The Case for Mixing Singles

In a recent post, I summarized some of the main advantages of whole formulas that have been cooked together to form a granule extract. At present, the use of whole formulas in granule form is particularly widespread in Japan and Taiwan, while the use of single herb extracts to elaborate formulas from scratch is more common in China. Not surprisingly, each region has research and rationales that support each respective approach, so today’s blog will focus on the advantages of mixing singles to provide an opposing perspective in the debate.

By any standard, we can clearly say that the patient numbers are adequate to show that both approaches have merit. According to data from Taiwan’s electronic medical records, granules are used for approximately 30 million patient visits per year; this significant volume implies a strong evidence base for the efficacy of the Taiwanese approach. Not surprisingly, the numbers are quite high for the mainland Chinese side as well: over 1000 hospitals in mainland China use granules and over 2 billion single dose sachets of granules have been used there. Furthermore, even with the comparatively small numbers of patient visits that we have here in the U.S., we can clearly see that both practitioners that mix singles and practitioners that use whole formulas are satisfied with their respective results.

As we mentioned in the previous post, there are some compelling arguments for the use of whole formulas that have been cooked together. However, there are also a number of valid arguments for mixing singles. One of the core arguments in favor of mixing singles is that the prescription can be created without any unnecessary ingredients. When starting with a whole base formula, the practitioner can add ingredients but they cannot subtract ingredients (i.e., if one uses Liu Wei Di Huang Wan, there is no way to remove the Mu Dan Pi, for example). Another challenge with whole formulas is that one may have duplication of ingredients if multiple formulas are combined together. For example, if several formulas are used together and each formula has a low dose of Gan Cao, the cumulative dose of Gan Cao may be higher than the dose of the sovereign herbs in the principle formulas. Proponents of mixing singles tend to appreciate the versatility of building formulas from scratch because it keeps the formula limited to exactly the ingredients that the practitioner wants to include.

The strongest arguments in favor of mixing singles relate to practical aspects of an ideal supply chain and optimal techniques of extraction. In China, nearly 600 items are available in granule form, and many herbs come in multiple pao zhi choices. The largest Chinese manufacturers tend to favor single herb extracts rather than formulas because single herbs are the only form of granules to be adopted on the Chinese hospital market. [Apparently the Chinese Pharmacopoeia is researching standards for whole formulas (marker constituent levels, TLC fingerprints for compound formulas, etc.), but at present official standards have only been formally developed in the mainland for single herb granule extracts.] Thus, the largest mainland Chinese suppliers have primarily based their QC standards and their research efforts around single herbs.

In mainland China, the vast scale of the population means that granule companies must source large amounts of raw materials. The largest granule companies tend to buy directly from the farms and original production regions, and they depend on the ability to secure an adequate supply of raw materials that meet their standards (in terms of constituents, growing region, grade, pesticide residues, heavy metals, etc). The large companies buy the herbs whole and apply most simple pao zhi techniques in-house before making granules, and they will typically produce the entire year’s supply once the fresh new crop is ready. Most herbs are best if they are first dried, but dried herbs that are sent to sit around for months at the wholesale markets are often destined to degrade from oxidation, and all too often items that spoil easily are treated with sulfur for the wholesale market. Granule companies can avoid this degradation by producing the entire run from freshly dried whole herbs and they also gain the option to work with herbs that are best fresh instead of dried (such as Qing Hao).

Producing the entire year’s batch of a given herb after harvest not only preserves freshness, it also allows a factory to more easily procure a consistent batch of raw materials from a single growing region or supplier. By contrast, the preparation of most whole formulas requires dried herbs from the open market, which opens up variables in terms of the freshness and growing conditions of the dried herbs. Each formula uses a small amount of any given single so there is less economy of scale (and often less thorough incoming raw material testing since each batch of raw materials is smaller and thus less economical to test); the herbs in the formula are also unlikely to come from the same harvest season so some will be more fresh than others.

Another argument in favor of mixing singles relates to the optimal conditions of extraction for any given medicinal. When decocting a whole formula together, one assumes that there is a beneficial interaction of ingredients that is potentially important for the preservation of the clinical effect. Many argue that the traditional method was a decoction and the historical evidence base thus depends on decocting medicinals together, but multiple other forms such as powders and pills have been used historically, and such formulas were not traditionally decocted together. Furthermore, in ancient times it would have been impractical to make a dozen separate decoctions instead of putting everything together in one of pot of water, so it may be that the standard decoction was done for practicality rather than assessed against an alternative method and selected based on merit.

When dealing with singles, one can do many experiments to find the ideal method of extraction for each medicinal, i.e., how much water, what temperature, what duration, which pao zhi methods, how many times the water should be changed, etc. When dealing with whole formulas, one can often make adjustments such as the pre-decoction of minerals but the general method, while tested by time, is somewhat generic and may be ideal for some medicinals in the formula but not ideal for others. When mixing singles, one lacks the interaction of the ingredients in the cooking pot but one has a better ability to tailor the extraction method to suit the unique characteristics of each medicinal.

Most likely, the interaction of ingredients in the cooking process is very important in some situations and less important in others. For example, one Chinese clinical trial compared the effect of 10 formulas given by mixing single granules vs. decoctions and found no clinical differences in eight of the formulas but measurable differences in two of the formulas (the decoction surpassed the mixed granules for two of the formulas). In other words, the decoction process made a difference for 20% of formulas, but not all of them. One study revealed that the yield of puerarin from Ge Gen was higher in the single Ge Gen extract than it was when the Ge Gen was cooked in Ge Gen Qin Lian Tang; another study showed that the cardiotonic effects of Si Ni Tang cooked together were superior while its toxicity was 4.1 times lower than the toxicity of the mixed singles. Furthermore, a variety of novel chemicals have been discovered as a result of the decoction process, but their significance largely remains unexplored (one such compound is formed in Sheng Mai San, for example). New compounds not found in either herb alone are difficult and expensive to characterize, and it is even more difficult and expensive to produce, isolate, and examine their pharmacological effects.

By nature, studies assessing the mixture of singles vs. formulas that have been cooked together often yield contradictory results, and hardly any clinical studies have been done to compare granule formulas mixed from singles with granule formulas that were cooked together. In fact, very few places in the world use both 100% mixed singles and full formula granules side by side- in mainland China there are hardly any granule whole formulas on the market, and in Taiwan it is extremely uncommon for a practitioner to mix from singles without using any whole granule formulas as a base. In mainland China all the research is based on single granules compared to bulk herb decoctions, and in Taiwan all the granule use and research assumes the use of pre-made base formulas. In a sense, the hybrid system that has evolved in the West has characteristics of both approaches and represents yet another new direction.

At present, we have more questions than answers. My own personal preference is still to use formulas that have been cooked together whenever possible, but ultimately I think there are many valid questions to be explored and I believe it is important to minimize the tendency to make sweeping assumptions about the efficacy of any given granule approach. Granules are a new delivery method in Chinese medicine with unique strengths and limitations, and we need to work together to learn how to best harness their potential.