Scientific Studies and Reports

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

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.

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