The pursuit of pleasure among clubbers and disco-goers often involves drug use. However, whether substance use may represent a relevant risk factor contributing to the development of psychiatric symptoms and of mental illness remains debated. The purposes of this study were to evaluate the percentage of subjects who developed long-lasting psychiatric symptoms in a sample of subjects reporting use of substances in nightclubs, and to evaluate the role of a previous psychiatric diagnosis in these subjects. Data were collected during three consecutive years in dedicated nursing units inside all the nightclubs of Ibiza, in emergency hospital rooms at the Can Misses Hospital and inside the psychiatric ward. A total of 10,163 subjects required medical assistance inside discos in the medical-nursing units, of which 223 required transfers to hospital emergency rooms. Of these, 110 required subsequent psychiatric hospitalization. Ninety-one (82.7%) of these patients had a positive psychiatric history, which was also found in thirty-one of the 113 subjects (27.4%) not requiring psychiatric hospitalization. Negative psychiatric history was negatively associated with hospitalization (Coefficient = −2.574; p = 0.000) and for subjects with a negative psychiatric history the odds to be hospitalized changed by a factor of 0.076. Gender, age, civil status and nationality were not significant predictors of hospitalization. Overall, the number of subjects who developed major psychiatric disorders appeared to be limited. However, the presence of a psychiatric history here played a crucial role. Club drugs are therefore able to induce psychiatric sequelae requiring hospitalization mainly in subjects who are already vulnerable from a psychopathological point of view.