Similar to the pomegranate synergy described above, three different fractions, namely alkaloids, lignans, and organic acids of the roots of Isatis tinctoria were evaluated for antiviral activity against respiratory syncytial virus in a mouse model. Each fraction exhibited antiviral properties, the strongest effect was when all three fractions were combined [23].

In the past, combination treatments for influenza were favored if they did not contribute to the emergence of drug resistant strains of virus or result in increased costs of treatment. If they did not prolong the virus’s eclipse phase, they were required to be used in combination with antiviral drugs that did [24].

The plant alkaloids emetine, from Psychotria ipecacuanhaand homoharringtonine, fromCephalotaxus fortunei synergized with the broad spectrum antiviral, Remdesivir, or the anti-HIV retroviral, Lopinavir, against SARS-CoV-2 [25]. Synergy was observed between hydroxychloroquine and azithromycin as probable competitive inhibitors to the SARS-CoV-2 virus at the host’s cell membranes [26]. Synergy was also central to a proposal for testing various deoxynucleosides with 5-fluorouracil which had become ineffective when used alone due to coronavirus recognition [27]. Recent three dimensional methods have been advanced to quantify synergy between different modern antiviral drugs, which could be as high as 180 fold when stimulated by a synergen [28, 29].

Many papers were published over the past two years regarding herbal treatments or potential treatments for COVID-19 [30, 31]. A sampling of this research, presented according to plant name, is presented in Table 1.

When a wine or fine spirit ages, its chemistry becomes more complex, or alternatively, its complexity increases. Aggregates of polyphenols increase during aging, and are associated with increased pharmaceutical potency [32, 33]. One bottle of Pinot Noir recovered from a French wine cellar and estimated to be between 200 and 300 years old was reported to have a higher amount of such aggregates, with its resveratrol also preserved [34]. Although during vinification a maximum phenolic concentration is achieved in about nine days, the antioxidant properties can continue to increase for many years, presumably related to the formation of such aggregation of polyphenols [35] and additional changes in flavanols and anthocyanins with the subjective sense being being mellow and smooth [36]. In one recent study, aging in wine resulted in increased inhibition of topoisomerase-2 [37], an enzyme required for viral replication [38].

Complexity may also occur in pharmaceuticals when many, even thousands, of compounds constitute the drug. Such “complex drugs” have some advantages, such as being able to impact multiple targets at once, and being less likely to cause drug resistance [39].

When I made a pilot mixture of ethanolic extracts from the tissues of 34 different herbs and two mushrooms for preventing or treating COVID-19 two years ago, I was guided by several constraints. Initially, the first constraint was whether I had the herb or foodstuff in my possession, and later, whether I could obtain it during increasing COVID-19 restrictions. Second, was that the material must be legal. Use of certain herbs may be prohibited by law. Third, the herb should not be too toxic. And finally, if possible, the solution should taste good, or at least, not taste too bad.

In herbal therapeutics, herbs of specific “temperament” such as being hot or cold, are used to balance or correct their opposites in the “temperament” of a patient. However, when designing a formula aimed to suit all for a specific task (preventing or treating COVID-19), it should have “round edges” and be well tolerated by persons regardless of their individual “temperaments”. So it was in this spirit that I combined the mostly certified organic, and if not organic, then usually wildcrafted herbs in the original formulation. Those herbs, extracted and concentrated to fit in a 1 liter laboratory bottle, have now aged for almost two years. In their present form, they might offer a point of departure for further studies.

I propose a rapid screen of in vitro antiviral activity in standard SARS-CoV-2 infected green monkey kidney vero cells. In addition to controls which will be infected but not treated, these infected cells will be subjected to 83 different herbal interventions aimed at preventing or inhibiting the progression of the infection. The first 41 interventions will be simply the same dry weight dose of each of the 96% food grade ethanolic extracts of each of the 41 different “herbs” listed in Table 2. The first of the next 41 interventions will be extracted from the single herb, Glycyrrhiza glabra (licorice). The second intervention will be licorice plus a second herb, according to the priority shown by Roman Numeral in Column 1 of Table 2, such that their total dry weight is equivalent to the dry weight of licorice only in the first intervention. Similarly, the third intervention will be licorice plus the next two more herbs according to the herb’s priority by Roman Numeral as indicated in the first column of Table 2. Successive interventions will include the herbs from the previous intervention plus one more, until in the 41st intervention, all 41 herbs will be present. The quantities of each herb in each intervention will be mathematically “weighted” to reflect their percentages in the complete 41 herb formula. Finally, a second 41 herb formula intervention, namely the aged, not the fresh, solution, will be tested (now nearly two years old) to assess possible difference in safety (intactness of the cellular hosts) and efficacy (weakening of the viral infection) of the aged relative to the freshly made formula. So, the first intervention will include one herb, the second intervention, two herbs, the third, three herbs, until the 41st, containing all 41 herbs has been achieved. Starting with licorice, Glycerrhiza, in the first experiment, additional single “herbs” will be added at each trial, one at a time, according to the Roman Numerals in Column 1 of Table 2. A 42nd intervention will employ the aged, not the fresh, 41 “herb” combination.

The hypothesis challenges the classical wisdom that “you can’t have your synergy and efficacy too” [40], as one author put it, because as you continue to add new herbs to the mix, you dilute the amounts of each herb, pushing the individual herbs into sub-effective doses. In other words, more is less, that is, more herbs means less of each. In the alternative and complementary view, more is more, because even though the amount of each herb will be less, the sum of all the herbs results in a greater, i.e., a synergistic effect.

The question of the impact of aging on the formula’s antiviral potency also goes against conventional wisdom which believes that the fresher the drug, i.e., that the closer it is to its date of production, the better, and the more potent it will be. The hypothesis that aging could improve the product may seem counterintuitive.

However, in either case, that of increasing the N, the number of herbs in a formula, or its aging, what number of herbs, or how long an aging, is optimum? When does synergy start, when does it peak, and when does it decline, and finally when does it become extinguished? These are all questions which the results of the proposed trial will possibly begin to answer, while illuminating pathways for further investigations. Practical applications for a safe and effective combination of herbal tinctures would include both internal and external uses, the latter for sterilizing sprays and for impregnating face masks.