The early years of the 21st century appeared opportune for renewed efforts to be made in regard to the discovery of new SMs and prototype biologically active compounds from animals, fungi, microorganisms and plants of both terrestrial and marine origin. Despite huge investments in combinatorial chemistry and natural product drug discovery, there have been disappointing numbers of single chemical entities being introduced as drugs in recent years. An unfortunate sequel to the introduction of new drugs at the end of a long-drawn pre-approval testing period following huge investments is the rapidity with which they are withdrawn from the market on grounds of new evidence of toxicity.

Concurrently, the last three decades have seen widespread use of herbal drugs with renewed popularity of phytomedicines world over. Herbal remedies are prescription products in Germany and several other countries of Western Europe. During the last decade, there has been a large influx of botanical products into community pharmacy practice and health food stores in the United States as a result of the Dietary Supplement Health and Education Act in 1994. A parallel increased interest in herbal remedies has occurred in Europe, Canada and Australia, in part because of an overall greater awareness of complementary and alternative therapies. This has opened a new door of research inquiry for natural product scientists world over.

• Some of the most popular and widely sold phytomedicines such as Indian gooseberry (Emblica officinalis), turmeric (Curcuma longa), ashwagandha (Withania somnifera), ginseng (Panax quinquefolius), valerian (Valeriana wallichii), ginkgo (Ginkgo biloba), St. John’s wort (Hypericum perforatum), etc., have considerable pharmacological and clinical evidence to support their use.
• These herbs are used in whole or as extracts in Ayurveda and traditional Chinese medicine (TCM). Combinations of herbs are fundamental to the philosophy of these systems and have been so used traditionally, much similar to the usage of multiple drugs for treating a single complaint such as hypertension, psychoses and cancer in CM. This applies also to single-plant extracts which are mixtures of several phytoconstituents.
• It is rather uncommon to find a pure molecule showing more activity than that shown by the parent extract. Since the individual molecules may not be sufficiently active to achieve the desired effect, most efforts in plant research are unable to reach a critical stage of identification of a prospective biomolecule and its final development to an effective drug.
• Today it is accepted that unlike compounds approved as single-chemical drugs, combinations of plant SMs are responsible for the physiological effects of herbal medicines. For example both the terpene lactone (e.g. Ginkgolide B) and flavonoid glycoside constituents of Ginkgo biloba leaves are regarded as being necessary for mediation of the symptoms of peripheral vascular disease, for which this phytomedicine is used in Europe.
• Thus attempts are not being made to isolate individual components from popular herbal remedies of long-time history of usage that are sold as standardized extracts. In several cases, the single active ingredient is either not known (St. John’s wort) or is unstable (ginger).
• Thorough phytochemical analysis of several herbal remedies has failed to yield a single active ingredient if not a novel chemical entity. Such an analysis has revealed them to be mixtures of well-known groups of compounds, such as polyphenols (myrobalans), poly-saccharides (ginseng, gymnema, aconite, dioscorea), simple organic acids (garcinia), flavonoids (Pterocarpus marsupium), steroids (ficus, ginseng, mMomordica charantia), etc. Thus the main active ingredients of even such drugs as St. John’s wort (Hypericum perforatum) are still under discussion.
• This has opened up understanding of the concept of ‘Synergism’ to explain the efficacy and superiority of single herbs and polyherbals over single chemical entities.
• Synergy broadly means a beneficial interaction of the constituents of a single herb or a poly-herbal mixture resulting in greater combined effect than would be expected from a consideration of individual contributions of each of the constituents. The interaction between the component constituents may involve a potentiation of therapeutic effects or an attenuation of toxicity or side effects within the preparation. The effect may be truly synergistic or additive.
• Generally a substantial decrease in toxicity levels is observed when whole plant extracts are compared with individual molecules derived from a plant even when used in the same proportion as found in the whole plant.
• Medical herbalists today insist that better results are obtained with whole plant extracts rather than with isolated compounds.
• Plants being subjected to selection pressure have, over millions of years, developed optimal chemical defences to resist threats such as radiation, reactive oxygen species and microbial attack in order to survive. The multicomponent composition of herbs thus simultaneously addresses effectively the causative factors of multifactorial human diseases better than single pure drugs.
• The benefits of multicomponent drugs may reside not only in enhancing therapeutic action through bioavailability improvement, but also in permitting the use of lower doses.
• Diseases are caused by a multiplicity of factors and complications rather than due to a single gene, receptor, enzyme or protein resulting in both visible and invisible symptoms. Illustrations of failed drugs that target a single protein and ignore a sophisticated network system of disease processes are numerous. Allelochemicals of a single plant can have complementary and overlapping activities on human physiology thus bringing relief.
• For example the side effects of ephedrine are not usually found with an extract of the herb Ephedra. Likewise initially whole extracts of Rauwolfia root were used clinically for their anti-hypertensive effects. The growing dominance of the reductionist model of reducing the extract to its active component however pushed chemists to isolate reserpine and use it as a drug. Relatively an effective and safe anti-hypertensive when combined with a thiazide diuretic, reserpine has been unjustly discarded from drug use, on grounds of adverse effects actually associated with the drug at doses higher than required to cause a hypotensive effect. The whole extract was safe and had better overall efficacy as a hypertensive and a calming sedative effect owing to synergism between the alkaloids and other constituents of Rauwolfia.
• Synergistic enhancement of activity has been reported with multiple herb combinations of several drugs of Ayurveda, TCM and European herbalism.
• Further research to demonstrate synergy and polyvalent action in phytomedicines has reported the attenuation of toxicity effect of herbs such as liquorice in polyherbals. Its detoxifying effect is due to an unspecified interaction of the non-glycyrrhizin components of liquorice during intestinal absorption. This reduces the bioavailability of glycyrrhizin as well as the actives of other drugs such as aconitine of aconite, etc.
• But then piperine of pepper is demonstrated to be a bioavailability enhancer of other drugs, probably as a result of its potent inhibitor effect on drug metabolism. Its inclusion in Ayurvedic drugs such as ‘trikatu’ is possibly to reduce the needed dosage of other drugs critical for activity.
• Synergy is implicated in the anti-ulcer effect of ginger widely used for its anti-emetic, anti-ulcer effect. A range of chemically unstable compounds probably acting synergistically are responsible for its anti-ulcer activity.
• Likewise it has been demonstrated that the anxiolytic effect of tetrahydrocannabinol, the main psychoactive ingredient of cannabis, is beneficially modulated by the psychoactive cannabidiol also present in it, thus producing an overall relaxant effect by the resin drug.
• It has been established that the physiological activity of herbs is the resultant effect of a variety of constituents interacting with each other synergistically, additively or modulatorily.
• Evidence such as decreased microbial resistance to antibiotics with herbal drug co-administration is accumulating to demonstrate clearly the therapeutic benefits of poly pharmacy.
• The age old wisdom of the benefits of using whole plant extracts over single drugs in traditional medicine has now been elevated in status from being a ‘superstition’ to ‘science’ in the understanding of modern medicine.

Pharmaceutical researchers recognize the concept of drug synergism but note that clinical trials may be used to investigate the efficacy of a particular herbal preparation. It is today conventional practice to use cocktails of chemotherapeutic agents for better treatment of cancer and AIDS. Whatever may be the mechanism involved, understanding the polyvalent action of herbal remedies is very essential towards developing methods of standardization.