Complementary Therapies in Medicine (2007) 15, 128138

The in vitro evidence for an effect of high homeopathic potenciesA systematic review of the literature
Claudia M. Witt a,, Michael Bluth b, Henning Albrecht c, Thorolf E.R. Weihuhn a, Stephan Baumgartner d, Stefan N. Willich a
Institute for Social Medicine, Epidemiology and Health Economics, Charit University Medical Center, e D-10098 Berlin, Germany b Klinik fr Tumorbiologie, D-Freiburg/Br, Germany u c Karl and Veronica Carstens-Foundation, D-Essen, Germany d Institute for Complementary Medicine (KIKOM), University of Bern, CH-Bern, Germany
Available online 28 March 2007 KEYWORDS
Homeopathy; Potency; Dynamization; Basic research; Quality assessment; Quality score; Modied SAPEH; BEPEV; Cell-free systems; Non-cellular; Cultured cells; Basophiles; Neutrophiles; Lymphocytes; In vitro
a

Summary Objective: Systematic assessment of the in vitro research on high potency effects. Method: Publications of experiments were collected through databases, experts, previous reviews, citation tracking. Inclusion criteria: stepwise agitated dilutions <1023 ; cells or molecules from human or animal. Experiments were assessed with the modied SAPEH score. Results: From 75 publications, 67 experiments (1/3 of them replications) were evaluated. Nearly 3/4 of them found a high potency effect, and 2/3 of those 18 that scored 6 points or more and controlled contamination. Nearly 3/4 of all replications were positive. Design and experimental models of the reviewed experiments were inhomogenous, most were performed on basophiles. Conclusions: Even experiments with a high methodological standard could demonstrate an effect of high potencies. No positive result was stable enough to be reproduced by all investigators. A general adoption of succussed controls, randomization and blinding would strengthen the evidence of future experiments. 2007 Elsevier Ltd. All rights reserved.

Introduction
Homeopathic remedies are prepared (potentized or dynamized) in steps of alternately diluting and succussing a homeopathic stock1 (historically known as mother tincture). After several steps,

Corresponding author. Tel.: +49 30 450529011; fax: +49 30 450529902. E-mail address: claudia.witt@charite.de (C.M. Witt).

0965-2299/$ see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctim.2007.01.011

In vitro research on high potencies the remedies reach calculatory dilutions beyond Avogadros number, implying a non-molecular action of remedies with specic healing properties. Research in this eld arranges around three core problems2 : (1) What are the therapeutic effects of homeopathic remedies? (2) What are the specic characteristics of potencies? (3) Through what mechanism(s) do they inuence the organism? Relating to (1) and (3), in vitro research searches for effects of potentized remedies on molecular or cellular systems. Reducing complexity this way allows a higher degree of standardization than clinical research, and may eventually provide model systems to reveal the mode of action of high dilutions devoid of pharmacologically active molecules. Previous reviews of the eld have been either descriptions of individual experiments without systematic evaluation37 , investigations of only the independence of replications8 , or do not present details and rationales of their scoring procedure.9 Other restrictions had been set on publications language3,4,6 or research area,7,8 so that a both broad and systematic assessment with transparent criteria does not exist. In this evaluation we therefore systematically assessed the in vitro research on effects of high potencies of a stock preparation by using a score system. Additionally, we tried to identify experimental models that provide reproducible results or promising approaches that should be replicated.

129 2005 by searching for homopathie + basic o research + experimental + in vitro in each of the following elds: immunology, toxicology, pharmacology, neurology, biochemistry. Medline was searched for publications of the years 1966 until December 2005 using MeSH and full text terms in various spellings. Searched was for homeopathy combined with each of the following terms: in vitro; cell culture; tissue culture; cells, cultured; granulocyte; lymphocyte; macrophage; neutrophil; basophil; enzyme; biomolecule; immunocompetent. Amed (Allied and Alternative Medicine) was searched from 1985 to December 2005 using the same search as in Medline. Previous reviews,36,8,9 and all obtained publications were screened for further references. In addition, we asked experts for information.

Data extraction
From the identied references, those too short for a sensible scoring were excluded, among them were all abstracts. From publications that were mostly or fully identical or obviously referring to identical experiments only the most detailed description was included. One author (MB) extracted data and scored the experiments except his own paper12 that was scored by another author (SB) who did not participate in this work, the data were discussed with a second author (CMW). For each experiment the following data were extracted: publication, objective, technique, ndings, substance tested, control or comparison, and solvent of potentizing, together with additional information of interest. All identied publications were classied by system: non-cellular systems (enzymes), or cellular systems of the categories cultured cells, erythrocytes, basophile granulocytes, neutrophile granulocytes, and lymphocytes/mononuclear cells (including experiments with both neutrophiles and lymphocytes). Strategies involved either cellular or cell-free systems, the former from healthy or from pathological donators. Indirect effects in which the potency modied the action of a stimulus on the target system were set apart from direct effects where the homeopathic preparation acted on the target system directly. Replications were recognized when they investigated the same experimental setup (cell, enzyme, stimulant, noxa, . . .) with the same homeopathic remedy in high (but not necessarily identical) potency. They were operationally dened as independent if the publication had a different rst author and less than half of their authors had published experiments with this model before.8 Finally,

Methods
Inclusion criteria and data sources
We searched for written publications of in vitro investigations on high potencies. In vitro was dened as concerning cellular or subcellular entities in isolation from a living organism. This included cells (also from cultures) or molecules, but not isolated organs. All systems had to be of human or animal origin. Pathological materials such as cancer cells or cells from allergic donators were accepted. Pretreatment before cell extraction, such as intoxication or sensitization, was allowed, but the application of homeopathic preparations had to be in vitro only. Tested remedies had to include high potencies that imply a calculatory dilution of at least 1023 (e.g. D23, C12). Remedy mixtures (complex remedies) were allowed. No other restrictions were imposed; all publication languages were included. References from the Basic Research Database of the Karl and Veronica Carstens-Foundation, D-Essen,10,11 were collected until December

130
Table 1 Item ObjectivesP Controls Declared Adequate Inadequate BlindingM RandomizationM ConsistencyM Experiment standardizationS Medium Incubation StatisticsM ResultsP
P Presentation, incubation. M

C.M. Witt et al.

The modied SAPEH (score for assessment of physical experiments on homeopathy) Points 1 1 +1 1 1 1 1 1 1 1 1
M Methodology, S Standardization:

Criteria Explicit statement what problem or hypothesis was investigated Stated use of controls Succussed or correspondingly potentized solvent Not checking contamination, e.g. unsuccussed Blinding of experimenter/tester State of the art samples randomization Similar results in two or more experiments or test series Use of a buffer or buffered medium if necessary Standardized temperature and incubation time Statistical analysis declared or described Comprehensible presentation of results
quality constructs built into the score. Modications check for buffer and

it was noted whether the publications stated or implied that the ndings supported the existence of effects of high potencies for at least one of the tested potencies, or, in multicenter trials, at least one laboratory.

Modied SAPEH assessment

To provide a transparent and differentiated insight into the strengths and weaknesses of the assessed research, we applied a modied version of the Score for Assessment of Physical Experiments on Homeopathy (SAPEH, Table 1). SAPEH had been developed to assess the quality of physical research in homeopathy.13 It is based on three quality constructs methodology, experiment standardization, presentation that divide into 8 items, checking for 10 criteria. Each item scores 1 point for an afrmative answer, except controls and experiment standardization with 2 points each. The methodology items check that the experimental design uses techniques to control factors that may cause bias (e.g. systematic or random errors). Mentioning controls scores 1 point that is subtracted again if their nature allows for chemical differences to the potencies. Identical composition is assumed if controls have undergone a similar contaminant-affecting preparation (succussion or potentizing)13 as the test potencies. It would earn 2 controls points, accepted are all meaningful descriptions such as produced like the verum or succussed (shaken, vortexed, sonicated, . . .) medium. Further methodology items cover blinding (preventing handling differences and bias effects), randomization (to prevent systematical errors), consistency (internal replications,

ensuring test system stability), and the use of statistics. Experiment standardization was adapted to the in vitro eld, instead of the somewhat unspecic original criteria external factors and experimental setup that can affect results, the item now checks for the use of a buffer or buffered medium, and for standardized temperature and incubation time. The remaining communication about the experiment is covered by presentation of objectives and results, which have to be reasonably detailed and understandable. The modied SAPEH should be read at item level to assess an experiment. The total SAPEH score and its subscores support only rough global impressions and should always be accompanied by score details. For the purposes of the present study, 6 or 7 points with controls of equal contamination would indicate a reasonable control for bias, and >7 points (including 2 for controls) would strengthen this.

Results
Literature
We identied and obtained 75 publications12,1487 that fullled inclusion criteria, among them one sufciently detailed correspondence.45 Seventeen redundant publications were identied (Fig. 1): Three doctoral theses12,33,35 were included that cover and extend the content of eight omitted papers: 7175, 76; 77, and 78, respectively. Two summaries79,87 of otherwise included experiments were ignored. From another summary62 those parts

In vitro research on high potencies

131 with seemingly identical content, the rst listed in each of the following groups was included: 31/80; 41/81; 66/83; 67/82; 68/84/85; 36/86. Two papers48,50 overlapped in content, the more detailed later one was included, whereas from the earlier publication we included only one additional experiment. Of two articles about the same research, two experiments were reviewed from the earlier publication14 and one additional experiment from the other.15 From one paper37 one already published experiment was ignored in favor of the earlier publication.34 Multiple experiments in a single publication12,19,37,42,62,70 were scored individually, resulting in 67 experiments from 58 publications. Table 2 (published in online version at http://www.sciencedirect.com/as supplementary data) lists the details, together with some contextual information to provide a broader overview. The included publications had appeared mostly in journal articles (n = 46), 25 of them were of

Figure 1 Publications and experiments.

were excluded that were less detailed than earlier papers.56,57 Where the analyzed data set of an earlier publication58 seemed to be not identical to the summary data88 we scored both. Of publications
Table 3

Modied SAPEH scores and classications of reviewed experiments

132
Table 3 (Continued)

C.M. Witt et al.

Publications languages: E = English, F = French, G = German. Research strategy: d/cf = direct effect on cell-free system; d/c/h = direct effect on cells from healthy probands; d/c/p = direct effects on cells from pathological donators; i/c/h = indirect effects on cells from healthy probands; i/c/p = indirect effects on cells from pathological donators. c For criteria, quality constructs (P = Presentation, M = Methodology, S = Standardization) and score points see text and Table 1. d 0* = (+11), see text. e Findings support the existence of a high potency effect (+) or not () (stated or implied). ** Only for histamine part.
b

the mainstream: organs of conventional medicine (n = 12), sciences in general (n = 7), or biological medicine (n = 6). The other 21 articles appeared in periodicals of homeopathy in general (n = 15), homeopathic research (n = 3), or complementary and alternative medicine (n = 3). The remaining 12 publications were dissertations (n = 7, including 1 comparable thesis for a homeopathy diploma (28)), congress presentations (n = 3), and books (n = 2). Most authors had published in English (57%), followed by German (25%) and French (18%).

Experiments
The investigated systems were mostly basophile granulocytes (42%), non-cellular systems (27%), and cultured cells (19%). Seldom lymphocytes (6%), erythrocytes (3%), or neutrophiles (3%) were chosen.

Measuring indirect effects on healthy proband cells was the most favoured approach (37%), followed by direct effects on cell-free systems (27%), indirect effects on cells from pathological sources (19%), direct effects on cells from healthy (10%) and pathological (8%) donators. Table 3 lists the classications of the assessed experiments. Presentation was sufciently good for most (79%) experiments (Table 3); 16% lacked a clear description of either objectives or results and 4% of both. Randomization was only reported for 18% and blinding for 33% of the experiments. For most investigations at least one successful replication was stated (83%), 31% checked contamination with succussed controls, in 4% no use of controls was stated. Statistical evaluation was common (76%). In 73% of the experiments buffer and incubation were standardized, in 22% only one of these was mentioned,

In vitro research on high potencies and in 4% none. The overall modied SAPEH mean was 6.1 (S.D. 1.9, median 6.0). Most experiments were done with basophiles models, here also the most positive results were found. From the 67 assessed experiments, 73% stated an effect of high potencies. So did 68% of the 18 experiments with succussed controls and a modied SAPEH score of at least 6 points. Eight of these 19 experiments have not been replicated. Of all scored experiments, 33% were replications. Positive results were reported for 73% of the replications, and for 18% of those with 6 or more points and succussed controls. Replications were most often performed with ow cytometry on basophiles, here mostly by independent teams and with positive results except one.63 All attempts to replicate effects on hydrolase activity were independent and successful but one.12 The action of anti-IgE potencies on basophiles was only reproduced by the same team.

133 But the existence of more negative studies would not rebut those high-scoring works that demonstrated an effect of potentizing beyond Avogadros number. Compared to a previous evaluation of physical research on high potencies13 we found in the present review more in vitro investigations for the same time frame (until 2001, 53 experiments in vitro versus 37 in physics). We observed also a greater percentage of experiments scoring at least 6 points with succussed controls (26% versus 14%), more replications (25% versus 8%), and more publications in renowned periodicals. Applying a score to assess publications systematically is not common in basic research on homeopathy. Although scores have limitations we decided for it because of the benets of systematizing the synopsis and making the assessment criteria transparent. Most relevant works are well known which made blinded scoring or split assessments of methods and results impossible. We tried to achieve high internal consistency by having all scoring done by one investigator. This review is limited to the presentation of experiments in the literature, as common for reviews, presuming correctness and accuracy of the reports, but it can never be sufciently detailed to set up reproductions. Because SAPEH was designed for quick and easy use, we accepted a limitation that lies in not accounting for the number of repetitions, which would have to be observed on several levels. The number of independently produced potencies, test runs per potency, samples per test run, variations in date or location, etc. would require a much more detailed score system. From the mostly self-explaining SAPEH score the items blinding, standardization, and controls require some discussion. In order to identify results that were the most robust to bias and systematic errors91 we included blinding as a criterion. Although probably rare, unconscious bias may creep in through processes that involve human interpretation or judgment, or minute differences in handling. The additional standardization through a buffered medium reduces the variability of results that otherwise might mask a difference between sample types. To prove that high potencies have a specic effect they should only differ from controls in being a potentized stock preparation. Several types of controls or comparisons are available: stock preparation (original material of remedy preparation), unsuccussed solvent, succussed solvent, and another remedy (potency of different stock preparation). A stock preparation would entail gross chemical differences. Untreated solvent has recently been found to be different from a potency

Discussion
We systematically assessed in vitro experiments on high potencies with the modied SAPEH score. The designs of the 67 evaluated experiments were very inhomogenous. We observed an uneven distribution of the investigated systems, ranging from two unrelated experiments each with neutrophile granulocytes or erythrocytes to 28 with basophiles (15 of them being replications). One third of the experiments were replications of earlier research. Nearly 3/4 of the identied experiments found a high potency effect. Even if only those experiments that tried best to exclude bias were considered (SAPEH score of 6 points or more and succussed controls), a positive effect was still demonstrated in more than 2/3 of the experiments. Although it seems unlikely, we could not be totally sure that the results of these experiments are unbiased. Publications on homeopathic research are widely scattered, often not entered into databases, and thus difcult to nd. The database of the Karl and Veronica Carstens-Foundation was very helpful. In addition citation tracking and expert contacts enlarged the number of found publications. Presentations at conferences of either basic or clinical research are not too often followed up by journal articles (e.g. only half of the conventional randomized clinical trials89 )the reason why we did not restrict our search to full articles. Publication bias that is very likely in the eld of homeopathy90 would cause a tendency to positive results. For example, unsuccessful pilot studies in search for a viable test system may not have been published.

134 in the concentration of contaminants that are introduced during the potentizing through interactions of solvent and container material.92 In multi-container potencies (Hahnemann technique), trace element concentrations had reached with the rst potency a level that remained constant in higher potencies.39,92 This applied to potentization with standard parameters93 that are commonly adopted in basic research. Differences between untreated and potentized36,37 or simply sonicated94 solvent have been observed in biological activity as well as physical measurements95 , they might be causally linked to contamination.92,95 . Trace elements are the rationale for our emphasis on succussed better: fully potentized controls. Other contaminants make the fully identical preparation more desirable, like acetate, formate or lactate from the human skin, or methanol and acetone used for cleaning, all easily being introduced with ordinary handling.96 A second remedy as control might in the lower (material) dilutions have its own interaction with container materials97 , making a solution of which the exact composition is unknown but which is likely to be different from the one of the rst potency. Both thus would differ not only in their known initial stock preparation. Moreover, the effect of both potencies on the measurements might be identical which would invalidate a clearly negative result to mean merely possibly negative, or possibly positive but differences cancelled out. For the purposes of the present review we asked for the type of control that allowed the clearest conclusions.

C.M. Witt et al. tion and blinding would strengthen the evidence of further experiments.

Acknowledgments
This work was supported by the Karl und Veronica Carstens-Foundation, D-Essen. We are very grateful to Mrs Hacke from the Karl und Veronica CarstensFoundation who assisted in the literature search. Mrs Menzel from the Charit University Medical e Center Library performed the Medline and Amed searches.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ctim.2007.01.011.

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Conclusions
The reviewed in vitro experiments with high homeopathic potencies were inhomogenous in design and quality. A surprisingly high number of different experimental approaches have been adopted. Two thirds of the experiments with higher scores and contaminant-checking controls demonstrated specic high potency effects. Some of them have also been successfully replicated, but no positive result could be reproduced in all attempts. Among those that have been replicated by independent investigators the action of mercuric bichloride on hydrolases and especially the action of histamine of the Anti-IgE triggered basophile granulocyte degranulation seemed to be the best reproducible. A publication bias in a highly controversial eld like homeopathy is not unlikely. More replications should be done independently to establish models that are stable across laboratories and teams. A general adoption of succussed controls, randomiza-

In vitro research on high potencies

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by very dilute antiserum against human IgE. Nature 1993;366:5257. Sainte-Laudy J, Belon P. Inhibition of human basophil activation by high dilutions of histamine. Agents Actions 1993;38:2457. Sainte-Laudy J, Belon P. Analysis of immunosuppressive activity of serial dilutions of histamine on human basophil activation by ow cytometry. Inamm Res 1996;45:334. Sainte-Laudy J, Belon P. Application of ow cytometry to the analysis of the immunosuppressive effect of histamine dilutions on human basophil activation: effect of cimetidine. Inamm Res 1997;46:278. Belon P, Cumps J, Ennis M, et al. Inhibition of human basophil degranulation by successive histamine dilutions: results of a European multi-centre trial. Inamm Res 1999;48:178. Brown V, Ennis M. Flow-cytometric analysis of basophil activation: inhibition by histamine at conventional and homeopathic concentrations. Inamm Res 2001;50:478. Sainte-Laudy J. Stimulatory effect of high dilutions of histamine on activation of human basophils induced by antiIgE. Inamm Res 2001;50:634. Lorenz I, Schneider EM, Stolz P, Brack A, Strube J. Inuence of the diluent on the effect of highly diluted histamine on basophil activation. Homeopathy 2003;92:118. Lorenz I, Schneider EM, Stolz P, Brack A, Strube J. Sensitive ow cytometric method to test basophil acitvation inuenced by homeopathic histamine dilutions. Forsch Komplementrmed Klass Naturheilkd 2003;10:31624. a Belon P, Cumps J, Ennis M, et al. Histamine dilutions modulate basophil activation. Inamm Res 2004;53: 1818. Guggisberg AG, Baumgartner S, Tschopp CM, Heusser P. Replication study concerning the effects of homeopathic dilutions of histamine on human basophil degranulation in vitro. CTIM 2005;13:1900. Fanselow G. Der Einu von Panzenextrakten (Echinacea Purpurea, Aristolochia Clematitis) und homopathischer o Medikamente (Acidum Formicicum, Sulfur) auf die Phagozytoseleistung humaner Granulozyten in vitro [Inuence of plant extracts (Echinacea Purpurea, Aristolochia Clematitis) and homeopathic remedies (Acidum Formicicum, Sulfur) on phagocytotic activity of human granulocytes in vitro]. Thesis. Mnchen: Medizinische Fakultt; Ludwigu a Maximilians-Universitt; 1984. a Chirumbolo S, Signorini A, Bianchi I, Lippi G, Bellavite P. Effects of homeopathic preparations of organic acids and minerals on the oxidative metabolism of human neutrophils. Br Hom J 1993;82:23744. Bildet J, Dupont H, Aubin M, et al. Action in vitro de dilutions innitesimales de Phytolacca americana sur la ` transformation lymphoblastique a la phytohmagglutinine e [In vitro action of innitesimal dilutions of Phytolacca americana on the transformation of lymphoblasts by phytohemagglutinine]. Hom Franc 1984;72:22530. Colas H, Aubin M, Picard P, Lebecq JC, Bastide JM. Inhi` bition du test de transformation lymphoblastique (TTL) a la phytohmagglutinine (PHA) par Phytolacca americana e en dilutions homopathiques [Inhibition of lymphoblast e transformation test (LTT) by phythemagglutinine (PHA) through Phytolacca americana in homeopathic dilutions]. Hom Franc 1984;72:21924. Chirila M, Hristescu S, Manda G, Neagu M, Olinescu A. The action of succussed substance on the human lymfocytes and granulocytis PMN in vitro stimulated with phytohaemagglutinin or zymosan opsonized. In: Proc Congr OMHI. 1990. p. 1727.

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69. Gibson SLM, Gibson RG. The effects of homoeopathic potencies of house-dust mite on the migration of housedust-sensitive human leucocytes. Complem Ther Med 1996;4:16971. 70. Sukul NC, De A, Sinhababu SP, Sukul A. Potentized mercuric chloride and Nux vomica facilitate water permeability in erythrocytes of a fresh-water catsh clarius batrachus under acute ethanol intoxication. J Altern Compl Med 2003;9:71925. 71. Delbancut A, Dorfman P, Cambar J. Inuence de la dure du e prtraitement avec de tr`s basses concentrations de cade e mium sur la cytotoxicit induite par le mtal sur cellules e e tubulaires de rein en culture [Inuence of the duration of pretreatment with very low concentrations of cadmium on cytotoxicity induced by the metal and on cultured kidney tubular cells]. In: Delbancut A, Dorfman P, Cambar J, editors. 5th GIRI meeting, 2930 November, Paris; 1991. p. 37. 72. Delbancut A, Dorfman P, Cambar J. Protective effect of very low concentrations of heavy metals (cadmium and cisplatin) against cytotoxic doses of these metals on renal tubular cell cultures. In: G.I.R.I., editor. 6th GIRI Meeting, 2627 October 1992. Mnchen, Germany: GIRI; 1993. u p. 19. 73. Delbancut A, Merlet D, Mellado M, Dorfman P, Cambar J. Etude de leffect protecteur de tr`s hautes dilutions de cade mium vis-`-vis de concentrations cytotoxiques de ce mme a e mtal sur des cultures cellulaires rnales [Study of proe e tective effects of very high dilutions of cadmium against the cytotoxic concentration of the same metal on renal tubular cell cultures]. Cahiers de Biotherapie 1993;120: 3944. 74. Delbancut A, Merlet D, Mellado M, Dorfman P, Cambar J. Nachweis der Schutzwirkung sehr hoher Verdnnungen von u Metallen auf mit Cadmium vergiftete Nierenzellkulturen [Proof of protective effect of very high dilutions of metals on cadmium intoxicated renal tubular cell cultures]. Dt J Hom 1995;14:16375. 75. Delbancut A, Barouillet MP, Cambar J. Evidence and mechanistic approach of the protective effects of heavy metal high dilutions in rodent and in renal cell cultures. In: Signals and images. selected papers from the 7th and 8th GIRI Meeting. Dordrecht: Kluwer; 1997. p. 7182. 76. Then C, Dittmann J, Schtte A, Bauer J, Harisch G. u In-vitro-Untersuchung zur Wirkung homopathischer Poteno zen von Thuja occidentalis an Zellkulturen mit Hilfe des MTT-Testes [In-vitro investigation on the effect of homeopathic potencies of Thuja occidentalis on cell cultures using the MTT test]. Forsch Komplementrmed 1996;3: a 2807. 77. Then C, Dittmann J, Schtte A, Bauer J, Harisch G. In-vitrou Untersuchung zur Wirkung von Arsenicum-album-Potenzen an Zellkulturen mit Hilfe des MTT-Testes [In-vitro investigation on the effect of potencies of Arsenicum album on cell cultures using the MTT test]. Forsch Komplementrmed a 1996;3:2228. 78. Witt C, Bluth M, Ldtke R, et al. Does potentized HgCl2 u (mercurius corrosivus) affect the activity of diastase and -amylase? J Alt Compl Med 2006;12:35965. 79. Dittmann J, Harisch G. Wirkungsunterschiede zwischen Potenzenaccorden und ihren Einzelpotenzen: In-vitroStudien mit cAMP- und Ubichinon-Prparaten [Differences a of efcacity between potency chords and their element potencies: in-vitro studies on preparations of cAMP and ubiqinone]. Biol Med 2000;29:1823. 80. Cotte J, Bernard A. The effects of mercurius corrosivus hahnemanian potencies upon the multiplication of cultured

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broblasts poisoned with mercury chloride. In: Boiron J, Abecassis J, Belon P, editors. Aspects of research in homeopathy. Lyon: Editions Boiron; 1983. p. 519. Poitevin B, Aubin M, Benveniste J. Approche dune analyse quantitative de leffet dApis mellica sur la dgranulation e des basophiles humains in vitro. Innov Tech Biol Med 1986;7:648. Colas H, Aubin M, Picard P, Lebecq JC, Bastide JM. Inhi` bition du test de transformation lymphoblastique (TTL) a la phytohmagglutinine (PHA) par Phytolacca americana en e dilutions homopathiques [Inhibition of lymphoblast transe formation test (LTT) by phythemagglutinine (PHA) through Phytolacca americana in homeopathic dilutions]. Ann Hom Franc 1975:62938. Bildet J, Dupont H, Aubin M, et al. Action in vitro de dilutions innitesimales de Phytolacca americana sur la ` transformation lymphoblastique a la phytohmagglutinine e [In vitro action of innitesimal dilutions of Phytolacca americana on the transformation of lymphoblasts by phytohemagglutinine]. Ann Hom Franc 1981;23:10211. Chirila M, Hristescu S, Manda G, Neagu M, Olinescu A. The action of succussed substances on the human lymphocytes and PMN granulocytes in vitro stimulated with phytohaemagglutinin (PHA) or zymosan opsonized (ZO). In: G.I.R.I., editor. 4th Meeting November 30December 1, 1990, Maison de la Recherche, Paris. Paris: GIRI; 1990. p. 11. Chirila M, Hristescu S, Manda G, Neagu M, Olinescu A. The in vitro action of a succussed substance on the proliferative response of human lymphocytes stimulated with phytohemagglutinin. Rev Roum Md Int 1992;30:637. e Carmine TC. Bestimmung der H2 O2 -Produktion von Neuroblastomzellen nach Stimulierung mit Hochpotenzen des Zytokins TNF alpha durch Chemolumineszenz: Ein mgliches o System zum Wirksamkeitsnachweis homopathischer Hocho potenzen [Chemoluminescence determination of H2 O2 produktion of neuroblastom cells after stimulation with high potencies of the cytokine TNF alpha: a possible system for the proof of efcacy of homeopathic high potencies]. AHZ 1996;241:14354. Sainte-Laudy J. Modulation of allergen and anti-igE induced human basophil activation by serial histamine dilutions. Inamm Res 2000;49:S56. Baumgartner S, Guggisberg A. Basophilendegranulation, dritter Akt: Homopathie und Basophilenreaktion o weniger klar, als manche das gerne htten. [Kommena tar zu Belon P, Cumps J, Ennis M, Mannaioni PF, Roberfroid M, Sainte-Laudy J, Wiegant FAC. Histamine dilutions modulate basophil activation. Inamm Res 2004; 53:181188] [Basophiles degranulation, third scene: Homeopathy and basophiles reaction less clear than some would like. (Commentary)]. Forsch Komplementrmed a Klass Naturheilkd 2005;12:524. Ezzo J, Berman BM, Vickers AJ, Linde K. Complementary medicine and the cochrane collaboration. JAMA 1998;280:162830. Shang A, Huwiler-Mntener K, Nartey L, et al. Are the u clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet 2005;366:72632. Baumgartner S, Heusser P, Thurneysen A, Methodological Standards. Problems in preclinical homoeopathic potency research. Forsch Komplementrmed 1998;5:2732. a Witt C, Ldtke R, Weihuhn T, Willich S. The role of trace u elements in homeopathic preparations and the inuence of container material, storage duration, and potentisation. Forsch Komplementrmed 2006;13:1521. a

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93. Bundesminister fr Gesundheit und Soziales. Homopau o thisches Arzneimittelbuch [Homoeopathic Pharmacopoeia]. Stuttgart: Deutscher Apotheker-Verlag; 1978. 94. Haseba T, Matsushita K, Asakura T, et al. Diminution of biological reactivity of ethanol by changing the solution structure by weak ultrasonication. Alcoholism Clin Exp Res 1993;17:9637. 95. Witt C, Ldtke R, Weihuhn TER, Willich SN. High homeu opathic potencies are different from potentized solvent

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when investigated with the REDEM technology. Forsch Komplementrmed Klass Naturheilkd 2005;12:613. a 96. Anick DJ. High sensitivity 1 H-NMR spectroscopy of homeopathic remedies made in water. MBMC Compl Alt Med 2004;4:15. URL: http://www.biomedcentral.com/14726882/4/15. 97. Walach H, Jonas WB, Ives J, Wijk RV, Weingartner O. Research on homeopathy: state of the art. J Altern Complement Med 2005;11:81329.

Online supplementary material for: Witt, C, Bluth, M, Albrecht, H, Weihuhn, TER, Willich, SN. The in Vitro Evidence for an Effect of High Homeopathic Potencies A Systematic Review of the Literature. Complementary Therapies in Medicine 15 (2), 2007, pp. 128138. Table 2: Reviewed Experiments
Publication Objective Technique Findings Merc-c and Sulf alternately inhibit and stimulate diastase until D60, Calc-m until D20. Inhibition of activity by Iris D6D25, Aur-m D6; stimulation by Jab D6, Iod D6D9. Stimulation alternates with inhibition or no effect until D45 (Ph-ac) or D100 (Iris). Ars D6 acts strongly stimulating, D15 inhibiting, no effects above D20, nor with Ins. Merc, Adren stimulate frog muscle enzymes; Adren effects show pseudosinusoidal curve with phases of activity and no effects until D40. No effects on bovine heart enzymes by Adren; only Coff and Glon inhibit until D15. Merc-c CC26CC30 stimulates activity of diastase. Effect decreases with storage time, not found after 3 months. Substance Tested Control or Comparison Solvent of Potentizing Not declared

Non-Cellular Systems Persson and Influence of potencies on Photometry Ginsberg, 1932 the activity of malt diastase?

Persson, 1933

Influence of potencies on Photometry the activity of trypsinogen? Influence of potencies on the activity of glycogen reducing enzymes from a) frog muscle and b) bovine heart? Effect of high potencies of Merc-c on malt diastase activity? Affects storage duration potency activity? Do potencies of phosphor modulate a reaction involving phosphate group transfer by pyruvate kinase or luciferase? a) Effects of Bell on acetyle cholinesterase from goat brain? b) Effects of Ars on human serum cholinesterase?? Modification of a 50% inhibition of enzymes Photometry

Merc-c, Sulf D6D60. Aur-m, Water Calc-m, Jab, Plat-m D6D30. Iris, Nit-ac D6D30. Bell, Benzac, Canth, Iod, Lyc, Ter, potency not stated Ars, Ins D3D30. Ph-ac Water D6D45. Iris D6D100

Not declared

Persson, 1938

Boyd and Brit 1954

Photometry

Ars, Coff, Glon, Lac-ac, Merc-c Water Phos, Stroph, Stry-n D3D30. Adren D3D40. Adon, Ins, Natsal, Thyroxin (potency not stated) Merc-c CC26-30 ABD

Not declared

ABD

Kraus et al., 1981

Bioluminescen ce

Activity of pyruvate kinase stimulated (C5, C9, C13) or inhibited (C6, C14) by Phos. Luciferase not affected.

Phos C3C15

ABD

Not declared

Jussal et al., 1984

a) Photometry, b) Comparison with standard curve Electrophoresi s; protein

a) Strong variability of activity. b) Ars ?27, ?28 inhibit activity.

a) Bell D1 D60. b) Ars ?27, ?28

a) 0-control b) EOH 10%

a) Not declared, b) EOH 10%

Petit et al., 1989

Arg-n, Cupr-s, Merc-c, Zinc-m D4 increase induced inhibition, higher potencies have no effect. No effects

Arg-n, Citrate, Cupr-s, Merc-c, molybdate, Phos, Zinc-m D4,

ABD

ABD

Publication

Objective (glucose-6 phospatase; NADPH-cytochrome-C reductase; galactosyl transferase; lactate dehydrogenase; 5'nukleotidase) by potencies of the inhibiting substance? a) Effect of D and C potencies of Merc-c on -amylase from human saliva? b) Influence of pH? c) Effect of several remedies at different pH? Differences between potencies, dilutions, potency chords, and dilution chords regarding their effect on the activity of glutathione-S transferase (GST), acid phosphatase (AP) and xanthine oxidase?

Technique assays; Radioactivity determination

Findings from Phos, citrate and molybdate.

Substance Tested D6, C5, C7, C9, C11, C13, C15, C20, C30 except molybdate and citrate C30, except Phos D4, D6

Control or Comparison

Solvent of Potentizing

Shabir et al., 1996

Photometry

a) Amylase inhibited by Merc-c D1, D2, C1; higher potencies (D9D15; C6C12) stimulate activity. b) Results differ at different pH: All potencies stimulated at pH 7.0. At pH 4.5, 5.5, 8.5, both inhibition and stimulation occurred. c) Substances in C30 usually activated at pH 5.5, 7.0; and inhibited at pH 8.5. GST is inhibited by ubiquinone D8, D30, D200 and dilution chord D. SP inhibited by all preparations except Ubichinon-Injeel forte ; dilutions chord Df differs from D12, D30, D200 and Ubichinon-Injeel . Ubiquinone D8, D30, and Ubichinon-Injeel forte stimulate activity of xanthine oxidase. Multiple differences between single potencies and potency chords. Dilutions chord D differs from Ubichinon-Injeel .

a) Merc-c D1D15. b) Merc-c C5, C10, C15, C20, C25. c) Acon, Ars, Bell, Graph, Led, Merc, Phyt, Puls, Sulf, Verat C30

Water

AD

Harisch and Dittmann, 1997

Photometry, comparison with standard curve

Ubiquinone D8, D12, D30, D200. Ubichinon-Injeel (=ubiquinone D12 + D30 + D200). Ubichinon-Injeel forte (=ubiquinone D8 + D12 + D30 + D200)

Harisch and Dittmann, 1998

Differences between potencies, dilutions, potency chords, and dilution chords of cAMP, regarding their effect on acid phosphatase (AP), glutathione-S transferase (GST), uricase, cAMPdependent proteine kinase (PKA)?

Photometry; HPLCanalysis; comparison with standard curve

Activity is inhibited (AP) or stimulated (uricase, PKA) by potencies and dilutions up to D200/dil200; GST not affected. Only difference between potencies and dilutions: D8/dil8 for uricase.

Water, Not declared chords of stepwise dilutions 1:10: 'Chord D' = ubiquinone dil12 + dil30 + dil200. Chord Df' = ubiquinone dil8 + dil12 + dil30 + dil200 cAMP D4, D6, D8, D12, D30, Stepwise Not declared D200. cAMP D6 + D12 + D30 + dilutions 1:10: D200. cAMP D12 + D30 + D200 cAMP dil4, dil6, dil8, dil12, dil30, dil200. cAMP dil6 + dil12 + dil30 + dil200. cAMP dil12 + dil30 + dil200. Water

Publication Harisch and Dittmann, 1999 (cAMP)

Objective Differences in the effect on acid phosphatase between cAMP potency chords, their constituents, and controls? Differences in the effect on potato acid phosphatase between ubiquinone potency chords, their constituents, and controls? Influence of longer preincubation? Effect of variation of D8 amount in potency chord? Effect of potencies on uricase, acid phosphatase (AP), and glutathione-Stransferase (GST)? Effects of Merc-c, Merc-i C30 on -amylase activity? Influence of storage duration (Merc-c only)? Effect of potencies on lipoperoxidation from homogenized rat brains compared to melatonin? Effect of HgCl2 potencies on activity of malt diastase and -amylase?

Technique Photometry; comparison with standard curve

Findings All potency samples differ from Water. Some samples (potencies or potency chords) differ from others (no regularity). Potency chord effects always less inhibiting than sum of constitutent's effects.

Substance Tested cAMP D6, D12, D30, D200, also in combinations. cAMPa Injeel (= cAMP D12 + D30 + a D200). cAMP-Injeel forte (= cAMP D6+ D12 + D30 + D200) Ubiquinone D8, D12, D30, D200, also in combinations. Ubichinon-Injeel (=ubiquinone D12 + D30 + D200). Ubichinon Injeel forte (=ubiquinone D8 + D12 + D30 + D200)

Control or Comparison Water

Solvent of Potentizing Not declared

Harisch and Dittmann, 1999 (Ubiquinone)

Photometry

All preparations inhibit activity. Ubichinon-Injeel forte inhibits more than all other preparations except D12. Effect of potency chords less than sum inhibition of components. After 40 min preincubation time, Ubichinon-Injeel decreases catalytic activity by 10%, Ubichinon-Injeel forte by 15%. Variation in D8 amount in potency chords influences results in a non-linear manner.

Water

Water

Dittmann et al., 2000

Photometry

Kali-cy D5, D6 inhibit uricase and AP; Kali-cy D8, D30 activate uricase. GST not affected.

Kali-cy D5, D6, D8, D30

Not declared

Not declared

Sukul et al., 2002

Photometry

Merc-c, Merc-i stimulate -amylase in AD and EOH; Merc-c more than Merc-i. Effect of Merc-c C30 decreases with Storage time, not found after 1 month.

Merc-c, Merc-i C30 ultrasound potentized, 4, 30, 365 days old

AD, 'EOH 90%' C30 ultrasonicate d, 4, 30, 365 days old Melatonin 1M, 0.5M, 0.25M, 0.125M ABD; ABD C2C30; HgCl2 dilutions 1:100: dil2 dil5

AD, EOH 90%

Batello, 2002

Photometry

Bluth, 2005

Photometry

Strongest inhibition with melatonin 1M and 0.5M. Ars C12, C30, Cupr C12, C30, and Mang C30 had moderate antiperoxidative effect compared to melatonin 0.125M. No difference between Merc-c potencies and succussed controls. Merc-c C2 inhibited -amylase like the corresponding dilution, all higher potencies inactive.

Ars, Cupr, Mang, Zinc C6, C12, C30

Not declared

Merc-c C2C30

ABD

Publication Cultured Cells Van Mansvelt and Amons, 1975

Objective

Technique

Findings

Substance Tested

Control or Comparison ABD

Solvent of Potentizing ABD

Aubin et al., 1980

Boiron et al., 1981

KandeferSzerszen et al., 1993

Delbancut, 1994

Does the growth inhibition of Merc-c on lymphoblast cells decrease to zero with increasing potency? Can the regeneration of in vivo CCl4 induced rat liver cell necrosis be modified in vitro by Phos (as globules, dilutions)? Do potencies of Merc-c have a protective effect on fibroblasts exposed to HgCl2? Effect of interferon- on tumor cell (A549) growth? Differences between D and C potencies? Exactly reproducible? Effect of heating initial interferon stock preparation? Effect of interferon- potencies on tumor cell (A549) antiviral activity against vesicular stomatitis virus? a) Prophylaxis for pig kidney cells (LLCPK1) against intoxication by pretreatment with the potentized noxa (Cadmmet, Cisplat)? b) Does Preincubation with Cadm-met potencies for 120 h influence growth? c) Optimal preincubation time for maximum

Coulter Cell Counter

Merc-c D5, D6 inhibit cell growth. Weak replicated inhibition with D16, D17.

Merc-c D5D25

Microscopy

Globules deteriorate, dilutions improve cellular regeneration compared to controls.

Phos C7, C15

a) NaCl 0.9%. b) Placebo globules 'ABD', potency not stated

Not declared

Microscopy

Pretreatment with Merc-c C5 increases mitotic index by Merc-c C5, C15 ca. 10% compared to controls; C15 is ineffective.

Not declared

Microscopy; photometry

Pseudosinusoidal stimulation-inhibition curve of cell growth, regular peaks/lows every 69 D potencies; similarly with C potencies. Every line of potentizing shifts peak/low location (no exact replications). More similar results when using the same potencies in intervals of one week. Potencies show no activity if initial solution is heated. No influence of interferon potencies on antiviral activity.

Medium Interferon- D1D40, C1C40 Interferon- dilution in medium. 'Medium' D80

Photometry; spectrometry; microscopy

a), c) Protective effect of Cadm-met C10 after 120 h Cadm-met, Cisplat C5, C10, but not after 48h preincubation. Strong protective effect C15, C20 after 120 h against Cadm-met in other high potencies up to C20. b) Preincubation with Cadm-met potencies alone has no influence on growth. d) Prophylactic effect increases with potency. e) Only low Cadm-met -5 doses (up to 3x10 M) can be countered. f) Against Cisplat, Cadm-met C20 increases mortality by 6%. g) With Cadm-met pretreated cells was found: less degeneration of cytoskeleton; less Cadm-met penetration into the cell (for low intoxication

'Medium' C5, C10, C15, C20

Medium

Publication

Objective

Technique

Findings concentrations); increased expression of (protective) metallothioneine, but decreased (more with higher potencies) when cells are incubated in presence of Cadm-met or Cisplat potencies without intoxication. h) Potentizing with EDTA prevents protection by Cadm-m C15 and increases mortality in only pretreated cells. i) Cycloheximide raises cell mortality of Cadm-m C15 pretreated cells after intoxication.

Substance Tested

Control or Comparison

Solvent of Potentizing

Pison et al., 1995

protection? d) Differences between potencies? e) Maximum preventable intoxication dose? f) Crossover protection between Cadm-met and Cisplat? g) What cellular mechanisms are triggered? h) Does a chelator (EDTA) affect the Cadm-met potency when added in potentizing? i) Are potencies effective in presence of a protein biosynthesis inhibitor (cycloheximide)? Proliferation of Photometry fibroblasts affected by high potencies? Potentized EOH different from unpotentized? Effect of homeopathic remedies in various pharmaceutical forms, in potencies or dilutions on cell cultures (EBL; HeLa; MDBK cells)? Prophylactic or curative effect of potencies against intoxication with their stock preparation? Effect of high potencies of TNF- on H2O2production of neuroblastoma cells? Photometry; microscopy

All investigated potencies including potentized potentizing solvents (EOH, lactose) inhibit growth similarly, differently from unpotentized EOH.

Bell, Thuj D8, D12, C30, C200, C1000

Then, 1995

Inhibition of cell growth by Ars up to D6, no difference to corresponding mixtures. Blends and triturations with lactose different for Ars D4, Merc-c D12. Prevention only found for Ars D7; no curative effects.

Ars, Cupr-s, Merc-c D3D10, D12, D15, D18, D24, D30, D200. Thuj D2D6, D8, D12, D30

EOH 43%, EOH 43% C30, lactose, cell culture medium, buffer ABD. EOH 70%. Lactose -4 -8 10 , 10 , -12 -15 10 , 10 , -18 10

EOH 43%, lactose (trituration)

ABD. EOH 70%. Lactose, medium

Carmine, 1997

Chemolumines D100 stimulates H2O2-production by +19%199%. cence Stimulation shows an oscillating curve (somewhat pseudosinusoidal) against potency, rising with higher potencies. Potentized ABD also increases H2O2-

TNF- D1D100

AAI. AAI D30, D70, D100

AAI

Publication

Objective Biological effects of potentized Water compared to unpotentized? Influence on cell-free reaction? Action of potencies on cell cultures of 1) neuroblastoma and human melanoma cells, 2) stimulated human leucozytes, 3) alveolar type II-cells from rat lungs?

Technique

Findings production. The biochemical reaction itself remains unchanged in presence of potencies.

Substance Tested

Control or Comparison

Solvent of Potentizing

Herberth and Pison, 1998

1) Enhanced chemolumines cence; 2) luminolchemolumines cence; 3) radiation of 14 C-choline; protein and phospholipid concentration Photometry; fluorometry

1) TNF- potencies did not influence chemoluminescence. 2) No potency altered the chemoluminescence of stimulated or resting leucozytes. 3) Inclusion of choline in phospholipid and protein production not influenced by tested preparations.

1) TNF- D10D100; Zymosan. 2) Zymosan D10D100; Bell , D8, C12C1000; Ferr-p, Thuj, potency not stated. 3) Bell, Colch, Lec, potency not stated

Jonas et al., 2001

Marotta et al., 2002

Neuroprotective effects of potentized glutamate for various neuron samples (of cerebral, cerebellar, spinal origin) against toxic doses of glutamate? Is the effect 2+ due to a decreased Ca influx? Protection of neuronal cells pretreated with potencies of the neurotoxins cycloheximide, NMDA or MPP-iodide against excitotoxic glutamate concentrations? Influence of potencies on erythrocyte aquaporins from Clarus batrachus, with and without prior ethanol intoxication?

Weak cell-type specific neuroprotective effect (mortality Glutamate C9C15 ca. -10%) in some potencies in somewhat sinusoidal curve against potency, peak locations vary with cell type. With higher glutamate concentrations only the highest potency (C15) increased survival. Intracellular 2+ Ca influx in spinal neurons not affected by glutamate C9, C11.

1) TNF- 10 10 -100 , 10 ; buffer. 2) Zymosan 0.5mg/ml, 10 10 -100 , 10 , 10 1000 ; AD; EOH 43%; buffer; saccharose. 3) Not declared 'Water + EOH 95% + Glycerol' C9C15

EOH 43%

Water + EOH 95% + Glycerol

Photometry

Cycloheximide C2 decreased neuronal survival by 18%, cycloheximide C13 increased it by 5%. All other tested potencies had no effect. Except Ca, K, Na, Si, 29 tested elements present only in negligible quantity, similar concentrations in controls.

Cycloheximide C2C5, C13, Water C31; NMDA C3C6, C14, C32; succussed MPP iodide C3C6, C14, C32 120 times

Deionized sterile filtered water

Erythrocytes Sukul et al., 2003

Erythrocyte weight loss from drying after hypotonic incubation

Water permeation was enhanced with Merc-c and Nux- Nux-v, Merc-c C30 (sonicated) v C30 compared to water controls. No reduction compared to ethanol intoxicated erythrocytes.

EOH C30; water; nullcontrol

EOH 90%

Publication

Objective

Technique

Findings

Substance Tested

Control or Comparison NaCl 0.9% with dissolved lactose globules NaCl 0.9%

Solvent of Potentizing NaCl 0.9% with dissolved lactose globules NaCl 0.9%

Basophile Granulocytes Murrieta et al., Antigen (mite) triggered 1985 degranulation of basophiles from allergic probands inhibited by Apis potencies? Poitevin et al., Antigen (mite) triggered 1985 degranulation of basophiles from allergic probands modified by Apis potencies? Sainte-Laudy 1) Effects of Histamine, and Belon, platelet activating factor 1986 (PAF), and lyso-PAF on degranulation of basophiles from allergic probands? 2) Influence of incubation time on PAF, lyso-PAF effects? 3) Influences of thermal treatment on potency effects? 4) Affect Histamine potencies the half maximum degranulation antigen dose? Belon, 1987 a) Effect of Histamine on D. pteronyssinus induced degranulation of basophiles from a sensitized proband? b) Can the effect of Histamine C6, C17 be reproduced for different allergen concentrations with basophiles from 30 house dust allergy patients?

Microscopy

No inhibition of degranulation found.

Apis C5, C9, C15, C30

Microscopy

Degranulation increased with Apis C5 by +20%, decreased by C9, C15 by -60%.

Apis C5, C9, C15

Microscopy

1) Effect peaks of Hist at C6, C7 and C16C18; ineffective potencies in between (C10C15). Maximum effects at C9, C10 for PAF and lyso-PAF. 2) Effect rises with incubation time; slower but to same dimension after 30 min with lyso-PAF. 3) Boiling destroys efficacy of Hist C7, PAF C10, C11, and lysoPAF C9C11. Repeated deep-freezing decreases effects. 4) Different potencies show different degranulation-antigen curves.

Hist C5C20. PAF, lyso-PAF C6C15

Buffer. AD C18

Not declared

Microscopy

a) Degranulation inhibited by some potencies, maxima at C6, C17. b) Marked inhibition by C6, C17 with at least 2 antigen concentrations for most probands. Effects stronger with lower antigen concentration.

Hist C1C24

AD

Not declared

Publication Davenas et al., 1988

Objective

Technique Microscopy

Findings a) Degranulation triggered by potentized anti-IgE, not by anti-IgG. b) Potencies made with dimethylsulfoxide ineffective. Heating, freezing and sonication decrease efficacy.

Substance Tested Anti-IgE D1D60, C1C60. Anti-IgG C1C60

a) Do high potencies of anti-IgE or anti-IgG induce degranulation of human basophiles? b) Influences of solvent, heating, deep freezing or sonication? Metzger and Do potencies of anti-IgE Dreskin, 1988 or dinitrophenyl induce degranulation of leucaemic rat basophiles? Poitevin et al., a) Do potentized lung 1988 histamine or Apis inhibit -9 anti-IgE induced (10 M) degranulation of human basophiles ? b) Do potencies of anti-IgE trigger degranulation that can be inhibited by potencies of lung histamine and Apis? c) Direct effect of potencies? Ruff et al., 1988 Inhibition of antigen induced degranulation of basophiles from allergic probands whole blood by potencies of pollen, Histamine, Ars? Sainte-Laudy, Effect on antigen 1989 induced degranulation of (Methylhistamin basophiles from allergic e part) probands whole blood by potencies of 4-methylhistamine? Benveniste et Do high potencies of al., 1991 Apis inhibit anti-IgE and anti-IgG induced

Control or Comparison Buffer. AntiIgE dilutions -1 -60 10 10

Solvent of Potentizing Buffer. dimethylsulfo xide

Autoradiograp hy

No effects of high potencies of allergen or antibodies.

Anti-IgE, dinitrophenyl-albumine Buffer D5D35

Not declared

Microscopy

a) Lung histamine C1, C9 increase, C5, C15 and Apis C8, C9, C10 inhibit degranulation induced by anti-IgE. b) Anti-IgE D16, D17, D18 induce degranulation that can be inhibited by potentized lung histamine or Apis. c) Without prior activation from anti-IgE, Apis and lung histamine do not affect degranulation.

Lung histamine, Apis C1C20. Anti-IgE D16D22

NaCl (concentratio n not stated) + 65% EOH for C1, C1C20

NaCl (concentratio n not stated) + 65% EOH for C1

Fluorometry

Only Ars inhibits degranulation triggered by grass pollen. Hist shows a tendency to inhibit. Dust mite antigen triggered degranulation not modified by the tested potencies.

Ars C15. Hist C7. Pollen C9

Buffer

AAI

Microscopy

Inhibition by 4-methyl-histamine at C6, C16.

4-Methyl-histamine C4...C19, prepared in polystyrene tubes or glass flask

Allergene free

Water

Microscopy

Degranulation was found for anti-IgE and anti IgG that is not induced by controls. Apis C30, C32, C34, C40 inhibit anti-IgE induced degranulation, potentized

a) Anti-IgE, anti-IgG D21D30. b) Apis C30C40

a) 'ABD' a) buffer. b) D21D30. b) NaCl 'NaCl' (concentratio

Publication

Objective degranulation of human basophiles?

Technique

Findings solvent does not.

Substance Tested

Sainte-Laudy et Do potencies of al., 1991 Histamine, Histidine modify degranulation of basophiles from probands being allergic to dust mite? Effects of adding cimetidine or histaminase to the potencies? Sainte-Laudy Do potencies of and Belon, Histamine inhibit anti-IgE 1991 induced degranulation of human basophiles? Influence of variations in protocol (concentrations of anti-IgE, number of controls, reproductions)? Ovelgnne et Do high potencies of al., 1992 anti-IgE induce degranulation of human basophiles? Hirst et al., Do potencies of anti-IgE 1993 induce degranulation of human basophiles?

Microscopy

Maximum inhibition of degranulation for Hist found at C6, C16, C26, C39, C51; no effects for Histid. Cimetidine suppresses the Hist effects (C4C19). Histaminase prevents effects of Hist C6,C7, but not of Hist C16, C17.

Hist C4C57. Histid C4C19

Control or Comparison (concentratio n not stated) D40 Allergene free control

Solvent of Potentizing n not stated)

Water

Microscopy

Higher potencies (Hist C15C18) are effective with low (0.2 l/ml) but not for higher (1, 5.0 l/ml) concentrations of anti-IgE.

Hist C6, C7, C15C18

'ABD' C15C18

ABD

Microscopy

No difference between potencies of anti-IgE and diluted controls.

Anti-IgE D21D30

Anti-IgE 10 2 -30 10

buffer

Microscopy

Sainte-Laudy and Belon, 1993

Do potencies of Microscopy Histamine inhibit anti-IgE induced degranulation of human basophiles?

No significant reproducible effect of potencies >C2. Succussed IgE, unsuccussed IgE and succussed buffer apparently different. High buffer potencies showed linear correlation of degranulation and potency. Inhibition of anti-IgE induced degranulation by Hist C10C38, most frequently by C9, C10, C16.

Anti-IgE C2C30

'Buffer' C2C30. Anti-IgE 10 2 -30 10 Water. AntiIgE free control

buffer

Hist C6C18

ABD

Sainte-Laudy and Belon,

Do potencies of Histamine inhibit

Flow cytometry Inhibition of CD63 expression by Hist C1, C2, C11, C17. No change in fluorescence density, nor in

Hist C1C20

0-Controls. Anti-IgE free

AD

Publication 1996

Objective

Technique

Findings percentage of anti-IgE+ cells (except Hist C2).

Substance Tested

expression of markers related to degranulation in anti-IgE activated human basophiles? Sainte-Laudy Do potencies of and Belon, Histamine inhibit 1997 expression of CD63 in anti-IgE activated human basophiles? Also in presence of cimetidine? Belon et al., Do potencies of 1999 Histamine inhibit anti-IgE induced degranulation of human basophiles? Brown and Do potencies of Ennis, 2001 Histamine inhibit anti-IgE induced CD63 expression in basophiles? Effect of heating or repeated deep freezing? Sainte-Laudy, Do potencies of Histidine 2001 or Histamine increase anti-IgE induced expression of human basophil CD63? Effect of cimetidine? Lorenz et al., Effects of potentized 2003 (Solvents) Histamine on CD63 expression in anti-IgE activated basophiles from human responders? Effects of different potentizing solvents? Lorenz et al., Influence of various 2003 protocols on Histamine (Protocols) potency induced CD63expression of anti-IgE activated basophiles

Control or Comparison controls

Solvent of Potentizing

Flow cytometry Hist C15, C16, C17 inhibit anti-IgE induced CD63 expression slightly (-1.4%3.6%) compared to presence of cimetidine.

Hist C10C20

Cimetidine. Anti-IgE free controls

AD

Microscopy

Minor significant inhibition of anti-IgE induced degranulation by high potencies of Hist in 3 of 4 participating laboratories (p=0.065 for the fourth).

Hist C15C19

'AD' C15C19

AD

Flow cytometry Hist C1, C2, C3, C7, C9, C10, C13 inhibit expression of Hist 10 M10 M (title says CD63; maximum with C10 (-43.8%). Activity decreased homeopathic concentration, by heating, unaffected by freezing the potencies. paper uses dilution terminology and units)

-2

-40

Isotype matched nonspecific antibodies

Not declared

Flow cytometry Hist C13 increases expression of CD63 (+42%) and activated cell percentage, while Hist C14 does not. Cimetidine diminishes this activation. Histid C13 not different from potentized AD.

Hist C13, C14. Histid C13

'AD' C13, C14

AD

Flow cytometry Solvent a) potencies of Hist inhibit CD63 activation in Hist D2D30 made in a) EOH 4.8% and stimulate in 22.6% of the experiments, + ABD + buffer, or b) brandy + 72.6% do not differ from controls. Solvent b) potencies ABD + buffer inhibit in 57.1% of experiments, 42.9% do not differ from controls. Solvents differ clearly in their inhibition at D10D30, varying with probands. Flow cytometry Basophile count varies (0.6-3.6%), optimal activation at Hist D2D34 prepared in 0.6g/ml anti-IgE (final concentration); still 20% antiglass, polystyrene, or IgE nonresponders must be excluded. Variance polypropylene decreases with increasing basophile count, therefore 10.000 cells per preparation are necessary; variance is

Hist D2. Solvent a). Solvent b)

a) EOH + AD + buffer. b) brandy + AD + buffer

Hist D2. Medium

AD. Solvent A. Solvent B (solvents not specified)

Publication

Objective from responder probands?

Technique

Findings lower in polypropylene containers than in polystyrene. Activation is stable for 2 days. In this optimized test system Hist D1D10 and D21D25 inhibits CD63 expression of anti-IgE (0.5g/ml) activated basophiles. #2) Histamine dilutions C14C18 inhibited degranulation in laboratory 4, only three potencies (C1, C2, C10) were active in lahboratory 3. In laboratory 1 Histamine dilutions C15C18 were different from controls. #3A) Histamine release was inhibited by all tested potencies. #3B) Ranitidine 104M and cimetidine 105M reduced the histamine induced inhibition for three of four tested potencies. Cimetidine 105M inhibited activation for Histamine C16 in a second experiment. #3C) Histamine C16 inhibited basophil activation. Histidine C16 potency was not active

Substance Tested

Control or Comparison

Solvent of Potentizing

Belon et al., 2004 (#2-#3)

Guggisberg et al., 2005

#2) Multicenter-study in 3 laboratories concerning the reproducability of the action of histamine on IgE-activated basophiles. #3A) Measurement of basophil activation due to histamine dilutions by means of histamine release. #3B) Modulation of histamine effect on basophil activation by H2-receptor antagonists? #3C) Comparison of Histidine to Histamine dilutions Effect of histamine potencies on anti-IgE induced degranulation? Influence of variations of protocol?

#2) Flow cytometry. #3A) Fluorimetrical measurement of histamine in supernatant and in cells. #3B) Flow cytometry. #3C) Flow cytometry

#2) Histamine C14C18, C2C20 and C15-C19 #3A) Histamine C5-C20. #3B) Histamine C14-C17. #3C) Histamine C16, Histidine C16

#2) Anti-IgE #3A) not stated. #3B) Anti-IgE. #3C) water

#2) AD #3A) AD. #3B) AD. #3C) AD

Flow cytometry Histamine C1, C11 inhibited CD63 expression. Against all controls pooled only C1 was significantly inhibiting. Results were influenced by position on microtiter plate, by storage and incubation times of potencies. Neither use of polystyrene tubes, cell culture plates or microtiter plates affected degranulation, nor did dextrane sedimentation. Microscopy Form-ac D3 stimulated phagocytosis, higher potencies ineffective.

Histamine C1C17

ABD C1C17

AD

Neutrophile Granulocytes Fanselow, 1984 Effect of form-ac potencies on phagocytosis rate of human neutrophiles? Chirumbolo et Do potencies influence al., 1993 the stimulated superoxide production or adhesion of human neutrophiles?

Form-ac D3, D6, D30.

NaCl

Not declared

Photometry

Low potencies act up to D6; high potencies only in three cases (Mag-p D30, D60; Phos D30). Experiments with Phos D6D200 show individual variations according to test subjects.

Alpha-ketoglutaric acid, Aconac, Cit-ac, Fuma-ac, Mag-p, Mal-ac, Mang-p, Phos, Sulf in 613 potencies from D2 to D600.

NaCl 0.9%

NaCl 0.9%

Publication Lymphocytes Bildet et al., 1984

Objective

Technique

Findings

Substance Tested

Control or Comparison NaCl 0.9%. 0-Control

Solvent of Potentizing Not declared

Colas et al., 1984

Effects of Phyt on PHA stimulated proliferation of human whole blood lymphocytes? Influence of variations in PHA dose, potency dose and application mode? Effect of Phyt on proliferation of rabbit lymphocytes ? Influence of PHA stimulation? Reaction of whole blood lymphocytes from healthy, allergic or immune suppressed probands to PHA stimulation and incubation with Phos or Apis? Does potentized house dust influence migration of leucocytes from allergic probands?

Microscopy

From 3 protocols only maximum PHA stimulation yields Phyt C7, C15 a significant result: Phyt C7 inhibits proliferation if applied 15 min before or after PHA. Higher effects when applying potency before PHA than vice versa.

Lymphocyte transformation test

Chirila et al., 1992

Lymphocyte transformation test

Phyt C5C15 ineffective on unstimulated Phyt C5, C7, C9, C15 lymphocytes. Proliferation diminished in PHA stimulated cells by the highest potency (C15) by 28%73%. Higher potencies more effective than lower. Lymphocyte proliferation of healthy and allergic Apis, Phos C7, C15, C30 probands inhibited by Apis, Phos; higher potencies (C30) more effective. Immune suppressed lymphocytes react weakly to PHA, here no effects of potencies.

Not declared

NaCl 0.9%? ("9% physiologique ") ATD

Succussed ATD

Gibson and Gibson, 1996

Microscopy

C4C13, C18, C27, C50, C200, C300, C400, C500, C1000 with abnormal migration; no effect of C14, C15, C20, C22, C25, C30, C100.

House dust in 25 potencies from C4 to C1000

EOH 20%

EOH 20%

If a publication listed above presented several experiments (1-5) these were scored individually (Table 3). AD = aqua destillata, ABD = aqua bidestillata, ATD = aqua tridestillata, AAI = aqua ad iniectione; EOH = ethanol. Not declared includes unspecific descriptions like according to national pharmacopea. Substances known as homeopathic remedies are listed with common abbreviations (6). Dn, Cn = decimal, centesimal potency of n potentizing steps, CCn = potentized with 1:200 dilution; diln = stepwise dilution (not succussed); 10-n = single-step dilution; = unpotentized; ?n = dilution ratio of potentizing not stated. a Heel GmbH, D-Baden-Baden; not commercially available.
References 1 Jussal, RL, Dua, RD, Mishra, RK, Meera, S, Agarwal, A. Effect of Ultradilutions on Neurotransmitter/Enzyme. Hahnemann Gleanings 1984;51:245-250. 2 Herberth, G, Pison, U. Homopathische Arzneimittel in zellbiologischen Systemen [Homeopathic Remedies in Cellbiological Systems]. In: Albrecht, H, Frhwald, M, editors. Jahrbuch der Karl und Veronica Carstens-Stiftung, Band 5 (1998). Essen: KVC; 1999. pp. 77-95. 3 Sainte-Laudy, J, Belon, P. Application de modles d`hypersensibilit du type I l'tude de l'activit de dilutions hahnemanniennes des mdiateurs de cette hypersensibilit [Application of hypersensitivity type I models on the study of the activity of Hahnemannian dilutions of mediators of this hypersensitivity]. Homopathie 1986;3:40-44. 4 Belon, P, Cumps, J, Ennis, M et al. Histamine dilutions modulate basophil activation. Inflamm res 2004;53:181-188. 5 Sukul, NC, De, A, Sinhababu, SP, Sukul, A. Potentized Mercuric chloride and Nux vomica Facilitate Water Permeability in Erythrocytes of a Fresh-Water Catfish Clarius batrachus Under Acute Ethanol Intoxication. J Altern Complement Med 2003;9:719-725. 6 Schroyens, F. Synthesis: Repertorium homoeopathicum syntheticum. Greifenberg: Hahnemann Institut fr homopathische Dokumentation; 1993.