The Nocebo Effect: History and Physiology1

Herbert Benson, M.D.2

Mind/Body Medical Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, 110 Francis Street, Suite 1A,Boston, Massachusetts 02215

INTRODUCTION

In addressing the concept of the nocebo effect, I willfirst describe how I got into this field and then, forcomparison, briefly discuss the placebo effect, the posi-tive aspect, before actually focusing on an extreme out-come of the nocebo effect: ‘‘Can the nocebo effect causedeath?’’ There is indeed literature that supports thiscontention and I will discuss it together with a descrip-tion of the neurophysiology, or a neurophysiological ap-proach, that could explain this.

About 20 years ago, I described the relaxation re-sponse, a physiological state opposite to the stressstate, and people kept saying that this is nothing butthe placebo effect. This then led me to studies of theplacebo effect and I found that the two effects are verydifferent. The relaxation response is essentially like apill—a certain way of thinking causes physiologicalchanges within the body, much like those expected ofand induced by a pharmaceutical agent. The placeboeffect, on the other hand, is nonspecific, related to thebelief system. Penicillin will work whether or not onebelieves in it. Likewise, cataract surgery will workwhether or not one believes in it. In these cases theeffectiveness is due to specific actions, whereas the pla-cebo effect, or for that matter the nocebo effect, willwork only if one believes that something positive, ornegative, will happen.

COMPONENTS OF THE EFFECT

There are three components that make up the pla-cebo and the nocebo effect. The first is the belief orexpectancy harbored by the patient. The second is thebelief or expectancy on the part of the physician, thenurse, or the healer. The third is the belief or expec-tancy that is engendered by the relationship betweenthe two. As examples of each, let us start with thebelief or expectancy on the part of a patient sufferingfrom the nausea and vomiting of pregnancy. In a studyconducted by Dr. Stuart Wolf in 1950, pregnant womenwere told they could be given a substance that wouldcure their nausea and vomiting [1]. They were asked to

swallow small intragastric balloons that were in noway bothersome but through which the contractions oftheir stomach could be measured. In truth, thesepeople were deceived; they were given ipecac, whichcauses vomiting. You may know that it is given to chil-dren to induce vomiting. Yet Dr. Wolf’s patients be-lieved that it would reverse their nausea and vomiting.Not only did the nausea and vomiting disappear, but inone patient the stomach contractions measuredthrough the device returned to normal. Here the beliefwas powerful enough to reverse the pharmacologicalaction of a drug.

Let me now speak to the second component of theplacebo effect, the belief or expectancy on the part ofthe physician. Angina pectoris is a chest pain broughtabout by a relative deficiency of oxygen to the heartmuscle [2]. The constricting pain is made worse by ex-ercise, emotions, or overeating. Over the years, the di-agnosis of angina pectoris has not changed. It was de-fined in 1774 by Dr. Heberden in England. We knowthat we are still talking about the same disease today.Over the years, however, a number of therapies thatwere believed in at one point were later shown to benothing more than a placebo. These involved variousdrugs or surgical procedures, all of which were shownto be bogus and without physiologic or pharmacologicbasis. Yet when the physicians administering thesetherapies believed in them, the therapies were 70–90%effective in relieving the pain the patient experienced,and actual electrocardiographic changes and changesduring exercise tolerance tests were noted. However,when it was proven to the physicians that these treat-ments had no worth, their effectiveness dropped by 30–40%. This phenomenon led Dr. Armand Trousseau, a19th-century physician, to recommend that new medi-cations be used as quickly as possible before they losttheir power to heal (cited in Ref. 2).

The third component of the placebo effect is the beliefor expectancy engendered by the relationship of thehealer to the patient. In an impressive study conductedat Massachusetts General Hospital, anesthetists sawpatients the evening before the operation [3]. Patientswere then randomly divided into two groups equivalentin age, sex, underlying disease, severity of disease, andtype of operation. Patients in the control group were

1 This article is taken from a speech made by Dr. Benson on No-vember 28, 1995.

2 Fax: (617) 632-7383

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0091-7435/97 $25.00Copyright © 1997 by Academic PressAll rights of reproduction in any form reserved.

addressed by the anesthetists in a cursory manner:‘‘My name is so and so: tomorrow I am going to give youanesthesia. Don’t worry; everything is going to be al-right.’’ The anesthetist then left. The patients in theexperimental group, visited by the same anesthetists,were spoken to in a warm and sympathetic fashion.Sitting on the patient’s bed, the anesthetist held thepatient’s hand, told him/her exactly what to expect inthe way of pain and suffering, and worked assiduouslyin a 5-minute period to establish a warm and sympa-thetic interchange. On the next day, the patients wereoperated upon and the surgeons, the nurses, and oth-ers caring for them afterward either did not know thata study was going on or—if they did know it—were notaware to which group the patients belonged. Patientsin the experimental and control group were allowed tohave as much pain killing medication as they required.Upon decoding, it became evident that those who weretreated in the compassionate fashion had required onlyhalf the amount of pain killing medication and thatthey were discharged from the hospital an average of2.6 days sooner than those in the other group. Thesimple 5-minute act of compassion led to tangible, mea-surably different results.

It was actually the placebo effect that sustainedmedicine until the time of Pasteur and Koch [4]. Acomplete discussion is not provided here, but the his-tory of medicine until the 1850s was the history of theplacebo effect. People often can stay alive by believingthey want to be alive. One of the most dramatic ex-amples is that both Thomas Jefferson and John Adamsdied on July 4, 1826, the 50th anniversary of the sign-ing of the Declaration of Independence. Jefferson’s lastwords were ‘‘Is this the four . . .?’’ Those of John Adamswere ‘‘Thomas Jefferson still lives. . .’’ [5].

THE NOCEBO EFFECT

I would now like to discuss the opposite effect, thenocebo effect. As stated in the Introduction, I want tofocus on the question whether the three-component be-lief system or expectancy, that on the part of the pa-tient, that on the part of the physician, and the rela-tionship between the two, can engender the extreme:death. To state the obvious, there are no controlledcrossover studies of this. But let us look at a few ex-amples and begin with the classic example, that of voo-doo death.

Voodoo death comes about when people believe thata hex has been placed upon them. One of the earliestdescriptions of voodoo death in Western literature isthat of Dr. Herbert Basedow, who wrote in 1925 aboutshamanism among Australian Aborigines [6]. Pointinga bone, the shaman would hex a member of the tribe.Basedow wrote of a person so treated:

The man who discovers that he is being ‘‘boned’’ is indeed apitiable site. He stands aghast with his eyes staring at the

treacherous pointer, and with his hands lifted as though to wardoff the lethal medium, which he imagines is pouring into hisbody. His cheeks blanch, his eyes become glassy, and the expres-sion of his face becomes horribly distorted . . . . He attempts toshriek but usually the sound chokes in his throat and all thatone might see is a froth at his mouth. His body begins to trembleand the muscles twist involuntarily. He sways backward andfalls to the ground, and after a short time appears to be in aswoon; but soon after he rises as if in mortal agony, and coveringhis face with his hands, begins to moan . . . . His death is only amatter of comparatively short time.

Walter B. Cannon, the famous Harvard MedicalSchool physiologist who described the ‘‘fight or flight’’response, the stress response to which the relaxationresponse is the opposite, also examined ‘‘tapu’’ (taboo),another form of voodoo death among the Maori aborigi-nes of New Zealand [7,8]. He relates the story of an18-year-old aborigine, whose hex was that he shouldnot eat wild game hen. One day, when this young manwas traveling, he stayed at a friend’s home and hadbreakfast. He asked whether the food contained wildgame hen and was assured that it did not, even thoughit actually did. The man ate this food and went off.When he visited this friend 2 years later, the friendasked, ‘‘Have you ever eaten wild game hen?’’ ‘‘No,’’replied the young man, whereupon his host said, ‘‘Ha,I tricked you 2 years ago.’’ Within 24 hours the hexedman passed away. In other words, it was clearly not theingestion of the wild game hen that had caused hisdemise.

A number of such incidents are described through-out the literature. The forefather of the founders ofthe renowned Menninger Clinic, Erich Menninger vonLerchenthal of Vienna, in the late 1700s, described acase [9] and reported an account that appeared in Jo-seph Haydn’s diary, in which the composer wrote:

On the 26th day of March at the concert of Mr. Bartholemon(London), there was an English clergymen who while hearingmy Andante, sank into the deepest melancholy because of thefact that on a previous night he had dreamed of such an Andantewhich announced his death. He immediately left [our] company,went to bed, and today, I heard through Mr. Bartholemon thatthis clergyman had died.

Dr. Menninger von Lerchenthal [9] went on to de-scribe another case involving a very unpopular assis-tant at the medical school in Vienna whom the stu-dents hated. They restrained this man, saying, ‘‘We aregoing to do away with you, you are about to be decapi-tated.’’ They actually tied his hands, blindfolded him,and held his head on a chopping block; then, swishinga broom to make the sound of a swinging ax, at a cer-tain point they simulated the ‘‘execution’’ by dropping awet cloth on his neck. The man died on the spot.

Dr. George L. Engel, a notable professor of medicineand psychiatry at the University of Rochester, de-scribed a whole biopsychosocial model, reminding usthat we cannot treat just with pharmaceuticals or sur-gery, but that we must bring other components to bear

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on the therapy [10,11]. He reviewed the modern medi-cal literature and found over a hundred cases of peoplewho had died suddenly. He found a consistent patternin that these people had felt a sense of powerlessness,an inability to cope with life. Their attitude toward lifewas primarily one of hopelessness and helplessness.

Dr. Leon J. Saul of Media, Pennsylvania, described aman who was in an intolerable situation [12]. At home,his family had been pulled apart, he was in financialdifficulties, and he did not know what to do with him-self. He boarded a train intending to go to a nearbytown to start a new life. In this totally unrealistic ap-proach there were no plans; there was nothing to do.Halfway to that new town, the train stopped, the mangot out, and when the conductor shouted, ‘‘All onboard,’’ the man recognized his dilemma. He was stuck;he could not go back; he could not go forward. He diedon the platform, yet another specific example of hope-lessness and helplessness.

Let me give you one additional example of this. Myfriend, the late Dr. Thomas P. Hackett, who was thechairman of the Department of Psychiatry at HarvardMedical School at Massachusetts General Hospital, in-terviewed, with Dr. Avery D. Weisman, hundreds ofpatients undergoing surgery. From among 600 whowere unusually apprehensive about the surgery, theychose 5 who seemed to have a profound premonition ofdeath. The physicians said that ‘‘These people reallyjust knew they were going to die.’’ All 5 of them did die[13]. Apparently, death held more appeal for these pa-tients than life because it promised a reunion with alost love, a resolution of a conflict, or relief from an-guish.

We know now that we can keep ourselves alive withbelief systems but that we can also die because of them.Let us take another look at anniversaries. What wouldyou predict are gender-related differences? Who wouldoutlive anniversaries, and who would die before them?Men or women? More among you think that womenwould die after an anniversary. Indeed, women tend tolive beyond anniversaries and then die; this is a gen-eral finding. Women want to live to that anniversary tohave a joyous reunion; this anticipation keeps themgoing, or that is the thesis. Among men, on the otherhand, deadlines often are viewed as signs of not havingachieved a goal. Anniversaries therefore produce an-guish about not having reached a goal that the mentend to pass away before the anniversary.

What could possibly be happening to explain ex-treme effects? Ultimately, all our thoughts come fromnerve cells that communicate with each other [4]. Wehave within our brain some hundred billion cells; eachone of these has anywhere between 5,000 and 500,000connections with other cells. So we are talking about anetwork in the range of hundreds of trillions of connec-tions. Each of these connections does not just come onor shut off, but is modulated. This results in trillions

upon trillions of possible connections. This is an enor-mous capacity. We are both genetically and environ-mentally neurologically ‘‘wired’’ as we go through life.Each event we participate in is interpreted in terms ofprevious events, in terms of ongoing activities, and interms of implications for the future. And this is occur-ring every single moment. Reading the very words thatI am writing here makes you a different person fromwhom you were before you read them. And this is hap-pening every second of our lives. When people are ill,the recall of information can be blocked, as occurs, forexample, in Alzheimer’s disease.

Let me give you an example from my own life. WhenI was an intern in Seattle, an Oriental patient cameinto the room. I thought I had never seen him before.As I looked up at him, I was immediately terrified ofhim, absolutely panicked. I broke out in a sweat; myheart raced. I managed to get hold of myself and, afterthe examination, I told him that I had this reaction. Helaughed and, with a characteristic gesture and pro-phetic intonation, he said: ‘‘Ha, ha, ha, okay now Yank,you die.’’

It turned out that he was a movie actor and in theearly days of WWII he played Tokyo Joe, the guy whowent to Standford and roomed with an American pilothe later shot down. In a later role he played the villainin the Charlie Chan movies. Although I was unable topinpoint the fear that had overtaken me, the reactiontoward this character actor was simply a part of me.

Obviously, we store memories that come to the foreat any given time from the bottom up when triggeredby impulses from our environment or from within thebody. Being wired, we are always scanning our bodyinternally. Is there a pain? Is there not a pain?

But there is also ‘‘top-down’’ thinking, which is in-duced by our thoughts. If you think a certain way, youcan either revoke or bring forth a memory. And so youcan ‘‘remember wellness’’; that is how I am redefiningthe placebo effect. You take a pill that has nothing butsugar in it; it will make your headache go away be-cause you believe in the healing effect of that pill, andyour memory is one of wellness, your being withoutpain. It is the same with fear. For example, people whohad been assaulted on the street and later died showedon autopsy no physical damage that could have beenthe cause of death. This was found for 11 of 15 cases. Itwas simply the fear of the assault that had led to death.The fear of being assaulted had liberated enough nor-epinephrine to actually induce myofibrillar degenera-tion and cause death [14]. Another example of fear ofdeath leading to death is that of a group of Laotianrefugees who fled Southeast Asia during the VietnamWar and came to the United States. They are known asthe ‘‘Hmong refugees’’; among their men they have adeath rate of 92 per 100,000, which would be equiva-lent to mortality from the fifth leading cause of deathin the United States. These men suffer from dreaming

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violent dreams of their life on the killing fields, and thephenomenon associated with their death is called thesudden unexpected nocturnal death syndrome orSUNDS. A man who had undergone this trauma and,fortunately, remained alive remembered that a fewmonths after first coming here, he had fallen asleepafter turning out the light. As many thoughts wentthrough his mind, he suddenly felt that he could notmove. He said: ‘‘I just know it, even though I do not seeanything. I try to move my hand but I cannot do so; Ikeep trying but I cannot move at all. I know that this istsog tsuam [in the Laotian culture tsog tsuam is an evilspirit]. I know it. I am so scared. I can hardly breathe.Who will help me? What if I die?’’ [15].

The death rate of 92 per 100,000 among the Hmongrefugees is, of course, extremely high, and we believethat we can identify a mechanism through which thisoccurs. Dr. Stephen M. Oppenheimer at Johns HopkinsUniversity identified in animals an area in the insularcortex that, when stimulated, brings about ventricularfibrillation [16]. On the basis of this finding one maybuild the hypothesis that the remembrance of a greatfear becomes so real, even in our dreams, that it canlead to the stimulation of this particular area of thebrain, which can cause a fatal heart arrhythmia[17,18].

CONCLUSION

Although I have emphasized the negative aspects ofthe nocebo effect, I want to close with the reminderthat we have the power within our minds to create bothwellness and illness. I believe, as Dr. Wynder haspointed out, that this is a grossly underestimated as-pect of our medicine. Of the people who go to physiciansand for whom neither pharmaceutical nor surgicaltreatment is effective, 60 to 90% may benefit frommind–body techniques including belief systems [4,19–21]. It is our hope that these will play a major part inthe medicine of the future.

REFERENCES

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2. Benson H, McCallie DP Jr. Angina pectoris and the placebo ef-fect. N Engl J Med 1979;300:1424–9.

3. Egbert LD, Battit GE, Welch CE, Bartlett ML. Reduction of post-operative pain by encouragement and instruction of patients. NEngl J Med 1964;270:825–7.

4. Benson H. Timeless healing: the power and biology of belief. NewYork: Scribner, 1996.

5. Adams J, Jefferson T. Statements as quoted in: Beck EM, editor.J Bartlett: familiar quotations. 14th ed. Boston: Little, Brown,1968.

6. Basedow H. The Australian Aboriginal. Adelaide: Preece, 1925.[As quoted in: Cannon WB. Voodoo death. Am Anthropol1942;44;169–81].

7. Cannon WB. The emergency function of the adrenal medulla inpain and the major emotions. Am J Physiol 1914;33:365–72.

8. Cannon WB. Bodily changes in pain, hunger, fear, and rage: anaccount of recent researches in the function of emotional excite-ment. New York: Appleton, 1929.

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10. Engel GL. A life setting conducive to illness: the giving-up–given-up complex. Bull Menninger Clin 1968;32:355–65.

11. Engel GL. Sudden and rapid death during psychological stress:folklore or folk wisdom? Ann Intern Med 1971;74:771–82.

12. Saul LJ. Sudden death at impasse. Psychoanal Forum 1966;1:88–9.

13. Weisman AD, Hackett TP. Predilection to death: death and dy-ing as a psychiatric problem. Psychosom Med 1961;23:232–56.

14. Cebelin MS, Hirsch CS. Human stress cardiomyopathy: myocar-dial lesions in victims of homicidal assaults without injuries.Hum Pathol 1980;11:123–32.

15. Adler SR. Ethnomedical pathogenesis and Hmong immigrants’sudden nocturnal deaths. Culture Med Psychiatry 1994;18:23–59.

16. Oppenheimer SM, Wilson JX, Guirauden C, Cechetto DF. Insu-lar cortex stimulation produces lethal cardiac arrhythmias: amechanism of sudden death? Brain Res 1991;550:115–21.

17. Oppenheimer SM. The broken heart: noninvasive measurementof cardiac autonomic tone. Postgrad Med J 1991;68:939–41.

18. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovas-cular effects of human insular cortex stimulation. Neurology1992;42:1727–32.

19. Cummings NA, VandenBoss GR. The twenty years Kaiser Per-manente experience with psychotherapy and medical utiliza-tion: implications for national health policy and national healthinsurance. Health Policy Q 1981;1:159–75.

20. Fry J. Profiles of disease: a study in the natural history of com-mon diseases. Edinburgh: Livingstone, 1966.

21. Kroenke K, Mangelsdorff AD. Common symptoms in ambulatorycare: incidence, evaluation, therapy, and outcome. Am J Med1989;86:262–6.

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