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
November 23, 2022
Alina Wilkowska, Wiesław Jerzy Cubała
17 citations
Treatment-resistant depression affects about 30% of people with depression, and the likelihood of remission drops with each subsequent episode. This condition contributes heavily to global disease burden, raises morbidity and mortality, and lowers quality of life. It involves repeated difficult-to-treat episodes, with resistance growing over time. Staging captures how these changes lead to worsening treatment resistance and overall functioning. Ketamine, a rapid-acting antidepressant that can promote neuroplasticity, is argued here to be able to reverse this worsening process when used as an add-on treatment, offering hope and countering therapeutic nihilism.
International Journal of Molecular Sciences
December 23, 2023
Adam Wojtas, Krystyna Gołembiowska
16 citations
Psychedelics, among the oldest psychoactive drugs, are gaining renewed interest for treating depression, substance use disorders, anxiety, and obsessive-compulsive disorder. This review summarizes preclinical research on the mechanisms, neurotoxicity, and behavioral effects of psychedelics, focusing on the selective 5-HT2A receptor agonists 25I- and 25B-NBOMe compared to the less selective drug psilocybin. NBOMes significantly increased glutamatergic, dopaminergic, serotonergic, and cholinergic neurotransmission in the frontal cortex, striatum, and nucleus accumbens, though not dose-dependently, likely due to 5-HT2A and subsequent 5-HT2C receptor activation.
International Journal of Molecular Sciences
December 20, 2023
Adam Wojtas, Agnieszka Bysiek, Marzena Maćkowiak et al.
16 citations
Depression involves reduced volume of the hippocampus and amygdala and enlargement of the nucleus accumbens. Ketamine, a fast-acting antidepressant, reverses these volume reductions. This study tested whether the psychedelic psilocybin similarly affects limbic system neurotransmission in rats. Using microdialysis, both psilocybin and ketamine increased dopamine and serotonin release in the nucleus accumbens, influenced glutamate and GABA release in the nucleus accumbens, hippocampus, and amygdala, and raised acetylcholine levels in the hippocampus. Long-lasting changes in D2, 5-HT1A, and 5-HT2A receptor density occurred in the nucleus accumbens and hippocampus. Psilocybin showed a marked anxiolytic effect acutely and 24 hours later in the open field test, providing a neurobiological basis for its antidepressant and anti-stress effects.
International Journal of Molecular Sciences
August 7, 2023
Alexander Pilozzi, Simmie Foster, David Mischoulon et al.
16 citations
Alzheimer's disease, the most common form of senile dementia, will impose a growing societal and healthcare burden as the population ages. With few treatments for symptomatic relief and unknown causes, more research is urgently needed. Psychedelic drugs target AD-related psychological pathology and symptoms such as depression. Through microdosing, they may help combat the disease by eliciting psychiatric benefits via serotonin and dopamine pathways. This review examines studied benefits of a few psychedelic compounds that may show promise in treating AD and attenuating its depressive symptoms. The putative mechanism of action is that psychedelics act mainly as serotonin receptor agonists and induce potential beneficial effects for treating AD and related depression.
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
December 4, 2022
Mireia Medrano, An Buckinx, Ilse Smolders et al.
11 citations
Serotoninergic psychedelics like psilocybin can produce lasting reductions in depressive symptoms, but their mechanism is unclear. In a mouse forced swim test model, the psychedelic DOI was tested for effects on behavior and 5-HT2A receptor levels in the medial prefrontal cortex. Mice exposed to swim stress developed passive coping behavior six days later, but this was not linked to increased head twitch responses or consistent changes in 5-HT2A receptor levels. A low dose of DOI (0.2 mg/kg) unexpectedly increased immobility, while a high dose (2 mg/kg) had no significant effect. DOI did cause a dose-dependent decrease in 5-HT2A levels in stressed mice. These results do not support the idea that downregulating 5-HT2A receptors in the medial prefrontal cortex underlies antidepressant-like effects of serotoninergic psychedelics.
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
October 4, 2022
Krystsina Liaukovich, Sergei Sazhin, Pavel Bobrov et al.
9 citations
Awakening from rapid eye movement (REM) sleep leads to faster recovery of consciousness compared to slow-wave sleep (SWS). In a study with healthy volunteers, it was observed that motor responses to auditory stimuli resumed within 20 seconds after alpha brain activity began during REM, versus 25 seconds for SWS. Notably, pre-attentive processing of stimuli occurred earlier during REM. This indicates that the presence of alpha activity alone does not guarantee awareness or motor response, shedding light on sleep disorders and consciousness dissociation.
International Journal of Molecular Sciences
March 20, 2020
David P. Herzog, Ratnadevi M. Mellema, Floortje Remmers et al.
9 citations
In a genetically modified mouse line (Arc-CreERT2 × CAG-Sun1/sfGFP), males and females differed in sociability and anxiety tests. The rapid-acting antidepressants ketamine and (2R,6R)-hydroxynorketamine (HNK) produced opposite effects in the forced swim test depending on sex: in males, ketamine reduced immobility compared to (2R,6R)-HNK, indicating a different behavioral profile between the two drugs. At the molecular level, female mice treated with ketamine showed increased Bdnf mRNA levels, a change previously observed in males.
International Journal of Molecular Sciences
August 1, 2025
Ł. Szałach, Klaudia Ciesielska-Figlon, A. Daca et al.
7 citations
In people with treatment-resistant depression, a single intravenous dose of ketamine (0.5 mg/kg) produces rapid, temporary shifts in immune markers. Within 4 hours, total T cells and certain helper T-cell subsets increased, while by 24 hours, activated T cells declined and the ratio of helper to cytotoxic T cells decreased. Blood levels of the anti-inflammatory cytokine IL-10 rose, while the pro-inflammatory cytokines IL-6 and IL-8 fell—IL-8 remained lower for at least 24 hours. In laboratory experiments, high-dose ketamine boosted the growth of helper T cells from depressed patients and increased secretion of IL-8 and IL-6 from activated immune cells. The sustained drop in IL-8 points to an anti-inflammatory effect and may serve as a biomarker for treatment response.
International Journal of Molecular Sciences
March 18, 2022
Francesco Paolo Busardò, Simona Pichini
7 citations
Over 1000 molecules are now classified as New Psychoactive Substances (NPSs), and the number continues to grow annually with new classes of compounds and newer generations of NPS families.
International Journal of Molecular Sciences
February 14, 2022
Bronislav Jurásek, Silvie Rimpelová, Martin Babor et al.
7 citations
A sample of the dissociative anesthetic methoxphenidine from the black market contained an unusual bromo- and chloro-zincate anion impurity. In vitro cytotoxicity tests on kidney, liver, and bladder cell lines showed that the street sample was markedly more toxic than a pure methoxphenidine standard, suggesting the impurity caused the increased toxicity. A method using X-ray powder diffraction (XRPD) was developed to identify such anions and distinguish different crystalline forms of methoxphenidine, providing additional data not captured by routine analysis.
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
May 30, 2023
Tobias Buchborn, Taylor Lyons, Chenchen Song et al.
6 citations
Shaking behavior—head twitches in mice and wet dog shakes in rats—is a reliable indicator of psychedelic drug action, thought to involve serotonin 2A receptors on cortical pyramidal cells, though direct evidence in living animals has been limited. Using cell type-specific voltage imaging in awake mice, researchers expressed a voltage indicator in layer 2/3 pyramidal neurons and captured cortical activity while mice displayed psychedelic shaking behavior. Shaking was preceded by high-frequency oscillations and overlapped with low-frequency oscillations in the motor cortex, spectrally mirroring the rhythm of the shakes. These findings reveal a cortical fingerprint of serotonin-2A-receptor-mediated shaking behavior, linking a cross-mammalian psychedelic effect to cell-type specific brain dynamics.
International Journal of Molecular Sciences
August 7, 2025
Liliana Rebolledo-Pérez, Jorge Hernández‐bello, Alicia Martínez-ramos et al.
5 citations
Tau protein, essential for neuron stability, becomes toxic when hyperphosphorylated or cleaved, contributing to Alzheimer's disease. Evidence from experimental, clinical, and postmortem studies indicates that chronic substance use alters Tau dynamics in substance-specific ways. Alcohol and opioids promote Tau hyperphosphorylation and fragmentation via kinases like GSK-3β and CDK5 and proteases like caspase-3, leading to neuroinflammation. Stimulants and dissociatives disrupt insulin signaling and increase oxidative stress, exacerbating Tau pathology. Cannabinoids and psychedelics may protect by modulating kinase activity and reducing inflammation; psilocybin and harmine decrease Tau phosphorylation in animal models. Tau emerges as a convergent target in substance-related cognitive disorders, offering a biomarker and therapeutic target.
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
September 7, 2020
Matas Vitkauskas, Ajay S. Mathuru
4 citations
Depression affects millions worldwide. Recent research explores the lateral habenula's role in depression and the potential of psychedelics like psilocybin and ketamine as treatments. Clinical trials are testing deep brain stimulation of the habenula and psychedelic therapies targeting the serotonergic system. Early results are promising but require cautious optimism; more animal studies in naturalistic settings, larger human trials with better neuroimaging, and understanding of genetic and molecular factors underlying comorbid disorders are needed. Advances in cerebral organoids may accelerate progress. This review covers developments in these areas and discusses future directions.
International Journal of Molecular Sciences
December 28, 2025
Mateusz Kowalczyk, David Aebisher, Jakub Szpara et al.
3 citations
Depression is a common and potentially life-threatening disorder affecting over 300 million people worldwide, with major depressive disorder increasing suicide risk. Its causes involve genetic vulnerability, chronic stress, HPA axis dysregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic plasticity. This review synthesizes data on pharmacological treatments—including SSRIs, SNRIs, TCAs, and MAOIs—and emerging therapies targeting glutamatergic, GABAergic, and dopaminergic systems, such as ketamine, esketamine, dextromethorphan-bupropion, neurosteroids, and selective receptor modulators. It also covers non-pharmacological neuromodulation like TMS, tDCS, and photobiomodulation, integrating molecular mechanisms with depression pathophysiology to inform precise, multimodal treatment strategies.
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.