Neuropsychopharmacol Rep • September 1, 2026
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.
Hearing research • August 1, 2026 • Shuhan Lu, Zhixin Zhang, Xinmiao Xue et al.
Tinnitus, the perception of sound without an external source, lacks effective treatments. Psilocybin, a psychedelic, shows promise by activating 5-HT2A receptors, boosting glutamate release, and upregulating BDNF, which increases dendritic spine density and synaptic proteins in the hippocampus and prefrontal cortex, restoring neural plasticity. This review connects these neuroplasticity mechanisms to tinnitus-related neural changes, highlighting psilocybin's regulatory effects on excitatory (glutamate, dopamine) and inhibitory (GABA) neurotransmitters and their receptors, suggesting a novel therapeutic pathway.
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.
European journal of pharmacology • July 10, 2026 • Amanda Gollo Bertollo, Vinicius Alexandre Wippel, Maiqueli Eduarda Dama Mingoti et al.
Psychedelic compounds show promise as rapid-acting antidepressants, especially for treatment-resistant depression. Their effects are primarily mediated through 5-HT2A receptor activation, which triggers intracellular signaling cascades involving Gq/11 and β-arrestin pathways, leading to neuroplasticity, synaptogenesis, and remodeling of neural circuits like the default mode network. These compounds also modulate glutamatergic transmission and have anti-inflammatory properties. Key transcription factors and epigenetic modifications contribute to enduring changes in gene expression. While 5-HT2A receptors play a central role, other receptors and neurotransmitter systems are also involved. The review identifies knowledge gaps regarding interactions between these mechanisms and suggests future research directions.
Figshare • July 10, 2026 • José Alexandre Salerno, Elizabeth R. Dominguez, Karina Karmirian et al.
A brief 24-hour exposure to the serotonergic psychedelic DMT increases proliferation of human neural stem cells derived from induced pluripotent stem cells. The effect was concentration-dependent, with half-maximal effect at 59.7 nM. DMT treatment also altered trophic gene expression, decreasing neurotrophin-3 while increasing nerve growth factor and brain-derived neurotrophic factor (BDNF) transcripts and intracellular BDNF protein. After DMT was removed, the primed stem cells formed larger neurospheres, with progenitor and early neuronal marker composition matching controls by day 10. These findings demonstrate that brief DMT exposure engages proliferative and neurotrophin-associated responses in human neural stem cells at concentrations consistent with those reported for DMT-induced plasticity in other systems.
Open Science Framework • July 9, 2026 • Raul Edison Luna Lazo, Nicole Milagritos Cardoso Azorza, Jatziri Yanina Vilca Yanac et al.
Psilocybin, a classic psychedelic that acts on serotonin 5-HT2A receptors, is being investigated as a potential treatment for obsessive-compulsive disorder (OCD), a chronic condition marked by intrusive thoughts and repetitive behaviors. Many patients do not respond adequately to first-line treatments like selective serotonin reuptake inhibitors and cognitive behavioral therapy. This scoping review, following JBI recommendations and PRISMA-ScR guidelines, will systematically search PubMed, Scopus, and Web of Science for preclinical and clinical studies on psilocybin or psilocin for OCD. The review aims to map current evidence, identify knowledge gaps, and guide future research, particularly for treatment-resistant patients.
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%).
Mol Psychiatry • July 7, 2026
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.
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.
Biomedicines • July 6, 2026 • Kasper Buczma, Katarzyna Kamińska, Kaja Kasarełło et al.
Psilocybin, a serotonergic hallucinogen, shows therapeutic promise for treatment-resistant depression, but its multi-organ safety profile remains unclear. This narrative review of preclinical studies, clinical data, and case reports found limited and heterogeneous evidence, with rare adverse events often confounded by polysubstance use and uncertain dosing. Biologically plausible mechanisms via serotonergic receptor activation warrant further investigation, yet controlled clinical data do not consistently indicate intrinsic multi-organ toxicity. The review highlights critical gaps in understanding psilocybin's organ-specific safety and calls for systematic evaluation.
Science • February 16, 2023 • 467 citations
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-HT2ARs is essential for psychedelic-induced cortical plasticity, but it is unclear why some 5-HT2AR agonists promote neuroplasticity while others do not. Using molecular and genetic tools, the authors demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. This work emphasizes location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
eLife • October 25, 2018 • Katrin H. Preller, Joshua B. Burt, Jie Lisa Ji et al. • 416 citations
Lysergic acid diethylamide (LSD) reduces associative brain connectivity while increasing sensory-somatomotor and thalamic connectivity. These neural effects, along with the subjective experience, are fully blocked by ketanserin, a selective 5-HT2A receptor antagonist. The spatial pattern of LSD's effects across the brain matches the distribution of 5-HT2A receptor gene expression in humans. These results strongly implicate the 5-HT2A receptor in LSD's neuropharmacology, informing the neurobiology of psychedelics and guiding development of psychedelic-based therapeutics.
Cell • January 26, 2017 • Daniel Wacker, Sheng Wang, J. Mccorvy et al. • 466 citations
The hallucinogen LSD binds to the human serotonin receptor 5-HT2B, and its crystal structure reveals conformational rearrangements that accommodate LSD, explaining the selectivity of its diethylamide group. LSD dissociates very slowly from both 5-HT2BR and 5-HT2AR, a key receptor for its psychoactive effects. Molecular dynamics simulations suggest that a 'lid' formed by extracellular loop 2 (EL2) at the binding pocket entrance may cause LSD's slow binding kinetics. A mutation that increases this lid's mobility greatly speeds up LSD's binding and selectively reduces LSD-mediated β-arrestin2 recruitment, providing a molecular explanation for LSD's actions at human serotonin receptors.
Journal of Psychopharmacology • September 11, 2014 • Mary P Cosimano, Matthew W. Johnson, Albert Garcia‐romeu et al. • 910 citations
In an open-label pilot study, 15 nicotine-dependent smokers received moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin as part of a structured 15-week smoking cessation program. At 6-month follow-up, 12 of 15 participants (80%) showed seven-day point prevalence abstinence, a rate substantially exceeding the typical 35% or less reported for other behavioral or pharmacological therapies. The authors note the open-label design prevents definitive conclusions about efficacy, but the findings suggest psilocybin may be a potentially useful adjunct to smoking cessation treatment.
BMC Pharmacology • March 3, 2006 • Dawn D. Han, Howard H. Gu • 419 citations
Cocaine blocks all three monoamine transporters (DAT, NET, SERT) at similar concentrations (KI values 0.2–0.7 μM). Methylphenidate inhibits DAT and NET around 0.1 μM but requires about 1000-fold higher concentration to inhibit SERT. Amphetamine and methamphetamine are most potent at NET (KI 0.07–0.1 μM), 5- to 9-fold less potent at DAT (KI ≈ 0.6 μM), and 200- to 500-fold less potent at SERT (KI 20–40 μM). MDMA shows higher potency at SERT than at DAT. Human and mouse transporters respond similarly to each drug, with KI values within 4-fold. These relative potencies indicate which neurotransmitter systems each stimulant disrupts most.
Neuroreport • December 1, 1998 • Franz X. Vollenweider, M. F. I. Vollenweider-scherpenhuyzen, Andreas Bäbler et al. • 1,023 citations
The hallucinogen psilocybin induces a psychosis-like state in healthy people that resembles early schizophrenia. In human volunteers, these effects were blocked in a dose-dependent manner by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. This provides the first human evidence that psilocybin-induced psychosis results from serotonin-2A receptor activation, independent of dopamine stimulation. The findings suggest that serotonin-2A overactivity may play a role in schizophrenia and that blocking this receptor may contribute to antipsychotic benefits.
The Lancet • October 1, 1998 • Ud Mccann, Z Szabò, Ursula Scheffel et al. • 664 citations
Using positron emission tomography (PET) with a ligand that selectively binds to serotonin transporters, researchers found direct evidence of a decrease in a structural component of brain serotonin neurons in people who use MDMA (ecstasy). This suggests MDMA use may damage or reduce serotonin neurons in the living human brain.
Archives of General Psychiatry • February 1, 1994 • Ruck J. Strassman • 454 citations
Intravenous DMT produces rapid, intense hallucinogenic effects that peak within two minutes and resolve within half an hour, closely tracking blood levels. At higher doses (0.2 and 0.4 mg/kg), volunteers experienced brightly colored, rapidly moving visual images, a dissociative state with alternating euphoria and anxiety, and a complete replacement of ongoing mental experience. Lower doses (0.05–0.1 mg/kg) primarily caused emotional and bodily sensations, with 0.1 mg/kg producing the least desirable effects. A new Hallucinogen Rating Scale captured dose-related differences better than biological measures, offering a tool for comparing DMT with other agents affecting brain receptors.
Proceedings of the National Academy of Sciences • March 1, 1992 • Gary Rudnick, S C Wall • 533 citations
MDMA (ecstasy) acts on serotonin transporters in both the plasma membrane and secretory vesicles. In plasma membrane vesicles from human platelets, MDMA inhibits serotonin transport and imipramine binding by directly interacting with the sodium-dependent serotonin transporter, and it stimulates serotonin efflux in a stereo-specific, sodium-dependent, and imipramine-sensitive manner via transporter-mediated exchange. In vesicles from bovine adrenal chromaffin granules containing the vesicular biogenic amine transporter, MDMA inhibits ATP-dependent serotonin accumulation and stimulates efflux by dissipating the transmembrane pH difference and directly interacting with the vesicular transporter.
Journal of Neuroscience • August 1, 1988 • Elizabeth O’hearn, Giuseppe Battaglia, Eb de Souza et al. • 546 citations
Two amphetamine derivatives, MDA and MDMA, cause lasting damage to serotonin-producing nerve fibers in the rat brain. Two weeks after repeated high doses, serotonin axons throughout the forebrain are profoundly lost, while dopamine and norepinephrine axons remain intact. The damage is selective to fine axon terminals; thicker fibers and the cell bodies in the raphe nuclei survive. Some brain regions, such as the hippocampus and parts of the neocortex, show partial sparing. Swollen and fragmented axons observed shortly after treatment confirm ongoing degeneration. MDA produces greater loss of serotonin axons than MDMA at the same dose. The findings establish that these drugs are toxic to serotonin axon terminals and cause long-term denervation of the forebrain.
Journal of Pharmacology and Experimental Therapeutics • September 1, 1987 • G. Battaglia, S. Yeh, E. O'hearn et al. • 459 citations
Repeated administration of MDMA and MDA to rats caused long-lasting damage to serotonin neurons. Two weeks after a four-day treatment, levels of the serotonin metabolite 5-hydroxyindoleacetic acid were reduced by 30-60% in several brain regions, and the density of serotonin uptake sites fell by 50-75%. No widespread changes occurred in norepinephrine or dopamine systems. The findings demonstrate that both drugs produce persistent neurotoxic effects on the structural and functional integrity of serotonergic neurons, and measuring serotonin uptake site density offers a way to quantify this damage.
Life sciences • December 17, 1984 • R A Glennon, M Titeler, J D Mckenney • 636 citations
The hallucinogenic potency of psychoactive agents, including LSD and related compounds, is closely linked to their ability to bind to 5-HT2 receptors in the brain. Binding affinities for 5-HT2 sites strongly correlated with both behavioral effects in animals (r = 0.938) and hallucinogenic potency in humans (r = 0.924). These findings indicate that activation of 5-HT2 receptors is a key mechanism underlying the hallucinogenic effects of these substances.