A systematic review and meta-analysis assessed the risk of psychedelic-induced psychosis in people with schizophrenia. Among population studies, the incidence was 0.002%; in uncontrolled trials, 0.2%; and in randomized controlled trials, 0.6%. In uncontrolled trials that included individuals with schizophrenia, 3.8% developed long-lasting psychotic symptoms. Of those who experienced psychedelic-induced psychosis, 13.1% later developed schizophrenia. The evidence suggests schizophrenia might not be an absolute exclusion for clinical trials on psychedelics for treatment-resistant depression and negative symptoms, but low study quality and limited data warrant a conservative approach until more research is done.
Serotonergic psychedelics, which are being explored for treatment-resistant depression, might also help with depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). Schizophrenia and depression share some underlying brain disturbances, including problems with dopamine, glutamate, and neuroplasticity, as well as abnormal brain network connectivity. Depressive symptoms in SSDs may combine features of both disorders, and psychedelics could potentially recalibrate maladaptive brain networks. Preclinical studies show psychedelics increase dendritic spines and BDNF and restore reward sensitivity. Clinical evidence is limited: uncontrolled psychedelic use is linked to increased psychosis, but controlled administration may be tolerated in stable individuals. Only one early-phase trial with MDMA in schizophrenia is ongoing; no randomized trials have tested psilocybin or LSD in SSDs. The authors conclude that psychedelics are biologically plausible but unproven for these symptoms.