Despite promising results in other psychiatric conditions, no modern clinical trials have tested psychedelics in patients with schizophrenia, except for semi-anecdotal studies from the 1950s and 1960s that noted improvements in negative symptoms and social cognition. Recent evidence suggests the mechanisms of psychedelics partially overlap with schizophrenia's pathology but in an opposite direction, providing a biological rationale for their use. This perspective paper reviews old experiments and recent molecular findings on neuroplasticity, connectivity, immune and TAARs systems, neurotransmitters, and neurotropic factors. The authors identify a therapeutic potential for negative symptoms and social cognition, proposing very low doses (microdosing) for a subpopulation of chronic patients predominantly burdened by negative symptoms, while carefully considering safety and feasibility to guide future trials.
Schizophrenia involves excessive loss of brain connections, partly due to overactive microglia that prune synapses. A genetic variant in complement component 4 (C4) is strongly linked to the disease and drives this pruning. Brain scans using a new tracer for synaptic vesicle glycoprotein 2A (SV2A) confirm lower synaptic density in the prefrontal cortex of people with schizophrenia, supporting the synaptic hypothesis. Psychedelics like LSD and psilocybin promote neuroplasticity and synaptogenesis in animal and lab studies, potentially counteracting synaptic loss and improving negative and cognitive symptoms. The authors suggest starting with microdoses in deficit schizophrenia patients, then escalating if results are positive.