eLife March 31, 2026 Jessica L Maltman, Javier González-Maeso
Exposure to psilocin, the active metabolite of the psychedelic psilocybin, increases structural complexity and strengthens synaptic connections in human neurons derived from stem cells. These changes suggest enhanced neuroplasticity at the cellular level.
Research Square March 31, 2026 Marcus W. Meinhardt, Ivan Skorodumov, Florian Walter et al.
A compound derived from ibogaine, oxa-noribogaine, reduces alcohol consumption in rats by strengthening learning from negative drinking outcomes. It produces sustained decreases in alcohol intake and relapse-like drinking, matching or exceeding ibogaine's efficacy without detectable motor or cardiac side effects. These effects involve transient changes in prefrontal brain activity, lasting alterations in glutamatergic signaling after aversion-related learning, and normalization of neurotrophic signaling in cortico-striatal circuits. The results generalize across multiple models, genetically diverse animals, and independent study sites, identifying oxa-noribogaine as a promising treatment candidate for alcohol use disorder.
eLife March 27, 2026 Malin Schmidt, Anne Hoffrichter, Mahnaz Davoudi et al. 3 citations
Psilocin, the psychoactive metabolite of psilocybin, increases BDNF abundance in human cortical neurons derived from induced pluripotent stem cells via the 5-HT2A receptor. Transcriptomic profiling shows gene expression changes that prime neurons for neuroplasticity. Morphologically, psilocin enhances neuronal complexity and increases synaptic proteins, especially in the postsynaptic compartment. Functionally, it leads to increased excitability and enhanced synaptic network activity. These findings suggest psilocin induces a state of enhanced neuronal plasticity, which may explain its therapeutic potential in neuropsychiatric disorders involving synaptic dysfunction.
Biomolecules March 24, 2026 Veronica Begni, Floriana de Cillis, Natascha Pfeiffer et al.
Classical and rapid-acting antidepressants alter how the brain responds to acute stress through different molecular programs. In mice exposed to swim stress, imipramine dampened stress-induced neural activation in the cortex and striatum, while ketamine preserved it. Hippocampal activation remained robust and unaffected by either drug. BDNF expression changed only in the striatum, where imipramine reduced the stress-related increase. Both drugs similarly promoted active coping behaviors, but through distinct mechanisms. The findings suggest that cortical and striatal transcriptional signatures differentiate classical from rapid-acting antidepressant action, though human studies are needed to confirm clinical relevance.
bioRxiv (Cold Spring Harbor Laboratory) March 23, 2026 Marco Taddei-Tardon, Lidia Medina-Rodríguez, Jessica L. Maltman et al.
Serotonergic psychedelics, including tryptamines, phenethylamines, and ergolines, promote structural and transcriptional changes in neurons through an integrated signaling network involving the 5-HT2A receptor and TrkB. Using a neural stem cell-derived model, the study shows that TrkB silencing blocks dendritogenesis induced by psychedelics, ketamine, and TrkB agonists, while 5-HT2A silencing selectively impairs psychedelic-induced plasticity. Most compounds increase synaptogenesis and immediate-early gene expression, though psilocin and the phenethylamines DOI and Ariadne show ligand-specific differences. Lactate production, dependent on 5-HT2A and both Gq/11 and Gi/o protein signaling, also occurs. These results establish a platform for dissecting psychedelic action.
International Journal of Molecular Sciences March 20, 2026 Ivan Anchesi, Ivana Raffaele, M. Astorino et al.
Tabernanthalog (TBG), a non-hallucinogenic analog of ibogaine, was designed to avoid life-threatening cardiotoxicity by eliminating interactions with the hERG potassium channel. Beyond its anti-addictive and antidepressant-like effects, recent 2024-2025 data show TBG is effective in preclinical models of neuropathic and visceral pain and reverses cognitive deficits associated with cancer-related cognitive impairment, including those induced directly by tumors. TBG's mechanism involves a multi-target profile: inhibition of nicotinic acetylcholine receptors, positive modulation of NMDA receptors, and crosstalk with mGlu2 receptors, rather than solely 5-HT2A receptor agonism. It induces structural neuroplasticity without widespread immediate early gene activation, decoupling therapeutic rewiring from psychedelic effects. TBG represents a promising scaffold for next-generation neurotherapeutics.
Journal of psychoactive drugs March 20, 2026 Marina A M Portes, Leandro J Bertoglio
Endurance athletes face unique psychological and physical stressors, yet their knowledge and attitudes toward psychedelic therapies are largely unknown. A survey of 28 Brazilian endurance athletes (mean age 37) found that 64% reported a lack of mental health support in their athletic environments. Only 11% had prior psychedelic experience, while 79% were open to legal, supervised psychedelic therapies. However, 61% were unaware of evidence for psychedelics in treating mental health conditions, and 78% mistakenly believed psychedelics are addictive. Women more often reported pharmacological treatment for depression or anxiety. The findings highlight unmet mental health needs, knowledge gaps, and misconceptions, pointing to a need for targeted, evidence-based education.
Molecules and Cells March 10, 2026 Victoria N. Chang, Roberto Ogelman, R. Vargas et al. 1 citation
Serotonin (5-HT) is a key neuromodulator that directly influences plasticity at excitatory synapses on dendritic spines. It activates 14 subtypes of G-protein-coupled receptors, each with distinct expression and signaling. Disruptions in serotonergic transmission during development or adulthood cause lasting changes in behavior and neuronal structure, particularly in dendritic spines, indicating serotonin's critical role in excitatory synaptic plasticity. This review summarizes how 5-HT receptors contribute to the development and maturation of excitatory postsynaptic synapses, from spinogenesis through stabilization, potentiation, and depression. It also highlights recent advances showing how atypical serotonergic signaling and psychedelics alter spine structure and function.
bioRxiv (Cold Spring Harbor Laboratory) March 8, 2026 Nitzan Geva, Sarah J. Jefferson, Emi Krishnamurthy et al.
MDMA increases spine density and the formation of new spines in the medial prefrontal cortex of mice, as shown by two-photon microscopy. Calcium imaging in the infralimbic cortex during fear extinction revealed that neural activity in this region became more correlated with the suppression of freezing behavior, indicating a strengthened role in extinction. Longitudinal cell registration showed accelerated representational drift across days in MDMA-treated mice, especially in neurons that suppressed activity to conditioned cues. These findings indicate that MDMA facilitates structural and functional neuroplasticity, which may underlie its enhancement of extinction learning.
Molecular and cellular neurosciences March 1, 2026 Mustafa M Shokr, Mohamed N Fawzy, Ahmed M Abdelaziz
The brain's ability to reorganize itself, known as neuroplasticity, is now understood to be more flexible and treatable in adults than previously believed. This review examines drugs that target key synaptic receptors (NMDA, AMPA, GABA), neuropeptide systems (BDNF, oxytocin, vasopressin), and psychedelic compounds (psilocybin, LSD, ketamine). Evidence shows that NMDA antagonists produce rapid antidepressant effects, classic psychedelics reorganize brain structure and function through 5-HT2A receptor activation, and neuropeptides support synaptic repair. The authors emphasize safety concerns, risks of harmful plasticity, and the need for controlled dosing and patient selection. Emerging non-hallucinogenic neuroplastogens and combination therapies may offer safer ways to enhance plasticity for treating neuropsychiatric and neurodegenerative disorders.
Molecular Psychiatry March 1, 2026 Tyler G. Ekins, Chloe Rybicki-Kler, Tao Deng et al. 9 citations
Classic psychedelics can strengthen connections in the retrosplenial cortex, a brain region important for memory and spatial orientation that is impaired in Alzheimer's disease, even though its neurons lack the serotonin 2A receptors thought necessary for such effects. Using a new genetic tool in mice, the research shows that this strengthening depends on presynaptic serotonin 2A receptors on incoming nerve fibers from the anterior thalamus, not on the postsynaptic receptors of the retrosplenial cortex itself. The finding suggests psychedelics may have broader therapeutic potential than currently recognized, possibly aiding conditions like Alzheimer's disease and post-traumatic stress disorder by boosting retrosplenial circuit function.