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
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
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
August 4, 2025
Masahide Arinaga, Jun Yamada, Shoichiro Maeda et al.
2 citations
Cancer-related cognitive impairment (CRCI), which includes anxiety, depression, and memory deficits, reduces quality of life but is often underrecognized. In a mouse model of Lewis lung carcinoma, tabernanthalog (TBG), a non-hallucinogenic psychedelic analog, reversed anxiety-like behavior and memory impairment. Tumor-bearing mice had reduced tryptophan levels in blood and hippocampus, downregulated serotonergic receptor genes, and upregulated pro-inflammatory cytokine genes, along with increased microglial density and activation. TBG treatment normalized microglial density and morphology and restored serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in microglial cells exposed to tumor-conditioned medium. These findings suggest TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation.
International Journal of Molecular Sciences
July 26, 2025
Lena M. Rudy, Michał M. Godlewski
2 citations
Sleep paralysis involves regaining awareness during REM sleep while the body remains paralyzed, often accompanied by vivid, distressing hallucinations such as sensing an evil presence, chest pressure, and intense fear. The paralysis mechanism is understood, but how hallucinations arise is not. Serotonergic activation of the 5-HT2A receptor is critical, and these hallucinations share features with those induced by psychedelics like LSD and psilocybin, which also target 5-HT2A but through different molecular mechanisms. This review proposes that the β-arrestin-2 signaling pathway does not directly cause hallucinations but creates a state of network susceptibility that allows them to emerge abruptly in sensory brain areas. Understanding these pathways may aid treating neuropsychiatric disorders involving serotonin receptor dysfunction.
International Journal of Molecular Sciences
February 13, 2023
Patricio Sáez‐briones, Boris Palma, Héctor Burgos et al.
1 citation
In rats, MDMA (ecstasy) impairs both short-term and long-term visuospatial memory while increasing long-term potentiation (LTP) in the prefrontal cortex. Its brominated analog, 2Br-4,5-MDMA, preserves long-term visuospatial memory and slightly accelerates short-term memory compared to controls, yet also increases LTP similarly to MDMA. These findings suggest that aromatic bromination of the MDMA molecule, which eliminates typical entactogenic-like effects, also modifies effects on higher cognitive functions like visuospatial learning. The cognitive changes do not appear linked to the increase in prefrontal cortex LTP.
International Journal of Molecular Sciences
June 26, 2026
M. Fernández‐guarino, Nicolás Yagüe-septién, Laura Marín-ochoa et al.
Several psychoactive compounds produce biological effects on the skin through neurochemical and immune pathways. Topical cannabinoids like THC show anti-inflammatory, antipruritic, and anti-aging properties. The antidepressant fluoxetine regulates pro-inflammatory cytokines in keratinocytes, promotes wound healing and cell regeneration, and may benefit allergic skin conditions. Psychedelics that activate serotonin receptors (5-HTR) can influence cellular aging and immune modulation; 5-HT receptor agonists prevent UV-induced photocarcinogenesis, and psilocybin reduces aging markers in human fibroblasts. Psilocin may alleviate acute itch via the kynurenine pathway. These findings bridge neuropharmacology and dermatology for new therapeutic strategies.
International Journal of Molecular Sciences
March 28, 2026
Jonathan Shaw, Aidan Yong, Jacky Lee et al.
Mescaline, the main active compound in Peyote and San Pedro cactus, has a long history in traditional medicine and is gaining renewed clinical interest. A systematic review of 2770 references found only 10 studies suitable for analysis. Reported therapeutic effects included improvements in depression, well-being, nicotine dependence, alcohol use, and obsessions. Bayesian analysis showed frequently reported side effects like hypertension, headache, nausea, and vomiting. The existing literature is limited and highly variable, preventing firm conclusions about mescaline's psychological and somatic effects. More research is needed on its safety. Collaboration between the Native American Church and hospitals is recommended to create a registry for standardized data collection on mescaline's effects in prevalent populations.
International Journal of Molecular Sciences
March 20, 2026
Ivan Anchesi, Ivana Raffaele, M. Astorino et al.
Tabernanthalog (TBG), a non-hallucinogenic analog of ibogaine, was designed to avoid life-threatening cardiotoxicity by eliminating interactions with the hERG potassium channel. Beyond its anti-addictive and antidepressant-like effects, recent 2024-2025 data show TBG is effective in preclinical models of neuropathic and visceral pain and reverses cognitive deficits associated with cancer-related cognitive impairment, including those induced directly by tumors. TBG's mechanism involves a multi-target profile: inhibition of nicotinic acetylcholine receptors, positive modulation of NMDA receptors, and crosstalk with mGlu2 receptors, rather than solely 5-HT2A receptor agonism. It induces structural neuroplasticity without widespread immediate early gene activation, decoupling therapeutic rewiring from psychedelic effects. TBG represents a promising scaffold for next-generation neurotherapeutics.
International Journal of Molecular Sciences
February 26, 2026
James Chmiel, Filip Rybakowski
Antidepressant response to psychedelic-assisted therapies depends more on what happens during the dosing session and how the therapeutic context shapes that experience than on static patient characteristics. Across 48 studies, greater emotional breakthrough, mystical experiences, and insight consistently predicted larger and more durable symptom reductions, while anxiety-dominant states attenuated benefit. A stronger therapeutic alliance and music perceived as resonant predicted both meaningful acute experiences and later clinical gains. Baseline factors such as PTSD comorbidity sometimes weakened outcomes, extensive prior psychedelic use was linked to smaller incremental benefits, and demographics were generally uninformative. Biological markers of increased neural flexibility and plasticity also correlated with better outcomes.
International Journal of Molecular Sciences
November 29, 2025
M. Bassi, Elisa Roda, Giorgia Corli et al.
3-chloromethcathinone (3-CMC), a synthetic cathinone involved in many poisonings, causes locomotor stimulation, rapid breathing, hypothermia, and sensorimotor alterations in mice, with prepulse inhibition changes only at high doses and minor sex differences. All 15 human intoxications in Italy from 2014 to 2025 were non-fatal, involving male patients with psychomotor agitation, psychosis, aggressiveness, CNS depression, cardiac arrhythmias, chest pain, and tachypnea. Predicted metabolic reactions include N-dealkylation, N-hydroxylation, and phenyl hydroxylation, and all compounds show potential for drug-drug interactions and cardiotoxicity.
International Journal of Molecular Sciences
August 18, 2021
Marina Gabaglio, Erica Zamberletti, Cristina Manenti et al.
Cannabis is widely used by adolescents, and animal studies have shown long-term harm from its main psychoactive component, THC, but often ignore other cannabinoids like CBD. In female rats, giving THC and CBD together in a 3:1 ratio—based on illegal cannabis samples—reduced some behavioral changes and alterations in CB1 receptors and microglia in the prefrontal cortex caused by THC alone. However, a combination resembling 'light cannabis' (CBD:THC at 33:1, total THC 0.3%) caused lasting cognitive problems and anhedonia, along with increased GAD67 levels in the prefrontal cortex, indicating possible long-term effects on GABA signaling.