Memorandum submitted by Professor Harald
Walach and Professor George Lewith (HO 14)
HOMEOPATHIC PATHOGENETIC TRIALSA SUMMARY
OF 20 YEARS OF REFLECTION, DATA COLLECTION AND ANALYSIS
1. INTRODUCTION
1.1 Homeopathic Pathogenetic Trials (HPTs),
or, as they used to be called, homeopathic remedy provings, are
the pillar of homeopathy. [1] Given their scientific importance,
we submit this document to the Commons Science & Technology
Committee in its Evidence Check of Homeopathy.
1.2 Hahnemann founded homeopathy on the
basis of his own experience by ingesting China bark; [2,3] these
were the first HPTs proper. The Hahnemannian version of an HPT
is the following idea: Take a purportedly medicinal substance
whose therapeutic or pharmacological effect you do not know. Have
some healthy volunteers ingest it in a dose that is likely not
harmful. Note down the symptoms these volunteers experience. Use
the symptoms to guide your application in ill people: whenever
ill people present with a collection of symptoms that could be
seen in healthy volunteers, use the same substance to treat the
ill person. Thus, the HPT is in fact an operationalisation of
the similia rule. In order to know what the similar symptoms are
that should be looked out for, you need to know them in the first
place. An HPT provides you with this knowledge.
1.3 A large part of the Materia Medica Pura
is actually a result of these early provings. Later on he discovered
a good way of diminishing the strong symptoms by diluting his
medications, serendipidously hitting at succussion and potentisation,
the other important principle of homeopathy. In his final edition
of the Organon, he made 30CH[35]
the standard potency for HPTs. This seems to be a practice adhered
to for quite some time. [4,5] In fact, a lot of the standard polychrest
medicines in use by homeopaths today date back to Hahnemann's
own HPTs. They have not gone unchallenged, [6-11] but pragmatically
seem to be still useful.
1.4 Although the first blinded and placebo
controlled trials in the history of medicine were such early HPTs,
[12-14] the circular epistemology of homeopathy placed less emphasis
on the methodological rigour of HPTs than on the usefulness of
the symptoms derived from them. It was only in more recent years,
during the revival of homeopathy research in the seventies and
eighties in Germany and elsewhere that the question was asked,
whether symptoms derived by such HPTs or provings are actually
different from the placebo. A recent systematic review of all
HPTs available from 1945 until 1995156 studies
altogetheris not very flattering regarding the methodological
sophistication of HPTs. [15,16]
2. THE NAÏVE
APPROACH
2.1 Testing the Individualised Difference
Hypothesis: Randomised Single Case Studies
2.1.1 Walach et al had participants
take Belladonna 12/30CH or placebo in a randomised order, double
blind. Randomising the sequence of Belladonna and placebo periods,
four weeks each, where only the first day of each week was a day
when a remedy was to be taken. Participants noted their symptoms
in diaries that collected a predefined set of symptoms, half of
which were Belladonna symptoms, the other half symptoms not typical
for Belladonna. This enabled straightforward randomisation tests
that allow the definition of statistical significance on an individual
level to determine whether the number of Belladonna symptoms was
different with Belladonna from placebo. Quite paradoxical results
were reported. [17,18] Of the 25 experiments, one individual
had significantly (p=0.01) more Belladonna symptoms with Belladonna,
one had significantly more Belladonna symptoms with placebo, and
in several cases there were interesting changes with Belladonna
that were graphically obvious but that were not significant.
2.2 Replicating the Naïve Approach
2.2.1 In the meantime Walach et al
ran a larger replication study using a similar design as in the
first Belladonna study, improved by several design features: [19]
they had more participants (n=87), we introduced a wash-out period
of one week between the experimental phases of the crossover-design
and reduced the intake of medication or placebo to two weeks each,
gave medication only during the first three days of the first
week and then had people observe for the rest of the two weeks.
They used the same structured diary and, based on our previous
study, formulated some hypotheses that guided us towards combining
symptom categories to clusters to be tested experimentally. Although
there was a clear and significant difference between baseline
and each of the experimental interventions in some of the variables,
there was no significant difference between homeopathy and placebo
in those predefined categories. Thus, the initial tentative results
were not replicable, and there was no indication from this study
that symptoms produced by placebo and those produced by Belladonna
30CH were in any way different from each other. [20]
3. SCRUTINISING
THE DATA
MORE CAREFULLY
USING GRADE-OF-MEMBERSHIP
ANALYSIS
3.1 Intrigued by the phenomenology of the
results Walach thought that something different was actually going
on in the background variability in both groups. The problem was
that there were not only any symptoms that were indistinguishable
under both conditions, but that Belladonna-specific symptoms
were seen to a large extent also with placebo. That was the scientific
puzzle. Having ruled out methodological artifacts, such as carryover
effects or response bias, we were quite convinced that this was
a genuine effect. To probe this further Walach employed a very
sensitive multivariate method: Grade-of-Membership (GoM) Analysis
on the dataset of the 2001 study. [21]
3.2 In essence GoM analysis is a multivariate
model. [22,23] While most multivariate analysis models, such as
the General Linear Model, use additive models, GoM uses a multiplicative
algorithm solved by an iterative maximum-likelihood approximation.
This allows for the multivariate usage of many variables even
with few cases and it is very sensitive. Normally, we think of
group membership as a categorical event: we either cast a vote
for a candidate, or we don't; we either belong to a group, or
we don't. GoM allows us to group people according to a grading,
a kind of probability judgment of belonging to a group, expressed
in percent. So a particular person might belong to an experimental
group to some degree of probability, and also, to a lesser degree
of probability, to another group. More importantly, the analysis
also defines the relevance of the variables that are used to reach
the decision.
Using GoM, Walach identified to which extent
each individual belonged to the Belladonna and to the placebo
condition and which variables predicted this group membership,
analysing the first and second half of the crossover design separately.
The results are revealing (Table 1):
3.3 Table 1Results of a Grade of
Membership Analysis of the Data from the Replication Belladonna
HPT: [19,21] Variables used to Predict Membership of Participants
to Groups in Phase 1 or Phase 2 of the Crossover Study,
and Likelihood of Group Membership Predicted by a Variable
Category | Homeop.
Phase 1
| Homeop.
Phase 2 | Placebo
Phase 1
| Placebo
Phase 2 |
forehead right | 12.6 | 2.4
| 9.2 | 11.8 |
nose | 60.6 | 5.1
| 6.6 | 29.8 |
mouth | 43.7 | 11.7
| 6.2 | 8.7 |
skull back right | 3.47 |
0 | 0 | 8.15 |
whole throat | 56.2 | 16.6
| 4.9 | 8.0 |
shoulder right | - | 8.28
| - | 0.0 |
genitals | 57 | 28.8
| 14 | 7.5 |
small of back | 22.8 | 12.2
| 0.0 | 0.0 |
whole body | 57.8 | 28.9
| 13.2 | 13.3 |
feelings, mind | 100 | 72.8
| 29.4 | 57.2 |
always | 100 | 56.6
| 40 | 40.9 |
afternoon | 100 | 41.2
| 6.3 | 31.7 |
pain | 100 | 55.8
| 27.8 | 54.4 |
| |
| | |
3.4 This is the output of the analysis using only the
most important variables to predict group membership. The first
column indicates the variable used, the following two columns
show the prediction of membership (expressed as percentage) in
the first and the second phase of the trial, when homeopathy (Belladonna
C30) is taken, the last two columns when placebo is taken. It
is interesting to compare the percentages of membership prediction
for columns Homeopathy phase 1 and Placebo phase 1, and then
the same for phase 2. Ideally, if separation of the groups were
perfect, the two homeopathy columns should be relatively similar
to each other and very different from two placebo columns. They
are not. So we see symptoms that define membership in the Belladonna
condition (symptoms of the nose, for instance, 60% membership
association with Belladonna in phase 1) that are virtually reduced
to unimportance in phase 2 (only 5%), and the other way round.
More importantly some of the symptoms are quite typical for Belladonna
(symptoms of the throat, for instance, or symptoms starting in
the afternoon). It seems that some symptoms typical for Belladonna
have emerged during the HPT. So the problem really is that the
typical symptom pattern is shifting to placebo, at least partially,
during the second half of the trial. Although only exploratory
it highlights the phenomenology of HPTs with a very sensitive
quantitative pattern-recognition technique. Most recently, a careful
German re-proving of Galphimia glauca has produced exactly this
result. [24]
3.5 The tentative conclusion from this re-analysis was
that obviously homeopathic remedies do produce some specific symptoms
but they also produce these specific symptoms under placebo. Is
it due to the shortcomings of our method, or is the phenomenon
real? Walach had started working on the assumption that the effects
of homeopathy are due to what we have called generalised entanglement
[25] and which I have used to render a rational reconstruction
of a non-classical model of homeopathy. [26] By that we mean that
the effects of homeopathy may be specific, but they are due to
non-local correlations as a consequence of the systemic set-up
of homeopathy and the treatment situation. This is a consequence
of how the whole system is formally constructed. A corollary of
this model is that it would predict some specific symptoms also
in the control group and that, with repeated experimentation,
the specificity is bound to vanish. [27]
3.6 This sets up a conundrum: How are we to prove experimentally
that homeopathic remedies are producing specific symptoms if,
by the very experimental set-up, we are likely to destroy this
effect?
4. EXPLORING NEW
ROADS
4.1 A New HPT Model
4.1.1 Walach et al developed a completely new
approach out of the experiences of the previous trials [28] and
decided to use a different HPT methodology. The methodological
reasoning is the following:
(a) A full phenomenological account of all experiences should
enter the database. All participants are encouraged to report
every occurrence that is unusual for them in a diary. To enhance
the recall of such events, a supervision interview is conducted
every day either by phone or personal interview by a supervisor.
(b) As controls we introduce blinding and randomisation. Hence
none of the participants knows what remedy is being used, nor
whether they are randomised to receiving placebo or real substance.
(c) In order to exclude any effects of suggestion and social
desirability, the substance is chosen out of a predefined list
by a third party at random, blinding also the director of the
study and all staff associated with handling data. This ensures
an unbiased experience and processing of symptoms as much as possible.
(d) Medication is taken individually, until symptoms appear.
If no symptoms appear after three days, the intake is stopped
and the individual taken out of the study.
(e) If the symptom database has been created and is closed,
all symptoms are scrambled up, dissociated from their temporal
and individual ordering by putting them into the head-to-foot-scheme
familiar from homeopathic repertories, in symptom units that correspond
to these rubrics.
(f) The database is then given to a materia medica expert
not otherwise associated with the study. This expert does not
have access to the randomisation code but is given the name of
the remedy tested. At this stage, this person and the pharmacist
who chose the remedy are the only ones privy to this information.
(g) The expert then uses a computerised repertory to decide,
for every symptom, whether it is a symptom typical for the remedy
according to the sources, or not. Thus, the remedy typical symptoms
are counted as "1", the atypical symptoms as "0".
(h) The database is transformed back into the group system.
For every participant we count the number of symptoms typical
for the remedy and the number of atypical symptoms, averaging
across the experimental and control group. This gives a clear
testable quantitative outcome score that can be easily tested.
4.2 Pilot Studies Using the New Methodology
4.2.1 Walach et al then completed four studies
following this model. The first two studies were pilot studies.
[29,30] In one study Cantharis (chosen randomly from a list of
12 lesser remedies) was evaluated against placebo, in the
other Calendula, Ferrum muriaticum (also chosen randomly from
a list) and placebo in a three-armed design. In the first study
there were more symptoms typical for Cantharis in the Cantharis
group than in the placebo group during and less atypical symptoms,
but there were also more symptoms typical for Cantharis in the
placebo group, which was unexpected (Figure 1).
4.2.2 Figure 1Results of the Cantharis Proving:
[30] Symptoms Typical for Cantharis and Atypical Symptoms During
Baseline and During the Proving Period, for the Cantharis and
the Placebo Group

4.2.3 Although the effect was not significant in this
pilot it was quite sizeable (d=0.4). When the group were randomised
to receive homeopathic Cantharis but were dosed with it later
there were also more symptoms typical for Cantharis. This effect
size was very larged=1.0. Ideally, one would have double
or triple-evaluation of the same database and only use symptoms
that all agree on for calculating inter-rater reliability. This
process mirrors faithfully normal practice where one homeopath
translates symptoms into remedy pictures.
4.2.4 In the three-armed study [29] we found a similar
and quite puzzling result. Here the total number of symptoms experienced
during the proving phase in the experimental groups was significantly
different between the experimental and the placebo control group,
as were the number of Calendula symptoms in the Calendula group
(Figure 2) with a large effect size of d=2.8.
4.2.5 Figure 2Three-Armed HPT of Calendula vs.
Ferrum muriaticum vs. Placebo (n=7 participants in each group):
Mean Number of Symptoms Typical for Calendula, Ferrum muriaticum
or Atypical Symptoms in each Group. [29]

4.2.6 What can also be seen is that significantly more
Calendula symptoms were experienced by participants who had taken
Ferr. mur. compared with those taking placebo (effect size d=1.75),
and that a sizeable number of Ferr. mur. symptoms were also observed
in the Calendula group. While this effect might also be due to
the fact that Ferrum muriaticum is a little known substance and
hence difficult to identify, the observation that Calendula symptoms
were more frequent in the Ferrum mur group is difficult to reconcile
with the assumption that these effects are artifacts.
4.3 Two Parallel Replication Studies
4.3.1 Following on from these observations Walach et
al conducted a study with two arms, placebo vs. homeopathy, another
one with three arms, comparing placebo to two different remedies
with one of the remedies being common to both studies. The remedies
chosen from a predefined list of 20 remedies, in this case
newly proven ones; Ozone and Iridium, with Ozone being the one
common to both studies. When both studies were combined, a clear
significant difference for symptoms typical for Ozone during the
treatment period emerged (Figure 3).
4.3.2 Figure 3Combination of Two Studies Testing
Ozone vs. Placebo. [31] Significantly More Symptoms Typical for
Ozone During the Experimental Phase in the Group Taking Ozone
than in the Group Taking Placebo

5. THE WAY
FORWARD
5.1 Walach et al believe they have proven the
case that this new methodology of re-proving homeopathic remedies
can now tease out at least partially the specificity of homeopathic
remedies vis-à-vis placebo in a rigorous experimental
design, where other recent approaches have failed. [32-35] While
HPTs can be conducted this way, one should avoid the direct replication
of any study by using the same types of remedies. A way forward
would be to test different remedies, perhaps in several studies
with more than two arms that have one or two remedies in common.
Then a decision could be made, after the fact and at random, which
arms to discard and which to combine. By the combination of changing
remedies each time a study is conducted and combining different
studies, it might be possible to produce enough single studies
with significant outcome testifying to the specificity of symptoms
and thus avoiding the observed decline effect. [36] This methodology
has only one purpose: to discover whether known homeopathic substances
are able to produce symptoms in healthy volunteers that are different
from those elicited by placebo. Its pre-supposition has been mentioned:
it can only be used if the medication in question is known.
5.2 To the novice and the outside observer it should
also be clear that the proving methodology of homeopaths for the
purpose of discovering new remedies is different from the author's
in several respects, as a rule: they very often do not have symmetrical
control groups, ie only few persons, though randomised and mostly
double-blinded, receive placebo, [9,24,37] and very often symptoms
appearing in the control group are also counted as remedy symptoms,
if they fulfil the typical criteria for a symptom defined by Bayr
and Stübler [38].
5.3 There is surely a common core to the proving methodology:
the careful observation of changes by experienced provers who
ingest a potentised substance unknown to them. The symptoms are
noted in a diary and verified with a supervisor on a daily basis.
Little has changed in principle since this methodology was invented.
[39] The only thing we have become suspicious about is how powerful
placebos are, and that there are likely a lot of specific symptoms
to be observed even under placebo. Everyone still adhering to
a classical pharmacological model when investigating homeopathy
will have difficulty explaining this conundrum. Homeopathic provings
are difficult to investigate but as we begin to understand the
process, our methodology improves as it becomes more informed.
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DECLARATION OF
INTERESTS
Professor George Lewith is a homeopathic practitioner and a researcher.
Professor Harald Walach is a researcher and has no conflict of
interest.
November 2009
35
ie a potency that has been diluted 30 times in the ratio
1:100 (hence "C" for centum-hundred) in separate
glass vials (hence "H" for "Hahnemann"). Back
|