Metabolife 356® for Weight Loss

January 2000; Volume 3: 1-6

By E-P. Barrette, MD

Obesity is all too common. unlike diabetes and hypertension, few drugs work well for this condition. The available prescription agents have significant adverse effects and meager, temporary benefit, if any. Frustrated by diet drugs’ ineffectiveness, physicians often avoid discussing obesity altogether. Many patients have lived with years of frustration themselves—failed diets, failed diet pills, and failed attempts to exercise enough to see a benefit.

It is not surprising that many have looked to herbal supplements for an answer. Supplement stores have expansive sections devoted to weight loss products. Metabolife 356® has become the most successful herbal product for weight loss and has garnered some publicity, having been recently featured on a prime time TV news program.1 To providers, however, the primary issues remain safety and effectiveness. Although some trials suggest modest weight loss with ephedrine and caffeine, the main components of Metabolife 356, legitimate concerns regarding the safety of ephedrine products exist. Also, the benefit of Metabolife 356, a complex mixture of many herbs, remains undocumented.

Background—Rx Agents

With the failure of dietary modification and exercise in many obese patients, pharmacologic agents have been the hoped-for solution. When weight loss was noted as a side effect of dextroamphetamine, prescriptions of amphetamines for weight control increased. Serious problems with tolerance and dependence resulted in a movement away from these and other agents. Although several drugs (phentermine and mazindol, among others) remained available in the 1980s, lingering concerns regarding their long-term safety and efficacy kept them out of the mainstream of medicine.

In the early 1990s two events reawakened the interest in the pharmacologic management of obesity: the long-term success of phentermine/fenfluramine combination (phen-fen) in a single trial and a greater understanding of the genetic basis of obesity (e.g., leptin). The use of phen-fen increased dramatically. However, with the discovery of valvular abnormalities in users of fenfluramine and dexfenfluramine, along with the development of primary pulmonary hypertension in users, both drugs were withdrawn in 1997. The release of newer agents (e.g., sibutramine and orlistat) has not persuaded many physicians to prescribe drugs for obesity again.2

Background—Metabolife

With the absence of substantial competition from prescription agent manufacturers, supplement suppliers aggressively market products for weight reduction. Metabolife 356 projects retail sales for this year of $850-900 million. Mike Ellis, CEO of Metabolife International, Inc., developed this supplement to increase energy levels in his father who had bone cancer. The combination of herbs, minerals, and vitamins was selected to decrease adverse effects and improve quality of life.

Ellis states that he was "dumbfounded" when others taking the supplement, which contains ephedrine, caffeine, and other compounds, noticed weight loss.3 While it is not generally known in the United States, ephedrine combined with caffeine has been used for more than 25 years in Denmark for weight loss. In 1972, a general practitioner there noted that asthmatic patients taking a combination of ephedrine, caffeine, and phenobarbitol had unexplained weight loss.4 By 1977 the "Elsinore pill," named after the town where the association was found, was used by 70,000 patients for weight control.

An increased number of dermatological reactions, some serious, among users resulted in a warning by the Danish Institute of Health. The skin reactions were attributed to phenobarbitol, which is known to cause dermatologic reactions in 1-2% of users. In 1981, researchers at the University of Copenhagen published the first trial of the "Elsinore pill" minus the phenobarbitol.4 Since then, they have published a series of weight control trials involving ephedrine and caffeine, both alone and together.

Pharmacology

Ephedrine is a sympathomimetic drug, structurally similar to epinephrine and methamphetamine. It has fewer CNS effects than do amphetamines because it has a lower lipid solubility than amphetamines. It has both alpha (nasal decongestion, increase blood pressure) and beta (increased cardiac contraction, bronchodilator) receptor effects. Caffeine, a methylxanthine, is structurally similar to theophylline. It is a CNS stimulant and a diuretic. The half-life of ephedrine is six hours; for caffeine, it is three to seven hours.

Mechanism of Action

Ephedrine stimulates the metabolic rate via norepinephrine released from sympathetic nerve endings. The proposed mechanism involves both an anorectic effect via adrenergic pathways in the hypothalamus and a thermogenic effect via increased metabolic rate. Both animal and human studies of ephedrine alone demonstrate a thermogenic effect. The addition of caffeine to ephedrine appears to blunt the negative feedback control on the release of norepinephrine in two ways. Caffeine turns off self-regulation at two points, as it both inhibits phosphodiesterase (therefore slowing the degradation of cyclic AMP within the cell) and inhibits adenosine release into the synaptic junction.5 Ephedrine plus caffeine increased the fasting metabolic rate twice as much as ephedrine alone in a human study.6

Animal Studies

The manufacturer of Metabolife states that acute, subacute, toxicology, and histopathology studies on animals showed Metabolife 356 to be safe. These studies are unpublished.

The most likely active ingredients in Metabolife 356® for weight loss are:

a. ma huang and guarana.

b. ma huang, guarana, and damiana.

c. ma huang and bee pollen.

d. ma huang, guarana, and chromium picolinate.


Clinical Studies

There are no published trials of Metabolife 356. Metabolife International posted on a Web site the full text of a 20/20 interview concerning its product,3 including an abstract of a 24-hour metabolic study done at Vanderbilt University. This double-blind, placebo-controlled crossover study included 17 moderately obese subjects who took two tablets of Metabolife 356 tid or placebo for one day. The 24-hour energy expenditure was 4.1% greater with Metabolife 356 than placebo (P = 0.02).3 This appears to confirm the study of Astrup, discussed below.7 The Web site also refers to an unpublished eight-week randomized, double-blind, placebo-controlled study measuring weight loss.

Although minimal evidence exists for the effectiveness of synthetic ephedrine with caffeine, which are in ma huang and guarana respectively, multiple searches of PubMed, MEDLINE, and references for CAM and herbal therapies were unsuccessful in finding any adequate clinical data supporting the use of any other ingredient (including chromium) in Metabolife 356, either alone or in combination, for weight loss.8 Trials of synthetic ephedrine with caffeine are discussed below.

Astrup et al performed a double-blind, placebo-controlled trial in 16 obese women to monitor changes in body composition and energy expenditure. Over eight weeks all maintained a 1,000 Kcal/d diet while half received either placebo or ephedrine (20 mg) with caffeine (200 mg) tid. Weight loss occurred equally in both arms (mean loss ephedrine/caffeine 10.1 +/-0.4 kg, placebo 8.4 +/-1.2 kg, P = NS). However, the ephedrine/caffeine group lost 4.5 kg more body fat and 2.8 kg less fat-free mass. Respiratory chamber measurements of the 24-hour energy expenditure in the placebo group decreased 13% but only 8% (P = 0.044) in the ephedrine/caffeine group. The authors estimated that 20% of the weight loss with ephedrine/caffeine was because of increased energy expenditure while 80% was because of the anorectic effect.7 In another study, this group of investigators demonstrated synergistic effects when the doses of ephedrine and caffeine were 20/200 mg but only additive effects if the doses were 10/200 mg or 20/100 mg.9

Five double-blind randomized, controlled clinical trials comparing ephedrine/caffeine combinations vs. placebo in obese subjects for weight loss have been published. (See Table 1.) Two are reported in abstract form only10,11 and three enrolled very small numbers. Study duration ranged from eight to 24 weeks. Doses varied widely: ephedrine 20-150 mg tid, caffeine 20-200 mg tid. One trial included aspirin with ephedrine/caffeine, while another added aminophylline to ephedrine/caffeine. Only 15% of the subjects in the combined trials were male. Mean body mass index (BMI) at entry was 33.1-38.5 kg/m2. Only one trial attempted to control dietary caffeine intake by limiting subjects to two cups a day.12

Table 1-Controlled trials of ephedrine with caffeine for weight loss
Study # Enrolled/# Completed Duration (Weeks) Intervention (mg) Weight Loss (kg)
Astrup13 180/141 24 P 13.2 +/-6.6
E/C 20/200 tid 16.6 +/-6.8, P < 0.01
E 20 tid 14.3 +/-5.9, P > 0.2
C 200 tid 11.5 +/-6.0, P > 0.2
Daly12 29/24 8 P 0.7 +/-0.6
E/C/A 75-150/150/330 tid 2.2 +/-0.7, P = 0.004
(E dose increased after 4 weeks)
Malchow-Moller4 132/108 12 P 4.1
E/C 40/100 tid 8.1, P < 0.01
Diethylpropion 25 tid 8.4, P < 0.01
Cesari10,21 22/20 16 P 7.6 +/-4.8
E/C 50/100 tid 9.2 +/-4.2, P > 0.05
E 50 tid 10.2 +/-3.3, P > 0.05
Mancini11 41/31 8 P 2.2 +/-2.8
E/C/Am 22/20/50 tid 4.5 +/-3.7, P < 0.05
Breum14 103/86 15 E/C 20/200 tid 8.3 +/-5.2, P = 0.12
Dexfen 15 bid 6.9 +/-4.3
Abbreviations: P = placebo, E = ephedrine, C = caffeine, A = aspirin, Am = aminophylline, Dexfen = dexfenfluramine


Four of the five trials showed a benefit of ephedrine/caffeine over placebo, including the largest and longest study. In this study,13patients were instructed to maintain a 1,000 Kcal/d diet. They also continued to consume their baseline five to seven cups of caffeine a day, which may have added up to 500 mg of caffeine daily. In this well-designed trial, ephedrine/caffeine achieved 3.4 kg of weight loss beyond the placebo arm. An additional double-blind randomized trial compared ephedrine/caffeine combination to dexfenfluramine without a placebo control.14Weight loss was similar at 15 weeks but a subgroup analysis of patients with a BMI > 30 kg/m2at entry showed a slight benefit with ephedrine/caffeine (ephedrine/caffeine 9.0 +/-5.3 kg vs. dexfenfluramine 7.0 +/-4.2 kg, P < 0.05).

An obese patient comes to you for advice regarding herbal weight loss products. Her BMI is 32 kg/m2. She has no significant medical problems and is taking no prescription medications or supplements. Her blood pressure is 115/85. Her physical examination is notable for her obesity. She used phen-fen for five months and lost 30 lbs but has regained this. She asks how much an average woman can expect to lose with ma huang. After explaining the lack of adequate trials of ma huang for weight loss, you review the evidence for ephedrine with caffeine. You tell her after six months on a 1,000 Kcal/d diet the average weight loss for those taking ephedrine with caffeine compared to placebo was:

a. 10.5 kg (23.1 lb).

b. 8.2 kg (18.0 lb).

c. 5.5 kg (12.1 lb).

d. 3.4 kg (7.5 lb).


Adverse Effects

Ephedrine acts as a sympathomimetic and has many known adverse effects: increased blood pressure (which can be dramatic), palpitations, tachycardia, chest pain, coronary spasm, psychosis, mania, tremor, insomnia, nervousness, vertigo, headache, diaphoresis, urinary retention, dry mouth, and nasal mucosa. Chronic use has been linked to cardiomyopathy. Caffeine may cause nervousness, insomnia, tremors, palpitations, dyspepsia, and gastroesophageal reflux.

In the clinical studies listed in Table 1, most of these adverse effects were observed. In two of the larger trials, side effects were reported in 60% and 54% of the ephedrine/caffeine arm compared to 24% in the placebo arm.13,14 Among the total of 507 subjects from the studies in Table 1, syncope was seen in two subjects and severe hypertension (185/125 mm Hg) in one. Note that subjects with hypertension, cardiovascular disease, diabetes, psychiatric disorders, pregnancy, and lactation were excluded from these studies. After stopping ephedrine/caffeine, withdrawal symptoms of headache and fatigue were seen in 65%.

The FDA has received hundreds of reports of adverse events associated with ephedrine supplements including several deaths.15 In 1997, after an extensive review, the FDA proposed to limit ephedrine to less than 8 mg per tablet, less than 24 mg per day, for no more than seven days.16 The supplement industry has ignored these limitations, and no limit exists today. Notably, some supplement labels are self-contradictory, with some recommending up to six tablets of their preparation daily, providing more than the daily limit of 100 mg of ephedrine stated elsewhere in a warning on the same bottle.

There are concerns regarding the other ingredients in Metabolife 356:

Nettle leaf and sarsaparilla are diuretics.17

Several adverse events with Siberian ginseng, which is not a ginseng but more accurately called eleuthero, are now felt to be caused by other plants incorrectly labeled as Siberian ginseng.

Damiana has been reported to have aphrodisiac properties for more than 100 years.18 However, there is no evidence to support this claim, and the Commission E lists it as an unapproved herb.

Both royal jelly and bee pollen are associated with many claims and few clinical trials. Bee pollen products have been reported to result in severe allergic reactions.

Chromium picolinate use and renal failure may be related.19,20

Contraindications

Ephedrine is contraindicated in those with hypertension, cardiovascular disease, and hyperthyroidism and in pregnant and nursing women. Its use in those with benign prostatic hyperplasia, glaucoma, diabetes, anxiety disorders, and seizures should be closely monitored.

Drug and Herb Interactions

Willow bark may decrease the renal excretion of ephedrine. MAO inhibitors and yohimbine may greatly increase the sympathomimetic effect of ephedrine and should not be used together with ephedrine or Metabolife.

You review with the patient your concerns regarding ephedrine/caffeine weight loss products. Which of the following have been documented in published trials?

a. Fifty-five to 60% of those taking ephedrine/caffeine experience some side effect.

b. Severe side effects have been seen, .e.g., syncope, marked hypertension.

c. Withdrawal symptoms of headache and fatigue are seen in 65% of those who used ephedrine/caffeine for six months.

d. All of the above.


Formulation

Metabolife 356 is a complex blend of many ingredients. Its active ingredients are most likely the alkaloids from ma huang (primarily ephedrine) and from guarana seed (primarily caffeine). Metabolife 356 also contains chromium picolinate, plus 15 other ingredients. (See Table 2.) Its supply of vitamin E, magnesium, zinc, and chromium is modest and easily achieved with a multivitamin or mineral supplement. The remaining ingredients are noted to add up to 728 mg but exact amounts are not provided, which makes it difficult for competitors to duplicate and for consumers to analyze.

Table 2-Metabolife 356® ingredients
Ingredient Amount per tablet
Ma huang equivalent 12 mg ephedrine
Guarana seed equivalent 40 mg caffeine
Vitamin E 6 IU
Magnesium chelate 75 mg
Zinc chelate 5 mg
Chromium picolinate 75 mcg
Lecithin *
Damiana leaf *
Ginger root *
Goldenseal aerial part *
Gotu kola aerial part *
Nettle leaf *
Sarsaparilla root *
Siberian ginseng root *
Bee pollen *
Bovine complex *
Royal jelly *
Spirulina algae *
*proprietary information
Source: FAQ. Web site presented by Metabolife International, Inc. Available at: www.metabolife.com/b_356_faq.html. Accessed: December 6, 1999.


Cost

Retail price, advertised on the company’s Web site, is $49.95 for a bottle of 90 tablets, although those taking it for weight loss and weighing more than 180 lbs will likely use six tablets a day. Many Web pages of Metabolife 356 distributors advertise a price of $35.95 per bottle. A visit to a supplement store will reveal a score of products containing some combination of ma huang, guarana, chromium picolinate, willow bark (presumably to boost the serum level of ephedrine), and Garcinia cambogia along with many other herbs, vitamins, and minerals. Several companies are clearly trying to reproduce Metabolife’s formula. Cost comparisons are not possible.

Conclusion

A serendipitous clinical observation in 1972 by a Danish general practitioner led to a series of publications on ephedrine and caffeine, both alone and together, as a thermogenic agent. These studies do suggest that ephedrine/caffeine support weight loss. However the sum of all the trials yielded only 507 subjects; two trials have been reported in abstract form only; and three had very low enrollment. Various doses and additives make comparison difficult. The best evidence suggest that six months of ephedrine/caffeine, 20/200 mg tid, will result in 3.4 kg (7.5 lbs) beyond a 1,000 Kcal diet alone in a motivated obese patient without most major medical problems.

The adverse effects of ephedrine are well known and may be serious. Some patients appear to be especially sensitive to ephedrine. Many common medical conditions associated with obesity may be worsened with ephedrine. At present there is no evidence that the additional ingredients in Metabolife 356 will provide any additive clinical benefit toward weight loss or will protect from any adverse effect. No adequate data exist to support its chronic use as a weight loss agent. Although Metabolife International claims its product is safe, these claims are based on unpublished animal studies.

Recommendation

Although the currently available prescription agents for obesity have their own limitations, e.g., costs, meager benefit, and significant adverse effects, there is no evidence that Metabolife is any better and may be worse. Ephedrine products should not be used in patients with hypertension, cardiovascular disease, hyperthyroidism, benign prostatic hyperplasia, glaucoma, diabetes, anxiety disorders, seizures, or by women who are pregnant or lactating. Based on the modest benefit, the known risks, and the lack of long-term safety data, Metabolife 356 is not recommended.

References

1. Duffy M. Side effects raise flag on dangers of ephedra. New York Times October 12, 1999:D7.

2. Ryan DH, Medicating the obese patient. Endocrinol Metab Clin North Am 1996;25:989-1004.

3. 20/20® interview. News Interview Web Site presented by Metabolife International, Inc. Available at: http://www.newsinterview.com. Accessed: December 6, 1999.

4. Malchow-Moller A, et al. Ephedrine as an anorectic: The story of the "Elsinore pill." Int J Obes Relat Metab Disord 1981;5:183-187.

5. Dulloo AG. Ephedrine, xanthines and prostaglandin-inhibitors: Actions and interactions in the stimulation of thermogenesis. Int J Obes Relat Metab Disord 1993;17(Suppl 1):S35-S40.

6. Dulloo AG, Miller DS. The thermogenic properties of ephedrine/methylxanthine mixtures: Human studies. Int J Obes Relat Metab Disord 1986;10:467-481.

7. Astrup A, et al. The effect of ephedrine/caffeine mixture on energy expenditure and body composition in obese women. Metabolism 1992;41:686-688.

8. McArdle WD, Moore BJ. Chromium shows little proof as weight loss supplement. Altern Med Alert 1998;1: 9-10.

9. Astrup A, et al. Thermogenic synergism between ephedrine and caffeine in healthy volunteers: A double-blind, placebo-controlled study. Metabolism 1991;40:323-329.

10. Cesari MP, et al. The therapeutic dilemma of ephedrine in obesity and the inefficacy of caffeine. Int J Obes Relat Metab Disord 1989;13(Suppl 1):152.

11. Mancini MC, et al. Ephedrine, caffeine, and aminophylline preparation (ECA): An alternative in the treatment of obesity. Int J Obes Relat Metab Disord 1990;14(Suppl 2):141.

12. Daly PA, et al. Ephedrine, caffeine and aspirin: Safety and efficacy for treatment of human obesity. Int J Obes Relat Metab Disord 1993;17(Suppl 1):S73-S78.

13. Astrup A, et al. 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 1992;16:269-277.

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

15. Adverse events associated with ephedrine-containing products—Texas, December 1993-September 1995. MMWR Morb Mortal Wkly Rep 1996;45:689-693.

16. Dietary supplements containing ephedrine alkaloids; proposed rule. Department of Health and Human Services, Food and Drug Administration. Federal Register 1997;62:30677-30724. Available at: http://vm.cfsan.fda.gov/~lrd/fr97064a.html. Accessed: December 6, 1999.

17. Foster S, Tyler VE. Tyler’s Honest Herbal. 4th ed. Binghamton, NY: The Haworth Herbal Press; 1999.

18. Lowry TP. Damiana. J Psychoactive Drugs 1984;16:267-268.

19. Wasser WG, et al. Chronic renal failure after ingestion of over-the-counter chromium picolinate. Ann Int Med 1997;126:410.

20. McCarty MF, et al. Over-the-counter chromium and renal failure. Ann Int Med 1997;127(8 Pt 1):654-656.

21. Pasquali R, Casimirri F. Clinical aspects of ephedrine in the treatment of obesity. Int J Obes Relat Metab Disord 1993;17(Suppl 1):S65-S68.