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The Placebo Effect: The Triumph of Mind Over Body
The Placebo Effect: The Triumph of Mind Over Body
Extracted from Nexus Magazine, Volume 14, Number 4 (June - July 2007) Source
Author: Peter Arguriou
A growing body of research reveals not just psychological and perceptual components to the placebo
effect but also a biochemical substrate to the mechanism.
A neglected phenomenon
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 Western medicine?
The placebo effect has been frequently abused by health professionals to denote and stigmatise a fraud
or fallacy. Alternative therapies have often been characterised 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 course. That is, the placebo effect is dependent not on the drug's
effectiveness but solely on therapeutic intention and expectation.
Effects of 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 definite: 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 intervention.
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 immunodepression. 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 immunodepression resulted in high- level mortality of the
specific group.6
A short 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 (Graves8), and through various intermediate stages (Evans and Hoyle, 19339; Gold, Kwit and Otto,
193710; Jellinek, 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 (200114, 200415) 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
better.16
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
tumours 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 tumours 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 tumours 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 stockmarket. 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 stockmarket!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
The placebo's pharmacomimetic behaviour 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
symptoms.23
The placebo 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 both groups.26
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
confessed, "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 effect.
Somatic pathways
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 Zubieta described, "...this [finding] 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. Analysing 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, utilises 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 real.
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 troublesome nought. 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 ignored."37
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
behaviour. 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
individual".38
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 bacillus.
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 Paracelsus (1493-1541) wrote: "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.
About the Author:
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 still unpublished). 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 petrosarguriou@hotmail.com.
References:
1. Rosenweig P, Brohier S, Zipfel A, "The placebo effect in healthy volunteers: influence of the
experimental conditions on the adverse events profile during phase I studies", Clin Pharmacol Ther 1993;
54:578-83.
2. Schweiger A, Parducci A, Pav J, "Nocebo: the psychologic induction of pain", Biol Sci 1981; 16:140-3.
3. Everson SA, Kaplan GA, Goldberg DE, Salonen R, Jukka T, "Hopelessness and 4-year progression of
carotid atherosclerosis: the Kuopio ischemic heart disease risk factor study", Arterioscler Thromb Biol
1997; 17:1490-5.
4. Glassman AH, Shapiro A, "Depression and the course of coronary artery disease", Am J Psychiatry
1998; 155:4-11;
Smith TW, Ruiz JM, "Psychosocial influences on the development and course of coronary heart disease:
current status and implications for research and practice", J Consult Clin Psychol 2002 Jun; 73(3):459-62.
5. Pollit RA, Daniel M, Kaufman JS, Lynch JW, Salonen GT, Kaplan GA, "Mediation and modification of
the association between hopelessness, hostility and progression of carotid atherosclerosis", J Behav Med
2005 Feb; 28(1):53-64.
6. Schliefer SJ, Keller SE, Camerino M,Thornton JC, Stein M, "Suppression of lymphocyte stimulation
following bereavement", J Am Med Assoc (JAMA) 1983; 250:374-7.
7. "Past and present of 'what will please the lord': an updated history of the concept of placebo", Minerva
Med 2005 Apr; 96(2):121-4.
8. Graves TC, "Commentary on a Case of Hystero-Epilepsy with Delayed Puberty: Treated with Testicular
Extract", The Lancet 1920 Dec 4; 196(5075).
9. Evans W and Hoyle C, "The Comparative Value of Drugs Used in the Continuous Treatment of Angina
Pectoris", Quarterly Journal of Medicine 1933 Jul; 2(7).
10. Gold H, Kwit NT, Otto H, "The xanthines (Theobromine and Aminophylline) in the treatment of cardiac
pain", JAMA 1937 Jun 26; 108(26):2173-79.
11. Jellinek EM, "Clinical Tests on Comparative Effectiveness of Analgesic Drugs", Biometrics Bulletin
1946 Oct; 2(5):87-91.
12. Beecher HK, "The powerful placebo", JAMA 1955 Dec 24; 159(17):1602-6.
13. Kirsch, Irving and Sapirstein, Guy, "Listening to Prozac but hearing placebo: A meta-analysis of
antidepressant medication", Prevention & Treatment 1998 Jun; 1(1).
14. Hróbjartsson A, Gotzsche PC, "Is the Placebo Powerless? An Analysis of Clinical Trials Comparing
Placebo with No Treatment", New England J Med (NEJM) 2001 May 24; 344(21):1594-602.
15. Hróbjartsson A, Gotzsche PC, "Is the placebo powerless? Update of a systematic review with 52 new
randomized trials comparing placebo with no treatment", J Intern Med 2004 Aug; 256(2):91-100.
16. Blackwell B, Bloomfield SS, Buncher C, "Demonstration to medical students of placebo responses and
non-drug factors", The Lancet 1972; 13:1-11;
Buckalew LW, Coffield KE, "An investigation of drug expectancy as a function of capsule colour and size
and preparation form", J Clin Psychopharmacol 1982; 2:245-8.
17. Klopfer, Bruno, "Psychological variables in human cancer", Journal of Projective Techniques and
Personality Assessment 1957; 21:331-34.
18. "Placebo Effect Can Last For Years", The New York Times, April 16, 1997.
19. Benedetti F, Amanzio M, Baldi S, Casadio C, Cavallo A, Mancuso M, Ruffini E, Oliaro A, Maggi G,
"The specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression",
Pain 1998 Apr; 75(2-3):313-9.
20. "Placebo effect shocks allergy drugs maker", BBC News, July 5, 1999.
21. Talbot, Margaret, "The Placebo Prescription", The New York Times, January 9, 2000.
22. Harrington, Anne (ed.), The Placebo Effect: An Interdisciplinary Exploration, Harvard University Press,
Cambridge, 1997.
23. Hahn RA, "The Nocebo Phenomenon: The Concept, Evidence, and Implications for Public Health",
Preventive Medicine 1997 Sep-Oct; 26(5):607-11; Spiegel H, "Nocebo: The Power of Suggestibility",
Preventive Medicine 1997 Sep-Oct; 26(5):616-21; Barsky AJ et al., "Nonspecific Medication Side Effects
and the Nocebo Phenomenon", JAMA 2002 Feb; 287(5):622-27;
24. Fieschi D, "Criteri anatomo-fisiologici per intervento chirurgico lieve in malati di infarto e cuore di
angina", Arch Ital Chir 1942; 63: 305-10.
25. Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA, "An evaluation of
internal-mammary-artery ligation by a double-blind technic", NEJM 1959 May 28; 260(22):1115-18.
26. Moseley JB, O'Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, Hollingsworth JC, Ashton
CM, Wray NP, "A controlled trial of arthroscopic surgery for osteoarthritis of the knee", NEJM 2002 Jul 11;
347(2):81-8.
27. Moseley JB Jr, Wray NP, Kuykendall D, Willis K, Landon G, "Arthroscopic treatment of osteoarthritis of
the knee: a prospective, randomized, placebo-controlled trial. Results of a pilot study", Am J Sports Med
1996 Jan-Feb; 24(1):28-34.
28. McRae C, Cherin E, Yamazaki TG, Diem G, Vo AH, Russell D, Ellgring JH, Fahn S, Greene P, Dillon
S, Winfield H, Bjugstad KB, Freed CR, "Effects of perceived treatment on quality of life and medical
outcomes in a double-blind placebo surgery trial", Arch Gen Psychiatry 2004 Apr; 61(4):412-20; Erratum
in Arch Gen Psychiatry 2004 Jun; 61(6):627.
29. Benedetti F, "The opposite effects of the opiate antagonist naloxone and the cholecystokinin
antagonist proglumide on placebo analgesia", Pain 1996 Mar; 64(3):535-43.
30. Wager TD, Rilling J K, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen
JD, "Placebo-induced changes in fMRI in the anticipation and experience of pain", Science 2004 Feb 20;
303(5661):1162-7;
Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, Mandelkern M, Mayer EA, "The neural
correlates of placebo effects: a disruption account", NeuroImage 2004 May; 22(1):447-55.
31. Pollo A, Vighetti S, Rainero I, Benedetti F, "Placebo analgesia and the heart", Pain 2003 Mar;
102(1-2):125-33;
Benedetti F, Amanzio M, Baldi S, Casadio C, Cavallo A, Mancuso M, Ruffini E, Oliaro A, Maggi G, "The
specific effects of prior opioid exposure on placebo analgesia and placebo respiratory depression", Pain
1998 Apr; 75(2-3):313-19.
32. Gavin, Kara, "Thinking the pain away? UM brain-scan study shows the body's own painkillers may
cause the 'placebo effect'", University of Michigan press release, August 23, 2005.
33. Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S, Jerabek PA, "The functional
neuroanatomy of the placebo effect", Am J Psychiatry 2002 May; 159(5):728-37.
34. De la Fuente-Fernandez R, Phillips AG, Zamburlini M, Sossi V, Calne DB, Ruth TJ, Stoessl AJ,
"Dopamine release in human ventral striatum and expectation of reward", Behav Brain Res 2002 Nov 15;
136(2):359-63.
35. Benedetti F, Colloca L, Torre E, Lanotte M, Melcarne A, Pesare M, Bergamasco B, Lopiano L,
"Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic
nucleus", Nat Neurosci 2004 Jun; 7(6):587-8; epub May 16, 2004.
36. Lynoe N, "Placebo is not always effective against nocebo bacilli. The body-mind interplay still
wrapped in mystery", Lakartidningen 2005 Sep 19-25; 102(38):2627-8.
37. Zajicek G, "The placebo effect is the healing force of nature", The Cancer Journal 1995 Mar-Apr; 8(2).
38. Wolf S, "Effects of Suggestion and Conditioning on the Action of Chemical Agents in Human Subjects:
The Pharmacology of Placebos", Journal of Clinical Investigation 1950 Jan; 29(1):100-09.
39. ibid.
Extracted from Nexus Magazine, Volume 14, Number 4 (June - July 2007) Source
Author: Peter Arguriou
A growing body of research reveals not just psychological and perceptual components to the placebo
effect but also a biochemical substrate to the mechanism.
A neglected phenomenon
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 Western medicine?
The placebo effect has been frequently abused by health professionals to denote and stigmatise a fraud
or fallacy. Alternative therapies have often been characterised 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 course. That is, the placebo effect is dependent not on the drug's
effectiveness but solely on therapeutic intention and expectation.
Effects of 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 definite: 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 intervention.
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 immunodepression. 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 immunodepression resulted in high- level mortality of the
specific group.6
A short 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 (Graves8), and through various intermediate stages (Evans and Hoyle, 19339; Gold, Kwit and Otto,
193710; Jellinek, 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 (200114, 200415) 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
better.16
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
tumours 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 tumours 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 tumours 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 stockmarket. 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 stockmarket!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
The placebo's pharmacomimetic behaviour 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
symptoms.23
The placebo 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 both groups.26
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
confessed, "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 effect.
Somatic pathways
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 Zubieta described, "...this [finding] 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. Analysing 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, utilises 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 real.
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 troublesome nought. 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 ignored."37
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
behaviour. 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
individual".38
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 bacillus.
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 Paracelsus (1493-1541) wrote: "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.
About the Author:
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 still unpublished). 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 petrosarguriou@hotmail.com.
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