Evaluating Nutritional Supplements – Ephedra & Caffeine Safe and Effective

This NIH funded study was conducted by some of the leading obesity researchers in America at St. Luke’s-Roosevelt Hospital, Columbia University in New York and the Beth Israel-Deaconess Medical Center, Harvard Medical School in Boston.

Some time ago, I suggested the media hype about the dangers of taking herbal ephedra supplements was overblown. I described a number of clinical studies indicating that use of synthetic ephedrine or herbal ephedra supplements (with or without caffeine) appeared to be among the most effective and safe strategies to promote fat loss in apparently healthy populations.1-13 Despite this efficacy and safety record, several groups have warned the public about the safety of ephedra-containing supplements.14,15 In addition, herbal ephedra supplements have been on the FDA’s watch list for some time.15 For example, Dr. Paul Coates, Director of the Office of Dietary Supplements (ODS) at the National Institutes of Health (NIH), indicated at the recent Performance Enhancement Products conference that “we will not enter the ephedra controversy unarmed.” So, what’s new? A landmark study funded by the NIH has just been published that reports data from a six-month clinical trial examining the efficacy and safety of herbal ephedra supplementation.16 This discussion overviews the results of this study to see if the concerns raised about herbal ephedra supplements are real or have been overblown.

Background: Getting Up to Speed

Ephedrine and caffeine (EC) have been shown to stimulate metabolism, increase energy expenditure and promote fat loss.(1-13) For example, Boozer and associates1 reported that eight weeks of ephedrine (72 mg/day) and caffeine (240 mg/day) supplementation promoted a 4.0 kilogram loss (8.8 pounds) in body mass and a 2.1 percent loss in body fat with minor side effects. Molnar and colleagues2 reported that overweight children treated for 20 weeks with ephedrine and caffeine observed a 14.4 percent loss in body mass and a 6.6 percent decrease in body fat with no differences in side effects when compared to placebo. Greenway and colleagues3 reported that ephedrine/caffeine was a more cost-effective and safer treatment for reducing weight, cardiac risk, and low density lipoprotein (LDL) cholesterol than several commonly prescribed weight loss drugs (fenfluramine with mazindol or phentermine). These findings and others have led a number of investigators to conclude that EC supplementation can serve as a safe and effective treatment for obesity.3,12,13

Thermogenic (fat-burning) supplements typically contain naturally derived sources of ephedrine (e.g., Ma Haung, Sida Cordifolia), caffeine (e.g., Gaurana, Bissey Nut, Kola), and/or other ingredients believed to increase energy expenditure and lipolysis, and/or promote fat loss (e.g., aspirin/salicin [Willow Bark Extract], synephrine [Citrus Aurantium, Bitter Orange], forskolin [Coleus Forskohlii]; calcium & sodium phosphate, thyroid stimulators [e.g., guggulsterones, L-tyrosine], cayenne & black pepper, ginger root, etc). Thermogenic weight loss supplements represent one of the largest segments in the weight loss/fat loss supplement category. In 1999 alone, an estimated 12 million people used herbal thermogenic supplements.17

Concerns over the safety of ephedra-containing supplements have been voiced for years. The basis of this concern has primarily come from case reports submitted to the FDA’s Adverse Event Monitoring System (AEMS). The AEMS is a voluntary system of reporting perceived side effects related to taking nutritional supplements. A number of reports to the AEMS have indicated that individuals who were taking ephedra-containing supplements (with or without other supplements) experienced some type of symptom, side effect or adverse event. Based on these reports, the FDA issued a warning about ingesting ephedrine-containing dietary supplements14 and attempted to ban sale of ephedra-containing supplements. The attempt to ban sale of ephedra supplements was quickly rescinded by Congress, which found there was insufficient data to support FDA claims that ephedra was not a safe nutritional supplement.

However, a paper published in the New England Journal of Medicine in the fall of 2000 renewed warnings about ephedra supplements.18 This study evaluated 141 cases reported to the AEMS from 1997 to 1999 that involved ephedra supplements. The researchers reported that it was their view that 31 percent of cases were considered definitely or probably related to the use of supplements containing ephedra alkaloids and 31 percent were deemed possibly related. Of these, 47 percent involved cardiovascular symptoms and 18 percent involved the central nervous system. Hypertension was the single most frequent adverse effect (17 reports), followed by palpitations and/or tachycardia (13); stroke (10); and seizures (7). According to these reviewers, 10 events resulted in death and 13 produced permanent disability. In most instances, excessive amounts of ephedra or ephedrine were apparently consumed (i.e., more than the apparent upper limit of safety of 90 mg/day). The authors concluded that use of dietary supplements containing ephedra alkaloids may pose a health risk to some persons. This report renewed efforts to call for a ban on the sale of herbal ephedra supplements and provided rationale for the NIH to fund a comprehensive study.

Landmark NIH-Sponsored Study

The background information on ephedra was meant to offer a full appreciation of the significance of the results of the latest study on herbal ephedra/caffeine. As you will see, results weren’t exactly what the anti-ephedra establishment had hoped for. The study was conducted by some of the leading obesity researchers in America at St. Luke’s-Roosevelt Hospital, Columbia University in New York and the Beth Israel-Deaconess Medical Center, Harvard Medical School in Boston.16 In the study, 167 overweight but otherwise healthy men and women were randomized to participate in a double blind and placebo controlled study to determine the safety and efficacy of herbal EC supplementation.
Subjects ingested a placebo or an herbal EC supplement 30 minutes prior to eating each of three meals per day for six months. This provided a total of 90 milligrams per day of ephedrine alkaloids (from Ma Huang) with 192 milligrams per day of caffeine (from Kola nut). Compliance in taking the supplements was closely monitored and was reported to be approximately 90 percent for the placebo and EC groups. Subjects were given nutritional education and exercise counseling.

In addition, subjects underwent a comprehensive medical exam and a battery of tests that included determination of body mass; bioimpedance-determined body composition; waist and hip circumference measurements; a comprehensive blood profile (including glucose, blood lipids, liver and renal function tests, electrolytes, complete blood counts, and thyroid stimulating hormone); toxicological analysis of urine; a 12-lead ECG analysis; a 24-hour Holter monitor analysis to assess heart rate and cardiac arrhythmias; ambulatory blood pressure analysis to assess blood pressure throughout the day; and a symptom/side effect review. Subjects underwent testing following one, two, four, 12, and 24 weeks of supplementation.

Results revealed that herbal EC supplementation promoted a significantly greater decrease in body weight (-11.7 vs -5.7 pounds), body fat (-9.5 vs -5.9 pounds) and LDL cholesterol (-8 vs -0 mg/dl) while increasing HDL-cholesterol (+2.7 vs -0.3 mg/dl). These findings support previous research indicating that ephedra/caffeine supplementation promotes weight loss/fat loss and may improve blood lipid profiles. Although these findings are not new, the landmark nature of this study was the comprehensive manner in which side effects were monitored. Safety analysis revealed that herbal EC supplementation promoted small changes in mean heart rate (+4 vs -3 beats/minute) and mean 24-hour blood pressure responses obtained at one, two and four weeks of supplementation (+3 vs -5 mmHg).

However, no significant differences were observed in mean, minimum or maximum systolic or diastolic blood pressure, mean arterial pressure, resting 12-lead ECGs, or the prevalence of cardiac arrhythmia following six months of supplementation. The researchers concluded that the changes in heart rate and blood pressure were marginal and not of clinical significance in a healthy population. Additionally, herbal EC supplementation had no effects on markers of liver function, kidney function, thyroid function, electrolyte levels, or complete blood counts. Analysis of self-reported symptoms revealed that subjects taking herbal EC experienced a slightly greater incidence of dry mouth, heart burn and insomnia, while reporting less incidence of diarrhea. No differences were seen in the incidence of irritability, nausea, chest pain, palpitations, or the number and/or reasons that subjects withdrew from the study. The researchers concluded that “herbal ephedra/caffeine supplementation, when used as directed by healthy overweight men and women in combination with healthy diet and exercise habits, may be beneficial for weight reduction without significantly increased risk of adverse events.”

Analysis of the Controversy

When I read this study, I kept thinking— here we go again, another study showing efficacy and safety of EC supplementation. So far, a number of clinical trials have been conducted to determine whether synthetic or herbal EC supplementation affects body composition and various markers of health. Moreover, a number of studies10,11 have evaluated the efficacy and safety of over-the-counter (OTC) thermogenic supplement formulations (e.g. Hydroxycut®, Xenedrine®, Norexin® and Ripped Fuel® etc). Most studies report positive effects on weight loss/fat loss and body composition with relatively few, if any, side effects reported. Yet, few supplements have created such a whirlwind of controversy.

Some researchers contend that most clinical trials were conducted using synthetic or pharmacological grade EC rather that herbal EC preparations found in dietary supplements that may lack quality control and/or purity.17 Therefore, results from well-controlled clinical trials using synthetic EC cannot be extrapolated to use of herbal EC preparations. Additionally, since naturally occurring ephedra may contain different types of ephedrine alkaloids, which are believed to have different physiological properties, it’s possible some individuals may be more sensitive to having adverse reactions to these various types of ephedrine alkaloids.17 Others contend that since these studies have been conducted on healthy individuals, possible adverse reactions to taking these supplements are unknown in individuals with underlying medical problems that may be contraindicated.16,17 While these concerns are valid, they are based more on speculation rather than any scientific evidence from controlled research studies.

The recent Boozer et al study16 provides the strongest evidence to date that herbal EC supplements are effective and apparently safe when used properly in a healthy but overweight population. Although subjects taking herbal EC experienced some minor side effects, the incidence of occurrence was relatively small and similar to subjects taking placebos in most cases. There was no evidence of an increased risk of significant adverse events such as cardiac arrhythmia, tachycardia, or severe hypertension. This is an important point because concerns are often raised about the safety of taking various supplements (e.g., ephedra, creatine, etc.) based on anecdotal reports of side effects. However, unless the incidence of side effects observed while taking a nutritional supplement is greater than that observed in individuals taking placebos, these side effects may simply reflect a normal rate of occurrence in a given population.

Interestingly, in 1997, the FDA proposed label restrictions for dietary supplements containing ephedrine alkaloids to no more than eight milligrams in a six-hour period, a total daily intake of no more than 24 milligrams per day, and use of ephedrine-containing supplements for no more than seven consecutive days. The FDA indicated that these safety measures were “based on the fact that long-term intake of ephedrine alkaloids increases the likelihood of serious adverse events.”14

In contrast, Cantox Health Sciences International, an independent research group commissioned to evaluate the literature on the safety and efficacy of ephedra by the Center for Responsible Nutrition, concluded that the upper tolerable safety limit for ephedrine was 90 milligrams per day.19 The Boozer et al study16 clearly indicates that ingesting 30 milligrams of ephedrine alkaloids (from Ma Huang) with 63 milligrams of caffeine (from Kola nut) three times per day (a total of 90 mg/day of ephedrine alkaloids and 192 mg/day of caffeine) for six months promoted fat loss and improved lipid profiles without serious adverse events. Obviously, this study and others have not supported the FDA’s position on the safety of dietary supplements containing ephedrine alkaloids. One is left to wonder why the FDA has focused so much attention on these supplements when they allow sale of compounds known to be of greater health risk— like tobacco, alcohol, and OTC cold medications (containing pseudoephedrine) and analgesics such as aspirin and acetaminophen.20-22

Bottom Line

This landmark research study clearly indicates that herbal EC supplementation can promote fat loss and improve blood lipid levels without significant adverse events. These findings add to the growing body of evidence indicating that EC supplementation can serve as an effective fat loss tool when used in a prudent manner in apparently healthy populations. However, herbal EC supplementation may not be for everyone and can be potentially dangerous if misused. Individuals considering use of thermogenic supplements containing EC should carefully consider the potential side effects, discuss possible use with a knowledgeable physician, and not exceed recommended dosages (typically 60-90 mg/day of ephedrine alkaloids and 100-200 mg/day of caffeine). Finally, recommendations about EC-containing dietary supplements (as with any other supplement) should be based on a rational analysis of the scientific and medical literature, not unfounded speculation.

Richard B. Kreider, Ph.D. is Professor and Chair, Department of Health, Human Performance & Recreation, at Baylor University. He is also President of the American Society of Exercise Physiologists. His research focus has been ergogenic aids and human physical performance. A Fellow of the ACSM, he is also the research digest editor for the International Journal of Sport Nutrition and editor of the popular reference Overtraining in Sport.

About The Author:

By Richard B. Kreider PhD, EPC, FACSM – from Fitness Rx Magazine

References

1. Boozer CN, Nasser JA, Heymsfield SB, Wang V, Chen G, Solomon JL. An herbal supplement containing Ma Huang-Guarana for weight loss: a randomized, double-blind trial. Int J Obes Relat Metab Disord. 25:316-24, 2001.
2. Molnar D, Torok K, Erhardt E, Jeges S. Safety and efficacy of treatment with an ephedrine/caffeine mixture. The first double-blind placebo-controlled pilot study in adolescents. Int J Obes Relat Metab Disord. 24(12):1573-8, 2000.
3. Greenway FL, Ryan DH, Bray GA, Rood JC, Tucker EW, Smith SR. Pharmaceutical cost savings of treating obesity with weight loss medications. Obes Res. 7(6):523-31, 1999.
4. Greenway FL, Raum WJ, DeLany JP. The effect of an herbal dietary supplement containing ephedrine and caffeine on oxygen consumption in humans. J Altern Complement Med. 6(6):553-5, 2000.
5. Breum L, Pedersen JK, Ahlstrom F, Frimodt-Moller J. 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. 18(2):99-103, 1994.
6. Astrup A, Breum L, Toubro S. Pharmacological and clinical studies of ephedrine and other thermogenic agonists. Obes Res. 4:537S-540S, 1995.
7. 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. 17(1):S73-8, 1993.
8. Toubro S, Astrup AV, Breum L, Quaade F. Safety and efficacy of long-term treatment with ephedrine, caffeine and an ephedrine/caffeine mixture. Int J Obes Relat Metab Disord. 17(1):S69-72, 1993.
9. Astrup A, Breum L, Toubro S, Hein P, Quaade F. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Int J Obes Relat Metab Disord. 16(4):269-77, 1992.
10. Kalman DS, Colker CM, Shi Q. Effects of a weight loss aid in healthy overweight adults: double blind, placebo-controlled clinical trial. Curr Ther Res. 61(4):199-207, 2000.
11. Colker CM, Torina GC, Swain MA. Double-blind, placebo controlled evaluation of the safety and efficacy of ephedra, caffeine, and salicin for short term weight reduction in overweight subjects. J Exercise Physiology online 2(4):a28, 1999.
12. Carek PJ, Dickerson LM. Current concepts in the pharmacological management of obesity. Drugs. 57(6):883-904, 1999.
13. Atkinson RL, Blank RC, Loper JF, Schumacher D, Lutes RA. Combined drug treatment of obesity Obes Res. 3(S4):497S-500S, 1995.
14. Food & Drug Administration. FDA proposes safety measures for ephedrine dietary supplements. Department of HHS Press Release. June 2, 1997. Available at: http://www.cfsan.fda.gov/~lrd/hhsephed.html
15. Blues Warn of Sports Supplement Dangers. Press release: July 17, 2001. Available: http://www.healthycompetition.org/
16. Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Nasser JA, Strauss R, Merideth T. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obesity. 26:593-604, 2002.
17. Dulloo AG. Herbal simulation of ephedrine and caffeine in treatment of obesity. Int J Obesity. 26:590-592, 2002.
18. Haller CA, Benowitz NL Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 21;343(25):1833-8, 2000.
19. Center for Responsible Nutrition. CANTOX Report: Safety assessment and determination of a tolerable upper limit for ephedra. Available: http://www.crnusa.org/CRNCantoxreportindex.html
20. Andrade SE, Martinez C, Walker AM. Comparative safety evaluation of non-narcotic analgesics. J Clin Epidemiol. 51(12):1357-65, 1998.
21. Curry SJ, Ludman E, Grothaus L, Donovan D, Kim E, Fishman P. At-risk drinking among patients making routine primary care visits. Prev Med. 31(5):595-602, 2000.
22. Single E, Robson L, Xie X, Rehm J. The economic costs of alcohol, tobacco and illicit drugs in Canada, 1992. Addiction. 93(7):991-1006, 1998.

CANTOX Report: Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra

Abstract

The present report critically reviews the available information related to the safety of ephedra/ephedrine alkaloids and establishes a safe upper intake based on the National Academy of Sciences Upper Limit Model (UL) for nutrients. Information that was evaluated included nNonclinical and clinical studies, published case reports, and animal data, along with adverse event reports (AERs) from the medical literature and the voluntary FDA reporting system. called Special Nutritionals/Adverse Event Monitoring System (SN/AEMS) under the direction of the Center for Food Safety and Applied Nutrition (CFSAN) were evaluated. The term Tolerable Upper Intake Level is defined as the maximum level of total chronic daily intake of a substance judged unlikely to pose a risk of adverse health effects to most members of the healthy population, including sensitive individuals, throughout the life stage, except in some discrete subpopulations (for example, those with genetic predispositions or certain disease states) that may be especially vulnerable to one or more adverse effects. Although the model was developed for application to nutrients, these food components are like all chemical agents in that they can produce adverse health effects if intakes are excessive. This UL is intended to provide a safety standard for dietary supplements containing ephedrine ephedra such that no significant or unreasonable risk of illness or injury would arise at or below this intake level under specified conditions of use.

The data evaluation process for the UL method requires the selection of the most appropriate or critical dataset(s) for deriving the UL. In the data evaluation process, and high quality human data are generally preferable to animal data; however, in the absence of appropriate human data, information from an animal species whose biological responses are most like those of humans is used. The available human data provide the most relevant kind of information for hazard identification potential of ephedra/ephedrine alkaloids. In terms of assessing the health effects of chemicals in humans, controlled, prospective clinical investigations provide the most reliable source of information. Following the assessment of the most critical dataset(s), a NOAEL dose or intake level for humans is identified. Based on the strengths of the study design, duration of study, number of subjects enrolled, and endpoints evaluated, 19 studies conducted in adultobese individuals were determined of sufficient quality and extent for inclusion as the critical dataset for the determination of a UL. A No Adverse Effect Level (NOAEL) was identified as 90 mg/day of ephedrine alkaloids in an herbal ephedra supplement, in a recent, well-conducted, placebo-controlled, long-term 6-month investigation by Boozer et al. (2000).

Following characterization of the NOAEL, safety factors or uncertainty factors (UF) are typically applied. Judgments are made regarding uncertainties associated with extrapolating from the observed data to the healthy population. The UF is typically applied to a NOAEL to derive the UL, which generally represents a lower estimate of the threshold above which the there may be a risk of adverse effects may increase. The UFs allocated are dependent on the nature and extent of the toxicity safety database. A UF of 1 was judged appropriate, based on considerations of pharmacokinetics of ephedrine, use patterns, duration of expected use, and animal studies, and the strong scientific findings reported by Boozer et al. (2000) in the 6-month ephedra study, and support ed by the of the clinical findings on ephedrine from Pasquali et al. (1985), Krieger et al. (1990), Astrup et al. (1992), Quaade et al., (1992), Daly et al. (1993), Toubro et al. (1993a,b), Nasser et al. (1999) and Molnár et al., 2000.

Application of the UF of 1 to the NOAEL of 90 derived a UL of 90 mg of ephedrine alkaloids in ephedra per day for a generally healthy population. This daily level of intake is unlikely to pose a risk of adverse health effects. The UL for ephedrine alkaloids in ephedra does not apply to specific groups of persons, and other conditions of use include label instructions that: consumers should check with their healthcare provider about taking the product; direct the consumer to split the daily dose into at least three parts, so that no dose exceeds 30 mg; the product is intended for use of not more than 6 months; and provide information to facilitate post-market monitoring.

Executive Overview

Background

The use of herbal products in the United States has increased dramatically, as evidenced by sales trends. Consumers annually spend approximately $14 billion on dietary supplements. The dietary supplement industry estimates that as many as 2 to 3 billion doses of dietary supplements containing ephedrine alkaloids as part of botanical ingredients are consumed each year in the United States (GAO, 1999; AHPA, 2000) primarily for weight loss and/or energy enhancement. Many botanical ingredients found in herbal products are generally regarded as safe; however, when not used properly, they can result in effects that are distinct from expected physiological responses to the agent.

Ephedra refers to a plant genus containing approximately 40 species throughout regions of Europe, Asia, and America. Only a few Ephedra species contain the alkaloid ephedrine, which was first isolated in 1885. In most species used commercially, the dominant alkaloid is ephedrine, which usually comprises between 40 to 90% of total alkaloids in the plant, depending on the species and other factors. Other related alkaloids are also present, such as pseudoephedrine, N-methylephedrine, N-methylpseudoephedrine, norpseudoephedrine and norephedrine (phenylpropanolamine). These alkaloids have been collectively termed ephedrine-type alkaloids, or simply ephedrine alkaloids. Proportions and total levels can vary from one species to another, time of year of harvest, weather conditions and altitude. Ephedrine content generally is 4 to 5 times greater than pseudoephedrine, but some sources of ephedra contain a 2:1 ratio of ephedrine and pseudoephedrine.

In general, all the ephedrine-type alkaloids (also referred to herein as “ephedrine alkaloids”) contained in Ephedra species show significant differences between diastereomers (e.g., ephedrine and pseudoephedrine) with regard to pharmacokinetic and pharmacodynamic effects. All have effects on the cardiovascular and respiratory system, but not to the same degree. It is important to note that the pharmacokinetic and toxicokinetic behavior of any isomer cannot be used with precision to predict that of any other ephedrine alkaloid isomers. In the literature, statements regarding ephedrine alkaloids sometimes consider them to be synonymous, which implies that the pharmacological activity of a particular alkaloid is equipotent and that the toxicity of all diasteromers is equivalent, which is not the case. In the assessment of all the evidence relevant to the safety of ephedra, literature on ephedrine is evaluated and the differences or similarities are recognized.

The physiological characteristics of Ephedra species are dependent upon its chemical composition. Since ephedrine is the dominant ephedrine alkaloid isomer of most Asian Ephedra species, the characteristics of ephedrine would provide a good indicator of the expected chemistry, pharmacology, and toxicology. Ephedra, for the purposes of this report, will generally refer to the complex mixtures that are extracts of the branchlets of Asian Ephedra species known as ma huang, or products containing these extracts. These ephedra extracts typically contain 6-8% ephedrine alkaloids. As with any mixture, the characteristics of only one, albeit major, component cannot account for all the constituents of ephedra, but ephedrine represents a significant portion of ephedra’s activity. Furthermore, since the effects of pseudoephedrine are somewhat weaker with respect to hypertensive effects and stimulation of the central nervous system, an assessment based on the ephedrine as a surrogate for total ephedrine alkaloid content provides a conservative evaluation of risk. Recently released data from the six-month, randomized, placebo-controlled clinical trial on ephedra performed by Columbia and Harvard universities (Boozer et al., 2000) made a major contribution to the database. Thus, information on ephedra itself, in addition to that on ephedrine, is relied upon in the risk assessment.

Objective of Risk Assessment

The purpose of the present report is to critically review the available information related to the safety of ephedra/ephedrine alkaloids. Nonclinical and clinical studies, published case reports, and animal data, along with adverse event reports (AERs) from the medical literature and the voluntary reporting system called Special Nutritionals/Adverse Event Monitoring System (SN/AEMS) under the direction of the Center for Food Safety and Applied Nutrition (CFSAN), were evaluated. The objective of this review was to establish a safe upper intake based on the National Academy of Sciences Upper Limit Model for nutrients. This Upper Limit (UL) is intended to provide a safety standard for dietary supplements containing ephedrine such that no significant or unreasonable risk of illness or injury would arise at or below this intake level. No attempt was made to review or comment on findings related to the potential benefits of ephedra/ephedrine alkaloids, or any risk versus benefit considerations.

The UL Model

The method used to establish a UL for ephedra/ephedrine alkaloids intake is the Tolerable Upper Intake Level risk assessment model (Food and Nutrition Board, 1998). The term Tolerable Upper Intake Level is defined as the maximum level of total chronic daily intake of a substance judged unlikely to pose a risk of adverse health effects to the most sensitive members of the healthy population. Although the model was developed for application to nutrients, these food components are like all chemical agents in that they can produce adverse health effects if intakes are excessive. In the UL model, as in all other risk assessment models, it is not possible to identify a single, realistic “risk-free” intake level for a nutrient that can be applied with certainty to all members of a population. It is possible to develop intake levels that are unlikely to pose risks of adverse health effects to most members of the healthy population, including sensitive individuals, throughout the life stage, except in some discrete subpopulations (for example, those with genetic predispositions or certain disease states) that may be especially vulnerable to one or more adverse effects.

The UL for ephedrine alkaloids in ephedra does not apply to specific groups of persons. In particular, ephedrine and related agents should not be taken by individuals with coronary thrombosis, diabetes, glaucoma, heart disease, hypertension, thyroid disease, impaired circulation of the cerebrum, pheochromocytoma (a type of adrenal cancer that releases epinephrine), or enlarged prostate. Patients with renal impairment may be at special risk for toxicity. Persons taking ephedrine alkaloid drugs, due to cumulative intake, should not consume ephedra-containing dietary supplements, and ephedra is contraindicated for persons taking monomine oxidase inhibitor drugs. Furthermore, ephedrine is not intended for use in infants, children, adolescents younger than 18 years, and pregnant or lactating women.

Data Evaluation

The data evaluation process for the UL method, as well as other common risk assessment techniques, requires the selection of the most appropriate or critical dataset(s) for deriving the UL. In the data evaluation process, high quality human data are generally preferable to animal data; however, in the absence of appropriate human data, information from an animal species whose biological responses are most like those of humans is used. The available human data provide the most relevant kind of information for hazard identification of ephedrine. Although the typical focus of the majority of clinical studies was efficacy, taken collectively with the recent clinical trial on safety and benefit (Boozer et al., 2000) they are of sufficient quality and extent to draw conclusions on the safety of ephedra. Observational data in the form of case reports were evaluated for their usefulness in developing hypotheses/relationships between exposure and effect.

The analysis of the clinical database involved a review of published case reports and of clinical trials and investigations involving normal healthy individuals, under special conditions (i.e., exercise) and special populations (e.g., obese, asthmatic). Spontaneous adverse events captured and reported by FDA were analyzed in Appendix A of the full report. Examination of clinical trials involving the use of ephedrine was limited to studies that investigated safety parameters. While valid and pertinent human data were considered superior to data derived from animals when assessing the potential risks to humans from exposure to chemicals, any data deficiencies in the human data must be explicitly considered.

In terms of assessing the health effects of chemicals in humans, controlled, prospective clinical investigations provide the most reliable source of information. For example, studies of this type are used to provide information related to the efficacy and safety of new pharmaceuticals (after appropriate animal testing has defined potential risks and supported the investigational dosing of humans). For most chemicals to which humans are exposed, prospective human studies are unavailable, and as a result, relevant information related to their health effects must be obtained retrospectively through the use of epidemiological methods, using standard principles, in an attempt to establish causation and dose-response relationships. Another source of information on the adverse effects of agents in humans is case reports. These are typically based upon observations in individuals or small groups and they serve the critical function of alerting the medical/scientific community to possible adverse events. Individual case reports generally cannot be relied upon to establish a cause-effect relationship, but confidence in the findings of individual reports increases when there is consistency in the observations published by different authors. As with all scientific investigations, case-reports must be carefully reviewed for limitations in methodology and the findings interpreted in the light of the weight-of-evidence. Finally, with respect to the FDA AER database for ephedra, reviewed in Appendix A, the reliability of the reported information was a major concern, (e.g., missing information, elapsed time before reporting). Only 10% of the reported AERs contained a minimally sufficient quantity of information, and no conclusive determination of unexpected effects or causality was possible.

Toxicology Studies

The nonclinical toxicology of ephedrine and ephedra was reviewed to assess its consistency with data obtained from clinical studies. The studies evaluated addressed the acute, subchronic and chronic safety, carcinogenicity, reproductive toxicity, and mutagenicity of ephedrine. Where available, data related to ephedra are emphasized; however, the database on ephedrine makes a significant contribution to the total evidence relevant to ephedra, and thus was considered in the risk assessment.

It is interesting to note that one study in the nonclinical literature compared the acute toxicity of ephedrine to that of botanical ephedra extract. Although only one study was located in the literature which compared the effects of ephedra versus ephedrine, these results support the conservative assumption that ephedrine can be used in a safety assessment as a surrogate for ephedra, since the potency of ephedrine overestimates the potential potency of ephedra itself.

The National Toxicology Program (NTP) studies, given the quality of the investigations, were used to support for the derivation of a UL based on the clinical data. Rat carcinogenicity data (103-week duration) were used, since mice were less sensitive to the effects of ephedrine. Thus, the use of the rat species conservatively estimates a lifetime No-Observed-Adverse-Effect Level (NOAEL) value. A NOAEL value was obtained in male rats, at an average daily consumption of approximately 9 mg/kg body weight/day. A dose of 9 mg/kg body weight/day from the male rat data extrapolated to a 60 kg (132 lb) person would be 540 mg/day.

Clinical Studies

Nine studies in normal healthy individuals investigated the effects of ephedrine intake (Bye et al., 1974; Drew et al., 1978; Kuitunen et al., 1984; Astrup et al., 1991; Astrup and Toubro, 1993; Liu et al., 1995; White et al., 1997; Gurley et al., 1998a; Shannon et al., 1999). Ephedrine exposures involved oral administration over a short-duration such as 24-hours. The range of total doses within these 9 studies was from 10 to 150 mg/day, given at a frequency of 1 to 3 times/day to achieve daily maximum specified. The foremost weakness in this healthy population dataset was its limited duration (<24 h) that reduces the utility of these data in the assessment of the UL. Nevertheless, these data are used to support the database in obese but healthy subjects.

Five studies in healthy normal individuals investigated the effects of exercise/physical parameters together with ephedrine use (Sidney and Lefcoe, 1977; Strömberg et al., 1992; Vanakoski et al., 1993; Bell et al., 1998; Bell and Jacobs, 1999). The range of total doses within these 5 studies was from 24 to 81 mg/day together with exercise, or some physical parameters, over a short duration of exposure (typically 24 hours).

Twenty studies in obese, but otherwise reportedly healthy individuals (19 in adults and 1 in children), investigated the effects of ephedrine intake (Astrup et al., 1985, 1992; Pasquali et al., 1985, 1987, 1992; Krieger et al., 1990; Daly et al., 1993; Molnár, 1993; Toubro et al., 1993a,b; Breum et al., 1994; Buemann et al., 1994; Kaats and Adelman, 1994; Moheb et al., 1998; Waluga et al., 1998; Nasser et al., 1999; Huber, 1999,2000; Boozer et al., 2000; Molnár et al., 2000 ). Ephedrine exposures involved oral administration over durations from 10 days to 26 months. The range of total doses within these studies was from 50 to 150 mg/day, given at frequencies of 1 to 3 times/day to achieve the daily maximum specified. Based on the strengths of the study design, duration of study, number of subjects enrolled and endpoints evaluated, studies conducted in obese individuals were determined to be of sufficient quality and extent for inclusion as the critical dataset for the determination of a UL. In particular, given the quality of design and protocol, the Columbia/Harvard clinical trial conducted by Boozer et al. (2000), was used to derive the UL which is supported by several other studies from the clinical literature.

The clinical database that has been considered involved administration of ephedrine singly, ephedrine together with other components such as caffeine and/or acetylsalicylic acid (ASA) or ephedra with caffeine. Since many dietary supplements which contain ephedrine often contain other ingredients, including these data in the safety assessment of ephedrine is relevant, especially given that these other ingredients are major components of ephedra preparations. The pharmacology of individual ephedrine-type alkaloids has been well characterized, but the effects of combinations of these other compounds are less well known. In addition, interactions between ephedrine-type alkaloids and xanthine alkaloids (e.g., caffeine), as well as biologically active compounds in other plant species that are constituents of many dietary supplements, have yet to be fully characterized. This risk assessment assumes that a combination product (i.e., ephedra together with a caffeine-containing ingredient) would be no more or less active than an equivalent dose of ephedrine singly. Since combination products were given in many of the clinical studies, this report evaluated the contribution/interaction of other ingredients typically contained in ephedrine preparations, insofar as they contribute to the analysis of ephedra itself.

Determination of Upper Limit (UL)

Following the assessment of the most appropriate or critical dataset(s), a NOAEL dose or intake level for humans is identified. In the absence of a NOAEL determination, a Lowest Observed Adverse Effect Level (LOAEL) is chosen. In principle, the primary aim of safety studies is to recognize the potential hazards associated with a particular chemical and identify a NOAEL or LOAEL from the dose-response data. Monitoring data for adverse effects following ephedra intake in obese individuals were used to identify the NOAEL of 90 mg/day, with the ephedra clinical trial by Boozer et al. (2000) identified as the critical study.

Following characterization of the NOAEL, safety factors or uncertainty factors are typically applied. Judgments are made regarding uncertainties associated with extrapolating from the observed data to the healthy population. The UF is typically applied to a NOAEL or LOAEL to derive the UL, which generally represents a lower estimate of the threshold above which the risk of adverse effects may increase. The application of safety factors or uncertainty factors has been used for over 30 years in the determination of a safe level of exposure to chemicals based on the studies in experimental animals and humans (Renwick, 1995). The UFs allocated are dependent on the nature and extent of the toxicity database.

A UF of 1 was judged appropriate, based on considerations of pharmacokinetics of ephedrine, use patterns, duration of expected use, and animal studies and the strong scientific findings reported by Boozer et al. (2000) and supported by the clinical findings from Pasquali et al. (1985), Krieger et al. (1990), Astrup et al. (1992), Quaade et al., (1992), Daly et al. (1993), Toubro et al. (1993a,b), Nasser et al. (1999) and Molnár et al., 2000. Given the quality of the long-term investigation of ephedrine alkaloids in an herbal ephedra supplement by Boozer et al. (2000), this study represents a pivotal clinical study in the safety evaluation of ephedra.

Application of the UF of 1 to the NOAEL of 90 derived a UL of 90 mg of ephedrine alkaloids in ephedra per day for a generally healthy population. This daily level of intake is unlikely to pose a risk of adverse health effects. Label instructions together with considerations of pharmacokinetics of ephedrine, use patterns, duration of expected use, and supportive animal studies further support a UF of 1. Label instructions would include statements that (1) consumers should check with their healthcare provider about taking the product; (2) use is contraindicated for certain people; (3) direct the consumer to split the daily dose into at least three parts, so that no dose exceeds 30 mg; (4) the product is intended for use of not more than 6 months; (5) persons younger than 18 years should not use the product; (6) pregnant and lactating women should not use the product; and (7) provide information to facilitate post-market monitoring.

Conclusion

For healthy adults:

NOAEL = 90 mg/day, and UF =1

UL = 90 mg/day total ephedrine alkaloids from ephedra

Obesity Statistics

According to a Study Released Recently by the U.S. Centers for Disease Control and Prevention (CDC):

• Nearly 40 million American adults are obese;
• The national obesity average has increased to 19.8% in 2000, up from 12% in 1991;
• Obesity-related diseases — “implicated” in 300,000 deaths annually — represent the second-leading cause of premature death in the U.S., behind smoking;
• The increase in obesity among Americans has contributed to a “parallel rise” in diabetes, with 15 million adult-onset cases diagnosed last year, compared with nine million in 1991; and
• CDC found that the “twin epidemics” of diabetes and obesity threaten to overwhelm the health care system.
• In 2000, the states with the highest percentage of obese individuals were Mississippi (24.3%), Alabama (23.5%) and West Virginia (22.8%)

Drs. Roland Sturm and Kenneth Wells of RAND, a nonprofit institution that helps improve policy and decision-making through research and analysis, studied the comparative effects of obesity, heavy drinking, and poverty on chronic health conditions and health expenditures. They discovered the following:

• Obesity is linked to very high rates of chronic illnesses (in terms of chronic conditions, being obese is like aging from 30 to 50).
• Obese Individuals spend more on health care (more is spent on services and medication than daily smokers and heavy drinkers).
• Obesity has become an epidemic (approximately 23 percent of Americans are obese).

For more information on overweight & obesity go to: http://www.cdc.gov/obesity/index.html
The following statistics are from The National Institute of Diabetes and Digestive and Kidney Diseases, a branch of the National Institutes of Health:

• Total number of overweight adults (20-74 years old): Approximately 58 million Americans, or about one-third
• Overweight adult females (20-74 years old): 32 million, as of 1990
• Overweight adult males (20-74 years old): 26 million, as of 1990
• Percentage of adult American women trying to lose weight at any given time: 35-40 percent
• Percentage of adult American men trying to lose weight at any given time: 20-24 percent
• Percentage of cardiovascular disease cases related to obesity: Nearly 70 percent
• Effect of obesity on high blood pressure: More than doubles one’s chances of developing high blood pressure

According to The National Women’s Health Resource Center:

• While Americans’ fat consumption has decreased over the past several decades from 40 percent to 34 percent, their rate of obesity has risen from 12 percent in 1991 to as much as 33 percent today.
• Another contributing factor to obesity: 60 percent of Americans don’t meet basic activity level recommendations, and 25 percent are completely sedentary.
• Obesity results in $100 billion in healthcare costs each year in the United States.
• One measure of obesity is your body mass index (BMI), which can be determined by dividing your weight in pounds by your height in inches squared and then multiplying by 705. For example, a woman who is 5′6″ and weighs 190 would have a BMI of 31, as follows:
  

  5′6″ = 66 inches 66 squared = 4356
  190 divided by 4356 = 0.0436
  0.0436 x 705 = 30.75 (rounded up to 31)

• If a woman’s BMI is 30 or greater, she is considered obese. Forty or more puts her in the severely obese category. However, if she has more muscle mass than normal, these numbers won’t apply, and her healthcare professional should measure her body composition to determine her degree of overweight.
• If a woman’s waist circumference is more than 35 inches, she is considered to have a high amount of visceral fat, which is the type of fat that surrounds the internal organs. This type of fat is associated with higher risk of certain diseases and conditions like diabetes and heart disease.
• If you eat 250 calories per day fewer than needed to maintain your weight, and exercise enough to burn an additional 250 calories a day, you will lose about a pound per week.
• Your basal metabolic rate, or the number of calories your body needs just to maintain its basic functions, is determined by multiplying your current weight by 10. You need additional calories to provide energy for daily activities; the more active you are, the more calories you need.

Harvard/Columbia Study: Herbal Ephedra/Caffeine for Weight Loss: A 6-Month Safety and Efficacy Trial

The data from this double-blind, placebo-controlled clinical study was published in the May 2002 issue of the International Journal of Obesity (IJO). The study, which used Holter monitors to provide extensive data on heart function and blood pressure, was designed to assess both the safety and efficacy of a “generic” Ephedra/caffeine combination product at a dose of 30 mg of ephedrine alkaloids per serving three times per day. Dr. Carol Boozer and Dr. Patricia Daly, study authors, concluded that:

…herbal ephedrine/caffeine herbal supplements, when used as directed by healthy overweight men and women in combination with healthy diet and exercise habits, may be beneficial for weight reduction without significantly increased risk of adverse events.

OVERVIEW: HARVARD/COLUMBIA LONG-TERM SAFETY AND EFFICACY TRIAL

Harvard/Columbia Long-Term Safety And Efficacy Trial Study Overview

On April 25, 2002, the International Journal of Obesity published the results of “the first reported long-term, clinical trial of a herbal preparation containing ephedrine alkaloids and caffeine in combination.” The trial was a prospective, two-arm, six-month, randomized, double-blind, placebo-controlled, clinical safety and efficacy trial conducted at two sites. The trial was conducted by a team of researchers, including Dr. Carol Boozer, the director of the New York Obesity Research Center, at St. Luke’s-Roosevelt Hospital and Columbia University, and Dr. Patricia Daly, formerly a professor at Beth Israel Medical Center, at Harvard Medical School¹.

Summary

• Safety: The researchers concluded that “[c]ompared with placebo, the tested product produced no adverse events and minimal side effects that are consistent with the known mechanisms of action of ephedrine and caffeine.” In fact, the number of research subjects removed from the study for potential treatment-related adverse events were similar in the active and placebo groups (collectively the “treatment groups”). The researchers noted that there “were no significant differences between treatment groups in self-reported chest pain, palpitations, blurred vision, headache, nausea or irritability at any time point.”
• Benefits: The researchers concluded that “[t]he present study demonstrated significant beneficial effects on body weight, body fat and blood lipids of a herbal Ma Huang/Kola nut mixture (90/192 mg/day ephedrine alkaloids/caffeine) in overweight men and women who were otherwise healthy. Moreover, the herbal combination promoted significantly greater reductions in waist and hip circumference in overweight subjects compared with placebo-treated subjects.
• Overall: The researchers concluded that “herbal ephedra/caffeine (90/192 mg/day) promoted body weight and body fat rejection and improved blood lipids without significant adverse events.”

Study Protocol ‚ The prospective, two-arm, six-month, randomized, double-blind, placebo-controlled trial involved 167 overweight subjects (84 subjects assigned to the placebo group and 83 subjects assigned to the ephedra/caffeine alkaloid group). For 6 months, the subjects were given either a placebo or 90 mg of ephedrine alkaloids, from herbal ephedra, and 192 mg of caffeine alkaloids, from Kola nut, per day in 3 divided doses, as well as diet and exercise counseling. Specifically, at randomization, the subjects were counseled to eat normally (but limit intake of dietary fat to 30% of calories) and to exercise moderately (e.g. walk 30 minutes per day, three times a week). Baseline and follow-up evaluations of the subjects included 24-hour blood pressure and cardiac Holter monitoring, as well as EKGs, routine laboratory tests, and urine samples.

Study Observations ‚ The treated group had significantly greater reductions in body weight, body fat, and waist and hip circumference than the placebo group. For example, subjects in the treated group lost an average of 11.7 pounds (5.3 kg) during the study, compared to an average of 5.7 pounds (2.6 kg) in the placebo group. The greater weight loss in the treated group was accompanied by improved cholesterol and blood glucose levels. The researchers observed small increases in heart rate and blood pressure variables in the treated group, without any increases in heart irregularities such as cardiac arrhythmias.

Side-Effects ‚ The researchers concluded that “[c]ompared with placebo, the tested product produced no adverse events and minimal side effects that are consistent with the known mechanisms of action of ephedrine and caffeine.” No subject in the study suffered from a serious adverse event, and the side-effects in both groups were transient and mild. The researchers noted that “[t]he symptoms that subjects reported to be most consistently increased by the herbal vs the placebo treatment were dry mouth, heartburn and insomnia.”

Withdrawals ‚ More subjects withdrew from the placebo group than the treatment group. Specifically, of the 80 subjects who withdrew from the study, 37 were from the treated group and 43 were from the placebo group. More than 50% of the withdrawals in both groups were not side-effect related. Moreover, the number of subjects removed from the study for a potential treatment-related side-effect was almost identical in the treatment and placebo groups. The researchers noted that “[t]here were no significant differences between treatment groups in self-reported chest pain, palpitations, blurred vision, headache, nausea or irritability at any time point.”

Impact of Clinical Research on Adverse Event Reports (”AERs”) ‚ As noted by the researchers, the absence of adverse effects in this study, and two previous studies on herbal ephedra/caffeine alkaloids, leads one to question how such results can be reconciled with the AERs that have been collected by the Food and Drug Administration (”FDA”). Although possible explanations vary, the researchers stated: “With millions of Americans consuming ephedra containing products, it is obvious that some number of adverse events is expected each year regardless of consumption of these products. The real question is not whether adverse events occur in a population undergoing treatment, but whether these occur at a rate that is higher than that of a matched, untreated group. This is impossible to determine from adverse event reports alone. The randomized, placebo-controlled trial allows evaluation of cause and effect relationships vs coincidental events.”

Conclusion ‚ The researchers stated the following: “Evidence from three completed placebo-controlled clinical trials of herbal ephedra/caffeine is consistent with that from a large number of studies with synthetic ephedrine/caffeine. In total, these suggest that herbal ephedra/caffeine herbal supplements, when used as directed by healthy overweight men and women in combination with healthy diet and exercise habits, may be beneficial for weight reduction without significantly increased risk of adverse events. The current widespread usage of herbal products and the increasing incidence of obesity warrant additional clinical trials to confirm and extend these results.”

¹Science Toxicology and Technology Consulting provided research support for the study, and the researchers were granted the right to publish study results regardless of outcome. Funding was provided by the Ephedra Research Foundation.