Oscillatory effects in a homeopathic clinical trial: an explanation using complexity theory, and implications for clinical practice

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1 (2002) 91, & 2002 The Faculty of PII: S (02) , available online at on ORIGINAL PAPER Oscillatory effects in a homeopathic clinical trial: an explanation using complexity theory, and implications for clinical practice M E Hyland 1 *, G T Lewith 2 1 Department of Psychology, University of Plymouth, Drake Circus PL4 8AA, Plymouth, UK; and 2 University of Southampton Four double-blind, randomised, placebo-controlled clinical trials of asthma or rhinitis treated with homeopathic immunotherapy (HIT) at a 30C potency have been published. The most recent study, involving house dust mite allergic asthmatics, failed to confirm a therapeutic improvement at the end of the study, but did provide preliminary evidence for an oscillation in outcome (both physiological and subjective) in with verum treatment to placebo. In this paper we show how such an oscillation is consistent with a complexity theory interpretation of how the body functions as a whole, and speculate on why different studies have produced different results. If the complexity theory interpretation is correct, then this will have a significant impact on the design of clinical trials in homeopathy and, possibly, other complementary medical interventions. (2002) 91, Keywords: isopathy; homeopathic immunotherapy; asthma; oscillation; aggravation; complexity; networks Introduction We have recently conducted a double-blind, placebocontrolled trial of homeopathic immunotherapy (HIT) in asthma. 1 Our main findings were different from those of two earlier HIT studies 2,3 and one later study. 4 Nevertheless, there were similarities between our results and unreported findings from those other studies. The purpose of this paper is to speculate on the mechanism responsible for the effects obtained in these four studies. 1 4 The studies Some of the parameters of the four studies are shown in Table 1. In all studies patients, either with asthma or *Correspondence: *M Hyland, Department of Psychology, University of Plymouth, Drake Circus, PL4 8AA Plymouth, UK. mhyland@plymouth.ac.uk Received 16 November 2001; revised 26 February 2002; accepted 25 March 2002 rhinitis, were treated with HIT which was administered in a randomised, double-blind trial, in a 30C potency with a placebo control. The same visual analogue scale (VAS) of perceived disease severity was used in all studies, where patients record their perception of disease severity on a daily basis. However, there were differences: sample size, the duration of treatment, the duration of the study and the methods for selecting patients differed between the four studies. Three of the studies 2 4 showed a clinical improvement in VAS at the end, one did not. 1 Two studies showed an initial aggravation or worsening on the VAS, 1,2 two did not. 3,4 Initial aggravation to homeopathy is said to occur in clinical practice in about 10 15% of patients receiving homeopathic treatment. Although our study 1 failed to show a clinical improvement at the end of the trial period, there was nevertheless a significant difference between active treatment compared to placebo over the course of the study. This difference was tested by repeated analysis of covariance which showed that the pattern of data collected over the course of the study was

2 146 Table 1 Summary of the four homeopathic immunotherapy (HIT) studies Reilly et al (1986) Reilly et al (1994) Taylor et al (2000) Lewith et al (2002) Disease Seasonal rhinitis Asthma Perennial rhinitis Asthma Duration of asthma 45 years 410 years 415 years 415 years Patient population General practice Hospital General practice General practice Formal disease diagnosis? Yes Yes Yes Yes Patient selection by homeopath No Yes Yes No Other inclusion criteria? Persistent hayfever over 2 summers Variable asthma with baseline recording Persistent perennial rhinitis Variable asthma with baseline recording Number entered/met entry requirements Number completed study Randomised placebo Yes Yes Yes Yes control study? Over what period was 2 weeks 1 day 1 day 1 day treatment administered? Type of treatment Pollen 30C Relevant allergen in Relevant allergen House dust 30C potency (usually in 30C potency mite, 30C house dust mite) (usually house dust mite) Duration of assessment from randomisation to end of treatment 2 weeks 4 weeks 4 weeks 16 weeks significantly differentfthis statistical method avoids the problem of multiple statistical testing between placebo and verum at each of the several time points. Thus, although the end points were not significantly different, and sometimes verum was better than placebo and sometimes vice versa, the pattern of data (ie, the degree of difference between verum and placebo of any kind over the course of the study) was statistically different from chance, at last at the 5% level. Using analysis of covariance, statistical significance was found for both physiological measures (for peak expiratory flow, PEF, P=0.025) and subjective measures (the VAS of patient perceived asthma severity, P=0.017, and for a category rating scale of mood, P=0.035). That is, in this study 1 and in contrast to others, significant effects were found not only for the VAS scale but also on other diary-based outcome measures. The pattern of data over the course of the study is shown in Figure 1, and examination of the data suggests that verum, compared to placebo approximates to an oscillation. Note, that the placebo is not constant over the course of the studyfplacebos often exhibit change due to trial and expectancy effects. Consequently, an interpretation of the verum oscillation must be understood in terms of the difference between verum and placebo. For each of the three variables, verum is worse than placebo at 3 and 5 weeks, verum is better than placebo at 7 and (except PEF) 9 weeks, worse again at 11 weeks and approaching equivalence at the end of the study. A qualitative impression is apparent from Figure 1 where it appears that oscillation has a period of about 3.5 weeks. The possibility of oscillation following HIT (ie, a second aggravation and improvement) has not been noted before. The authors of the other three studies 2 4 have provided an aggregate of all their previous data in their last publication. 4 Inspection of their figure suggests the possibility of oscillation, though the shorter time scale compared to Figure 1 1 makes comparison difficult. Whenever a new type of data, such as these are presented, there is always doubt over whether the data are replicable. It is certainly possible that our data are a Type 1 error, but if, until shown otherwise, we assume that the finding will stand the test of time, then two questions require explanation. First, what is the reason for the pattern of oscillation which is indicated in both psychological and physiological measures in 1 (Figure 1) and suggested in other studies 4? Second, why is clinical improvement noted in only three out of the four studies? The intelligent body hypothesis The starting point for understanding the action of homeopathic remedies is not the remedy itself, but the body. One only needs to consider the disparate symptoms that are described for each individual remedy within any materia medica to realise that homeopathy is based on the implicit metatheoretical assumption that the body is a complex system. Complex systems have emergent properties, and in particular, those that are network systems sometimes have emergent properties, such as intelligence (eg, pattern recognition, self-organisational adaptation), they are often historically sensitive and they also sometimes exhibit chaotic behaviour. The intelligent body hypothesis 5,6 suggests that the body is organised in two different ways. First, it is organised as a simple system (eg, a jumbo jet) such as that implicitly proposed in conventional Western medicine. This model is clearly applicable to the treatment of acute diseases such as orthopaedic trauma; in these clinical

3 Adjusted mean PEF Adjusted mean asthma VAS Adjusted mood mean Placebo am am Baseline Week Figure 1 Significant oscillations obtained in a large placebocontrolled trial. Note: All graphs are adjusted so placebo and verum start at the same point. Each point in the graph is based on the means of each patient s recordings during that week (ie, the overall mean of the patients means). PEF=peak expiratory flow and is a measure of physiology of the lung. Asthma VAS=visual analogue scale of patient perceived asthma severity. Mood=patient s rating of mood on a category rating scale. Reprinted from Lewith GT, Watkins AD, Hyland ME, Shaw S, Broomfield JA, Dolan G, Holgate ST. A double-blind, randomised, controlled clinical trial of ultramolecular potencies of house dust mite in house dust mite allergic asthmatic patients. BMJ 324: Reproduced with permission. situations it is simply about mending or replacing a damaged area in an otherwise healthy system. Second, it is organised as an intelligent, chaotic network that extends throughout the body, a network that is at least as intelligent as recent developments in artificial intelligence. Causal connections in this extended network are achieved neurologically as well as through ligands and receptorsfrather like a telephone system that can operate using fixed lines as well as mobile phones. According to this hypothesis, there is a single intelligent network that co-ordinates the many control systems of the body, by altering the parameters of those control systems so as to achieve genetically specified outcomes (ie, the extended network acts as a second- or third-order control system). The extended network operates according to rules, one of which is the compensation rule. 6 This rule states that the network compensates for external disturbances, so as to achieve genetically specified outcomes, and therefore this rule can explain the evolution of control systems in the body. In essence, the network checks that its control systems (or other systems) are operating correctly (ie, according to genetically predetermined rules) and makes adjustments if it finds they are not. The compensation rule can explain the development of disease because sometimes this process of checking and adjustment is at the root of the pathological change that occurs in persistent chronic illness. In particular, the rule creates dysregulation in the network when the network is receiving incompatible signals. The compensation rule has been used to explain the excessive inflammatory response of asthma in the lung. 7 According to the two-phase network theory of asthma, a major factor in asthma causation is the repeated combination of immune challenge (eg, virus, house dust mite) and immune suppression (eg, air pollutants). Under these circumstances, the network detects that the immune response is sub-optimal (because it has been suppressed) and therefore adjusts the immune response in an upwards direction. Asthma is like a thermostatically controlled room where the window has been left open so that adjustments to the thermostat are made and the boiler provides excessive heat. The excessive and dysregulated immune activity of asthma is a response of the system detecting, over a period of time, that immune activity is insufficient. However, because there is just one extended network, dysregulation in one part has ramifications throughout the network. Physiological treatments should have psychological effects (and vice versa) as the brain is just one part of the network. The covariation of psychological and physiological outcomes is therefore consistent with these outcomes being driven initially by changes in the network. Some networks can become stuck in semi-stable states. These semi-stable states can be referred to as local minima (ie, states which the network relaxes into but which are not the most stable as would be the case with an overall or global minimum), or as attractors in that the network is attracted to (or round) the state described as an attractor. Either way, networks can become stuck in particular kinds of dynamically or statically described states, and although they can be shifted from these stuck states, doing so requires additional energy. Asthma (and many other chronic diseases) can be treated as stuck states of a network. That is, the underlying pathology remains because the network is unable, by itself, to achieve the healthy state of effective regulatory competency. Although the consequences of being stuck in a state of dysregulation can be treated (eg, treating asthmatics with inhaled steroids), the underlying pathology remains and the disease becomes chronic, therefore conven- 147

4 148 tional preventative treatment is suppressive rather than curative. To treat the network, it is necessary to find a way of disturbing it in some way that will re-set its thermostat and allow it to become unstuck and thereby return the organism to a healthy state of dynamic interaction. Theoretically, there are two possible way of doing this: either by shifting the dynamics of the network in the direction of the desired state, or by shifting it in the opposite direction and catching it on the rebound which the network naturally produce in response to any disturbance. Fhow it affects the network Although the idea that networks are relevant to homeopathy is presented elsewhere, 8 the present hypothesis suggests that homeopathy and allopathic medicine work in fundamentally different ways. 5 Whereas allopathic medicine treats the body by correcting faults in a simple system (ie, like correcting broken parts of a jumbo jet), complementary and alternative medicine works primarily by unsticking the networkfie, by subtle therapy in contrast to robust therapy. Our hypothesis is similar to that proposed by Bellavite et al 9 in suggesting that homeopathy mimics one of the body s communication system. Bellavite et al believe that homeopathy mimics one of the signalling systems in a control loop (in control theory terminology either the input or output signals), and the homeopathic effect is some kind of control compensatory reaction to the signal of increased symptoms. However, because of evidence that control systems are themselves controlled by a network system (ie, the second-order control systems have additional emergent properties) we believe that feedback is more likely to be that associated with genetic specification in the higher order network system. That is, homeopathy mimics a signal which shows to what extent this self-adapting system functions correctly, with the homoepathic signal indicating that the system is dysfunctioning. Then, due to the compensation rule, the network responds to this disturbance by compensating, and this compensation pushes the network back in the direction of good health. Our theory therefore differs from Bellavite et al 9 in suggesting that, in addition, homeopathy works at some higher order level than that of the dysregulated control loopfand consequently can explain, in addition to symtomatological treatment, the higher order patterns associated with characterological treatment. It also provides some explanation for why compensation occurs. In a more recent paper, Bellavite et al 10 introduces complexity theory to model possible higher-order systems in the body (the five elements theory of traditional Chinese medicine), showing how these produce oscillations in system behaviour. These oscillations would be consistent with intrinsic variability in chronic diseases, such as asthma. There is therefore considerable overlap our two theoretical perspectives. We both suggest there is a level of organisation in the body that operates like a parallel processing network, and therefore exhibits properties of complex systems. There are differences, however. Bellavite et al 10 show how stable networks exhibit oscillatory behaviour. The network is stable in the sense that is not undergoing self-organisational change, and the oscillation is the result of the nonchanging activation pattern in the network. In our case, the compensation rule shows how the activation pattern of the network changes: the network is undergoing self-organisational change and so is not stable. In our case, the oscillation is a property of the system: the oscillation is in the system rather than the result of a stable system that is exhibiting oscillatory behaviour. Our oscillations are therefore at a metalevel compared to those of Bellavite et al, and our prediction is that the these oscillations could be a complex pattern. As the activation rules of the network change, sometimes giving rise to stable and sometimes to oscillatory patterns of behaviour, the overall behaviour of the system reflects this complex interplay of levels, and so the pattern of oscillatory behaviour is likely to be person specific. Interpretation of data: oscillation The most recent study 1 did not find a therapeutic effect of a homeopathic remedy, but did provide evidence that the remedy had an effect on the body that was different from placebo. These data are consistent with the remedy setting up a self-organisational oscillation in the network, but where the network, instead of becoming fixed in a more healthy state simply oscillates backwards and forwards around the original state of health. The network is behaving rather like a bag of jelly which is pushed in at one side and slowly oscillates in and out. Theoretically, it is likely that there are many different periods of oscillation both within an individual patient and also that there are differences in periodicity between patients. The oscillation found in Figure 1 1 is likely to be an average description of this oscillatory behaviour of a particular sample, but there may be several different kinds of oscillation that are unique to individual patients. Interpretation of data: differences in obtaining clinical effects There are several reasons why the most recent study 1 did not show an overall improvement whereas the earlier studies did. First, most of the data in the earlier studies 2 4 was obtained with rhinitis, whereas the most recent was an asthma study. 1 Although a clinical

5 improvement was reported in an asthma study, 3 the sample size is small and, unusually for a clinical trial, the placebo condition showed a deterioration. It is common to obtain a placebo improvement in asthma clinical trialfeither psychologically mediated or because of better compliance with conventional asthma medication. A second reason for the difference in results may arise over the selection of patients. The use of a homeopath to veto or control entry into the study with or without baseline pre-randomisation homeopathic remedies is likely to enhance the selection of volunteers who respond to homeopathy so that these volunteers are more likely to improve following HIT. Complex systems are historically sensitive, and there may be some way in which the homeopath selects those patients whose history predisposes them to respondfor those patients whose current state predisposes them to respond. Finally, differences may arise over the time period of the studies. It is interesting to note that if the study by Lewith et al 1 ended at point at the top of an oscillation (see Figure 1), then comparison between baseline and the end of trial could well have produced a significant effect. Implications of our data We believe that homeopathic treatment may disturb the self-organisation of a network, and in so doing set up an oscillation which has a patient specific pattern. However, whether that oscillation ends up as a longterm therapeutic improvement depends on other factors inputting into the network. Consequently, a single remedy based on the diagnosis of an individual s allergy may be ineffective therapeutically, because the oscillation in itself is non-therapeutic. Most homeopaths would expect a patient with asthma to require several different individualised remedies, possibly including HIT, over a period of some months in order to obtain clear therapeutic benefit. This may involve several homeopathic aggravations. Unsticking the system appears clinically to be a complex process in asthma and one that is unlikely to respond to a single split dose of HIT. Rhinitis appears be simpler to treat and may be more responsive to HIT, possibly because fewer rhinitis patients take long-term inhaled steroids. We should also consider that in order to achieve therapeutic benefit, the network may need other therapeutic inputs as well as a homeopathic remedy. There are several candidates for this, but they will all have in common that they provide a shift of the network towards a more healthy or optimised state. These additional inputs could include the context of the consultation (a therapeutic consultation), various psychological therapies or the simultaneous use of nutritional medicines and/or herbal remedies in conjunction with the homeopathic treatment. The implication is that combined therapies may work in a fundamentally different way from therapies in isolation. We should consider the possibility that homeopathy, and indeed probably all complementary and alternative therapies, are complex interventions and will require a different clinical trial methodology from that currently employed for us to understand and evaluate them. Our observations of an oscillatory effect may offer some clues as to the mechanisms that underlie this complexity. At this moment in time, replication is needed to confirm this observation of oscillation (or at last a second aggravation) and we ask other researchers to consider this possibility as a plausible line of investigation in their research. Acknowledgement We thank Dr Dan Joyce for helpful advice on systems dynamics. References 1 Lewith GT, Watkins AD, Hyland ME, Shaw S, Broomfield J, Dolan G, Holgate ST. A double-blind, randomised, controlled clinical trial of ultramolecular potencies of house dust mite in asthmatic patients BMJ 2002; 324: Reilly DT, Taylor MA, McSharry C, Aitchison T. Is homoeopathy a placebo response? Controlled trial of homoeopathic potency, with pollen in hayfever as model. Lancet 1986; 2: Reilly D, Taylor MA, Beattie NGM, Campbell JH, McSharry C, Aitchison TC, Carter R, Stevenson RD. Is evidence for homoeopathy reproducible? Lancet 1994; 344: Taylor MA, Reilly D, Llewellyn-Jones RH, McSharry C, Aitchison TC. Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ 2000; 321: Hyland ME. The intelligent body. New Scientist 2001; 170: Hyland ME. The intelligent body and its discontents. J Health Psychol 2002; 7: Hyland ME. A two-phase network theory of atopy and asthma causation: a possible solution to the impact of genes, hygiene and air quality. Clin Exp Allergy 2001; 31: Torres JL. Homeopathic effect: a network perspective. Br Hom J (in press). 9 Bellavite P, Lussignoli S, Semizzi ML, Ortolani R, Signorini A. The similia principle: from cellular models to regulation of homeostasis. Br Hom J 1997; 86: Bellavite P, Semizzi M, Lussignoli S, Andrioli G, Bartocci U. A computer model of the five elements theory of traditional Chinese medicine. Compl Ther Med 1998; 6: