Nature reviews. Neuroscience
February 1, 2025
Clara Liao, Alisha N Dua, Cassandra Wojtasiewicz et al.
60 citations
A feature of major depressive disorder is impaired excitatory synapses in the prefrontal cortex. Treatments with rapid antidepressant effects—ketamine, electroconvulsive therapy, and non-invasive neurostimulation—appear to enhance neural plasticity, but the specific forms and mechanisms linking these interventions to restoring excitatory synaptic function remain unknown. This review highlights preclinical research from the past 15 years showing that ketamine and psychedelic drugs can trigger growth of dendritic spines in cortical pyramidal neurons.
Proceedings of the National Academy of Sciences
April 14, 2025
Jeremy R Tuck, Lee E Dunlap, Yara A Khatib et al.
32 citations
A newly designed compound, (+)-JRT, structurally similar to LSD but with reduced hallucinogenic effects, promotes the growth of dendritic spines in the cortex—a process that is diminished in neuropsychiatric diseases such as depression, addiction, and schizophrenia. In behavioral tests, (+)-JRT showed antidepressant-like and cognition-enhancing effects without worsening signs related to psychosis. This suggests that nonhallucinogenic compounds that promote neuroplasticity could be safer alternatives to psychedelics for treating conditions where psychedelics pose risks.
Nature medicine
February 6, 2026
Joshua S Siegel, Conor Liston, Ginger E Nicol et al.
10 citations
Classic psychedelics, acting at the serotonin 5-HT2A receptor, alter brain function and consciousness. Research converges on two complementary processes: acute neural desynchronization, which destabilizes entrenched network patterns, and subacute neuroplasticity, which opens a window for psychological and behavioral change. Evidence of therapeutic response across neuropsychiatric indications is reviewed, integrating mechanistic findings. Challenges include discrepancies between preclinical evidence that non-hallucinogenic psychedelic analogs engage putative therapeutic mechanisms and clinical evidence linking subjective experience to therapeutic response, risks of enhanced neuroplasticity, and questions about trial design, scalability, and regulatory approval. The growth of psychedelic science may compel a rethinking of the relationship between subjective experience and biological change in psychiatry.
Cell
April 30, 2026
Hermany Munguba, Anisul Arefin, Ryota Hasegawa et al.
4 citations
Ketamine's rapid antidepressant effects depend on mu-opioid receptors (MORs) located on somatostatin-expressing interneurons in the medial prefrontal cortex. Chronic stress causes these interneurons to become hypertrophic, leading to excessive inhibition of pyramidal neurons, a disruption that ketamine reverses. By identifying GPCRs enriched in these interneurons through RNA sequencing, the authors validate several antidepressant targets and show that activating multiple GPCRs synergistically produces potent antidepressant-like effects with fewer side effects. This approach offers a general strategy for discovering GPCR-based treatments for brain disorders.