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Memorandum submitted by Dr Peter Fisher HO 21
Homeopathy: the Evidence from Basic Research
Background 1. Its 'implausibility' from a scientific standpoint is often cited as a reason for scepticism about homeopathy, even in the face of positive clinical evidence. For instance a systematic review of clinical trials, published in the BMJ stated 'we would accept that homoeopathy can be efficacious, if its mechanism of action were more plausible' [1]. Contrary views have also been expressed: 'Indeed it is often stated...that the burden of proof it requires should be much greater than for other scientific hypotheses. Such an attitude may itself be considered unscientific: the same level of supporting evidence should be accepted for all scientific developments. If a lower level of proof is set for hypotheses that fit prior beliefs then we bias our view of science in favour of such beliefs and may be easily misled'.[2]
2. This submission examines the basic science evidence concerning homeopathy and related areas of science to cast light on the alleged implausibility of homeopathy.
3. Homeopathy is based on the idea of 'like cures like', also known as the similarity principle. Medicines are selected on the basis that they may, in healthy people, provoke syndromes similar to those from which the patient is suffering. Homeopathy emphasises the 'secondary' effects of medicines, these are the reactions of living systems to drugs, as opposed to the primary actions of drugs per se.
4. The most controversial aspect of homeopathy is its use of very high dilution. These are prepared by a process of sequential dilution with vigorous shaking at each stage of dilution, known as succussion. Dilution is usually in steps of 1:10 or 1:100, referred to as x or d (decimal) or c (centesimal) respectively.
5. Avogadro's Constant (also known as Loschmidt's Constant) is the number of particles (atoms or molecules) in a gram mole of a pure substance. Its value is 6.02 x 1023 mol-1. The implication is that material quantities of the original substance are extremely unlikely to remain in homeopathic medicines diluted to concentrations greater 12c or 24x (10-24 M). Such dilutions are referred to as are referred to as 'ultramolecular' or BRAN (Beyond the Reciprocal of Avogadro's Number).
6. It is important to note that the use of ultramolecular dilutions is not a defining characteristic of homeopathy. Many homeopathic medicines are not in ultramolecular dilutions.
7. It is sometimes claimed that it is impossible for such highly diluted substances to have 'real' physiological effects. Randomised placebo-controlled trials are, in principle, capable of demonstrating such effects for homeopathic medicines. But they are expensive, cumbersome and difficult to repeat. The question of whether extreme dilutions are capable of exerting 'real' (as opposed to psychologically mediated) effects, and if so, how such effects might be mediated is best answered by laboratory experiments.
8. This submission focuses on: · Scientific research on 'like cures like'. · Evidence from biological experiments that very high dilutions can have effects. This includes work based on intact animals, plants and isolated cells and cell cultures. · Research concerning possible ways in which such effects might be mediated, this is mostly in the form of physical and physical chemistry research.
Similarity 9. The primary principle of homeopathy is that of similarity. In this area there is substantial overlap with other areas of science including toxicology and pharmacology.
10. In Toxicology hormesis, the stimulatory or beneficial effects of small doses of toxins[3],[4],[5],[6] has been extensively studied. The recent concept of 'postconditioning hormesis' refers to a small stimulus exerting a beneficial effect after a biological system has experienced a harmful stress of similar nature.[7]
11. The main competing toxicological hypothesis to hormesis is the threshold dose response model. This model predicts that the effects of a toxin decline in a linear fashion with reducing dose; hormesis predicts a J-shaped or 'hockey stick' curve, with a reverse effect at low dose levels. Analysis of a very large dataset of a standard cancer drug screening method based on yeast show the hormesis model to be more accurate in predicting response at low doses.[8]
12. Wiegant's group at the University of Utrecht, Netherlands studied the specificity of low dose responses in cultured rat hepatoma cells. The cells were subjected to heat shock followed by low doses of chemical toxins. The greater the similarity between the two stresses, the greater the cell survival.[9]
13. Relevant pharmacological concepts include drug rebound effects, dose-dependent reverse effects and paradoxical pharmacology[10],[11],[12]. Such effects are very widely observed. For instance that β-agonist drugs which stimulate the heart and have positive effects in acute heart failure, increase mortality in the chronic heart failure while the reverse is true for β-antagonist drugs.
14. The toxicological and pharmacological phenomena mentioned above have in common the occurrence secondary, reverse or paradoxical effects of drugs and toxins in living organisms as a function of dose or time
15. In some cases the biological basis of these secondary reversed effects is understood: known mechanisms include 'chaperone' protein induction, cell surface receptor up- or down-regulation and enzyme induction. In other cases the mechanism is unknown.
Biological models of high dilution effects 16. A meta-analysis led by Prof Claudia Witt of the
Charité University Medical Centre,
17. The most frequently used in-vitro model was basophils, used in 42% of experiments. Basophils are white blood cells involved in the immune response. One series of experiments comprises 17 experiments on the inhibition of basophil activation by high dilutions of histamine. It spans over 25 years and includes multi-centre and independent replications.[14],[15],[16] There has been steady refinement of the method, including automation. All but two repetitions have reported positive results. There is growing insight into possible mechanisms of action, for instance the response is highly specific to histamine. It is not induced by the structural analogue histidine, and it is blocked by histamine antagonist drugs. Experiments with series of dilutions show alternating peaks and troughs of effect at different dilutions. The reason for this is not understood, but there is a consistent peak of activity at 16c (Histamine 10-32M), well into the ultramolecular range
18. Another cellular system which has been the subject of repeated experiments over a long period is the effect of ultramolecular dilutions of aspirin on blood clotting. The effect is the reverse of that found with substantial doses: ultramolecular dilutions promote clotting.[17],[18] Recent work with 'knock-out' mice demonstrates that the effect depends on the enzyme COX-2.[19]
19. Several white blood cell models indicate that homeopathic medicines modulate cytokine expression. These suggest testable hypotheses on the locus of in-vivo effects of homeopathic medicines.[20],[21],[22],[23]
20. Among plant models the most reproduced is that examining the effects of ultramolecular, homeopathically diluted arsenic on arsenic-intoxicated wheat seedlings.[24],[25],[26]
21. The most robust animal model is the effect of thyroxine on the rate of metamorphosis of frogs. In substantial dose thyroxine increases the rate of metamorphosis, it has the reverse effect in ultramolecular dilution.[27], This effect has been reproduced in multi-centre experiments[28] and by independent workers with different species of frog.[29]
22. Many other biological model experiments in homeopathy have been conducted. The HomBRex Database on Fundamental Homeopathy Research is maintained by the Carstens Foundation.[30] It contains details of approximately 1300 such experiments using intact organisms or parts of organisms (including organs, cells, subcellular structures). The most commonly studied animal is the rat, used in 67 experiments. The most frequent type of model was intoxication, most frequently with arsenic. Other rat studies examined behaviour, oedema and inflammation and hormonal disturbances among others. There are also a number of biological models including cell, plant and animal models which consistently show effects with ultramolecular dilutions of various biologically active substances including drugs, toxins, hormones and immune mediators.
23. There is thus substantial scientific evidence that biologically active substances including drugs and toxins may have reversed or paradoxical secondary effects as a function of time or dose, and that these effects are highly specific.
Possible mechanisms of action of ultramolecular dilutions 24. These findings pose a challenge in terms of understanding the mechanism of action. Homeopathic medicines are prepared in water alcohol mixtures and most attention has focussed on structural or coherence effects induced in water by the preparation process. It has been suggested that hydrogen bond mediated structural or coherence effects, dissolved gases and perhaps dissolved silicates from the glassware play a role.
25. Experiments using a range of standard physical and physico-chemical methods have reported structural anomalies in water prepared according to the homeopathic method. Methods include low temperature thermoluminesence, flux calorimetry, conductometry, pHmetry Raman and Ultra-Violet-Visible (UV-VIS) spectroscopy and Nuclear Magnetic resonance (NMR).
26. Low temperature thermoluminesence involves freezing water to the temperature of liquid nitrogen, bombarding it with x- or γ rays, then warming it, whereupon it emits a characteristic glow. The 'signature' of lithium is detectable in ultramolecular lithium chloride by this method[31]. This result has been independently verified.[32] The effect appears to be dependent on the atmosphere in which the dilution is conducted, the effect is more marked with dilutions prepared in an oxygen atmosphere and less so in dilutions prepared under reduced pressure, compared to normal atmosphere.[33]
27. The group led by Elia
at the
28. NMR results have varied, depending on the parameters measured.[38],[39] But when 20MHz T1 and T2 water proton NMR relaxation rates are measured, homeopathic dilutions of histamine are distinguishable from solvents up to ultramolecular levels. The effect is attributed to stable supramolecular structures, involving nanobubbles of atmospheric gases and highly ordered water around them. It is deleted by heating.[40],[41],[42]
29. Work from the Materials Research Institute of Pennsylvania State University shows that ultradilute homeopathic medicines can be distinguished from controls and each other by Raman and Ultra-Violet-Visible (UV-VIS) spectroscopy[43],[44] . These effects may be due to epitaxy, the transfer of information, not material, from the surface of one material, usually solid, to another, usually liquid. Semiconductor manufacturing often uses epitaxial growth to generate specific types of microtransistors and integrated circuitry.
30. Diverse but standard physical and physico-chemical methods have detected structural anomalies of water in homeopathic preparations. There is convergence among the results which suggest mesoscale (of the order of microns) organisation of water molecules in ultramolecular dilutions prepared by the homeopathic method. Dissolved gases may play an important role. It appears likely that this organisation is hydrogen-bond mediated.
Criticisms 31. The claim that water can 'remember' substances with which it has been in contact, and that such 'memory' is mediated by hydrogen bonds has been criticised, mostly on theoretical grounds.[45] Such arguments mostly involve the short duration of individual hydrogen bonds in liquid water (about a picosecond).
32. But this does not imply that the mesoscale structure of water must change on the same time scale. For instance in ice hydrogen bonds are also very shortlived but an ice sculpture can 'remember' its shape over extended periods. On a smaller scale, cation hydrates are commonly described with particular structure (eg the octahedral Na+(H2O)6 ion) even though the individual water molecules making up such structures have very brief residence times (microseconds).2
33. Such arguments ignore the fact that the behaviour of a large population of water molecules may be retained even if that of individual molecules is constantly changing: a wave can cross an ocean, remaining a wave although its molecular content is continuously changing.
34. Evidence denying the long life of water clusters is mostly based on computer simulations but these cover only nanoseconds of simulated time. Such short periods are insufficient to show longer temporal relationships, for example those produced by oscillating reactions. They also involve relatively few water molecules (100-1000), small (nanometre) dimensions, insufficient to show mesoscale (micron) effects. They use models of the water molecule whose predictions correspond poorly to the real properties of water.
35. Certain 'memory' effects in water are well established and uncontroversial: for instance the formation of clathrate hydrates from aqueous solutions whereby previously frozen clathrates within the solution, when subsequently melted, predispose later to more rapid clathrate formation.[46] This is explained by the presence of nanobubbles, extended chain silicates or induced clathrate initiators.[47]
Conclusions 36. I have examined basic science research of relevance to homeopathy with a view to establishing how 'implausible' it is. I have briefly reviewed the evidence in three main domains: similarity, using toxicological and pharmacological sources; biological models of ultramolecular response, including isolated call, plant and whole animal models; possible mechanisms by which effects of ultramolecular dilutions might be mediated, drawing on physical, physico-chemical and materials science.
37. Toxicological and pharmacological phenomena such as hormesis, drug rebound effects and paradoxical pharmacology are very widely observed. They have in common the occurrence secondary, reverse or paradoxical effects of drugs and toxins in living organisms as a function of dose or time and are closely analogous to the homeopathic concept of secondary drug action.
38. There is a substantial body of work on the effects of ultramolecular dilutions in various biological models, including isolated cells, plants and animals. Several lines of research now yield repeatable results. These include inhibition of basophil activation by ultramolecular dilutions of histamine, the effect of ultramolecular dilutions of aspirin on blood clotting; and the effect of ultramolecular thyroxine on the rate of metamorphosis of frogs. Several models suggest loci for these effects.
39. Experiments using a range of standard physical and physico-chemical methods have detected structural anomalies of water in ultramolecular homeopathic preparations. Methods include low temperature thermoluminesence, flux calorimetry, conductometry, Raman and Ultra-Violet-Visible spectroscopy and Nuclear Magnetic resonance.
40. The contention that homeopathy is implausible, impossible or isolated from other areas of science is untenable. Although the total volume of research in the area is relatively small, high-quality and repeated experiments have yielded positive results. These raise important and unanticipated scientific questions
Declaration of Interest I
am Director of Research and Clinical Director of the
References (note: I have not attempted to give comprehensive references. Where there are multiple references to a body of work, I have attempted to span it by giving references which reflect the duration and scope). [1] Kleijnen J, Knipschild P, ter Riet G (1991). Clinical trials of homoeopathy British Medical Journal, 302:316-323 [2] Chaplin MF. The Memory of Water: an overview. Homp 2007; 96: 143-150. [3] Stebbing ARD Hormesis ‑ the stimulation of growth by low levels of inhibitors. Sci Tot Environ 1982;22:213‑234 [4] Calabrese, E. J., Blain, R. (2005). The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: An overview. Toxicol. Appl. Pharmacol. 202, 289-301. [5] Calabrese, E. J., Staudenmayer, J., Stanek E. J. (2006). Drug development and hormesis. Changing conceptual understanding of the dose response creates new challenges and opportunities for more effective drugs. Curr. Opin. Drug Discov. Devel. 9, 117-123. [6] Calabrese,EJ Staudenmayer JW, Stanek EJ, Hoffmann GR.Hormesis Outperforms Threshold Model in National Cancer Institute Antitumor Drug Screening Database. Toxicol Sci 2006:94;368-378 [7] Calabrese EJ, Bachmann KA, Bailer AJ. et al. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework. Toxicol Appl Pharmacol 2007; 222: 122-128. [8] Calabrese EJ, Staudenmayer JW, Stanek EJ Hoffmann GR. Hormesis Outperforms Threshold Model in National Cancer Institute Antitumor Drug Screening Database. Toxicological Sciences (2006) 94, 368-378 [9] Wiegant FAC, Souren JEM, Van Wijk R. Stimulation of survival capacity in heat-shocked cells by subsequent exposure to minute amounts of chemical stressors: Role of similarity in hsp-inducing effects. Hum Exp Toxicol 1999; 18, 460-470. [10] Bond RA (2001). Is paradoxical pharmacology a strategy worth pursuing? Trends in Pharmacological Sciences, 22:273-276. [11] Teixeira MZ (2006). Evidence of the principle of similitude in modern fatal iatrogenic events. Homeopathy, 95:229-236. [12] Teixeira MZ. (2007) Bronchodilators, fatal asthma, rebound effect and similitude Homeopathy;96:135-137 [13] Witt CM, Bluth M, Albrecht H, Weißhuhn T, Baumgartner S, Willich SN. The in vitro evidence for an effect of high homeopathic potencies - A systematic review of the literature. Compl Therap Med (2007) 15, 128-138. [14] Sainte-Laudy J., Belon P. Inhibition of human basophil activation by high dilutions of histamine. Agents Actions 1993; 38: 525-7. [15] Belon P., Cumps J., Ennis M. Mannaioni P.F., Roberfroid M., Sainte-Laudy J., Wiegant F.A.C.Histamine dilutions modulate basophile activation. Inflamm Res 2004; 53: 181-188. [16] Chirumbolo S., Brizzi M., Ortolani R., Vella A., Bellavite P. Inhibition of CD203c membrane upregulationin human basophils by high dilutions of histamine: a controlled replication study. Inflamm Res. 2009: DOI 10.1007/s00011-009-0044-4 [17] Lalanne M, Doutremepuich C, De Seze O, Belon P. What is the effect of acetylsalicylic acid at ultra low dose on the interaction platelets/vessel wall? Thrombosis Res 1990 60: 231-236. [18] Eizayaga FX, Aguejouf O, Desplat V, Belon P, Doutremepuich C. Modifications produced by indomethacin and L-NAME in the effect of ultralow-dose aspirin on platelet activity in portal hypertension. Pathophysiol Haemostasis Thrombosis. 2007; 35: 357-363 [19] Aguejouf O, Eizayaga FX, Desplat V, Belon P, Doutremepuich C. Prothrombotic and Hemorrhagic Effects of Aspirin. Clinical Appl Thrombosis/Hemostas, 2008 doi:10.1177/1076029608319945. [20] Fimiani V, Cavallaro A, Ainis O, Bottari C. Immunomodulatory effect of the homoeopathic drug Engystol-N on some activities of isolated human leukocytes and in whole blood. Immunopharmacol-Immunotoxicol 2000; 22: 103-115. [21] Ramachandran C, Nair PK, Clèment RT, Melnick SJ. Investigation of cytokine expression in human leukocyte cultures with two immune-modulatory homeopathic preparations. J Altern Complement Med 2007; 13: 403-407. [22] de Oliveira CC, de Oliveira SM, Goes VM, Probst CM, Krieger MA, Buchi DD. Gene expression profiling of macrophages following mice treatment with an immunomodulator medication. J Cell Biochem 2008; 104: 1364-1377. [23] Smit E, Pretorius E, Anderson R, Oommen J, Potjo M. Differentiation of human monocytes in vitro following exposure to Canova in the absence of cytokines. Ultrastruct Pathol 2008; 32: 147-152. [24] Betti L., Brizzi M., Nani D., Peruzzi M., Effect of high dilutions of Arsenicum album on wheat seedlings from seed poisoned with the same substance, Br Hom J 1997; 86: 86-89. [25] Brizzi M., Lazzarato L., Nani D., Borghini F., Peruzzi M., Betti L., A Biostatistical Insight into the As2O3 High Dilution Effects on the Rate and Variability of Wheat Seedling Growth. Res Compl Med / Forsch Komplementärmed 2005; 12: 277-83. [26] Binder M., Baumgartner S., Thurneysen A., The Effects of a 45x Potency of Arsenicum album on Wheat Seedling Growth - a Reproduction Trial, Res Compl Med / Forsch Komplementärmed 2005;12: 284-291. [27] Endler,
P.C., Pongratz, W., van Wijk, R., Kastberger, G., Haidvogl, M. Effects of
Highly Diluted Succussed Thyroxin on Metamorphosis of Highland Frogs. [28] Welles, S.U., Suanjak-Traidl, E., Weber, S., Scherer-Pongratz, W., Frass, M., Endler, P.C., Spranger, H., Lothaller, H. Pretreatment with thyroxine (10e-8) and the effect of homeopathically prepared thyroxin (10-30) on highland frogs - a multi-researcher study. Res Compl Med / Forsch Komplementärmed 2007; 14: 353-357. [29] Guedes J. R. P., Ferreira C. M., Guimaraes H. M. B., Saldiva P. H. N., Capelozzi V. L. Homeopathically prepared dilution of Rana catesbeiana thyroid glands modifies its rate of metamorphosis. Homeopathy 2004; 93: 132-137. [30] www.carstensstiftung.de/hombrex [31] Rey L (2003). Thermoluminescence of ultra-high dilutions of lithium chloride and sodium chloride. Physica (A), 323:67-74. [32] van Wijk R, Bosman S, van Wijk EP. Thermoluminescence in ultra-high dilution research. J Alternative Complementary Med 2006; 12: 437-443. [33] Rey L. Can low temperature thermoluminescence cast light on the nature of ultra-high dilutions?. Homp 2007; 96: 170-174. [34] Elia V, Niccoli M. Thermodynamics of extremely diluted aqueous solutions. Ann NY Acad Sci 1999; 879: 241 [35] Elia V, Napoli E, Niccoli M, et al. New physico-chemical properties of extremely diluted aqueous solutions. A calorimetric and conductivity study at 25 1C. J Therm Anal Calorimetry 2004; 78: 331-342. [36] Elia V, Elia L, Marchettini N, Napoli E, Niccoli M, Tiezzi E. Physico-chemical properties of aqueous extremely diluted solutions in relation to ageing. J Therm Anal Calorim 2008;93:1003-1011. [37] Prigogine
I. From Being to Becoming. Time and Complexity in the Physical Sciences. [38] Aabel S, Fossheim S, Rise F. Nuclear magnetic resonance (NMR) studies of homeopathic solutions. Br Homoeop J 2001; 90: 14-20. [39] Anick DJ. High sensitivity 1H-NMR spectroscopy of homeopathic remedies made in water. BMC Complementary Alternative Med 2004; 4:15doi:10.1186/1472-6882-4-15 [40] Demangeat J.-L. NMR water proton relaxation in unheated and heated ultrahigh aqueous dilutions of histamine: Evidence for an air-dependent supramolecular organization of water, J. Mol. Liq. (2008) doi:10.1016/j.molliq.2008.07.013. [41] Demangeat J-L, Gries P, Poitevin B et al. Low-field NMR water proton longitudinal relaxation in ultrahighly diluted aqueous solutions of silica-lactose prepared in glass material for pharmaceutical use. Appl Magn Reson 26 ( 2004) 465-481 [42] Demangeat J.-L. NMR water proton relaxation in unheated and heated ultrahigh aqueous dilutions of histamine: Evidence for an air-dependent supramolecular organization of water. Mol. Liquids 144 (2009) 32-39. [43] Roy R,
Tiller WA, [44] Rao ML, Roy R, Bell I. Characterization of the structure of ultra dilute sols with remarkable biological properties. Mater Res Innovation 2007; 1(1): 3-18. [45] Teixeira J. Can water possibly have a memory? A sceptical view. Homp 2007; 96: 158-162. [46] Ohmura R, Ogawa M, Yasuoka K, Mori YH. Statistical study of clathrate-hydrate nucleation in a water/hydrochlorofluorocarbon system: search for the nature of the ''memory effect''. J Phys Chem B 2003; 107: 5289-5293. [47] Zeng H, Wilson LD, Walker VK, Ripmeester JA. Effect of antifreeze proteins on the nucleation, growth, and the memory effect during tetrahydrofuran clathrate hydrate formation. J Am Chem Soc 2006; 128: 2844-2850.
Director of Research Royal
November 2009 |