Molecular Psychiatry
February 18, 2026
1 citation
Esketamine, a fast-acting antidepressant, improves depression in both sexes among adults with treatment-resistant depression. However, females showed greater overall improvement and higher odds of treatment response than males toward the end of four-week trials, regardless of whether they received esketamine or placebo. Females also experienced more pronounced reductions in sadness, detachment, and neurovegetative symptoms at certain time points. In contrast, males showed a significant reduction in sadness symptoms two days after esketamine. These findings indicate that sex assigned at birth influences the trajectory and symptom profile of antidepressant response, highlighting its importance for personalized treatment strategies.
Molecular Psychiatry
November 5, 2025
Dino Luethi, Grant C. Glatfelter, Eline Pottie et al.
1 citation
Psychedelic-like effects of ring-substituted amphetamines are primarily mediated by 5-HT 2A receptors. Small lipophilic substituents at the 4-position of 2,5-dimethoxyamphetamine enhance clinical potency. This study examined 4-alkylated 2,5-dimethoxyamphetamines (methyl, ethyl, propyl, butyl, amyl) for in vitro receptor activity and in vivo effects in mice using the head-twitch response (HTR) assay. Increasing 4-alkyl chain length raised affinity at 5-HT 2A receptors. The 4-propyl analog showed the highest potencies for 5-HT 2A receptor activation (1–9 nM) in vitro; other chain lengths ranged from 2–56 nM. In mice, maximal HTR counts varied from 23 to 119, with potencies from 0.42 to 2.76 mg/kg.
Molecular Psychiatry
October 21, 2025
Pol Puigseslloses, Núria Nadal‐gratacós, Berta Fumàs et al.
1 citation
A novel class of halogenated DMT derivatives—5-F-DMT, 5-Cl-DMT, and 5-Br-DMT—was characterized for pharmacological activity and therapeutic potential. Halogen substitution at the 5-position modulates receptor affinity across serotonin receptors and the serotonin transporter. 5-Br-DMT activated the 5-HT2A receptor but did not induce the head twitch response in mice, suggesting non-hallucinogenic activity. It upregulated immediate early genes linked to neuroplasticity in the mouse prefrontal cortex and hippocampus and promoted dendritic growth in cortical neurons. A single 10 mg/kg dose of 5-Br-DMT in a mouse model of stress-induced depression significantly reduced depressive-like behavior, indicating rapid antidepressant effects. The findings highlight 5-Br-DMT as a non-hallucinogenic psychoplastogen with antidepressant properties.
Molecular Psychiatry
July 10, 2026
Cong Lin, Xiaohui Wang
Classic psychedelics like LSD, psilocybin, DMT, and mescaline, as well as the antidepressant ketamine, can cause lasting changes in brain function and behavior beyond their immediate effects. This review examines how these substances may influence epigenetic regulation—changes in gene activity that do not alter the DNA sequence itself—through mechanisms such as DNA methylation, histone modifications, and non-coding RNA dynamics. The authors propose that psychedelics also affect metabolic pathways, altering the availability of key molecules like acetyl-CoA and SAM, which in turn may impact gene expression and synaptic connectivity. Understanding these processes could help explain how short-term psychedelic exposure leads to sustained therapeutic benefits and guide the development of new treatments for neuropsychiatric conditions.
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%).
Molecular Psychiatry
July 3, 2026
Yu Wang, Ji-Tao Li, Lin-Lin Zhu et al.
Mitochondrial dysfunction—including DNA abnormalities, impaired energy production, disrupted quality control, and redox imbalance—is a central feature of major depressive disorder. Beyond energy deficits, mitochondria act as upstream regulators of neuroinflammation: damage-associated molecular patterns and reactive oxygen species activate innate immune signaling, and inflammation in turn compromises mitochondrial integrity. This bidirectional, self-reinforcing interaction may contribute to disease onset, progression, and clinical heterogeneity. Conventional antidepressants gradually restore mitochondrial function and suppress oxidative and inflammatory stress, while rapid-acting agents like ketamine induce acute metabolic reprogramming and mitophagy. Mitochondria-targeted antioxidants, metabolic modulators, and psychedelic compounds further highlight the therapeutic potential of targeting mitochondrial pathways.
Molecular Psychiatry
February 12, 2026
Sixtine Fleury, Katherine M. Nautiyal
correction
Research in mice implicates the 5-HT1BR, a nonhallucinogenic serotonin receptor, as a potential mediator of the behavioral and neural effects of psilocybin. The 5-HT1BR influences brain-wide neural changes following psilocybin administration and may contribute to its enduring antidepressant-like effects in mice. However, the data do not address whether 5-HT1BR is sufficient for these effects.
Molecular Psychiatry
February 3, 2026
Pablo Mallaroni, S. Parker Singleton, Natasha L. Mason et al.
The psychedelic phenethylamine 2C-B produces less dysphoria and subjective impairment than the tryptamine psilocybin. In 22 healthy volunteers, 7 Tesla resting-state functional MRI mapped acute effects of matched doses of 20 mg 2C-B, 15 mg psilocybin, and placebo. Both compounds selectively reduced intranetwork static functional connectivity while broadly increasing between-network and subcortical-cortical connectivity. Compared to psilocybin, 2C-B showed less pronounced reductions in between-network dynamic connectivity variability but elevated transmodal static connectivity. Both increased brain complexity similarly. PET density modeling linked neural effects to differences in monoaminergic transporter and serotonergic receptor binding beyond 5-HT2A. Behavioral markers of psychedelic effects reflected decoupling of the transmodal axis of functional brain organization.
Molecular Psychiatry
November 14, 2025
Núria Nadal‐gratacós, Pol Puigseslloses, Laura Hernández‐guzmán et al.
Three novel phenethylamine derivatives—25C-NBF, 25B-NBF, and 25I-NBF—show high affinity and selectivity for the 5-HT2A receptor, with signaling bias toward Gq over β-arrestin pathways similar to serotonin. In mice, they cause moderate head-twitch responses without affecting movement or sensorimotor gating. No rewarding or reinforcing effects were observed, and accumbal dopamine levels in rats remained unchanged. 25C-NBF promotes dendritogenesis, spinogenesis, and increased Bdnf mRNA in vitro and in vivo, reduces despair-like behavior after acute stress, and produces rapid antidepressant effects in a chronic corticosterone model of anhedonia. These findings suggest 25C-NBF may offer a fast-acting antidepressant with no abuse potential or sensorimotor deficits.