Molecular psychiatry
February 1, 2025
Jacopo Sapienza, Francesca Martini, Stefano Comai et al.
11 citations
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.
International journal of molecular sciences
September 14, 2025
Jacopo Sapienza, Marco Spangaro, Stefano Comai et al.
2 citations
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.
Schizophrenia Research
March 13, 2026
Michel Sabé, Paul Grof, Nathan B. Sackett et al.
1 citation
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.
Molecular psychiatry
May 29, 2026
Mickael Eskinazi, Rayan Nasserdine, Romane M Cusin et al.
A systematic review of 23 studies examined whether serotonergic psychedelics (psilocybin, LSD, mescaline, DMT/ayahuasca) or MDMA can trigger manic or hypomanic symptoms. Rates of such symptoms ranged from 5.8% in controlled trials of psilocybin-assisted therapy for depression to 30% in naturalistic studies of people with bipolar disorder. When manic symptoms occurred, they were typically acute and self-limited. Higher risks were seen in individuals with bipolar I disorder, family vulnerability, polysubstance use, or unsupervised use. Registry data showed a 4% prevalence of later transition to bipolar disorder, with little evidence for a hallucinogen-specific signal. The authors conclude that these substances pose a low but clinically meaningful relative risk of transient mood symptoms in susceptible individuals while remaining relatively safe in controlled settings.