Eighteen Clashes, also known as Eighteen Incompatibilities, is an equivocal rule of Chinese medicine. It is about the prescription, contradiction of eighteen drug pairs such as Radix Glycyrrhizae against Radix Euphorbiae Pekinensis, Radix Aconiti against Bulbus Fritillariae Cirrhosae, Radix et Rhizoma Veriatri Nigri against Radix Ginseng, and so on. This rule is always followed by a majority of doctors of traditional Chinese medicine (TCM), and is one of the major parts of the Chinese herbal property theory. Most of the TCM doctors believe that using anti-drugs simultaneously could generate or enhance the toxicity and damage to human body, and thus they emphasize that the drugs which contradict each other cannot be used in the same prescription. The Eighteen Clashes was compiled into pithy formula and has been passed down for nearly a thousand years since Jin Dynasty and Yuan Dynasty.

As an important convention for drug contraindication, Eighteen Clashes has been adopted so far and caused limited clinical applications of anti-drugs. Nonetheless, there have been a lot of literatures on simultaneous use of anti-drug pairs from ancient to modern times. In the ancient formularies such as “Shang Han Lun”, “Jin Gui Yao Lue” and “Bei Ji Qian Jin Yao Fang” authored by Zhang Zhongjing and Sun Simiao, two famous doctors in ancient China, recorded the prescriptions using anti-drugs, and both of these two medical scientists had a plenty of applications of anti-drug pairs. They believed that antidrugs could complement each other while inter-restricting. Thus there have been quite a few successful clinical practices that using anti-drug pairs simultaneously to treat diseases with complex pathogenesis. Hence, whether the Eighteen Clashes should be absolutely avoided has been continuously argued by scholars and clinicians.

Chinese medicine is a distinct theory which was established on the basis of thousands of year’s medical practice. It has been demonstrated to be effective; however, some rules of it including Eighteen Clashes have not been proved by modern science and technology. Although many efforts have been made to explain its toxicology, Eighteen Clashes is still unveiled. Chinese prescription is always a complex compound containing a couple of drugs which are further classified into monarch, ministerial, adjuvant, and guiding drugs by their specific action. These drugs may counteract or synergize each other under certain conditions, so it is possible that the drugs involved in Eighteen Clashes may be against each other in one prescription but not the case in another due to difference of composition. In addition, different organism status has a different reaction to Chinese medicine. May be anti-drug pair is only toxic toward an individual under certain pathological conditions, and it may be tolerable or necessary to an individual under different pathological conditions. In other words, certain pathological conditions may be a necessary condition of toxicity or the foundation of the effects. Therefore, it is not appropriate to confirm or deny the Eighteen Clashes before the incompatibility conditions are not fully understand.

Most of the drugs concerned in Eighteen Clashes are toxic themselves and could result in poisoning and even fatal accident due to overdose, improper decoction or patients with weak health conditions, even if they are not combined with others. It has been uncertain whether this poisoning is due to compatibility or drug toxicity itself. However, the Eighteen Clashes has been passed down nearly a thousand years without being abandoned or lost, there should be its raison d’etre. May be that is to warn doctors and patients that part of the combination of drugs could lead to some adverse reactions and side effects.

To a certain extent, the Eighteen Clashes is explained through ancient and modern clinical practice, pharmacological and chemical composition research. But results are not consistent, perhaps indicating that the Eighteen Clashes is not an absolute incompatibility. The antidrugs could benefit therapy if being used properly, and vice versa. The research of Eighteen Clashes involves molecular biology, pharmacology, immunology, medicinal chemistry, bioinformatics, mathematics, computer science and so on. With fast development of contemporary science and technology, the development and intersection of these disciplines will provide a solid basis for scientific reveal of this time honored mystery.

This work was supported by the Free Topic Project of Beijing University of Chinese Medicine (No. 532/0100602099).