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.
Psychedelic substances have been used for millennia, yet systematic understanding of the brain processes underlying the nonordinary states of consciousness (NSC) they induce has only recently become possible. Brain imaging reveals dynamic changes, and observations of spontaneously occurring NSC in major mood disorders show that the propensity for NSC increases at peaks of oscillatory brain activity and fully unfolds when oscillations exceed normal range. Neurobiological correlates of experientially opposite states—melancholy and mania—appear qualitatively the same, supporting the idea that experiential content emerges from nonlocal consciousness. Psychedelic experiences are triggered by the drug but shaped by mental set and setting, and their transformative process can be used psychotherapeutically for healing and inner restructuring.