Microdosing Psychedelics to Restore Synaptic Density in Schizophrenia.

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.

Study at a glance

Abstract

Schizophrenia is a highly polygenic disease, and several genetic variants associated with the disease converge on altered synaptic homeostasis. In particular, the gene encoding complement component 4 (C4) showed the strongest association with schizophrenia, and this protein is involved in complement-dependent and microglia-mediated synaptic pruning. As a matter of fact, microglia are overactive in schizophrenia, and reduced synaptic arborization, especially in the prefrontal cortex (PFC), is an established hallmark of schizophrenia, likely associated with gray matter loss, cortical thinning, hypofrontality, and deficit syndrome. The recent development of a new radioligand targeting the synaptic vesicle glycoprotein 2A (SV2A) demonstrated in vivo lower synaptic density at the PFC level in individuals with schizophrenia, corroborating the synaptic hypothesis of thedisease first proposed by Feinberg in 1982. Interestingly, robust preclinical evidence (in vitro and animal models) showed the ability of psychedelics to promote neuroplasticity and synaptogenesis, potentially counteracting the excessive synaptic loss, restoring volume loss, and possibly explaining improvements in negative and cognitive symptoms described by old clinical studies. Overall, microdoses should be explored first as a possible treatment in a selected sample of patients affected by deficit schizophrenia, followed by low and full doses if encouraging results were to emerge.