Neuroenhancement offers the prospect of improving the cognitive, emotional and motivational functions of healthy individuals. Of all the conceivable interventions, psychopharmacology provides the most readily available ones, such as antidepressants which are thought to make people “better than well”. However, up until now, whether they possess such an enhancing ability remains controversial and therefore in this systematic review we will evaluate the effect and safety of modern antidepressants in healthy individuals. A search of MEDLINE and EMBASE databases and cross-references was (...) carried out and the pharmaceutical industry was contacted for suitable data. Trials published in any language through the third week of July 2007 were regarded. Included were single or double blind randomised or quasi-randomised controlled trials that compared a placebo to one or more of the following antidepressants: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, moclobemide, paroxetine, reboxetine, sertraline or venlafaxine in any dose or dosing schedule. Eligible studies were those involving healthy people of any age and either sex who showed no evidence of a psychiatric disorder, cognitive decline or other disease. One hundred thirty-five articles met our inclusion criteria reporting single dose trials and trials with repeated drug administration. Sixty-five of these articles were eligible for a statistical analysis. Based on a linear mixed model, a meta-analysis and a fixed effects meta-regression were performed. Pooling of results by meta-analysis was stratified by the outcome measures mood, emotional processing, wakefulness, attention, memory, and executive functions. On a significance level of p < 0.05 the following significant results emerged: After a single dose of an antidepressant, a significant effect was shown in two of the analysed outcomes. Firstly, there was a small yet significant negative effect on wakefulness. On memory, a positive effect after several measurements was found, but this result could be traced to the results of the one study out of all included studies, which had that many assessment points. The analysis of trials with repeated drug administration yielded the following effects: on mood, a non-significant positive effect was detected that was continuously increasing and reached significance at the last assessment point. Regarding attention, a fluctuating effect was found, while for memory, the fact that the two groups started with a group difference confounded the results. For wakefulness there was no significant effect in any particular assessment point, while for emotional processing and executive functions, the small number of studies did not allow for any effect to emerge. In summary, no consistent evidence for enhancing effects of antidepressants could be found. There is little evidence so far to support the popular opinion that antidepressants have a positive effect on the mood of healthy individuals after repeated administration. No evidence of a significant adverse event profile could be found. The studies included in this systematic review not only provide insufficient evidence for or against any effect in healthy people, but they are inapt to be used for answering this question. This may be explained by the fact that most of them were not designed to examine neuroenhancement effects. The growing public interest in neuroenhancement stands in stark contrast to the paucity of data on enhancement effects of available psychopharmacological agents. (shrink)