testing the nanoparticle-allostatic cross-adaptation ... · original paper testing the...

Homeopathy (2013) 102, 66e81� 2012 The Faculty of Homeopathy

http://dx.doi.org/10.1016/j.homp.2012.10.005, available online at http://www.sciencedirect.com

ORIGINAL PAPER

Testing the nanoparticle-allostatic

cross-adaptation-sensitization model

for homeopathic remedy effects

Iris R Bell1,2,3,*, Mary Koithan1,2,3 and Audrey J Brooks2

1Department of Family and Community Medicine, The University of Arizona College of Medicine, Tucson, AZ USA2Arizona Center for Integrative Medicine, Department of Medicine, The University of Arizona College of Medicine,Tucson, AZ USA3The University of Arizona College of Nursing, Tucson, AZ USA

*Correspnity Med1450 N CE-mail: ibReceivedOctober 2

Key concepts of the Nanoparticle-Allostatic Cross-Adaptation-Sensitization (NPCAS)

Model for the action of homeopathic remedies in living systems include source nanopar-

ticles as low level environmental stressors, heterotypic hormesis, cross-adaptation, allo-

stasis (stress response network), time-dependent sensitization with endogenous

amplification and bidirectional change, and self-organizing complex adaptive systems.

The model accommodates the requirement for measurable physical agents in the rem-

edy (source nanoparticles and/or source adsorbed to silica nanoparticles). Hormetic

adaptive responses in the organism, triggered by nanoparticles; bipolar, metaplastic

change, dependent on the history of the organism. Clinical matching of the patient’s

symptom picture, includingmodalities, to the symptom pattern that the sourcematerial

can cause (cross-adaptation and cross-sensitization). Evidence for nanoparticle-related

quantum macro-entanglement in homeopathic pathogenetic trials.

This paper examines research implications of the model, discussing the following hy-

potheses: Variability in nanoparticle size, morphology, and aggregation affects remedy

properties and reproducibility of findings. Homeopathic remedies modulate adaptive al-

lostatic responses, withmultiple dynamic short- and long-term effects. Simillimum rem-

edy nanoparticles, as novel mild stressors corresponding to the organism’s dysfunction

initiate time-dependent cross-sensitization, reversing the direction of dysfunctional re-

activity to environmental stressors.

The NPCASmodel suggests a way forward for systematic research on homeopathy. The

central proposition is that homeopathic treatment is a form of nanomedicine acting by

modulation of endogenous adaptation and metaplastic amplification processes in the

organism to enhance long-term systemic resilience and health. Homeopathy (2013)

102, 66e81.

Keywords: Nanoparticle; Homeopathy; Allostasis; Time-dependent sensitization;Metaplasticity; Cross-sensitization; Research design; Complex adaptive systems;Physiological stress response

ondence: Iris R Bell, Department of Family and Commu-icine, The University of Arizona College of Medicine,herry, MS 245052, Tucson, AZ 85719, United [email protected] April 2012; revised 25 October 2012; accepted 25012

IntroductionBell and Koithan1 have proposed the Nanoparticle-

Allostatic Cross-Adaptation (hormesis)-Sensitization(NPCAS) Model for the action of homeopathic remedies inliving systems. (See Table 1 for definitions of some of theconcepts referred to in this paper). Themodelmakes three as-sumptions, derived from extensive literature research:

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Table 1 Glossary of key terms in the NPCAS Model

Term Definition

NP A small particle with one or more dimensions measuring 100 nm or less.1,13,24 NPshave different properties from their bulk forms in terms of mechanical, optical, electrical,magnetic, chemical, biological, and quantum behaviors.NPs adsorb proteins, DNA, and other substances onto their surfaces; cross membranes easily;act as highly reactive and catalytic agents that lower the amount of drug or herb needed toproduce a given effect.25,115

Stress Any environmental or endogenous change that serves to perturb physiological or cellularhomeostasis in an organism, i.e., the stable internal state of functioning necessary for maintenanceof life.3,4

Hormesis A biphasic doseeresponse relationship involving low dose stimulation (beneficial compensatorychanges) and high dose inhibition (toxicity); an adaptive response of cells and organisms to a moderateintermittent stress.27,38,39,51,55e57

Adaptation Evolutionary process affecting structure, behavior, and/or physiology in which an organism changesto survive and thrive over time within a given environment. A form of biological learning or plasticity.42e45

Cross-adaptation Physiological phenomenon in which exposure to a given adverse environment leads to an increasein tolerance not only for the original environment, but also to changes in tolerance to other adversefactors that the adapted organism had never previously encountered.41,43,45

Allostasis Physiological adaptive process of achieving or restoring homeostasis through physiological and/orbehavioral change involving positive and/or negative feedback.3,4

Allostatic overload Adverse physiological consequences of long-term exposure to repeated or chronic stress, leading todisease; involves nonlinear interactions of central and autonomic nervous systems, neuroendocrine,immune, and metabolic networks of the organism.3,4

TDS Progressive amplification of the response of an organism from the repeated intermittent exposureto the same or a cross-sensitizing stressor or agent (drug, chemical, biological factor); atphysiological limits, TDS can oscillate in biphasic directions.10e12,47

Metaplasticity Adaptive plasticity of synaptic plasticity in which the past history of the synaptic activity determinesits current plasticity, including the direction and magnitude of the response to a subsequent stimulus.8,9

Important in learning and memory processes in brain areas involved in regulating cognitive, emotional,and somatosensory functioning.8,9,32e36

Complex adaptive system A complex self-organizing collection of components that interact with one another and adapt to changesin the environment, i.e., learn, to optimize fitness for survival. The systemic behavior is an emergentevolving property not seen in any single component by itself, and the organism operates far fromequilibrium conditions. A healthy CAS is resilient and can recover from effects of environmentalstress or change.2 A cell and an organism are both examples of complex adaptive systems. In ananimal or plant, a cell is also a component of the organism, an interactive part of a lower level oforganizational scale within a larger organism.

Nonlinear dynamical system A complex system whose output is not proportionate to its input; a complex system that changesnonlinearly over time in ways that make outcomes difficult to predict; the initial conditions or startingstates influence the subsequent pattern of change.2

Scale free network A complex network of interconnected, interdependent components such as an organism or cell,whose organization follows a scale free power law distribution; an ultra small world network.2,155

The NPCAS model for homeopathyIR Bell et al

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(A) Human beings are complex adaptive systems.2

(B) The allostatic stress response network of intercon-nected nervous, endocrine, immune, and metabolicpathways is the major hub within the organism that in-terfaces with the environment to maintain homeostasis.

(C) Progressive allostatic overload of the adaptive capacityof the organism by higher intensity stressors leads overtime to the emergence of disease in a unique complex,nonlinear, dynamical pattern of maladaptive function,determined by genetic and epigenetic factors.3e6

The current disease state of the system reflects previousmetaplastic priming7e9 by cumulative effects of higherintensity stressors, with persistent changes in allostaticfunction.3 Low dose homeopathic remedy nanoparticles(NPs) act on the disease-primed system7 as novel physio-logical stressors reflecting its dysfunction. The result is toelicit amplified, cross-adapted oscillatory changes in theopposite direction10e12 to those caused by the disease.When the remedy is the simillimum for the individualpatient, the process ultimately leads to healing across theperson as a complex adaptive network, with greatersystemic resilience to future stressors.

The NPCAS model is based on four main consider-ations:1,13

(1) Homeopathic remedies are considered as sourceNPs,14e20 and/or remedy source-modified silicaNPs,15,19,20 not bulk form material drugs. NPs havealtered physical, chemical, biological, optical,electrical, magnetic, and quantum properties that candiffer substantially from the bulk forms of the samesubstance.21e24 NPs are by nature highly reactive andserve as enhanced drug and herb delivery vehicleswhich can reduce the amount of agent needed toachieve a given effect.21,22,25e27

(2) Remedy NPs initiate a complex adaptive response inthe allostatic network,3,4,28 with cascading effects thatemerge across the entire self-organizing organismover time.2

(3) The mediating processes for the remedy effects arephysiological, not pharmacological. These processesinclude well-documented physiological phenomena in-volving bidirectional adaptive metaplasticity (plasticitymodified by the history of prior activity)9,10 andplasticity.9,29e36 Mediating processes include,

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hormesis (low dose beneficial stimulation rather thaninhibition of adaptive function),37e39 cross-adaptation(one stressor can initiate adaptive changes that improveor worsen resilience to entirely different types ofstressor),40e46 and time-dependent sensitization(TDS)10,47e49 (progressive endogenous responseamplification over time, including cross-sensitized os-cillation in the direction of responses at physiologicallimits).

(4) The homeopathic simillimum medicine consists ofNPs27 which act as low level stressors ultimately en-hancing resilience to higher intensity homeostatic dis-ruptors as a complex adaptive system at wholeorganism and local levels of organization.50 The highlyreactive characteristics of NPs21,22 shift the already lowhormetic doseeresponse curve even lower in terms ofthe dose needed to mobilize adaptive changes.27,51

The endogenous adaptations include multiple, interact-ing shifts in central nervous system (CNS) function,9,52,53

autonomic balance,54 heat shock protein activation,55e57

cortisol release,58e65 inflammatory cytokineexpression,66,67 and/or immune system mobilization.68e70

A homeopath might describe the patient as “never havingbeen well since” an adverse life event.71 The resulting mal-adaptive allostatic pattern of dysfunction, not the receptorswhich merely mediate end-organ symptoms, is what theremedy NPs address and reverse.As a result, the system responds differently to subse-

quent low intensity, heterotypic stressors which reflectthe dysfunction: the remedy NPs. The process of homeo-pathic prescribing71 takes advantage of cross-adaptationbetween different types of stressors (post-conditioning het-erotypic hormesis).41,72 In contrast, isopathic prescribing73

involves low dose reversal of direction in manifestationsof high dose toxicity from the same agent or stressor12

(post-conditioning isotypic hormesis).55,57 Low dosehomeopathic NPs stimulate specific compensatoryresponses within the organism, reversing the direction ofadaptations. In the CNS, for example, metaplasticsynaptic changes, which can occur at subthreshold doselevels,74 prime the system to reverse plastic changes thatthe neuronal synapses will later make in response to thenext encounter with the same or a cross-adapted stimulusor stressor.74

Although priming and cross-adaptive responses to lowdose homeopathically-prepared remedies75 and/or envi-ronmental NPs76,77 also occur in isolated cell systems,the brain is a central controller hub, the coordinator ofallostatic network regulation for the intact organism.78 Me-diators of inflammatory, endocrine, immune, and meta-bolic responses interact bidirectionally with the CNS andwith one another to mount an overall homeostatic regula-tory response to environmental stressors.3,48,49 Then, ashomeostatic changes develop in the allostatic stressresponse network components,79 the indirect effects withinthe larger system trigger an evolving series of changes inother interconnected systems and the whole organism.80

Improved health and greater resilience are the outcomes.2

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The NPCAS model provides a testable theory for how ho-meopathic remedies act and leads to hypothesis-driven re-search. The results will support or refute the basic tenets,and/or suggest appropriate modifications of the model toaccommodate the scientific data as it accumulates.Figure 1 summarizes the allostatic model of disease and

NPCAS model for homeopathic remedy actions. Notably,the homeopathic remedy mobilizes multiple componentsof the allostatic stress response network; it likely has littleto no effect on conventional pharmacological receptors. In-dividual differences in coping styles and biological adapta-tion patterns contribute to the emergent dysfunctionalsymptom picture in disease and the capacity to improve un-der treatment with the simillimum remedy.The purpose of the current paper is to explore the impli-

cations of the NPCAS model for a research program81 ofbasic and translational science on homeopathic practicetheory and, ultimately, improve homeopathic clinicalcare. Rather than outline a long list of possible studies,we will focus on key methodological and design issuesthat the NPCAS model raises for future homeopathic re-search.13

HomeopathicremediesaresourceNPs,notbulkmaterialdrugsHypothesis: Variability in NP size, morphology, and ag-

gregation will affect remedy properties, effects and repro-ducibility of findings.

Background findings on NPs

One of the challenges in both homeopathic practice andresearch has been difficulty in reproducing previous re-sults.82,83 Skeptics argue that homeopathy is a placebowith no true biological effects. The NPCAS modelsuggests alternative hypotheses. Current data suggest thatremedy effects are present on average and replicableacross different laboratories e but not in everyexperiment or every laboratory.84 How would variationsin the remedy NPs contribute to the reproducibility issue?The nature of NPs provides valuable clues to the an-

swer.85 Existing basic science data show that the ways inwhich homeopathic remedies are prepared (trituration, suc-cussions, glass containers, dilution in ethanolewaterfluids, manual transfers from one dilution step to thenext) can lead to different NP sizes and shapes,14,19 andthus to different properties.21,86,87 These homeopathicprocedures are crude manual methods for ‘topedown’mechanical attrition or grinding and microfluidizationtechniques used now in modern nanotechnologymanufacturing processes.88,89 By their nature, topedownmanufacturing methods are prone to generatingvariability in sizes, shapes and structural defects in theresultant NPs.85

For instance, Chikramane et al.14 found that the NPs ofthe same metal remedy at the same potency manufacturedby two different homeopathic manufacturers showed sig-nificant variation. Within batch variation was much less.

Figure 1 NPCAS Model for homeopathic remedy effects.


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Both manufacturers reportedly make their remedies byclassical manual methods involving trituration and 10 suc-cussions per dilution step. Nanotechnology studies haveshown that plant mother tinctures can biosynthesize NPsfrom silica,90,91 silver20 or gold25 chemical precursors. Dif-ferent amounts of trituration (mechanical grinding) cangenerate different lactose nanostructures, themselves withvariations in surface adsorptive capacity for remedy sourcematerials.92e94 Data show that the resultant NPs varyin sizes and biological effects as a function of theplant sources with which they were originallymanufactured.20,95 Notably, Upadhyay and Nayak alsoobserved variable sizes and shapes of nanostructures andsilicon in three different homeopathic plant remedypotencies from 1C to 15C.19

In another study, Bhattacharyya et al.96 reported thatsuccussion in glass versus polypropylene vials, as well asthree different methods of succussion (hand, vortexing,or sonication) produced measurably different fluorescenceemission spectra findings on the same remedy (Gelse-mium). Even when a homeopathic manufacturer uses glassvials, variations in the NPs of silica, boron, and other ma-terials released from the walls of containers from differentglassware manufacturers during succussion would contrib-ute more variability in experimental results.15,16,19,94,97,98

Different amounts of remedy source plants,20 animal pro-teins,26,93,99 nosode DNA, and other metal NPs canadsorb to the surfaces22 of the silica or polypropyleneNPs from containers, causing differences in remedy char-acteristics as a function of the source material and typeof container, as well as dilution and succussionprocedures.25,100e102 Nanosilica can also self-assemblespecific larger, ‘bottom up’ nanostructures in solutionover time, using DNA, proteins, cells or other crystals astemplates,103,104 thereby adding even more variability tothe final remedy. As in NP technology,98,105,106 the mere re-cency of preparation could alter particle dispersion, sizes,shapes, and surface adsorption capacity as well. These fac-tors could each contribute to the variability in homeopathicremedy effects in both basic science and clinical studies.82

Elia et al.107 observed an aging effect in homeopathicremedies simply stored in small volume containers atroom temperature. Older solutions of a given remedy re-

lease more heat in calorimetry than do younger solutionsof the same material when exposed to changes in pH.The changes in physico-chemical properties could occurviamodifications in self-assembly and aggregation of rem-edy source and silica NPs85,103,108 originally created in thesuccussion process and left to interact in small volume col-loidal solutions. Smaller particles will form larger particlesin solution over time in solution, i.e., Ostwald ripening.108

Different size and shape NPs have different physical chem-istry and biological properties from each other and fromtheir respective bulk forms.20e22,86

Elia et al.’s findings included not only heat release, butalso increases in electrical conductivity with pH changescompared to untreated solvent controls. The conductivityobservations are another physical chemistry finding consis-tent with the presence of NPs in remedy solutions.15,19,94,96

Nanosilica, for example, exhibits increased electricalconductivity with increases in temperature.109 Diluteaqueous solutions appear to foster solute aggregation,including with NPs.110 Together these data suggest thatrequiring more specificity in research reporting details ofremedy preparation and storage could contribute toreducing inter-experimental variability in homeopathicstudies.In addition to the multiple factors affecting the nano-

structure nature of remedies, the recipient cells or organ-isms will bring their own nonlinear dynamics into playinteracting with any given remedy.111,112 That is, succes-sive potencies of the same remedy produce nonlinear ef-fects,113 i.e., in opposite directions or with markedlydifferent magnitudes (see Figure 2a for ArgentumNitricumeffects on plant development114). The 25D (25X) potencyproduced effects smaller than those of the 24D and 26D po-tencies of the same remedy. By comparison, successivelylarger platinum NP cluster sizes produce nonlinear oscilla-tion in the magnitude of their catalytic effects21

(Figure 2b). Similarly, Figure 3 shows a markedly nonlin-ear, sinusoidal doseeresponse curve for homeopathically-prepared formaldehyde on bacterial cell metabolism car-ried through successive serial dilutions and succussionsfrom a 1C to the 20C potency.113 Even with improved stan-dardization of glassware, ethanol concentration, and suc-cussion procedures in remedy manufacturing, specific

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Figure 2 (a,b). Oscillatory nonlinear doseeresponse effects of a successive series of homeopathic remedy potencies and of NP cluster sizes.


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NPs inherently acquire unique nonlinear properties. Differ-ent sizes and morphologies of the ‘same’ material at nano-scale could lead to very different effects.20,21

NPs of silica, gold, silver, carbon, polystyrene, and othersubstances can self-assemble into various larger nanostruc-tures and adsorb proteins, DNA, drugs, and herbs onto theirsurfaces.22,99,103 Their properties, including biologicaleffects, would then differ from those of the ‘same’material at the bulk form macro level,86 if only in termsof improved bioavailability and enhanced effects at a lowerdose.20,21,25,26,115,116 The extent of the effects themselvescan vary simply as a function of particle size.86 Such con-siderations could have major implications for clinical selec-tion of remedy potencies and dosing frequencies.117,118 Thepotential interaction of nonlinear sinusoidal hormeticdoseeresponse relationships113 with specific potencies(which would reflect specific differences in NP sizes,shapes, and properties) would be factors in the nature anddirection of treatment effects (Figure 3).If homeopathic remedies are complex colloidal solutions

of NPs of silica with remedy source material adsorbed,26 inaddition to NPs of the remedy source material itself, thenumber and force of succussions (or vortexing/sonicationtime) could change the nature and properties of the resultantproduct.105,119 Compared with some other NP materials,nanosilica has awell-documented ability tomobilize the im-mune/inflammatory and stress response networks of thebody.120,121 However, even those findings depend on thesize and concentration of the silica NPs and the type of cells

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that they encounter. 122e124 Such data highlight the potentialvalue of evaluating remedies as nanostructures, guided bythe large and growing research literature on themanufactur-ing parameters and testing protocols for biological effects ofNPs at systemic and local cellular levels.125,126

The original homeopathic literature varies in the numberof manual succussions used, from one to 150 succussionsafter each dilution. Higher potencies by definition willhave undergone more succussions, and higher remedy po-tencies can exert longer duration effects.127 For compari-son, simply increasing amounts of sonication of a carbonnanofluid generates smaller nanocluster sizes, but highlynonlinear variations in the physico-chemical properties ofthe colloidal solution.105 A moderate duration of 40 minproduced the maximal effects compared with either notime or maximal duration (1355 min) of sonication. How-ever, in homeopathic remedy manufacturing, it is not justthe number and force of succussions that might modifythe characteristics of the resultant NPs; the type of con-tainer (glass, polypropylene, other material), proportionof ethanol solvent, and the method of succussion (manual,mechanical arm, vortexing, sonication etc) and volumecould all cause variation in the resultant NP sizes, shapes,quantities, and properties.96

In general, remedies are manufactured at room tempera-ture, but differences in ambient temperature, e.g., variableamounts of air conditioning or heating, could also subtlyaffect the resultant NP sizes and morphologies.119

Figure 4 illustrates how differences in the type of solvent

Figure 3 Demethylation of veratric acid by Rhodococcus erythropolis cells. Metabolic tests were performed after a 6-h incubation with suc-cessive formaldehyde (FA) dilutions in water or in 75%ethanol, together with control values for water and 75% ethanol. Each dilution factor isin a ratio of 1/100, with 1 = 1C and 20 = 20C on the x-axis. Succussions (‘dynamically shaken’) were reported, but number and type of suc-cussion method were not specified. Reprinted with permission from reference 113.


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used and sonication power can lead to variations in the re-sultant nanostructures at a given temperature. Differentconcentrations of ethanol, for instance, can alter theamount of surface area on the NPs available to adsorb othermaterials in solution.119,128

Any model for homeopathic remedy actions must ac-count for as much as possible of the empirical data. Wa-lach, Milgrom and others have reported puzzling clinicalresearch evidence of suggesting quantum macro-entangle-ment in homeopathic pathogenetic trials and double-blindplacebo-controlled treatment trials.129e134 Although be-yond the scope of this paper, the evidence for macroscopicentanglement between two spatially-separated quantumdots (colloidal semiconductor nanocrystals) of NPs ona chip135 is an intriguing example from the nanotechnologyliterature that may be relevant to macro-entanglement inhomeopathy. Certain semiconductor (many of which aresilica based) or metal NP crystallites can possess‘pseudo-atom’ quantum properties (quantum dots), inpart because of their extremely large surface to volume ra-tio and the delocalized positioning of the source materialelectrons close to the surface of each particle.21,22 Thus,while demonstration of actual macro-entanglement proper-ties of homeopathic remedy NPs per se awaits direct em-pirical testing, the discovery of NPs in remedies14,19

places homeopathy in a scientifically plausible andtestable framework that could relate biological adaptiveprocesses to their unique chemical properties as low levelstressors,27,51 as well as quantum macro-entanglement-like phenomena.129,136,137

Research implications for remedy NPs

Taken together, NP research data suggest the need forsystematic studies in homeopathy on the parameters of rem-edy manufacturing.96 Nanotechnology assessment methodssuch as transmission electron microscopy, atomic force mi-croscopy138 and other NP characterization techniques suchas dynamic light scattering or NP tracking analysis139 per-mit detection and characterization of aggregates or evensingle NPs. Factors requiring systematic re-examinationas potentially critical variables in optimizing remedy NPpreparation and product reliability14 would include:

�Materials in the container (specific type of glass or poly-mer)15,96,98

� Size of container107�Method of dilution (Hahnemannian vs. Korsakovian)�Method of succussion96

� Number and force of triturations (mechanical grinding)and succussions (microfluidization)88

� Concentration of ethanol in diluent119,128

� Other physico-chemical parameters (pH, tempera-ture)103,119

The importance ofNPs (either of the sourcematerial or de-rived from the glassware etc) makes their size, shape, andproperties potential criteria for developing additional qualityassessment standards for homeopathic pharmacopoeias inthe future.96 For example, itmight be useful to establishmin-imum/maximum quantities of source NPs or tolerance spec-ifications of particle morphology in finished products.14

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Figure 4 Variability in silver bromide (AgBr) nanostructure sizes as a function of preparation parameters. Particle images are scanning elec-tron micrographs. Reprinted with permission from reference 119.


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Improving reporting standards140 on methods of homeo-pathic remedy preparation might reduce and/or help accountfor some of the inter-experimental variability observed in thefield to date.82

Moreover, directly comparing biological effects of spe-cific homeopathically-prepared remedies with their morestandardized commercial NP counterparts, e.g., silica,gold, silver, copper, platinum, or calcium phosphate, mayalso reveal valuable new insights into possible clinicalstrengths and limitations of both homeopathy and modernnanomedicines. Studies could explore features and effectsof higher and lower concentrations of specific commercialNPs, testedwith andwithout additional dilutions and/or suc-cussions versus homeopathic remedy and solvent con-trols.25,141 The research might help control for and limitvariability in remedyNPs by determining the relative contri-butions of remedy variability versus other factors, e.g., thestate of the recipient organism,142 in reproducibility of ef-fects in basic science and clinical studies. Studying of NPswill facilitate additional research to determine the way(s)

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in which remedy NPs alert the organism to the foreignnessor threat that they pose.27,51 Available data indicate thatthe NPs could convey such organism-specific informationwith chemical, electromagnetic, magnetic, structural, and/or even optical or quantum effects.21,102,135,143e146

RemedyNPselicitacomplexadaptiveresponsein theallostaticnetworkHypothesis: Homeopathic remedies modulate patterns

of allostatic responses in the biological components ofthe stress response network (in vitro and in vivo), with mea-surable, multiple dynamical short- and long-term effects,based upon systemic priming by higher intensity stressorsthat have previously affected the organism.In the NPCAS model, it is the stimulus quality of the sa-

lient remedy NPs that disrupts the disease-related, dysfunc-tional allostatic setpoint and initiates the re-organizingeffects on living systems. Silica NPs generated during rem-edy manufacturing in glass would serve not only as remedy


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delivery vehicles, but also as non-specific biological ampli-fiers of the cellular stress response.13,26,120,121,147 A wellmatched homeopathic medicine mobilizes changes in theadaptive plasticity of the biological stress responsesystem (allostasis).1,13 Individual symptoms recede as theconditions for their expression from interactions of thenetwork of stress response mediators are eliminated bythe hormetic compensatory responses.27,51 To initiate thehealing process, the organism has to recognize a novelstimulus from the entry of low doses of the salientremedy NPs into the system.1 The correct remedy wouldneed to cross-adapt with the cumulative maladaptationsthat the organism has accumulated in its failed attemptsto restore homeostasis after disruptions from previousstressors. The reversal of direction from disease towardhealth stems from the ability of low doses of NPs to initiatehormesis, i.e., compensatory adaptive changes prepare theorganism to better resist the pre-established or future ad-verse effects of the same or cross-adapted stressors.The well-documented, albeit complex, process of meta-
plasticity9 offers a neurophysiological basis for learningand memory, including the bidirectionality of future re-sponsivity to a stressor. In addition to short-term adaptiveplasticity changes, a stimulus also initiates metaplasticity.Metaplastic changes prime synapses to alter their subse-quent plasticity. Metaplastic changes persist long afterthe original stimulus has ended.148 After the priming event,the arrival of the next stimulus (including low doses of sim-illimum remedy NPs) activates the same synapses or neigh-boring synapses and causes opposite effects to the originalstimulus. High intensity and low intensity stressors mayproduce subsequent biobehavioral effects in opposite di-rections, depending on the intensity of original prestres-sor.12 Adaptive plasticity is not limited to the brain; ina living system, other cells also exhibit the capacity tochange function and reverse the direction of shifts in set-point as a result of prior activity.72,75 Metaplasicbidirectionality reflects the organism’s innate homeostatictendency to maintain function within a range arounda setpoint. Thus, change in one direction prepares thesystem to reverse direction upon the next encounter witha stressor or cross-adapted stressor. For recovery fromchronic disease with homeopathy, the net effect is to cancelthe disease-related dynamics in the system, as the setpointaround which the function operates shifts back toward thenormal range.This perspective offers insight into homeopathic prac-

tice and a rationale for the clinical materia medica and rep-ertories used to determine appropriate remedies. Given theemphasis in the NPCAS model on the allostatic stress re-sponse network as the locus of action, the diversity ofsymptoms described for each remedy begins to makesense. The goal in homeopathic prescribing is to identifythe single remedy that is cross-adapted to the cumulativepattern of disease-related maladaptations. Homeopaths at-tempt to find a pattern match between documented effectsof a homeopathic medicine and the individual patient’sunique clinical picture. Biological, infectious, chemical,dietary, physical and psychological aggravating and ame-

liorating factors could converge in the allostatic stress re-sponse network to create an unique symptompattern.1,40,42,149 The better the pattern match to themaladaptive state at highest level of organizational scalein the organism (generalities, recurring functionalthemes, or network motifs found in both global and localsymptoms80), the more likely it is that the remedy NPs inlow dose could evoke compensatory changes to reversedirection of the existing maladaptative state, improvewell-being, and strengthen systemic resilience.150 If thecross-adapted pattern match for the remedy NPs is ata lower level of organizational scale in the organism,e.g., local physical dysfunction in one organ, more limitedchanges and more modest clinical improvements would re-sult.151,152

Research implications of allostatic stress responsenetwork involvement

A starting point for translational studies would be evalu-ating patterns of nonlinear effects of individualized homeo-pathic remedy treatment on mediators of the stress responsenetwork.28,75,78,153e155 This interconnected, interactive setof subsystem includes immune, inflammatory and anti-inflammatory cytokines, endocrine, central, autonomic,and peripheral nervous systems, oxidative stress andmetab-olism, which collectively contribute to a wide range of clin-ical conditions. This suggests that homeopathic treatmentcould thus be particularly effective not only for stress-related problems e broadly defined, but also for many dif-ferent conditions involving imbalances or disturbances inregulatory subsystems of the organism that stresse biolog-ical, infectious, chemical, physical, and/or psychologicaleinitiates or exacerbates.154,156e160

For instance, in an animal model of autism, a conditionthat homeopathic treatment has been claimed to help,161 el-evated pro-inflammatory interleukin IL-6 changes neuro-nal dendritic spine patterns and leads to autistic-likebehavioral, cognitive and learning impairments.159 Studydesigns would include testing the ability of the correct rem-edy to reverse changes in CNS structure and function, andcytokine IL-6 (and the other interconnected subnetwork ofcytokines with which it interacts). Changes in nonlineardynamics of the EEG in autism may also be a useful func-tional biomarker in the brain as a complex adaptive net-work.162

The NPCAS model suggests that measuring intermedi-ary biomarkers such as changes in inflammatory cyto-kines163 or heat shock protein patterns55,57 would bemore sensitive options apart from self-report or other clin-ical outcomes to assess homeopathic remedy effects inshorter-tem, small sample studies. Asthma is one such can-didate condition for study. The homeopathic clinical liter-ature includes many reports of successful treatment ofasthma,164,165 but the randomized clinical trial (RCT) find-ings are limited and less favorable.166,167 Asthma is one ofthemanymedical conditions associated with adverse child-hood experiences and/or stressors.156,168,169 Research hasshown that unfavorable psychosocial circumstances earlyin life lead to persistent pro-inflammatory epigenetic and

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cytokine patterns.170 Treatment with low doses of cyto-kines can modulate underlying immune system imbalancesand resolve allergic asthma bronchial hyperresponsivity inanimals.171 Thus, the testable hypothesis is that thecorrectly-chosen homeopathic remedy in an identifiablesubset of children or adults with asthma will elicit ananti-inflammatory response involving detectable reversalof pre-treatment epigenetic, immune, and cytokine activa-tion patterns.As in systems biology,172 the major focus for homeopa-

thy research would then become multivariate mediatingprocesses173 and patterns174e179 of change in the biologicalstress response network, rather than the isolated specificendpoints typical of many pharmacologically-driven clini-cal trial designs.180 In the NPCAS model, changes in theclinical endpoints occur distal in time and space to the orig-inal locus of action of the simillimum remedy.111,112 There-fore the methodological approaches of quantitative holisticsystems biology,172,174,175,181 with the ability to analyzecomplex gene activation arrays, protein complexes, and/or metabolic profiles for multivariate functional modifica-tions57,182 are more likely to be relevant in testing theNPCAS model. As with NPs,24,26,183,184 some studiesalready offer evidence that homeopathic remedies canmodulate epigenetic and biological signaling expressionpatterns.117,182,185,186 Salient biological signaling eventsthat start at the local cellular level can initiate a cascadeof system-wide effects.125

The overarching hypothesis is that NPs of the matchingremedy act in low doses as dynamical biological triggers tomodulate multiple interactive functions in the allostaticstress response network of the individual. Especially in pa-tients with chronic diseases, intermediate patterns ofchange in components of the allostatic network are the pre-dicted measurable outcome,75 before function of a specificlocal organ and associated symptoms would improve. Foracute diseases, the time frame of adaptive changes ismuch faster.

Themediatingprocessesforhomeopathiceffectsarephysiological,notpharmacologicalHypothesis: Active remedies will initiate and/or elicit

TDS-based (progressive amplification) reversal of environ-mental stressor reactivity.Corollary hypothesis: The effects of the simillimum rem-

edy NPs on the organism are cross-adapted and cross-sensitized to the previously-established maladaptive pro-cesses that allow the emergence of disease from priorhigh level stressors.

Time-dependent endogenous response amplification:physiological phenomena

The NPCAS model states that salient homeopathic rem-edy NPs serve as a novel and foreign low dose stressorfor the organism, initiating compensatory adaptivechanges.1,13 The organism-dependent amplification of ef-

athy

fects derives from TDS of the adaptations to the adminis-tration of intermittently administered, sometimesrepeated, remedy doses. In order for the nonlinear healingresponse to the simillimum remedy to develop and evolve,the body amplifies the responsewith the passage of time. In1994, Davidson originally suggested the possibility thatsensitization plays a role in homeopathic remedy ac-tions.187 If so, then the correct remedy, like any othertype of low intensity stressor to which the organism is sen-sitized, should set the biology of TDS into motion. Whenthe sick organism receives the simillimum, the cumulativepast high level stressors in the allostatic overload have al-ready initiated TDS (Figure 1). In that circumstance, thecorrect remedy acts as a low level stressor elicitinga cross-sensitized, cross-adapted response in the oppositedirection to the original direction that led to dysfunctionand disease. In general, it should be possible to use thesame types of biomarkers, for instance EEG spectral powerchanges188e191 or cardiovascular reactivity,192,193 or cyto-kine patterns (interleukins 1 and 2, tumor necrosis factor(TNF))47 that other types of stressors can sensitize in testsof remedy sensitization and oscillatory responses.We have already found supportive evidence for TDS re-

sponses in human subjects given one or more doses of anindividually matched homeopathic remedy. In the firststudy, fibromyalgia (FM) patients underwent a series ofthree separate laboratory sessions (baseline, 3 months, 6months) in which they repeatedly sniffed either their con-stitutional remedy diluted in LM (Q) potencies or a watersolvent placebo control. Between laboratory sessions,half of the subjects were randomized under double-blindconditions to take their constitutional remedy daily inoral LM potency and half to take a placebo. The verumgroup improved significantly more in clinical outcomemeasures,194 and also showed a progressive increase inEEG alpha magnitude over time e i.e., TDS. In contrast,the placebo group showed a progressive decrease in EEGalpha activity.189 From the first encounter with the remedy,the best responders to verum also exhibited a unique pat-tern of prefrontal EEG changes in an algorithm-based mea-sure called cordance (derived from the ratio of relative andabsolute EEG power at each electrode site) during remedysniffs.195 The best responder cordance patterns differedfrom those of placebo patients and other verum patientsat each time point. EEG alpha cordance correlates withchanges in brain blood flow and/or metabolism.196 Inturn, prefrontal brain areas regulate executive cognitiveability, including decision-making and changing behavioras new information becomes available. This relates to theflexibility and resilience seen in higher-functioning indi-viduals.111,112,197,198 Better responders to any type of inter-vention program across various different conditions havebetter executive function.199e204 The prefrontal cordancedifference of the best responders remained significantlydifferent from the other groups’ at 3 and 6 months. How-ever, the magnitude and direction of the cordance effectprogressively changed from very negative to moderatelynegative to very positive over time (Figure 5). That is,the best responders differed from others, but the polarity

Figure 5 Shifts in the magnitude and direction of prefrontal EEGcordance responses to individualized homeopathic treatment inexcellent clinical responders with fibromyalgia from initial treat-ment day to 3 and 6 month follow-up. Excellent responderswere defined by both large gains in global health and reductionsin local tender point pain during double-blind examinerpressure-based challenge testing. Reprinted with permissionfrom reference 198.


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of the response difference gradually reversed from the be-ginning to end of treatment. This study provides physiolog-ical data consistent with the NPCAS model for remedyactions.A second study from our laboratory also demonstrated

complex nonlinear patterns of short-term EEG responseswithin sessions and over sessions to matched remedy by ol-factory administration in healthy young adults.205 The sub-group with higher levels of the individual different trait ofchemical intolerance (CI) or sensitivity, the reportedly‘universal provers’ of homeopathic pathogenetic trials,206

diverged in their patterns from those of the subgroup lowerin trait CI.207 Of note, females are more sensitizable thanmales in both human and animal TDS research.188 Previousstudies have demonstrated that high CI individuals havesensitized EEG responses to repeated low level exposurechallenges to a variety of common chemical odors,190 su-crose,208 milk,193 and stress.209 Randolph described theseindividuals as highly susceptible to specific adaptationsto environmental agents and prone to food addic-tions.149,210 TDS is a leading model for the developmentof cravings in addictions,211 chronic pain,212 multiplechemical sensitivity,213 and posttraumatic stress disor-ders.49 A large proportion of fibromyalgia patients alsoscore high in measures of both CI and carbohydrate crav-ing.208 Specific food cravings and aversions, as well asameliorating and aggravating foods, are taken account ofin clinical remedy selection.TDS is a form of neural learning and memory. Based on

the animal literature on TDS and metaplasticity, when thesystem reaches its physiological limits but then encountersa relevant cross-sensitized stressor, the direction of the eli-cited responses may reverse or oscillate with repeated in-

termittent dosing.10 For instance, if the cumulativeallostatic load has previously induced a specific patternof maladaptive changes in the stress response network,then NPs of the relevant remedy, as a low intensity stressor,could evoke a salutary reversal in the direction away frommaladaptative functioning. In TDS, lower and higher inten-sity stressors prime the system with metaplastic effects thatcan lead to changes in opposite directions.12 The systemhas a cellular memory for its response to past encounterswith an environmental stimulus.9 As a result, the organismwill try to keep functioning within physiological bounds bymaking compensatory adjustments in a different directionthe next time that the same or a cross-sensitized stimulusactivates the same neurons.The ability of a low dose of homeopathic remedy NPs to

produce beneficial effects is highly dependent on the cross-adaptational pattern match between the remedy and thepre-established disease state. With TDS, the magnitudeof the response to an intermittent, pulsed remedy challengeshould grow spontaneously over time, between repeatdoses. The emergence of the healing process derives onlyindirectly from the properties of the treatment. The self-organization of the cells155 and organism as a complexadaptive system dictates the process and pathways of thehealing.2

Research implications of metaplasticity, cross-adaptation, and TDS

Because of the importance of evolution and emergenceof recovery over time following administration of a doseof the simillimum, prospective study designs are essential.Such studies must also employ assessment methods thatcapture the process of change,173 not merely static end-points. Research on the processes and patterns of changeafter a dose of remedy will ultimately help improve clinicalselection of dosing regimes. Study designs should includerepeated challenge tests. Many studies have demonstratedthat resting states and/or single challenges are often inade-quate to detect pre-existing sensitization or change overtime. In animal research on TDS, sensitized and nonsensi-tized animals exhibit similar baseline and resting physio-logical and behavioral findings, but diverge significantlywith the passage of time between repeated intermittent(pulsed) challenges with the initiating agent or stressor ora cross-sensitized agent or stressor.58,214 The effects ofTDS include priming subsequent elicited changes in gluco-corticoid hormone responsivity, amplified behavioral re-sponses to drugs, chemical, sucrose, and/or stress,progressive increases in cardiovascular reactivity, and in-creases in EEG alpha power on subsequent re-challenge.11,60,191e193,213,215e217

A testable hypothesis is that administering the next doseis only appropriate if the organism has manifestations ofdisease and the remedy-related adaptive compensatory re-sponse to the previous remedy dose, if any, has plateaued orrelapsed.142 LM or Q may be more suitable such experi-ments, they are typically administered daily in liquidform, with intermediate dilutions and succussions in regu-lar but small increments of potency. Hahnemann

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introduced LM potency dosing late in his career, asa method to accelerate recovery from chronic diseases.218

Two positive randomized, placebo-controlled clinical trialsof homeopathy (one in fibromyalgia194 and one inattention-deficit hyperactivity disorder219) used LM poten-cies. From a TDS perspective, the daily LM dilution andsuccussion steps would introduce incremental novelty ofthe remedy NPs for each successive dose to challenge theorganism’s adaptive processes. Hahnemann indicated thatLM treatment had to continue until some dose eventuallyelicited a new clinical worsening rather than progressiveimprovement.218 This reversal would be the point at whichbeneficial adaptive changes in TDS reach the organism’sphysiological limits and, therefore, reverse direction.10,47

At such a point, continued dosing would reversedirection of the systemic changes reverting towardmaladaptation and disease relapse.10

Measuring allostatic network biomarkers,75,220 e.g., in-flammatory and anti-inflammatory cytokine activation pat-terns,221 would permit testing the above hypothesis aftereach remedy dose. If symptoms worsen again in a patienttaking LM potencies, it should be possible to demonstratethat the organism has again shifted the direction of its adap-tive responses to the remedy NPse e.g., from the beneficialanti-inflammatory back toward adverse inflammatoryphysiological patterns. In terms of NPCAS model, the or-ganism has reached allostatic overload from excessive rep-etition of challenges.The most responsive conditions in the NPCASmodel for

homeopathic remedy actions will involve prior sensitiza-tion of components of the stress response system, includingthe CNS.222 For example, fibromyalgia223 is a functionalchronic pain syndrome whose primary mechanisms in-clude central and peripheral nervous system sensitiza-tion.208,224,225 Diverse environmental factors contributeto triggering fibromyalgia, including road traffic accidents,psychological stress, chemical exposures, and childhoodabuse.226e229 Two double-blind RCTs have shown signifi-cant efficacy of individualized homeopathic remedies overplacebo.194,230 The hypothesis would be that properly-timed remedy NPs will reverse the central sensitizationin response to painful stimuli that characterizes fibromyal-gia. Empirically, not only tender point pain evoked by stan-dardized physical examination,194 but also other types ofexperimentally-elicited pain should decrease under suc-cessful homeopathic remedy NP treatment in FM pa-tients.231

Thenetclinicaloutcomeof thesimillimumremedyinteractionisimprovement inglobalhealthandsystemicresilienceto futurestressors,inaddition toresolutionof localsymptomsHypothesis: The simillimum remedy administered to

a sick person will produce persistent improvement in sys-

athy

temic resilience, including global well-being and resolu-tion of local symptoms.195,232

Corollary hypothesis: A remedy corresponding to ele-ments of the disease maladaptations and state of the organ-ism will change a subset of the total symptoms withoutimproving global well-being or strengthening systemic re-silience.151

Corollary hypothesis: A remedy with no correspondenceto the specific maladaptations and state of the organismwill initiate little or no change, but minor adverse meta-plastic changes without improvements in symptoms or sys-temic resilience.Corollary hypothesis: A remedy or remedy potency that

is repeated too often will cause or worsen symptoms andlower systemic resilience.142

Resilience as a manifestation of emergent health in thecomplex adaptive system

Vaiserman has proposed that hormetic adaptations tolow intensity stressors earlier in life could mobilize sys-temic epigenetic reorganization of the organism andlong-term resilience to subsequent higher intensitystressors.233,234 For other experimental tests of this notion,experts in complex adaptive systems emphasize the impor-tance of perturbing the system andmeasuring the direct andindirect effects of the perturbation across the organ-ism.155,235 For instance, Fredrickson and Losada foundmore flexible and resilient behaviors in higher-functioning than in lower-functioning social systems givenan interactive group task to perform under pressure.197

Thus, an essential consideration for proper tests of theNPCAS model is that researchers should test the resilienceof the system under stress, not at rest. Prospective studieswould need to examine the stress reactivity and recoveryof the same patients at pre-treatment and post-treatment.Again, stress is any biological, infectious, physical, chem-ical, electromagnetic, or psychosocial factor that disruptshomeostasis.Krug et al.,177 among others, have emphasized that

physiological challenge tests, i.e., experimental stressors,elicit interindividual variation in otherwise phenotypicallysimilar human subjects. In metabolic studies, challengetests can reveal metabolic types not apparent in restingmeasurements by showing different metabolite profiles orpatterns of change. In the specific adaptation literature,Randolph pointed out the clinical necessity of using foodand environmental chemical challenge testing to determineeach of the multiple specific offending agents that couldtrigger the same set of food addiction cravings and/or ad-verse sensitivity symptoms in a given patient.149,210

A requisite step in homeopathic treatment is to identifythe correct, best-matched remedy or simillimum, for thepatient’s total clinical picture. The clinical picture includesnot only patterns of specific symptoms, but also the modal-ities and generalities of global adaptive behaviors that ame-liorate or worsen symptoms. Thus, in complex systemsterminology, the simillimum is a microcosmic encapsula-tion of personalized coping behaviors within the


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cumulative experienced environment, or fitness land-scape236 (Figure 6). The organism as a complex adaptivesystem is continually trying to survive as well as possiblewithin his/her world.237 Successful treatment stimulatescompensatory cross-adaptations that optimize ability tofunction as well as possible within the individual’s fitnesslandscape, manifested as resilience to future stress.
Research implications of systemic resilience asa primary clinical outcome

Resilience as a concept revolves around the ability ofa system to adapt to change. In complex adaptive systemsterms, Pincus has defined resilience as “the meta-flexibilityof the system; the ability to respond to a perturbation by ei-ther becoming rigid and robust, or flexible and fluid with-out becoming stuck or falling apart respectively.”2 If thehypothesized locus of remedy action is the stress responsesystem and the process involved is adaptation, it will be es-sential to go beyond assessments of resting states and eval-uate the system’s response to a novel stressor before andafter treatment. A limited but accessible outcome measurefor research would be validated questionnaires on psycho-social resilience, such as the ConnoreDavidson ResilienceScale.238,239 However, resilience is not limited to the psy-chosocial realm. In view of the need to examine not justsubjectively perceived changes, but also the dynamics ofobjective physiological resilience over time, standardizedphysical (e.g., high or low temperature or altitude environ-

Figure 6 Diagrammatic representation of a rugged fitness land-scape. It offers an analogy for the experienced environment thatthe homeopathic remedy simillimum needs to encapsulate in or-der to stimulate the evolution of salutary cross-adaptations, opti-mal healing resilience, and well-being (fitness) in the individualpatient over time.Note: This diagram actually represents evolution of genetic codesin a rugged fitness landscape (a cartoon illustration) .r1, r2 ˛ r:random codes with the same block structure as the standardcode. o1, o2˛ o: codes obtained from r1, r2˛ r: after optimization.R1, R2 ˛ R: random codes with fitness values greater than the fit-ness of the standard code. O1, O2 ˛ O: codes obtained from R1,R2 ˛ R: after optimization. Figure used with Creative CommonsLicense from an open access source (http://www.biology-direct.com/content/2/1/24).236

ments), physiological (e.g., treadmill test), metabolic (e.g.,glucose tolerance test), and psychological (e.g., Treier So-cial Stress Test of simulated job interview)240 stress testsare preferable.At a practical level, studying remedy NP effects on

short-term changes in resilience may be initially more fea-sible than planning long-term outcome studies. For in-stance, stress response measures before and after 3e6months of treatment would include reactivity to and recov-ery from acute stressors, using patterns of not only mood,but also EEG, neurochemical, autonomic, stress hormone(glucocorticoids, dehydroepiandrosterone (DHEA)), cyto-kine, and metabolic (including heat shock protein)changes.55,57 At the cellular level,55,57 it may be possibleto characterize patterns of heat shock protein responsesto in vitro stressors and develop adjunctive laboratoryblood tests that will assist in individualized selection ofthe correct remedy for a patient’s current state. Duringtreatment, biomarker measures would be followed ateach assessment point from resting baseline to peakchange, with examination of time to recovery to baselineor failure to regain normal baseline after a specifiedperiod of time.241 Applying nonlinear time series analytictechniques242 and cusp catastrophe or network modelingto physiological patterns of change are sensitiveapproaches to evaluating systemic resilience under stress.2

Other methods such as state space grids evaluate thequantitative and qualitative dynamics of behavioral reac-tivity (organism level of organizational scale) during socialinteractions in a specified interpersonal task.243 State spacegrid study designs can assess the degree of behavioral andphysiological flexibility and resilience versus rigidity un-der social stress. The social task stressor in these studieselicits the typically less structured, real-world behaviorswith which patients interact with family members, friends,or strangers.173,244,245

As noted above, another primary target of the allostaticstress response network for study might be the inflamma-some protein complexes,76 inflammatory and anti-inflammatory cytokines, and their regulatory role in theorganism.246 These endogenous mediators play major rolesin modulating inflammation, responses to immune chal-lenges, and CNS function. Cytokine dysregulation and in-flammation contribute to poorer mental and physicalhealth, and impair quality of life and well-being in manydisorders.159,247e249 Adaptive changes in allostasis initi-ated by low dose NPs during homeopathic treatment couldhelp restore more normal balance between pro- andanti-inflammatory cytokines, as suggested by previousstudies.66e69,163,182,185,250e252 The result would beimprovements of both psychological and physical well-being across a wide range of conditions, as is claimed inhundreds of anecdotal case reports from homeopaths andsupported by a number of observational trials.253,254

Other practical design considerations are important. Al-lopathic drugs can interfere with the subtle physiologicalregulation, adaptation, and modulation of components ofthe stress response network, e.g., glucocorticoids and/orTNF-alpha inhibitors in rheumatoid arthritis. Patients

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taking such drugs might be treated less successfully witheven properly-chosen homeopathic remedies. Indeed,RCT studies of classical homeopathy in rheumatoid arthri-tis showmore mixed results,255,256 especially with more re-cent studies done after the introduction of TNF-alphainhibitor disease-modifying drugs.255 TNF-alpha playsa significant role in stress-related central sensitiza-tion.257,258 Animal studies suggest that the ability to acti-vate glucocorticoid reactivity plays a role in initiation ofTDS and subsequent reactivity to stressors.58,64

Pharmacologic agents which interfere with endogenousregulatory pathways for glucocorticoids or cytokineTNF-alpha in the allostatic network might impede or dis-tort the ability to regulate endogenous adaptive mecha-nisms. On the other hand, antioxidants, some herbalagents and acupuncture may also modify components ofthe allostatic network by blocking inflammation, genera-tion of reactive oxygen species and/or the biology of neuralsensitization.259e263 Hormetic effects from low doses ofantioxidant substances may be cytoprotective.264 BothNPs23,24,265,266 and homeopathic remedies267e269 bythemselves modulate generation of reactive oxygenspecies and oxidative stress responses. Consequently, oneclinically-relevant NPCAS-theory-driven line of integra-tive medicine research would include systematic investiga-tion of specific exogenous agents that may impair orfacilitate hormesis and the capacity to recover from diseasein response to homeopathic treatment.270

SummaryanddiscussionA homeopathic remedy is a small stimulus that initiates

a large response in the organism.271e274 Homeopathic ef-fects are inherently nonlinear in nature. The dose level ofthe remedy NP stimulus as an environmental stressor islow, in the hormetic dose range,27,275 and not capable of di-rectly causing large pharmacological effects. However,NPs are highly reactive, possessing different mechanical,biological, physical, chemical, electrical, magnetic, opti-cal, and quantum properties than their respective bulkforms.21,22,135 The correctly chosen homeopathic remedymust be capable of triggering (and therefore reversing)the same types and patterns of adaptations that theorganism has the capacity to make in response to othertypes of higher intensity stressors. Clinical indicators ofthe allostatic adaptations include Generalities andModalities that modulate symptom expression, includingbut not limited to, amelioration or aggravation fromextremes of heat or cold, altitude or sea level, specificfoods, times of day, social environments, and specificbehavioral states.Cells and organism detect and react to the remedy NPs as

a salient, novel, and foreign threat to survival, i.e., a rele-vant environmental stressor,276,277 thereby mobilizing pre-viously disease-primed adaptive responses. At that point,the organism produces a response amplification to thelow dose of NPs via endogenous changes in a variety of bi-ological mechanisms involved in adaptive plasticity, cross-sensitization, and cross-adaptation.9,30,33,35 These changes

athy

were previously primed by larger magnitude biological andpsychosocial stressors that originally led to maladaptiveprocesses and disease. The NPCAS model postulates thatthe initial locus of action is the allostatic stress responsenetwork, which includes the central and autonomicnervous systems, endocrine, immune, inflammatory andanti-inflammatory mediators, and metabolic regulators.The components of the allostatic network which first en-counter and react to the remedy NPs initiate complex reg-ulatory signaling277 and homeostatic adaptive changesthroughout the rest of the network.276 With the true simil-limum, epigenetic changes may occur.186

Consequently, the isolated single specific endpoints thatpharmacological research designs employ to assess conven-tional drug actions are not well-suited to capture the nonlin-ear dynamical effects of homeopathic remedies on livingsystems.111,112 Good homeopathic treatment outcomes in-clude global and local improvements.195,278 Because of themulticomponent dynamical complexity involved in allo-static network adaptations, research on the model must in-clude multivariate profiles of systems biology and time-dependent, iterative complex systems science methods onnonlinear dynamics.111 The prior history of the organismwith stressors will shape the nonlinear patterns of allostaticchange observed in response to a remedy. The evolution ofchanges in the whole organism over time, e.g., the develop-ment of more robust immune responses and commonly-observed emergence of acute infections early in homeo-pathic treatment278 must be accounted for in the proper as-sessment of homeopathic treatment effects.

ConclusionsThe NPCAS model and the research program derived

from it offer a path out of the circular and unproductive de-bate over whether or not a homeopathic remedy, which isclearly not an allopathic drug, has allopathic drug-like prop-erties. We hypothesise that homeopathic medicines consistof NPs279 which are low level environmental stressors phys-iologically cross-adapted in varying degrees to the allostaticoverload to which the individual has previously developedmaladaptive responses. The large and growing literature onNPs, hormesis, the allostatic stress response network, meta-plasticity, and bidirectional TDS can inform progress in ho-meopathic research and the nature of systemic healing.

Conflictof interestsDrs Bell and Brooks are consultants to Standard Homeo-

pathic/Hylands Inc, a U.S.-based manufacturer of homeo-pathic medicines. This company did not provide anyfinancial support for the paper or its publication costs,and none of the homeopathic studies cited here utilizedtheir products.

AcknowledgementsThis work was supported in part by NIH/NCCAM grant

T32 AT01287.


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SupplementarymaterialSupplementary references numbered 100e279 associ-

ated with this article can be found in online at http://dx.doi.org/10.1016/j.homp.2012.10.005.

References

1 Bell IR, Koithan M. A model for homeopathic remedy effects: low

dose nanoparticles, allostatic cross-adaptation, and time-dependentsensitization in a complex adaptive system. BMC Complem Altern

Med 2012; 12(1): 191.2 Pincus D, Metten A. Nonlinear dynamics in biopsychosocial resil-

ience. Nonlinear Dynam Psychol Life Sci 2010; 14(4): 353e380.3 Danese A, McEwen BS. Adverse childhood experiences, allostasis,

allostatic load, and age-related disease. Physiol BehavApr 12 2012;106(1): 29e39.

4 Karatsoreos IN, McEwen BS. Psychobiological allostasis: resis-tance, resilience and vulnerability. Trends Cogn Sci Dec 2011;

15(12): 576e584.5 Poston L. Intergenerational transmission of insulin resistance and

type 2 diabetes. Prog Biophys Mol Biol Jul 2011; 106(1): 315e322.6 Crews D, Gillette R, Scarpino SV, Manikkam M, Savenkova MI,

Skinner MK. Epigenetic transgenerational inheritance of alteredstress responses. Proc Natl Acad Sci USA 2012; 109(23):

9143e9148.7 Bellavite P, Ortolani R, Pontarollo F, Pitari G, Conforti A. Immunol-

ogy and homeopathy. 5. The rationale of the ‘Simile’. Evid BasedComplement Alternat Med Jun 2007; 4(2): 149e163.

8 Abraham WC, Bear MF. Metaplasticity: the plasticity of synapticplasticity. Trends Neurosci Apr 1996; 19(4): 126e130.

9 Abraham WC. Metaplasticity: tuning synapses and networks for

plasticity. Nat Rev Neurosci May 2008; 9(5): 387.10 Antelman SM, Caggiula AR. Oscillation follows drug sensitization:

implications. Crit Rev Neurobiol 1996; 10(1): 101e117.11 Antelman SM, Caggiula AR, Edwards DJ, et al. Long-term oscilla-

tion of corticosterone following intermittent cocaine. J NeuralTransm 2000; 107(3): 369e375.

12 Antelman SM, Caggiula AR, Kocan D, et al. One experience with‘lower’ or ‘higher’ intensity stressors, respectively enhances or di-

minishes responsiveness to haloperidol weeks later: implicationsfor understanding drug variability. Brain Res 1991; 566(1e2):276e283.

13 Bell IR, Schwartz GE. Adaptive network nanomedicine: an inte-

grated model for homeopathic medicine. Front Biosci (ScholarEd.) 2013; 5(2): 685e708.

14 Chikramane PS, Suresh AK, Bellare JR, Kane SG. Extreme homeo-pathic dilutions retain starting materials: a nanoparticulate perspec-

tive. Homeopathy 2010; 99(4): 231e242.15 Ives JA, Moffett JR, Arun P, et al. Enzyme stabilization by glass-

derived silicates in glass-exposed aqueous solutions. HomeopathyJan 2010; 99(1): 15e24.

16 Anick DJ, Ives JA. The silica hypothesis for homeopathy: physicalchemistry. Homeopathy 2007; 96(3): 189e195.

17 Rao M, Roy R, Bell IR. Characterization of the structure of ultra di-lute sols with remarkable biological properties.Mater Lett 2008; 62:

1487e1490.18 Rao ML, Roy R, Bell IR, Hoover R. The defining role of structure

(including epitaxy) in the plausibility of homeopathy. HomeopathyJul 2007; 96(3): 175e182.

19 Upadhyay RP, Nayak C. Homeopathy emerging as nanomedicine.Int J High Dilution Res 2011; 10(37): 299e310.

20 Das S, Das J, Samadder A, Bhattacharyya S, Das D, Khuda-Bukhsh AR. Biosynthesized silver nanoparticles by ethanolic ex-

tracts of Phytolacca decandra, Gelsemium sempervirens, Hydrastis

canadensis and Thuja occidentalis induce differential cytotoxicitythrough G2/M arrest in A375 cells. Colloids Surf B Biointerfaces

2013; 101: 325e336.21 Roduner E. Size matters: why nanomaterials are different. Chem

Soc Rev 2006; 35(7): 583e592.22 Buzea C, Pacheco II, Robbie K. Nanomaterials and nanoparticles:

sources and toxicity. Biointerphases 2007; 2(4): MR17eMR71.23 Kovacic P, Somanathan R. Biomechanisms of nanoparticles (toxi-

cants, antioxidants and therapeutics): electron transfer and reactiveoxygen species. J Nanosci Nanotechnol Dec 2010; 10(12):

7919e7930.24 Winnik FM, Maysinger D. Quantum dot cytotoxicity and ways to

reduce it. Acc Chem Res 2012 July 9 epub ahead of print.25 Prakash DJ, Arulkumar S, Sabesan M. Effect of nanohypericum

(Hypericum perforatum gold nanoparticles) treatment on restraintstress induced behavioral and biochemical alteration in male albino

mice. Pharmacognosy Res Nov 2010; 2(6): 330e334.26 Al-Sadoon MK, Abdel-Maksoud MA, Rabah DM, Badr G. Induc-

tion of apoptosis and growth arrest in human breast carcinoma cellsby a snake (Walterinnesia aegyptia) venom combined with silica

nanoparticles: crosstalk between Bcl2 and Caspase 3. Cell PhysiolBiochem 2012; 30(3): 653e665.

27 Iavicoli I, Calabrese EJ, Nascarella MA. Exposure to nanoparticles

and hormesis. Dose Response 2010; 8(4): 501e517.28 McEwen BS. Central effects of stress hormones in health and dis-

ease: understanding the protective and damaging effects of stressand stress mediators. Eur J Pharmacol Apr 7 2008; 583(2e3):174e185.

29 Barbieri M, Boccardi V, Papa M, Paolisso G. Metabolic journey to

healthy longevity. Horm Res Jan 2009; 71(Suppl. 1): 24e27.30 Karst H, Berger S, Erdmann G, Schutz G, Joels M.Metaplasticity of

amygdalar responses to the stress hormone corticosterone. ProcNatl Acad Sci U S A Aug 10 2010; 107(32): 14449e14454.

31 Delvendahl I, Jung NH, Mainberger F, Kuhnke NG, Cronjaeger M,Mall V. Occlusion of bidirectional plasticity by preceding low-

frequency stimulation in the human motor cortex. Clin Neurophy-siol Apr 2010; 121(4): 594e602.

32 Wang SZ, Tao HW. History matters: illuminating metaplasticity inthe developing brain. Neuron Oct 29 2009; 64(2): 155e157.

33 Moussawi K, Pacchioni A, Moran M, et al. N-Acetylcysteine re-verses cocaine-induced metaplasticity. Nat Neurosci Feb 2009;

12(2): 182e189.34 Kalantzis G, Shouval HZ. Structural plasticity can produce meta-

plasticity. PLoS ONE 2009; 4(11): e8062.35 Dudai Y. Predicting not to predict too much: how the cellular ma-

chinery of memory anticipates the uncertain future. Philos TransR Soc Lond B Biol Sci May 12 2009; 364(1521): 1255e1262.

36 Yu X, Shouval HZ, Knierim JJ. A biophysical model of synapticplasticity and metaplasticity can account for the dynamics of the

backward shift of hippocampal place fields. J Neurophysiol Aug2008; 100(2): 983e992.

37 Stebbing AR. Adaptive responses account for the beta-curve-hormesis is linked to acquired tolerance. Nonlinearity Biol Toxicol

Med Oct 2003; 1(4): 493e511.38 Calabrese EJ, Jonas WB. Homeopathy: clarifying its relationship to

hormesis. Hum Exp Toxicol Jul 2010; 29(7): 531e536.39 Calabrese EJ, Jonas WB. Evaluating homeopathic drugs within

a biomedical framework. Hum Exp Toxicol Jul 2010; 29(7):

545e549.40 Ning XH, Chen SH. Mild hypothermic cross adaptation resists hyp-

oxic injury in hearts: a brief review. Chin J Physiol Oct 31 2006;49(5): 213e222.

41 Hale HB. Cross-adaptation. Environ Res 1969; 2: 423e434.42 Adolph EF. General and specific characteristics of physiological ad-

aptations. Am J Physiol 1956; 184: 18e28.43 Launay JC, Besnard Y, Guinet-Lebreton A, Savourey G. Acclima-

tion to intermittent hypobaric hypoxia modifies responses to cold

Homeopathy




80

Homeop

at sea level. Aviat Space Environ Med Dec 2006; 77(12):1230e1235.

44 Banti V, Loreti E, Novi G, Santaniello A, Alpi A, Perata P. Heat ac-climation and cross-tolerance against anoxia in Arabidopsis. Plant

Cell Environ Jul 2008; 31(7): 1029e1037.45 Lunt HC, Barwood MJ, Corbett J, Tipton MJ. ‘Cross-adaptation’:

habituation to short repeated cold-water immersions affects the re-sponse to acute hypoxia in humans. J Physiol Sep 15 2010; 588(Pt

18): 3605e3613.46 Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of

stimuli-responsive nanocarriers for drug and gene delivery. J Con-trol Release Mar 20 2008; 126(3): 187e204.

47 Antelman SM, Levine J, Gershon S. Time-dependent sensitization:the odyssey of a scientific heresy from the laboratory to the door of

the clinic.[comment]. Mol Psychiatry 2000; 5(4): 350e356.48 Pacheco KA. Epigenetics mediate environment: gene effects on oc-

cupational sensitization. Curr Opin Allergy Clin Immunol Apr2012; 12(2): 111e118.

49 Hauger RL, Olivares-Reyes JA, Dautzenberg FM, Lohr JB, Braun S,Oakley RH. Molecular and cell signaling targets for PTSD patho-

physiology and pharmacotherapy. Neuropharmacology Feb 2012;62(2): 705e714.

50 Seery MD, Leo RJ, Holman EA, Silver RC. Lifetime exposure to

adversity predicts functional impairment and healthcare utilizationamong individuals with chronic back pain. Pain Sep 2010; 150(3):

507e515.51 Nascarella MA, Calabrese EJ. A method to evaluate hormesis in

nanoparticle dose-responses. Dose Response 2012; 10(3): 344e354.52 Bell IR, Howerter A, Jackson N, Brooks AJ, Schwartz GE. Multi-

week resting EEG cordance change patterns from repeated olfac-tory activation with two constitutionally-salient homeopathic reme-

dies in healthy young adults. JAltern Complement Med 2012; 18(5):445e453.

53 Bell IR, Howerter A, Jackson N, Aickin M, Baldwin CM,Bootzin RR. Effects of homeopathic medicines on polysomno-

graphic sleep of young adults with histories of coffee-related insom-nia. Sleep Med May 2011; 12(5): 505e511.

54 Mishra N, Muraleedharan KC, Paranjpe AS, Munta DK, Singh H,Nayak C. An exploratory study on scientific investigations in home-

opathy using medical analyzer. J Altern Complement Med Aug2011; 17(8): 705e710.

55 VanWijk R,Wiegant FA. Postconditioning hormesis and the similiaprinciple. Front Biosci (Elite Ed.) 2011; 3: 1128e1138.

56 Wiegant F, Van Wijk R. The similia principle: results obtained ina cellular model system. Homeopathy Jan 2010; 99(1): 3e14.

57 Van Wijk R, Wiegant FA. Postconditioning hormesis and the ho-meopathic Similia principle: molecular aspects. Hum Exp Toxicol

Jul 2010; 29(7): 561e565.58 Sorg B, Bailie T, Tschirgi M, Li N, Wu W. Exposure to repeated

low-level formaldehyde in rats increases basal corticosterone levelsand enhances the corticosterone response to subsequent formalde-

hyde. Brain Res 2001; 898(2): 314e320.59 Frank MG, Thompson BM,Watkins LR, Maier SF. Glucocorticoids

mediate stress-induced priming of microglial pro-inflammatory re-sponses. Brain Behav Immun Feb 2012; 26(2): 337e345.

60 Frank MG, Watkins LR, Maier SF. Stress- and glucocorticoid-

induced priming of neuroinflammatory responses: potential mecha-nisms of stress-induced vulnerability to drugs of abuse.Brain Behav

Immun Jan 21 2011; 25(Suppl. 1): S21eS28.61 Chourbaji S, Vogt MA, Gass P. Mice that under- or overexpress glu-

cocorticoid receptors as models for depression or posttraumaticstress disorder. Prog Brain Res 2008; 167: 65e77.

62 Mormede P, Andanson S, Auperin B, et al. Exploration of thehypothalamic-pituitary-adrenal function as a tool to evaluate animal

welfare. Physiol Behav Oct 22 2007; 92(3): 317e339.63 Fee JR, Sparta DR, Picker MJ, Thiele TE. Corticotropin releasing

factor-1 receptor antagonist, CP-154,526, blocks the expression of

athy

ethanol-induced behavioral sensitization in DBA/2J mice. Neuro-science Nov 30 2007; 150(1): 14e21.

64 Chida Y, Sudo N, Sonoda J, Hiramoto T, Kubo C. Early-life psycho-logical stress exacerbates adult mouse asthma via the

hypothalamus-pituitary-adrenal axis. Am J Respir Crit Care MedFeb 15 2007; 175(4): 316e322.

65 PrasadBM,Ulibarri C, SorgBA. Stress-induced cross-sensitization tococaine: effect of adrenalectomy and corticosterone after short- and

long-term withdrawal. Psychopharmacology 1998; 136(1): 24e33.66 Roeska K, Seilheimer B. Antiviral activity of Engystol� and Gripp-

Heel�: an in-vitro assessment. J Immune Based Ther Vaccines2010; 8: 6.

67 Glatthaar-Saalmuller B. In vitro evaluation of the antiviraleffects of the homeopathic preparation Gripp-Heel on selected

respiratory viruses. Can J Physiol Pharmacol Nov 2007; 85(11):1084e1090.

68 Smit E, Oberholzer HM, Pretorius E. A review of immunomodula-tors with reference to Canova. Homeopathy Jul 2009; 98(3):

169e176.69 Burbano RR, Leal MF, da Costa JB, et al. Lymphocyte proliferation

stimulated by activated human macrophages treated with Canova.Homeopathy Jan 2009; 98(1): 45e48.

70 Aleixo DL, Ferraz FN, de Melo CS, et al. Changes of RAPD profile

of Trypanosoma cruzi II with Canova and Benznidazole. Homeop-athy Apr 2008; 97(2): 59e64.

71 Vithoulkas G. The science of homeopathy. N.Y.: Grove Weidenfeld,1980.

72 Wiegant FA, Prins HA, Van Wijk R. Postconditioning hormesis putin perspective: an overview of experimental and clinical studies.

Dose Response 2011; 9(2): 209e224.73 Banerjee P, Biswas SJ, Belon P, Khuda-Bukhsh AR. A potentized

homeopathic drug, Arsenicum Album 200, can ameliorate genotox-icity induced by repeated injections of arsenic trioxide in mice. J Vet

Med A Physiol Pathol Clin Med Sep 2007; 54(7): 370e376.74 Bortolotto ZA, Collett VJ, Conquet F, Jia Z, Collingridge GL. An

analysis of the stimulus requirements for setting the molecularswitch reveals a lower threshold for metaplasticity than synaptic

plasticity. Neuropharmacology Sep 2008; 55(4): 454e458.75 Wiegant FA, Spieker N, van Wijk R. Stressor-specific enhancement

of hsp induction by low doses of stressors in conditions of self- andcross-sensitization. Toxicology May 15 1998; 127(1e3): 107e119.

76 Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes inhealth and disease. Nature Jan 19 2012; 481(7381): 278e286.

77 Powell JJ, Faria N, Thomas-McKay E, Pele LC. Origin and fate ofdietary nanoparticles and microparticles in the gastrointestinal tract.

J Autoimmun May 2010; 34(3): J226eJ233.78 McEwen BS. Physiology and neurobiology of stress and adaptation:

central role of the brain. Physiol Rev Jul 2007; 87(3): 873e904.79 Dagenais M, Skeldon A, Saleh M. The inflammasome: in memory

of Dr. Jurg Tschopp. Cell Death Differ Jan 2012; 19(1): 5e12.80 Vasquez A, Dobrin R, Sergi D, Eckmann JP, Oltvai ZN,

Barabasi AL. The topological relationship between the large-scaleattributes and local interaction patterns of complex networks.

Proc Natl Acad Sci U S A 2004; 101(52): 17940e17945.81 Platt JR. Strong inference. Science 1964; 146(3642): 347e353.82 Baumgartner S. The state of basic research on homeopathy. In:

Witt C, Albrecht H (eds). New Directions in Homeopathy Research.Essen, Germany: KVC Verlag, 2009, p. 107e130.

83 Baumgartner S, Shah D, Schaller J, Kampfer U, Thurneysen A,Heusser P. Reproducibility of dwarf pea shoot growth stimulation

by homeopathic potencies of gibberellic acid. Complement TherMed Aug 2008; 16(4): 183e191.

84 Belon P, Cumps J, Ennis M, et al. Histamine dilutions modulate ba-sophil activation. Inflamm Res 2004; 53(5): 181e188.

85 Cao G, Wang Y. Nanostructures and nanomaterials: synthesis,properties, and applications. 2nd edn. New Jersey:World Scientific,

2011.


81
86 Shi Z, HuangX, Liu B, Tao H, Cai Y, Tang R. Biological response of
osteosarcoma cells to size-controlled nanostructured hydroxyapa-

tite. J Biomater Appl Jul 2010; 25(1): 19e37.87 Napierska D, Thomassen LC, Rabolli V, et al. Size-dependent cyto-

toxicity of monodisperse silica nanoparticles in human endothelialcells. Small Apr 2009; 5(7): 846e853.

88 Keck CM, Muller RH. Drug nanocrystals of poorly soluble drugsproduced by high pressure homogenisation. Eur J Pharm Biopharm

Jan 2006; 62(1): 3e16.89 Merisko-Liversidge E, Liversidge GG. Nanosizing for oral and par-

enteral drug delivery: a perspective on formulating poorly-watersoluble compounds using wet media milling technology. Adv

Drug Deliv Rev May 30 2011; 63(6): 427e440.90 Perry CC, Keeling-Tucker T. Aspects of the bioinorganic chemistry

of silicon in conjunction with the biometals calcium, iron and alu-minium. J Inorg Biochem Feb 15 1998; 69(3): 181e191.

91 Perry CC, Keeling-Tucker T. Model studies of colloidal silica pre-cipitation using biosilica extracts from Equisetum telmateia. Col-

loid Polym Sci Jul 01 2003; 281(7): 652e664.92 Caron V, Willart JF, Lefort R, Derollez P, Danede F,

Descamps M. Solid state amorphization kinetic of alpha lactoseupon mechanical milling. Carbohydr Res Nov 29 2011;

346(16): 2622e2628.

93 Tavares Cardoso MA, Talebi M, Soares PA, Yurteri CU, vanOmmen JR. Functionalization of lactose as a biological carrier for

bovine serum albumin by electrospraying. Int J Pharm Jul 292011; 414(1e2): 1e5.

94 Demangeat JL. NMR relaxation evidence for solute-induced nano-sized superstructures in ultramolecular aqueous dilutions of silica-

lactose. J Mol Liquids 2010; 155: 71e79.95 Bhattacharyya SS, Das J, Das S, et al. Rapid green synthesis of sil-

ver nanoparticles from silver nitrate by a homeopathic mother tinc-ture Phytolacca Decandra. Zhong Xi Yi Jie He Xue Bao May 2012;

10(5): 546e554.96 Bhattacharyya SS,Mandal SK, Biswas R, et al. In vitro studies dem-

onstrate anticancer activity of an alkaloid of the plant Gelsemiumsempervirens. Exp Biol Med (Maywood) Dec 2008; 233(12):

1591e1601.97 Ives JA, Jonas WB, Frye JC. Do serial dilutions really dilute? Ho-

meopathy Oct 2010; 99(4): 229e230.98 Liu L, Randolph TW, Carpenter JF. Particles shed from syringe fil-

ters and their effects on agitation-induced protein aggregation. JPharm Sci Aug 2012; 101(8): 2952e2959.

99 Song L, Yang K, Jiang W, Du P, Xing B. Adsorption of bovine se-rum albumin on nano and bulk oxide particles in deionized water.

Colloids Surf B Biointerfaces Jun 1 2012; 94: 341e346.

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