Combination Therapy as a Cauldron for Synergy


Benton Bramwell, ND, and Matt Warnock, MBA, JD

One of the most fascinating aspects of combination therapy is the potential for the effect of a combination of medicinal ingredients to be synergistic.  Practitioners of many kinds, and perhaps especially naturopathic physicians, rightly have a great affection for the term synergism because it speaks to maximizing benefit after bringing together the best fitting combination of available ingredients to fill a patient’s needs.  But what exactly do we mean when we speak of synergy?   In addition to crystallizing in our minds what we mean when we speak of synergy, in this article we explore how synergy in combination therapy occurs and suggest ways in which a traditional approach to combination botanical therapy can facilitate this phenomenon.  

As reviewed by Breitinger,1 the word “synergy” is derived from the Greek term “syn-ergos,” which means “to work together” and means that “the combination and interaction of two or more agents or forces is such that combined effect is greater than the sum of their individual effects.”  There are many ways that an overall synergistic effect can be achieved, including interactions that affect how a medicine moves through the body (absorption, distribution, metabolism, and excretion–pharmacokinetics) and interactions that affect how a medicine acts on the body (pharmacodynamics).  We take a broad view of what constitutes synergy, e.g. any combination of interactions that is greater than the sum of individual effects, and pause briefly to differentiate synergistic effects from additive effects by emphasizing the view that additive effects are those effects that have no interaction at all between them.2 

Simply put, synergy is when effect interactions come together to have a greater overall impact than can be achieved without effect interactions, while individual effects that are free from interactions with each other are better described as additive (since each effect adds independently to whatever turns out to be the overall impact). 

It might actually be less confusing to one day simply refer to additive effects as non-interactive effects.  And, in truth, when one considers the broad potential for ingredients to interact in unforeseen ways across complex body systems, it might be the case that truly additive effects, in vivo, are rare exceptions.

Formulation philosophies centered in combination therapy facilitate synergy, not just in the basic fact that multiple botanicals are combined but because of the intentional roles that formulators seek to fill when adding ingredients.  For example, in the Traditional Chinese Medicine (TCM) approach, a “Monarch” herb of main effect is mixed with a “Minister” herb to enhance the effects of the Monarch, an “Assistant” herb to offset toxicity of the Monarch/Minister herbs, and a “Guide” herb to help improve delivery of the other herbs.3 

Thus, if an Assistant herb effectively offsets toxicity of a Monarch herb, the combination medicine is more effective than the singly administered Monarch herb because the combination becomes more tolerable. If a Minister herb interacts with the Monarch herb in favorably affecting pharmacodynamics at a target receptor, the effect of the dynamic change may be better than if just the Minister or Monarch herb were given; and a Guide herb with minimal therapeutic value by itself may improve the pharmacokinetics of delivery of the Monarch and Minister herbs to the point that the combination has significantly more action at a target site or target sites.  We will use this analogy of herbs with different functions from TCM when describing examples of synergistic combinations below, whether or not the examples specifically originate from a TCM formula.

A simple example of herbal synergism manifests in the study of the traditional formula, Shuanlong, composed of Panax ginseng and Salvia miltiorrhiza.  When the effect of the individual ingredients of the traditional formula are compared to their combination in a rat model of myocardial infarction, a synergistic improvement in efficacy is found.4 Specifically, the herbal combination was shown to intensify the ability of rats to recover normal energetic metabolism after an MI; and while each herb helped protect cardiac muscle to a degree from necrosis, neither herb was equally as protective as the combination.  As both of the herbs in this example show some effect by themselves that is not equal to their effect when combined, this is a good example of synergism through the combination of “Monarch” and “Minister” herbs.

Another important example of synergism, and an example of a “Guide” ingredient producing synergism in combination with a “Monarch” ingredient, is the combination of an active ingredient from one of the Traditional Ayurvedic medicines Trikatu, along with poorly absorbed curcumin.  When piperine, an active of the black and long pepper in Trikatu, is given in conjunction with curcumin in a rat model of depression induced by chronic stress, curcumin’s ability to decrease immobility and restore brain neurotransmitter levels is significantly enhanced compared to the effects seen with curcumin alone.5  Importantly, application of what was shown to be a synergistic combination in basic science work has then translated to clinical efficacy of curcumin and piperine as an adjunctive treatment for depression in a sizeable clinical trial.6  

As a combination of bioavailability enhancers, the piperazine-containing peppers Trikatu contains, along with its gingerol-providing ginger, may be one of the superior synergizing formulas refined over its long period of empirical use.  This is in part because, as it turns out, both ingredients enhance the surface area of the absorptive surface and increase its membrane fluidity, while also potentially slowing biotransformation pathways (Phase I, Phase II, and p-glycoprotein action).7-12 Moreover, gingerol is known to increase mineral absorption (sodium) through TRPV1 agonism, a receptor also known to be agonized by piperazine.13,14

A modern example of how principles of combination therapy can lead to synergism is found in recent research examining the effects of combining the chemotherapy drug 5-fluorouracil (5-FU) with a Chinese medicine Bu-zhong-yi-qi (itself an herbal combination of 10 different herbs).15  When this chemotherapy-herbal combination is administered to mice injected with murine gastric cancer cells, the survival time of mice receiving the chemotherapy-herbal combination is significantly greater than mice receiving the chemotherapy drug by itself.  This is in spite of the fact that the tumor-inhibiting action of the herbs by themselves is much less than that exhibited by 5FU by itself.   

In humans given the same chemotherapy drug or drug plus herbs, it is also observed that those receiving the combination vs drug alone had a significantly lower proportion of CD8+PD-1+ cells.  As PD-1 expression is a compensatory response known to be induced by the chemotherapy drug that allows some cancer cells to escape immune detection, in this instance, the entire herbal combination is acting as the “Assistant” to help offset the toxicity of the “Monarch” chemotherapy drug, with a good indication of synergy (the prolonged survival seen in the evaluable animal data).

Delightfully, positive synergistic interactions that are quite unanticipated can also occur (as can negative interactions that should be screened for and excluded whenever possible).  An example of this is when a medicine that we think is only an “Assistant” used to offset adverse effects turns out also to have some “Minister” effects.  An example of this is when N-acetylcysteine, which is used to antidote acetaminophen’s hepatotoxicity, shows evidence that in its own right it can exert an analgesic effect in concert with acetaminophen’s, as measured with the hot plate test in rats. 16 (By the way, can anyone think of a good reason why acetaminophen is not already manufactured with NAC as a co-ingredient?)

While not all interactions can be predicted when herbal ingredients are included to fill roles in formulation, with centuries of empirical observation and modern research many positive interactions can be found and their effects exploited to clinical benefit.  This reality does not to any degree diminish the real need for careful pharmacists and clinicians to invest time in order to avoid detrimental interactions, which is critical in order to promote safety; it’s just also the case that there is a synergistic portion of the interaction equation that should be balanced in order to also provide the best intervention possible.


References

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Published May 6, 2023


About the Authors

Benton Bramwell, ND is a 2002 graduate of National College of Naturopathic Medicine who practiced primarily in Utah while helping to expand the prescriptive rights of naturopathic physicians in that state.  Currently, he owns and operates Bramwell Partners, LLC, providing scientific and regulatory consulting services to both dietary supplement and conventional food companies.  He and his wife, Nanette, have six children and two grandchildren; they live in Manti, Utah.

Matt Warnock is an accidental herbalist, who received his MBA and Juris Doctor from BYU, then worked as an attorney, litigator, and business consultant until 2000. He then joined RidgeCrest Herbals, a family business started by his father, and started learning about herbal medicine, focusing especially on complex herbal formulas. He has two U.S. patents for herbal formulations and methods. He lives near Salt Lake City with his wife, Carol; they are the parents of three children and four grandchildren.