Neuropharmacology
November 1, 2026
Vincenzo Crunelli, Tatiana P Morais, William M Connelly et al.
Serotonin 5-HT2A receptors (5-HT2ARs) in the thalamus increase in expression during development, shifting from interneurons to thalamocortical neurons in the ventrobasal region. Activating these receptors with the agonist TCB-2 reduces GABA uptake and enhances tonic GABAA currents in ventrobasal thalamocortical neurons, an effect absent in δ-subunit GABAA receptor knockout mice and independent of postsynaptic signaling. Bilateral injection of TCB-2 into the ventrobasal thalamus of freely moving rats induces spike-and-wave discharges and behavioral arrest, which are blocked by ethosuximide, indicating absence seizures. The findings suggest that 5-HT2AR signaling can shape thalamocortical dynamics and increase susceptibility to aberrant rhythmic activity.
Neuropsychopharmacol Rep
September 1, 2026
Daisuke Ibi, Rika Takaba, Keisuke Yoshida et al.
In a mouse model of social defeat stress, the serotonin 5-HT2A receptor mediates the ability of psilocin to restore deficits in social behavior. Mice repeatedly subjected to social defeat stress showed reduced social interaction, and treatment with psilocin reversed this impairment. The therapeutic effect of psilocin was blocked by a 5-HT2A receptor antagonist and absent in mice lacking the 5-HT2A receptor, indicating that this receptor is necessary for the prosocial action of psilocin. These findings suggest that the 5-HT2A receptor is a key target for psilocin's effects on social behavior deficits caused by chronic stress.
bioRxiv (Cold Spring Harbor Laboratory)
July 20, 2026
Neil K. Savalia, Ling-Xiao Shao, Cory A. Knox et al.
Psilocybin transiently increases calcium event rates in apical dendritic tufts of pyramidal tract neurons in the mouse medial frontal cortex, an effect that parallels the drug's brain pharmacokinetics. This acute effect occurs selectively during quiet wakefulness and depends on the 5-HT2A receptor. Under normal conditions, dendritic calcium signaling predicts subsequent spine formation, but psilocybin disrupts this relationship. The findings suggest that the mechanisms linking acute dendritic activity to long-term structural plasticity differ between physiological and psychedelic-induced plasticity.
Molecular Psychiatry
July 16, 2026
Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman et al.
Serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network that drives neuroplastic changes. Using a neural stem cell-derived in vitro model, a panel of tryptamines, phenethylamines, and ergolines was tested alongside ketamine and TrkB agonists. TrkB silencing abolished dendritogenic responses to all tested compounds, while 5-HT2A receptor silencing selectively impaired psychedelic-induced plasticity. Most compounds increased synaptogenesis and induced c-Fos and Egr-2 expression, with ligand-specific differences for psilocin, DOI, and Ariadne. Gq/11 or Gi/o protein coupling differentially modified neuroplastic and transcriptional responses. Psychedelics also induced a 5-HT2A receptor-dependent lactate response sensitive to disruption of either Gq/11 or Gi/o coupling.
British Journal of Pharmacology
July 14, 2026
Darta Stalberga, Robert Kronstrand, Bianca Schranz et al.
Synthetic cathinones, a large class of new psychoactive substances, primarily inhibit dopamine, norepinephrine, and serotonin transporters, with high dopamine transporter selectivity linked to abuse potential. In vitro testing of 58 substances showed that N-pyrrolidine cathinones combined with methylenedioxy groups—MDPiHP, MDPEP, and MDPV—had the highest potency at the dopamine transporter. Other N-pyrrolidine cathinones, such as 3F-α-PHP, 3F-α-PiHP, and 4F-α-PiHP, showed the greatest dopamine transporter selectivity relative to the serotonin transporter. Chloromethcathinone and methylmethcathinone compounds, like 3-CMC, displayed an amphetamine-like profile with comparable potency at dopamine and norepinephrine transporters. Some cathinones at high concentrations and phenethylamines at micromolar concentrations also activated the 5-HT2A receptor, while 2C-like arylcyclohexylamines targeted the receptor without transporter inhibition. The majority of compounds, especially N-pyrrolidine cathinones, suggest high abuse potential based on their dopamine transporter selectivity.
ACS Medicinal Chemistry Letters
July 10, 2026
Anna C. Renner, Robert B. Kargbo
The psychedelic therapeutics field is moving beyond classical hallucinogens to integrated treatment platforms that combine optimized pharmacology, drug delivery, and clinical implementation. Recent patent applications describe selective 5-HT2A receptor activators, precision aerosol delivery technologies for psychedelic compounds, and structured 5-MeO-DMT treatment regimens for depression. These innovations represent a convergence toward scalable, safer, and clinically practical neuropsychiatric therapies that may reshape the future of serotonergic medicine.
Molecular Psychiatry
July 8, 2026
Granville J. Matheson, Johan Lundberg, Martin Gärde et al.
The serotonin 1B receptor (5-HT1BR) can be imaged in living humans using a PET tracer called [11C]AZ10419369 and is linked to major depressive disorder (MDD) and its treatment. Ketamine and electroconvulsive therapy (ECT) are rapid-acting antidepressants that raise serotonin levels, but whether they directly alter serotonin receptors was unclear. Reanalyzing 222 PET scans from three centers—including MDD patients before and after ketamine (19 completers), saline placebo (10), or ECT (13 completers)—using a hierarchical Bayesian method, the authors demonstrate large increases in 5-HT1BR binding after both ketamine (6.4%, 95% CI: 3.1–9.6%) and ECT (9.3%, 95% CI: 4.3–14.2%).
Zenodo (CERN European Organization for Nuclear Research)
July 7, 2026
Combined use of MDMA and SSRIs may increase the risk of serotonin syndrome, though evidence is limited or indirect. Healthcare providers are advised to remain alert for symptoms of this condition and to discourage such drug interactions.
Mol Psychiatry
July 7, 2026
Axel F. Rosado, Abigail L. Yu, Jen-Hau Yang et al.
Psilocybin and MDMA are both psychedelic drugs but produce different behavioral effects. MDMA, but not psilocybin, raises both serotonin and norepinephrine in the medial prefrontal cortex. Blocking norepinephrine release reveals head-twitch responses (a rodent correlate of psychedelic effects) from MDMA, suggesting that noradrenergic signaling opposes serotonin 2A receptor effects. Artificially raising norepinephrine also reduces psilocybin-induced head-twitch responses. Activating the noradrenergic alpha-2 receptor alone suppresses these responses, even in mice lacking the locus coeruleus, indicating action via heteroreceptors. Importantly, alpha-2 receptor activation does not block psilocybin's antidepressant-like effects in the forced swim test. This suggests that side effects of serotonin 2A activation can be reduced without losing therapeutic benefits.
ACS Medicinal Chemistry Letters
July 3, 2026
Ram W. Sabnis, Anika R. Sabnis
The document describes novel 6,5-bicyclic compounds that act as agonists of the 5-HT2A receptor. It covers pharmaceutical compositions containing these compounds, their potential use in treating depression, anxiety, substance abuse, and headaches, and processes for synthesizing them. This is a patent or chemical disclosure focused on drug discovery and pharmacology, not an empirical study with results.