Current systematic reviews yielded relatively small efficacy effect sizes of different psychopharmacological agents compared to placebo. It seems that these effect sizes have decreased compared to earlier meta-analyses. We speculate about factors explaining the decrease of effect size such as lower methodological requirements for earlier randomised controlled trials, but in particular enormous methodological problems of current trials such as chronic patient populations, exclusion of severely ill patients by the protocols, sponsoring by the pharmaceutical industry and so-called professional patients. A few examples from general medicine are used to illustrate that the effect sizes of other medications are often also surprisingly small. Psychotropic drugs are efficacious, but they need to be prudently applied according to evidence-based criteria.