Psychiatry Research
August 18, 2025
Ilenia Rosa, L. Padula, Francesco Semeraro et al.
2 citations
Treatment-resistant depression (TRD) challenges standard approaches, prompting a shift toward non-monoaminergic interventions like neuromodulation and glutamatergic agents. This narrative review examines the endocannabinoid system (ECS) as a potential common pathway for these treatments. Evidence indicates that repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) increase endocannabinoids anandamide and 2-arachidonoylglycerol, correlating with clinical improvement. Ketamine and esketamine modulate CB1 receptors, while psilocybin restores 2-AG and enhances CB1 expression in mood-related brain regions. These findings suggest ECS modulation may unify diverse antidepressant mechanisms in TRD, offering a promising target for novel therapies.
Scientific reports
March 27, 2026
Gianmauro Palombelli, Valentina Zecca, Marta Boffa et al.
1 citation
In a rat model of treatment-resistant depression (Wistar-Kyoto rats exposed to chronic mild stress), brain scans revealed metabolic and structural changes distinct from non-depressed controls. Magnetic resonance spectroscopy showed reduced glutamate, glutamine, and taurine in the prefrontal cortex and decreased glutamine and choline compounds in the hippocampus, along with increased myo-inositol in the prefrontal cortex. Diffusion tensor imaging indicated higher mean diffusivity in both regions, consistent with demyelination or axonal loss, and lower fractional anisotropy in the hippocampus, suggesting compromised white-matter integrity. These findings mirror depression- and stress-related brain changes in humans, supporting the model's use for testing novel treatments like rTMS and psychedelics.
Translational Psychiatry
June 24, 2026
Mauro Pettorruso, Giacomo D’andrea, Antonio Inserra et al.
Emerging clinical and preclinical evidence suggests that the therapeutic benefits of psychedelics for depression and anxiety may be separable from their consciousness-altering effects. Psychedelics produce profound brain changes, including suppression of the default mode network, leading to intense subjective experiences such as ego dissolution. These effects require extensive preparation and integration, exclude individuals with certain psychiatric vulnerabilities, and raise scalability concerns. Pharmacological strategies like serotonin 2A receptor antagonism and development of biased psychedelic analogues might retain therapeutic efficacy without psychedelic experiences. Preclinical data indicate that downstream molecular and network-level mechanisms could mediate therapeutic effects independently of subjective states. Confirming this dissociation could enable more scalable, accessible treatments for broader psychiatric populations.
Clinical Neuropsychopharmacology and Addiction
April 17, 2026
Antonio Inserra, Francesca Zoratto, Mauro Pettorruso et al.
No Summary
The International Journal of Neuropsychopharmacology
August 1, 2025
Giovanni Martinotti, Clara Cavallotto, G D’andrea et al.
Psilocybin, a psychedelic compound that acts on serotonin receptors, shows promise for treatment-resistant depression, with remission rates up to 70% in some studies. The antidepressant and psychedelic effects may be separable, with the latter linked to 5-HT2A receptors. By co-administering the 5-HT2A antagonist ketanserin, psilocybin's hallucinogenic effects can be minimized, reducing bias from the mystical experience and improving clinical feasibility. A proposed study will randomly assign 68 treatment-resistant depression patients to receive either non-psychedelic psilocybin (two 25 mg doses, preceded by ketanserin) or accelerated repetitive transcranial magnetic stimulation (arTMS). Outcomes will be compared at day 60 using psychometric tests, EEG, and fMRI.