Since the early 1990s, hallucinogenic drugs, such as psilocybin, have been increasingly used to investigate the neuronal basis of altered states of consciousness and psychosis. Furthermore, renewed interest has emerged in using these drugs as an adjunct to psychotherapy. Nevertheless, the therapeutic and experimental use of these substances is still controversial due to fears of potential harm. Although the experience of many in- vestigators suggests that potential risks are minimal when these drugs are administered in a carefully monitored clinical or research environment, the subjective tolerability of these drugs under these conditions has not yet been evaluated in large samples. The revival of hallucinogen research during the past 20 years has also greatly increased the need for well-validated instruments assessing the the acute subjective effects of these drugs. Although Adolf Dittrich’s questionnaires for the assessment of altered states of consciousness (ASCs) were frequently used for this purpose, especially in Europe, the factorial structure of these questionnaires is not clearly established because previ- ous psychometric investigations have serious methodological limitations. Finally, the effects of hallucinogens are believed to be critically dependent on non-pharmacological variables (e.g., the user’s personality, current mood state and environment), but few empirical studies have investigated several of these predictor variables at a time. Thus, little is known about the order of importance of these variables. To solve these problems, three empirical studies were conducted, all of which were based on pooled data from Prof. Vollenweider’s research group at the University Hospital of Psychiatry in Zurich. Vollenweider’s group was one on the first to restart human hallucinogen research in the early 1990s and since then has collected an amount of data that is unrivaled in the world. In the first study, acute, subacute, and long-term subjective effects of psilocybin were investigated by analyzing the pooled data of eight double-blind placebo-controlled experimental studies. The sample included 110 healthy subjects who had received 1-4 oral doses of psilocybin in a dose range of 45-315 μg/kg body weight. It was found that the effects of psilocybin were generally well tolerated. Most subjects described the experience as pleasurable, enriching, and non-threatening. Strong anxiety and/or dysphoria occurred only in the two highest dose conditions in a relatively small proportion of subjects and in all cases resolved by providing emotional support and without pharmacological intervention. Complaints 24 h after drug intake were mild and mostly included headache and fatigue. Furthermore, follow-up interviews conducted 8-16 months after the psilocybin sessions indicated that all of the subjects were healthy and that none of them had experienced any of the most feared negative consequences of hallucinogen exposure, that is, flashbacks, prolonged psychosis, or subsequent drug abuse. The second study critically examined the psychometric properties of the altered states of consciousness rating scale OAV in a sample of psilocybin (n = 327), ketamine (n = 162), and MDMA (n = 102) induced ASCs. The factorial structure was analyzed by using exploratory factor analysis (EFA), hierarchical item clustering (ICLUST) and various techniques of structural equation modeling (SEM), including confirmatory factor analysis (CFA), exploratory structural equation modeling (ESEM) and multiple indicators and multiple causes (MIMIC) modeling. The results indicated that the originally proposed factorial structure did not fit the data well. An improved model with 11 factors and 42 items provided a much better fit to the data. MIMIC modeling indicated that this factorial structure was sufficiently stable across drugs, settings, questionnaire versions, and sexes. Compared to the original OAV scales, the new OAV scales differentiated better among the three drug groups, were more homogeneous, and had better convergent and discriminant validities. The aim of the third study was to detect the most important predictors of psilo- cybin response. The effects of 24 predictor variables were examined in a sample of 409 psilocybin sessions. It was found that drug dose was by far the most important predictor. However, several non-pharmacological variables also played an important role in the effects of psilocybin. Specifically, having a high score in the personality trait “absorption”, being in an emotionally excitable and active state immediately before drug intake, having experienced few psychological problems in the past weeks, no previous experience with classical hallucinogens, and moderate THC and alcohol consumption increased the intensity of pleasurable effects and/or visual alterations, whereas settings involving PET measurements, emotional excitability, and low age contributed to the experience of unpleasant and/or anxious reactions. Taken together, the three studies have demonstrated that psilocybin induced altered states of consciousness in a carefully monitored research environment are generally well tolerated, can be reliably and validly assessed by 11 new subscales of the OAV questionnaire, and are dependent on several non-pharmacological variables.