GABA (Anxiety)

BACKGROUND: Anxiety disorders (AnxDs) are highly prevalent and often untreated or unresponsive to treatment. Although proton magnetic resonance spectroscopy (1H-MRS) studies of AnxDs have been conducted for over 25 years, a consensus regarding neurometabolic abnormalities in these conditions is lacking. METHODS: A systematic review and meta-analysis of 1H-MRS studies of AnxDs (social anxiety disorder, generalized anxiety disorder, and panic disorder) identified 25 published datasets meeting inclusion criteria. These compared neurometabolites between 370 patients and 342 controls, including n-acetlyaspartate (NAA), total creatine, total choline (tCho), myo-inositol, glutamate, glutamate+glutamine, GABA, and lactate. RESULTS: Across AnxDs, tCho was significantly reduced in prefrontal cortex and across all cortical regions. Effect sizes for cortical tCho were significantly more negative in studies with better measurement quality, with Hedges' g = -0.64 and an 8% mean reduction. NAA was unchanged in prefrontal cortex but reduced across all cortical regions (after exclusions). These abnormalities did not differ between the three disorders. No other neurometabolites differed significantly. DISCUSSION: Reduced choline-containing compounds in cortical regions is a consistent, transdiagnostic abnormality in AnxDs. Notably, arousal-related neuromodulators, including norepinephrine, alter membrane phospholipid homeostasis and methylation reactions, which influence brain tCho levels. This suggests that chronically elevated arousal in AnxDs may increase neurometabolic demand for choline compounds without a proportionate increase in brain uptake, leading to reduced tCho levels. Reduced cortical NAA suggests compromised neuronal function in AnxDs. Future studies may clarify the clinical significance of reduced cortical tCho and the possibility that appropriate choline supplementation could have therapeutic benefit in anxiety disorders. © 2025. The Author(s).

BACKGROUND: Gabapentin supplementation may have some potential in pain control after lumbar laminectomy and discectomy, and this meta-analysis aims to explore the impact of gabapentin supplementation on postoperative pain management for lumbar laminectomy and discectomy. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials assessing the effect of gabapentin supplementation on the pain control of lumbar laminectomy and discectomy. RESULTS: Five randomized controlled trials were finally included in the meta-analysis. Overall, compared with control intervention for lumbar laminectomy and discectomy, gabapentin supplementation was associated with significantly lower pain scores at 2 hours (MD = -2.75; 95% CI = -3.09 to -2.41; P < .00001), pain scores at 4 hours (MD = -2.28; 95% CI = -3.36 to -1.20; P < .0001), pain scores at 24 hours (MD = -0.70; 95% CI = -0.86 to -0.55; P < .00001) and anxiety score compared to control intervention (MD = -1.32; 95% CI = -1.53 to -1.11; P < .00001), but showed no obvious impact on pain scores at 12 hours (MD = -0.58; 95% CI = -1.39 to 0.22; P = .16). In addition, gabapentin supplementation could significantly decrease the incidence of vomiting in relative to control intervention (OR = 0.31; 95% CI = 0.12-0.81; P = .02), but they had similar incidence of nausea (OR = 0.51; 95% CI = 0.15-1.73; P = .28). CONCLUSIONS: Gabapentin supplementation benefits to pain control after lumbar laminectomy and discectomy.

BACKGROUND: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The recommendations were based on level of evidence, efficacy (meta-analysis of the outcomes pain, sleep, fatigue and health-related quality of life), acceptability (total dropout rate), risks (adverse events) and applicability of treatment modalities in the German health care system. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. RESULTS AND CONCLUSION: Amitriptyline and-in case of comorbid depressive disorder or generalized anxiety disorder-duloxetine are recommended. Off-label use of duloxetine and pregabalin can be considered in case of no comorbid mental disorder. Strong opioids are not recommended. The English full-text version of this article is available at SpringerLink (under "Supplemental").

Gamma-aminobutyric acid, or GABA, the major inhibitory neurotransmitter, acts both through the central nervous system and via microbial production in the gut. Strains able to augment gut GABA production could be novel targets for modulation of sleep and mood. We previously demonstrated that Lactiplantibacillus plantarum Lp815 improves symptoms of anxiety. The current study investigates the impact of Lp815 on subjective sleep, mood, digestion and objective wearable sleep data over 6 weeks in adults with self-reported sleep disturbance. The trial was decentralized, double-blind, randomized and placebo controlled. Participants were screened for at least moderate symptoms of insomnia and blindly assigned to receive either a placebo capsule or 5 billion CFU of Lp815 per day. 139 Individuals (5 billion CFU Lp815 n = 70, placebo n = 69) were evaluated, aged 44 ± 13 years, 51.1% female and 55.4% Caucasian. A sub cohort (n = 17, 5 billion CFU Lp815 n = 9, Placebo n = 8) submitted a urinary time series for neurotransmitter analysis. Participants who received 5 billion CFU Lp815 exhibited significantly lower insomnia severity index scores at 6 weeks compared to placebo (p < 0.05). This result was clinically meaningful, with 77.3% of participants in the 5 billion CFU Lp815 cohort exhibiting improvement by 4 + points in their insomnia severity index at week 6, compared to 57.8% in the placebo group (p = 0.02). Anxiety scores were significantly reduced compared to placebo (p < 0.05), with a more pronounced effect among women (p < 0.01). Additionally, subjective night sweat severity decreased, and objective measures of sleep duration were increased in the 5 billion CFU Lp815 cohort compared to placebo (p < 0.05). Finally, the 5 billion CFU Lp815 cohort exhibited an increase in urinary GABA compared to placebo during the first week of use (p < 0.05) and urinary GABA was inversely correlated with insomnia and anxiety scores at week 2 (r2=-0.30 and - 0.48, respectively). All adverse events potentially related to product use were mild. A daily probiotic containing 5 billion CFU Lp815 significantly improved subjective symptoms of insomnia and anxiety, as well as objective measures

Background: Insomnia is prevalent and difficult to treat safely over the long term. Given the role of the microbiota-gut-brain axis in melatonin and hypothalamic-pituitary-adrenal (HPA) regulation, and preclinical evidence for Limosilactobacillus fermentum PS150, we evaluated whether a heat-treated formulation (HT-PS150) could improve sleep and modulate endocrine/circadian markers in adults with poor sleep. Methods: In a randomized, double-blind, placebo-controlled trial, 84 adults aged 20-60 years with PSQI ≥ 5 and ISI < 22 were assigned to receive either placebo or HT-PS150 for eight weeks. Outcomes included patient-reported sleep (PSQI, ISI), anxiety/depression (GAD-7, PHQ-9), quality of life (QLESQ-SF), gastrointestinal symptoms (VAS-GI), wrist actigraphy (Fitbit Inspire 3), and sleep-relevant biomarkers measured from urine, saliva, and/or blood samples (melatonin, cortisol, orexin, serotonin, GABA, and/or norepinephrine). Repeated measures were analyzed using generalized estimating equations. An exploratory proportional regulation analysis classified individual biomarker changes as up- or down-regulated and compared proportions between study arms. Per-protocol analyses required ≥80% compliance. Results: Improvements in the primary outcomes, PSQI and ISI, were observed over time in both groups, while no significant group × time interactions were detected. In exploratory proportional analyses, a higher proportion of participants in the HT-PS150 group exhibited up-regulated nocturnal melatonin secretion and improved daytime plasma orexin levels, as well as a tendency toward greater reductions in nocturnal salivary cortisol compared with placebo. In subgroup analyses with higher baseline insomnia severity (ISI ≥ 8), HT-PS150 was associated with greater improvements in PSQI (notably sleep duration and efficiency) and reduction in anxiety (GAD-7) upon post hoc testing. Conclusions: Although group mean scores on sleep symptom scales did not differ significantly in the full cohort, HT-PS150 appeared to modulate sleep-wake regulation by enhancing nocturnal melatonin secretion, attenuating HPA-axis activity, and stabilizing wakefulness. Clinical benefits were most ev

Patients in the intensive care unit (ICU) with unhealthy alcohol use often experience agitation during mechanical ventilation, which can contribute to post-traumatic stress disorder (PTSD). The BACLOREA trial investigated whether high-dose baclofen could reduce agitation in these patients, but its long-term effects on PTSD symptoms remained unclear. This study aimed to assess whether baclofen administered during ICU stay to reduce the incidence of agitation could reduce the 5-year PTSD symptoms in adult patients with unhealthy alcohol use and improve long-term quality of life and psychological status. This observational follow-up study was conducted between September 2021 and February 2024 and included patients alive five years after participation in the BACLOREA trial, a randomized, placebo-controlled trial evaluating high-dose baclofen for the prevention of agitation-related events during mechanical ventilation in critically ill patients with unhealthy alcohol use. The primary outcome was the prevalence of PTSD symptoms measured using the Impact of Event Scale-Revised (IES-R), with a score ≥ 33 indicating PTSD symptoms. Secondary outcomes included the prevalence of PTSD symptoms using the PTSD Checklist Scale (PCL-S), the quality of life assessed through the SF-36, EQ-5D, and HADS scales. Among the 152 patients who survived five years after ICU admission, 94 (61.8%) completed the follow-up and were included in the BACLO-PTSD study. In this cohort, the 5-year prevalence of PTSD symptoms was 14.9%. For the primary outcome assessed with the IES-R, PTSD symptom prevalence was similar in the baclofen and placebo groups (13.0% vs. 16.7%, p = 0.62). Mean IES-R scores were 10.4 ± 12.5 in the baclofen group and 12.2 ± 13.5 in the placebo group (p = 0.49), while mean PCL-S scores were 25.4 ± 8.6 and 25.5 ± 7.0, respectively (p = 0.94). Quality of life and psychological status, assessed using the SF-36, EQ-5D, and HADS, were also comparable between groups. High-dose baclofen administered during mechanical ventilation did not reduce the 5-year prevalence of PTSD symptoms, nor did it impact quality of life or symptoms of anxiety and depression. Further research is needed t

Individuals with 22q11.2 deletion syndrome are susceptible to psychosis and cognitive impairments. These symptoms have been linked to a disruption in the balance of glutamate (excitatory) to GABA (inhibitory) transmission. This clinical trial aimed to determine whether the glutamate and GABA-modulating drug riluzole reduces psychotic or cognitive symptoms within 22q11.2 deletion syndrome. 32 participants with a 22q11.2 deletion and psychotic and/or cognitive symptoms were enrolled in this placebo-controlled, fixed-order crossover trial. Participants received placebo for 8 weeks, followed by 8 weeks of 100mg/day riluzole. The Positive and Negative Syndrome Scale (PANSS) and Pennsylvania Computerized Neurocognitive Battery (CNB) were used to assess psychotic and cognitive symptoms, with PANSS total and subscale scores and CNB accuracy and reaction time as primary outcome measures. Correcting for family-wise error rate, riluzole improved performance on executive function (p = 0.036), social cognition (p = 0.041), and non-verbal reasoning (p = 0.005) tasks in comparison to baseline. Following correction, no significant effects of riluzole were found on the PANSS total score and subscales, or on accuracy and reaction time on the CNB compared to placebo. Exploratory analyses of individual PANSS items indicated that riluzole reduced anxiety (p = 0.001) and impairments in abstract thinking (p = 0.039) compared to baseline. Our results suggest riluzole may have beneficial effects on mental health and cognition. Further research is needed to confirm these findings and establish a responsive phenotype.

BACKGROUND: No clinically useful biomarkers currently predict antidepressant response to ketamine in treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD). This study investigated whether baseline thyroid-stimulating hormone (TSH) levels are associated with ketamine's antidepressant, anti-anhedonic, and anti-suicidal effects. METHODS: This was a secondary exploratory analysis of data drawn from four NIH-sponsored, randomized, placebo-controlled, double-blind crossover studies of ketamine in inpatients with current MDD (n = 39) or bipolar depression (n = 44). Baseline TSH levels were measured before the first intravenous saline or ketamine infusion (0.5 mg/kg). A two-week washout preceded the second infusion. Depression and anhedonia were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale, respectively. Suicidal ideation (SI) was measured as a weighted average of the Beck Depression Inventory and the MADRS suicide items. Linear mixed models were used to evaluate baseline TSH levels as a moderator of response to ketamine (versus placebo), controlling for thyroid disease, lithium use, and depression severity at 230 min and days 1, 2, and 7 post-infusion. RESULTS: In individuals with BD, higher baseline TSH levels were associated with greater decreases in the severity of depressive (drug*TSH, p < 0.0007) and anhedonia (drug*TSH, p < 0.0001) symptoms post-ketamine. TSH levels were not associated with changes in depression, anhedonia, or SI severity in MDD post-ketamine. CONCLUSION: Baseline TSH levels were associated with ketamine's antidepressant and anti-anhedonic effects in BD but not MDD. These findings suggest that TSH may serve as a predictive biomarker of response and highlight a potential thyroid-glutamate influence in ketamine's mechanism of action. Published by Elsevier B.V.

Background: An imbalance in the immune system, stress response, and gut microbiota can contribute to the onset and progression of anxiety and depression. This pilot study aimed to explore the effect of Weizmannia coagulans BC99 on anxiety and depression through the gut microbiota-brain axis. Methods: A total of 79 participants with Hamilton Depression Rating Scale (HAMD-17) ≥ 8 or Hamilton Anxiety Rating Scale (HAMA-14) ≥ 7 were included and completed the study. The participants were randomly assigned to either the placebo group or the BC99 intervention group. The intervention lasted 8 weeks, with participants receiving either dextrin (3 g/day) or BC99 probiotics (3 g/day, 5 × 109 CFU) daily. Pre- and post-intervention comparisons were made on HAMD and HAMA scores, inflammatory cytokines, neurotransmitters, gut microbiota, and short-chain fatty acids. Results: Results showed that after 8 weeks, BC99 and placebo intervention were effective in reducing HAMD and HAMA scores, and HAMD and HAMA scores in BC99 group were reduced by 2.40 and 5.53 points compared the placebo group, and the response and remission rates were also higher than that of the placebo, but there was no significant difference. BC99 also could regulate the levels of inflammatory cytokines IL-17 and IL-10, and increase neurotransmitter levels of γ-GABA and NO. Moreover, compared with the placebo group, BC99 also enhanced the abundance of beneficial bacteria such as Faecalibactrium, Megamonas, Dialister, and Agathobacter, which were closely associated with clinical indicators of mental disorders, and increased the production of short-chain fatty acids. Conclusions: These preliminary findings suggested that BC99 might alleviate anxiety and depression symptoms by regulating the level of neurotransmitters or the change of microbiota, which needed further verification in subsequent animal or clinical experiments.

Increasing evidence suggests that modulations of the gut-brain axis with probiotics impact healthy ageing. This double-blinded, randomised, placebo-controlled study compared effects of micro-encapsulated and non-encapsulated Lacticaseibacillus rhamnosus HN001 in 87 community-dwelling elderly (60-80 years). Resting state functional connectivity differed significantly in regions involved in visual processing and perception between the two probiotic groups (p < 0.0001). Brain morphometry was not altered. Significant time*group effects (p < 0.05) were observed for processing speed, non-significant effects were observed for short-term memory and anxiety symptoms, while other cognitive domains, depression, perceived stress, and sleep quality were unaffected. Distribution of available and stored peripheral serotonin was significantly affected (p < 0.05), while levels of γ-aminobutyric acid and glutamate in striatum and circulating brain-derived neurotrophic factor did not show significant time*group effects. Micro-encapsulated probiotics target the gut differently, which impacts the effects on brain health assessed by (functional) magnetic resonance imaging in older adults. The trial is registered at ClinicalTrials.gov under ID: NCT05801042.

Objectives: Concurrent with global aging epidemics, cognitive decline has become an increasing public health concern. Dietary supplementation may offer neuroprotective benefits, and 5-hydroxytryptophan (5-HTP) has gained interest due to its role in serotonin synthesis, thereby regulating cognitive function and mood. However, there is limited evidence on its effect on cognitive function, especially among older Asian adults. Therefore, the study aimed to investigate the effects of 5-HTP supplementation on cognitive function and mood in Singaporean older adults. Methods: This was a single-blinded, 12-week randomized controlled trial, and 30 participants (66 ± 3 years) were randomly assigned to consume 100 mg of 5-HTP daily or not consume it. Cognitive function and mood were assessed via the Montreal Cognitive Assessment (MoCA), Geriatric Anxiety Inventory (GAI), and Geriatric Depression Scale (GDS). Cognitive function-related blood biomarkers, including amyloid beta (Aβ)40, Aβ42, gamma-aminobutyric acid, and serotonin, were also determined. Results: A significant time effect was observed in the MoCA score, which was mainly explained by a significant increase in the 5-HTP group (week 0 vs. week 12: 26.6 ± 1.4 a.u. vs. 27.6 ± 1.4 a.u., p < 0.05). Moreover, the 5-HTP group showed a significant increase in serum serotonin levels. Additionally, the GDS score improved in the 5-HTP group (week 0 vs. week 8: 1.2 ± 1.7 a.u. vs. 0.7 ± 1.2 a.u., p < 0.05). However, no effects on GAI and other biomarkers were observed. Conclusions: 5-HTP supplementation can enhance cognitive performance and reduce symptoms of depression in Singaporean older adults, potentially through serotonergic modulation. However, given the relatively small sample size (n = 30) and short-term (12-week) intervention, these findings should be interpreted cautiously, and further long-term studies with a larger sample size are warranted to confirm these preliminary results.

BACKGROUND: This randomized controlled trial investigated the therapeutic effects of transcutaneous electrical acupoint stimulation (TEAS) on insomnia, negative emotions, and neurotransmitter levels in patients undergoing methamphetamine (METH) withdrawal. METHODS: We enrolled 84 eligible patients from the Kangxin Hospital of Guizhou Province, China (August 2023-December 2024), randomly allocating them to TEAS (n = 42) or sham-TEAS (n = 42) groups. The patients were divided into a TEAS group of 42 cases and a sham-TEAS group of 42 cases according to the randomized, single-blind and control principle. The 2 groups patients were given TEAS or sham-TEAS treatment for 45 minutes after treated with sleep health education. Interventions described above in weekdays were given once a day for 4 weeks, with a total of 4 consecutive weeks. The Pittsburgh Sleep Quality Index (PSQI), insomnia severity index (ISI), METH withdrawal symptom score, Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), serum levels of 5-hydroxytryptamine, noradrenaline, gamma-aminobutyric acid and dopamine of each group were compared before treatment, after treatment and in follow-up period. RESULTS: Baseline characteristics were comparable between groups (both P > .05). After 4 weeks of treatment, the scores of PSQI, ISI, METH withdrawal symptom, HAMA, HAMD in the TEAS group were significantly lower than those in the sham-TEAS group and the difference was statistically significant (both P < .001), serum levels of 5-hydroxytryptamine, gamma-aminobutyric acid and dopamine in the TEAS group were significantly higher than those in the sham-TEAS group, and serum levels of noradrenaline in the TEAS group were significantly lower than those in the sham-TEAS group (both P < .001). In follow-up period, the scores of PSQI, ISI, METH withdrawal symptom, HAMA, HAMD in the TEAS group were significantly lower than those in the sham-TEAS group, and the difference was statistically significant (both P < .001). CONCLUSION: TEAS effectively improved insomnia, anxiety and depression after METH withdrawal, it is worth of clinical application and promotion while significantly affecting serum levels of neu

BACKGROUND: There is growing interest in developing pharmacological agents to reverse alcohol (ethanol) intoxication, akin to naloxone for opioids. GABAergic modulation offers a potential pathway for reversing alcohol effects, specifically by targeting extrasynaptic GABA-A receptors with a benzodiazepine partial inverse agonist. We tested the hypothesis that iomazenil, a benzodiazepine partial inverse agonist, can counteract alcohol intoxication. METHODS: In a randomized, double-blind, placebo-controlled, within-subject design, healthy male volunteers (n = 33) were administered intravenous alcohol (ethanol) or placebo, followed by intravenous iomazenil or placebo. Biphasic Alcohol Affects Scale, which assesses the stimulant and sedative effects of alcohol, was used as the primary outcome measure. For secondary measures, the Visual Analog Scale was used to assess "high," "drowsiness," "Buzzed," and "anxiety." In addition, all subjects were asked to rate the number of standard alcohol drinks they believed had been administered. RESULTS: Alcohol produced greater sedation and stimulation when compared to placebo. Iomazenil produced the expected effect of increased anxiety compared to the placebo. However, Iomazenil did not attenuate the sedative or stimulatory effects of alcohol intoxication. Similarly, iomazenil did not significantly change feelings of "High," "Drowsy," "Anxious," or "Buzzed" produced by alcohol. CONCLUSIONS: Although GABA-A receptors are thought to mediate the subjective effects associated with ethanol intoxication, this study failed to demonstrate a significant attenuation of ethanol intoxication by the benzodiazepine partial inverse agonist, iomazenil. This study raises questions as to the role of particular GABA-A receptor subtypes in ethanol intoxication and the extent to which GABA-A receptor subtype function must be reduced to attenuate human ethanol intoxication.

Combining Piper nigrum, Piper retrofractum, and Zingiber officinale var. Rubrum, Trikatu essential oil (TREO) exhibits promise as an inhaled aromatherapy agent with a range of biological activities. The antioxidant, anti-inflammatory, anxiolytic, and neuroprotective properties of the bioactive compounds in TREO are reviewed in this article along with scientific evidence supporting them. According to analysis, substances like β-Caryophyllene α-Pinene, linalool, D-Limonene, and Eucalyptol can interact with important molecular targets, such as GABAA, CB2, and 5-HT1A, 5-HT, 5-HT2A receptors, also inhibits 5-HT3 receptor, which are involved in the regulation of anxiety and the protection of brain. Furthermore, these substances work in concert to inhibit oxidative stress, lower the expression of pro-inflammatory cytokines like TNF-α and IL-1β, and promote neuroplasticity through the BDNF pathway. The synergistic effects of TREO offer more potential than when used on its own, particularly when it comes to reducing inflammation, oxidative stress, and nervous system modulation. Essential oils in TREO are typically extracted through hydro-distillation with the Clevenger apparatus, which help preserve the integrity of volatile active constituents. The potential of TREO as an aromatherapy agent is assessed in this article along with its chemical composition, biological activities, and potential uses in promoting both physical and mental well-being. © 2025 Pramitha et al.

The citrus peel flavonoid tangeretin (TAN) has diverse biological activities, including antioxidant, anti-inflammatory, antitumor, hepatoprotective, and neuroprotective effects. This study investigates the sedative effects of TAN, in Swiss albino mice using in vivo and in silico approaches. TAN (10 and 20 mg/kg, i.p.) was administered alone and in combination with diazepam (DZP, 2 mg/kg, i.p.) and flumazenil (FLU, 0.1 mg/kg, i.p.) to evaluate its impact on thiopental sodium (TS)-induced sleep, locomotor activity, and dark-light behavior. Results demonstrated that TAN at 10 mg/kg significantly (p < 0.05) reduced sleep onset latency and increased sleep duration, with a synergistic effect observed when combined with DZP. In locomotor activity tests, TAN dose-dependently decreased the distance traveled, while the combination with DZP further enhanced this effect. Dark-light tests revealed that TAN increased dark residence time, indicating potential anxiolytic properties. Molecular docking studies showed that TAN binds to the GABAA receptor (α1 and β2 subunits) with a binding affinity of -6.6 kcal/mol, suggesting its interaction with GABAergic pathways. Pharmacokinetic analysis indicated high intestinal absorption and compliance with Lipinski's rule of five, with a favorable safety profile (LD50 = 5000 mg/kg). Overall, TAN enhances the sedative effects of DZP through GABAA receptor modulation, highlighting its potential as a natural sedative agent. Further research should explore the long-term effects, bioavailability, blood-brain barrier permeability, and synergistic interactions of TAN, with comprehensive in vitro studies and clinical trials needed to validate its potential as a natural sedative.

Sesamol (SES) and linalool (LIN) are aromatic compounds that have neuroprotective effects. The main purpose of this study is to evaluate the anxiolytic activity of LIN and SES co-treatment on Swiss albino mice and analyze its possible mechanism through in silico study. In this sense, the mice were given the gamma-aminobutyric acid type A receptors (GABAA) agonist diazepam (DZP; 3 mg/kg, p.o.) as a positive control. A vehicle (10 mL/kg) was served as control. The tested chemicals, single-dose LIN (50 mg/kg) and SES (50 mg/kg), as well as a combination (LIN + SES) and (DZP + LIN + SES), were administered orally in order to conduct several behavioral tests, including open-field, swings box, hole-crossing, and dark-resident time tests. Further, molecular docking studies of LIN, SES, and DZP were carried out through different software. The results showed that LIN and SES individually have significant anxiolytic-like activity in mice. Further, when LIN was combined with SES and with (SES + DZP), it exhibited a relatively lower locomotor activity in mice compared to individual treatment groups, indicating a synergistic action. In addition, the molecular docking analysis revealed that LIN and SES have a moderate binding affinity (-5.0 and -5.1 kcal/mol) toward the GABAA receptor α3 subunit. In conclusion, our findings suggest that LIN and SES exerted synergistic anxiolytic activity on Swiss albino mice, possibly through the GABAergic interaction pathways. © 2024 Wiley Periodicals LLC.

The β-Carboline FG-7142 is a partial inverse agonist at the benzodiazepine allosteric site on the GABA-A receptor that induces anxiogenic, proconvulsant, and appetite-reducing effects in many species, including humans. Seizure-kindling effects have been well studied, however anxiogenic properties are relatively unexplored. This study aimed to investigate concentration-dependent effects of FG-7142 on anxiety-like behaviour and fear responses in zebrafish (Danio rerio) using the open-field test (OF) and novel object approach test (NOA). A U-shaped distribution was found with maximal responses in increased immobility and reduced distance moved at 10 µM in the NOA but not the OF. Follow up experiments demonstrated a lack of effect in repeated OF testing and no changes in opercular movements. Furthermore, the effect of FG-7142 was reversed with ethanol treatment. These results suggest that FG-7142 elicits a 'freezing' response in zebrafish via the introduction of novelty, suggesting fear-induction. These findings indicate that FG-7142 may act as an agent to promote acute fear responses in zebrafish. © 2024. The Author(s).

BACKGROUND: Cue-exposure therapy (CET) is an effective approach for anxiety-related disorders, but its effectiveness for substance use disorders is less clear. One potential means of improving CET outcomes is to include a cognitive-enhancing pharmacotherapy. This study evaluated d-cycloserine (DCS) and RY-023, putative cognitive enhancers targeting glutamate and GABA systems, respectively, in a monkey model of CET for alcohol use disorder. METHODS: Male rhesus monkeys (n = 4) underwent multiple cycles of the CET procedure. During baseline (Phase 1), monkeys self-administered an ethanol solution under a fixed-ratio schedule and limited access conditions such that every 5th response in a 3-h session resulted in 30-s access to a drinking spout and a change in ethanol-paired cue lights from white to red. Behavior then was extinguished (Phase 2) by omitting the ethanol solution yet retaining the ethanol-paired stimulus lights. Monkeys also received injections of vehicle, DCS (3 mg/kg), a partial agonist at the glycine modulatory site on glutamatergic NMDA receptors, or the α5GABAA receptor-selective inverse agonist RY-023 (0.03 or 0.3 mg/kg). Once responding declined, monkeys underwent a cue reactivity test (Phase 3), and then returned to self-administration the following day to assess reacquisition (Phase 4). RESULTS: Through multiple cycles, self-administration remained stable. Compared to vehicle, DCS facilitated extinction of ethanol seeking (Phase 2) and delayed reacquisition of ethanol self-administration (Phase 4). In contrast, RY-023 facilitated extinction (Phase 2) and reduced cue reactivity (Phase 3). CONCLUSIONS: Adjunctive pharmacotherapy can improve CET outcomes, but the choice of pharmacotherapy should be dependent on the outcome of interest.

Neuropathic pain is a chronic debilitating condition caused by injury or disease of the nerves of the somatosensory system. Although several therapeutic approaches are recommended, none has emerged as an optimal treatment leaving a need for developing more effective therapies. Given the small number of approved drugs and their limited clinical efficacy, combining drugs with different mechanisms of action is frequently used to yield greater efficacy. We demonstrate that the combination of trazodone, a multifunctional drug for the treatment of major depressive disorders, and gabapentin, a GABA analogue approved for neuropathic pain relief, results in a synergistic antinociceptive effect in the mice writhing test. To explore the potential relevance of this finding in chronic neuropathic pain, pharmacodynamic interactions between low doses of trazodone (0.3 mg/kg) and gabapentin (3 mg/kg) were evaluated in the chronic constriction injury (CCI) rat model, measuring the effects of the two drugs both on evoked and spontaneous nociception and on general well being components. Two innate behaviors, burrowing and nest building, were used to assess these aspects. Besides exerting a significant antinociceptive effect on hyperalgesia and on spontaneous pain, combined inactive doses of trazodone and gabapentin restored in CCI rats innate behaviors that are strongly reduced or even abolished during persistent nociception, suggesting that the combination may have an impact also on pain components different from somatosensory perception. Our results support the development of a trazodone and gabapentin low doses combination product for optimal multimodal analgesia treatment.

Literature regarding the clinical use of psychotropic drugs in exotic animals remains scarce. Psychotropic drugs acting on serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid pathways work by decreasing fear and anxiety, reactivity, and hypervigilance, and by improving impulse control. They are indicated for some cases of aggression, self-mutilation, and compulsive and anxiety disorders, including feather-damaging behavior. Side effects are rarely seen when dosages are appropriately adjusted to the individual, starting with a low dose and slowly titrating to effect. Several drug interactions exist between psychotropic drugs and other classes. Psychotropic drugs cannot be used to replace appropriate environmental conditions in exotic animals. before "Side effects".

Opiate analgesics are one of the treatment options for severe chronic pain, including late-stage cancer, chronic back pain and other disorders. The recent resurgence in opioid overdose has highlighted the serious need for alternative medicines for pain management. While a role for potentiators of α2/3-containing GABAA receptors in the modulation of pain has been known for several years, advancements in this area required data from selective compounds. KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3- yl)oxazole) and analogs selectively potentiate GABAA receptors containing α2/3 subunits and have recently been shown to attenuate pain behaviors in several acute and chronic pain models in rodents. The present study was designed to ascertain whether KRM-II-81 and the structural analog MP-III-80 (3-ethyl-5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)-1,2,4-oxadiazole) would block chemotherapeutic agent paclitaxel-induced pain in male, C57BL/6 mice. Both compounds significantly inhibited pain behaviors evoked by cold and tactile stimulation in paclitaxel-treated mice as did the neuropathic pain drug gabapentin. Subchronic dosing for 22 days with KRM-II-81 and MP-III-80 demonstrated enduring analgesic efficacy without tolerance development, while the effects of gabapentin showed evidence of tolerance development. KRM-II-81 and MP-III-80 also decreased marble-burying behavior in this mouse strain as did the anxiolytic drug chlordiazepoxide. In contrast to KRM-II-81 and MP-III-80, chlordiazepoxide had motor-impairing effects at anxiolytic-like doses. The data add to the literature documenting that these selective potentiators of α2/3-containing GABAA receptors are effective in a host of animal models used to detect novel analgesic drugs. The anxiolytic-like efficacy of these compounds fits well with the comorbidity of anxiety in patients with chronic pain and cancer.

Salvia tiliifolia is used in folk medicine as a relaxant agent and for the treatment of diarrhea and neurodegenerative diseases. Tilifodiolide (TFD) is a diterpene obtained from this plant. The purpose of this work was to evaluate the antidiarrheal, vasorelaxant, and neuropharmacological actions of TFD. These effects were selected based on the folk medicinal use of S. tiliifolia. The antidiarrheal activity of 1-50 mg/kg p.o. TFD was assessed with the castor oil related tests. The vasorelaxant effect of TFD (0.9-298 μM) was performed with smooth muscle tissues from rats, and its mechanism of action was evaluated using different inhibitors. The sedative, anxiolytic, and antidepressant effects of 1-100 mg/kg TFD were assessed. The possible mechanisms of action of the anxiolytic and antidepressant effects of TFD were evaluated using inhibitors. TFD exhibited antidiarrheal (ED50 = 10.62 mg/kg) and vasorelaxant (EC50 = 48 ± 3.51 μM) effects. The coadministration of TFD with N(ω)-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), reverted the vasorelaxant action showed by TFD alone. TFD exerted anxiolytic actions (ED50 = 20 mg/kg) in the cylinder exploratory test, whereas TFD (50 mg/kg) showed antidepressant actions in the tail suspension test by 44%. The pretreatment with 2 mg/kg flumazenil partially reverted the anxiolytic actions of TFD, whereas the pretreatment with 1 mg/kg yohimbine abolished the antidepressant effects of TFD. In summary, TFD exerted antidiarrheal activity by decreasing the intestinal fluid accumulation and vasorelaxant effects mediated by nitric oxide and cyclic guanosine monophosphate. TFD showed anxiolytic and antidepressant effects by the partial involvement of gamma-Aminobutyric acid (GABA) receptors and the possible participation of α2-adrenoreceptors, respectively. © 2019 Wiley Periodicals, Inc.

Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extracts have been marketed as dietary supplements in the United States for memory health and pain management. We have recently reviewed the pharmacokinetics (PK) and first-pass hepatic metabolism of ingested AGN supplements in humans for the signature pyranocoumarins decursin (D, Cmax 1x), decursinol angelate (DA, Cmax ~ 10x) and their common botanical precursor and hepatic metabolite decursinol (DOH, Cmax ~ 1000x). Here we update in vivo medicinal activities of AGN and/or its pyranocoumarins and furanocoumarin nodakenin in cancer, pain, memory loss, cerebral ischemia reperfusion stroke, metabolic syndrome and vascular endothelial dysfunctions, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, osteoporosis and osteoarthritis. Given their polypharmacology nature, the pertinent mechanisms of action are likely misrepresented by many cell culture studies that did not consider the drug metabolism knowledge. We report here Rho-associated protein kinases (ROCK1/2) as novel targets for DA and DOH. Combining with published inhibitory activity of DOH on acetylcholinesterase, agonist activity of DOH and antagonist/degrader activity of DA/D on androgen and estrogen receptors, D/DA promoting activity for glutamic acid decarboxylase (GAD)- gamma-aminobutyric acid (GABA) inhibitory axis and inhibition of glutamate dehydrogenase (GDH), monoamine oxidase-A (MAO-A) and transient receptor potential vanilloid 1 (TRPV1), we postulate their contributions to neuro-cognitive, metabolic, oncologic, vascular and other beneficial bioactivities of AGN extracts. A clinical trial is being planned for an AGN extract to manage side effects of androgen deprivation therapy in prostate cancer patients. © 2025. The Author(s).

BACKGROUND: Pregabalin binds to the α2δ auxiliary subunit of voltage-gated calcium channels, which are widely distributed throughout the central and peripheral nervous systems and modulate calcium-dependent neurotransmitter release. Pregabalin is indicated for the treatment of peripheral and central neuropathic pain, partial seizures with or without secondary generalization, and treatment of generalized anxiety disorder (GAD). OBJECTIVE: The purpose of this study was to assess the bioequivalence of two different formulations of pregabalin 150-mg capsules in healthy Korean male subjects under fasting conditions. METHODS: This bioequivalence study was based on an open-label, single-dose, randomized, 2-period, 2-sequence crossover design with a washout period of 7 days. Blood samples for pharmacokinetic (PK) evaluation were collected up to 24 hours postdose. Plasma concentrations of pregabalin were determined using a validated LC-MS/MS method. PK parameters were determined using noncompartmental analysis. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of log-transformed Cmax and AUClast values met the bioequivalence criteria specified by Korean regulatory guidelines (90% CI 0.8 - 1.25). RESULTS: The extent of exposure in terms of AUClast amounted to 26,018.3 - 3,580.8 µg×h/L for the test formulation and 25,680.2 ± 3,083.6 µg×h/L for the reference formulation. Cmax reached values of 4,782.7 ± 1,124.2 µg/L and 4,654.0 ± 911.4 µg/L for the test product and reference product, respectively. The geometric mean ratio and 90% CIs of the test product to the reference product were 1.0132 (0.9862 - 1.0351) for AUClast and 1.0153 (0.9351 - 1.1044) for Cmax, which were well within the range necessary to establish bioequivalence (90% CI 0.8 - 1.25). CONCLUSIONS: The bioequivalence between test and reference formulations under fasting conditions was confirmed both in terms of the rate and extent of absorption. .

BACKGROUND: Clinical trials from various countries have reported the efficacy of pregabalin for reducing peripheral neuropathic pain. OBJECTIVE: This study assessed the efficacy and tolerability of pregabalin in Korean patients with neuropathic pain. METHODS: This was a Phase III, 10-week, randomized, double-blind, placebo-controlled, multicenter study. Patients aged ≥ 18 years with neuropathic pain (diabetic peripheral neuropathy, postherpetic neuralgia, or posttraumatic neuropathic pain) were enrolled and randomly assigned (2:1 ratio) to pregabalin (150-600 mg/d) or matching placebo. Randomization was performed using a proprietary telerandomization system. The primary end point was the difference in week 8 least squares (LS) mean Daily Pain Rating Scale (DPRS) score (rated once daily from 0 ["no pain"] to 10 ["worst possible pain"]) between pregabalin and placebo, calculated using the average of the last 7 available DPRS scores. Secondary efficacy measures included the following: the proportion of responders whose DPRS scores were reduced by ≥ 30% or ≥ 50% versus baseline, the Daily Sleep Interference Scale (DSIS; 11-point scale, scored daily), the Euro Quality of Life assessment (EQ-5D; 2 items scored separately), the Medical Outcomes Study (MOS) Sleep Scale (12 items each scored separately), the Hospital Anxiety and Depression Scale (HADS; 2 items scored from 0 to 21), the Patient Global Impression of Change (PGIC) and the Clinical Global Impression of Change (CGIC; each scored on a 7-point scale), and tolerability assessments. Adverse events and vital signs were monitored throughout the study with laboratory measurements, physical examinations, neurologic examinations, and 12-lead ECG tests. Data were analyzed using ANCOVA or Cochran-Mantel-Haenszel test, and P < 0.05 was considered statistically significant. RESULTS: The treatment groups (n = 162 pregabalin; n = 78 placebo) were well matched at baseline (pregabalin: 51.2% [83/162] female; mean [SD] age, 59.7 [10.8] years; weight, 63.6 [9.3] kg; placebo: 59.0% [46/78] female; mean age, 61.3 [12.9] years; weight, 62.0 [9.5] kg). All patients were Korean. The mean doses at end point were 480 mg/d for pregabal

BACKGROUND: Diabetic neuropathy is one of the most common complications of diabetes, affecting about half of all people with the disease. Among these, 30%-50% experience nerve-related pain, characterized by abnormal sensations, burning, or stabbing pain, a condition known as painful diabetic neuropathy (PDN). PDN not only severely impairs quality of life but is also closely associated with sleep disturbances, depression or anxiety, and foot complications. Together, these problems substantially increase healthcare costs and place a considerable economic burden on both families and society. METHODS: We systematically searched multiple databases from their inception to 1 November 2025 to identify randomized controlled trials evaluating pregabalin combined with duloxetine for the treatment of painful diabetic neuropathy. The methodological quality and risk of bias of the included trials were assessed using the Cochrane risk-of-bias tool (version 2.0). Statistical analyses were performed with RevMan 5.4. RESULTS: Three randomized trials involving a total of 471 patients were included. In two studies that could be pooled, combination therapy produced significantly greater pain relief than monotherapy (MD=-1.82, 95%CI=-2.10, -1.54, P<0.00001). For secondary continuous outcomes reported in single studies, all results favored the combination, pain intensity on the visual analogue scale (VAS, MD=-1.42, 95%CI=-1.83, -1.01, P<0.00001), brief pain inventory-modified short form (BPI-MSF, MD=-1.46, 95%CI=-2.35, -0.57, P = 0.001), and neuropathic pain symptoms on the pain detect questionnaire (PDQ, MD=-3.00, 95%CI=-5.55, -0.45, P = 0.02). The proportion of patients achieving at least 50% pain reduction was also higher with the combination than with duloxetine 120 mg alone (RR = 1.81, 95%CI=1.17, 2.81, P = 0.008). In contrast, there were no significant differences between combination therapy and monotherapy in the overall risk of adverse events (RR = 1.10, 95%CI=0.84, 1.46, P = 0.48) or in key individual adverse effects, including somnolence (RR = 0.79, 95%CI=0.30, 2.08, P = 0.63) and nausea/vomiting (RR = 2.02, 95%CI=0.77, 5.27, P = 0.15). The certainty of evidence ranged from

Pregabalin, a gamma-aminobutyric acid analogue, is extensively used for neurological and psychiatric disorders, such as neuropathic pain, anxiety, and epilepsy. Although its clinical efficacy is not in doubt, increasing evidence indicates a high risk of psychological side effects and abuse, and concerns regarding safety and dependency. Our systematic review found severe psychiatric symptoms such as psychosis, hallucinations, anxiety, and depression with pregabalin. These effects were intensified by factors such as high doses, sudden withdrawal, and preexisting psychiatric illness. Sexual disinhibition and dependency cases were reported, especially in substance-dependent patients. Effective management involved tapering doses gradually, adjunct psychiatric treatment, and close monitoring.

Pregabalin is an antiseizure medication indicated for a wide range of medical conditions other than epilepsy, such as neuropathic pain and generalized anxiety disorder. Preclinical observations have suggested reproductive toxicity for this agent, with skeletal malformations and growth retardation. Human data is sparse and studies lead to contradictory results. Our objective was to conduct a systematic review and meta-analysis on the risk of major congenital malformations (MCMs) associated with pregabalin use in monotherapy during the first trimester of pregnancy. References were identified through a snowballing approach until 2015 and through electronic databases (MEDLINE and Embase) from 2015 to June 30, 2024. All comparative studies including pregnant women exposed to pregabalin monotherapy during the first trimester of pregnancy were included. Two reviewers independently screened citations for eligibility and extracted data using a proprietary collaborative Web-based meta-analysis platform (metaPreg.org). The risk of MCMs between pregabalin exposed and non-exposed pregnancies, and its 95 % confidence interval were estimated using a random effects model. Seven studies, retrospective and prospective cohorts, included data from 3,336,224 pregnant women. Among them, 701 were exposed to pregabalin monotherapy during the first trimester of pregnancy. There was no significant association between the risk of MCMs and first trimester exposure to pregabalin monotherapy (pooled OR 1.79, 95 %CI [0.80; 3.99]). Some between-study heterogeneity was observed (I2 = 51 %;). No significant association between pregabalin monotherapy and the risk of MCMs was found. This result should be interpreted with caution given the small number of studies included and their critical risk of bias.

BACKGROUND AND OBJECTIVES: Baclofen, a traditional treatment for spasticity, is gaining interest for its use in alcohol use disorder (AUD). To assist clinicians in using baclofen for effective and safe treatment of AUD, we investigated the optimal target dosage of baclofen through a systematic review and dose-response meta-analysis. METHODS: We searched Cochrane, EMBASE, MEDLINE via PubMed, PsycINFO, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for randomized controlled trials on 1 and 2 April 2024. Inclusion criteria were patients aged ≥ 18 years diagnosed with AUD according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV, DSM-IV-TR, or International Classification of Diseases (ICD)-10, and treated with baclofen monotherapy. Continuous outcomes-percent days abstinent, drinks per drinking day, heavy drinking days (HDDs), craving, and anxiety-were analyzed as mean or standardized mean differences. Binary outcomes-relapse and dropout, including due to adverse events-were analyzed as odds ratios. Each outcome was assessed using the Cochrane Risk of Bias 2.0 tool. A one-stage random-effects dose-response meta-analysis was performed using restricted cubic splines with fixed knots at 10%, 50%, and 90% percentiles. RESULTS: A total of 14 trials (1344 patients) were included. Increasing the dose of baclofen up to 50-60 mg/day was associated with a higher percent days abstinent and reduced craving. However, a higher baclofen dose increases the risk of dropout due to adverse events. Commonly observed adverse events were drowsiness, sedation, somnolence and fatigue. Baclofen up to 50-60 mg/day did not significantly affect drinks per drinking day, HDDs, anxiety, relapse or dropout. Doses > 60 mg/day lacked reliable evaluation due to limited data and study heterogeneity. CONCLUSIONS: Baclofen up to 50-60 mg/day may increase percent days abstinent and reduce craving, but may increase dropout due to adverse events. Clinicians should carefully consider individual patient factors when prescribing baclofen to patients with AUD. © 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

BACKGROUND: Among the available pharmacological treatments for acute major depressive disorder (MDD), vortioxetine, a serotonin transporter inhibitor (SERT), has been widely used for its multimodal action on serotonin neurotransmission, which produces essential changes also on glutamate, gamma amino butyric acid (GABA), norepinephrine, acetylcholine, and dopamine. AIM: This systematic review and meta-analysis aimed to evaluate the acute efficacy of vortioxetine across multiple dosing and to evaluate whether there is a dose-response effect and as well there is a dose-response issue with respect to side effects in acute depression. METHODS: According to PRISMA guidelines, we systematically searched three major electronic databases (PubMed/MEDLINE, PsycINFO, and Cochrane Central Register of Controlled Trials) for Randomized Controlled Trial (RCT) studies published between January 2013 and April 2024. Twenty-four studies were included in the review and two meta-analyses were conducted to determine whether the mean Montgomery-Asberg Depression Rating Scale (MADRS) scale values in the placebo groups differ significantly from the mean MADRS scale values in the group receiving vortioxetine 10 mg or vortioxetine 20 mg. RESULTS: Vortioxetine significantly improved acute depression severity, anxiety symptoms, and cognitive function, with high response and remission rates in acute MDD. It was also well tolerated with a relatively low occurrence of severe or serious treatment-emergent adverse events (TEAEs). Observing the results of the meta-analysis, the effect was significant for both vortioxetine 10 and 20 mg, with a greater effect size for vortioxetine 20 mg. CONCLUSION: Vortioxetine should be considered efficacious as a first- and second-line therapy.