Pharmacology, biochemistry, and behavior
May 29, 2026
Madeline T Van Fossen, Alexia G Dalton, Adam J Prus
Dextromethorphan, an FDA-approved drug for major depressive disorder when combined with bupropion, acutely reduces compulsive-like drinking in a rat model of obsessive-compulsive disorder. The drug acts as an inhibitor of serotonin transporters and an antagonist of sigma-1 and NMDA receptors. In the study, rats were trained in a schedule-induced polydipsia procedure, which models compulsive behavior, and were divided into low and high drinkers. Dextromethorphan dose-dependently decreased water consumption in both groups, while the NMDA receptor antagonist ketamine selectively reduced drinking only in high drinkers. However, none of the tested antagonists reversed dextromethorphan's effects, suggesting further investigation into its potential as an OCD treatment.
Journal of psychopharmacology (Oxford, England)
May 29, 2026
Elliot Hampsey, Kirsty Martin, Michail Kalfas et al.
A systematic review of 32 trials in healthy adults found that LSD and psilocybin show dose-proportional peak concentrations (Cmax), while DMT's oral and intravenous formulations differ in ways that may be clinically significant. LSD was the most studied psychedelic, followed by DMT and psilocybin; mescaline appeared in only two trials. Single studies examined intravenous LSD, intravenous psilocybin, inhaled 5-MEO-DMT, and intranasal 5-MEO-DMT. Variations in absorption, distribution, and elimination among the compounds may have important implications for clinical and research settings.
Cell Discov
May 29, 2026
Gang Pei
The authors propose a spatiotemporal gating hypothesis to resolve a paradox in how psilocybin produces lasting neural plasticity. Psilocybin activates 5-HT₂A receptors, but the plasticity it induces requires TrkB signaling, even though psilocybin does not directly bind TrkB. The hypothesis suggests that 5-HT₂A activation creates a specific pattern of neural activity—a spatiotemporal gate—that indirectly engages TrkB signaling, reconciling the two mechanisms. This framework aims to explain how a brief psychedelic experience can lead to sustained changes in brain structure and function.
Clinical Pharmacology & Therapeutics
May 28, 2026
Gia Han Le, Sabrina Wong, Danica E. Johnson et al.
The serotonin 5-HT2B receptor sits at a crossroads between potential antidepressant effects in the brain and serious heart valve risks when activated peripherally. This narrative review of preclinical and clinical literature finds that peripheral activation of 5-HT2B receptors causes valvular heart disease through cell proliferation and scarring, as seen with older drugs like fenfluramine and some dopamine agonists. In the brain, the receptor's effects are mixed: astrocytic activation may support metabolism and plasticity, while neuronal blockade can normalize dopamine and glutamate activity. Several approved antidepressant adjuncts (aripiprazole, brexpiprazole, cariprazine) antagonize this receptor without observed heart valve problems. The authors propose developing centrally selective, periphery-sparing 5-HT2B antagonists for treatment-resistant depression, with early cardiac monitoring to ensure safety.
ACS Chemical Neuroscience
May 27, 2026
Grant C. Glatfelter, Serena S. Schalk, Donna Walther et al.
Tryptamine psychedelics produce their effects mainly by activating serotonin 2A receptors, but many also affect other targets. 4-MeO-MiPT, a compound that both activates 5-HT2A receptors and blocks the serotonin transporter (SERT), produces blunted psychedelic effects in humans. In mice, 4-MeO-MiPT and its analogs with stronger SERT blockade showed fewer head twitch responses (a proxy for psychedelic-like effects) than their 4-hydroxy counterparts. Pretreating mice with the SERT inhibitor fluoxetine reduced head twitch responses from 4-hydroxy compounds to levels seen with the 4-methoxy analogs. The findings suggest that dual 5-HT2A/SERT ligands may have therapeutic potential with reduced acute psychedelic effects.
PsyArXiv
May 24, 2026
Naja Bralic, Elena Bragagnolo, Mikael Palner
preprint
Serotonergic psychedelics such as psilocybin and DOI show anxiolytic-like effects in animal models, though anxiogenic and null results also occur, indicating context-dependent outcomes influenced by dosage, administration pattern, biological variables, and experimental conditions. A systematic review of 18 preclinical studies found generally acceptable predictive and face validity in behavioral tests, but construct validity had limitations and inconsistencies in experimental conditions need standardization. Psilocybin produced consistent anxiolytic-like effects, possibly through 5-HT2A receptor agonism, suggesting therapeutic potential for anxiety. Future research should focus on mechanisms, sex-specific effects, and improved behavioral test combinations.
ACS Omega
May 13, 2026
Darío Martínez-afani, Breno A. Soares, Jaime Mella-Raipán et al.
1 citation
A set of 22 tryptamine and 22 5-methoxytryptamine derivatives with various N-benzyl substituents were synthesized and tested for affinity and potency at serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. The data enabled QSAR analysis, which showed that meta-substitution on the benzyl ring improves activity, while para-substitution reduces it. These effects are attributed to favorable van der Waals interactions at the meta position and steric hindrance at the para position. The findings suggest that N-benzyltryptamines, previously overlooked as psychedelic ligands, could be leads for treating cognitive disorders, substance abuse, or depression.
International Journal of Molecular Sciences
May 9, 2026
Marta Jóźwiak-Bębenista, Anna Stasiak, Monika Sienkiewicz et al.
Aging involves chronic low-grade inflammation that contributes to depression and neurodegenerative diseases like Alzheimer's and Parkinson's. Psilocybin, acting through its active metabolite psilocin as a partial agonist at the 5-HT2A receptor, may address these challenges by modulating cortical glutamate transmission, enhancing TrkB/BDNF pathways, and influencing neuroimmune cascades including NF-κB. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP. Psilocybin's rapid onset, short half-life, and phase-II glucuronidation reduce drug interaction risks, making it potentially advantageous for older adults. Controlled studies show rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging signals in neurodegeneration. The review integrates current evidence and calls for targeted studies in older adults.
Journal of psychopharmacology (Oxford, England)
May 2, 2026
Zarmeen Zahid, Rick J. Strassman, Clifford Qualls et al.
Blocking the 5-HT1A receptor with pindolol before giving a low dose of DMT to experienced hallucinogen users intensified the drug's subjective effects, with a moderate effect size. Blood pressure also increased shortly after DMT administration, while heart rate was unchanged. The findings suggest that 5-HT1A receptor activity normally dampens the subjective effects of psychedelics, pointing to a functional role for this receptor in shaping the psychedelic experience.
American Journal of Respiratory and Critical Care Medicine
May 1, 2026
S Pack, T Ellett, J Pham et al.
A 46-year-old man developed life-threatening serotonin syndrome after consuming ayahuasca at a retreat and later taking dextromethorphan and diphenhydramine. He presented with agitation, hyperthermia, tachycardia, and respiratory failure requiring intubation and intensive care. Treatment with cyproheptadine and midazolam led to full recovery within three days. The case highlights the dangerous interaction between ayahuasca's monoamine oxidase inhibitors and over-the-counter serotonergic medications, which can synergistically cause severe toxicity.
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.