Evidence Based Research Supporting Homeopathic Medicine

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Some of Bryce's 'favorites' By Category

Note: Not too long ago, an outfit who call themselves "Skeptic North" posted an online thread criticising Bryce and his "21 Favorite Papers" on homeopathy. Well, those papers are not his only favorites. I hope anyone with a scientific mind will enjoy reading below. Music teachers and OT's are welcome too.

Clinical trials

Jacobs J, Jonas WB, Jimenez-Perez M, Crothers D (2003). Homeopathy for childhood diarrhea: combined results and metaanalysis from three randomized, controlled clinical trials. Pediatric Infectious Disease Journal, 22:229–234.

Vickers A, Smith C (2006). Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes (Cochrane review). In: The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd. CD001957.

Taylor MA, Reilly D, Llewellyn-Jones RH, et al. (2000). Randomised controlled trials of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. British Medical Journal, 321:471–476.

Frass M, Linkesch M, Banyai S, et al. (2005). Adjunctive homeopathic treatment in patients with severe sepsis: a randomized, double-blind, placebo-controlled trial in an intensive care unit. Homeopathy, 94:75–80.

Oberbaum M, Yaniv I, Ben-Gal Y, et al. (2001). A randomized, controlled clinical trial of the homeopathic medication Traumeel S in the treatment of chemotherapy-induced stomatitis in children undergoing stem cell transplantation. Cancer, 92:684–690.

Frei H, Everts R, von Ammon K, et al. (2005). Homeopathic treatment of children with attention deficit hyperactivity disorder: a randomised, double blind, placebo controlled crossover trial. European Journal of Pediatrics, 164:758-767.

Brinkhaus B, Wilkens JM, Lüdtke R, et al. (2006). Homeopathic arnica therapy in patients receiving knee surgery: Results of three randomised double-blind trials. Complementary Therapies in Medicine, 14:237–246.

Adler UC, Paiva PM, Cesar AT et al. (2009).Homeopathic Individualized Q-potencies versus Fluoxetine for moderate to severe depression: double-blind, randomized non-inferiority trial. Evidence-based Complementary and Alternative Medicine: eCAM. doi:10.1093/ecam/nep114

Cost effectiveness

Rossi E, Crudeli L, Endrizzi C, Garibaldi D (2009). Cost–benefit evaluation of homeopathic versus conventional therapy in respiratory diseases. Homeopathy, 98:2–10.

Witt C, Keil T, Selim D, et al. (2005). Outcome and costs of homeopathic and conventional treatment strategies: a comparative cohort study in patients with chronic disorders. Complementary Therapies in Medicine, 13:79-86.

Kneis KC, Gandjour A (2009). Economic evaluation of Sinfrontal® in the treatment of acute maxillary sinusitis in adults. Applied Health Economics and Health Policy, 7: 181–191

Outcomes

Witt CM, Lüdtke R, Baur R, Willich SN (2005). Homeopathic medical practice: long-term results of a cohort study with 3,981 patients. BMC Public Health, 5:115.

Spence D, Thompson EA, Barron SJ (2005). Homeopathic treatment for chronic disease: a 6-year university ­hospital based outpatient observational study. Journal of Alternative and Complementary Medicine, 5:793-798.

Biological models

Belon P, Cumps J, Ennis M, et al. (2004). Histamine dilutions modulate basophil activation. Inflammation Research, 53:181–188.

Aguejouf O, Eizayaga FX, Desplat V, et al. (2008). Prothrombotic and Hemorrhagic Effects of Aspirin. Clinical and Applied Thrombosis/Hemostasis, doi:10.1177/1076029608319945.

Witt CM, Bluth M, Albrecht H, et al. (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.

Endler PC, Thieves K, Reich C, Matthiessen P, Bonamin L, Scherr C, Baumgartner S
Repetitions of fundamental research models for homeopathically prepared dilutions beyond 10-23: a bibliometric study. Homeopathy, 2010; 99: 25-36

Physics

Rey L (2007). Can low temperature thermoluminescence cast light on the nature of ultra-high dilutions? Homeopathy, 96:170–174.

Elia V, Napoli E, Germano R (2007). The “memory of water”: an almost deciphered enigma. Dissipative structures in extremely dilute aqueous solutions. Homeopathy, 96:163–169.

Chaplin MF (2007). The memory of water: an overview. Homeopathy, 96: 143–150.

Others:

Teixeira MZ (2006). Evidence of the principle of similitude in modern fatal iatrogenic events. Homeopathy, 95:229–236.

Kleijnen J, Knipschild P, ter Riet G. Clinical trials of homeopathy. Br Med J 1991; 302: 316–23.

Linde K, Clausius N, Ramirez G, et al. Are the clinical effects of homoeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 1997; 350: 834–43.

Linde K, Scholz M, Ramirez G, et al. Impact of study quality on outcome in placebo controlled trials of homeopathy. J Clin Epidemiol 1999; 52: 631–6.

Cucherat M, Haugh MC, Gooch M, Boissel JP. Evidence of clinical efficacy of homeopathy – A meta-analysis of clinical trials. Eur J Clin Pharmacol 2000; 56: 27–33.

Shang A, Huwiler-Muntener K, Nartey L, et al. Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet 2005; 366: 726–32.

Bornhöft G, Wolf U, Ammon K, et al. Effectiveness, safety and cost-effectiveness of homeopathy in general practice – summarized health technology assessment. Forsch Komplementärmed 2006; 13 Suppl 2: 19–29.

Jacobs J, Jonas WB, Jimenez-Perez M, Crothers D. Homeopathy for childhood diarrhea: combined results and metaanalysis from three randomized, controlled clinical trials. Pediatr Infect Dis J 2003; 22: 229–34.

Vickers A, Smith C. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes (Cochrane Review). In: The Cochrane Library. Chichester, UK: John Wiley & Sons, Ltd. 2006; CD001957.

Barnes J, Resch K-L, Ernst E. Homeopathy for postoperative ileus - a meta-analysis. J Clin Gastroenterol 1997; 25: 628–33.

Jonas WB, Linde K, Ramirez G. Homeopathy and rheumatic disease – Complementary and alternative therapies for rheumatic diseases II. Rheum Dis Clin North Am 2000; 26: 117–23.

Wiesenauer M, Lüdtke R. A meta-analysis of the homeopathic treatment of pollinosis with Galphimia glauca. Forsch Komplementärmed Klass Naturheilkd 1996; 3: 230–6.

Taylor MA, Reilly D, Llewellyn-Jones RH, et al. Randomised controlled trials of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. Br Med J 2000; 321: 471–6.

Bellavite P, Ortolani R, Pontarollo F, et al. Immunology and homeopathy. Clinical studies – Part 2. eCAM 2006; 3: 397–409.

Schneider B, Klein P, Weiser M. Treatment of vertigo with a homeopathic complex remedy compared with usual treatments: a meta-analysis of clinical trials. Arzneimittelforschung 2005; 55: 23–9.

Fisher P. An experimental double-blind clinical trial method in homoeopathy. Use of a limited range of remedies to treat fibrositis. BrHomeopath J 1986; 75: 142–7.

Bell I, Lewis D, Brooks A, et al. Improved clinical status in fibromyalgia patients treated with individualized homeopathic remedies versus placebo. Rheumatology 2004; 43: 577–82.

Shealy CN, Thomlinson RP, Cox RH, Borgmeyer RN. Osteoarthritic pain: a comparison of homeopathy and acetaminophen. Am J Pain Manage 1998; 8: 89–91.

van Haselen RA, Fisher PAG. A randomized controlled trial comparing topical piroxicam gel with a homeopathic gel in osteoarthritis of the knee. Rheumatology 2000; 39: 714–9.

Friese K-H, Zabalotnyi DI. Homeopathy in acute rhinosinusitis. A double-blind, placebo controlled study shows the effectiveness and tolerability of a homeopathic combination remedy. HNO 2007; 55: 271–7.

Zabolotnyi DI, Kneis KC, Richardson A, et al. Efficacy of a complex homeopathic medication (Sinfrontal) in patients with acute maxillary sinusitis: a prospective, randomized, doubleblind, placebo-controlled, multicenter clinical trial. Explore (NY) 2007; 3: 98–109.

Jacobs J, Springer DA, Crothers D. Homeopathic treatment of acute otitis media in children: a preliminary randomized placebo-controlled trial. Pediatr Infect Dis J 2001; 20: 177–83.

Zell J, Connert WD, Mau J, Feuerstake G. Treatment of acute sprains of the ankle. Controlled double-blind trial to test the effectiveness of a homeopathic ointment. Fortschr Med 1988; 106: 96–100.

Diefenbach M, Schilken J, Steiner G, Becker HJ. Homeopathic therapy in respiratory tract diseases. Evaluation of a clinical study in 258 patients. Z Allgemeinmed 1997; 73: 308–14.

Weatherley-Jones E, Nicholl JP, Thomas KJ, et al. A randomized, controlled, triple-blind trial of the efficacy of homeopathic treatment for chronic fatigue syndrome. J Psychosom Res 2004;56: 189–97.

Yakir M, Kreitler S, Brzezinski A, et al. Effects of homeopathic treatment in women with premenstrual syndrome: a pilot study. Br Homeopath J 2001; 90: 148–53.

Witt C, Keil T, Selim D, et al. Outcome and costs of homeopathic and conventional treatment strategies: a comparative cohort study in patients with chronic disorders. Complement Ther Med 2005; 13: 79–86.

Witt CM, Lüdtke R, Baur R, Willich SN. Homeopathic medical practice: long-term results of a cohort study with 3,981 patients. BMC Public Health 2005; 5: 115.

Trichard M, Chaufferin G Nicoloyannis N. Pharmacoeconomic comparison between homeopathic and antibiotic treatment strategies in recurrent acute rhinopharyngitis in children. Homeopathy 2005; 94: 3–9.

Spence D, Thompson E, Barron S. Homeopathic treatment for chronic disease: a 6-year university hospital based outpatient observational study. J Altern Complement Med 2005; 5: 793–8.

Sharples F, van Haselen R, Fisher P. NHS patients’ perspective on complementary medicine. Complement Ther Med 2003; 11:
243–8.

Rey L. Thermoluminescence of ultra-high dilutions of lithium chloride and sodium chloride, Physica (A) 2003; 323: 67–74.

Bell IR, Lewis DA, Brooks AJ, et al. Gas discharge visualisation evaluation of ultramolecular doses of homeopathic medicines under blinded, controlled conditions. J Altern Complement Med 2003; 9: 25–38.

Elia V, Niccoli M. Thermodynamics of extremely diluted aqueous solutions. Ann N Y Acad Sci 1999; 879: 241–8.

Linde K, Jonas WB, Melchart D, et al. Critical review and meta-analysis of serial agitated dilutions in experimental toxicology. Hum Exp Toxicol 1994; 13: 481–92.

Belon P, Cumps J, Ennis M, et al. Histamine dilutions modulate basophil activation. Inflamm Res 2004; 53: 181–8.

Witt CM, Bluth M, Albrecht H, et al. The in vitro evidence for an effect of high homeopathic potencies – A systematic review of the literature. Complement Ther Med 2007; 15: 128–38.

Homeopathy: the Evidence from Basic Research

A Memorandum submitted by Dr Peter Fisher

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, Berlin evaluated the quality and results of in-vitro biological experiments with ultramolecular stepwise agitated dilutions. Quality was assessed by a modified SAPEH score. 75 publications were found of which 33% were replications. 73% showed an effect with ultramolecular dilutions including 68% of high quality experiments. 73% of replication experiments were also positive. [13]

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 University of Naples has, over a decade published series of papers investigating physico-chemical properties of ultramolecular dilutions. They have detected, using standard methods, anomalies of specific conductivity, heat of mixing and other parameters.[34],[35],[36]These findings suggest the extended, ordered dynamics involving liquid water molecules, in the form of dissipative structures, within such dilutions. Dissipative structures, described by the Nobel Laureate Ilya Prigogine, are complex, self-organising systems, far from thermodynamic equilibrium.[37] Within a dissipative structure there is long-range interaction between particles, and they exchange energy and matter with their environment. Examples include cyclones, lasers and living organisms

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 Royal London Homoeopathic Hospital, part of University College London Hospitals NHS Foundation Trust. I occasionally accept speaking fees from homeopathic manufacturers, and have undertaken research projects funded by such companies. I do not have a private practice.

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. Berlin J Res Hom 1991; 1: 151-160.
[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.
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[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.
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Director of Research
Royal London Homoeopathic Hospital

Memorandum submitted by The British Homeopathic Association

By Robert T Mathie PhD, Research Development Adviser

1.  BACKGROUND

  1.1  Homeopathic medicines are normally prescribed to patients by homeopathic practitioners and on an individualised basis, with importance placed on the unique character and lifestyle of the person concerned. Some randomised controlled trials (RCTs) of homeopathy have reflected this approach. Others have investigated a given, standardised, homeopathic medicine taken by the entire sample of eligible patients, and where the input of a homeopathic practitioner may or may not have been involved.

  1.2  This document is a summary and update of the overview submitted jointly by the British Homeopathic Association and the Faculty of Homeopathy in 2008 to the Government Office for Science.[4] It is a factual account of best clinical research evidence in homeopathy published in peer-reviewed scientific journals up to and including October 2009. It focuses primarily on systematic reviews of published RCTs and reconciles those data with results obtained in the original RCT literature. Findings from non-randomised clinical studies are presented in brief. We conclude with a number of recommendations for future research development in homeopathy.

2.  SYSTEMATIC REVIEWS OF RANDOMISED CONTROLLED TRIALS

2.1  Comprehensive systematic reviews (all medical conditions with homeopathy research)
  Four out of five comprehensive systematic reviews of RCTs in homeopathy have reached the qualified conclusion that homeopathy differs from placebo.[1,2,3,4] One of those four reviews also stated there was "insufficient evidence […] to draw conclusions about the efficacy of homeopathy for any specific medical condition".[4] The fifth systematic review concluded there was "weak evidence for a specific effect of homeopathic remedies";[5] the methodology of that review and its conclusions have been challenged.[6] The value of any comprehensive systematic review, moreover, is limited by the small number of RCTs in homeopathy, the differing criteria used by reviewers for data extraction, the disparate modes of homeopathy investigated, the narrow focus typically on placebo controlled trials, and by the heterogeneous range of medical conditions being examined collectively.

2.2  Systematic reviews focusing on particular medical conditions
  The issue of heterogeneity of medical condition has been avoided in each of 17 systematic reviews that have focused, to date, on homeopathy RCTs (individualised or standardised treatment) in one of 16 particular clinical conditions. Five reviews concluded there was positive evidence for homeopathy (childhood diarrhoea;[7] post-operative ileus;[8] seasonal allergic rhinitis;[9,10] vertigo[11]); three concluded there was little or no evidence (attention-deficit hyperactivity disorder;[12] delayed-onset muscle soreness;[13] headache and migraine prevention[14]); nine did not offer a clear conclusion either way (anxiety;[15] chronic asthma;[16] dementia;[17] depression;[18] headache and migraine treatment;[19] HIV/AIDS;[20] induction of labour;[21] influenza;[22][5] osteoarthritis[23]).

2.3  Systematic reviews focusing on particular groups of diagnoses
  There are seven systematic reviews in this category. Four of these reviews were positive (allergies;[24] upper respiratory tract infections;[25,26] rheumatic diseases[27]); two were negative (ailments of childhood and adolescence;[28] cancer[29]); one was non-conclusive (cancer side-effects[30]). Homeopathic Arnica montana (often used in RCTs of post-operative pain or swelling) has itself been the subject of two systematic reviews: one was negative;[31] a more recent one was non-conclusive.[32]

3.  RANDOMISED CONTROLLED TRIALS OF HOMEOPATHY: THE ORIGINAL PEER-REVIEWED RESEARCH LITERATURE

3.1  Criteria and methods for data extraction
  3.1.1  We set clear criteria for including research papers in this overview. Non peer-reviewed research such as book chapters, conference proceedings and theses were excluded from consideration, as were papers in which the medicine tested had concentration greater than the homeopathic dilution 1X. This overview therefore contains references to all full papers of RCTs of homeopathy (any medical condition, treatment or prevention) that have been published in explicitly peer-reviewed journals in any country and in any language from 1950 to October 2009 inclusive. RCTs were categorised by whether: (a) they were controlled by placebo or by other than placebo (usual treatment or no treatment); and (b) the mode of homeopathic treatment was individualised or standardised.

  3.1.2  A peer-reviewed trial was eligible for inclusion only if a minimum standard of intrinsic quality was met. A study was defined as an RCT if the paper unequivocally stated there had been prospective random assignment to treatment. In the case of placebo-controlled trials, explicit mention of double blinding was also required; for other-than-placebo controlled (including equivalence) trials, observer blinding was sufficient for inclusion. These and a number of additional criteria of quality were met by a total of 142 RCTs in 129 peer-reviewed journal papers.

  3.1.3  Fewer than half the eligible RCTs included a power calculation and the associated pre-defined minimum effect that would be regarded as clinically important. In view of this low proportion of properly powered trials, positive or negative RCT findings are described here in terms only of their statistical significance, not their clinical importance.[6]

  3.1.4  A statistically conclusive trial result required that the 95% confidence interval (CI) of the mean difference in the outcome variable did not include 0 (or P<0.05); a statistically non-significant trial result meant that the 95% CI included 0 (or P>0.05). A study reporting statistically significant findings was either "positive" or "negative", depending on whether the homeopathy group was superior or inferior to control in at least one principal outcome. Relevant corresponding criteria were applied to other-than-placebo controlled trials.

  3.1.5  To be regarded as statistically conclusive, we required at least one significant finding out of no more than three statistical analyses of a given study's principal outcomes. Secondary outcomes were disregarded. This approach avoided the possibility of interpreting a trial as statistically conclusive based on merely one statistically significant positive or negative result out of many.

3.2  Randomised controlled trial findings
  3.2.1  Summary based on nature of control group: One hundred and twenty out of the total of 142 RCTs (85%) were placebo controlled. The other 22 RCTs (15%) were controlled by other than placebo. Of the 142 trials overall, the summary finding was positive in 44%, negative in 8% and statistically non-conclusive in 48%. Findings in the other-than-placebo controlled RCTs were conclusively positive or negative more frequently than those in placebo controlled RCTs:

  3.2.2  Summary based on mode of homeopathy: Forty out of the total of 142 RCTs (28%) have reflected the normal individualised mode of homeopathic treatment. Each of the other 102 RCTs (72%) has investigated a standardised homeopathic medicine. The percentage distribution of the summary findings does not differ between the two modes of treatment:

  3.2.3  The above RCTs represent research in a total of 80 different medical conditions. There is replicated research (>2 peer-reviewed RCTs per medical condition) in each of 28 conditions (90 RCTs in total). There is a singleton RCT for each of the other 52 conditions.

  3.2.4  Of the 28 conditions for which there is replicated research in RCTs, there are 13 that have not been the subject of formal systematic review to date. Viewed per condition, the balance of evidence from these RCTs is positive for fibromyalgia[33,34,35] and sinusitis,[36,37,38,39] and non-conclusive for insect bites,[40,41] menopause in breast cancer survivors,[42,43] post-operative pain or swelling (Arnica montana used in the majority of trials),[44,45,46,47,48,49,50] stroke,[51,52] and warts.[53,54] There was no identifiable balance of evidence in dermatitis,[55] irritable bowel syndrome,[56,57] leg ulcers,[58] otitis media[59,60] or post-operative analgesic intake.[61]

4.  NON-RANDOMISED RESEARCH

4.1  Controlled trials
  Non-randomised, controlled, parallel-group design has been applied to homeopathy. It has focused on homeopathy for either a particular medical condition (eczema;[62] insomnia;[63] otitis media;[64] vertigo[65]) or a specified range of complaints.[66,67,68] Results have been positive; in the absence of group randomisation, however, one cannot infer a clear causal relationship between the intervention and the clinical outcome in this type of trial.[69]

4.2  Non-controlled studies
  Non-randomised, non-controlled, studies can make a useful contribution to developmental research in complementary medicine including homeopathy.[70,71] Findings from studies in this category may be considered as an adjunct to research evidence obtained from RCTs and from non-randomised controlled trials; they do not in themselves constitute research evidence. Findings have been strongly positive, including those for dysmenorrhoea,[72] headache,[73] menopausal flushes[74] and sinusitis.[75] A cross-sectional survey undertaken collectively by the five NHS homeopathic hospitals reported improved patient-reported outcome whose extent and timing varied between the different principal medical complaints (eczema, chronic fatigue syndrome, menopausal symptoms and osteoarthritis).[76] This paper emphasised homeopathy's contribution to the healthcare of patients with multiple, complex, morbidities.

5.  SUMMARY OF CLINICAL RESEARCH IN HOMEOPATHY TO DATE

  5.1  Most comprehensive systematic reviews of RCTs in homeopathy (individualised or standardised treatment) have concluded there is evidence that the homeopathic intervention differs from placebo treatment.

  5.2  Condition-specific systematic reviews have indicated effectiveness of homeopathy (individualised or standardised treatment) in childhood diarrhoea, post-operative ileus, seasonal allergic rhinitis, and vertigo. They indicate non-effectiveness in attention-deficit hyperactivity disorder, delayed-onset muscle soreness, and in prevention of headache and migraine. Findings are non-conclusive for all other conditions that have been the subject of review.

  5.3  Homeopathy research has focused on a total of 80 different medical conditions, in which there is a total of 142 peer-reviewed RCTs that met a number of key quality criteria for this overview. Findings in 44% of those RCTs were positive, 8% were negative and 48% were non-conclusive. The majority of trials have examined standardised homeopathy and used placebo-controlled design. There has been replicated RCT research in each of only 28 medical conditions; of those without formal systematic review to date, there is a balance of positive RCT evidence for fibromyalgia and sinusitis.

6.  RECOMMENDATIONS

  6.1  New and independently conducted RCTs are essential to confirm or refute the currently available research evidence in homeopathy for specific conditions. There is a need to enhance the quantity and the quality of research on the effectiveness of individualised homeopathy, particularly in chronic conditions, as well as on efficacy of specific homeopathic medicines compared with placebo. Future trials must be statistically powered to ensure conclusions may be made about clinically relevant effects.

  6.2  Greater collaboration between homeopathic practitioners, conventional physicians and basic scientists would enhance the scope and quality of homeopathy research. Integration of homeopathic research in existing academic and clinical settings (by practitioners of homeopathy working within the NHS, where regulated and safe clinical practice is assured) raises standards of research in homeopathy, encouraging mutual understanding and promoting agreement on the interpretation of findings. An example of this approach recently has been the effective collaboration between the Universities of Leeds and Sheffield with Barnsley Hospital NHS Foundation Trust in an RCT of individualised homeopathy for fibromyalgia.[35]

  6.3  In focusing research on areas in homeopathy where positive findings from RCTs might be corroborated, the most promising targets include those with already replicated findings, such as fibromyalgia, seasonal allergic rhinitis, sinusitis, and vertigo. Attention must also be paid to areas where there is mainly non-conclusive or negative trial evidence to date.

  6.4  Moreover, emphasis should be placed on those clinical areas where RCT evidence is currently scanty but where homeopathy is frequently used in NHS practice,[76,77] particularly in diagnoses that are difficult to treat using conventional medicine and that have promising data from non-randomised studies. In this respect, especially worthwhile research targets include atopic eczema, chronic fatigue, depression, irritable bowel syndrome, menopausal symptoms, otitis media and premenstrual syndrome. Patients with complex medical predicaments are not normally eligible for RCT research but should be included in suitable clinical outcome studies, most notably in the clinical context of the homeopathic hospitals.

  6.5  The above recommendations for research development are consistent with comments made about homeopathy in the GO-Science Review of the Department of Health:
"A programme for a stronger evidence base would necessitate agreement between practitioners, patients and researchers on what should be evaluated, and on relevant endpoints. Flagship trials should be run in the most promising areas, chosen on plausibility, and patient demand. These should be well planned, including pre-defined agreement on what constitutes a minimally important clinical effect, and adequate resource, so that the results were clear-cut. […] The Health Technology Assessment Programme provided a framework that should be as applicable to research on homeopathy as to any other therapy."
GO-Science Review of the Department of Health, Annex 1 (2008). Government Office for Science: Department for Innovation, Universities and Skills; Paragraph 3.16.

7.  DECLARATION OF INTEREST

  The author of this overview is Robert T Mathie PhD, Research Development Adviser, British Homeopathic Association; he is not a homeopathic practitioner. The sole aim of this document is to provide a transparent, balanced and constructive summary of the clinical research evidence in homeopathy.

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Robert T Mathie PhD