U.S. House of Representatives: Committee on Energy and Commerce, Republicans Prepared Witness Testimony: Heymsfield, Steven

Subcommittee on Oversight and Investigations
July 23, 2003
10:00 AM
2123 Rayburn House Office Building

Dr. Steven Heymsfield M.D.
Deputy Director
Obesity Research Center St. Luke's-Roosevelt Hospital
1111 Amsterdam Avenue
New York, NY, 10025

There exist three categories of chemical agents available for weight loss treatment. The first two categories are prescription drugs and over-the-counter drugs. The Federal Drug Administration (FDA) regulates these agents under carefully controlled guidelines for safety and efficacy. The process is particularly rigorous for weight loss agents as over 60% of Americans are now overweight or obese, excess adiposity effects increasing numbers of vulnerable children and adolescents, and drug treatments for weight loss have a notorious past history of both abuse and damaging physical and behavioral effects extending back over a century. Prescription and over-the-counter drugs are rigorously tested using modern scientific guidelines and procedures to ensure public and individual safety.

In 1994 a third category of agents emerged referred to as "dietary supplements". The term dietary supplements is a legal one as stated by the FDA: "FDA regulates dietary supplements under a different set of regulations than those covering "conventional" foods and drug products (prescription and Over-the-Counter). Under the Dietary Supplement Health and Education Act of 1994 (DSHEA), the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed. FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market. Generally, manufacturers do not need to register with FDA nor get FDA approval before producing or selling dietary supplements. Manufacturers must make sure that product label information is truthful and not misleading. FDA's post-marketing responsibilities include monitoring safety, e.g. voluntary dietary supplement adverse event reporting, and product information, such as labeling, claims, package inserts, and accompanying literature. The Federal Trade Commission regulates dietary supplement advertising." Dietary supplements for weight loss, unlike traditional drugs, often include multiple ingredients; the word "supplement" is misleading as most agents do not "add" to the natural body stores of the compound nor does the agent usually prevent or correct a deficiency state.

Weight loss can be produced when ingestion or absorption of calories or energy is less than energy released from the body as heat. Dietary supplements purportedly produce weight loss by suppressing appetite, reducing absorption, increasing heat production or metabolic rate, and changing the proportion of calories stored as fat and muscle.

The ephedra alkaloids, discussed below, are thought to suppress appetite and increase energy expenditure, by two different mechanisms. These actions are enhanced with herbal sources of caffeine and aspirin are added to the ephedra-containing product.

Some agents are reported to reduce fat and thus energy absorption from the gastrointestinal tract, notably chitosan. Chitin is a substance derived from the exoskeletons (shells) of arthropods such as crabs, shrimps, and lobster.

Some dietary supplements reportedly increase the storage of ingested nutrient as muscle and decrease the proportion stored as fat. These include the herbal ingredient garcinia cambogia and the widely used group of compounds referred to as chromium picolinate and other chromium salts.

I would now like to focus some specific comments on dietary supplements that include MaHuang as the main active ingredient. I select MaHuang because consumers are exposed with these products to a potentially dangerous family of ingredients, the ephedra alkaloids, that not only produce weight loss but that may lead to strokes and heart attacks with associated disability and death in selected susceptible patients.

A key concern is that overweight and obese patients are particularly vulnerable to taking purported dietary supplement weight loss products because they are often desperate, want to lose weight quickly, find physician evaluations time consuming and costly, and have often tried dietary and medical therapies of limited current effectiveness.

By avoiding medical oversight, overweight and obese consumers purchasing dietary supplements make the false assumption that dietary supplements and herbal preparations are inordinately safe and may pose no or very little risk. Moreover, many overweight and obese consumers harbor "silent" diseases such as high blood pressure and narrowing of the coronary arteries that manifest under the biological conditions produced with ingestion of the purported weight loss agent. The overweight consumer of dietary supplements who harbors a potentially silent killer may be bypassing the critical medical oversight needed to detect, prevent, or treat a serious underlying medical condition. A large percentage of overweight and obese Americans have undiagnosed and untreated medical conditions (2).

MaHuang, now defined as a dietary supplement in the US, is primarily used today as an ingredient in herbal weight loss products and acts to lower appetite and potentially increases energy expenditure through stimulant mechanisms (3-12).

MaHuang is the Chinese name of Ephedra sinica, an acrid tasting stimulant herb (1). Other Ephedra species include Ephedra equisentina and Ephedra intermedia.

The ephedra alkaloids represent a family of compounds that vary in proportion depending on plant species, harvest season, weather conditions, geographic location, and other factors. The ephedra content of dietary may vary substantially from label claims (13).

The ephedra alkaloids include the major component, up to 90%, (-)-ephedrine, up to 30% pseudoephedrine, and lesser amounts of (+/-)-norephedrine or phenylpropanolamine, and (+)-norpseudoephedrine or cathine. The +/- refers to the three dimensional positioning of atoms within the molecule and this feature of a molecule may influence its biological activity.

Ephedrine, an ephedra extract, was synthesized in 1927 and is also widely used today in weight loss and other pharmaceutical preparations, particularly in Europe. Although studies are limited, the pharmacokinetics of synthetic and botanical forms of ephedrine appear similar (14; Appendix I); some questions on drug disposition remain and more studies are needed (15). Pharmacokinetic properties of a drug describe its absorption, distribution, and elimination from the body.

The chemical structures of ephedrine and other ephedra alkaloids are very similar to the hormones epinephrine or adrenaline and nor-epinephrine. These are the "flight and fight" hormones that have many important biological effects including increasing blood pressure, respiration, heart rate, and arousal. Ephedra alkaloids are also very similar in structure to the banned group of chemical compounds referred to as amphetamines (Appendix II). Widely used five decades ago for weight loss and other stimulant effects, amphetamines are addicting and have many serious other side effects.

Ephedrine alkaloids appear to exert their main weight loss effects by suppressing appetite and thus food intake via central "sympathomimetic" (beta-agonist) actions. Ephedrine alkaloids also appear to have a small effect on increasing energy expenditure (16). Taken collectively, the ephedra family of compounds promotes negative energy balance and weight loss by lowering both energy intake and increasing energy expenditure. Ephedrine and other Ephedra alkaloids have variable stimulant effects (1,16).

Ephedrine and ephedra alkaloids alone have modest weight loss effects and their efficacy appears to be enhanced by addition of caffeine and aspirin either as the pharmaceutical grade ingredients or as their natural counterparts such as Guarana and Willow-bark, respectively (17-21).

Addition of caffeine (i.e., "Guarana") and aspirin (i.e., Willow-bark) to MaHuang purportedly potentiates the actions of ephedrine. Caffeine competitively antagonizes adenosine receptors and may be an adrenaline antagonist; adenosine is a hormone produced by endothelial cells that dilates blood vessels. Many commercial weight loss preparations include varying proportions of these three components. Caffeine has a small thermogenic (i.e., heat-producing) effect in humans (16,17). Aspirin has actions that also potentiate ephedrine actions.

There are many studies that have examined the effectiveness of ephedrine alone or in combination with other ingredients; fewer studies examine the weight loss effects of ephedra alkaloids in combination with other natural sources of caffeine and aspirin.

The collective studies strongly support the premise that ephedrine, particularly in combination with caffeine and also aspirin, promote significant short-term (~3-6 months) weight loss when ingested as part of an intervention program including dietary and lifestyle management. Long-term (>6 months) controlled trials with large and diverse subject populations are lacking. The evidence for ephedra efficacy is summarized in the recent Rand Report (Appendix III).

The efficacy of MaHuang, separate from that of chemically synthesized ephedrine, is supported by fewer published abstracts and papers, although conceptually, there is no reason to expect a "large" difference between "natural" ephedra and chemically-synthesized ephedrine. As noted earlier, the pharmacokinetics of chemically synthesized and botanical sources of ephedrine appear similar (Appendix I).

A major limitation of reviewed research is that most studies administered ephedrine or MaHuang in forms that mimic commercially available preparations and thus: the efficacy of ephedrine as a sole weight loss agent is not entirely clear and is questionable; the efficacy of ephedrine with varying amounts of caffeine and aspirin is difficult to ascertain as studies failed to include varying amounts of these other agents independent of ephedrine or as separate experimental limbs in controlled trials.

Ephedrine is used in association with caffeine and aspirin, or their herbal equivalents guarana and willow bark, to produce the "fat-burning stack (18)." The stack has some evidence to support its efficacy and is used in Europe. The three compounds, when taken in the following ratio, 200 mg caffeine/60mg epihedrine/300mg aspirin, produces a significant thermogenic effect. Very limited published information is available on the safety and efficacy of the "stack" or related products.

A concern is that the concentration of ephedrine in the plant and method of preparation vary widely among products (13). Product labels may therefore not reflect actual ingredient content or bioavailability.

Why do we know that ephedra alkaloids may be unsafe in some consumers? Scientists know that ephedra alkaloids, particular when used in combination with potentiating agents that include caffeine and aspirin, produce variable increases in blood pressure, heart rate, cardiac output, and respiration (Table 1). These effects in susceptible individuals can trigger heart attacks and strokes. These effects are well summarized in JAMA's patient page attached in Appendix IV.

The molecular basis of the stimulant effect for the class of compounds, "sympathomimetic agents", is well known. While the effects of ephedra alkaloids alone or in combination are often small in magnitude and transient, given the large and potentially medically vulnerable obese population taking these agents we can predict that some individuals will have a relatively large drug-induced biological effect. Others may have only a small effect, but remain medically vulnerable due to silent underlying heart or cerebrovascular diseases. Many of the patients taking these agents do so in the complete absence of medical supervision or evaluation. They may inadvertently take a large dose due to product variation or consciously in the hope of boosting their weight loss. Unsupervised, they may unduly exercise or take excessive amounts of caffeinated beverages or aspirin. The predictable result, given the millions of Americans taking these products, is serious medical events including heart attacks and strokes.

Given the well-recognized risks of this group of dietary supplements and the appropriate lack of interest in the area by pharmaceutical companies, there exist very few careful safety and efficacy trials that meet the current standards set forth for evaluation of pharmaceutical weight loss agents.

In the studies carried out by my colleagues and I using a commercial weight loss product containing ephedra and caffeine as active ingredients, some patients in the "active" treatment group experienced untoward effects at "usual" doses such as palpitations, blood pressure elevations, and other typical stimulant effects that led to their discontinuation in the study (21). I have observed similar effects in other unpublished ephedra studies carried out at our institution. These effects are the well characterized sympathomimetic effects that I mentioned earlier and that support our projection that some medically unscreened patients with underlying disease may suffer heart attacks and strokes following ingestion of this or similar dietary supplements. This projection is supported by the study of Haller and Benowitz (23)(Appendix V) and Bent et al (Appendix VI).

A concern regarding the well controlled clinical trials is that subjects were appropriately medically screened prior to entry into the trial so as to reduce the medical risks of those exposed. One such trial was carried out at our institution (22) and only those subjects deemed medically acceptable were entered into treatment. Rigorous testing of blood pressure and heart rhythm was used to detect and eliminate those subjects who may have suffered a serious adverse event during the trial. The lack of serious injuries and side effects in trials such as these cannot be interpreted as a safety endorsement as the actual consumer population still includes the medically vulnerable and unscreened individual who may harbor a potentially lethal silent disease manifest by ingestion of ephedra alkaloids.

Specifically, concerns have been raised about the safety of products containing MaHuang/ephedra. Several serious case-reports of adverse effects and fatalities have appeared in the literature. Strokes, myocardial infarction, and cardiac arrhythmias are reported in association with ephedra ingestion. Benowitz and Haller (23; Appendix VI) provided the FDA with an independent review of adverse events related to ephedra alkaloid containing supplements. The authors concluded that ephedra alkaloids may pose a health risk for selected individuals. Some of the reported side effects in patients occurred within the commonly used therapeutic ranges.

Ephedrine alone or combination with other ingredients may raise heart rate and blood pressure (e.g., systolic BP increase ~3-7 mmHg) in some subjects (1-23), although the magnitude and length of time for which these adverse effects remain evident is not well established. Restlessness, headache, and insomnia have been reported by subjects ingesting some commercial dietary supplements and with synthetic ephedrine-caffeine combinations. Subjects with bleeding tendencies may be at risk when taking aspirin-like compounds.

MaHuang taken alone or combination with other agents may place certain subjects at risk of adverse and potentially fatal effects. More long-term safety data, beyond six months, is needed, particularly in selected populations such as the elderly.

Finally, there exists particularly vulnerable populations such as pregnant or lactating women, the elderly, and subjects with eating disorders in whom particular concern exists for their use of weight loss dietary supplements.

Although my review here has been brief and focused, we can envision four groups of dietary supplement for weight loss: safe and ineffective; effective but unsafe; ineffective and unsafe; effective and safe. At present most of the available dietary supplements fall into one of the first two categories.

Safe and ineffective: This group of products provides false hope to the unwitting highly vulnerable overweight or obese consumer and may delay their entry into an appropriate medical or nutritional care system.

Effective but unsafe: This group of products is more dangerous and actual product efficacy will lure consumers into trying the product while erroneously assuming dietary supplements, because of their herbal or natural ingredients are unduly safe compared to their pharmaceutical counterparts. As stated in the JAMA patient papge (Appendix IV), the risks of ephedra far outweigh benefits.

Improved product safety testing, quality control, labeling, and nomenclature are all needed in order to forestall or eliminate the problems now inherent with the dietary supplement category of weight loss products.

Table 1. Patterns of Signs and Symptoms Associated With Dietary Supplements Containing Ephedrine Alkaloids.[1]

Organ/system involved	Clinical significance	Signs and symptoms
Cardiovascular system	Serious	Dysrhythmias, severe hypertension, cardiac arrest, angina, myocardial, infarction, and stroke[2]
	Less clinically significant	Tachycardia, mild hypertension, palpitations.

Nervous system	Serious.	Psychosis, suicidal, altered or loss of consciousness (including disorientation or confusion), and seizures.
	Less clinically significant	Anxiety, nervousness, tremor, hyperactivity, insomnia, altered behavior, memory changes.

Gastrointestinal (GI)	Serious	Altered serum enzymes, hepatitis.
	Less clinically significant	GI distress (nausea, vomiting, diarrhea, constipation).

Dermatologic	Serious	Exfoliative dermatitis
	Less clinically significant	Less clinically significantNonspecific rashes.
General manifestations		Numbness, tingling, dizziness, fatigue, lethargy, weakness.

[1] Reproduced from Federal Register: June 4, 1997 (Volume 62, Number 107), Dietary Supplements Containing Ephedrine Alkaloids.

[2] For the purposes of this document, strokes (i.e., cerebrovascular accidents) are considered to be related to

the cardiovascular system, because predisposing or inciting factors include hypertension, dysrhythmias and

ischemia, although it is recognized that the consequences affect the central nervous system.

1. Allison D, Fontaine K, Heshka S, Mentore J, Heymsfield SB, Alternative Treatments for Weight Loss: A Critical Review. Food Science and Nutrition. Food and Nutrition, 41(1): 1-28(2001).

2. Davidson M, DiGirolamo M, Foreyt J, Halstead C, Hauptman J, Heber D, Heimburger D, Heymsfield SB, Lucas C, Robbins D, Chung J. Long-term weight control and reduction in risk factors in obese subjects receiving orlistat: a lipase inhibitor. JAMA 281 (3): 235-242, 1999.

3. Astrup A, Lundsgaard C, Madsen J, Christensen NJ. Enhanced thermogenic responsiveness during chronic ephedrine treatment in man. Am J Clin Nutr 1985;42:83-94.

4. Astrup A, Madsen J, Holst J., and Christensen NJ. The Effect of Chronic Ephedrine Treatment on Substrate Utilization, the Sympathoadrenal Activity, and Energy Expenditure During Glucose-Induced Thermogenesis in Man. Metabolism 1986:35; 260-265.

5. Astrup A, Toubro S, Cannon S, Hein P, Breum L, Madsen J. Caffeine: a double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers. Am J Clin Nutr 1990;51:759-67.

6. Astrup A, Toubro S, Cannon S, Hein P, Madsen J: Thermogenic, metabolic, and cardiovascular effects of a sympathomimetic agent, ephedrine. Currrent Therapeutic Research 1990;48:1087 1100.

7. Astrup A, Toubro S, Cannon S, Hein P, Madsen J: Thermogenic synergism between ephedrine and caffeine in healthy volunteers: a double blind placebo controlled study. Metabolism 1991;40.

8. Astrup, A., Breum, L., Toubro, S., Hein P., and 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. International Journal of Obesity & Related Metabolic Disorders. 1992;16(4):269-77.

9. Astrup, A., Beuman, B., Christensen, NJ, Toubro, Thorbeck, G, Victor OJ, and Quaade, F. The effect of ephedrine/caffeine mixture on energy expenditure and body composition in obese women. Metabolism 41: 686-688, 1992.

10. Astrup A, Toubro S. Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. International Journal of Obesity and Related Metabolic Disorders 1993;17 (suppl):S41-S43. 11. Astrup, A., Breum, L., and Toubro, S. Pharmacological and clinical studies of ephedrine sand other thermogenic agonists. Obesity Res. 1995;3 Suppl 4:537S-540S.

12. Breum L, Pedersen JK, Ahlstrom F, FrimodtMoller J. Comparison of an ephedrine/caffeine combination and dexfenfluramine in the treatment of obesity: a double-blind, multi-centre trial in general practice. International Journal of Obesity and Related Metabolic Disorders 1994;18:99-103.

13. Gurley BJ, Gardner SF, Hubbard MA. Content Versus label Claims in Ephedra-Containing Dietary Supplements. Am J Health-Syst Pharm 2000;57:963-9.

14. Gurley BJ, Gardner SF, White LM, Wang P. Ephedrine pharmacokinetics after the ingestion of nutritional supplements containing Ephedra sinica. Therapeut Drug Mort 1998 20:439-445.

15. White LM, Gardner SF, Gurley BJ, Marx MA, Wang PL, Estes M. Pharmacokinetics and cardiovascular effects of MaHuang in normotensive adults. J Clin Pharmacol 1997 37:116-22.

16. Dulloo AG, Miller DS: The thermogenic properties of ephedrine/methylxanthine mixtures:human studies. Int J Obesity 1986;10:467 481.

17. 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 and Relat Metab Disord 1993;17:S73 S78.

18. Malchow-Moller, A., Larsen, S., Hey, H., Stokholm, K. H., Juhl, E., and Quaade, F . Ephedrine as an anorectic: the story of the 'Elsinore pill'. International Journal of Obesity. 1981;5(2):183-187.

19. Pasquali, R., Casimirri, F., Melchionda, N., Grossi, G., Bortoluzzi, L., Morselli , Labate, A. M., Stefanini., C., and Raitano, A . Effects of chronic administration of ephedrine during very-low-calorie diets on energy expenditure, protein metabolism and hormone levels in obese subjects. Clinical Science. 1992;82(1):85-92.

20. Toubro S, Astrup A, Breum L, Quaade F: Safety and efficacy of long term treatment with ephedrine, caffeine, and ephedrine/caffeine mixture. Int J Obes and Relat Metab Disord 1993;17:S69 S72.

21. Boozer CN, Nasser JA, Heymsfield SB, Wang V, Chen JL, Solomon JL. An Herbal Supplement Containing Ma Huang-Guarana for Weight Loss: a Randomized, Double-Blind Trial. Intern J Obesity 2001:25:316-324.

22. Boozer CN, Daly PA, Homel P, Solomon JL, Blanchard D, Nasser JA, Strauss R, Meredith T.Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord 2002 May;26(5):593-604

Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids.

Haller CA, Benowitz NL.

Department of Medicine, University of California, San Francisco, and the California Poison Control System, 94143-1220, USA.

BACKGROUND: Dietary supplements that contain ephedra alkaloids (sometimes called ma huang) are widely promoted and used in the United States as a means of losing weight and increasing energy. In the light of recently reported adverse events related to use of these products, the Food and Drug Administration (FDA) has proposed limits on the dose and duration of use of such supplements. The FDA requested an independent review of reports of adverse events related to the use of supplements that contained ephedra alkaloids to assess causation and to estimate the level of risk the use of these supplements poses to consumers. METHODS: We reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra alkaloids that were submitted to the FDA between June 1, 1997, and March 31, 1999. A standardized rating system for assessing causation was applied to each adverse event. RESULTS: Thirty-one percent of cases were considered to be definitely or probably related to the use of supplements containing ephedra alkaloids, and 31 percent were deemed to be possibly related. Among the adverse events that were deemed definitely, probably, or possibly related to the use of supplements containing ephedra alkaloids, 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, tachycardia, or both (13); stroke (10); and seizures (7). Ten events resulted in death, and 13 events produced permanent disability, representing 26 percent of the definite, probable, and possible cases. CONCLUSIONS: The use of dietary supplements that contain ephedra alkaloids may pose a health risk to some persons. These findings indicate the need for a better understanding of individual susceptibility to the adverse effects of such dietary supplements.

Issues Relating to Ephedra-containing Dietary Supplements.