International journal of molecular sciences
December 5, 2024
Simone Pardossi, Andrea Fagiolini, Alessandro Cuomo
43 citations
Brain-derived neurotrophic factor (BDNF) supports neuroplasticity and neuronal survival, and its expression is reduced in depression-related brain regions. This narrative review summarizes human studies of BDNF changes in patients treated with ketamine or esketamine. Traditional antidepressants can increase BDNF levels, and ketamine and esketamine produce rapid antidepressant effects partly through glutamate pathways and neurotrophic mechanisms involving BDNF. Clinical findings are mixed; most studies report increased plasma BDNF after intravenous ketamine, but some contradict this. Few studies examine BDNF and esketamine. More research with larger samples and intranasal esketamine, approved for treatment-resistant depression, is needed.
International journal of molecular sciences
December 17, 2020
Veronica Cocchi, Sofia Gasperini, Patrizia Hrelia et al.
32 citations
Several psychedelic and stimulating phenethylamines, including 2C-H, 2C-I, 2C-B, and 25B-NBOMe, but not MDMA, damaged DNA in a human cell line (TK6 cells). The genetic damage was detected as an increase in micronucleus frequency. All genotoxic substances also elevated reactive oxygen species (ROS) levels, suggesting ROS production as a likely mechanism. Even at doses that do not cause immediate severe harm, exposure to these substances may still pose long-term risks through genotoxicity.
International journal of molecular sciences
June 20, 2024
Hana Shafique, Julie C Demers, Julia Biesiada et al.
29 citations
NMDA receptor antagonists show promise for neurological and psychiatric conditions such as neurodegenerative diseases, epilepsy, traumatic brain injury, substance use disorder, and major depressive disorder. (S)-ketamine was the first rapid-acting antidepressant approved for medical use. Its stereoisomer, (R)-ketamine (arketamine), is under development for treatment-resistant depression and has shown efficacy in multiple animal models. Two clinical studies reported efficacy in treatment-resistant depression and bipolar depression, though a sponsor study failed to meet primary endpoints; post hoc analysis indicated efficacy. (R)-ketamine is less sedating, produces fewer psychotomimetic or dissociative effects, and has lower abuse potential than (S)-ketamine. Its antidepressant mechanisms may involve NMDA receptor antagonism and non-NMDA receptor pathways. Further clinical research may lead to improved treatments for underserved neurological and psychiatric disorders.
International journal of molecular sciences
August 31, 2024
Beldisa Taflaj, Nunzia La Maida, Roberta Tittarelli et al.
22 citations
New psychoactive substances (NPSs) are diverse drugs sold as legal substitutes for controlled drugs, and their psychiatric consequences are not well understood. A review of 109 NPS-related intoxication cases published between 2013 and 2024 found that synthetic cannabinoids were the most common cause of acute or chronic psychiatric symptoms, followed by synthetic cathinones, hallucinogens, natural NPSs, and stimulants. The most frequent acute symptoms included hallucinations, aggressiveness, and psychotic or bizarre behavior, linked to neurotransmitter imbalances in the central nervous system. The absence of clear diagnostic criteria and toxicological analyses complicates psychiatric diagnosis; implementing toxicological screening in emergency rooms and follow-up care is recommended.
International journal of molecular sciences
March 27, 2025
Blerida Banushi, Jemma Collova, Helen Milroy
19 citations
Trauma can affect individuals within a single generation and also pass to future generations through a mix of biological and environmental factors. This review describes epigenetic mechanisms linked to trauma's transmission, such as DNA methylation, histone modifications, and non-coding RNAs, which regulate stress-related genes like NR3C1 and FKBP5. While animal studies suggest possible epigenetic pathways for intergenerational effects, applying these to humans is difficult due to confounding variables, methodological limits, and ethical concerns. Emerging therapies, including psychedelic-assisted treatments and mind-body interventions, may address both psychological and epigenetic aspects of trauma. Enriched environments, cultural reconnection, and psychosocial interventions also show promise. The review emphasizes interdisciplinary approaches to break cycles of trauma and foster resilience.
International journal of molecular sciences
November 30, 2021
Thomas J F Angenoorth, Stevan Stankovic, Marco Niello et al.
18 citations
Many psychoactive compounds primarily interact with high-affinity monoamine transporters, but their interactions with low-affinity, high-capacity transporters like human organic cation transporters (hOCTs) and the plasma membrane monoamine transporter (hPMAT) are understudied. Using radiotracer-based uptake inhibition assays in HEK293 cells, 17 psychoactive substances were tested. Most compounds inhibited hOCT1 and hOCT2 in the low micromolar range, while few affected hOCT3 or hPMAT. Methylphenidate and ketamine selectively inhibited hOCT1 or hOCT2, respectively, and MDMA potently inhibited hOCT1, hOCT2, and hPMAT. Enantiospecific differences were observed for R- and S-α-PVP and R- and S-citalopram. These findings highlight the importance of studying drug interactions with hOCTs and hPMAT for regulating monoamine concentrations and xenobiotic clearance.
International journal of molecular sciences
May 22, 2023
Abdelmounaim Baslam, Abdelfatah Aitbaba, Asmae Lamrani Hanchi et al.
16 citations
MDMA dependence in rats alters the gut microbiome, increasing E. coli and reducing beneficial bacteria like Lactobacillus and Bifidobacter. Treatment with an aqueous extract of Anacyclus pyrethrum reversed these changes, restoring a healthier microbial composition. The findings suggest that modulating the gut microbiome could be a target for treating substance use disorders.
International journal of molecular sciences
January 23, 2019
Giuseppe Floresta, Maria Dichiara, Davide Gentile et al.
16 citations
Ibogaine, a psychoactive alkaloid, binds strongly to the sigma-2 receptor, which is implicated in neurological disorders such as Alzheimer's disease, schizophrenia, alcohol abuse, and pain. Because ibogaine's serious side effects prevent clinical use, researchers sought ibogaine derivatives with better sigma-2 receptor affinity. They performed a deconstruction of ibogaine's tricyclic moiety and scaffold-hopping of its indole part, using a 3D-QSAR model to predict sigma-2 receptor binding affinities and molecular docking on a homology-modeled sigma-2 receptor to validate top candidates. Pinoline, a carboline derivative, was tested in a radioligand binding assay and showed predicted high micromolar affinity and good selectivity. These results may guide design of simplified ibogaine analogs with improved sigma-2 receptor binding.
International journal of molecular sciences
December 20, 2024
Zuzanna Antos, Xawery Żukow, Laura Bursztynowicz et al.
14 citations
Ketamine shows rapid antidepressant effects primarily by blocking NMDA receptors, which reduces GABAergic inhibition and increases glutamate release. This activates AMPA receptors and downstream BDNF-TrkB and mTOR pathways, promoting synaptic growth and regeneration. Neuroimaging reveals changes in the Default Mode, Central Executive, and Salience networks—brain networks often disrupted in depression. The opioid system may play a permissive role in ketamine's effects, though ketamine is not a direct opioid agonist. Significant gaps remain in understanding its full mechanisms, safety, long-term efficacy, and how genetic factors like BDNF polymorphisms influence treatment response.
International journal of molecular sciences
October 16, 2024
Ciprian Pușcașu, Cornel Chiriță, Simona Negreș et al.
14 citations
Neuropathic pain, a complex condition affecting millions worldwide, often responds poorly to existing treatments with significant side effects. This review examines N-methyl-D-aspartate receptor (NMDAR) antagonists—ketamine, memantine, methadone, amantadine, carbamazepine, valproic acid, phenytoin, dextromethorphan, riluzole, and levorphanol—as potential therapies. By analyzing preclinical and clinical studies, the authors evaluate these agents' efficacy for neuropathic pain relief, highlighting the growing interest in targeting NMDARs.
International journal of molecular sciences
January 5, 2024
Sofía Villalba, Bruno González, Stephanie Junge et al.
9 citations
Noribogaine, the primary metabolite of ibogaine, produces sexually dimorphic effects in mice, with some responses depending on the 5-HT2A receptor. A single 40 mg/kg dose reduced locomotion in male but not female wild-type mice. Gene expression of immediate early genes and glutamate receptors differed by sex and genotype. 5-HT2A receptor mRNA increased in the medial prefrontal cortex after noribogaine at 10 mg/kg in males and 40 mg/kg in females. Electrophysiology showed that 40 mg/kg reduced NMDA-mediated postsynaptic current density in layer V pyramidal neurons of the medial prefrontal cortex only in male wild-type mice, an effect absent in 5-HT2A receptor knockout males and all females. The genetic removal of the 5-HT2A receptor blunted noribogaine's effects on NMDA synaptic transmission.
International journal of molecular sciences
July 11, 2025
Sofia Sakopoulos, Mcwelling Todman
6 citations
Ketamine infusion therapy produces rapid antidepressant effects in people with treatment-resistant depression, and combining it with weekly psychotherapy yields the strongest symptom reduction. A retrospective chart review of patients receiving single or repeated ketamine infusions, with or without concurrent psychotherapy, measured depression severity using Beck Depression Inventory scores before treatment and 30 days after. All groups showed significant symptom improvement, but those who also attended weekly psychotherapy experienced the most pronounced effects. The number of infusions did not significantly change outcomes. The findings suggest that integrating psychotherapy with ketamine treatment enhances therapeutic response, possibly by taking advantage of ketamine-induced neural plasticity.
International journal of molecular sciences
June 13, 2024
Teodora Vidonja Uzelac, Nikola Tatalović, Milica Mijović et al.
6 citations
Ibogaine, an alkaloid used in alternative addiction treatment, caused dose-dependent heart muscle cell death (necrosis) in rats 6 and 24 hours after a single oral dose of 1 or 20 mg/kg. This cardiotoxicity was not driven by inflammation. No consistent changes in antioxidant defenses or oxidative damage markers were observed, leaving the role of oxidative stress in ibogaine-induced heart damage unclear. The findings help explain the often-fatal cardiac side effects seen in humans using ibogaine, but definitive conclusions about redox processes require further study.
International journal of molecular sciences
April 10, 2025
Mădălina Iuliana Mușat, Ana-Maria Ifrim-Predoi, Smaranda Ioana Mitran et al.
5 citations
Ketamine relieved anhedonia and anxiety-like behavior in mice with both depression and non-alcoholic fatty liver disease (NAFLD), regardless of liver damage. It improved sociability, especially in older mice, but did not improve memory in those with liver injury. Acute ketamine did not worsen liver damage but appeared to affect brain cell changes (astrogliosis and neuronal loss). The findings suggest ketamine's antidepressant effects persist even with liver disease, though responses vary by age.
International journal of molecular sciences
June 17, 2025
James M Robertson
3 citations
A novel hypothesis proposes that astrocytes, which form a global syncytium throughout the neocortex, are the locus of consciousness by integrating synaptic signals. Earlier criticism noted that intercellular calcium waves are too slow for consciousness but ideal for memory formation. Recent technical advances have overcome the challenge of separating syncytial electrical responses from neuronal activity, revealing that the astroglia syncytium is isoelectric with minimal impedance and conducts electricity as rapidly as neural networks. This suggests the syncytium can transmit integrated local synaptic signaling globally across the neocortex in the timeframe required for consciousness, potentially binding all functional brain areas.
International journal of molecular sciences
May 15, 2025
Xinyan Yang, Yinyu Chen, Gaolin Zheng et al.
3 citations
The mitochondrial calcium uniporter (MCU) is a key channel for calcium uptake into mitochondria, and its dysfunction contributes to neurotoxic damage from psychoactive substances like MDMA, cocaine, and morphine. MCU dysfunction causes calcium overload, oxidative stress, and apoptosis, leading to neuronal injury. While MCU inhibitors show promise in reducing calcium overload and improving neural function, their selectivity and long-term safety need further study. Future research should focus on the precise regulatory mechanisms of MCU in drug-induced neurotoxicity and the development of targeted therapies.
International journal of molecular sciences
March 20, 2025
Sabrine Bilel, Cristina Miliano, Giorgia Corli et al.
3 citations
The synthetic psychedelic 25I-NBOMe, a selective 5HT2A receptor agonist abused as a counterfeit LSD, alters dopamine transmission, behavior, and synaptic plasticity in mice. At the highest dose tested (1 mg/kg), it increased dopamine levels in the nucleus accumbens shell. It also increased reaction time within 30 minutes after administration and disrupted prepulse inhibition, indicating sensorimotor gating deficits. In brain slices, 25I-NBOMe prevented long-term potentiation in the medial prefrontal cortex, an effect not reversed by a selective 5HT2A antagonist. These findings highlight risks of 25I-NBOMe use, including altered neurotransmission and impaired cognitive processes.
International journal of molecular sciences
September 14, 2025
Jacopo Sapienza, Marco Spangaro, Stefano Comai et al.
2 citations
Schizophrenia involves excessive loss of brain connections, partly due to overactive microglia that prune synapses. A genetic variant in complement component 4 (C4) is strongly linked to the disease and drives this pruning. Brain scans using a new tracer for synaptic vesicle glycoprotein 2A (SV2A) confirm lower synaptic density in the prefrontal cortex of people with schizophrenia, supporting the synaptic hypothesis. Psychedelics like LSD and psilocybin promote neuroplasticity and synaptogenesis in animal and lab studies, potentially counteracting synaptic loss and improving negative and cognitive symptoms. The authors suggest starting with microdoses in deficit schizophrenia patients, then escalating if results are positive.
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.
International journal of molecular sciences
April 12, 2026
James Chmiel, Agnieszka Malinowska, Donata Kurpas
Interest in using psychedelics for ADHD has grown, but evidence remains scarce. A systematic review of five prospective studies—three naturalistic microdosing cohorts, one randomized placebo-controlled trial of low-dose LSD, and one ayahuasca retreat pilot—found that uncontrolled studies reported short-term symptom reductions and improved well-being, but these were highly vulnerable to expectancy and self-selection bias. The only randomized controlled trial showed improvement in both LSD and placebo groups, with no statistically significant advantage for LSD on ADHD outcomes. Current evidence does not separate pharmacological effects from contextual influences and is insufficient to support psychedelics as an evidence-based ADHD treatment.