Cardiotoxicity of Ma Huang/Caffeine or Ephedrine/Caffeine in a Rodent Model System

Abstract

Ma Huang (equivalent to 0, 12.5, 25, or 50 mg/kg ephedrine) or ephedrine (0, 6.25, 12.5, 25 mg/kg) were administered as one bolus oral dose to male F344 rats with and without caffeine. The herbal medicine Ma Huang (ephedra) in combination with caffeine caused rapid clinical signs of toxicity including salivation, hyperactivity, ataxia, and eventually lethargy, and failure to respond to stimuli. When this syndrome of clinical signs emerged, animals were moribund sacrificed, and a histological analysis for heart lesions performed. Cardiotoxicity included hemorrhage, necrosis, and degeneration in the ventricles or interventricular septum within 2-4 hours after treatment with Ma Huang (ephedra)/caffeine or ephedrine (the principal active component in Ma Huang)/caffeine. There was a steep dose response curve for cardiotoxicity with minimal toxicity seen at levels of Ma Huang (equivalent to 12.5 mg/kg ephedrine) with caffeine. However, cardiotoxic lesions occurred in 28% of animals with Ma Huang dosages equivalent to 25 mg/kg ephedrine with 15 or 30 mg/kg caffeine, and in 90% of animals at Ma Huang exposures equivalent to 50 mg/kg ephedrine with 15 or 30 mg/kg caffeine. Cardiotoxic lesions occurred in 47% of animals in the 25 mg/kg ephedrine groups with caffeine at 7.25, 15, or 30 mg/kg. There was no statistical difference in the occurrence of cardiotoxic lesions when 15 or 30 mg/kg caffeine was combined with Ma Huang equivalent to 25 or 50 mg/kg ephedrine; likewise there was no statistical difference in the occurrence of cardiotoxic lesions when 7.25, 15, or 30 mg/kg caffeine was combined with 25 mg/kg ephedrine. These results show that the cardiotoxic effects of the herbal medicine, Ma Huang, are similar to that of ephedrine, the principal active ingredient in the herbal medicine. The combination of Ma Huang or ephedrine with caffeine enhanced the cardiotoxicity over that with the herbal medicine or the active ingredient alone.

Combined Effects of Ephedrine-Containing Dietary Supplements, Caffeine, and Nicotine on Morphology and Ultrastructure of Rat Hearts

“…Although specific cell types were not differentiated, noncardiac cell type volume fractions indicated significant cardiotoxicity among treatment groups due to pyknotic nuclei and the infiltration of inflammatory cells. These results support earlier findings of cardiotoxicity in rats exposed to caffeine and ephedrine, 19,20 and facilitate more specific measurement of these changes.…”

“…Caffeine alone has not been shown to induce cardiotoxicity 19,20 ; this was substantiated in the present study. Here, in saline-pretreated animals, caffeine did not affect the number of atypical cardiac cells in rats.…”

“…The cardiotoxicity caused by combination dosing of Ephedra and caffeine has already been shown 19,20,35 ; however, the present study revealed an enhancement of cardiotoxicity when nicotine was administered in combination with Ephedra and caffeine.…”

“…17,18 Recent studies have also shown that ephedrine, particularly that in the form of Ma Huang (Ephedra), in combination with caffeine can produce myocardial necrosis as well as other structural changes in the heart. 19,20 Taken together, these findings suggest that ephedrine/caffeine combinations posed a greater risk for adverse health effects.…”

“…Dunnick et al 20 found significant cardiotoxicity and morbidity at 25 or 50 mg ephedrine/kg, in combination with 15 or 30 mg caffeine/kg after a single dose. Interestingly, ephedrine administered as Ephedra (Ma Huang) was found to be more toxic than purified ephedrine given in a similar combination dosage.…”