The history of Ephedrine: from the laboratory to sport

Ephedrine is one of the oldest substances in sports pharmacology: from a decoction of ma huang through asthma medicine to "fat burners" and high-profile disqualifications. The editorial team traced how the attitude of medicine, sport and regulators toward this stimulant changed.

Ma huang: a thousand-year prehistory

The history of ephedrine begins not in a laboratory but in traditional Chinese medicine. The plant ephedra (Ephedra sinica), known as ma huang, was used in China for thousands of years. It is mentioned in classical pharmacological treatises as a remedy for cough, shortness of breath and colds.

Ephedra is a small shrub with thin green stems and almost no leaves. It is precisely in the stems that alkaloids accumulate, the main of which is ephedrine, as well as pseudoephedrine, norephedrine and other related compounds. The alkaloid content depends on the plant species, the place of growth and the season of harvest.

Traditional healers empirically noticed that a decoction of ma huang eases breathing, causes sweating and alertness. Modern pharmacology explains this by stimulation of adrenergic receptors: dilation of the bronchi, an increase in blood pressure and an effect on the central nervous system.

Other species of ephedra grew in Europe and Central Asia too, but it was precisely the Chinese tradition that became the starting point for the scientific study of the plant at the end of the 19th century.

Isolation of ephedrine and its arrival in Western medicine

In 1885 the Japanese chemist Nagai Nagayoshi, who studied in Germany, isolated the pure active substance from ephedra and named it ephedrine. However, at the time the discovery did not attract wide attention from clinicians.

The real breakthrough came in the 1920s. The pharmacologists Ko Kuei Chen and Carl Schmidt of the Peking Union Medical College systematically studied the action of ephedrine and in 1924 published a work in which they described its effect on blood pressure, the heart and the bronchi. They drew attention to the similarity of the effect to adrenaline, but with an important advantage — activity when taken orally and a longer duration of action.

Ephedrine soon became a popular remedy for bronchial asthma. Demand for it grew rapidly, and dependence on natural raw material limited production. This stimulated the search for synthetic substitutes.

One of the results of these searches was the amphetamines: at the end of the 1920s the chemist Gordon Alles, looking for a substitute for ephedrine, studied the action of amphetamine. Thus ephedrine indirectly influenced the appearance of a whole class of stimulants.

Ephedrine in sport: from asthma to doping

The stimulating properties of ephedrine could not go unnoticed by athletes. It increases alertness, reduces the feeling of fatigue, and in combination with caffeine gives a more pronounced stimulating effect. The review by Magkos and Kavouras (2004) examines in detail the physiological effects of this combination.

One of the most famous stories occurred at the 1972 Olympic Games in Munich. The American swimmer Rick DeMont won gold in the 400 meters freestyle but was stripped of the medal because of detected ephedrine — the substance was contained in an asthma medication he was taking. This case became a textbook example of how treatment can conflict with anti-doping rules.

At the 2000 Olympics in Sydney, the Romanian gymnast Andreea Răducan lost her gold medal in the all-around because of pseudoephedrine in a cold medicine. These stories shaped the practice by which athletes must check any medications for colds and asthma.

Today ephedrine is on the WADA Prohibited List in class S6 "Stimulants" as a specified substance banned in-competition. For ephedrine, methylephedrine, pseudoephedrine and cathine, threshold concentrations in urine have been established, exceeding which is considered a violation.

The era of "fat burners" and the ban in the USA

In the 1980s–1990s ephedrine took on a new role — a weight-loss aid. Studies by Astrup and co-authors showed that the combination of ephedrine with caffeine promoted somewhat greater weight loss on a diet than placebo. In bodybuilding the term "ECA stack" appeared — a combination of ephedrine, caffeine and aspirin.

In the USA plant extracts of ephedra were sold en masse as dietary supplements for weight loss and "energy." Regulation of supplements was much softer than that of drugs, and the products reached a wide audience without medical oversight.

Soon reports of serious side effects began to accumulate. In 2000 Haller and Benowitz in the New England Journal of Medicine analyzed reports of adverse events and described cases of hypertension, strokes, heart attacks, seizures and sudden death associated with ephedra supplements.

The meta-analysis by Shekelle and co-authors (2003) in JAMA summarized: ephedrine and ephedra provide only a modest short-term weight reduction, and evidence of improved athletic performance is limited; at the same time their use was associated with an increased risk of psychiatric, autonomic and gastrointestinal symptoms and palpitations.

In 2003 the death of the baseball player Steve Bechler from heatstroke, in the context of which the use of an ephedra supplement was discussed, drew wide public attention. In 2004 the FDA banned the sale of dietary supplements containing ephedrine alkaloids, recognizing that they pose an unreasonable risk.

Ephedrine today

In modern medicine ephedrine has retained its place. Intravenous forms are used in anesthesiology for the treatment of arterial hypotension, for example in spinal anesthesia. In some countries ephedrine is still part of over-the-counter asthma remedies, although its role in the treatment of asthma has decreased significantly with the advent of selective bronchodilators.

The second aspect of its modern status is control as a precursor. Ephedrine and pseudoephedrine can be used for the illegal synthesis of methamphetamine, so in many countries, including Ukraine, their circulation is strictly regulated.

In the sports nutrition market, ephedrine has gradually been displaced by other stimulants, some of which subsequently also fell under a ban due to similar risks. That is why the "ephedrine" experience remains relevant: a new substance with a similar mechanism of action does not become safer merely because it has a different name.

• Medicine: anesthesiology, individual over-the-counter drugs in some countries.
• Sport: WADA ban in-competition with threshold concentrations.
• Supplements: ban in the USA since 2004, strict restrictions in many other countries.
• Regulation: control as a precursor of narcotic substances.

The history of ephedrine is an example of how a natural substance with a thousand-year tradition of use traveled the path from an asthma medicine to a "fitness supplement" and back to a strictly controlled medical agent. The main lesson was the need to assess the safety of stimulants not by individual reviews but by systematic data.

Editorial conclusions

Ephedrine has come a long way from the ma huang plant to the alkaloid isolated by Nagai, the studies of Chen and Schmidt, and mass use in asthma.

The sporting page of its history is connected with high-profile disqualifications, and the era of "fat burners" ended with a ban on ephedra supplements in the USA after the accumulation of data on cardiovascular and neurological risks.

Today ephedrine is a medical drug and a controlled precursor, banned in-competition in accordance with WADA rules.

Next we recommend: ephedrine overdose, the history of levothyroxine, the interaction of levothyroxine with stimulants and other drugs.

References

1. Chen KK, Schmidt CF. The action of ephedrine, the active principle of the Chinese drug Ma Huang. J Pharmacol Exp Ther. 1924;24:339–357.
2. Magkos F, Kavouras SA. Caffeine and ephedrine: physiological, metabolic and performance-enhancing effects. Sports Med. 2004;34(13):871–889.
3. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343(25):1833–1838.
4. Shekelle PG, Hardy ML, Morton SC, et al. Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA. 2003;289(12):1537–1545.
5. U.S. Food and Drug Administration. Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk. Federal Register. 2004;69(28).
6. World Anti-Doping Agency. The World Anti-Doping Code: International Standard — Prohibited List. Montreal: WADA; чинна редакція.
7. Astrup A, Breum L, Toubro S, Hein P, 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. Int J Obes Relat Metab Disord. 1992;16(4):269–277.