An Alternative Hypothesis and the Connection with Hormesis...In a recent article entitled, “Metal nanoparticle induced hormetic activation: A novel mechanism of homeopathic medicines,” Chikramane et al
In a recent article entitled, “Metal nanoparticle induced hormetic activation: A novel mechanism of homeopathic medicines,” Chikramane et al have considered source-drug material as an essential active ingredient, even in high dilutions (potencies) of homeopathic medicine. This concept is causing much confusion in the understanding of homeopathic medicine itself. Hence, it is critical first to undertake a detailed analysis of the concept before any endeavour to understand the observed hormetic activation.
Chikramane et al formed this concept in their earlier work titled “Extreme homeopathic dilutions retain starting materials: A nanoparticulate perspective.” They studied six metal-based homeopathic medicines in three potencies, namely 6C, 30C and 200C. These medicines, prepared by two different manufacturers, were purchased from standard commercial outlets. In most of these increasing high dilutions, they unexpectedly found their source-drug metals were still present and often imbedded in nanoparticles present in them. To explain it, they hypothesised that during preparation of a potency, after succussion, all the source-drug nanoparticulate metal floats on the surface with the help of nanobubbles forming a monolayer. This monolayer forms 1% of the total volume but contains all the source-drug metal; and all of this monolayer is poured out into a new vial as ‘seed’ for preparing its higher potency, thus retaining the source-drug. 
Chikramane et al upheld this hypothesis as true by ‘physically’ taking gold nanoparticles in simulation. However, homeopathic medicine and its methods of preparation contradict this hypothesis due to the following reasons:
The Korsakoff method is generally used to raise higher potencies.
It is practically impossible to assume monolayer as 1% of the total volume containing all the source-drug and further assume that 100% of the pouring out of this monolayer would be possible to raise the next higher potency. Moreover, potencies are not a few in number but up to CM (105) and even higher with virtually no upper limit.
In homeopathic pharmacopoeia, the top layer is not talked about nor any special value assigned to it.
A higher potency of a medicine can be prepared, even after decades, from its present potency.
Medicine (potency) is consumed up to its last drop for medication or preparing a higher potency.
Medicines based on non-material source-drugs, such as X-ray and magnetic fields, exist.
The potencies of a medicine are also raised in solid form by trituration, taking lactose as a diluent.
Direct sunlight exposure can destroy the medicinal properties of a potency.
The dose-quantity of a potency (medicine) is inconsequential if it is sufficient to produce an effect on a patient.
Furthermore, in the study of Chikramane et al, the question of contamination cannot be ignored. In fact, contaminations in homeopathic medicines have been so common that even the World Health Organization has issued an advisory against it.
Two things should be clear regarding the presence of contaminants in homeopathic medicine. First, though homeopathic medicines are extremely diluted, they cannot be extremely pure. One basic reason behind this is that so-called pure water does not exist.  Second, as preparation of homeopathic medicine is still traditional, much impurity even in trace level can be expected.
In the case of laboratory-made homeopathic samples, Witt et al observed that contaminations from containers and vehicle reached its maximum at the very first potency and afterwards remained more or less the same. It was obvious because every potentising step was a repetition of the same process under the same or similar conditions. Thus, concentrations of contaminants reach a plateau from the very first potency onwards. So, it is understandable that Chikramane et al observed a plateau of the source-drug of the medicine at 6C potency onwards, where it was only left in traces at this stage.
There is an important route for contaminants to get in, which is hardly paid attention to, especially in commercial manufacturing where many potencies of a medicine or of different medicines are prepared simultaneously or soon one after another in a room. Chaplin cautions that when a bottle is opened after succussion, aerosol can spread in the room for an extended period of time, contaminating other preparations. Though ignored in homeopathy, it is important for microbiologists to take care of such type of situations in their work.
The chemical analysis data by Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) of Chikramane et al on the presence of source-drugs in market-purchased medicines speaks for itself. For example, in some samples, source-drug metals were not detected. Nevertheless, a variation up to 40% was observed in the samples from one batch of the same manufacturer, and up to 1550% was observed in the samples from different batches or different manufacturers. The enormously large variation indicates that these data are erratic in nature. This suggests that the presence of source-drug metals in their high-potency medicines was more likely due to contamination as opposed to the hypothesis by Chikramane et al.
Temgire et al repeated the experiment in which they used some water-soluble source-drug-based medicines purchased from the market and claimed the validation of the hypothesis by Chikramane et al. However, how could this be possible? Can the 1% part of a solution contain all the solute of the solution? Can, in the homeopathic dilution process, source-drug material be produced out of the vacuum state? Physics does not suggest the possibility of material extraction from it, even if nanoparticles are involved. Energy, however, may be drawn from it.
Similarly, in preparing potencies in solid form, the 1% part of the triturated material called ‘seed’ cannot typically contain all the source-drug present. Nanoparticles cannot alter this fact. The source-drug can be of any type, including metal-based as Chikramane et al studied.
In addition, it should not be forgotten that the selection of potency is most important after the selection of remedy for a patient. Nonetheless, the hypothesis of Chikramane et al is blind to different potencies of a medicine. They believe dilutions are only apparent at 6C potency onwards, retaining the source-drug material nearly in the same size distribution of nanoparticles and their clusters.
At the time of publication of the hypothesis of Chikramane et al, even guest editors Ives et al raised a finger on it through the Korsakoff method of potency preparation. Bellavite et al were also not satisfied with the hypothesis despite technological advancements.
Using state-of-the-art techniques, Chikramane et al and Temgire et al revealed, like Upadhyay et al, the presence of nanoparticles in homeopathic medicine, throwing light on their structure. They did their experiments meticulously; however, the observation of Chikramane et al of source-drug ‘survival’ from 6C potency onwards cannot be explained, except in terms of contamination. In this regard, their materialistic hypothesis  is also of no help. In fact, it is irrelevant to homeopathic medicine, for which it was proposed. It may work materially in nanoscience where a few quick steps of turbulent liquid dilutions are performed using only the top layer.
Interestingly, during Hahnemann's lifetime, when the world was unaware of Avogadro's number, there was no theoretical objection to homeopathic high dilutions. Nonetheless, it is amazing that Hahnemann realised that his medicine did not contain source-drug. He took his medicine ‘spirit-like’, which remains no more mystical now as it could contain source-drug specific ‘information’.
Some models were proposed in the past to explain homeopathic medicine and its seemingly bizarre ‘memory’; but they fell short of expectations. This vacuity seems to open doors for Chikramane et al to propose their hypothesis “thereby resolving the homeopathic conundrum and reconciling it with atomistic theory of matter.”
Recently, Calabrese has appreciated the hypothesis by Chikramane et al as “outside the box” thinking. The aversion or even fear of associating ‘memory’ with homeopathic medicine has been prevailing, especially after the debacle of the so-called memory of water. 
The above scene is changing again in favour of ‘memory’, but in a different way. This could happen after some new discoveries in nanoscience, homeopathic medicine, and water. Recently, a novel ‘Nanoparticle–EZ Shell Model’ has been proposed, which explains homeopathic medicine wholly in its different and diverse aspects, along with magnet-treated water. This model is an extension of the previous work of Upadhyay et al and it is based on the following three facts:
Nanoparticles can be an environmental sensor.
Homeopathic medicine contains silica-rich nanoparticles, which may retain source-drug specific ‘information’.
Exclusion Zone water is formed on a hydrophilic surface and it excludes nearly everything.
Interestingly, the protection against impurities is a fundamental feature of this model. This model explains why homeopathy could take birth two centuries ago at the time of impure chemistry when Hahnemann even made his medicine occasionally in whisky. Similarly, the work of Chikramane et al made a shocking revelation, which was never paid attention to; that source-drug may be present even in significant quantity in homeopathic high dilution. This presence was a big challenge for homeopathic theoreticians to explain why it would not vitiate the medicinal properties acquired at that dilution.
Homeopathic medicine contains source-drug up to 12C potency (Avogadro's limit). In this potency range, homeopathic medicinal effects may be divided into two parts, namely source-drug based and source-drug specific ‘information’ based. Their medicinal effects are under the Similia principle, probably using different pathways. ‘The Nanoparticle–EZ Shell Model’ explains that at 3C potency, the source-drug specific ‘information’ is completely acquired by nanoparticles and their EZ shells; and at 4C potency, this acquired ‘information’ becomes independent of its source-drug. So from 3C potency onwards, homeopathic medicine would work through the acquired source-drug specific ‘information’. By then, most of the source-drugs have already become too diluted in themselves to be therapeutically effective.
Homeopathy is the best known medical analogue of hormesis. While homeopathy is a therapeutic system of healing, hormesis is an effect. The common thread linking them is that they involve the secondary paradoxical effects of drugs and toxins in biological systems as a function of dose or time.
Wiegant and Van Wijk have done pioneer work in, now called, ‘post-conditioning hormesis’ at the cellular level. They, however, used unpotentised low material doses of chemical stressors, but they verified the validity of the Similia principle at the cellular level.
Bellavite et al have done extensive study related to hormesis, developing a pre-conditioning model using homeopathic medicine within material range.
Presently, Calabrese is very cautious to maintain distance from any homeopathy that claims itself without the presence of source-drug material. His caution is not without reason. His statement, “....it is not possible to kill an idea if it is real” is, however, encouraging.
It is important to note that clinical homeopathic practice can be taken as related to pre- and post-conditioning hormesis, when it is for prophylaxis and treatment respectively. In both the cases, especially for the latter, medicines are often prescribed beyond material range.
Furthermore, the proving of a medicine in homeopathy is performed on healthy persons with its source-drug material as well as with its high potency. The proving by higher potencies is particularly needed to bring out the finer characteristics of the medicine. The source-drug of the medicine can be toxic or even poisonous. Thus, the ‘Nanoparticle–EZ Shell Model’ already covers hormetic agents. The source-agent is potentised even beyond Avogadro's number. According to this model, by the process of potentisation, nanoparticles and their EZ shells acquire and preserve source-agent specific ‘information’. Acquiring this ‘information’, which this model assures, is one thing but responding to (‘reading’) it by biological systems is another. As homeopathic toxic source-drugs are also hormetic agents, this assures their acquired specific ‘information’ as bioactive, probably for all chemical (including radiation) hormetic agents.
After the analysis and discussion above, recent observations of Chikramane et al regarding cellular hormetic activation can now be examined. In these experiments, Chikramane et al are appreciated for using high-potency, metal-based medicines. These commercially made market-purchased medicines contain their respective source-drug metals at “a billion-fold lower concentration” than synthetic nanoparticles of the same metals (controls) to cause hormesis. A question arises here that at such a low-level concentration, abundant impurities, including many other homeopathic source-drugs and toxic materials, remain present in homeopathic medicines. As a consequence, in terms of material, such a medicine is a cocktail of numerous contaminants present in it. Then how can the observed hormetic effect be attributed to the source-drug metal of the medicine used? Moreover, how is it possible to claim a new phenomenon on the basis of contamination?
The observed hormetic effect seems to be at a billion-fold lower concentration of the source-drug than required, and this was in fact ‘extraordinary’. The nanoparticle morphology and stress based explanation, provided by Chikramane et al, for this unusual observation falls short for the occasion, which seems to demand an unusual explanation. Such possible explanation is that, instead of the source-drug metal, the source-drug metal specific ‘information’ that is carried by the medicine, as per the ‘Nanoparticle–EZ Shell Model’, be made responsible for it. What is required here is to design such experiments that could catch this possible phenomenon explicitly. Medicines used in such experiments must be laboratory made, so that they could be as pure as possible and genuine controls could be available to counter unwarranted effects. To avoid any contamination, rarely available suitable hormetic agents that are potentised beyond material range can also be a part of the study.
The most controversial aspect of homeopathy is its medicine, even beyond Avogadro's number. Such a medicine, however, makes homeopathy unique. Homeopathy will do a great service to hormesis if it is able to extend hormesis beyond Avogadro's number, where most of homeopathic medicines are based. This theory could potentially be a response to Fisher regarding the contribution of homeopathy to hormesis. In addition, homeopathy would get legitimacy and a powerful tool to understand itself better. Homeopathy and hormesis can consequently be united, as Calabrese now aspires.