Biological models

Similia principle

The validity of the similia principle as a specific type of regulation is essential to characterise homeopathy as a regulation therapy. Evidence from experiments, both human and animal, demonstrates that all substances (including pesticides and carcinogens) which show an inhibitory effect at high concentrations, have a stimulatory effect at low concentrations. This phenomenon is called hormesis and occurs in all biological domains tested, with growing research support (Bellavite; Calabrese). In pharmacology, acute and chronic effects of drugs often have opposite action (paradoxical pharmacology: Bond), and many modern pharmaceutical agents display paradoxical secondary or rebound effects (Teixeira). Up to now, relatively few studies have been performed in this field. The most significant ones were conducted at the University of Utrecht, the Netherlands, which were able to show that self-recovery on the cellular level is stimulated by small doses of threatening conditions applied according to the similia principle (Van Wijk, Wiegant).
[Bellavite P, Andrioli G, Lussignoli S, Signorini A, Ortolani R, Conforti A (1997). Scientific reappraisal of the ‘Principle of Similarity’. Medical Hypotheses, 49: 203-212]
[Bellavite P, Lussignoli S, Semizzi ML, Ortolani R, Signorini A (1997). The similia principle. From cellular models to regulation of homeostasis. British Homeopathic Journal, 86: 73-85]
[Calabrese EJ (2010). Hormesis is central to toxicology, pharmacology and risk assessment. Human & Experimental Toxicology, 29:249–261]
[Calabrese EJ, Blain R (2005). The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. Toxicology and Applied Pharmacology, 202:289-301]
[Calabrese EJ (2005) Hormetic dose-response relationships in immunology: occurrence, quantitative features of the dose response, mechanistic foundations, and clinical implications. Critical Reviews in Toxicology, 35:89–295]
[Calabrese EJ (2005). Paradigm lost, paradigm found: The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences. Environmental Pollution, 138:379-412]
[Bond RA (2001). Is paradoxical pharmacology a strategy worth pursuing? Trends in Pharmacological Sciences, 22:273-276]
[Teixeira M (2003). Homeopathic use of modern medicines: utilisation of the curative rebound effect. Medical Hypotheses, 60:276-283]
[Van Wijk R, Wiegant FAC (1994). Cultured mammalian cells in homeopathic research -The similia principle in self-recovery, Utrecht University, the Netherlands]
[Van Wijk R, Wiegant FAC (1997) The similia principle in surviving stress; mammalian cells in homeopathy research, Utrecht University, the Netherlands]
[Van Wijk R, Wiegant FAC (1997). The similia principle as a therapeutic strategy: a research programme on stimulation of self-defense in disordered mammalian cells. Alternative Therapies in Health and Medicine, 3:33-39]
[Wiegant FAC, Souren JEM, Van Rijn J, Van Wijk R (1994). Stressor specific induction of heat shock protein in rat hepatoma cells. Toxicology, 94:143–159]
[Wiegant FAC, Van Rhijn J, van Wijk R (1997). Enhancement of the stress response by minute amounts of cadmium in sensitized Reuber H35 hepatoma cells. Toxicology, 116: 27-37]
[Wiegant FAC, Spieker N, van Wijk R (1998). Stressor-specific enhancement of hsp induction by low doses of stressors in conditions of self- and cross-sensitization. Toxicology, 127:107-119]
[Wiegant FAC, Souren J, van Wijk R (1999). Stimulation of survival capacity in heat shocked cells by subsequent exposure to minute amounts of chemical stressors; role of similarity in hsp-inducing effect. Human and Experimental Toxicology, 18:460-470]

Experimental intoxication

The largest body of research on biological models in homeopathy is based on experimental intoxication. A critical review and meta-analysis focused on 135 experiments published in 105 articles exploring the protective effect of homeopathic dilutions against toxins (Linde). The studies were extremely diverse and included many different experimental models: 95 experiments were conducted in animals, 29 in plants, 7 in isolated organs and 4 in-vitro. The quality of most studies was poor, but more than 70% of the high quality studies reported positive effects. The report included a meta-analysis of 26 experiments involving experimental intoxication with arsenic and mercury: the mean protection due to high dilution treatments was about 20% (CI, 6.2–33.2).
[Linde K, Jonas WB, Melchart D, Worku F, Wagner H, Eitel F (1994). Critical review and meta-analysis of serial agitated dilutions in experimental toxicology. Human and Experimental Toxicology, 13:481–492]

A recent meta-analysis evaluated 67 in-vitro experiments in 75 publications of research on homeopathic dilutions. A majority of them reported high-potency effects. Positive findings were obtained in nearly three-quarters of all replicated studies. Even experiments with a high methodological standard could demonstrate an effect of high potencies. However, no positive result was stable enough to be reproduced by all investigators.
[Witt CM, Bluth M, Albrecht H, Weißhuhn TER, Baumgartner S, Willich SN (2007). The in vitro evidence for an effect of high homeopathic potencies – A systematic review of the literature. Complementary Therapies in Medicine, 15:128–138].

Degranulation of human basophils

The most significant studies have been conducted on human basophils, using the degranulation test. Massive doses of IgE are used to trigger degranulation and histamine is used to produce an inhibitory effect in serially agitated high dilutions up to C19 (a dilution beyond Avogadro’s number). The first experiments (Davenas) have not proved to be reproducible (Ovelgönne; Hirst). However, more recent studies using a modified method, including a multi-centre trial in four independent laboratories in four different European countries in 1999 showed that histamine, at very high dilutions (15th – 19th centesimal), inhibits anti-IgE induced basophil degranulation. In 3/4 of the laboratories a statistically significant inhibition was found and in the fourth laboratory the results approached significance. Later on this study was repeated, but with an automated counting protocol (instead of hand-counted which may be biased by human error). The earlier findings have been confirmed: histamine solutions, both at pharmacological concentrations and diluted out of existence, lead to statistically significant inhibition of basophil activation by anti-IgE. (Belon, 1999/2004; Brown; Lorenz; Chirumbolo). Guggisberg, however, was not able to replicate the effects observed.
[Davenas E, Beauvais F, Amara J, Oberbaum M, Robinzon B, Miadonna A, Tedeschi A, Pomeranz B, Fortner P, Belon P, Sainte-Laudy J, Poitevin B, Benveniste J (1988). Human basophil de-granulation triggered by very dilute antiserum against IgE, Nature, 333:816–818]
[Ovelgönne JH, Bol AW, Hop WC, van Wijk R (1992). Mechanical agitation of very dilute antiserum against IgE has no effect on basophil staining properties. Experientia, 48:504–508]
[Hirst SJ, Hayes NA, Burridge J, Pearce FL, Foreman JC (1993). Human basophil degranulation is not triggered by very dilute antiserum against human IgE. Nature, 366:525–527]
[Belon P, Cumps J, Ennis M, Mannaioni PF, Sainte-Laudy J, Roberfroid M, Wiegant FA (1999). Inhibition of human basophil degranulation by successive histamine dilutions: results of a European multi-centre trial. Inflammation Research, 48 (Suppl 1):S17–18]
[Brown V, Ennis M (2001). Flow-cytometric analysis of basophil activation: inhibition by histamine at conventional and homeopathic concentrations. Inflammation Research, 50(Suppl 2):S47–S48]
[Lorenz I, Schneider EM, Stolz P, Brack A, Strube J (2003). Sensitive flow cytometric method to test basophil activation influenced by homeopathic histamine dilution. Forschende Komplementärmedizin, 10:316–324]
[Belon P, Cumps J, Ennis M, Mannaioni PF, Roberfroid M, Sainte-Laudy J, Wiegant FA (2004). Histamine dilutions modulate basophil activation. Inflammation Research, 53:181–188]
[Guggisberg A, Baumgartner SM, Tschopp CM, Heusser P (2005). Replication study concerning the effects of homeopathic dilutions of histamine on human basophil degranulation in vitro. Complementary Therapies in Medicine, 13:91–100]
[Chirumbolo S, Brizzi M, Ortolani R, Vella A, Bellavite P (2009). Inhibition of CD203c membrane up-regulation in human basophils by high dilutions of histamine: a controlled replication study. Inflammation Research, 58:755-764]

Other studies of effects of serially agitated high dilutions

Some other interesting studies of the effects of serially agitated high dilutions are the following:
- effects of serially agitated high dilutions of acetylsalicylic acid on bleeding time, platelet aggregation and coagulation
[Doutremepuich C, de Seze O, Le Roy D, Lalanne MC, Anne MC (1990). Aspirin at very ultra low dosage in healthy volunteers: Effects on bleeding time, platelet aggregation and coagulation. Haemostasis, 20:99–105] 
[Doutremepuich C, Aguejouf O, Pintigny D, Sertillanges M. and De Seze O (1994). Thrombogenic properties of ultra-low-doses of acetylsalicylic acid in a vessel model of laser-induced thrombus formation. Thrombosis Research, 76:225–229]
[Eizayaga FX, Aguejouf O, Belon P, Doutremepuich C (2005). Platelet aggregation in portal hypertension and its modification by ultra-low doses of aspirin. Pathophysiology of Haemostasis and Thrombosis, 34:29–34]
[Eizayaga FX, Aguejouf O, Desplat V, Belon P, Doutremepuich C (2006). Modifications produced by indomethacin and L-NAME in the effect of ultralow-dose aspirin on platelet activity in portal hypertension. Pathophysiology of Haemostasis and Thrombosis, 35:357–363]
[Eizayaga FX, Aguejouf O, Desplat V, Belon P, Doutremepuich C (2007) Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension. World Journal of Gastroenterology 13:5065-5070]

- effects of serially agitated high dilutions of thyroxine on the rate of amphibian metamorphosis (= a more or less discrete transformation between larval and adult stages in amphibians, which is steered by thyroxin)
[Endler P, Pongratz W, Kastberger G, Wiegant F, Schulte J (1994). The effect of highly diluted agitated thyroxine on the climbing activity of frogs. Veterinary and Human Toxicology, 36:56–59]
[Endler P, Pongratz W, Smith C, Schulte J (1995). Non-molecular information transfer from thyroxine to frogs with regard to homeopathic toxicology. Veterinary and Human Toxicology, 37:259–260]
[Endler P, Lüdtke R, Heckmann C, Lassnig H, Scherer-Pongratz W, Haidvogl M, Frass M (2003). Pretreatment with thyroxin (10-8 parts by weight) enhances a "curative" effect of homeopathically prepared thyroxin (10-13) on lowland frogs. Research on Complementary Medicine, 10:137–142]
[Welles SU, Endler PC, Scherer-Pongratz W, Suanjak-Traidl E, Weber S, Spranger H, Frass M, Lothaller H (2006). Pretreatment with thyroxin 10-8 and the effect of homeopathically prepared thyroxin 10-30 on highland frogs - a multi-researcher study. Forschende Komplementärmedizin, 14:353-357]
[Graunke H, Endler PC, Scherer-Pongratz W, Frass M, Lothaller H (2007) Treatment of Lowland Frogs from the Spawn Stage with Homeopathically Prepared Thyroxin (10e-30). The Scientific World Journal, 7: 1697-1702]
[Weber S, Endler PC, Welles SU, Suanjak-Traidl E, Scherer-Pongratz W, Frass M, Spranger H, Peithner G, Lothaller H (2008): The effect of homeopathically prepared thyroxine (10e-30) on highland frogs: influence of electromagnetic fields. Homeopathy, 97: 3-9]

- protective effect of serially agitated high dilutions of mercury on the mortality of poisoned mice
[Datta S, Biswas SJ, Khuda-Bukhsh AR (2004) Comparative efficacy of pre-feeding, post-feeding and combined pre- and post-feeding of two microdoses of a potentized homeopathic drug, Mercurius solubilis, in ameliorating genotoxic effects produced by mercuric chloride in mice. Evidence Based Complementary and Alternatative Medicine, 1:291–300]
[Datta S, Mallick P, Khuda-Bukhsh AR (1999). Efficacy of a potentized homeopathic drug (Arsenicum Album-30) in reducing genotoxic effects produced by arsenic trioxide in mice: I. Comparative studies of pre-, post- and combined pre- and postoral administration and comparative efficacy of two microdoses. Complementary Therapies in Medicine, 7:62–75]
[Datta S, Mallick P, Khuda-Bukhsh AR (1999). Efficacy of a potentized homeopathic drug (Arsenicum Album-30) in reducing genotoxic effects produced by arsenic trioxide in mice: II. Comparative efficacy of an antibiotic, actinomycin D alone and in combination with either of two microdoses. Complementary Therapies in Medicine, 7:156–163]
[Kundu SN, Mitra K, Bukhsh AR (2000). Efficacy of a potentized homoeopathic drug (Arsenicum-album-30) in reducing cytotoxic effects produced by arsenic trioxide in mice: III. Enzymatic changes and recovery of tissue damage in liver. Complementary Therapies in Medicine, 8:76-81]
[Kundu SN, Mitra K, Khuda Bukhsh AR (2000). Efficacy of a potentized homeopathic drug (Arsenicum-Album-30) in reducing cytotoxic effects produced by arsenic trioxide in mice: IV. Pathological changes, protein profiles, and content of DNA and RNA. Complementary Therapies in Medicine, 8:157–165]
[Mallick P, Mallick JC, Guha B, Khuda-Bukhsh AR (2003). Ameliorating effect of microdoses of a potentized homeopathic drug, Arsenicum Album, on arsenic-induced toxicity in mice. BMC complementary and alternative medicine, 3:7]

 - effects of serially agitated high dilutions of bursin and thymulin on humoral and cellular immune responses
[Bastide M, Daurat V, Doucet-Jaboeuf M, Pelegrin A, Dorfman P (1987). Immunomodulatory activity of very low doses of thymulin in mice, International Journal of Immunotherapy, 3:191–200]
[Daurat V, Dorfman P, Bastide M (1988). Immunomodulatory activity of low doses of interferon alpha,beta in mice. Biomedicine & Pharmacotherapy, 42:197–206]
[Youbicier-Simo B, Boudard F, Mekaouche M, Bastide M, Baylé J (1993). Effects of embryonic bursectomy and in ovo administration of highly diluted bursin on adrenocorticotropic and immune responses of chickens. International Journal of Immunotherapy, 9:169–180]
[Youbicier-Simo B, Boudard F, Mekaouche M, Baylé J, Bastide M (1996). Specific abolition reversal of pituitary-adrenal activity and control of the humoral immunity in bursectomized chickens through highly dilute bursin. Journal of Immunopathology and Pharmacology, 9: 43–51]

- effects of serially agitated high dilutions of arsenic on the toxic effect of material doses of arsenic trioxide on wheat shoot growth (Betti, 1997; Brizzi, 2005) and wheat germination (Brizzi, 2000) and in treating the lesions induced by tobacco mosaic virus on tobacco plants (Betti, 2003).
[Betti L, Brizzi M, Nani D, Peruzzi M (1997). Effect of high dilutions of Arsenicum album on wheat seedlings from seeds poisoned with the same substance. British Homeopathic Journal, 86:86–89]
[Brizzi M, Nani D, Peruzzi M, Betti L (2000). Statistical analysis of the effect of high dilutions of arsenic in a large dataset from a wheat germination model. British Homeopathic Journal, 89:63–67]
[Brizzi M, Lazzarato L, Nani D, Borghini F, Peruzzi M, Betti L (2005). A biostatistical insight into the As(2)O(3) high dilution effects on the rate and variability of wheat seedling growth. Forschende Komplementärmedizin und Klassische Naturheilkunde, 12:277–283]
[Betti L, Lazzarato L, Trebbi G, Brizzi M, Calzoni GL, Borghini F, Nani D (2003). Effects of homeopathic arsenic on tobacco plant resistance to tobacco mosaic virus. Theoretical suggestions about system variability, based on a large experimental data set. Homeopathy, 92:195–202]