### TL;DR Randomized controlled trials are the most reliable me...
A randomized controlled trial is a scientific experiment used to te...
Homeopathy is a system of alternative medicine created by German ph...
You can find more information about the original paper by the Truth...
Reminds one of the phrase attributed to Max Planck: “Science advanc...
Although it was a double-blind trial all biases could not be elimin...
> "*punctum saliens*, the crucial element of their design: one must...
FUN FACT: The first blind experiment was conducted by the French...
Inventing the randomized double-blind trial: the
Nuremberg salt test of 1835
MStolberg
J R Soc Med 2006;99:642–643
Additional material for this article is available from the James Lind
Library website [http://www.jameslindlibrary.org], where this
paper was previously published.
Control groups, randomization, blinding, placebos and
related methods designed to eliminate bias have become
widely recognized as key features of efforts to identify more
effective and safer treatments. As others have shown,
1,2
many of these methods were first developed and applied in
the context of controversies between mainstream medicine
and new, ‘alternative’ types of medicine. A very early
example of randomization and double blinding was an
evaluation of homeopathy conducted in Nuremberg in 1835
by a ‘society of truth-loving men.’
3–5
At the time, homeopathy had garnered considerable
support among the upper classes in the then Kingdom of
Bavaria. In Nuremberg, one of Bavaria’s largest and most
affluent cities, Karl Preu and Johann Jacob Reuter had
treated some of the most prominent families with
homeopathy, including members of the high aristocracy.
In 1834, annoyed by homeopathy’s rising popularity,
Friedrich Wilhelm von Hoven, the city’s highest ranking
public health official and head of the local hospitals,
published a devastating critique of homeopathy under the
pseudonym ‘E_.F_.Wahrhold’,
6
which he had used
previously in a way that allowed readers to identify the
true author. Von Hoven accused homeopathy of lacking any
scientific foundation. He suggested that homeopathic drugs
were not real medicines at all and alleged homeopathic
cures were either due to dietetic regimens and the healing
powers of nature, or showed the power of belief. He called
for an objective, comparative assessment by impartial
experts. If, as he expected, homeopathic treatment proved
ineffective, the government would need to take drastic
measures to protect the lives of deceived patients.
In 1835, by which time Karl Preu had died, Johann
Jacob Reuter was the sole remaining physician homeopath
in the city. He reacted to Wahrhold/von Hoven’s attack
with an ardent defence of homeopathy
7
and pointed out that
even children, lunatics and animals had been successfully
cured. Based on Hahnemann’s assertions, he challenged
Wahrhold/von Hoven to try the effects of a C30 dilution of
salt on himself. The odds were ten to one, he claimed, that
his opponent would experience some extraordinary
sensations as a result—and these were nothing compared
to the much stronger effects on the sick.
Perhaps surprisingly, Reuter’s opponents took up his
challenge. Various (allopathic) pharmacists and physicians
conducted individual tests, following Reuter’s indications.
Then it was decided to stage a larger-scale trial. It remains
uncertain who took the initiative for this, but it was
probably von Hoven and the circle of physicians around
him. They were supported by George Lo
¨
hner, the owner
and editor of the daily Allgemeine Zeitung von und fu
¨
r Bayern,
who later compiled the trial report. Lo
¨
hner had no medical
training but his newspaper had repeatedly carried polemical
attacks against homeopathy.
Following a widely publicized invitation to anyone who
was interested, more than 120 citizens met in a local
tavern. The minimum number needed to proceed had been
fixed at 50. The design of the proposed trial was explained
in detail. In front of everyone, 100 vials were numbered,
thoroughly shuffled and then split up at random into two
lots of 50. One lot was filled with distilled snow water, the
other with ordinary salt in a homeopathic C30-dilution of
distilled snow water, prepared just as Reuter had
demanded: a grain of salt was dissolved in 100 drops of
distilled snow water and the resulting solution was diluted
29 times at a ratio of 1 to 100. Great care was taken to
avoid any contamination with allopathic drugs. The two
pharmacists in charge had taken two days off before the
experiment. They had taken a bath and they used new
weighing scales which had not even come close to an
allopathic pharmacy.
A list indicating the numbers of the vials with and
without the salt dilution, respectively, was made and sealed.
The vials were then passed on to a ‘commission’ which
distributed 47 of the vials to those among the audience who
had declared their willingness to participate (the report
speaks of 48 vials but this included an unnumbered vial with
salt dilution given to a physician by the name of Lochner).
The participants’ names and the number of the vial that each
had received were written in a second list. Seven more
FROM THE JAMES LIND LIBRARY
642
JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 99 December 2006
Institut fu¨ r Geschichte der Medizin, Oberer Neubergweg 10a, 97074 Wu¨ rzburg,
Germany
E-mail: michael.stolberg@mail.uni-wuerzburg.de
numbered vials were distributed after the meeting by one of
the members of the commission.
Three weeks later, at a second meeting, the participants
were asked to report whether they had experienced
anything unusual after ingesting the vial’s content. Those
who did not come to the meeting were asked to send this
information in. Responses were thus obtained from 50 of
the 54 participants. Those participants who had perceived
something unusual described their symptoms, as required
by the protocol.
Finally, the sealed lists were opened to see who had
received water and who the homeopathic dilution, and a list
of results was compiled. It turned out that only eight out of
the 50 participants who reported back had experienced
anything unusual. Five of them had received the dilution,
three had received water (somewhat confusingly, the report
mentions Dr Lo
¨
hner as a 51st reporting participant and the
9th who had experienced symptoms; but he was aware that
he had taken the salt dilution and thus had not actually
participated in the trial). The vast majority of those who had
received the homeopathic salt dilution had thus not
experienced any ‘effect’. The investigators concluded that
Reuter was wrong.
From a modern point of view, the major features of the
trial can be summarized as follows:
(1) The trial design (protocol) was carefully set out and the
details of the study were made public in advance;
(2) The number of participants was relatively large and the
differences between the two groups would have been
significant if Reuter had been right;
(3) Assignment to one group or the other was apparently
perfectly randomized;
(4) A control group receiving only placebo was used;
(5) The trial was double blind: neither the participants nor
those who organized the trial, distributed the vials and
documented the effects had any idea whether a vial
contained the homeopathic high dilution or merely
water;
(6) A rough comparative statistics of the results was
compiled;
(7) Irregularities were carefully recorded, such as the
failure of four participants to report back, and the fact
that several vials were distributed only after the first
tavern meeting.
The organizers concluded that the symptoms or changes
which the homeopaths claimed to observe as an effect of
their medicines were the fruit of imagination, self-deception
and preconceived opinion—if not fraud. In spite of their
efforts to achieve perfect blinding and randomization, they
seem to have been aware, however, that the homeopaths
could come up with solid methodological reasons for not
accepting this interpretation: in this specific setting, even
randomization and double blinding could not eliminate bias.
Most participants seem to have opposed homeopathy, and if
they wanted to discredit it, they could do so simply by
reporting that they had not experienced anything unusual.
No matter whether they actually had received the dilution
or not, this would invalidate Reuter’s claims. Only if the
participants were, in principle, convinced that the substance
might have an effect would this problem have been
overcome and double blinding could have served its
intended purpose.
Historically, the value of the trial report thus lies above
all in the principles it set out. The organizers called on
others and, in particular, on the homeopaths themselves, to
perform and repeat similar trials, with different dilutions,
and to make the results public. They stressed once more the
punctum saliens, the crucial element of their design: one
must avoid anything that might enable the participants and
those responsible for the trial to guess whether the actual
medicine was given or not.
REFERENCES
1 Kaptchuk TJ. Intentional ignorance: a history of blind assessment and
placebo controls in medicine. Bull Hist Med 1998;72:389–433
2 Dean ME. The Trials of Homeopathy. Origins, Structure and Development.
Essen, Germany: KVC Verlag, 2004
3 Stolberg M. Die Homo
¨
opathie auf dem Pru
¨
fstein. Der erste
Doppelblindversuch der Medizingeschichte im Jahr 1835. Mu
¨
nchener
medizinische Wochenschrift 1996;138:364–6
4 Stolberg M. Die Homo
¨
opathie im Ko
¨
nigreich Bayern (1800–1914).
Heidelberg: Haug, 1999
5 Lo
¨
hner G, on behalf of a society of truth-loving men. Die
homo
¨
opathischen Kochsalzversuche zu Nu
¨
rnberg [The homeopathic salt
trials in Nuremberg]. Nuremberg, 1835
6 Wahrhold EF. Auch Etwas u
¨
ber die Homo
¨
opathie. Nuremberg, 1834
7 Reuter JJ. Sendschreiben an Dr E Fr Wahrhold als Erwiederung auf dessen
Schrift ‘Auch etwas u
¨
ber die Homo
¨
opathie’. Nuremberg, 1835
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JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Volume 99 December 2006

Discussion

A randomized controlled trial is a scientific experiment used to test the effectiveness of new treatments by reducing sources of bias. It’s main features are: - Subjects are randomly allocated to two or more groups - control and experimental groups. - The groups received different interventions being assessed - The experimental group receives the intervention being evaluated - The control group receives no intervention or a placebo - Compare the measured responses of the control and experimental groups In order to measure the effectiveness of the experimental intervention the results of the experimental groups are compared to those of the control group. The trials can be blind or double blind: - **blind:** the information is from part of the participants of the experiment. - **double-blind:** the information is withheld from participants and organizers of an event. Good blinding reduces the sources of experimental bias. Here is a flowchart of a randomized trial: ![flowchart](https://i.imgur.com/j2x0Bmz.png) ### TL;DR Randomized controlled trials are the most reliable method available for testing new treatments. They have become the standard that pharmaceutical companies must meet for calculating and proving the level of efficacy and safety of an experimental drug. Randomized double blind placebo control trials are considered the **“gold standard” of epidemiological studies.** A double-blind study is one in which neither the participants nor the experimenters know who is receiving a particular treatment. It is of utmost importance to **prevent bias in research results.**, it is particularly useful for preventing bias due to demand characteristics or the placebo effect. This paper describes how the first Randomized double blind placebo control trial took place and its results. > "*punctum saliens*, the crucial element of their design: one must avoid anything that might enable the participants and those responsible for the trial to guess whether the actual medicine was given or not." You can find more information about the original paper by the Truth-loving men published in 1835 here: [Löhner G, on behalf of a Society of truth-loving men (1835)](https://www.jameslindlibrary.org/lohner-g-on-behalf-of-a-society-of-truth-loving-men-1835/) !["original paper"](https://i.imgur.com/HyCfGSi.jpg) Although it was a double-blind trial all biases could not be eliminated. It is possible that there was a **selection bias**, i.e. the participants that signed for the trial could have mainly been anti-homeopathy people and thus report false results if they wanted to discredit it. Because of selection bias there is no guarantee that the sample obtained is representative of the population intended to be analyzed. Homeopathy is a system of alternative medicine created by German physician Christian Friedrich Samuel Hahnemann in 1796. Hahnemann believed that a substance that causes the symptoms of a disease in healthy people would cure similar symptoms in sick people. Homeopathic preparations are manufactured using a process of homeopathic dilution - a substance is diluted with distilled water or alcohol and then vigorously shaken. Hahnemann believed that this process activated the *"vital energy"* of the diluted substance, and that successive dilutions increased the potency of the preparation. !["Samuel Hahnemann"](https://i.imgur.com/0Jgi4f4.jpg) FUN FACT: The first blind experiment was conducted by the French Academy of Sciences in 1784 to investigate the claims of [mesmerism](https://en.wikipedia.org/wiki/Animal_magnetism). **King Louis XVI of France commissioned the French Academy of Sciences to investigate mesmerism and its therapeutic claims. The Academy appointed several prominent citizens to the committee, including Benjamin Franklin and Antoine Lavoisier** along with other prominent scientists of France. The commission conducted a series of experiments to evaluate the use of Mesmerism to treat neurological and other syndromes including headache and epilepsy, using blindfolds and screens. Their report demonstrated the usefulness of blinding to reduce bias in clinical research, yet despite this early discovery, blinding was not widely accepted or routinely used until the 20th century. Reminds one of the phrase attributed to Max Planck: “Science advances one funeral at a time.” Thus selection bias does not -> Because of selection bias there is no Is "buas" by any chance just an accidental misspelling of "bias"? Yes. Good catch. Corrected. Thanks for the suggestion. Updated.