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
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
April 19, 2023
Maitane Oscoz-Irurozqui, Carmen Almodóvar-Payá, Maria Guardiola-Ripoll et al.
2 citations
In patients with first-episode psychosis, cannabis use and genetic variants in cannabinoid receptor genes jointly affect brain activity in regions linked to reward, including the caudate nucleus, cingulate cortex, and orbitofrontal cortex. The study genotyped 40 patients (half cannabis users, half non-users) for two single-nucleotide polymorphisms in the CNR1 and CNR2 genes and measured brain activity with fMRI during a working-memory task. Interaction models showed that cannabis use combined with specific genotypes influenced activation in these areas, suggesting a joint role for cannabis and genetic background in brain function during early psychosis.
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
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.
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
July 7, 2026
Gary W Arendash
A unifying theory of consciousness and memory is proposed, centered on neuronal microtubules (MTs). The theory combines the Orchestrated Objective Reduction (Orch OR) theory and the Environmental-Induced Decoherence (EID) theory. For consciousness, MT vibrations and superposition qubit (SPQ) formation/entanglement occur in Layer V of the cerebral cortex, with continuous collapse due to EID rather than objective reduction. For memory, Orch OR is modified to include endogenous radiofrequency (RF) vibrations from MTs forming a vibrational fabric with MT crystalline water cores, SPQ formation for short-term memory, and objective reduction in cortical Layers II/III for long-term storage via Quantum Darwinism.
International Journal of Molecular Sciences
February 25, 2026
Mengchan Su, Qingran Li, Ping Liao et al.
Astrocytes undergo extensive molecular reprogramming during transitions of consciousness. Proteomic and phosphoproteomic analyses of rat cortical astrocytes across wake, sleep, and sevoflurane-induced general anesthesia revealed state-specific molecular signatures. Sleep and anesthesia shared similar changes such as downregulated structural proteins and upregulated membrane transport complexes, but diverged in molecular expression. Anesthesia specifically suggested potential activation of cellular differentiation and structural plasticity pathways, while implying disruption of metabolism and molecular clearance compared to sleep. Phosphoproteomics identified downregulated phosphorylation of NUCKS1 at Ser188 during anesthesia, suggesting suppressed nuclear transcription or cell cycle activity as a potential molecular signature of the anesthetic state. Sleep was associated with upregulated mRNA processing, while anesthesia indicated potential enhancement of synaptic signaling and suppression of development-related programs.
International Journal of Molecular Sciences
December 18, 2025
Johanna Rehn, Lucas Admeus, Bernat Kocsis
The cannabinoid 1 receptor (CB1R) is abundant in the hippocampus and linked to schizophrenia risk when cannabis is used during adolescence. In rats, adolescent pre-treatment with the CB1R agonist CP-55940 caused a lasting decrease in hippocampal theta oscillations in adulthood, a brain rhythm essential for memory and cognition. The impairment was more severe when exposure occurred in early adolescence (postnatal days 32–36) compared to late adolescence (days 42–46). These findings suggest that early adolescence is a critical window during which cannabis exposure can permanently disrupt neural network synchronization, potentially increasing vulnerability to psychiatric disorders.
International Journal of Molecular Sciences
October 13, 2022
Stephen M Stahl, Sara de Martin, Andrea Mattarei et al.
Esmethadone (REL-1017) and other uncompetitive NMDAR antagonists may rapidly relieve depression by preferentially blocking hyperactive GluN2D subtypes, restoring physiological neural plasticity. In major depressive disorder, upregulated tonic calcium currents through GluN2D subtypes reduce homeostatic availability of synaptic proteins, contributing to depressive behaviors. Low-potency NMDAR antagonists' selectivity for GluN2D may explain their rapid antidepressant effects without dissociative side effects.
International Journal of Molecular Sciences
August 26, 2021
R. Estrada-Reyes, Daniel Quero-Chávez, C. Trueta et al.
A combination of a non-effective dose of ketamine and melatonin (KET/MEL) increased neurogenesis and produced antidepressant-like effects in mice without altering locomotor activity, after both single and triple administration protocols. The authors strongly suggest that this combination could promote neurogenesis, revert neuronal atrophy, and induce antidepressant-like effects, potentially offering a treatment that avoids the psychomimetic side effects of ketamine alone.
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.
International Journal of Molecular Sciences
July 17, 2021
Sabrine Bilel, Micaela Tirri, Raffaella Arfè et al.
A novel psychoactive substance, 1-cyclohexyl-x-methoxybenzene, exists as three stereoisomers (ortho, meta, para) structurally similar to tramadol and phencyclidine. In vitro tests showed all three stereoisomers and tramadol were inactive at mu, kappa, and delta opioid receptors. In mice, systemic administration of the stereoisomers impaired sensorimotor responses, altered spontaneous motor activity, produced modest analgesia, and affected thermoregulation and cardiorespiratory responses, resembling effects of tramadol and phencyclidine. Naloxone only partially prevented visual sensorimotor impairments from the stereoisomers, not other effects. The findings indicate these derivatives cause pharmaco-toxicological effects through both opioid and non-opioid mechanisms, suggesting potential for abuse and harm.
International Journal of Molecular Sciences
October 1, 2020
M. Bowman, M. Vitela, K. Clarke et al.
Ketamine rapidly inhibits the clearance of serotonin from the hippocampus in mice, an effect that depends on the serotonin transporter (SERT) and the plasma membrane monoamine transporter (PMAT). In mice lacking either SERT or PMAT, ketamine no longer slows serotonin clearance and fails to produce antidepressant-like effects in the forced swim test. The findings suggest that ketamine's ability to block serotonin reuptake via both transporters may contribute to its rapid antidepressant action, alongside its known NMDA receptor antagonism. This work may guide development of depression treatments with fewer side effects than ketamine.
International Journal of Molecular Sciences
June 29, 2020
In Soo Ryu, Oc-Hee Kim, Young Eun Lee et al.
The designer drug 4'-F-PCP, a derivative of the dissociative anesthetic phencyclidine (PCP), shows a high potential for abuse. In rodents, a 10 mg/kg dose increased movement and rearing, and produced conditioned place preference, indicating rewarding effects. Intravenous self-administration of 1.0 mg/kg/infusion was robust, with a higher breakpoint under progressive ratio schedules, suggesting strong reinforcing properties. The drug altered dopamine transporter and D1 receptor expression in the nucleus accumbens and increased phosphorylated ERK, CREB, c-Fos, and FosB/ΔFosB, indicating activation of dopamine-related signaling pathways. These findings indicate that 4'-F-PCP has significant abuse liability.
International Journal of Molecular Sciences
January 18, 2017
Qiang Wang, Qinghui Wu, Junpeng Wang et al.
Long-term methoxetamine, a ketamine analog used recreationally, causes bladder dysfunction and inflammation in rats. Female rats injected daily with 30 mg/kg methoxetamine or ketamine for 4 or 12 weeks showed increased urination frequency, damaged bladder lining, inflammatory cell infiltration, and fibrosis. Treated rats had elevated levels of pro-inflammatory cytokines and markers of fibrosis. Methoxetamine also directly damaged human urothelial cells and increased inflammatory signals. The findings suggest methoxetamine's bladder effects resemble ketamine-induced cystitis.