Molecular Psychiatry
April 1, 2026
Zijian Lv, Qifeng Xie, Kecan Li et al.
3 citations
Chronic stress changes behavior in both people and animals. By testing different chronic restraint stress (CRS) protocols in male mice, researchers identified that short, intense stress (6 hours/day for 3 days) caused persistent avoidance and repetitive behaviors, while longer, milder stress (2 hours/day for 10–14 days) progressively reduced reward-seeking and coping behaviors. A 10-day CRS protocol marked a threshold for reward-seeking deficits and served as a model combining avoidance and reward-processing impairments. The antidepressant ketamine reversed reward-seeking and coping deficits, while paroxetine alleviated both repetitive/avoidance behaviors and coping/reward-seeking deficits. These findings support CRS as a valid male mouse model of stress-related neuropsychiatric disorders.
Molecular Psychiatry
May 1, 2026
Sixtine Fleury, Katherine M. Nautiyal
2 citations
Psilocybin's persisting antidepressant-like effects in mice involve not only the serotonin 2A receptor but also the serotonin 1B receptor (5-HT1BR). Mice lacking 5-HT1BR showed altered brain-wide neural activity after psilocybin, measured by c-Fos expression in emotion- and cognition-related regions such as the amygdala. While the acute head twitch response was unaffected, 5-HT1BR absence reduced psilocybin-induced hypolocomotion. Longer-term effects on anhedonia and anxiety-like behavior depended on 5-HT1BR, with influences from sex and stress. Network analysis identified circuits through which 5-HT1BR may modulate psilocybin's effects. The findings suggest 5-HT1BR contributes to psilocybin's enduring antidepressant-like actions in mice.
Molecular Psychiatry
August 26, 2025
Ross J. Purple, Rahul Gupta, Christopher W. Thomas et al.
2 citations
After a therapeutically relevant dose of psilocybin, high-frequency oscillations at 100 Hz appear in the infralimbic cortex of rats, lasting about an hour, while overall neuron firing rates and spike-train complexity decrease. These acute effects are stronger when the animal is at rest than during a sustained attention task. Over the following days, power in beta and low-gamma frequencies (20–60 Hz) gradually increases in the infralimbic cortex. The findings point to infralimbic network oscillations as potential markers of psychedelic-induced plasticity that unfold over multiple days, revealing details not easily seen in human brain imaging.
Molecular Psychiatry
April 6, 2025
James J Gattuso, Carey Wilson, Anthony J. Hannan et al.
2 citations
A study in a mouse model of obsessive-compulsive disorder (OCD)-like behaviors tested a psychedelic mushroom extract (PME) for potential therapeutic benefits. The research used SAPAP3 knockout mice, which exhibit compulsive grooming and other OCD-like behaviors. The findings suggest that PME may reduce these behaviors, indicating possible therapeutic effects. This work underscores the need for well-designed preclinical studies in the growing field of psychedelic research for psychiatric disorders.
Molecular Psychiatry
July 1, 2026
Waki Nakajima, Tetsu Arisawa, Susumu Jitsuki et al.
1 citation
A novel compound, K-4, which positively modulates AMPA receptors, produced longer-lasting antidepressant-like effects in a rat model of treatment-resistant depression than ketamine alone. K-4 reduced expression of the enzyme NOX-1 in the medial prefrontal cortex. Blocking NOX-1, either with an inhibitor or by genetic knockdown, prolonged ketamine's antidepressant-like effects and reduced abnormal bursting in the lateral habenula, a brain region linked to depression. Suppressing NOX-1 may be a promising strategy for extending the benefits of ketamine in treatment-resistant depression.
Molecular Psychiatry
April 8, 2026
Johannes G. Ramaekers, Kim P. C. Kuypers, Franz X. Vollenweider
1 citation
MDMA, originally developed for military purposes and later used recreationally, is now being tested in clinical trials for PTSD. A narrative review of placebo-controlled single-dose studies in healthy volunteers found that 75-125 mg of MDMA acutely enhances mood, empathy, trust, and arousal while transiently impairing memory encoding through increased serotonin signaling. Motor coordination and cognitive flexibility decline modestly, but inhibitory control and executive function remain largely intact. Post-acutely, fatigue and low mood may occur. These effects may support trauma processing by facilitating fear extinction and disrupting negative memory reconsolidation, though they also complicate trial design by compromising blinding and inflating expectancy.
Molecular Psychiatry
April 1, 2026
Josh Allen, Mujun Sun, Tamara L Baker et al.
1 citation
In a rat model of recurrent intimate partner violence brain injury (daily mild traumatic brain injury plus non-fatal strangulation for five days followed by 16 weeks of recovery), a single dose of psilocybin (1 mg/kg) reversed injury-induced anxiety-like behavior in the elevated plus-maze, increased sucrose preference (indicating reduced anhedonia), and improved reversal learning in the water maze and spatial memory in the Y-maze. Psilocybin also prevented the increase in microglial cells in the dorsal hippocampal molecular layer and the loss of reelin-positive cells in the subgranular zone seen in saline-treated injured rats. Pre-treatment with a 5-HT2A receptor antagonist blocked psilocybin's behavioral effects, indicating these benefits depend on 5-HT2A receptor activation.
Molecular Psychiatry
March 5, 2026
Waki Nakajima, Mai Hatano, Yohei Ohtani et al.
1 citation
About 30% of people with depression have treatment-resistant depression (TRD). Ketamine can help, but how it works in the human brain was unclear. Using a PET tracer that shows AMPAR density, researchers found that AMPAR density was lower in patients with more severe TRD, and its distribution differed from healthy people. After ketamine, changes in AMPAR density in certain brain areas correlated with antidepressant effects, partially restoring normal AMPAR patterns. AMPAR dynamics underlie ketamine's antidepressant effect in TRD.
Molecular Psychiatry
February 18, 2026
Marie Huc, Sara Siddiqi, Mysa Myers et al.
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 18, 2025
Cassandre Corvo, Sébastien Goutal, Indira Mendez-David et al.
1 citation
In a mouse model of anxiety/depression, a single dose of ketamine produced rapid antidepressant effects in behavior tests, but no change in synaptic density was detected by PET imaging 24 hours later. After three weekly doses, ketamine restored synaptic density to healthy control levels, an effect that coincided with delayed antidepressant effects. The PET tracer 11C-UCB-J reliably tracked these changes, and its binding correlated with levels of synaptic proteins. The findings support using SV2A PET imaging to monitor drug-induced rebuilding of brain connections as a marker of antidepressant efficacy.
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
November 1, 2024
H Nur Eken, Crystal Spotts, Benjamin Panny et al.
1 citation
A combination of ketamine infusion and a digital training program called automated self-association training (ASAT) produced more positive implicit self-associations immediately after treatment in adults with treatment-resistant depression, compared to control groups that received only one active component. These changes in implicit self-worth tracked with concurrent depression symptom improvement across all groups and specifically predicted longer-term depression relief at 30 days for the combined treatment group. The findings indicate that shifting implicit self-esteem during a post-ketamine 'plasticity window' is a key mechanism behind the combined treatment's antidepressant effect, confirming the intended cognitive target.
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
June 27, 2026
David R. Roalf, Tyler M Moore, Jacquelyn Stifelman et al.
Cannabis use is linked to higher psychosis risk, and this study examined whether brain glutamate levels in the anterior cingulate cortex (ACC) relate to symptoms depending on cannabis use. Among 79 participants across the psychosis spectrum, higher ACC glutamate independently predicted greater positive and negative symptoms. However, in cannabis users, lower glutamate was associated with more positive symptoms. Psychosis patients who used cannabis had lower ACC glutamate, suggesting glutamatergic dysfunction may amplify symptom severity. The findings implicate ACC glutamate as a transdiagnostic correlate of symptom burden, especially in cannabis users with psychosis.
Molecular Psychiatry
June 25, 2026
Clotilde Guidetti, Maurizio Fava, George I. Papakostas
Major depressive disorder and treatment-resistant depression affect many people, and over half of patients do not respond adequately to first-line antidepressants. This review examines promising rapid-acting treatments, including psychedelic compounds like psilocybin, which is in late-stage trials, and neuroplastogen compounds. It also discusses repetitive transcranial magnetic stimulation, including the SAINT protocol, which has shown rapid antidepressant effects and is FDA-cleared for treatment-resistant depression. The ALTO-300 trial is evaluating an adjunctive treatment guided by an EEG biomarker, and a Phase 2 study reports outcomes varying by genotype, suggesting potential for genetically personalized interventions. Challenges include unblinding in psychedelic trials, scalability of neuromodulation, and need for validated biomarkers.
Molecular Psychiatry
May 29, 2026
Mickael Eskinazi, Rayan Nasserdine, Romane M Cusin et al.
A systematic review of 23 studies examined whether serotonergic psychedelics (psilocybin, LSD, mescaline, DMT/ayahuasca) or MDMA can trigger manic or hypomanic symptoms. Rates of such symptoms ranged from 5.8% in controlled trials of psilocybin-assisted therapy for depression to 30% in naturalistic studies of people with bipolar disorder. When manic symptoms occurred, they were typically acute and self-limited. Higher risks were seen in individuals with bipolar I disorder, family vulnerability, polysubstance use, or unsupervised use. Registry data showed a 4% prevalence of later transition to bipolar disorder, with little evidence for a hallucinogen-specific signal. The authors conclude that these substances pose a low but clinically meaningful relative risk of transient mood symptoms in susceptible individuals while remaining relatively safe in controlled settings.
Molecular Psychiatry
April 13, 2026
Xin Zhao, Xinyu Zhang, Shiying Yuan et al.
Ketamine, a drug used for anesthesia and rapid antidepressant effects, also modulates systemic immunity and protects organs through interactions with the gut microbiota, microbial metabolites, and immune-cell trafficking. Along the gut-brain axis, ketamine restores microbial balance, normalizes short-chain fatty acid levels, and reduces migration of gut-derived immune cells to the central nervous system, correlating with reduced neuroinflammation and depressive-like behaviors. Through the gut-lung axis, ketamine limits bacterial translocation and reduces pulmonary infiltration of pro-inflammatory cells, suggesting potential relevance in acute lung injury. Arketamine appears to provide more sustained neuroprotection with fewer adverse effects than esketamine. The findings suggest broad therapeutic potential for neuropsychiatric and inflammatory diseases, but causal studies are needed.
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.
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.
Molecular Psychiatry
June 1, 2026
Xin Yi, Yuan-Bo Zhang, Tong-Zhou Yu et al.
Post-traumatic stress disorder persists when stress biases memory systems, broadening threat engrams and weakening context-appropriate inhibition. Integrating preclinical and human evidence, the authors argue that extinction can be stabilized by engaging hippocampal-prefrontal-amygdala pathways and their thalamic coordinators. Targeted training and sleep-based reactivation strengthen top-down control over intrusions and sharpen safety-threat discrimination. Brief, prediction-error-rich retrieval opens a reconsolidation window through which maladaptive content can be updated; pairing this with state-aligned neuromodulation or psychedelic pharmacology biases plasticity toward safety. Integrating extinction reinforcement with voluntary memory control and reconsolidation editing offers a coherent route to more durable relief from traumatic memories in PTSD.