Update on research in homeopathy. Peter Fisher FRCP, FFHom Director of Research Royal London Hospital for Integrated Medicine

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1 Update on research in homeopathy Peter Fisher FRCP, FFHom Director of Research Royal London Hospital for Integrated Medicine

2 Dr Peter Fisher Director of Research and Consultant Physician Royal London Hospital for Integrated Medicine (University College Hospitals NHS Foundation Trust) FRCP, Accredited in rheumatology and homeopathy Member, WHO expert panel on Traditional and Complementary Medicine Member, Advisory and Editorial Board, Cochrane Collaboration Complementary and Alternative Medicine Field Editor-in-Chief, Homeopathy Physician to HM The Queen

3 Contents What is homeopathy? Who uses homeopathy? Real world clinical effectiveness studies Randomized controlled clinical trials Biological models Safety

4 What is Homeopathy? key features Treatment of like with like Similia similbus curentur Minimum dose including ultramolecular dilutions Holism Constitution, terrain Sensitivity

threshold/non-threshold model StebbingARD Hormesis-the

5 Related concepts: Hormesisin animals hormesis = stimulatory or beneficial effect of low dose of toxin v linear threshold/non-threshold model StebbingARD Hormesis-the stimulation of growth by low levels of inhibitors. Sci Tot Environ 1982;22:

6 Related concepts: Vital Reaction Vital reaction is fundamental to homeopathy High dilutions trigger reaction without primary action Extensively experimentally verified hormesis, hormoligosis, paradoxical pharmacology, rebound effects, dose-dependent reverse effects etc mechanisms include up/down regulation, enzyme induction, cybernetic feedback but often uncertain presensitization crucial

Samuel Hahnemann Essay on a new curative principle Hufeland s Journal 1796 Described his self pathogenesis of China (Cinchona rubra) source of quinine Same year as vaccination introduced by Jenner

7 Samuel Hahnemann Essay on a new curative principle Hufeland s Journal 1796 Described his self pathogenesis of China (Cinchona rubra) source of quinine Same year as vaccination introduced by Jenner This seems to be the reason for this beneficial remarkable fact namely that since the general distribution of Jenner s Cow-pox vaccination, human small-pox never again appeared as epidemically or virulently as years before when one city visited lost at least one-half and often three-quarters of its children by death of this miserable pestilence. Footnote to para 46 Organon6 th edition

99 parts Succussion 10-2 1c/cH Succussion 10-4

8 Preparation of homeopathic dilutions 1 part mother tincture 1 part 99 parts water/ethanol 99 parts Succussion c/cH Succussion c/cH Succussion c/cH Lactose or sucrose pills

9 Avogadro s Law (Loschmidt s constant) The number of particles in one gram mole of a pure substance is x It is extremely unlikely that dilutions beyond 12c/cH or 23x/dH contain any molecule of the starting substance

10 Who uses homeopathy? How do the results of family physicians who use homeopathy compare with those who do not?

11 Homeopathy use in USA: National Health Interview Survey 2012 Harvard Division of General Medicine and Primary Care 2.1% of US population used homeopathy in past 12 months 15% increase since 2007 More likely to be female, healthier lifestyle, highly educated Respiratory, ORL most common (18.5%) Homeopathy users more likely to use multiple complementary and integrative therapies and to perceive it as helpful than supplement users. Uncommon, users perceive it as helpful Dossett M et al. Homeopathy Use by US Adults: Results of a National Survey. AJPH 2016 doi: /AJPH

12 No CIM Use (n=23009)* Other CIM Use (n=5298)* Supplements Without Homeopathy (n=5500)* Homeopathy Use (n=718)* Homeopathy use in USA: Estimated U.S. Population (66.4) (15.6) (15.8) (2.1) Size^ Sex Female (48.6) demographics 3341 (60.6) 3136 (54.5) 521 (69.9) Male (51.4) 1957 (39.4) 2364 (45.5) 197 (30.1) Age (22.9) 1111 (22.3) 793 (16.3) 115 (18.2) (24.9) Supplementary 1572 Table (29.8) A: Population 1325 Demographics (24.0) 220 (31.1) (33.3) 1779 (34.9) 2174 (41.1) 289 (39.4) (18.9) 836 (13.0) 1208 (18.7) 94 (11.3) Race White (78.1) 4184 (83.6) 4432 (84.5) 597 (87.0) Black 4233 (14.3) 515 (7.5) 518 (7.1) 53 (4.9) American Indian/ 246 (0.9) 58 (0.8) 41 (0.6) -- Alaskan Native Asian 1389 (5.3) 407 (6.1) 354 (5.1) 33 (3.9) Other 415 (1.5) 134 (2.0) 155 (2.7) 31 (3.3) Hispanic 4520 (17.3) 666 (10.3) 599 (9.8) 74 (8.9) Education Region Northeast 3910 (18.9) 972 (19.5) 773 (14.1) 119 (17.6) Midwest 4536 (21.2) 1274 (25.3) 1249 (26.7) 134 (20.3) South 9275 (40.1) 1574 (30.2) 1501 (28.1) 186 (28.3) West High School or 5288 (19.7) 1478 (24.9) 1977 (31.2) 279 (33.8) Marital Status Married/Living Equivalent (58.5) 2713 (62.7) 2869 (64.3) 377 (66.2) with Partner Widowed 2408 (6.6) 372 (4.3) 470 (5.5) 35 (2.4) Divorced > High School (11.3) 901 (10.8) 977 (11.7) 140 (12.8) Never Married 5630 (23.4) 1302 (22.2) 1174 (18.4) 164 (18.3) (52.3) Education < High School 4609 (17.6) 411 (6.7) 443 (6.9) 24 (4.6) High School or 6703 (29.5) 1051 (20.3) 1099 (20.1) 85 (10.7) Equivalent > High School (52.3) 3826 (72.8) 3947 (72.8) 609 (84.7) Family Income < $34, (35.4) 1764 (24.3) 1762 (23.8) 216 (23.1) $35,000 - $74, (30.0) 1573 (28.8) 1742 (31.4) 229 (29.7) $75,000 - $99, (10.6) 602 (12.9) 669 (13.5) 92 (15.8) $100, (17.4) 1102 (28.8) 1097 (27.0) 143 (25.4) < High School 4609 (17.6) 411 (6.7) 443 (6.9) 24 (4.6) 6703 (29.5) 1051 (20.3) 1099 (20.1) 85 (10.7) 3826 (72.8) 3947 (72.8) 609 (84.7)

13 Homeopathy use in USA: perceived helpfulness of therapies

14 Comparative effectiveness of homeopathy in French family practice: EPI-3 EPI3-laser largest cohort study of homeopathic care ever compared conventional, mixed and homeopathic General Practitioners representative sample of patients consulting for MSDs Cohorts for Musculoskeletal disease upper respiratory tract infections sleep disorders, anxiety and depression Clinical benefit, medical care and medication, adverse effects, loss of therapeutic opportunity Rossignol M et al. Impact of physician preferences for homeopathic or conventional medicines on patients with musculoskeletal disorders: results from the EPI3-MSD cohort. Pharmacopepidemiol. Drug Saf. 2012, 21(10):

15 Demographics & patient attitudes: EPI-3 Patients of homeopathic v conventional primary care physicians slightly more female higher education no big difference in comorbidities or quality of life Large differences healthier lifestyle belief in holistic and natural treatments attitude to participating in own care LertF et al. Characteristics of patients consulting their regular primary care physician according to their prescribing preferences for homeopathy and complementary medicine. Homp 2014:103, 51-57

16 EPI-3 Musculoskeletal Disease N=1153 CM=conventional medicine, MP= Mixed practice, Ho=homeopathy

17 Diagnoses of patients attending primary care physicians: EPI-3 Conventional, mixed, homeopathy n=6379

18 EPI-3 MSD: results Patients did not differ except for chronicity Higher for homeopathy Similar clinical progression Functional scores same after controlling for baseline NSAID use over 12 months almost half in homeopathy group Homeopathic 4%, Mixed GPs 20% in France Considerable impact on population health and healthcare costs

19 EPI-3 sleep disorder cohort 346 patients Homeopathy group more severe 41.3 v 24.3% Homeopathy much less psychotropic drugs OR 0.25, CI months adjusted multivariate analyses Same improvement in sleep disorders Grimaldi-Bensouda L, Abenahim L, Massol J et al. Utilization of psychotropic drugs by patients consulting for sleeping disorders in homeopathic and conventional primary care settings: the EPI3 cohort study Homeopathy (2015)

20 EPI-3 sleep disorder cohort

21 Comparative effectiveness of homeopathy in primary care in Germany 493 patients (315 adults, 178 children) Greater improvement in patients assessments after homeopathic v conventional adults: homeopathy 5.7 to 3.2; conventional 5.9 to 4.4 (p = 0.002) children 5.1 to 2.6 ;4.5 to 3.2 Physician assessments morefavourable for children with homeopathy 4.6 to 2.0 and ; p < 0.001). Costs no significant differences between groups adults: 2155 v 2013 p = children, 1471 versus 786, p = 0.137

002 Patient assessment of severity (0-10, 10 = worst possible)

22 Comparative effectiveness of homeopathy in primary care in Germany: results patient assessment Adults: Conv Homp P=0.002 Patient assessment of severity (0-10, 10 = worst possible) adjusted for gender, age, educational level, symptom duration and gender/age interaction

23 Swiss Health Technology Assessment: Homeopathy for upper respiratory tract infections and allergies (URTI/A)

24 Homeopathy for URTI/A types of homeopathy

25 Homeopathy for URTI/A: results 6/7 trials comparing to standard treatment, showed equivalence 1 (penicillin vs. homeopathy for streptococcal tonsillitis) inferior 8/16 placebo-controlled significant result in favour of homeopathy none individualized 4 trend, 4 no advantage

26 Swiss HTA Homeopathy for URTI/A: conclusions 24/29 trials positive significance or trend favouring homeopathy compared with placebo or standard treatment...the trial results showed probable effectiveness of homeopathy for allergies and infectious diseases of the upper respiratory tract. BergemannSM et al. Clinical studies on the effectiveness of homeopathy for URTI/A. In BornhöftG, MatthiessenPF. Homeopathy in healthcare effectiveness, appropriateness, safety, costs. Berlin: Springer 2011

27 Randomized controlled trials and meta-analyses of RCTs

28 No evidence!? randomized controlled trials of homeopathy June 2016: 1118 clinical trials of homeopathy 299 randomized controlled trials 66 individualized v placebo 15 individualized v other treatment 177 non-individualised v placebo 41 non-individualized v other treatment Approximately 45% positive, 45% inconclusive<10% negative

29 Recent meta-analysis of best randomized controlled trials of individualized homeopathy 32 RCTs, 24 medical conditions 22 trials analysable 95% confidence interval most reliable trials OR = % CI Mathie RT et al. Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis. Syst Rev 2014;3:142 Royal London Hospital for Integrated Medicine

30 Recent meta-analysis of best randomized controlled trials: all trials Royal London Hospital for Integrated Medicine

31 Recent meta-analysis of best randomized controlled trials: effect of focussing on best trials Better quality

32 High quality RCT: Individualized homeopathy v placebo for FMS Double-blind, parallel group randomised controlled Trial 62 patients, 3 months treatment homeopathy as indicated (41 different medicines) Rhus tox and Calcarea carbonica most frequently used Homeopathy significantly better than placebo for: tender point count tender point pain global health quality of life Trend for depression

33 Individualized homeopathy for FMS: results POMS=Profile of Mood States. Statistical analysis by ANOVA Bell I et al. Improved clinical status in fibromyalgia patients treated with individualized homeopathic remedies versus placebo Rheumatology 2004;43:

34 Isopathy for respiratory allergy: meta-analysis Isopathy= treatment of same with same eg homeopathic dilutions of pollen for hayfever 4 RCTs 2 hayfever (mixed pollen 30c) 1 asthma (individualised allergen, mostly house dust mite 30c) 1 perennial rhinitis (individualised, mostly house dust mite 30c) Total n=253 Highly statistically significant P=0.0007, 95% CI Reilly D et al Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ 2000; 321:471-6

35 Isopathy in respiratory allergy: summary of results

36 Biological models

Gelsemium in mouse model of anxiety In Light-Dark test, Gelsemium 5, 9 and 30c were associated with statistically significant increase in number of transitions between compartments Indicates

37 Gelsemium in mouse model of anxiety In Light-Dark test, Gelsemium 5, 9 and 30c were associated with statistically significant increase in number of transitions between compartments Indicates anxiolytic activity comparable to buspirone. non-linear Includes ultramolecular dilutions. Bellavite P et al. Assays of homeopathic remedies in rodent behavioural and psychopathological models. Homp 2009; 98,

38 Gelsemium in mouse model of anxiety Magnani P et al Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice Psychopharmacology DOI /s

39 Effect of Gelsemium in rat limbic system Effect of Gels on production of the neurosteroid allopregnanolone (3a,5a-THP) production in rat hippocampus and amygdala slices Venard C et al. Comparative Analysis of Gelsemine and Gelsemium sempervirens activity on Neurosteroid Allopregnanolone Formation in the Spinal Cord and Limbic System. ecam 2009 doi: /ecam/nep083

40 Hypericum in nerve injury model Rat sciatic nerve transected sham operation v silicon tube v silicon tube + Hypericum Hypericum 30c twice daily for 1 week. studied 4, 8, 12 weeks after surgery Significantly better function, muscle mass, nerve histology with Hypericum Mohammadi R et al. Homeopathic treatment for peripheral nerve regeneration: an experimental study in a rat sciatic nerve transection model. Homeopathy 2012; 101:

41 Hypericum in nerve transection:mean axon Done at Western College of Veterinary Medicine University of Saskatchewan *P < 0.05 Sil/Hypericum v Sil (ANOVA)

42 Arnica and gene expression in human macrophages: PCR quantitation THP-1 human macrophages, differentiated: mature macrophages IL-4 activated involved in tissue healing Arnica 2, 3, 5, 9, 15c Real-time quantitative Reverse Transcription Polymerase Chain Reaction (PCR) expression of key genes cytokines, receptors and transcription factors

43 Arnica and macrophage phenotypes

44 Arnica and gene expression in human macrophages: PCR quantitation In macrophages differentiated to wound healing phenotype Arnica affected gene expression CXC chemokine ligand 1 (CXCL1) coding for chief chemokine also CXC chemokine ligand 2 (CXCL2), Interleukin8 (IL8) and bone morphogenetic protein (BMP2) MMP1 coding for a metalloproteinase downregulated.

45 Arnica and gene expression in human macrophages: effect of IL-4 treatment

46 Effect of Arnica on CXCL1 gene expression in IL4 treated human macrophages 24h 2h

47 Arnica and gene expression in human macrophages: conclusions Positive influence of Arnica on neutrophil recruitment and on angiogenesis New insights into action as a promoter of healing Some genes it modifies key regulators of tissue remodelling, inflammation and chemotaxis.

48 Safety

49 Safety of homeopathy: multi-source systematic review Systematic review reports of adverse effects of homeopathic medicines including homeopathic companies and regulatory agencies Incidence of AEs greater with homeopathic medicines than placebo in controlled clinical trials (9.4 v 6.1)

50 Safety of homeopathy: multi-source systematic review conclusions Case reports often incorrectly identified `homeopathic products often herbal Homeopathic medicines prescribed by trained professionals probably safe, unlikely to provoke severe AEs Main risks indirect DantasF, RampesH. Do homeopathic medicines provoke adverse effects? A systematic review. Br Hom J , S1, S35-S38

51 Summary: Who uses and clinical effectiveness Patients who use homeopathy highly educated, healthy life style Clinical effectiveness studies show Acute: better results in routine practice Chronic: equivalent results with fewer harmful drugs Health technology assessment positive (Switzerland)

52 Summary: Randomized controlled trials >1000 clinical trials, ~300 RCTs Metanalyses positive Including high quality Particularly allergy and URTI

53 Summary: Biological models Animal models Mouse anxiety Nerve regeneration Arnica in cultured human macrophages High-tech, PCR

54 Summary: Safety Very safe Risks relate to poorly trained or dogmatic practitioners

Recent research in Clinical Homeopathy

Recent research in Clinical Homeopathy https://www.dropbox.com/s/mjq49 pvtpeeckwm/june%2024%20onc ology%20symposium%20jean%2 0Claude%20Karp%2C%20MD%2 Peter Fisher FRCP, FFHom 0and%20Christelle%20Charvet%