Microdosing Psychedelics to Restore Synaptic Density in Schizophrenia.
Jacopo Sapienza, Marco Spangaro, Stefano Comai, Michel Sabé, Joseph T. la Torre, Matteo Buonarroti, Roberto Cavallaro, Marta Bosia
International Journal of Molecular Sciences September 14, 2025 DOI: 10.3390/ijms26188949 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | LSD Microdosing Neuroplasticity Psilocybin |
| Keywords | Sv2a Complement 4 Negative symptoms Psychosis Synaptogenesis Reduced synaptic density Overactive microglia Schizophrenia symptoms cognition Psychedelic Neurotherapeutics LSD Rebuild connections |
| Citations | 2 |
| Key findings | Psychedelics may counteract excessive synaptic loss in schizophrenia by promoting neuroplasticity and synaptogenesis, warranting clinical exploration starting with microdoses. |
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.
Comparable studies
Other narrative reviews on LSD and microdosing, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The risk of chronic psychedelic and MDMA microdosing for valvular heart disease | 2023 | Review | |
| Macrodosing to microdosing with psychedelics: Clinical, social, and cultural perspectives | 2022 | Review | |
| Is microdosing a placebo? A rapid review of low-dose LSD and psilocybin research | 2024 | Rapid review | n = 19 |
| Side effects of microdosing lysergic acid diethylamide and psilocybin: A systematic review of potential physiological and psychiatric outcomes | 2025 | Review | |
| Self-medication with psychedelics: a scoping review and narrative synthesis of review-level evidence Self-medicating individuals | 2026 | Scoping review |
Citations in the library
Cited by 3
- Psychedelics for treatment of negative symptoms and depressive symptoms in schizophrenia spectrum disorder: A narrative review Schizophrenia Research March 13, 2026
- Variability in outcomes and subjective effects of psychedelic use in psychotic populations: Case-based evidence from naturalistic settings Psychedelics May 14, 2026
- Sustained abstinence in severe ketamine use disorder following ibogaine treatment case report Frontiers in Psychiatry July 20, 2026
Cites 46
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- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
and 41 more in the library