Stephen Holt, MD, PhD, DSc, LLD, DNM, ChB, FRCP (C), MRCP (UK), FACP, FACG, FACN, FACAM, KSJ, Distinguished Professor of Medicine (Emeritus), Scientific Adviser to

Definition: Synergy
“According to Webster’s Unabridged Dictionary: Synergy, [Gr. synergia, joint work, from synergein, to work together.] is combined or co-operative action or force: specifically, in medicine, (a) the combined or correlated action of different organs or parts of the body, as in performing complex movements; (b) the combined or correlated action of two or more drugs.”
Who said that a “little bit” of this combined with a “bit” of that provided a better treatment outcome than a lot of this or that alone? An acknowledgement of the therapeutic power of synergy may answer this “gobbledygook” question. The power of synergy is apparent when one considers the common therapeutic failure of single receptor drug interventions and the complex biochemistry or physiology of the “harmony of life” (Claude Bernard, circa 1860). All body functions and structures rely upon carefully coordinated cascades of biological or physiological events. These “cascades” cannot be completely responsive to a unitary intervention such as a single drug, nutrient or botanical compound. These notions form the basis of the “completeness” of treatment approaches (holism) that must be present in the practice of Integrative Medicine. Welcome to the domains of “synergy.”1-7
One must accept the phenomena of dose responses in therapeutics and the clear distinction between physiological and pharmacological effects of different amounts of the same compound. For example, small dosages of vitamins exert different pharmacodynamic effects than large dosages, e.g. vitamin C at modest intake is an antioxidant, but in large (unopposed) dosages it may have a pro-oxidant effect. The objective of this short article is to highlight the power of the combination of nutrients, herbs and botanicals when they are used in synergistic formulations. One may note that synergy exists among different treatment modalities, beyond the relevance of specific therapeutic agents. There is a well founded belief that lifestyle factors, “physical treatments” and holistic care work in synergy with drug or nutraceutical interventions. This holistic approach is a clear objective of therapeutic approaches in the practice of Integrative Medicine.1-7

The Power of Synergy© (1+1=3)
Synergy (synergism) may be best understood as the additive or reinforcing actions of separate agents that can produce a greater overall effect than when such agents are used in a single manner (singly). While I focus on the notion of using dietary supplements in a synergistic manner, the principles under discussion apply to drug use or even the interactions of organs in the coordinated harmony of body functions. The most effective way of revealing the power of synergy is to review special areas of natural therapeutics in which synergy appears to be emerging with superiority in clinical outcome.

Synergy in Nutrient Supplementation2
Modern approaches to the provision of general nutritional insurance include more than a recommendation for multivitamins. Many phytochemical compounds found in greens, berries, fruits and vegetables provide co-factors for the effective utilization of vitamins and mineral supplements. Essential fatty acids, of the Omega-3 type, are valuable supplements to the Standard American Diet (SAD), but these compounds cannot be bio-incorporated or utilized to exert their maximum function without vitamin co- factors. In other words, baseline nutritional support with vitamins and minerals are best given in powders that contain whole food micro-nutrients derived from berries, greens, etc. Standard nutritional support in the professional practice of integrative medicine has moved towards this holistic approach to baseline nutrient supplementation. This is the synergistic approach to “nutritional insurance for health”.2

Synergy in Immune Modulation3
Single or unitary dietary supplements to used “boost” immunity are limited in their effects “Boosting” certain aspects of the complex series of events in some immune-related diseases may sometimes do more harm than good. The additive benefits and versatile nature of many different natural agents in a dietary supplement that can work on different aspects of immune events may help modulate or balance many different immune functions (Table 1)
• Andrographis paniculata ● Oregon grape
• Acanthopanax senticosa ● Shitake mushroom
• Green tea ● Echinacea purpurea
• Tumeric ● Goldenseal
• Grape seed extract ● Goldenthread
• Zinc ● Aloe Vera
• Vitamin C ● Garlic
• Ashwagandha ● Astragalus
● Echinacea purpurea ● Korean ginseng
• Golden seal ● Coriolus versicolor
● Beta glucan ● Active Hexose Correlated
• Compound (AHCC)
Table 1. Nutrients, herbs and botanicals with good scientific agreement of nutritional benefits for immune function. The basis of a patent-pending formula (Holt MD Labs).
I have proposed that there is a way of producing an improved, synergistic, dietary supplement that can be used in combination to stimulate immune function, in a more global manner.1,3
Any natural agent that exerts an antioxidant function can be potentially valuable in promoting healthy immune function. Oxidative stress (free-radical damage) to components of the immune system is a common reason for disordered immunity. In particular, the following antioxidants are of value for immune well-being: Vitamin C, zinc, green tea, turmeric, grape seed extract and other antioxidants that are found in a variety of herbs and botanicals (Table 1) 1
Botanical agents with specific immune-enhancing power include: several species of mushrooms; Coriolus versicolor, Shitake mushroom, natural components such as AHCC, plant or yeast sources of beta glucan, Echinacea, and the potent and versatile herb Andrographis paniculata (AP). Recent research implies that AP may be a very powerful stimulator of immune function by its specific actions on chemical signals in certain cells; and AP has reported antiviral properties, A synergistic formula (tablet or capsule) of natural substances has been found to outperform single (unitary) agents in global immune stimulation or modulation.1 Not only may a synergistic formula be more potent in stimulating NK cell function, it induces cytokine changes that are not observed with unitary formulations of dietary supplements..
Synergy in Sleep 4, 5
The nation’s epidemic of insomnia is best approached by simple, gentle and natural options to promote sleep. The use of synergy in dietary supplement formulations has been applied for the nutritional support of the complex biophysical cascades of events that initiate and maintain restful sleep.4
Synergy in supplement formulations leads to the use of relatively small dosages of a number of natural agents that have helper or additive effects. This approach helps to avoid “tolerance” that occurs when a single drug or supplement is used for the nutritional support of sleep. The combination of proprietary blends of adaptogenic or hypnotic herbs with 5 – hydroxytryptophan, magnesium and selected B vitamins (a synergistic formula) has been used in millions of unit dosages, with a high level of safety, patient acceptability and satisfaction.4
Synergy in Longevity Promotion 6,7
The aging process involves many complex biological processes. Specific antiaging nutritional factors work in concert by reducing oxidative stress, altering methyl donation, reducing the formation of advanced glycation – end products (AGEs)and regulating cell apoptosis.5 Add hormonal regulation to nutritional support and this is a clear synergistic approach to antiaging.5 The use of calorie restriction or mimetic compounds that reproduce the biochemical or physiological changes caused by calorie restriction (calorie restriction mimetics) are best used in synergistic combinations.6
Synergy in Stem Cell Support 8, 9
Several nutrients appear to have an effect on mobilizing bone marrow stem cells. Such substances include vitamin D 3, oleic and linoleic acids, blueberry extract, carnosine, fucoidan and blue green alge.8 Recent studies show that the combination of the use of natural substances that mobilize Adult Stem Cells are much more powerful than when these substances are used in isolation or limited combinations.8,9
Synergy in Antioxidant Use 1, 2
A plethora of medical research shows that antioxidants work in “networks” with helper functions that amplify free radical scavaging.1,2 For example, the interaction of vitamin C and E is such that they are highly interdependent in their effects. Synergistic use of antioxidants is optimal in therapeutics by applying combinations of antioxidants that have different REDOX potential with affinity for both lipophilic and hydrophilic tissue compartments. “Antioxidant blankets” exist in synergistic formulations that provide comprehensive protection against free radical damage.2

Synergy in Syndrome X 10,11
The variable combination of an overweight status, hypertension and abnormal blood cholesterol, linked by insulin resistance constitutes the Metabolic Syndrome X. This constellation of problems is associated with many diseases (Syndrome X, Y, Z…). This very important public health initiative can only be managed by a comprehensive synergistic treatment program involving lifestyle change and complex combinations of nutraceuticals that have been termed “Syndrome X Nutritional factors.10,11 Good scientific agreement exists to support the notion that Syndrome X is best managed by integrated strategies.
My proposals about “the power of synergy” are neither novel nor new. They are well known to scholars of “classic” alternative medicine teachings. The power of synergy in therapeutics is “crystal clear” but it is often forgotten. An extension of the concepts of synergy underlies the practice of anti aging medicine. Aging is a complex cascade of bio physiological events that require multipronged (synergistic) interventions. While a tendency exists in natural therapeutics to shun pharmaceutical interventions, one must be cautious to not ignore the proven value of many allopathic treatments. The notion of combining supplements with drug treatments is not rejected in the modern practice of Integrative Medicine. “It is yet one more example of synergy.”1

1. Holt S. A Primer of Natural Therapeutics: A Certification Program for Dietary Supplement Counselors, Little Falls, NJ, Holt Institute of Medicine Press, 2008 (
2. Holt S. Natural therapeutics. Observations on multivitamins, Townsend Lett. Feb/Mar 2009.
3. Holt S, Aids: Exploring Alternative and Complementary Therapies, Townsend Letter 75-83.
4. Holt S, Sleep Naturally, Nov. 2008, Wellness Publishing, NJ 2003 (
5. Holt S, Sleep Deprivation, Diseases and Dissonance, Townsend Letter, 74-79, Dec. 2008
6. Holt S, Specific Anti-Aging Factors for Natural Clinicians, Townsend Letter, July 2008, 90-96
7. Holt S, Natural Therapeutics: Calorie Restriction Mimetics Townsend Letter, 98-101, October 2009.
8. Bickford PC, Tan J, Shytle RD, Sanberg CD, El-Badri N, Sanberg PR, Nutraceuticals synergistically promote proliferation of human stem cells, Stem Cell Dev, 2006: 15 (1): 118-123.
9. Holt S, Stem Cell Support: The Nutraceutical Induction of Adult Stem Cell Recruitment (IASCR), Townsend Letter, Dec. 2009.
10. Holt S, Combat Syndrome X, Y and Z, Little Falls, NJ Wellness Publishing, 2003 (
11. Holt S, Wright JV, Taylor TV, Holt FGS, (FJ Vagnini) “Nutritional Factors For Syndrome X, Wellness Publishing, Little Falls, NJ, 2003 (

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