systematic review in vitro evidence for an effect of high homeopathic potencies 2007

Complementary Therapies in Medicine (2007) 15, 128—138

The in vitro evidence for an effect of highhomeopathic potencies—–A systematic review ofthe literature

Claudia M. Witta,∗, Michael Bluthb, Henning Albrechtc,Thorolf E.R. Weißhuhna, Stephan Baumgartnerd, Stefan N. Willicha

a Institute for Social Medicine, Epidemiology and Health Economics, Charite University Medical Center,D-10098 Berlin, Germanyb Klinik fur Tumorbiologie, D-Freiburg/Br, Germanyc Karl and Veronica Carstens-Foundation, D-Essen, Germanyd Institute for Complementary Medicine (KIKOM), University of Bern, CH-Bern, Germany

Available online 28 March 2007

KEYWORDSHomeopathy;Potency;Dynamization;Basic research;Quality assessment;Quality score;Modified SAPEH;BEPEV;Cell-free systems;Non-cellular;Cultured cells;Basophiles;

SummaryObjective: 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<10−23; cells or molecules from human or animal. Experiments were assessed withthe modified SAPEH score.Results: From 75 publications, 67 experiments (1/3 of them replications) were eval-uated. Nearly 3/4 of them found a high potency effect, and 2/3 of those 18 thatscored 6 points or more and controlled contamination. Nearly 3/4 of all replicationswere positive. Design and experimental models of the reviewed experiments wereinhomogenous, most were performed on basophiles.Conclusions: Even experiments with a high methodological standard could demon-strate an effect of high potencies. No positive result was stable enough to bereproduced by all investigators. A general adoption of succussed controls, random-

Neutrophiles;Lymphocytes;In vitro

ization and blinding would strengthen the evidence of future experiments.© 2007 Elsevier Ltd. All righ

∗ Corresponding author. Tel.: +49 30 450529011;fax: +49 30 450529902.

E-mail address: [email protected] (C.M. Witt).

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0965-2299/$ — see front matter © 2007 Elsevier Ltd. All rights reservdoi:10.1016/j.ctim.2007.01.011

ts reserved.

ntroduction

omeopathic remedies are prepared (‘potentized’r ‘dynamized’) in steps of alternately dilutingnd succussing a homeopathic stock1 (historicallynown as ‘mother tincture’). After several steps,

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n vitro research on high potencies

he remedies reach calculatory dilutions beyondvogadro’s number, implying a non-molecularction of remedies with specific healing proper-ies. Research in this field arranges around threeore problems2: (1) What are the therapeuticffects of homeopathic remedies? (2) What are thepecific characteristics of potencies? (3) Throughhat mechanism(s) do they influence the organism?elating to (1) and (3), in vitro research searchesor effects of potentized remedies on molecularr cellular systems. Reducing complexity this wayllows a higher degree of standardization than clin-cal research, and may eventually provide modelystems to reveal the mode of action of high dilu-ions devoid of pharmacologically active molecules.

Previous reviews of the field have been eitherescriptions of individual experiments without sys-ematic evaluation3—7, investigations of only thendependence of replications8, or do not presentetails and rationales of their scoring procedure.9

ther restrictions had been set on publicationsanguage3,4,6 or research area,7,8 so that a bothroad and systematic assessment with transparentriteria does not exist. In this evaluation we there-ore systematically assessed the in vitro researchn effects of high potencies of a stock preparationy using a score system. Additionally, we tried todentify experimental models that provide repro-ucible results or promising approaches that shoulde replicated.

ethods

nclusion criteria and data sources

e searched for written publications of in vitronvestigations on high potencies. In vitro wasefined as ‘concerning cellular or subcellular enti-ies in isolation from a living organism’. Thisncluded cells (also from cultures) or molecules,ut not isolated organs. All systems had to bef human or animal origin. Pathological materialsuch as cancer cells or cells from allergic donatorsere accepted. Pretreatment before cell extrac-

ion, such as intoxication or sensitization, wasllowed, but the application of homeopathic prepa-ations had to be in vitro only. Tested remedies hado include high potencies that imply a calculatoryilution of at least 10−23 (e.g. ≥D23, ≥C12). Rem-dy mixtures (‘complex remedies’) were allowed.o other restrictions were imposed; all publication

anguages were included.References from the Basic Research Database

f the Karl and Veronica Carstens-Foundation,-Essen,10,11 were collected until December

ppal

129

005 by searching for ‘homoopathie + basicesearch + experimental + in vitro’ in each of theollowing fields: immunology, toxicology, phar-acology, neurology, biochemistry. Medline® was

earched for publications of the years 1966 untilecember 2005 using MeSH and full text terms

n various spellings. Searched was for ‘home-pathy’ combined with each of the followingerms: ‘in vitro’; ‘cell culture’; ‘tissue culture’;cells, cultured’; ‘granulocyte’; ‘lymphocyte’;macrophage’; ‘neutrophil’; ‘basophil’; ‘enzyme’;biomolecule’; ‘immunocompetent’. Amed® (Alliednd Alternative Medicine) was searched from 1985o December 2005 using the same search as inedline. Previous reviews,3—6,8,9 and all obtainedublications were screened for further references.n addition, we asked experts for information.

ata extraction

rom the identified references, those too short for aensible scoring were excluded, among them werell abstracts. From publications that were mostlyr fully identical or obviously referring to identi-al experiments only the most detailed descriptionas included. One author (MB) extracted data and

cored the experiments except his own paper12 thatas scored by another author (SB) who did notarticipate in this work, the data were discussedith a second author (CMW). For each experiment

he following data were extracted: publication,bjective, technique, findings, substance tested,ontrol or comparison, and solvent of potentizing,ogether with additional information of inter-st. All identified publications were classified byystem: non-cellular systems (enzymes), or cel-ular systems of the categories cultured cells,rythrocytes, basophile granulocytes, neutrophileranulocytes, and lymphocytes/mononuclear cellsincluding experiments with both neutrophiles andymphocytes).

Strategies involved either cellular or cell-freeystems, the former from healthy or from patholog-cal donators. Indirect effects in which the potencyodified the action of a stimulus on the target sys-

em were set apart from direct effects where theomeopathic preparation acted on the target sys-em directly.

Replications were recognized when they investi-ated the same experimental setup (cell, enzyme,timulant, noxa, . . .) with the same homeopathicemedy in high (but not necessarily identical)
otency. They were operationally defined as ‘inde-endent’ if the publication had a different firstuthor and less than half of their authors had pub-ished experiments with this model before.8 Finally,

130 C.M. Witt et al.

Table 1 The modified SAPEH (score for assessment of physical experiments on homeopathy)

Item Points Criteria

ObjectivesP 1 Explicit statement what problem or hypothesis was investigated

ControlsM

Declared 1 Stated use of controlsAdequate +1 Succussed or correspondingly potentized solventInadequate −1 Not checking contamination, e.g. unsuccussed

BlindingM 1 Blinding of experimenter/testerRandomizationM 1 State of the art samples randomizationConsistencyM 1 Similar results in two or more experiments or test series

Experiment standardizationS

Medium 1 Use of a buffer or buffered medium if necessaryIncubation 1 Standardized temperature and incubation time

StatisticsM 1 Statistical analysis declared or describedP preh

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Results 1 ComPPresentation, MMethodology, SStandardization: quality consincubation.

it was noted whether the publications stated orimplied that the findings supported the existenceof effects of high potencies for at least one of thetested potencies, or, in multicenter trials, at leastone laboratory.

Modified SAPEH assessment

To provide a transparent and differentiated insightinto the strengths and weaknesses of the assessedresearch, we applied a modified version of theScore for Assessment of Physical Experiments onHomeopathy (SAPEH, Table 1). SAPEH had beendeveloped to assess the quality of physical researchin homeopathy.13 It is based on three qualityconstructs — methodology, experiment standard-ization, presentation — that divide into 8 items,checking for 10 criteria. Each item scores 1 point foran affirmative answer, except controls and experi-ment standardization with 2 points each.

The methodology items check that the experi-mental design uses techniques to control factorsthat may cause bias (e.g. systematic or randomerrors). Mentioning controls scores 1 point that issubtracted again if their nature allows for chemicaldifferences to the potencies. Identical compositionis assumed if controls have undergone a simi-lar contaminant-affecting preparation (succussionor potentizing)13 as the test potencies. It wouldearn 2 controls points, accepted are all mean-ingful descriptions such as ‘‘produced like theverum’’ or ‘‘succussed (shaken, vortexed, soni-
cated, . . .) medium’’. Further methodology itemscover blinding (preventing handling differences andbias effects), randomization (to prevent system-atical errors), consistency (internal replications,
cpsw

ensible presentation of results

s built into the score. Modifications check for buffer and

nsuring test system stability), and the use of statis-ics.

Experiment standardization was adapted to then vitro field, instead of the somewhat unspecificriginal criteria ‘external factors’ and ‘experimen-al setup’ that can affect results, the item nowhecks for the use of a buffer or buffered medium,nd for standardized temperature and incubationime.

The remaining communication about the exper-ment is covered by presentation of objectives andesults, which have to be reasonably detailed andnderstandable.

The modified SAPEH should be read at item levelo assess an experiment. The total SAPEH score andts subscores support only rough global impressionsnd should always be accompanied by score details.or the purposes of the present study, 6 or 7 pointsith controls of equal contamination would indi-ate a reasonable control for bias, and >7 pointsincluding 2 for controls) would strengthen this.

esults

iterature

e identified and obtained 75 publications12,14—87

hat fulfilled inclusion criteria, among them oneufficiently detailed correspondence.45 Seventeenedundant publications were identified (Fig. 1):hree doctoral theses12,33,35 were included that
over and extend the content of eight omittedapers: 71—75, 76; 77, and 78, respectively. Twoummaries79,87 of otherwise included experimentsere ignored. From another summary62 those parts

In vitro research on high potencies

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Figure 1 Publications and experiments.

ere excluded that were less detailed than earlierapers.56,57 Where the analyzed data set of an ear-ier publication58 seemed to be not identical to theummary data88 we scored both. Of publications

t

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Table 3 Modified SAPEH scores and classifications of revie

131

ith seemingly identical content, the first listed inach of the following groups was included: 31/80;1/81; 66/83; 67/82; 68/84/85; 36/86.

Two papers48,50 overlapped in content, the moreetailed later one was included, whereas fromhe earlier publication we included only one addi-ional experiment. Of two articles about the sameesearch, two experiments were reviewed fromhe earlier publication14 and one additional exper-ment from the other.15 From one paper37 onelready published experiment was ignored in favorf the earlier publication.34 Multiple experimentsn a single publication12,19,37,42,62,70 were scoredndividually, resulting in 67 experiments from 58ublications. Table 2 (published in online version atttp://www.sciencedirect.com/as supplementary

ual information to provide a broader overview.The included publications had appeared mostly

n journal articles (n = 46), 25 of them were of

wed experiments

http://www.sciencedirect.com/as

132 C.M. Witt et al.

Table 3 (Continued)

a Publications languages: E = English, F = French, G = German.b Research strategy: d/cf = direct effect on cell-free system; d/c/h = direct effect on cells from healthy probands; d/c/p = directeffects on cells from pathological donators; i/c/h = indirect effects on cells from healthy probands; i/c/p = indirect effects oncells from pathological donators.c For criteria, quality constructs (P = Presentation, M = Methodology, S = Standardization) and score points see text and Table 1.

r not

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d 0* = (+1−1), see text.e Findings support the existence of a high potency effect (+) o** Only for histamine part.

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

Experiments

The investigated systems were mostly basophilegranulocytes (42%), non-cellular systems (27%), andcultured cells (19%). Seldom lymphocytes (6%), ery-throcytes (3%), or neutrophiles (3%) were chosen.

cStd

(−) (stated or implied).

easuring indirect effects on healthy proband cellsas the most favoured approach (37%), followed byirect effects on cell-free systems (27%), indirectffects on cells from pathological sources (19%),irect effects on cells from healthy (10%) andathological (8%) donators. Table 3 lists the clas-ifications of the assessed experiments.

Presentation was sufficiently good for most (79%)xperiments (Table 3); 16% lacked a clear descrip-ion of either objectives or results and 4% ofoth. Randomization was only reported for 18% andlinding for 33% of the experiments. For most inves-igations at least one successful replication wastated (83%), 31% checked contamination with suc-
ussed controls, in 4% no use of controls was stated.tatistical evaluation was common (76%). In 73% ofhe experiments buffer and incubation were stan-ardized, in 22% only one of these was mentioned,

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nd in 4% none. The overall modified SAPEH meanas 6.1 (S.D. ± 1.9, median 6.0). Most experimentsere done with basophiles models, here also theost positive results were found.From the 67 assessed experiments, 73% stated

n effect of high potencies. So did 68% of the 18xperiments with succussed controls and a mod-fied SAPEH score of at least 6 points. Eight ofhese 19 experiments have not been replicated.f all scored experiments, 33% were replications.ositive results were reported for 73% of the repli-ations, and for 18% of those with 6 or more pointsnd succussed controls. Replications were mostften performed with flow cytometry on basophiles,ere mostly by independent teams and with posi-ive results except one.63 All attempts to replicateffects on hydrolase activity were independent anduccessful but one.12 The action of anti-IgE poten-ies on basophiles was only reproduced by the sameeam.

iscussion

e systematically assessed in vitro experimentsn high potencies with the modified SAPEH score.he designs of the 67 evaluated experiments wereery inhomogenous. We observed an uneven distri-ution of the investigated systems, ranging fromwo unrelated experiments each with neutrophileranulocytes or erythrocytes to 28 with basophiles15 of them being replications). One third of thexperiments were replications of earlier research.early 3/4 of the identified experiments found aigh potency effect. Even if only those experimentshat tried best to exclude bias were consideredSAPEH score of 6 points or more and succussedontrols), a positive effect was still demonstratedn more than 2/3 of the experiments. Although iteems unlikely, we could not be totally sure thathe results of these experiments are unbiased.

Publications on homeopathic research are widelycattered, often not entered into databases, andhus difficult to find. The database of the Karlnd Veronica Carstens-Foundation was very helpful.n addition citation tracking and expert contactsnlarged the number of found publications. Pre-entations at conferences of either basic or clinicalesearch are not too often followed up by journalrticles (e.g. only half of the conventional ran-omized clinical trials89)—–the reason why we didot restrict our search to full articles. Publication
ias that is very likely in the field of homeopathy90
ould cause a tendency to positive results. Forxample, unsuccessful pilot studies in search for aiable test system may not have been published.

apgr

133

ut the existence of more negative studies wouldot rebut those high-scoring works that demon-trated an effect of potentizing beyond Avogadro’sumber. Compared to a previous evaluation of phys-cal research on high potencies13 we found in theresent review more in vitro investigations for theame time frame (until 2001, 53 experiments initro versus 37 in physics). We observed also areater percentage of experiments scoring at leastpoints with succussed controls (26% versus 14%),ore replications (25% versus 8%), and more publi-

ations in renowned periodicals.Applying a score to assess publications sys-

ematically is not common in basic research onomeopathy. Although scores have limitations weecided for it because of the benefits of systematiz-ng the synopsis and making the assessment criteriaransparent. Most relevant works are well knownhich made blinded scoring or split assessments ofethods and results impossible. We tried to achieve

igh internal consistency by having all scoring doney one investigator. This review is limited to theresentation of experiments in the literature, asommon for reviews, presuming correctness andccuracy of the reports, but it can never be suffi-iently detailed to set up reproductions. BecauseAPEH was designed for quick and easy use, weccepted a limitation that lies in not accountingor the number of repetitions, which would haveo be observed on several levels. The number ofndependently produced potencies, test runs perotency, samples per test run, variations in date orocation, etc. would require a much more detailedcore system.

From the mostly self-explaining SAPEH scorehe items blinding, standardization, and controlsequire some discussion. In order to identify resultshat were the most robust to bias and system-tic errors91 we included blinding as a criterion.lthough probably rare, unconscious bias may creep

n through processes that involve human inter-retation or judgment, or minute differences inandling. The additional standardization through auffered medium reduces the variability of resultshat otherwise might mask a difference betweenample types.

To prove that high potencies have a specificffect they should only differ from controls ineing a potentized stock preparation. Several typesf controls or comparisons are available: stockreparation (original material of remedy prepa-ation), unsuccussed solvent, succussed solvent,
nd another remedy (potency of different stockreparation). A stock preparation would entailross chemical differences. Untreated solvent hasecently been found to be different from a potency

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in the concentration of contaminants that areintroduced during the potentizing through inter-actions of solvent and container material.92 Inmulti-container potencies (Hahnemann technique),trace element concentrations had reached withthe first potency a level that remained constantin higher potencies.39,92 This applied to potentiza-tion with standard parameters93 that are commonlyadopted in basic research. Differences betweenuntreated and potentized36,37 or simply sonicated94

solvent have been observed in biological activityas well as physical measurements95, they mightbe causally linked to contamination.92,95. Traceelements are the rationale for our emphasis on suc-cussed — better: fully potentized — controls. Othercontaminants make the fully identical preparationmore desirable, like acetate, formate or lactatefrom the human skin, or methanol and acetoneused for cleaning, all easily being introduced withordinary handling.96 A second remedy as controlmight in the lower (material) dilutions have its owninteraction with container materials97, making asolution of which the exact composition is unknownbut which is likely to be different from the one ofthe first potency. Both thus would differ not onlyin their known initial stock preparation. Moreover,the effect of both potencies on the measurementsmight be identical which would invalidate a clearly‘negative’ result to mean merely ‘possibly nega-tive, or possibly positive but differences cancelledout’. For the purposes of the present review weasked for the type of control that allowed the clear-est conclusions.

Conclusions

The reviewed in vitro experiments with high home-opathic potencies were inhomogenous in designand quality. A surprisingly high number of differ-ent experimental approaches have been adopted.Two thirds of the experiments with higher scoresand contaminant-checking controls demonstratedspecific high potency effects. Some of them havealso been successfully replicated, but no positiveresult could be reproduced in all attempts. Amongthose that have been replicated by independentinvestigators the action of mercuric bichloride onhydrolases and especially the action of histamineof the Anti-IgE triggered basophile granulocytedegranulation seemed to be the best reproducible.A publication bias in a highly controversial field
like homeopathy is not unlikely. More replicationsshould be done independently to establish modelsthat are stable across laboratories and teams. Ageneral adoption of succussed controls, randomiza-
C.M. Witt et al.

ion and blinding would strengthen the evidence ofurther experiments.

cknowledgments

his work was supported by the Karl und Veronicaarstens-Foundation, D-Essen. We are very gratefulo Mrs Hacke from the Karl und Veronica Carstens-oundation who assisted in the literature search.rs Menzel from the Charite University Medicalenter Library performed the Medline® and Amed®

earches.

ppendix A. Supplementary data

upplementary data associated with this arti-le can be found, in the online version, atoi:10.1016/j.ctim.2007.01.011.

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58. Brown V, Ennis M. Flow-cytometric analysis of basophilactivation: inhibition by histamine at conventional andhomeopathic concentrations. Inflamm Res 2001;50:47—8.

59. Sainte-Laudy J. Stimulatory effect of high dilutions ofhistamine on activation of human basophils induced by anti-IgE. Inflamm Res 2001;50:63—4.

60. Lorenz I, Schneider EM, Stolz P, Brack A, Strube J. Influenceof the diluent on the effect of highly diluted histamine onbasophil activation. Homeopathy 2003;92:11—8.

61. Lorenz I, Schneider EM, Stolz P, Brack A, Strube J. Sen-sitive flow cytometric method to test basophil acitvationinfluenced by homeopathic histamine dilutions. ForschKomplementarmed Klass Naturheilkd 2003;10:316—24.

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63. Guggisberg AG, Baumgartner S, Tschopp CM, Heusser P.Replication study concerning the effects of homeopathicdilutions of histamine on human basophil degranulation invitro. CTIM 2005;13:19—00.

64. Fanselow G. Der Einfluß von Pflanzenextrakten (EchinaceaPurpurea, Aristolochia Clematitis) und homoopathischerMedikamente (Acidum Formicicum, Sulfur) auf die Phagozy-toseleistung humaner Granulozyten in vitro [Influence ofplant extracts (Echinacea Purpurea, Aristolochia Clemati-tis) and homeopathic remedies (Acidum Formicicum,Sulfur) on phagocytotic activity of human granulocytes invitro]. Thesis. Munchen: Medizinische Fakultat; Ludwig-Maximilians-Universitat; 1984.

65. Chirumbolo S, Signorini A, Bianchi I, Lippi G, BellaviteP. Effects of homeopathic preparations of organic acidsand minerals on the oxidative metabolism of human neu-trophils. Br Hom J 1993;82:237—44.

66. Bildet J, Dupont H, Aubin M, et al. Action in vitro dedilutions infinitesimales de Phytolacca americana sur latransformation lymphoblastique a la phytohemagglutinine[In vitro action of infinitesimal dilutions of Phytolaccaamericana on the transformation of lymphoblasts by phyto-hemagglutinine]. Hom Franc 1984;72:225—30.

67. Colas H, Aubin M, Picard P, Lebecq JC, Bastide JM. Inhi-bition du test de transformation lymphoblastique (TTL) ala phytohemagglutinine (PHA) par Phytolacca americanaen dilutions homeopathiques [Inhibition of lymphoblasttransformation test (LTT) by phythemagglutinine (PHA)through Phytolacca americana in homeopathic dilutions].Hom Franc 1984;72:219—24.

68. Chirila M, Hristescu S, Manda G, Neagu M, Olinescu A. Theaction of succussed substance on the human lymfocytes andgranulocytis PMN in vitro stimulated with phytohaemagglu-tinin or zymosan opsonized. In: Proc Congr OMHI. 1990. p.172—7.

I
69. Gibson SLM, Gibson RG. The effects of homoeopathicpotencies of house-dust mite on the migration of house-dust-sensitive human leucocytes. Complem Ther Med1996;4:169—71.

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71. Delbancut A, Dorfman P, Cambar J. Influence de la duree dupretraitement avec de tres basses concentrations de cad-mium sur la cytotoxicite induite par le metal sur cellulestubulaires de rein en culture [Influence of the duration ofpretreatment with very low concentrations of cadmium oncytotoxicity induced by the metal and on cultured kidneytubular cells]. In: Delbancut A, Dorfman P, Cambar J, edi-tors. 5th GIRI meeting, 29—30 November, Paris; 1991. p.37.

72. Delbancut A, Dorfman P, Cambar J. Protective effect ofvery low concentrations of heavy metals (cadmium and cis-platin) against cytotoxic doses of these metals on renaltubular cell cultures. In: G.I.R.I., editor. 6th GIRI Meet-ing, 26—27 October 1992. Munchen, Germany: GIRI; 1993.p. 19.

73. Delbancut A, Merlet D, Mellado M, Dorfman P, Cambar J.Etude de l’effect protecteur de tres hautes dilutions de cad-mium vis-a-vis de concentrations cytotoxiques de ce mememetal sur des cultures cellulaires renales [Study of pro-tective effects of very high dilutions of cadmium againstthe cytotoxic concentration of the same metal on renaltubular cell cultures]. Cahiers de Biotherapie 1993;120:39—44.

74. Delbancut A, Merlet D, Mellado M, Dorfman P, Cambar J.Nachweis der Schutzwirkung sehr hoher Verdunnungen vonMetallen auf mit Cadmium vergiftete Nierenzellkulturen[Proof of protective effect of very high dilutions of met-als on cadmium intoxicated renal tubular cell cultures]. DtJ Hom 1995;14:163—75.

75. Delbancut A, Barouillet MP, Cambar J. Evidence and mech-anistic approach of the protective effects of heavy metalhigh dilutions in rodent and in renal cell cultures. In: Sig-nals and images. selected papers from the 7th and 8th GIRIMeeting. Dordrecht: Kluwer; 1997. p. 71—82.

76. Then C, Dittmann J, Schutte A, Bauer J, Harisch G.In-vitro-Untersuchung zur Wirkung homoopathischer Poten-zen von Thuja occidentalis an Zellkulturen mit Hilfe desMTT-Testes [In-vitro investigation on the effect of home-opathic potencies of Thuja occidentalis on cell culturesusing the MTT test]. Forsch Komplementarmed 1996;3:280—7.

77. Then C, Dittmann J, Schutte A, Bauer J, Harisch G. In-vitro-Untersuchung zur Wirkung von Arsenicum-album-Potenzenan Zellkulturen mit Hilfe des MTT-Testes [In-vitro investi-gation on the effect of potencies of Arsenicum album oncell cultures using the MTT test]. Forsch Komplementarmed1996;3:222—8.

78. Witt C, Bluth M, Ludtke R, et al. Does potentized HgCl2(‘mercurius corrosivus’) affect the activity of diastase and�-amylase? J Alt Compl Med 2006;12:359—65.

79. Dittmann J, Harisch G. Wirkungsunterschiede zwischenPotenzenaccorden und ihren Einzelpotenzen: In-vitro-Studien mit cAMP- und Ubichinon-Praparaten [Differences
of efficacity between potency chords and their elementpotencies: in-vitro studies on preparations of cAMP andubiqinone]. Biol Med 2000;29:18—23.
80. Cotte J, Bernard A. The effects of mercurius corrosivushahnemanian potencies upon the multiplication of cultured

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81. Poitevin B, Aubin M, Benveniste J. Approche d’une analysequantitative de l’effet d’Apis mellifica sur la degranulationdes basophiles humains in vitro. Innov Tech Biol Med1986;7:64—8.

82. Colas H, Aubin M, Picard P, Lebecq JC, Bastide JM. Inhi-bition du test de transformation lymphoblastique (TTL) ala phytohemagglutinine (PHA) par Phytolacca americana endilutions homeopathiques [Inhibition of lymphoblast trans-formation test (LTT) by phythemagglutinine (PHA) throughPhytolacca americana in homeopathic dilutions]. Ann HomFranc 1975:629—38.

83. Bildet J, Dupont H, Aubin M, et al. Action in vitro dedilutions infinitesimales de Phytolacca americana sur latransformation lymphoblastique a la phytohemagglutinine[In vitro action of infinitesimal dilutions of Phytolaccaamericana on the transformation of lymphoblasts by phyto-hemagglutinine]. Ann Hom Franc 1981;23:102—11.

84. Chirila M, Hristescu S, Manda G, Neagu M, Olinescu A.The action of succussed substances on the human lym-phocytes and PMN granulocytes in vitro stimulated withphytohaemagglutinin (PHA) or zymosan opsonized (ZO). In:G.I.R.I., editor. 4th Meeting November 30—December 1,1990, Maison de la Recherche, Paris. Paris: GIRI; 1990. p.11.

85. Chirila M, Hristescu S, Manda G, Neagu M, Olinescu A.The in vitro action of a succussed substance on the pro-liferative response of human lymphocytes stimulated withphytohemagglutinin. Rev Roum Med Int 1992;30:63—7.

86. Carmine TC. Bestimmung der H2O2-Produktion von Neu-roblastomzellen nach Stimulierung mit Hochpotenzen desZytokins TNF alpha durch Chemolumineszenz: Ein moglichesSystem zum Wirksamkeitsnachweis homoopathischer Hoch-potenzen [Chemoluminescence determination of H2O2produktion of neuroblastom cells after stimulation withhigh potencies of the cytokine TNF alpha: a possible systemfor the proof of efficacy of homeopathic high potencies].AHZ 1996;241:143—54.

87. Sainte-Laudy J. Modulation of allergen and anti-igE inducedhuman basophil activation by serial histamine dilutions.Inflamm Res 2000;49:S5—6.

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Online supplementary material for: Witt, C, Bluth, M, Albrecht, H, Weißhuhn, 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. 128–138.

Table 2: Reviewed Experiments

Publication Objective Technique Findings Substance Tested Control or Comparison

Solvent of Potentizing

Non-Cellular Systems Persson and Ginsberg, 1932

Influence of potencies on the activity of malt diastase?

Photometry Merc-c and Sulf alternately inhibit and stimulate diastase until D60, Calc-m until D20. Inhibition of activity by Iris D6…D25, Aur-m D6; stimulation by Jab D6, Iod D6…D9.

Merc-c, Sulf D6…D60. Aur-m, Calc-m, Jab, Plat-m D6…D30. Iris, Nit-ac D6…D30. Bell, Benz-ac, Canth, Iod, Lyc, Ter, potency not stated

Water Not declared

Persson, 1933 Influence of potencies on the activity of trypsinogen?

Photometry 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.

Ars, Ins D3…D30. Ph-ac D6…D45. Iris D6…D100

Water Not declared

Persson, 1938 Influence of potencies on the activity of glycogen reducing enzymes from a) frog muscle and b) bovine heart?

Photometry 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.

Ars, Coff, Glon, Lac-ac, Merc-c Phos, Stroph, Stry-n D3…D30. Adren D3…D40. Adon, Ins, Nat-sal, Thyroxin (potency not stated)

Water Not declared

Boyd and Brit 1954

Effect of high potencies of Merc-c on malt diastase activity? Affects storage duration potency activity?

Photometry Merc-c CC26…CC30 stimulates activity of diastase. Effect decreases with storage time, not found after 3 months.

Merc-c CC26-30 ABD ABD

Kraus et al., 1981

Do potencies of phosphor modulate a reaction involving phosphate group transfer by pyruvate kinase or luciferase?

Bioluminescence

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

Phos C3…C15 ABD Not declared

Jussal et al., 1984

a) Effects of Bell on acetyle cholinesterase from goat brain? b) Effects of Ars on human serum cholinesterase??

a) Photometry, b) Comparison with standard curve

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

Modification of a 50% inhibition of enzymes

Electrophoresis; protein

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



(glucose-6 phospatase; NADPH-cytochrome-C reductase; galactosyl transferase; lactate dehydrogenase; 5'nukleotidase) by potencies of the inhibiting substance?

assays; Radioactivity determination

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

Shabir et al., 1996

a) Effect of D and C potencies of Merc-c on α-amylase from human saliva? b) Influence of pH? c) Effect of several remedies at different pH?

Photometry a) Amylase inhibited by Merc-c D1, D2, C1; higher potencies (D9…D15; C6…C12) 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.

a) Merc-c D1…D15. 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

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?

Photometry, comparison with standard curve

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®.

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

Water, chords of stepwise dilutions 1:10: 'Chord D' = ubiquinone dil12 + dil30 + dil200. ‘Chord Df' = ubiquinone dil8 + dil12 + dil30 + dil200

Not declared

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, cAMP-dependent proteine kinase (PKA)?

Photometry; HPLC-analysis; 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.

cAMP D4, D6, D8, D12, D30, D200. cAMP D6 + D12 + D30 + D200. cAMP D12 + D30 + D200

Stepwise dilutions 1:10: cAMP dil4, dil6, dil8, dil12, dil30, dil200. cAMP dil6 + dil12 + dil30 + dil200. cAMP dil12 + dil30 + dil200. Water

Not declared



Harisch and Dittmann, 1999 (cAMP)

Differences in the effect on acid phosphatase between cAMP potency chords, their constituents, and controls?

Photometry; comparison with standard curve

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.

cAMP D6, D12, D30, D200, also in combinations. cAMP-Injeela (= cAMP D12 + D30 + D200). cAMP-Injeel fortea (= cAMP D6+ D12 + D30 + D200)

Water Not declared

Harisch and Dittmann, 1999 (Ubiquinone)

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?

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.

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

Water Water

Dittmann et al., 2000

Effect of potencies on uricase, acid phosphatase (AP), and glutathione-S-transferase (GST)?

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

Effects of Merc-c, Merc-i C30 on α-amylase activity? Influence of storage duration (Merc-c only)?

Photometry Merc-c, Merc-i stimulate α-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 ultrasonicated, 4, 30, 365 days old

AD, EOH 90%

Batello, 2002 Effect of potencies on lipoperoxidation from homogenized rat brains compared to melatonin?

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.

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

Melatonin 1M, 0.5M, 0.25M, 0.125M

Not declared

Bluth, 2005 Effect of HgCl2 potencies on activity of malt diastase and α-amylase?

Photometry No difference between Merc-c potencies and succussed controls. Merc-c C2 inhibited α-amylase like the corresponding dilution, all higher potencies inactive.

Merc-c C2…C30 ABD; ABD C2…C30; HgCl2 dilutions 1:100: dil2… dil5

ABD



Cultured Cells Van Mansvelt and Amons, 1975

Does the growth inhibition of Merc-c on lymphoblast cells decrease to zero with increasing potency?

Coulter Cell Counter

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

Merc-c D5…D25 ABD ABD

Aubin et al., 1980

Can the regeneration of in vivo CCl4 induced rat liver cell necrosis be modified in vitro by Phos (as globules, dilutions)?

Microscopy Globules deteriorate, dilutions improve cellular regeneration compared to controls.

Phos C7, C15 a) NaCl 0.9%. b) Placebo globules

Not declared

Boiron et al., 1981

Do potencies of Merc-c have a protective effect on fibroblasts exposed to HgCl2?

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

Merc-c C5, C15 'ABD', potency not stated

Not declared

Kandefer-Szerszen et al., 1993

Effect of interferon-α on tumor cell (A549) growth? Differences between D and C potencies? Exactly reproducible? Effect of heating initial interferon stock preparation? Effect of interferon-α potencies on tumor cell (A549) antiviral activity against vesicular stomatitis virus?

Microscopy; photometry

Pseudosinusoidal stimulation-inhibition curve of cell growth, regular peaks/lows every 6…9 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.

Interferon-α D1…D40, C1…C40 Interferon-α dilution in medium. 'Medium' D80

Medium

Delbancut, 1994

a) Prophylaxis for pig kidney cells (LLCPK1) against intoxication by pretreatment with the potentized noxa (Cadm-met, Cisplat)? b) Does Preincubation with Cadm-met potencies for 120 h influence growth? c) Optimal preincubation time for maximum

Photometry; spectrometry; microscopy

a), c) Protective effect of Cadm-met C10 after 120 h but not after 48h preincubation. Strong protective effect 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 doses (up to 3x10-5M) 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

Cadm-met, Cisplat C5, C10, C15, C20

'Medium' C5, C10, C15, C20

Medium



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)?

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.

Pison et al., 1995

Proliferation of fibroblasts affected by high potencies? Potentized EOH different from unpotentized?

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

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

EOH 43%, ‘EOH 43%’ C30, lactose, cell culture medium, buffer

EOH 43%, lactose (trituration)

Then, 1995 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?

Photometry; microscopy

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 D3…D10, D12, D15, D18, D24, D30, D200. Thuj D2…D6, D8, D12, D30

ABD. EOH 70%. Lactose 10-4, 10-8, 10-12, 10-15, 10-18

ABD. EOH 70%. Lactose, medium

Carmine, 1997 Effect of high potencies of TNF-α on H2O2-production of neuroblastoma cells?

Chemoluminescence

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

TNF-α D1…D100 AAI. ‘AAI’ D30, D70, D100

AAI



Biological effects of potentized Water compared to unpotentized? Influence on cell-free reaction?

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

Herberth and Pison, 1998

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?

1) Enhanced chemoluminescence; 2) luminol-chemoluminescence; 3) γ- radiation of 14C-choline; protein and phospholipid concentration

1) TNF-α 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-α D10…D100; Zymosan. 2) Zymosan D10…D100; Bell Ø, D8, C12…C1000; Ferr-p, Thuj, potency not stated. 3) Bell, Colch, Lec, potency not stated

1) TNF-α 10-

10, 10-100; buffer. 2) Zymosan 0.5mg/ml, 10-

10, 10-100, 10-

1000; AD; EOH 43%; buffer; saccharose. 3) Not declared

EOH 43%

Jonas et al., 2001

Neuroprotective effects of potentized glutamate for various neuron samples (of cerebral, cerebellar, spinal origin) against toxic doses of glutamate? Is the effect due to a decreased Ca2+ influx?

Photometry; fluorometry

Weak cell-type specific neuroprotective effect (mortality 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 Ca2+ influx in spinal neurons not affected by glutamate C9, C11.

Glutamate C9…C15 'Water + EOH 95% + Glycerol' C9…C15

Water + EOH 95% + Glycerol

Marotta et al., 2002

Protection of neuronal cells pretreated with potencies of the neurotoxins cycloheximide, NMDA or MPP-iodide against excitotoxic glutamate concentrations?

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 C2…C5, C13, C31; NMDA C3…C6, C14, C32; MPP iodide C3…C6, C14, C32

Water succussed 120 times

Deionized sterile filtered water

Erythrocytes Sukul et al., 2003

Influence of potencies on erythrocyte aquaporins from Clarus batrachus, with and without prior ethanol intoxication?

Erythrocyte weight loss from drying after hypotonic incubation

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

Nux-v, Merc-c C30 (sonicated) EOH C30; water; null-control

EOH 90%



Basophile Granulocytes Murrieta et al., 1985

Antigen (mite) triggered degranulation of basophiles from allergic probands inhibited by Apis potencies?

Microscopy No inhibition of degranulation found. Apis C5, C9, C15, C30 NaCl 0.9% with dissolved lactose globules

NaCl 0.9% with dissolved lactose globules

Poitevin et al., 1985

Antigen (mite) triggered degranulation of basophiles from allergic probands modified by Apis potencies?

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

Apis C5, C9, C15 NaCl 0.9% NaCl 0.9%

Sainte-Laudy and Belon, 1986

1) Effects of Histamine, platelet activating factor (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?

Microscopy 1) Effect peaks of Hist at C6, C7 and C16…C18; ineffective potencies in between (C10…C15). 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 lyso-PAF C9…C11. Repeated deep-freezing decreases effects. 4) Different potencies show different degranulation-antigen curves.

Hist C5…C20. PAF, lyso-PAF C6…C15

Buffer. ‘AD’ C18

Not declared

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 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 C1…C24 AD Not declared



Davenas et al., 1988

a) Do high potencies of anti-IgE or anti-IgG induce degranulation of human basophiles? b) Influences of solvent, heating, deep freezing or sonication?

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

Anti-IgE D1…D60, C1…C60. Anti-IgG C1…C60

Buffer. Anti-IgE dilutions 10-1…10-60

Buffer. dimethylsulfoxide

Metzger and Dreskin, 1988

Do potencies of anti-IgE or dinitrophenyl induce degranulation of leucaemic rat basophiles?

Autoradiography

No effects of high potencies of allergen or antibodies. Anti-IgE, dinitrophenyl-albumine D5…D35

Buffer Not declared

Poitevin et al., 1988

a) Do potentized lung histamine or Apis inhibit anti-IgE induced (10-9M) 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?

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 C1…C20. Anti-IgE D16…D22

NaCl (concentration not stated) + 65% EOH for C1, C1…C20

NaCl (concentration not stated) + 65% EOH for C1

Ruff et al., 1988 Inhibition of antigen induced degranulation of basophiles from allergic probands whole blood by potencies of pollen, Histamine, Ars?

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

Sainte-Laudy, 1989 (Methylhistamine part)

Effect on antigen induced degranulation of basophiles from allergic probands whole blood by potencies of 4-methyl-histamine?

Microscopy Inhibition by 4-methyl-histamine at C6, C16. 4-Methyl-histamine C4...C19, prepared in polystyrene tubes or glass flask

Allergene free

Water

Benveniste et al., 1991

Do high potencies of Apis inhibit anti-IgE and anti-IgG induced

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 D21…D30. b) Apis C30…C40

a) 'ABD' D21…D30. b) 'NaCl'

a) buffer. b) NaCl (concentratio



degranulation of human basophiles?

solvent does not. (concentration not stated) D40

n not stated)

Sainte-Laudy et al., 1991

Do potencies of Histamine, Histidine modify degranulation of basophiles from probands being allergic to dust mite? Effects of adding cimetidine or histaminase to the potencies?

Microscopy Maximum inhibition of degranulation for Hist found at C6, C16, C26, C39, C51; no effects for Histid. Cimetidine suppresses the Hist effects (C4…C19). Histaminase prevents effects of Hist C6,C7, but not of Hist C16, C17.

Hist C4…C57. Histid C4…C19 Allergene free control

Water


Do potencies of Histamine inhibit anti-IgE induced degranulation of human basophiles? Influence of variations in protocol (concentrations of anti-IgE, number of controls, reproductions)?

Microscopy Higher potencies (Hist C15…C18) are effective with low (0.2 µl/ml) but not for higher (1, 5.0 µl/ml) concentrations of anti-IgE.

Hist C6, C7, C15…C18 'ABD' C15…C18

ABD

Ovelgönne et al., 1992

Do high potencies of anti-IgE induce degranulation of human basophiles?

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

Anti-IgE D21…D30 Anti-IgE 10-

2…10-30 buffer

Hirst et al., 1993

Do potencies of anti-IgE induce degranulation of human basophiles?

Microscopy 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.

Anti-IgE C2…C30 'Buffer' C2…C30. Anti-IgE 10-

2…10-30

buffer


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

Microscopy Inhibition of anti-IgE induced degranulation by Hist C10…C38, most frequently by C9, C10, C16.

Hist C6…C18 Water. Anti-IgE free control

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 C1…C20 0-Controls. Anti-IgE free

AD



1996 expression of markers related to degranulation in anti-IgE activated human basophiles?

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


Do potencies of Histamine inhibit expression of CD63 in anti-IgE activated human basophiles? Also in presence of cimetidine?

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

Hist C10…C20 Cimetidine. Anti-IgE free controls

AD

Belon et al., 1999

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

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 C15…C19 'AD' C15…C19

AD

Brown and Ennis, 2001

Do potencies of Histamine inhibit anti-IgE induced CD63 expression in basophiles? Effect of heating or repeated deep freezing?

Flow cytometry Hist C1, C2, C3, C7, C9, C10, C13 inhibit expression of CD63; maximum with C10 (-43.8%). Activity decreased by heating, unaffected by freezing the potencies.

Hist 10-2M…10-40M (title says “homeopathic concentration”, paper uses “dilution” terminology and units)

Isotype matched nonspecific antibodies

Not declared

Sainte-Laudy, 2001

Do potencies of Histidine or Histamine increase anti-IgE induced expression of human basophil CD63? Effect of cimetidine?

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

Lorenz et al., 2003 (Solvents)

Effects of potentized Histamine on CD63 expression in anti-IgE activated basophiles from human responders? Effects of different potentizing solvents?

Flow cytometry Solvent a) potencies of Hist inhibit CD63 activation in 4.8% and stimulate in 22.6% of the experiments, 72.6% do not differ from controls. Solvent b) potencies inhibit in 57.1% of experiments, 42.9% do not differ from controls. Solvents differ clearly in their inhibition at D10…D30, varying with probands.

Hist D2…D30 made in a) EOH + ABD + buffer, or b) brandy + ABD + buffer

Hist D2. Solvent a). Solvent b)

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

Lorenz et al., 2003 (Protocols)

Influence of various protocols on Histamine potency induced CD63-expression of anti-IgE activated basophiles

Flow cytometry Basophile count varies (0.6-3.6%), optimal activation at 0.6µg/ml anti-IgE (final concentration); still ≥20% anti-IgE nonresponders must be excluded. Variance decreases with increasing basophile count, therefore 10.000 cells per preparation are necessary; variance is

Hist D2…D34 prepared in glass, polystyrene, or polypropylene

Hist D2. Medium

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



from responder probands?

lower in polypropylene containers than in polystyrene. Activation is stable for 2 days. In this optimized test system Hist D1…D10 and D21…D25 inhibits CD63 expression of anti-IgE (0.5µg/ml) activated basophiles.

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

#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

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

#2) Histamine dilutions C14–C18 inhibited degranulation in laboratory 4, only three potencies (C1, C2, C10) were active in lahboratory 3. In laboratory 1 Histamine dilutions C15–C18 were different from controls. #3A) Histamine release was inhibited by all tested potencies. #3B) Ranitidine 10–4M and cimetidine 10–5M reduced the histamine induced inhibition for three of four tested potencies. Cimetidine 10–5M inhibited activation for Histamine C16 in a second experiment. #3C) Histamine C16 inhibited basophil activation. Histidine C16 potency was not active

#2) Histamine C14–C18, C2-C20 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

Guggisberg et al., 2005

Effect of histamine potencies on anti-IgE induced degranulation? Influence of variations of protocol?

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.

Histamine C1…C17 ABD C1…C17

AD

Neutrophile Granulocytes Fanselow, 1984 Effect of form-ac

potencies on phagocytosis rate of human neutrophiles?

Microscopy Form-ac D3 stimulated phagocytosis, higher potencies ineffective.

Form-ac D3, D6, D30. NaCl Not declared

Chirumbolo et al., 1993

Do potencies influence the stimulated superoxide production or adhesion of human neutrophiles?

Photometry Low potencies act up to D6; high potencies only in three cases (Mag-p D30, D60; Phos D30). Experiments with Phos D6…D200 show individual variations according to test subjects.

Alpha-ketoglutaric acid, Acon-ac, Cit-ac, Fuma-ac, Mag-p, Mal-ac, Mang-p, Phos, Sulf in 6…13 potencies from D2 to D600.

NaCl 0.9% NaCl 0.9%



Lymphocytes Bildet 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?

Microscopy From 3 protocols only maximum PHA stimulation yields 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.

Phyt C7, C15 NaCl 0.9%. 0-Control

Not declared

Colas et al., 1984

Effect of Phyt on proliferation of rabbit lymphocytes ? Influence of PHA stimulation?

Lymphocyte transformation test

Phyt C5…C15 ineffective on unstimulated lymphocytes. Proliferation diminished in PHA stimulated cells by the highest potency (C15) by 28%…73%. Higher potencies more effective than lower.

Phyt C5, C7, C9, C15 Not declared NaCl 0.9%? ("9% physiologique")

Chirila et al., 1992

Reaction of whole blood lymphocytes from healthy, allergic or immune suppressed probands to PHA stimulation and incubation with Phos or Apis?

Lymphocyte transformation test

Lymphocyte proliferation of healthy and allergic probands inhibited by Apis, Phos; higher potencies (C30) more effective. Immune suppressed lymphocytes react weakly to PHA, here no effects of potencies.

Apis, Phos C7, C15, C30 Succussed ATD

ATD

Gibson and Gibson, 1996

Does potentized house dust influence migration of leucocytes from allergic probands?

Microscopy C4…C13, 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; Ø = 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. Homöopathische Arzneimittel in zellbiologischen Systemen [Homeopathic Remedies in Cellbiological Systems]. In: Albrecht, H, Frühwald, 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 modèles d`hypersensibilité du type I à l'étude de l'activité de dilutions hahnemanniennes des médiateurs de cette hypersensibilité [Application of hypersensitivity type I

models on the study of the activity of Hahnemannian dilutions of mediators of this hypersensitivity]. Homéopathie 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 für homöopathische Dokumentation; 1993.

systematic review in vitro evidence for an effect of high homeopathic potencies 2007

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