Tyrosine induces must be a centrally mediated response at a central locus.11,12 L-Tyrosine is an exceptionally safe compound found in many foodstuffs. We suggest the addition of L-Tyrosine to any thermogenic/lipolytic stack, especially when a calorie restricted diet it used.


Phenylpropanolamine {dl-norephedrine} is a synthetic compound that has been used for several decades as an OTC decongestant, bronchodilator and anorectic. It is the active ingredient in most OTC weight loss products that you find in your local drug store (e.g. Dexatrim, Accutrim), Long overlooked by most of the bodybuilding community, phenylpropanolamine (dl-PPA) is actually superior to ephedrine in its thermogenic, lipolytic, and anorectic properties. In at least one study involvong various congeners and isomers of dl-PPA, it was shown to be significantly more thermogenic than ephedrine and not much less potent a thermogen than dl-amphetamine.13 (DL-amphetamine is a highly addictive medication that is a prescription only, Schedule C-II Controlled Substance in The Unites States while dl-PPA is an incredibly inexpensive substance with a cost factor similar to ephedrine.)

In one study, the effects of chronic treatment with dl-PPA on bodyweight (BW), food intake (FI), water intake (WI) and intercapsular brown adipose tissue (IBAT) thermogenesis in adult male Sprague-Dawley rats were evaluated. In the study, the rats were treated with either placebo or 5, 10, or 20 mg/kg of dl-PPA twice a day for 12 days. Rats in the 20 mg/kg treatment group exhibited significant decreases in FI and BW but not WI. Basal IBAT temperature was slightly increased in the chronic 20 mg/kg dl-PPA rats and there was no evidence of tolerance to the acute IBAT thermogenic effect of 20 mg/kg dl-PPA.14 Also, much like ephedrine, caffeine demonstrates a positive thermogenic and lipolytic synergy when co-admininstered with dl-PPA.

Another experiment using the same type of rats clearly demonstrated that the combination of caffeine and dl-PPA produced significantly greater thermogenesis than the use of dl-PPA alone.15 However, dl-PPA does not meet all of the inclusion criteria we originally set forth in above. Being a synthetic compound, dl-PPA is an OTC drug and NOT a food supplement. However, one of the isomers, the "levo" form, or l-PPA is naturally occurring and as luck would have it, the naturally occurring l-PPA possesses about twice the potency of the synthetic d-PPA with regards to thermogenesis, effect on bodyweight, and effect on decreasing food intake.11 Thus, l-PPA could easily be utilized and sold as a food supplement and not an OTC drug.

We feel that in addition to being a more potent thermogen and lipolytic when compared with ephedrine, l-PPA (or even dl-PPA) is a superior anorectic. This property may be of significant importance to individuals utilizing calorie-restrictive diets in addition to supplementation for weight reduction. The ability to stave off the pangs of hunger may have a dramatic and positive psychological effect in ANY weight reduction program. Phenylpropanolamine also has a better safety profile than ephedrine does and the potential side effects (e.g. increased nervousness, insomnia, tachycardia, hypertension, dry mouth, etc.) are typically more prevalent and exacerbated with ephedrine than with phenylpropanolamine. Thus, we suggest dl-PPA or the racemate, l-PPA if available, over ephedrine in any thermogenic/lipolytic stack.

Second Generation Thermogenic Stack

Based on a current review of literature and the various studies cited in this article, we feel that it is prudent to "reformulate ECA" to increase efficacy and improve safety. As previously stated, we feel that aspirin should be eliminated as an unnecessary potential hazard and L-Tyrosine and yohimbine should be added. We also feel that ephedrine should be eliminated and replaced with the vastly superior phenylpropanolamine (dl-PPA or preferentially, l-PPA). We offer the following suggested dosing schema which we call "The Schmitz and Kneller Formulation."

The Schmitz and Kneller Formulation (per serving/dose)

L-Tyrosine: 200 mg
Yohimbine: 2.9 mg
Caffeine: 100 mg
DL-Phenylpropanolamine: 25 mg*
L-Phenylpropanolamine: 18 mg*

*Either DL-Phenylpropanolamine or L-Phenylpropanolamine, not both.

We would suggest this combination be taken 1-3 times per day, preferably every four hours and immediately after meals. People who are currently taking Monoamine Oxidase Inhibitor medications, have hypertension, cardiovascular disease, thyroid problems, prostate problems, or who are pregnant or about to become pregnant or are currently nursing should not utilize this stack nor any of it's components. We feel that our stack, much like ECA, will work best if undertaken with a healthy diet and proper exercise. Always consult your healthcare provider before undertaking any new diet, exercise or supplement regimen.

EDITOR'S NOTE: This formulation is not available in stores or anywhere else, for that matter. However, given that the individual ingredients are readily available, it would be possible for someone to "blend" the mixture on his own.

About the Authors

Stephen Schmitz, MD, MPH is a pharmacoepidemiologist and Associate Medical Director for Drug Safety and Medical Information for a biopharmaceutical company in Cambridge, MA. Stephen is board certified in both Family Medicine and Occupational Medicine and has completed an approved fellowship in Preventive Medicine. He has been a health care practitioner for over 15 years.

Bruce Kneller, BSN, RN is a Clinical Data Manager researching the effectiveness of small molecule drugs in the treatment of Congestive Heart Failure and Resistant Cirrhotic Ascites for a biopharmaceutical company located in Cambridge, MA. Bruce has authored over three dozen article published in various bodybuilding magazines and has over 10 years experience in supplement research as well as over 4 years experience in drug development.



1) Goodman and Gillman, The Pharmacological Basis of Therapeutics, Ninth Edition, p.221.
2) FDA New Final Rule Regarding Serious Adverse Events (effective 04/06/98).
3) Office of Special Nutritionals: Market Review of Dietary Supplements Containing Ephedrine Alkaloids, August 27, 1996.
4) Lak CR, Rosenberg DB, Gallant S, et al. Phenylpropanolamine Increases Plasma Caffeine Levels. Clinical Pharmacology and Therapeutics, 1990;47:675-684.
5) Federal Register, Vol. 62(107). 21 CFR Part 111, Dietary Supplements Containing Ephedrine Alkaloids, Proposed Rule.
6) Horton TJ, Geissler CA. Post-prandial Thermogenesis with Ephedrine, Caffeine and Aspirin in Lean, Predisposed Obese and Non-obese women. Int J Obes Relat Metab Disorder, 1996 Feb;20(2):91-95.
7) Horton TJ, Geissler CA. Aspirin Potentiates the Effect of Ephedrine on the Thermogenic Response to a Meal in Obese but not Lean Women. Int J Obes, 1991 May;15(5):359-366.
8) Kucio C, Jonderko K, Piskorska D. Does Yohimbine Act as a Slimming Drug? Isr J Med Sci 1991 Oct:27(10):550-556.9) Galitzky J, Vermorel M, Lafontan M, Montastruc P. Thermogenic and Lipolytic Effect of Yohimbine in the Dog. Br J Pharmacol 1991 Oct;104(2):514-518.
10) Berlan M, Galitzky J, et al. Plasma Catecholamine Levels and Lipid Mobilization Induced by Yohimbine in Obese and Non-obese Women. Int J Obes 1991 May;15(5):305-315.
11) Hull KM, Maher TJ. Effects of L-tyrosine on Mixed Acting Sympathomimetic-induced Pressor Actions. Pharmacol Biochem Behav 1992 Dec;43(4):1047-1052.
12) Kull KM, Maher TJ. L-tyrosine Fails to Potentiate Several Peripheral Actions of the Sympathomimetics. 1991 Jul;39(3):755-759.
13) Wellman PJ, Marmon MM. Comparison on Brown Adipose Tissue Thermogenesis Induced by Congeners and Isomers of Phenylpropanolamine. Life Sci 1985 Sep 16;37(11):1023-1028.
14) Wellman PJ, Sellers TL. Weight Loss Induced by Chronic Phenylpropanolamine: Anorexia and Brown Adipose Tissue Thermogenesis. Pharmacol Biochem Behav 1986 Mar;24(3):605-611.
15) Welman, PJ, Marmon MM. Synergism Between Caffeine and DL-Phenylpropanolamine on Brown Adipose Tissue in the Adult Rat. Pharmacol Biochem Behav 1985 May;22(5):781-78.
I read the majority of that. Very good article. I dig this kind of stuff.
nice read but it seems really difficult to come up with all those compounds in that exact dose. did i miss something?? ECA was just so damn easy ie one asprine one vivrine and one ephedrine. how do we come up with all these in these doses??
um this shit gave me several panic attacks, felt like i was having a stroke, and didnt do jack shit,

i strongly urge u not to do this people have died..with the shittiest doses

i still suffer panic attacks till this day
Way to post mis-information. This was your experience... there were/are literally thousands of people who use/have used many things in this thread successfully.
Are you nuts. did you drink any water.....

You need to tell people you have panic attacks anyway. THe ECA stack worked so well that the pharmaceutical industry pushed congress to outlaw Effedrine over 150 cases of people misusing the product. Even though effedra has been used for thousands of years.