Search Results (354)

Background/Objectives. Chronic benzodiazepine (BDZ) use is frequently maintained beyond recommended durations due to neuroadaptation, psychological dependence, and withdrawal-related issues. Passiflora incarnata L., herba (P. incarnata) has shown anxiolytic and GABAergic activity that may mitigate withdrawal symptoms, while cognitive-behavioural therapy (CBT) targets maladaptive beliefs and behaviours sustaining BDZ misuse. This study investigates the independent and interactive effects of P. incarnata and CBT on BDZ dose reduction during a three-month tapering program. Methods. This retrospective observational study included 186 outpatients with anxiety or depressive disorders in clinical remission undergoing BDZ tapering, of whom 93 received a dry extract of P. incarnata as adjunctive treatment and 93, matched for diagnosis, age and sex, followed a standard tapering protocol. BDZ doses were assessed at baseline and three months. CBT was recorded as a binary variable based on the information documented in the medical records. An ANCOVA was performed to assess the impact of CBT and P. incarnata on BDZ reduction (change in mg diazepam equivalents), adjusting for sex, age, education, baseline anxiety and depression scores, initial BDZ and antidepressant dosage. A subgroup analysis was conducted to investigate the role of P. incarnata dosage in BDZ reduction. Results. Both CBT and P. incarnata were associated with significantly greater reductions in BDZ dosage at three months (CBT: p = 0.005, effect size: 0.032; P. incarnata: p < 0.001, effect size: 0.128). A significant interaction between CBT and P. incarnata was also observed (p = 0.037, effect size: 0.018), indicating a synergistic effect when both interventions were combined. Baseline sociodemographic characteristics, BDZ and antidepressant dosage and symptom severity did not differ significantly between groups. Patients taking 400–600 mg of P. incarnata dry extract showed a higher BDZ reduction compared to those taking 200 mg. Conclusions. These findings suggest that P. incarnata and CBT exert independent yet complementary effects in supporting BDZ tapering. Their combination appears to enhance dose reduction beyond either intervention alone, supporting a multimodal approach that addresses both neurobiological and psychological components of BDZ addiction. Prospective controlled studies are needed to confirm these results and to clarify their impact on long-term discontinuation outcomes. Full article

Background/Objectives: Oral health-related quality of life (OHRQoL) may influence mental health outcomes, yet longitudinal evidence on its association with depression remains limited. This study aimed to examine whether oral health status and OHRQoL are associated with a change in self-reported depression status among adults in Japan. Methods: We analyzed data from the Japan COVID-19 and Society Internet Survey (JACSIS), conducted in 2022 and 2023. A total of 15,068 participants aged ≥20 years without depression at baseline were included. Depression status was identified by self-reported measures between the two survey waves. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for change in self-reported depression status in relation to OHRQoL and oral health status, adjusting for sociodemographic and behavioral factors. Results: During follow-up, 218 participants (1.45%) reported a change in self-reported depression status. Poorer OHRQoL was significantly associated with a change in self-reported depression status (OR: 1.018; 95% CI: 1.001–1.036; p = 0.039). Additional risk factors included younger age (OR: 0.974; 95% CI: 0.964–0.985), participation in hobbies and cultural activities (OR: 2.224; 95% CI: 1.498–3.302), habitual use of sleeping pills or anxiolytics (current use OR: 3.512; 95% CI: 2.267–5.442), increased loneliness (OR: 1.217; 95% CI: 1.140–1.299), lower life satisfaction (OR: 0.900; 95% CI: 0.836–0.969), and poor self-rated health (OR: 2.921; 95% CI: 1.810–4.715). Conclusions: Impaired OHRQoL was associated with a change in self-reported depression status, potentially through psychosocial mechanisms. These findings suggest that oral health and OHRQoL may be relevant factors to consider in integrated oral and mental health approaches in clinical practice. Full article

Chronic stress disrupts neuroendocrine regulation, neurotransmitter balance, and neuronal redox homeostasis, thereby contributing to the development of anxiety-related neuropathology. Arecoline, the predominant alkaloid of Areca catechu L., displays diverse neuropharmacological properties, yet its role in stress-induced emotional dysfunction has not been fully elucidated. This study examined the anxiolytic-like and neuroprotective effects of arecoline in mice exposed to chronic unpredictable mild stress (CUMS). Arecoline administration markedly improved behavioral outcomes, reflected by increased central exploration in the open-field test, prolonged time in the light compartment, and enhanced open-arm activity in the elevated plus maze. These behavioral benefits were accompanied by normalization of serum corticosterone levels, restoration of hippocampal neurotransmitters, reinforcement of antioxidant enzyme activities, and attenuation of pro-inflammatory cytokines. At the molecular level, arecoline elevated brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), cAMP response element-binding protein (CREB), N-methyl-D-aspartate receptor (NMDAR), and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), indicating enhanced synaptic plasticity, while concurrently diminishing oxidative and inflammatory stress. Collectively, the findings suggest that arecoline exerts multifaceted neuroprotective actions under chronic stress by coordinating neuroendocrine modulation, neurotransmitter homeostasis, antioxidant defenses, and synaptic plasticity. This study provides new mechanistic evidence supporting the potential relevance of arecoline as a functional neuroactive compound for managing stress-induced anxiety disorders. Full article

The rise in psychotropic drug use among students, particularly in Veterinary Medicine, correlates with high rates of mental disorders like depression and anxiety, often exacerbated by academic stress. Factors such as high academic demands, emotional exhaustion, and poor sleep quality contribute to the increased use of medications like antidepressants and anxiolytics. However, in Brazil, there is limited research on the profile and factors associated with this drug use among veterinary students. This study aims to assess the prevalence, patterns, and associated factors of psychotropic drug use at the Federal University of Santa Maria. A descriptive-correlational cross-sectional study was conducted using a survey covering sociodemographic data and psychotropic drug use. A total of 245 students participated in this study. The collected data included age, sex, semester, physical activity, sleep quality, drug use, family income, place of birth, and residence. In total, 36.7% of students reported using psychotropic medications during their undergraduate studies, with 77.1% being women and 22.9% men. Additionally, 45.6% reported insufficient sleep, defined as 4 to 6 h per day. Inactive students had a 94.5% higher likelihood of using psychotropic medications. Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines were the most reported drug classes. The findings highlight the emotional and academic burden of veterinary education, underscoring the need for institutional actions that prioritize student mental health. Full article

Serotonin receptors, in particular 5-HT_1A and 5-HT_2A receptors, are important molecular targets for the central nervous system (CNS) disorders, such as schizophrenia, depression, anxiety disorders, memory deficits, and many others. Here, we present structural and pharmacological evaluation of a serotonin receptor ligand, SERAAK2, identified in a structure-based virtual screening campaign. Molecular docking studies revealed that SERAAK2 binds with its molecular targets via Asp3.32 as the main anchoring point, which is typical for orthosteric ligands of aminergic GPCRs. Molecular dynamics simulations confirmed the stability of the ligand binding poses in the studied receptors. MMGBSA calculations were in accordance with the receptor in vitro binding affinity studies, which indicated that SERAAK2 is a potent ligand of 5-HT_1A and 5-HT_2A receptors. It was also found that SERAAK2 displays favorable ADMET parameters. The demonstrated anxiolytic- and antidepressant-like effects of SERAAK2 in animal models, which may involve its interaction with 5-HT_1A receptors, warrant further studies to confirm these activities and elucidate the underlying mechanisms. Full article

Background/Objectives: Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder affecting almost 10% of the general population, characterized by recurrent abdominal pain and altered bowel habits. Its pathophysiology is incompletely understood, but it is established that symptoms result from an interplay between several environmental- and patient-related factors. This study aimed to analyze the influence of a widespread shift in lifestyle habits and multidimensional stress on IBS manifestations. Methods: An online survey was administered during the COVID-19 lockdown in 2020 to three groups of people representative of the general population. The survey contained questions regarding socio-demographic data, dietary habits, alcohol, smoking, physical activity, sleeping, working activities, stress level, and the characteristics of gastrointestinal symptoms related to both the pre-pandemic period and the lockdown period. The definition of IBS was based on the Rome IV criteria. Multivariate analyses were used to evaluate the association between environmental variables and the occurrence/resolution of IBS. Results: A total of 2735 participants were enrolled. Among them, 122 patients (46.2%) reported symptoms’ improvement during the observation period, while 118 previously healthy subjects (4.8%) developed IBS symptoms. Reduced general stress (OR = 2.2, 95%CI 1.1–4.6, p = 0.029), increased fiber intake (OR = 2.8, 95%CI 1.6–5.0, p < 0.001), and increased hours of sleep (OR = 2.0, 95%CI 1.1–3.8, p = 0.031) were associated with a high probability of IBS resolution, while increased anxiolytic pill intake (OR = 0.14, 95%CI 0.04–0.46, p = 0.001) showed a low likelihood of IBS resolution. Reduced physical activity (OR = 2.0, 95%CI 1.3–3.2, p = 0.002), increased anti-inflammatory effects (OR = 2.4, 95%CI 1.4–4.1, p = 0.002), anxiolytic pill intake (OR = 3.5, 95%CI 2.1–5.9, p < 0.001), and increased work-related stress (OR = 1.8, 95%CI 1.2–2.8, p = 0.009) were risk factors for IBS symptoms’ occurrence. Reduced alcohol consumption was a protective factor (OR = 0.5, 95%CI 0.3–0.8, p = 0.006). The resolution of IBS did not affect upper gastrointestinal functional symptoms (OR = 0.2, 95%CI 0.1–0.3, p < 0.001). Conclusions: The widespread lifestyle change forced by the pandemic created a protective “Cocoon Effect”, resulting in a beneficial effect in almost half of patients with IBS. Our findings provide large-scale evidence that environmental factors play a pivotal role in the pathophysiology of IBS. Specifically, stress levels, fiber intake, sleep patterns, and alcohol consumption are key modifiable drivers of symptom occurrence and resolution. Full article

Background/Objective: Serotonin and dopamine are key neurotransmitters involved in regulating mood, anxiety, and locomotor activity. Specific transporters mediate their reuptake, SERT and DAT, making them targets for drugs such as Fluoxetine and Methylphenidate. Zebrafish (Danio rerio), due to their genetic and neurochemical similarity to humans, serve as a valuable model for studying the behavioral effects of these drugs. This study aimed to compare the behavioral phenotypes induced by SERT and DAT blockers in adult zebrafish using the Novel Tank Diving Test (NTT), thereby generating a swimming profile for drugs acting on these monoamine transporters that can be utilized in drug discovery and behavior. Methods: Adult zebrafish were administered Fluoxetine or Methylphenidate and subjected to the NTT. Behavioral endpoints measured included bottom-dwelling time (anxiety-like behavior), swimming velocity (locomotor activity), and transitions to the upper zone (exploratory behavior). Results: Fluoxetine treatment significantly reduced bottom-dwelling behavior, increased transitions to the upper zone, and decreased erratic swimming, indicating reduced anxiety and enhanced exploration. In contrast, Methylphenidate administration led to prolonged bottom-dwelling and reduced exploration, suggesting increased anxiety-like behavior and decreased exploration. These findings highlight distinct behavioral profiles resulting from selective modulation of serotonergic and dopaminergic pathways. Conclusions: The study demonstrates that SERT and DAT blockades produce divergent behavioral effects in adult zebrafish, with Fluoxetine exhibiting anxiolytic and exploratory-promoting actions. At the same time, Methylphenidate induces anxiety-like and less exploratory behaviors. These results underscore the utility of zebrafish as a valuable translational model for neuropharmacological research and drug discovery, providing insights into the differential impact of serotonergic and dopaminergic modulation on behavior. Full article

Background: Echinacea purpurea (L.) Moench (EP) and Onopordum acanthium (L.) (OA) are promising medicinal plants with diverse biological activities but there is no information on the effects of their combinations. To harness the therapeutic potential of both while minimizing the risk of adverse effects, we prepared two combinations (CE1 and CE2) of EP and OA in ratios 1:1 and 3:1, respectively. Methods: Oxygen radical absorbance capacity (ORAC), hydroxyl radical absorbance capacity (HORAC), and an electrochemical assay were used to determine the antioxidant activity of the extracts in vitro. The anxiolytic and immunomodulatory properties were studied in rats. Animals were subjected to acute cold stress and anxiety-like behavior was evaluated by the elevated plus maze (EPM) and social interaction test (SIT). Serum IFN-γ, TNF-α and IL-10 levels were measured by ELISA. Results: CE2 demonstrated the highest antioxidant activity (1841.7 μmolTE/g by ORAC, 277.2 GAE/g by HORAC, and 39.6 by electrochemical method). Moreover CE2 produced anxiolytic-like effects—significantly increasing the open arms entries ratio (OAER; p < 0.001), open arms time ratio (OATR; p < 0.01) in the EPM, and prolonging the social interaction time (p < 0.05) versus the stressed control. OA increased OAER (p < 0.01) and OATR (p < 0.001), while EP increased only OAER (p < 0.01). CE1 showed no significant behavioral consequences. CE2 significantly reduced IFN-γ (p < 0.05), and IL-10 levels were elevated in OA and CE2 groups (p < 0.01). No significant changes in TNF-α levels were observed across groups. Conclusions: These findings indicate that CE2 and OA attenuate anxiety-like behavior and modulate the immune response primarily by stimulating IL-10 production. Full article

Background: Chronic pain affects nearly one in five adults worldwide and remains a major healthcare burden due to its persistence, multidimensional impact, and resistance to conventional therapies. The opioid crisis has further highlighted the urgent need for safer and more effective alternatives. Psilocybin, a serotonergic psychedelic compound, has re-emerged as a potential therapeutic option for chronic pain given its effects on neuroplasticity, neuroinflammation, and emotional regulation. Methods: This narrative review synthesized evidence from published preclinical and clinical studies. The focus was on the mechanisms of action of psilocybin, animal models of neuropathic and inflammatory pain, and early human trials exploring its effects on pain, mood, and quality of life. Results: Preclinical studies demonstrated that psilocybin promotes synaptogenesis via BDNF-TrkB signalling, modulates 5-HT2A receptor activity, and reduces neuroinflammatory processes, leading to persistent analgesic and anxiolytic effects. Animal models of chemotherapy-induced neuropathy and inflammatory pain showed long-lasting antinociceptive responses. Clinical studies, though limited, reported improvements in depression, anxiety, resilience, and quality of life in patients with advanced cancer and chronic conditions, with preliminary evidence of analgesic benefit. Conclusions: Psilocybin shows promise as a multidimensional therapy for chronic pain, addressing both sensory and affective components. However, ethical issues, safety concerns, and regulatory barriers necessitate careful management, and robust randomized controlled trials are essential to confirm efficacy and guide clinical translation. Full article

Background: Royal jelly is a protein-rich honeybee secretion that is used in the nutrition of larvae and adult queens. Previous studies have reported that royal jelly had induced pro-cognitive, anxiolytic, and antidepressant-like effects in laboratory rats. Since serotonin (5-HT), noradrenaline, and dopamine play an important role in the control of several mental functions, changes in the excitability of monoaminergic neurons may be involved in the mechanisms of the behavioral and neurochemical effects of royal jelly. The present study aimed to test this hypothesis. Methods: Adult male Wistar rats were treated with royal jelly for two weeks. Thereafter, their cognitive performance was evaluated using the novel object recognition (NOR) test. The excitability of monoaminergic neurons was assessed using in vivo single-unit extracellular electrophysiology. Results: We found that rats treated with royal jelly had a higher recognition index in the NOR test and a higher burst activity of dopaminergic neurons of the ventral tegmental area (VTA) compared to the vehicle-treated controls. The firing activities of 5-HT neurons of the dorsal raphe nucleus (DRN) and the noradrenergic neurons of the locus coeruleus (LC) were not altered. Conclusions: We conclude that the pro-cognitive effect of royal jelly is mediated, at least in part, by mechanisms involving the excitability of mesolimbic dopaminergic neurons. The present findings encourage further research towards the improvement of the safety and efficacy of currently available therapies for cognitive dysfunction. Full article

Introduction: According to research data, 1,3-oxazines are pharmacologically active substances, as well as the substrates for the synthesis of heterocyclic and acyclic compounds. However, bis(1,3-oxazin-6-one) derivatives are little studied class of compounds, which makes their research a promising direction for the development of modern synthetic chemistry and pharmacy. The aim of this work is to obtain bis(4-hydroxy-6H-1,3-oxazin-6-ones), study their alcoholysis reaction, prove the structure of the obtained products and evaluate their pharmacological potential in silico. Methods: The reflux of isophthalic acid diamide with a twofold excess of substituted malonyl chloride in 1,2-dichloroethane for 15 h led to the production of bis(4-hydroxy-6H-1,3-oxazin-6-ones) (1, 2). As a result of their reflux with absolute ethanol for 5 h acyclic esters of malonamic acids (3, 4) formed. The structure of the obtained compounds was proved by ¹H and ¹³C NMR spectroscopy. The prediction of biological activity was carried out using the GUSAR and PASS online web resources. Results: The yields of compounds 1–4 were 90%, 90%, 93%, 89%, respectively, depending on the nature of the substituent at position C₅ of the oxazine cycle. According to the in silico assessment of biological activity, bis(1,3-oxazine-6-ones) exhibited high probability of antitumor activity, while ethyl esters of malonamic acids showed promising anxiolytic, antieczematous, fibrinolytic activities. Conclusions: New bridging 1,3-oxazin-6-ones were synthesized. The reaction of their cleavage by absolute ethanol to malonamic acid esters was studied. The potential biological activity was predicted in silico. Full article

Anxiety-like behavior in fish is commonly assessed using non-invasive behavioral paradigms such as the Light/Dark preference, Novel Tank, and Open Field tests. In this study, we validated these three assays in rainbow trout (Oncorhynchus mykiss), a species of commercial relevance, to characterize their anxiety-related responses. To explore behavioral changes associated with feeding anticipation and satiety, we implemented a feeding schedule consisting of two daily meals and conducted behavioral tests at specific times before and after feeding. Trout exhibited clear patterns of scototaxis, geotaxis, and thigmotaxis, consistent with anxiety-like behavior described in other teleosts. Our results showed a significant increase in anxiety-like responses before feeding, coinciding with food anticipatory activity observed prior to expected feeding schedules, which diminished after food intake, as evidenced by each test individually. Moreover, multivariate analysis combining parameters from all three tests improved discrimination between anxious and relaxed fish. The behavioral states before and after feeding resembled anxiety-like and anxiolytic conditions reported in other species, supporting that food anticipatory activity reflects an anxious state in rainbow trout as well. These findings endorse using a multi-test behavioral battery to assess anxiety-like states and provide a framework for studying neurobiological mechanisms of emotional regulation related to feeding in teleosts. Full article

Background/Objectives: The antiseizure effects of cannabidiol (CBD) were extensively studied when used as a monotherapy. However, there is conflicting evidence regarding its use in combination with levetiracetam (LEV). Methods: This study explored the effects of chronic co-administration of CBD and LEV in a pentylenetetrazole-kindling rat model to evaluate potential antiseizure and neuropsychiatric interactions. Male and female Wistar rats (n = 48) were divided into four treatment groups: one control and three treated by receiving LEV 300 mg/kg and LEV + CBD at 10 and 60 mg/kg, respectively. Seizure parameters were assessed using the Racine scale, and behavior was evaluated using the open field (OF), novel object recognition (NOR), and social interaction (SI) tests. Results: While both combinations, LEV + CBD 10 mg/kg and 60 mg/kg, significantly reduced maximal seizure intensity, the LEV + CBD 10 mg/kg attenuated LEV’s anti-kindling effect. Additionally, only LEV + CBD 60 mg/kg reduced seizure duration compared to LEV alone (p = 0.0002). In behavioral assessments, LEV + CBD 10 mg/kg showed anxiolytic effects in the OF test by increasing central activity (p = 0.0141). In contrast, the LEV + CBD 60 mg/kg impaired social behavior in both sexes (p = 0.0019). LEV improved the cognitive performance of female rats in the NOR test (p = 0.0301), but this improvement was not observed in LEV + CBD groups. Conclusions: CBD exhibited dose-dependent effects when combined with LEV: low doses might offer anxiolytic effects but promote kindling, and high doses enhance seizure control but potentially worsen social interaction. The results support the therapeutic potential of LEV-CBD co-treatment, while highlighting the need for careful dose optimization when considering CBD as an adjunctive therapy. Full article

This study investigates the neuroprotective and anxiolytic effects of Solanum macrocarpon L. leaf n-butanol extract (SMB) in a zebrafish model of scopolamine (SCOP; 100 μM)-induced cognitive and behavioral impairments. SCOP, a muscarinic receptor antagonist, is commonly used to mimic memory deficits and anxiety-like behaviors associated with neurodegenerative conditions. Zebrafish were chronically exposed to SMB at concentrations of 1, 3, and 6 mg/L. Behavioral assessments included anxiety-related paradigms, such as novel tank diving (NTT), novel approach (NA), and light–dark transition (LD) tests, as well as cognitive assays, including the Y-maze and novel object recognition (NOR) tests. SMB significantly mitigated SCOP-induced anxiety-like behaviors and cognitive deficits in a dose-dependent manner. Biochemical analyses demonstrated that SMB inhibited acetylcholinesterase (AChE) overactivity, indicating restoration of cholinergic function. Furthermore, SMB enhanced the activity of endogenous antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) and significantly reduced oxidative stress biomarkers, including malondialdehyde (MDA) and protein carbonyls. These findings suggest that SMB may exert neuroprotective effects through modulation of cholinergic signaling and oxidative stress. Overall, SMB represents a promising phytotherapeutic candidate for mitigating cognitive and anxiety-related symptoms linked to oxidative damage. Further investigations are warranted to characterize its active constituents and assess long-term efficacy and safety in models of neurodegeneration. Full article

For thousands of years, medicinal plants and their constituents have been used, mostly empirically/ethnopharmacologically, to cure patients with central nervous system (CNS) disorders. Anxiolytics derived from natural products (NPs) often share similar mechanisms of action to synthetic ones (e.g., benzodiazepines, BDZs). Although typically as effective as synthetic anxiolytics, NPs are considered to be devoid of the serious side effects linked to the use of BDZs. 8-Methoxypeucedanin (8-MP) is a rare furanocoumarin present in the fruits of Peucedanum luxurians Tamamsch. (Apiaceae). The primary objective of the presented study was to assess the anxiolytic activity of 8-MP using a zebrafish (Danio rerio) model of anxiety. Danio rerio larvae at 5 days post-fertilization (dpf) were used, with reversed thigmotaxis considered as an index of the anxiolytic activity. In addition to the behavioral study, qPCR analyses were performed to assess the role of 8-MP in modulating the expression of c-fos and bdnf, two key genes involved in neural activity. As evidenced by the behavioral study, 8-MP (1.5–15 µM) exhibited a significant influence on anxiety, with a U-shape dose–response effect. Moreover, the expression of c-fos and bdnf genes was significantly downregulated, providing novel insights into the mechanisms of action of the tested furanocoumarin. Full article