i look at the power of belief to produce profound changes in people s experience . one of the earliest reports on the power of placebo was the seminal work of stewart wolf , who demonstrated the ability of placebos to block the effect of potent drugs ( 5 ) . a pioneer in the investigation of placebo effects , wolf reported three successful experimental attempts at reversing the effects of active medications that typically induce abdominal discomfort . in each case , the reversal was brought about by misinforming the subject about the nature of the drug being administered , and in each case the subjective changes were verified by physiological assessment . one of wolf 's subjects was a 28-year - old pregnant woman who was suffering from nausea and vomiting . wolf gave her ipecac , a drug that interrupts normal gastric contractions , thereby inducing vomiting and nausea . although ipecac is commonly used to induce vomiting when toxic substances have been swallowed , wolf misinformed his patient that it was a medicine which would alleviate her nausea . prior to taking ipecac , the patient displayed an absence of gastric contractions . within 20 minutes of ingesting the drug , normal gastric contractions resumed and the nausea ended . the most impressive of these reports involves the suggestion - related production and inhibition of contact dermatitis ( 6 ) . contact dermatitis is a skin condition produced by chemical substances to which people have become sensitized . in the study reported by ikemi and nakagawa , 13 students were touched on one arm with leaves from a harmless tree , but were told that the leaves were from a lacquer or wax tree ( japanese trees that produce effects similar to poison ivy and to which the boys had reported being hypersensitive ) . on the other arm , the subjects were touched with poisonous leaves , which they were led to believe were from a harmless tree . all 13 subjects displayed a skin reaction to the harmless leaves ( the placebo ) , but only two reacted to the poisonous leaves . although a meta - analysis published in the new england journal of medicine concluded that the placebo effect is not very powerful ( 7 ) , wampold and his colleagues have reanalyzed those data and calculated the number needed to treat ( nnt ) for placebo compared to no treatment at all ( 8) . nnt is the number of patients that need to be treated to achieve one success by means of a particular treatment . although this is not a large effect , it is instructive to compare it to the nnt for various accepted medical treatments , as published in a growing database of published studies provided online ( http://www.cebm.utoronto.ca/glossary/nntsprint.htm ) by the university of toronto s centre for evidence - based medicine . the nnt for radiotherapy for breast cancer , for example , is shown on that database to be 8 , that for beta - blockers for chronic heart failure is 24 , the flu vaccine has an nnt of 12 , and aspirin as a prophylactic for myocardial infarction has an nnt of 208 . the nnt of 7 for placebo treatment was calculated across studies of many different clinical conditions . but there is good reason to believe that the placebo effect should be even greater on depression . this is because hopelessness is a core feature of depression , and one of the presumed effects of a placebo is to instill hope ( 9 ) . if you ask depressed patients what the worst thing in their life is , many will tell you that it is their depression . they feel stuck in an intolerable condition and they are hopeless about the possibility of getting better ( 10 ) . so it stands to reason that a treatment promising relief would bring some relief , merely on the basis of hope - instilling promise . indeed , a meta - analysis of the published antidepressant literature indicates that the placebo effect ( placebo  no - treatment ) is twice as large as the drug effect ( drug  placebo ) ( 11 ) . clinical experience shows that antidepressant drugs work , in the sense that patients get better when given medication . the clinical trials showed substantial and clinically significant improvement , as did those given placebo . hence they have no way of comparing the effects of the drugs they prescribe to placebos . when they prescribe a treatment and it works , quite naturally they ascribe the cure to the treatment . but the history of medicine is replete with cures that were  known  to work by doctors and their patients . these apparently effective treatments , that we now consider to have been placebos , include dolphin s genitalia , lizard s blood , crocodile dung , pig 's teeth , putrid meat , frog s sperm , powdered stone , human sweat , worms , and spiders . that is why placebo - controlled trials are required in order to demonstrate drug efficacy . when the administration of a drug is followed by improvement , the improvement might not be due to the drug s chemical composition . placebo - controlled trials are used to separate the drug effect from such factors as the placebo effect , spontaneous remission , and regression towards the mean . this is absolutely true . in fact , our data show a small advantage for drug over placebo that is statistically significant , but not clinically significant . we proven that antidepressants do nt work , but we also havent proven that their effect is below the threshold of clinical significance . what we have shown is that the data upon which drug approval was based does not show clinical significance . but it is always possible that future studies , perhaps with better experimental methods or measures of depression , will show a greater effect . . the onus should not be on critics to demonstrate that a treatment is ineffective , but rather for proponents to demonstrate that it is . if all that is needed is an absence of proof that a treatment does not work , then perhaps we ought to resume using treatments crocodile dung and dolphin genitalia until well - enough designed clinical trials prove conclusively that they are not more effective than placebo . this is indeed possible . in fact , we found evidence of greater drug effectiveness in a small subset of studies involving patients with exceptionally high levels of initial depression , although it seemed that they were less responsive to the placebo , rather than more responsive to the drug . we also found that the drug - placebo difference was zero for people who were moderately depressed . for this rather large group of sufferers , anti - depressants seemed to have no drug effect at all . it is feasible that there are other subgroups of patients for which antidepressants are more effective , but simply asserting this possibility is not enough . one must identify those subgroups and demonstrate the clinically - significant benefit they obtain from active medication over placebo . for example , gender is most certainly identified in the data sets of most , if not all , clinical trials . it would be a simple matter , for example , to reanalyze these data to test whether women are in fact more responsive to ssris and men to tricylic medication , as has been suggested ( 12 ) . note that if there are some groups of patients that respond better than the overall mean , then there must also be some that respond worse . given how small the advantage is over placebo overall , this should be of considerable concern . if some are responding substantially better , then others must not be responding at all  or even being made worse by the active medication , compared to how they would have fared on placebo . if this is the case , it would be important to know it so that antidepressant medication could be prescribed more selectively . understandably , pharmaceutical companies might be reluctant to carry out analyses of this sort , as they have the potential to cut into sales substantially . one way around this is to require that raw data for all approved medications be available for researchers to reanalyze . this could easily be done with full protection of the anonymity of those who participated as subjects . greater transparency and availability of the data would be in the best interests of patients , doctors , third - party payers , health researchers , and government agencies . defenders of antidepressants have noted a number of flaws in the clinical trials used to evaluate them . in fact , using the american psychiatric association classification scheme , the mean baseline severity was in the very severe range for all but one of the trials we analyzed . the one exception was a clinical trial involving moderately depressed patients , in which the response to drug was virtually identical to the response to placebo . one possibility is that clinical trial researchers distort the data . according to a spokesperson for the fda , patients may be rated as more severely depressed than they actually are so that they will qualify for the trial ( 4 ) . now if this is true , then the response of treatment is even less than the clinical trials indicate , unless of course the researchers also inflate scores at the end of the trial . equally troubling if the data have been distorted , then perhaps the drugs should not have been approved in the first place . whereas some critics have complained that the patients in the clinical trials we assessed were not depressed enough , an editorial in nature reviews drug discovery , for example , complained that  all but one trial analyzed involved groups with mean initial depression scores in the  very severe range , limiting the strength of extrapolations  ( 13 ) . the drug companies did not conduct any trials on patients between the very severely depressed and moderately depressed categories . but here too , the evidence should be on the compani s to demonstrate efficacy for the severely  but not very severely  depressed patients . there may be many flaws in clinical trials , including relatively short durations , unrepresentativeness of the sample , and the breaking of blind by patients and doctors on the basis of side effects ( 14 ) . but these trials are the data on the basis of which the drugs were approved . if they are flawed , then we have no evidence of drug effectiveness , and the drugs should not have been approved in the first place . finally , some have argued that even if the drugs do nt work , it was wrong of my colleagues and me to publish our studies . we should nt tell patients that the drugs do nt work because it will undermine their faith in treatment . , patients and physicians can not make informed treatment decisions , researchers will be asking the wrong questions , and policymakers will be implementing misinformed policies . if the antidepressant effect is largely a placebo effect , it is important that we know this . it means that improvement can be obtained without reliance on addictive drugs with potentially serious side effects ( 15 , 16 ) .