SCIENTIFIC STUDIES IN HOMEOPATHY

Today I would like to present to you the current evidence base of homeopathy. Is homeopathy based on evidence? You may ask: “Is this important for us to know? We know that homeopathy can be effective!” But outsiders ask us to demonstrate the effectiveness and show the evidence. The concept of evidence-based medicine (EBM) is key in modern medicine. Doctors are expected to be aware of the latest evidence when taking clinical decisions. So, is homeopathy evidence based medicine? To answer that question I would like to start with explaining what evidence based medicine actually is, because I know that there are some misunderstandings about it.

According its founding fathers Sackett and Feinstein evidence based medicine is “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients”. They emphasise that it is not "cookbook" medicine, but requires a bottom up approach that integrates the best external evidence with individual clinical expertise and patients' choice.

In fact EBM has three pillars: external evidence, clinical expertise and patients’ choice whereas all three are equally important. Our clinical expertise including our expertise in homeopathy is one of the leading factors in clinical decision making. And so is the choice of the patient. It carries substantial weight if the patient prefers homeopathy to conventional medicine.

However, when EBM comes into the picture, the external evidence often receives most attention. So this is also the main subject of my presentation.

Traditionally scientists use a hierarchy of evidence. Case studies are low in the hierarchy, cohort studies or observational studies are placed higher in the hierarchy, randomised controlled trials (RCTs) higher, and systematic reviews are considered to be the top.

Looking at the clinical research in homeopathy, we find hundreds of thousands of case histories, recording successful cases. That is impressive, and still, according to modern EBM standards, this is considered to be very low evidence.

Observational studies are positioned higher in the hierarchy. Several of them have been conducted in thousands of patients in Germany, Switzerland and the United Kingdom. They show consistent positive results in 40-70% of the patients as regards disease symptoms, overall wellbeing and the reduction of the use of conventional medication. And, importantly, we have to take into account that these studies do not concern patients with acute self-limiting diseases. The majority of patients had chronic conditions, many had multiple pathologies and many had not responded to previous conventional treatment.

Several cost-effectiveness studies conducted in Germany, France and Switzerland show that GPs practising homeopathy have better results at comparable costs in comparison with conventionally practising GPs. Although homeopathic medicines are less expensive, consultations often last longer and can therefore be more expensive than conventional consultations.

Some other studies show that from a long-term and large-scale perspective homeopathy is cost-effective because general health (not only the presented symptoms) has improved, future consultations are less frequent, absenteeism is shorter, fewer visits to medical specialists are needed, hospitalisation is shorter, all in comparison with patients who receive conventional treatment only.

Higher in the hierarchy pyramid we see experimental research, i.e. studies in which one group receives the treatment under study and the control group receives a placebo or other treatment that already has proven its effectiveness. These studies are usually randomised and therefore named ‘randomised controlled trials’ (RCTs). Although the concept of evidence is multi-faceted, in recent years it has become progressively reduced to accepting RCTs as the gold standard. RCTs, however, have also drawbacks.

While RCTs can be useful in assessing the effects of a single intervention on a single symptom or outcome, they are far less suitable when studying the overall effects of a holistic therapy in a complex organism with multiple problems.

Notwithstanding this a considerable number of RCTs in homeopathy have been published with far more positive than negative outcomes. 142 RCTs have been published in peer-reviewed scientific journals. From them 120 (85%) RCTs were placebo controlled, 22 RCTs (15%) were controlled by other than placebo. Summary finding in 44% of the RCTs was positive for homeopathy, negative in 8% and statistically non-conclusive in 48%.

Going to the top of the pyramid, 4 out of 5 systematic reviews of all RCTs in homeopathy conclude that homeopathy has an effect that is greater than placebo. The 5th, the well-known 2005 Lancet meta-analysis, concluded that “There was weak evidence for a specific effect of homoeopathic remedies, but strong evidence for specific effects of conventional interventions. This finding is compatible with the notion that the clinical effects of homoeopathy are placebo effects”. It was heavily criticised for being biased and not meeting basic (QUOROM) scientific standards. I will go into some more detail about this meta-analysis.

The 2005 Lancet review/meta-analysis was originally a part of the Swiss CAM Evaluation project PEK and was performed by a team led by a very competent opponent of homeopathy, professor Matthias Egger. They started with 110 clinical trials of homeopathy, which were to be matched with 110 clinical trials of conventional medicine. They then reduced these 110 homeopathy trials to 21‘higher-quality trials’ and then to 8 ‘larger higher-quality trials’. The final conclusion was based on these 8 studies.

Interestingly, the authors found that “trials of homeopathy tended to be of higher methodological quality than conventional-medicine trials, although most trials of either type of medicine were of low or uncertain quality”. In fact there they found 21 high-quality trials in homeopathy and only 9 high-quality trials in conventional medicine.

But the problem was that the definition of ‘higher quality’ was based on opaque, unpublished criteria. And the trials on which the conclusion was based, were not mentioned in the publication.

The Evaluation Committee of the Swiss PEK Study criticised the authors for that in April 2005; in the Lancet publication (August 2005) these data were still missing. After publication the authors still refused to disclose these data. After more pressure the data were disclosed in December 2005, but no Odds Ratios, Confidence Intervals, or Standard Errors were given.

After disclosure the data were re-analysed by Luedtke and Rutten. One of the things they found out was that the Lancet study discarded four out of six best studies in Linde's meta-analysis (1997). These studies were: (Reilly 1986, Hofmeyr 1990, De Lange-de Klerk 1994, Reilly 1994). So there was selection bias.

They defined ‘larger trials’ as ‘trials with Standard Error in the lowest quartile’. Using this definition they concluded that there were 8 higher-quality trials, leading to a negative outcome for homeopathy.


INDICATION HOMEOPATHY CONV. MEDICINE
Diarrhoea Jacobs n=116 Kaplan n=256
Treatment of influenza Papp n=334 Nicholson n=319, De Flora n=248
Prevention of influenza Rottey n=501
Plantar warts Labrecque n=162
Weight loss Schmidt n=208
Muscle soreness Vickers n=400
Headache Walach n=98
Sinusitis Weiser n=104
Stroke (venous) Horn n=454
Upper genital tract infection Crowley n=273
Seasonal allergic conjunctivitis Moller n=146

The included homeopathy studies were a positive study of the effect of individualised homeopathy in childhood diarrhoea (Jacobs), a positive study of Oscillococcinum in the treatment of flu (Papp), a positive study of a complex homeopathic medicine containing potencies of various influenza viruses and bacteria all in 200K in the prevention of flu (Rottey), a negative study of a combination of Thuya occidentalis 30C, Antimonium crudum 5C, Acidum nitricum 7C on plantar warts (Labrecque), a negative study of the effect of Thyreoidinum 30C on weight loss in fasting individuals (Schmidt), a negative study of the effect of Arnica montana 30D on muscle soreness in marathon runners (Vickers), and a negative study of individualised homeopathy patients suffering from headache (Walach).

The definition of ‘larger trials’ normally means ‘larger than median (= middle value)’. When Luedtke/Rutten re-analysed the trials using the usual ‘larger than median’ criterion, they found 14 larger higher-quality trials (n > 65), leading to a significantly positive result for homeopathy.

So the meta-analysis results depend on how the threshold for ‘large’ studies was defined. The result was positive for homeopathy if the normal ‘larger than median’ criterion is used, negative if the unusual ‘Standard Error in the lowest quartile’ criterion is used, as Shang et al. did. Intention or coincidence?

Another interesting finding was the effect of including a particular diagnosis in the set of higher-quality trials. 4 of the 21 higher-quality trials in homeopathy dealt with the prevention or treatment of muscle soreness in marathon runners. 3 out of the 4 were negative for homeopathy. 4 matched conventional trials for the same indication were too small and low quality and were not included.

Of course, it is highly doubtful if muscle soreness in - very healthy - marathon runners is a medical condition that can be ‘cured’. When Luedtke/Rutten excluded the studies on muscle soreness and restricted their analyses to the remaining 17 trials, they found an overall statistically significant positive effect for homeopathy.

So, the overall results – and the conclusions drawn from them – change depending on which subset of homeopathic trials is analysed. The choice of other meaningful subsets could lead to the opposite conclusion. Intention or coincidence?

Surprisingly, the authors themselves highlight – but dismiss – the fact that 8 trials of homeopathy in upper respiratory tract infections have strongly positive findings overall.

They state that 8 studies is too few to question their conclusion about the whole set of publications. Their conclusion about the whole set, however, was also based on 8 studies. Is eight enough or not? The authors simply refuse to believe the positive results of clinical trials of homeopathy.

So, four out of five major systematic reviews of RCTs in homeopathy have concluded that homeopathy has an effect greater than placebo. The fact that these meta-analyses showed positive evidence for homeopathy is remarkable because meta-analyses are far from appropriate when trials are extremely heterogeneous – as in homeopathy – not only in results but also in the interventions and health conditions under study (over 80 different medical conditions and different types of homeopathy) and when a therapeutic system works in some but not all indications. The Cochrane Handbook for Systematic Reviews recommends that: "Meta-analysis should only be considered when a group of trials is sufficiently homogeneous in terms of participants, interventions and outcomes to provide a meaningful summary".

That means that the question “Are the effects of homeopathy placebo?” does not make sense. Similarly it does not make sense to ask whether conventional medicine is placebo. It is more important to look at specific diseases or areas of diseases.

There are systematic reviews focused on RCTs of homeopathy in 15 specific areas. And these condition-specific systematic reviews have indicated effectiveness of homeopathy in childhood diarrhoea, post-operative ileus, hay fever, vertigo, allergies, upper respiratory tract infections and rheumatic conditions. In addition, there is a balance of positive RCT evidence for fibromyalgia and sinusitis.

So there is clinical evidence for the effectiveness of homeopathy. And still critics do not accept that and maintain that homeopathy cannot possibly work. They assert that homeopathy is a sort of super-placebo. In their opinion, the long doctor-patient contacts can explain why people experience improvements in their health status. A recent German study , however, demonstrated that the placebo effect in placebo controlled double blind RCTs in individualised homeopathy is not larger than in conventional treatment.

Why do these critics not accept the evidence? A famous epidemiologist stated: “A reflection on the scientific behaviour of adherents of conventional medicine toward one form of alternative medicine — homeopathy — teaches us that physicians do reject seemingly solid evidence because it is not compatible with theory ”.

Dr Iain Chalmers, director of the UK Cochrane Centre and ardent proponent of systematic reviews, said a few years ago: “Critics of complementary medicine often seem to operate a double standard, being far more assiduous in their attempts to outlaw unevaluated complementary medical practices than unevaluated orthodox practices.

These double standards might be acceptable if orthodox medicine was based solely on practices which had been shown to do more good than harm, and if the mechanisms through which their beneficial elements had their effects were understood, but neither of these conditions applies. “

Why exactly do sceptics refuse to accept the effectiveness of homeopathy? They assert that there is no scientific explanation for its effectiveness, that the similia principle lacks all logic, that ultramolecular homeopathic preparations (concentrations < Avogadro) do not contain any molecules, that molecules are necessary for effectiveness, and that therefore all positive clinical evidence for homeopathy is unreliable.

In one sentence: “I cannot understand how it could be possible, so it is not possible.”

What these sceptics do not know is that there is accumulating evidence in basic research for the similia principle and measurable effects of even serially agitated high dilutions.

As to the similia principle, toxicological and pharmacological phenomena such as hormesis, drug rebound effects and paradoxical pharmacology are very widely observed. They have in common the occurrence of 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.

Dutch cell biologists Wiegant and Van Wijk examined the validity of similia principle on a cellular level. They demonstrated that low stress doses (heat, arsenic or cadmium) can stimulate self-recovery if these cells were exposed to high doses of these stressors beforehand. In other words, the similia principle seems to be a biological phenomenon.

In homeopathy various potencies, i.e. serially agitated dilutions, are used, from low to high. Many homeopathic medicines are not in ultramolecular dilutions. Relatively low potencies can have a usual molecular effect; from biology we know that low concentrations down to 10-22 M can be biologically active. But the question is: can ultramolecular preparations have a measurable effect?

Well, there is replicated high-quality basic research in biological experiments on intact animals, plants and isolated cells and cell cultures, as well as in physical experiments, that clearly demonstrate that even ultramolecular preparations have measurable effects.

A recent meta-analysis reviewed 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.

To give you a few examples, in biological experiments there has been replicated results in the following areas:
• inhibitory effect of serially agitated high dilutions of histamine on the activation of basophil leucocytes,
• effect of serially agitated high dilutions of acetosal on bleeding time, platelet aggregation and coagulation,
• effect of serially agitated high dilutions of thyroxine on the rate of amphibian metamorphosis,
• protective effect of serially agitated high dilutions of mercury on the mortality of poisoned mice,
• effects of serially agitated high dilutions of arsenic on the toxic effect of material doses of arsenic trioxide on wheat shoot growth.

In physical research most attention has focussed on structural or coherence effects induced in water by the preparation process. Several experiments have demonstrated structural changes of water in ultramolecular homeopathic preparations.

I will just list a few of the methods used: low temperature thermoluminescence, flux calorimetry, conductometry, Raman and Ultra Violet spectroscopy, and NMR (Nuclear Magnetic Resonance).

An international association of around 100 pharmacologists, biologists, physicians, chemists and physicists working in the field of ultramolecular preparations is the GIRI = Groupe International de Recherche sur l'Infinitésimal = International Research Group on High Dilution and Very Low Dose Effects. These scientists have published their papers in conventional scientific journals as well as in the International Journal of High Dilution Research. The Homeopathy Basic Research Experiments (‘HomBRex’) Database contains over 1400 experiments in 1000 publications.

So, as a conclusion we can state that he theory/belief that homeopathy, by its use of ultramolecular preparations, is implausible or impossible, is not correct.

Now we come back to the question: how convincing is the evidence?

Thomas Kuhn in his well-known book “The Structure of Scientific Revolutions” maintains that a paradigm, or shared view, persists for a while but then becomes obsolete because it becomes disturbed by too many ‘anomalies’, which do not fit into, and cannot be explained by, the existing paradigm. It is then replaced by a new paradigm, which is able to explain the anomalies. He calls this phenomenon paradigm shift. And I believe we are close to such a paradigm shift.

I can see that in the near future possible explanatory models will come from emerging sciences, such as systems biology and biosemiotics. System biology considers a biological system such as a human individual as a hierarchically organised network of interactions. Homeopathy has the same perspective on the human being.

In biosemiotics, the sign rather than the molecule is the basic unit for studying life. In homeopathy it is the information of the remedy rather than the pharmacological action that helps the organism to recover from disease.

Dear colleagues, I hope you are now well aware of the actual evidence base for homeopathy. I have also showed you why the sceptics are wrong. They simply do not know the facts. You know the facts. Please tell the whole world about them. Homeopathy is evidence based medicine.

Thank you for your attention.


Notes
1. [Shang A et al. (2005) Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet, 366:726-32]
2. Nuhn T, Lüdtke R, Geraedts M (2010). Placebo effect sizes in homeopathic compared to conventional drugs – a systematic review of randomised controlled trials
3. Vandenbroucke JP, de Craen AJP (2001) Alternative Medicine: A “Mirror Image” for Scientific Reasoning in Conventional Medicine. Annals of Internal Medicine, 135:507-513
4. Witt CM 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


Author: Dr. Ton Nicolai, president of European Committee of Homeopathy (ECH).
Presentation at the IV Congreso Nacional de Homeopatía in Barcelona, 11 June 2010.