Extracted from Nexus
Volume 14, Number 4
(June - July 2007)
body of research reveals not just psychological and
perceptual components to the placebo effect but also a
biochemical substrate to the mechanism.
Peter Arguriou was born in Greece in the summer
of 1973. He studied medicine at the University of Athens
Medical School, but left disappointed by the mechanistic
perceptions governing medicine. Later, he briefly
studied classical homoeopathy at the Aegean University
under Alternative Nobel Prize winner George Vithoulkas.
He writes for the Greek press and is the author of eight
books (fiction, science fiction, poetry - most of them
He is a
member of the Hellenic MENSA and currently is working on
a book regarding novel epidemics, bad science, the gene
promise, the media travesty in coverage of science news,
orchestrated propaganda and the corruption of the
scientific establishment by big business and political
agendas. He can be contacted by email at
One of the most commonly used terms in medical language is the word
placebo. The placebo effect is used as a scale for evaluating the
effectiveness of new drugs. But what exactly is the placebo effect
and what are its consequences in the deterministic structure of
The placebo effect has been frequently abused by health
professionals to denote and stigmatize a fraud or fallacy.
Alternative therapies have often been characterized as merely
placebos. But the placebo effect is not a fraudulent, useless or
malevolent phenomenon. It occurs independently of the intentions of
charlatans or health professionals. It is a spontaneous, authentic
and very factual phenomenon that refers to well-observed but
uninterpreted and contingent therapies or health improvements that
occur in the absence of an active chemical/pharmacological
substance. Make-believe drugs - drugs that carry no active chemical
substances - often act as the real drugs and provoke therapeutic
effects when administered to patients.
In many drug trials, the manufacturers of the drug sadly discover
that their product is in no way superior to the effect of a placebo.
But that does not mean that a placebo equates to a null response of
the human organism. On the contrary, a placebo denotes non-chemical
stimuli that strongly motivate the organism towards a therapeutic
That is, the placebo effect is dependent not on the drug's
effectiveness but solely on therapeutic intention and expectation.
positive and negative thinking
The placebo effect has been often misunderstood as a solely
psychological and highly subjective phenomenon. The patient,
convinced of the therapy's effectiveness, ignores his symptoms or
perceives them faintly without any substantial improvement of his
health; that is, the patient feels better but is not healthier. But
can the subjective psychological aspect of the placebo effect
account for all of its therapeutic properties?
The answer is
the placebo effect refers to an alternative curative
mechanism that is inherent in the human entity, is motivated by
therapeutic intention or belief in the therapeutic potential of a
treatment, and implies biochemical responses and reactions to the
stimulus of therapeutic intention or belief.
But placebos are not always beneficial: they can also have adverse
effects. For example, administering a pharmacologically inactive
substance to some patients can sometimes bring about unexpected
health deteriorations. A review of 109 double-blind studies
estimated that 19 per cent of placebo recipients manifested the
nocebo effect: unexpected deteriorations of health.1
In a related experiment,
researchers falsely declared to the volunteers that a weak
electrical current would pass through their head; although there was
no electrical current, 70 per cent of the volunteers (who were
medical students) complained of a headache after the experiment.2
In a group of patients suffering from carotid atherosclerosis,
prognosis and progression of the disease were burdened when their
psychological health was bad (i.e., they were affected by
hopelessness or depression). In another group of carotid
atherosclerosis patients, prognosis and progression were burdened
not only by hopelessness but also by hostility.3 In patients with
coronary heart disease, hopelessness was a determinative risk
factor.4 Social isolation, work stress and hostility comprised
additional risk factors.5
Positive or negative thinking seems to be a decisive risk factor for
every treatment, perhaps even more important than medical
The nocebo effect appears to have a specific biological substrate. A
group of 15 men whose wives suffered from terminal cancer
participated in a small perspective study. After their wives'
deaths, the men experienced severe grief that caused immuno-depression.
The spouses' lymphocytes
for a period of time after their wives' deaths responded poorly to
mitogenes. Grief had assaulted their immune system. The study
proposed that grief and grief-induced immuno-depression resulted in
high-level mortality of the specific group.6
history of a small miracle
The term placebo (meaning "I shall please") was used in mediaeval
prayer in the context of the phrase Placebo Domino ("I shall please
the Lord") and originated from a biblical translation of the fifth
century AD.7 During the 18th century, the term was adopted by
medicine and was used to imply preparations of no therapeutic value
that were administered to patients as "decoy drugs".
The term began to
transform in 1920 (Graves 8), and through various intermediate stages
(Evans and Hoyle, 1933 9; Gold, Kwit and Otto, 1937
194611) was fully transformed in 1955 when it finally claimed an
important portion of the therapeutic effect in general. Henry K.
Beecher, in his 1955 paper "The Powerful Placebo", attributed a
rough percentage of 30 per cent of the overall therapeutic benefit
to the placebo effect.12
In certain later studies, the placebo effect was estimated at even
higher, at 60 per cent of the overall therapeutic outcome. In a
recent review of 39 studies regarding the effectiveness of
antidepressant drugs, psychologist Guy Sapirstein concluded
that 50 per cent of the therapeutic benefits came from the placebo
effect, with a poor percentage of 27 per cent attributed to drug
intervention (fluoxetine, sertaline and paroxetine). Three years
later Sapirstein, along with a fellow psychologist Irving Kirsch,
processed the data from 19 double-blind studies regarding depression
and reached an even higher percentage of therapeutic results
attributed to the placebo effect: 75 per cent of depression
therapies or ameliorations were placebo induced! 13
Hróbjartsson and Gotzsche (2001 14, 2004
15) doubted the
effectiveness of the placebo phenomenon, attributing it solely to
the subjective factors of human psychology. And indeed, there is a
major aspect of the placebo effect related to psychology. In two
studies where placebos were exclusively administered, the placebo
effect seemed to be effected from the subject's perception of the
applied therapy, i.e., two placebo pills were better than one,
bigger pills were better than smaller, and injections were even
The placebo induced a reaction not only to the therapy but also to
its form, suggesting that the placebo phenomenon is shaped according
to the personal symbolic universe of the patient. Before the placebo
response occurs, human perception has already interpreted the
applied therapy and has prepared a certain response to it. It would
appear that not only chemical but also non-chemical stimuli
participate in the motivation of the human organism towards therapy.
But is the placebo reaction solely a psychological phenomenon or
does it have additional tangible somatic effects?
One of the more dramatic events regarding placebo therapy was
reported in 1957 when a new wonder drug, Krebiozen, held promise as
the final solution to the cancer problem. A patient with metastatic
tumors and with fluid collection in his lungs, who demanded the
daily intake of oxygen and the use of an oxygen mask, heard of
Krebiozen. His doctor was participating in Krebiozen research and
the patient begged him to be given the revolutionary drug.
Bent by the patient's
hopelessness, the doctor did so and witnessed a miraculous recovery
of the patient. His tumors melted and he returned to an almost
normal lifestyle. The recovery didn't last long. The patient read
articles about Krebiozen's not delivering what it promised in cancer
therapy. The patient then had a relapse; his tumors were back. His
doctor, deeply affected by the aggravation, resorted to a desperate
trick. He told his patient that he had in his possession a new,
improved version of Krebiozen. It was simply distilled water.
The patient fully
recovered after the placebo treatment and remained functional for
two months. The final verdict on Krebiozen, published in the press,
proved the drug to be totally ineffective. That was the coup de
grace for the patient, who died a few days later.17
In spite of the melodrama of the Krebiozen case, there is no single
case or personal testimony that can denote or prove a therapy to be
effective. Statistical studies, not personal testimonies, can verify
a proposed therapy's effectiveness, and well-planned studies are
able to concur that the placebo phenomenon has somatic properties.
One such study was implemented in 1997. The two study groups
consisted of patients with benign prostatic hypertrophy. One group
took actual medication while the control group received placebo
treatment. The placebo recipients reported relief from their
symptoms and even amelioration of their urinary function.18
A placebo has also been reported to act as a bronchodilator in
asthmatic patients, or to have the exact opposite action-respiratory
depression-depending on the description of the pharmacological
effect the researchers gave to the patients and therefore the effect
the patients anticipated.19
A placebo proved highly efficient against food allergies and,
subsequently, impressively effective in the sinking of
biotechnologies on the stock-market. How could that be? Peptide
Therapeutics Group, a biotech company, was preparing to launch on
the market a novel vaccine for food allergies. The first reports
were encouraging. When the experimental vaccine reached the clinical
trials stage, the company's spokesperson boasted that the vaccine
proved effective in 75 per cent of the cases-a percentage that
usually suffices to prove a drug's effectiveness. But the good news
didn't last long.
The control group, given
a placebo, did almost as well: seven out of 10 patients reported
getting rid of their food allergies. The stock value of the company
plunged by 33 per cent. The placebo effect on food allergies created
a nocebo effect on the stock-market! 20 In another case, a genetically
designed heart drug that raised high hopes for Genentech was
clobbered by a placebo.21
As aptly put by science historian Anne Harrington, placebos are,
"ghosts that haunt
our house of biomedical objectivity and expose the paradoxes and
fissures in our own self-created definitions of the real and
active factors in treatment".22
pharmaco-mimetic behavior can even imitate a drug's side effects. In
a 1997 study of patients with benign prostate hypertrophy, some
patients on a placebo complained of various side effects ranging
from impotence and reduced sexual activity to nausea, diarrhoea and
constipation. Another study reported placebo side effects as
including headaches, vomiting, nausea and a variety of other
effect in surgery
But how deep can the placebo effect trespass into the well-defined
area of medicine? Surely it can't joust with medicine's strike
force; it cannot challenge surgery. Or can it?
In 1939, an Italian surgeon named Davide Fieschi invented a new
technique for treating angina pectoris (chest pain due to ischaemia
or lack of blood/oxygen getting to the heart muscle, usually due to
obstruction of the coronary arteries).24 Reasoning that increased
blood flow to the heart would reduce his patients' pain, he
performed tiny incisions in their chests and tied knots on the two
internal mammary arteries. Three quarters of the patients showed
improvement; one quarter of them was cured. The surgical
intervention became standard procedure for the treatment of angina
for the next 20 years.
But in 1959, a young
cardiologist, Leonard Cobb, put the Fieschi procedure to the test.
He operated on 17 patients: on eight of them he followed the
standard procedure; on the other nine he performed only the tiny
incisions, letting the patients believe that they'd had the real
thing. The result was a real upset: those who'd had the sham surgery
did as well as those who'd had the Fieschi technique.25 That was the
end of the Fieschi technique and the beginning of the documented
surgical placebo effect.
In 1994, surgeon J. Bruce Moseley experimented with the surgical
placebo. He split a small group of patients suffering from
osteoarthritis of the knee into two equal groups. Both groups were
told that they would undergo arthroscopic surgery, but only the
first group got the real thing. The other group was left virtually
untreated, with the doctor performing only tiny incisions to make
the arthroscopic scenario credible. Similar results were reported in
Moseley, stunned by the outcome, decided to perform the trial with a
larger statistical sample in order to reach safer conclusions. The
results were replicated: arthroscopic surgery was equal
therapeutically to the placebo effect.27 The placebo had found its
way into surgical rooms.
Perhaps the most impressive aspect of surgical placebo arose in a
groundbreaking 2004 study. In the innovative field of stem-cell
research, a new approach was taken with Parkinson's disease. Human
embryonic dopamine neurons were implanted through tiny holes in the
patients' brains. Once again, the results were encouraging. And once
again, the procedure failed to do better than a placebo. In this
case, the placebo involved tiny holes incised in the skull without
implantation of stem cells.
As the researchers
"The placebo effect
was very strong in this study".28
But how can it be that
the therapeutic expectancy alone often produces results equal to
those from actual surgery?
It appears that the mind is exerting
control over somatic processes, including diseases. The biochemical
traces of this influence are only beginning to be outlined. Modern
research indicates a biological, tangible substrate to the placebo
In the mid-1990s, researcher Fabrizio Benedetti conducted a novel
experiment whereby he induced ischaemic pain and soothed it by
administering morphine. When morphine was replaced by a saline
solution, the placebo presented analgesic properties. However, when
naloxone (an opiate antagonist) was added to the saline solution,
the analgesic properties of the water were blocked. Benedetti
reached the conclusion that the placebo's analgesic properties were
a result of specific biochemical paths. Naloxone blocked not only
morphine but also endogenous opioids-the physical pain-relievers.29
The endogenous opioids, endorphins, were discovered in 1974 and act
as pain antagonists. Benedetti's suggestion of a placebo-induced
release of endorphins was supported by findings produced with MRI
and PET scans.30 Placebo-induced endorphin release also affects
heart rate and respiratory activity.31
As researcher Jon-Kar
deals another serious blow to the idea that the placebo effect
is a purely psychological, not physical, phenomenon".32
Further findings support
the notion that the placebo effect presents a biochemical substrate
in both depression and Parkinson's disease. Analyzing the results of
PET scans, researchers estimated the glucose metabolism in the
brains of patients with depression. Glucose metabolism under placebo
presented differentiations that were similar to those caused by
antidepressants such as fluoxetine.33
In patients suffering
from Parkinson's disease, a placebo injection promoted dopamine
secretion in a similar way to that caused by amphetamine
administration.34 Benedetti demonstrated that the placebo effect
provoked decreased activity in single neurons of the subthalamic
nucleus in patients with Parkinson's disease.35
From numerous research findings, it is logical and rather safe to
conclude that there is a biochemical substrate to the placebo
effect. But what is more intriguing to it is its relation to
perception. It would appear that perception and the codes and
symbols that the animate computer, the brain, utilizes in order to
process internal and external information strongly determine the
potency and form of placebo response.
In a recent study, patients were purposely misinformed that they had
been infected by hazardous bacilli and they subsequently underwent
treatment. However, there were no bacilli and the treatment
administered was a placebo.
Guess what? Some of the study subjects
developed infection-like conditions that were not treatable by the
placebo medication.36 The mind interpreted the fictional bacilli as
hazardous and instructed the body to respond to them as if they were
Despite the placebo's
potency and its importance for a new perception of health where body
and mind heavily interact, large numbers of scientists continue to
regard the placebo as an insignificant systematic error, a
According to cancer
researcher Gershom Zajicek:
"There is nothing in
the pharmacokinetic theory which accounts for the placebo
effect. In order to keep the theory consistent, the placebo
effect is regarded as random error or noise which can be
One of the most
perceptive placebo researchers was Stewart Wolf, "the father of
psychosomatic medicine", who as early as 1949 had given it a
thorough description. Wolf not only defended the placebo as a
non-fictional and very "real" phenomenon but also described the
placebo's pharmacomimetic behavior. He was perhaps the first
researcher to correlate the placebo effect not only with psychology
and predisposition but also with perception.
More than half a
century ago, he stated that,
"the mechanisms of
the body are capable of reacting not only to direct physical and
chemical stimulation but also to symbolic stimuli, words and
events which have somehow acquired special meaning for the
In this context, a pill
is not merely an active substance but also a therapeutic symbol and
thus the organism is able to respond not only to its chemical
content but also to its symbolic content. Likewise a bacillus,
beyond its physical properties, acquires symbolic properties that
can cause an organism's reaction even in the absence of the
The presence and extent of the nocebo effect should also be studied
in regard to drug resistance. Perhaps drug resistance is a multifactorial phenomenon involving not only microbial evolutionary
aptness but also human psyche mechanics. Placebo and nocebo
phenomena might prove fundamental not only on the personal level but
also in the public health arena.
They might even provide the foundation stone for a new model of
health, a new medicine that was envisioned by Wolf in the 1950s:
"...in the future,
drugs will be assessed not only with reference to their
pharmacologic action but also to the other forces at play and to
the circumstances surrounding their administration".39
Five centuries ago, Swiss alchemist and physician
"You must know that
the will is a powerful
adjuvant of medicine."
It seems that our scientific arrogance has
blinded us to the teachings of the past.
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