One verbal battle between herbalists, pharmacists, and physicians, if not chemists, often centers around the word synergy, a word difficult to define, and in biological systems and mixtures, at least, a process a bit difficult to prove. To us, synergy is best defined as the interaction of two or more agents such that the combined effect is greater than the expected sum of the individual effects. This is perhaps an antonym of antagonism, the interaction of two or more agents such that the combined effect is less than the sum of the expected individual effects. Intermediate is additive, the interaction of two or more agents where the combined effect is exactly the sum of their individual effects.
For the sake of argument, let us pretend that we stumbled onto a nice new mutation, a new plant species with a succulent edible leaf with a well-balanced array of amino-acids, fatty acids, minerals, vitamins, and other important nutrients, with absolutely no distasteful antinutrient or harmful compounds in it. There are no such leaves, but some bland head lettuce comes close! We will call it Sweet Leaf. We like it. So do a lot of bacteria, insects, fungi, and viruses. If we all eat it before it has had a chance to reproduce itself, Sweet Leaf becomes extinct. In an evolutionary sense, it does not have a chance, because it has been devoured without reproducing itself. But suppose one or two individuals of Sweet Leaf, through mutation (a rearrangement of a fragment of its genetic and hereditary mechanisms) modifies one of its heretofore tasty and salubrious compounds to produce a new and bitter compound, distasteful to us, the bacteria, insects, fungi, herbivorous mammals, and/or the viruses. We have a distasteful new incipient species which we will call Bitter Leaf. One of Bitter Leaf's edible amino acids has become a distasteful bitter chemical which we will call Alkaloid-1. The herbivores much prefer Sweet Leaf to Bitter Leaf, eating more and more of Sweet Leaf, and less and less of Bitter Leaf. With no more leaves, individuals of the Sweet Leaf species cannot make a living (photosynthesize) and literally starve to death before they have progeny. Bitter Leaf, on the other hand, thanks to its bitter Alkaloid-1, is rejected as food by the grazers (herbivores) and continues to make a living. The uninitiated grazer may take a bite, taste the alkaloid, spit it out and move on to Sweet Leaf. The grazers prefer Sweet Leaf and eat more of it than of Bitter Leaf. With more leaves left intact than Sweet Leaf, Bitter Leaf prospers and has a lot more progeny, all bearing the bitter Alkaloid-1, which makes them distasteful to grazers. The Bitter Leaf progeny prosper and have a lot of offspring. Gradually there are more great "grandchildren" of Bitter Leaf as Sweet Leaf hovers on the verge of extinction.
Among the progeny a second mutation occurs to Alkaloid-1 producing a second distasteful Alkaloid-2, which is chemically very similar to Alkaloid-1, but is twice as bitter. The interactions of this pair of alkaloids may be synergistic, additive, or antagonistic in their distaste or bitterness to grazers. Roughly speaking, if the two are synergistic, the combination of 1 and 2 = >3, i.e., the mixture is more distasteful than an equivalent amount of 1 or 2. If the two are additive, 1 + 2 = 3. If the two are antagonistic, 1 + 2 = <3. Evolution, again, could favor the more distasteful species, which, being less grazed and more photosynthetic, would produce more offspring bearing its synergistic combination of alkaloids. Conversely, evolution would not look so favorably on the progeny if the alkaloids were antagonistic, leaving the plant more tasty than its parents. Under these oversimplified circumstances, nature would favor synergistic, over additive, over antagonistic interactions among antifeedant, antifungal, antihelminthic, antiseptic, and antiviral alkaloids (or other types of phytochemicals).
In the senior author's dozen years of compiling data on the biologically active phytochemicals in plants (Figures 6.1 and 6.2), it seems the rule rather than the
exception to have a suite of closely related antitumor compounds, choleretic compounds, carminative compounds, antioxidant compounds, antifeedant compounds, allelochemic compounds within a species. For example, the long-famous Madagascar periwinkle may contain more than 500 indole alkaloids, many of them antileukemic and/or antitumor. Two, vinblastine and vincristine, have been major antileukemic drugs for close to 40 years. In the mayapple (Podophyllum peltatum), a derivative of which was first approved for cancer treatment in 1984, there are at least four cytotoxic lignans, proven synergistic against the herpes virus. And in the yew, there are more than a dozen compounds closely related to taxol, first approved for ovarian cancer treatment in 1992. All of these billiondollar drugs are based on compounds distasteful or downright toxic to herbivores. But toxic is relative. Only the dose determines whether it is medicine or poison. It seems logical, to us at least, to conclude that where the several compounds possess some characteristic that also makes them distasteful to grazers or repellent to fungi, etc., synergies would be passively selected and antagonisms rejected or selected against.
It is nice to read, 3 years after writing in the Science News,1 that breeders have developed plants with high concentrations of allelochemicals. They find that fall armyworm, tomato fruitworm, and tomato hornworm respond differently to three allelochemicals — chlorogenic acid, rutin, and tomatine — depending on the temperature and other chemicals present. "Since the chemicals varied in their effects on a particular insect, plants would fare best if armed with all three allelochemicals."1 Thinking is becoming the same about HIV, humans, and anti-HIV drugs. Witness their synergistic anti-AIDS cocktail (at $16,000/year). In a decade they will be seeking the natural synergies they are now reluctant to admit, as we lose the battles with evolving disease-resistant public enemies, like AIDS, tuberculosis, and yeast. But now, in modern medicine, we often just take one of the synergistic compounds that imparts a selective advantage to the plant, and use it for our own ailments, leaving behind the other compounds and their synergies. We do this, we believe, largely in our search for replicability. The whole nonhomogeneous plant, containing thousands of compounds, is not as likely to give us replicable results in a clinical trial as a single compound. For that and other reasons, modern pharmacy goes for the "silver bullet", not the "herbal shotgun". But a standardized and consistent homogeneous mixture of four active ingredients, say those four lignans in mayapple, should give us more antiherpetic activity than an equivalent amount of any one of those lignans. Would results with a consistently standardized mixture of four compounds be as replicable in clinical trials as with a single compound? Atropine, berberine, and caffeine demonstrate the rather cosmopolitan distribution of medicinal and pesticidal compounds, and they also demonstrate the potential for synergies. We think, and many agree with us, that the function of many of the secondary metabolites produced by medicinal plants is to protect the plants, not to protect us (see Chapter 2).
Atropine has viricidal activities in addition to its numerous medicinal activities. Often found in the same plant species that provides atropine is scopolamine, which is sold as a prescription transdermal drug for vertigo and sea sickness. Berberine, found in several over-the-counter (OTC) preparations is both pesticidal and medicinal. Its pesticidal properties are medicinal, e.g., amebicide, antigiardial, antileishmannic, antimalarial, bactericide, candidicide, fungicide, and viricide. Berberine may or may not be synergistic with the sanguinarine, found as an antiplaque agent in Viadent™ toothpaste. Caffeine, in addition to its antiasthmatic central nervous system (CNS)-stimulant properties, has antifeedant, herbicide, insecticide, and viricide properties. It may or may not be synergistic with the other antiasthmatic drugs, theobromine and theophylline, which co-occur with it, at least reportedly in cacao (Theobroma cacao).2
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