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.