Herb-Drug Interactions: Ephedra

Ephedra sinica Stapf., Ephedra gerardiana Wall., Ephedra equisetina Bunge (Ephedraceae)

Synonym(s) and related species

Ma huang.


The main active components of ephedra are the amines (sometimes referred to as alkaloids, or more properly pseudoalkaloids) ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, ALmethylephedrine, ephedroxane, maokonine, a series of ephedradines and others. Other constituents include the diterpenes ephedrannin A and mahuannin, catechins, and a trace of volatile oil containing terpinen-4-ol, alpha-terpineol, linalool and other monoterpenes.

Use and indications

Ephedra is used traditionally for asthma, bronchitis, hayfever and colds, but recently the herb has become liable to abuse as a stimulant and slimming aid. For this reason the herb has been banned by the FDA in the US. Its main active constituents are ephedrine and pseudoephedrine; however, ephedra herb is claimed to have many more effects than those ascribed to ephedrine and its derivatives. It is these compounds that also give rise to the toxic effects of ephedra.


No relevant pharmacokinetic data found.

Interactions overview

Ephedra herb contains ephedrine and pseudoephedrine, and therefore has the potential to interact in the same manner as conventional medicines containing these substances. The most notable of these interactions is the potential for hypertensive crises with MAOIs; it would therefore seem unwise to take ephedra during, or for 2 weeks after, the use of an MAOI. There do not seem to be any reports of drug interactions for ephedra itself, with the exception of caffeine.

Ephedra + Caffeine

Ephedrine can raise blood pressure and in some cases this may be further increased by caffeine. Combined use has resulted in hypertensive crises in a few individuals. Isolated reports describe the development of acute psychosis when caffeine was given with ephedra.

Clinical evidence

A review of reports from the FDA in the US revealed that several patients have experienced severe adverse effects (subarachnoid haemorrhage, cardiac arrest, hypertension, tachycardia and neurosis) after taking dietary supplements containing ephedrine or ephedra alkaloids with caffeine. However, it is not possible to definitively say that these effects were the result of an interaction because none of the patients took either drug separately. Similarly, a meta-analysis assessing the safety of ephedra or ephedrine and caffeine found a two- to threefold increase in the risk of adverse events (including psychiatric symptoms and palpitations) with ephedra or ephedrine, but concluded that it was not possible to assess the contribution of caffeine to these events.

Two episodes of acute psychosis occurred in a 32-year-old man after he took Vigueur fit tablets (containing ephedra alkaloids and caffeine), Red Bull (containing caffeine) and alcohol. He had no previous record of aberrant behaviour despite regularly taking 6 to 9 tablets of Vigueur fit daily (about twice the recommended dose). However, on this occasion, over a 10-hour period, he consumed 3 or 4 bottles of Red Bull (containing about 95 mg of caffeine per 250-mL bottle) and enough alcohol to reach a blood-alcohol level of about 335 mg%. No more episodes occurred after he stopped taking the Vigueur fit tablets. Ephedra alkaloids (ephedrine and pseudoephedrine) may cause psychosis and it appears that their effects may be exaggerated by an interaction with caffeine and alcohol. In another case report, an ischaemic stroke that occurred in a 33-year-old man was thought to be due to taking a supplement called Thermadrene, (now reformulated, but which at the time contained ephedrine, guarana, caffeine, cayenne pepper and willow bark). The use of bupropion may have been a contributory factor. A similar case of stroke is reported in a man who took a creatine supplement with ephedra plus caffeine. In this case, the interaction was attributed to creatine. See Creatine + Herbal medicines; Ephedra with Caffeine.

Experimental evidence

In a study, rats were given an oral solution of ephedra (containing up to 50mg/kg ephedrine) with, and without, caffeine. Ephedra with caffeine increased the clinical signs of toxicity (salivation, hyper-activity, ataxia, lethargy, failure to respond to stimuli) in the treated rats, when compared with ephedra alone. Histological analysis for cardiotoxicity showed some evidence of haemorrhage, necrosis, and tissue degeneration within 2 to 4 hours of treatment. No statistical difference in the occurrence of cardiotoxic lesions was found when animals treated with ephedrine were compared with those treated with ephedra, indicating that the cardiotoxic effects of ephedra are due to ephedrine.

Another study also reported that cardiac toxicity was observed in 7- and 14-week-old male rats administered ephedrine (25 mg/kg) in combination with caffeine (30 mg/kg) for one or two days. The ephedrine and caffeine dosage was approximately 12-fold and 1.4-fold, respectively, above average human exposure. Five of the seven treated 14-week-old rats died or were sacrificed 4 to 5 hours after the first dose, and massive interstitial haemorrhage was reported.


Ephedrine and caffeine may cause catecholamine release and an increase in intracellular calcium release which leads to vasoconstriction. Myocardial ischaemia may occur as a result of this vasoconstriction (in the coronary artery), and this may result in myocardial necrosis and cell death.

Importance and management

The interaction between ephedra alkaloids and caffeine is fairly well established. However, it has to be said that there seem to be few reports of adverse interactions specifically with ephedra alkaloids. One possible explanation for this could be that these interactions may go unrecognised or be attributed to one drug only, whereas caffeine may also have been taken either as part of the preparation or in beverages or foods (often not reported). Nevertheless, a number of serious adverse events have been reported and these preparations may pose a serious health risk to some users. The risk may be affected by individual susceptibility, the additive stimulant effects of caffeine, the variability in the contents of alkaloids or pre-existing medical conditions.

Note that the FDA has banned combinations of caffeine and herbal products containing ephedra. It would seem prudent to avoid concurrent use.

Ephedra + Food

No interactions found.

Ephedra + Herbal medicines

No interactions found.