The Entourage Effect: Science or Folk Belief? |

While pre-scientific folk medicine traditions have always relied on trial-and-error learning passed down through generations, most have also had underlying theoretical frameworks used to explain the origins of disease and to guide the choice of treatments. In this blog, and in my book, I have explored some of these frameworks, such as those behind Traditional Chinese Medicine, Ayurvedic Medicine, and homeopathy.

There are many common elements to these systems, even when they arose in very different places and eras. We all share ways of seeing and understanding the world as a result of the inherent structure and operation of human brains, so it is not surprising that we should often come to similar conclusions about how it works.

For example, vitalism, the notion that living things are distinguished from inanimate objects by the presence of a non-physical vital essence, is common to nearly all such systems. The human mind seems bound to see intention and agency everywhere, and to attribute life to an invisible internal force, which admittedly is a lot more intuitively appealing than the bewilderingly complex array of electrical and molecular events that science describes, if less useful.

In herbal medicine traditions, another frequently shared notion is that whole plants or combinations of plants are inherently safer and more effective that isolated chemicals, such as those used in science-based medicine. There are a number of rationales for this, which often relate back to the religion or philosophy underlying the particular folk medicine system. Chinese medicine involves a lot of Taoist ideas about balance and harmony in nature, whereas Western folk traditions may claim that God intended plants to be remedies for human ailments and so designed them to contain beneficial mixtures of substances. None of these explanations, of course, are scientific or empirically testable.

The leading textbook on veterinary herbal medicine¹ explicitly promotes the idea that a multiplicity of compounds in an herbal remedy is inherently a good thing:

In herbal medicine¹, polypharmacy is de rigeur…When asked which is the active ingredient of any herb, the drumbeat of the herbalist will always be: The Plant Is the Active Constituent!

The whole herb or whole extract is already understood from history and clinical trials.

The herb’ constituents have complex actions that may benefit the patient through additive, antagonist, or synergistic effects.

Most active constituents may be unknown

Offering a plant drug with multiple actions gives the body a multitude of possible solutions at one time.

As proponents of herbal medicine attempt to generate more scientifically compatible explanations for beliefs like this that they already hold, they come up with other ways of describing such ideas. One common belief among the more scientifically minded advocates of herbal treatments is the concept of the “entourage effect.” (EE) This is most frequently used to describe the belief that the multiplicity of compounds in cannabis have beneficial effects in combination that are not seen in isolated components, such as THC or CBD. As one author put it,²

Herbalists contend that polypharmaceutical herbs provide two advantages over single-ingredient synthetic drugs: (1) therapeutic effects of the primary active ingredients in herbs may be synergized by other compounds, and (2) side effects of the primary active ingredients may be mitigated by other compounds. Thus, cannabis has been characterized as a “synergistic shotgun…

This idea has become quite entrenched, and it is often treated as an accepted and proven phenomenon. However, there a few problems with the concept of the EE. For one thing, there is no logical reason that the interaction of multiple compounds in a plant should always be beneficial (reducing side-effects and increasing intended effects) and never harmful. This is not consistent with the basic principles of chemistry, and the assumption is rooted in philosophical notions of nature as inherently benign, even if modern herbalists are explicitly less committed to those kinds of explanations these days.

More importantly, there is virtually no reliable evidence that there is always a net benefit to whole herbs or mixtures with multiple components. There is, in fact, evidence of examples where the reverse is true. In some cases, mixing CBD and THC reduces the effectiveness in children with seizures or exacerbates the side effects. And as I have discussed elsewhere, the development of the antimalarial medication artemisinin is also an example of the superiority of pharmacognosy (isolating medicines from plants) over folk herbalism.

Derived from a plant used in Traditional Chinese Medicine, artemisinin is an effective treatment for malaria. Dr. Youyou Tu was awarded the Nobel Prize in Medicine in 2015 for discovery of this drug. This well-deserved honor is often cited as evidence that TCM herbalism is a validated medical practice. However, the true lesson of Dr. Tu’s work is that science is much more effective at creating effective treatments for disease than the anecdotal, trial-and-error processes of folk medicine.

In the 1960s and 1970s, Dr. Tu evaluated about 2,000 Chinese herbal preparations and found over 600 that had some effect on the malaria parasites in mice. Hundreds of specific chemical compounds were isolated from these preparations and evaluated. After many years of work one, artemisinin, was found to inhibit the growth of this parasite in a way that could be clinically useful.

However, the amount of artemisinin produced varies dramatically different species of the Artemisia plant. There is too little present in most species to extract for medical use. Many different species of Aretemisia were tested, and the one with the highest quantity of artemisinin was used as a source for the compound, which was then extracted and purified for medical use.

Even more research and modification of the original remedy were then necessary to make an effective medicine. Artemisinin itself has pretty weak effects on the malarial parasite, so Dr. Tu also had to alter the compound chemically to make it more stable and more effective. And it turned out a capsule form allowed for much better absorption of the drug than a pill or the original plant material.

Ultimately, however, after decades of work, Dr. Tu had found an important, life-saving medicine in a plant used by TCM. So isn’t this evidence that TCM is a worthwhile medical approach which can sometimes accomplish things scientific medicine can’t?

There are a number of reasons why this view of Dr. Tu’s story doesn’t hold up. For one thing, Artemisia wasn’t used in TCM specifically to treat malaria, it was used to treat fevers of any kind. This is because TCM doesn’t distinguish fevers caused by viral infections, bacterial infections, autoimmune diseases, or parasites such as the one that causes malaria. Without a scientific understanding of the different causes of these diseases, the potential value of Artemisia for malaria patients was unrecognized, and it was commonly used in many other patients for whom it would have no benefit. What is more, the raw plant itself would not be effective even for patients with malaria since, as I mentioned, there is not enough artemisinin in the plant tissues to effectively inhibit the parasite, and what is present is unstable and poorly absorbed when eaten whole or drunk in an infusion, as is usually done in TCM.

Furthermore, to find this one medicine, Dr. Tu had to hundreds of compounds from thousands of herbal preparations in rigorous scientific studies, from mice in the laboratory to human patients in the field. The vast majority of the remedies and compounds she tested were not useful. Despite thousands of years of trial and error with herbal remedies, TCM never properly identified the cause of malaria and never found an effective treatment for it even when it had such a such a treatment hidden in its collection of herbal remedies. Dr. Tu’s research illustrates not only the power of science to find useful treatments for disease but the inability of haphazard folk medicine methods to do so.

A few authors^2-3 have questioned the EE and pointed out the absence of compelling evidence to support the concept, but you will still see this idea taken as fact even in discussions of cannabis and other remedies that are relatively science-based and free of folk beliefs. It is important for pet owners and veterinarians to understand that such ideas are a residue of the mysticism and unscientific beliefs that underlie many herbal medicine practices.

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