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Background: Novel abortive treatments for migraine, ditans and gepants, have promising implications in triptan-insufficient responders with minimal existing comparative data. Our study aims to synthesize evidence through a systematic review and network meta-analysis to assess the comparative efficacy of lasmiditan, rimegepant and ubrogepant in triptan-insufficient responders. Method: We searched PubMed, Embase, CENTRAL, and EBSCO Open Dissertations up to May 2024. We included randomized controlled trials (RCTs) that compared novel abortive treatments, including lasmiditan, rimegepant, and ubrogepant, in migraine patients who self-reported insufficient response to triptans. Outcomes are represented using relative risks with corresponding 95% confidence intervals (CI). The surface under the cumulative ranking curve (SUCRA) was used to rank each medication. Results: A total of five phase 3 RCTs involving 3,004 patients were included in the analysis. All three agents were significantly superior to placebo for two-hour pain freedom (RR = 1.93, 95% CI [1.52, 2.46]), freedom from the most bothersome symptoms at two hours (RR = 1.55, 95% CI [1.37, 1.75]), and pain relief at two hours (RR = 1.46, 95% CI [1.35, 1.58]). No statistically significant differences in efficacy outcomes were observed among the three agents. However, lasmiditan 200 mg had the highest cumulative probability for two-hour pain freedom and relief (SUCRA 0.9, 0.8, respective), while rimegepant led in relieving the most bothersome symptoms (SUCRA 0.7). Conclusion: Lasmiditan, rimegepant, and ubrogepant are effective for acute treatment of migraine in triptan-insufficient responders, with high-dose lasmiditan showing the highest efficacy for pain control. [ABSTRACT FROM AUTHOR]

Tegaserod (1-{[(5-methoxy-1H-indol-3-yl)methyliden]amino}-3-pentylguanidine) is a potent agonist at human recombinant 5-HT4 serotonin receptors. Consequently, tegaserod is utilized in the treatment of bowel diseases. The objective of this study was to test the hypothesis that tegaserod stimulates human cardiac atrial 5-HT4-receptors via cyclic adenosine monophosphate (cAMP)-dependent pathways. Tegaserod exerted positive inotropic effects (PIEs) and positive chronotropic effects (PCEs) in isolated left and right atrial preparations, respectively, from mice with cardiac-specific overexpression of the human 5-HT4 serotonin receptor (5-HT4-TG) in a concentration- and time-dependent manner. However, no effect was observed in the hearts of littermates of wild-type mice (WT). Western blot analysis revealed that the expression of 5-HT4 receptors was significantly higher in 5-HT4-TG mice compared to WT mice. The specificity of the signal for the 5-HT4 receptor was confirmed by the absence of the signal in the hearts of 5-HT4 receptor knockout mice. Furthermore, tegaserod increased the force of contraction (at concentrations as low as 10 nM), reduced the time of tension relaxation, and increased the rate of tension development in isolated electrically stimulated (at a rate of 60 beats per minute) human right atrial preparations (HAPs, obtained during open-heart surgery) when administered alone. The potency and efficacy of tegaserod to raise the force of contraction were enhanced in the presence of cilostamide, a phosphodiesterase III inhibitor. The positive inotropic effect of tegaserod in HAPs was found to be attenuated by the 5-HT4 serotonin receptor antagonist GR 125487 (0.1 µM). The efficacy of tegaserod (10 µM) in raising the force of contraction in HAPs was less pronounced than that of serotonin (10 µM) or isoprenaline (1 µM). Tegaserod shifted the concentration–response curve of the force of contraction to serotonin to the right in HAPs, indicating that it is a partial agonist at 5-HT4 serotonin receptors in this model. We propose that the mechanism of action of tegaserod in HAPs involves cAMP-dependent phosphorylation of cardiac regulatory proteins. [ABSTRACT FROM AUTHOR]

The article "In memoriam Lambertus (\"Bert\") A. Peletier 29 March 1937–16 December 2023: Furthering quantitative pharmacology through applied mathematics" published in CPT: Pharmacometrics & Systems Pharmacology honors the life and contributions of Lambertus (Bert) A. Peletier, a respected mathematician known for his work in partial differential equations. Peletier's career spanned from academia to mathematical pharmacology, where he applied advanced mathematical concepts to PK–PD modeling, impacting drug discovery and development. His mentorship and teaching style emphasized the importance of mathematical rigor and cross-disciplinary collaboration, leaving a lasting legacy in the scientific community. [Extracted from the article]

Chronic orofacial pain disorders are common debilitating conditions, affecting the trigeminal system. Its underlying pathophysiological mechanisms are still unclear and the therapy is often unsatisfactory, therefore, preclinical models are crucial to identify the key mediators and novel treatment options. Complete Freund's adjuvant (CFA)-induced orofacial inflammatory allodynia/hyperalgesia is commonly used in rodents, but it has not been validated with currently used drugs. Here we tested the effects of the adjuvant analgesic/antiepileptic voltagegated Na+ channel blocker complex mechanism of action topiramate in comparison with the gold standard antimigraine serotonin 5-HT1B/D receptor agonist sumatriptan in this model. CFA was injected subcutaneously into the right whisker pad of male Sprague-Dawley rats (250-300 g), then mechanonociceptive threshold values were investigated with von Frey filaments (3, 5, and 7 days after CFA injection). Effects of topiramate (30 mg/kg per os) and sumatriptan (1 mg/kg subcutaneous) on the adjuvantinduced chronic inflammatory orofacial allodynia were investigated 60, 120, and 180 min after the treatments each day. To determine the optimal concentration for drug effect analysis, we tested the effects of two different CFA-concentrations (1 and 0.5 mg/mL) on mechanonociceptive thresholds. Both concentrations of CFA induced a chronic orofacial allodynia in 60% of all rats. Although, higher CFA concentration induced greater allodynia, much more stable threshold reduction was observed with the lower CFA concentration: on day 3 the thresholds decreased from 18.30 g to approximately 11 g (low) and 5 g (high), respectively, however a slight increase was observed in the case of higher CFA concentration (on days 5, 7, and 11). In all investigation days, topiramate showed significant anti-allodynic effect comparing the pre and post drug dose and comparing the vehicle treated to the drug treated groups. Sumatriptan also caused a significant threshold increase compared to pre dose thresholds (day 3) and also showed a slight anti-allodynic effect compared to the vehicle-treated group (day 3 and 5). In the present study CFA-induced chronic orofacial allodynia was reversed by topiramate in rats validating the model with the adjuvant analgesic. Other than establishing a validated orofacial pain-related syndrome model in rats, new ways are opened for the repurposing of topiramate. [ABSTRACT FROM AUTHOR]

Background and objectives: About a quarter of migraine cases among women have menstrual migraine (MM), which is usually more severe, longer lasting, and less responsive to treatment than typical migraine. Randomized controlled trials (RCTs) have evaluated the efficacy of several medication in the acute and preventive treatment of MM; this meta-analysis compared the effectiveness of these treatments. Methods: We conducted systematic searches in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases. The primary outcomes of acute treatment trials were pain relief at 2 and 24 h after treatment compared with placebo or another treatment. The three endpoints we checked for studying MM prevention were: no recurrence of headaches each month, a 50% reduction in monthly migraine days from baseline, and a decrease in the mean number of headache days per month. Results: Out of 342 studies, 26 RCTs met the criteria. Triptans, combined with or without other analgesics, were superior to placebo in providing pain relief in the acute treatment and prevention of MM. Among the treatments, sumatriptan and lasmiditan demonstrated superior pain relief at 2 h (OR: 4.62) and 24 h (OR: 4.81). Frovatriptan exhibited effectiveness in preventing headache recurrence, whereas galcanezumab and erenumab displayed significant preventive benefits in reducing headache days per month. Conclusion: Sumatriptan and lasmiditan are effective first-line treatments for acute MM. For prevention, frovatriptan may be the more effective of triptans. Compared with triptans, CGRP monoclonal antibodies, here including erenumab and galcanezumab, are more effective in reducing headache days, and therefore, in preventing MM. [ABSTRACT FROM AUTHOR]

Introduction and purpose Cariprazine is an atypical antipsychotic drug approved for the treatment of schizophrenia, as well as manic and mixed episodes associated with bipolar disorder. It functions as a dopamine multifunctional agent, a partial agonist at dopamine and serotonin receptors. Unlike the majority of antipsychotics, which primarily target positive symptoms through dopaminergic antagonism, often neglecting negative, cognitive, and affective symptoms, the unique cariprazine's pharmacological profile, particularly potent blockade of D3 dopamine receptors, suggests the potential for numerous clinical applications. The aim of this study is to present current knowledge of cariprazine, focusing particularly on its mechanism of action, potential applications, adverse effects, and pharmacokinetic properties that could impact its clinical use. Methods and materials A review of the literature available in the PubMed database was performed using the key words: cariprazine; atypical antipsychotic drug; antipsychotic medication; schizophrenia treatment; bipolar disorder treatment; mania treatment; depression treatment, dopamine agonist. Conclusions Cariprazine demonstrates a unique pharmacological profile, offering potential benefits in managing a wide range of psychiatric disorders, including schizophrenia, bipolar disorder (mania, depression, mixed episodes), unipolar depression, and co-occurring substance use disorders. Clinical studies have shown efficacy in reducing symptoms and improving negative and cognitive function, with a favorable metabolic profile, minimal impact on cardiovascular system, and generally mild adverse effect profile. However, further research is necessary to explore its full therapeutic potential and optimize its clinical use in diverse patient populations. [ABSTRACT FROM AUTHOR]

Zacopride (4-amino-5-chloro-2-methoxy-N-(quinuclidin-3-yl)-benzamide) is a potent agonist in human 5-HT4 serotonin receptors in vitro and in the gastrointestinal tract. Zacopride was studied as an antiemetic drug and was intended to treat gastric diseases. Zacopride has been speculated to be useful as an antiarrhythmic agent in the human ventricle by inhibiting cardiac potassium channels. It is unknown whether zacopride is an agonist in human cardiac 5-HT4 serotonin receptors. We tested the hypothesis that zacopride stimulates human cardiac atrial 5-HT4 serotonin receptors. Zacopride increased the force of contraction and beating rate in isolated atrial preparations from mice with cardiac-specific overexpression of human 5-HT4 serotonin receptors (5-HT4-TG). However, it was inactive in wild-type mouse hearts (WT). Zacopride was as effective as serotonin in raising the force of contraction and beating rate in atrial preparations of 5-HT4-TG. Zacopride raised the force of contraction in human right atrial preparations (HAP) in the absence and presence of the phosphodiesterase III inhibitor cilostamide (1 µM). The positive inotropic effect of zacopride in HAP was attenuated by either 10 µM tropisetron or 1 µM GR125487, both of which are antagonists at 5-HT4 serotonin receptors. These data suggest that zacopride is also an agonist at 5-HT4 serotonin receptors in the human atrium. [ABSTRACT FROM AUTHOR]

Background Purpose Cyclic vomiting syndrome (CVS) is identified as one of the “episodic syndromes that may be associated with migraine,” along with benign paroxysmal torticollis, benign paroxysmal vertigo, and abdominal migraine. It has been proposed that CVS and migraine may share pathophysiologic mechanisms of hypothalamic activation and altered dopaminergic signaling, and impaired sensorimotor intrinsic connectivity. The past decade has brought groundbreaking advances in the treatment of migraine and other headache disorders. While many of these therapies have yet to be studied in episodic syndromes associated with migraine including CVS and abdominal migraine, the potential shared pathophysiology among these conditions suggests that use of migraine‐specific treatments may have a beneficial role even in those for whom headache is not the primary symptom.This manuscript highlights newer therapies in migraine. Calcitonin gene‐related peptide (CGRP) and its relation to migraine pathophysiology and the therapies that target the CGRP pathway, as well as a 5HT1F receptor agonist and neuromodulation devices used to treat migraine are briefly discussed as they may potentially prove to be useful in the future treatment of CVS. [ABSTRACT FROM AUTHOR]

Cannabis Use Disorder (CUD) has no FDA-approved treatment. Serotonin-2c (5HT2c) agonists have preclinical and human laboratory evidence for their potential efficacy for CUD. We assessed the tolerability and effects of lorcaserin (5HT2c agonist) on CUD. In a 10-week, open label, uncontrolled trial, the tolerability of lorcaserin was tested in outpatients with CUD. Adverse events (AE) were assessed weekly. Cannabis use was assessed twice weekly by the Timeline follow-back and quantitative urine metabolites. Seventeen participants enrolled, and 14 received medication. Participants' average age was 35 years; majority were male (N = 12). The medication was well tolerated in males. There were no serious adverse events (SAE). The most common AE's were headache/migraine (N = 4, all females), anorexia (N = 3), and irritability (N = 2). Participants decreased their frequency of cannabis use significantly (p < 0.001), adjusted for baseline use. By the end of the trial, participants decreased by 1.76 (SE = 0.47) cannabis using days/week. Average daily amount of cannabis and urine THC metabolite levels did not change significantly. Lorcaserin was well tolerated in males but not females, suggesting possible sex differences. Future trials of other 5HT2c agonists (lorcaserin was withdrawn at the request of the FDA) should consider longer dose titration phases. [ABSTRACT FROM AUTHOR]

Aim: Diet, including foods and beverages, affects migraine. Conversely, the influence of migraine therapies on dietary habits is largely unknown. This study aimed at investigating the effects of triptan intake on foods and drinks consumed by adults with migraine with and/or without aura. Methods: An exploratory questionnaire‐based survey took place online between November 2022 and June 2023. Participants were recruited through advertisements shared on social media accounts (e.g., Facebook and Instagram) and seasonal newsletters of three Danish patient associations. In addition, posters and flyers in headache and pain centers at Danish hospitals and private neurological, pain, and physiotherapeutic clinics were utilized. Results: A total of 314 adults with migraine with and/or without aura completed the survey. Among the respondents, 236 individuals (75.2%) regularly used triptans to treat their migraines. Compared with non‐triptan users, individuals using triptans were characterized by significantly more foods and/or drinks triggering migraine (74.2% vs. 56.4%, p = 0.005). Alcoholic beverages and most specifically red wine were overreported as migraine triggers by triptan users (48.3% vs. 21.8%, p < 0.001). In the week preceding the survey, red wine was significantly less consumed by triptan users than non‐triptan users (92.4% vs. 76.9%, p < 0.001). Conclusions: Patients who regularly consume triptans report red wine most frequently as a migraine trigger. Triptan users are characterized by a lower consumption of red wine than non‐triptan users, suggesting that a regular triptan intake may promote an increased sensitivity to red wine‐induced migraine. [ABSTRACT FROM AUTHOR]

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13‐17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure–response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13‐17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model‐based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13‐17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long‐term open‐label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson's disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care. [ABSTRACT FROM AUTHOR]

Background: Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. Methods: A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. Results: Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5 µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. Conclusion: This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the serotonin receptors, to produce analgesia. [ABSTRACT FROM AUTHOR]

Psychosis in patients with dementia‑related disorders has long been a challenging issue to be tackled by the medical fraternity. Although atypical antipsychotics (AP) are in use for the same reason, there has always been a question regarding their safety and tolerability in this group of patients. Pimavanserin, a serotonin receptor inverse agonist or antagonist, is the only drug that is Food and Drug Administration‑licensed to be used for the treatment of Parkinson’s disease psychosis. This systematic review, which was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta‑analyses 2020, had the objective of examining the effects of pimavanserin in patients with dementia‑related psychosis (DRP). Among the publications (January 1, 2013–July 12, 2023) we gathered and examined were case–control and cohort studies, systematic reviews, meta‑analyses, clinical trials, literature reviews, and randomized and nonrandomized control trials. The databases used to construct this list of publications were PubMed, Cochrane Library, and Google Scholar. These three databases yielded 157 reports in total once the relevant filters were applied. They were then further screened and put through quality evaluation processes, which led to the final nine papers that were included in this systematic review. We concluded from our review that pimavanserin proves to be a promising alternative for the treatment of DRP, showing significant improvements and fewer side effects compared to other atypical AP. [ABSTRACT FROM AUTHOR]

Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both. [ABSTRACT FROM AUTHOR]

Background: The objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting. Methods: This was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator's discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses. Results: In total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change – Migraine Headache Condition (56.5% vs 33.4%–52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%–83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency. Conclusions: Based on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs. Trial registration: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018–001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018. [ABSTRACT FROM AUTHOR]

Introduction and purpose Migraine is a common disease mostly affecting women. It has a huge influence on patients' life strongly decreasing its quality by cause of repetitive headache episodes and often comes with unpleasant and burdensome symptoms like photophobia, nausea or vomiting. This article focuses on migraine treatment, especially on new drugs. Primary drugs used in migraine attacks are non-steroid anti-inflammatory drugs (NSAI) and triptans. Because of their side effects and impact on internal organs, these substances are often contraindicated or inefficient. The same applies to triptans, which cannot be used by patients with cardiovascular diseases. Due to the need of a new migraine treatment path development, new remedies have been found, bringing hope for patients who could not use prior options. They are divided into two groups: ditans (lasmiditan), which are 5-HT1F serotonin receptor agonists and gepants (ubrogepant, rimegepant, atogepant and zavegepant), which are CGRP receptor antagonists. A summary of the current state of knowledge is intended to increase the awareness of physicians and patients when selecting the appropriate treatment. Material and methods The following review was based on articles obtained from the PubMed and Google Scholar databases. Key search terms included migraine, ditans, gepants, migraine treatment. Conclusions Drugs described in this study clearly show the new pathway of migraine treatment and prevention. They are safer and show more benefits than substances currently used. They can also be used in wider range of patients with conditions marked as contraindications for current schemes. However more research is still needed to fully describe their characteristics. [ABSTRACT FROM AUTHOR]

Background: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene–related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. Methods: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). Results: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. Conclusions: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. Trial registration: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309). [ABSTRACT FROM AUTHOR]

Psilocybin, an innate compound produced by mushrooms belonging to the Psilocybe genus, is primarily known for its agonistic effects on the serotonin 5-HT2A receptor. This receptor's functioning is involved in many neurological processes. In the context of this research, our primary aim was to comprehensively investigate the influence of psilocybin as a serotonin receptor agonist on the intricate cascade of events involved in THP-1 macrophages stimulated by lipopolysaccharide (LPS). THP-1 monocyte cells were subjected to differentiation into macrophages through a controlled incubation with phorbol 12-myristate 13-acetate (PMA). The next step involved the induction of an inflammatory response by exposing THP-1 macrophages to 500 ng/mL LPS for 4 h. Subsequently, we triggered the activation of the second phase of the NLRP3 inflammasome by introducing adenosine triphosphate (ATP) immediately following LPS stimulation. Our findings have revealed a dose-dependent inverse correlation between psilocybin exposure and the production of LPS-induced proinflammatory cytokines and proteins. Our work indicates that psilocybin likely mediates these responses by influencing key signaling pathways, including NF-κB, IL-6/TYK2/STAT3, and TYK2/STAT1. [ABSTRACT FROM AUTHOR]

1-(3-(2-(Dimethylammonio)ethyl)-1H-indol-5-yl)-N-methylmethanesulfonamide succinate (sumatriptan succinate, HSum+·HSucc−) is a serotonin receptor agonist used to treat migraines. By the recrystallization of this substance from ethanol, its hemi(ethanol solvate), HSum+·HSucc−·0.5EtOH, was obtained. The solid was characterized by X-ray diffraction and FT-IR spectroscopy. In HSum+·HSucc−·0.5EtOH, solvent molecules link succinate anions into infinite O–H...O bonded chains, which are further connected by N–H...O interactions with cations into H-bonded layers. [ABSTRACT FROM AUTHOR]

Cerebral ischemia and reperfusion are related to various situations like injuries after various traumas, oxidative stress, increased calcium ion, capillary hypoperfusion, microvascular hyperpermeability, leukocyte infiltration, and blood–brain barrier disruption. An antidepressant Agomelatine which is a melatonin receptor (MT1/MT2) agonist and serotonin receptor (5‐HT2C) antagonist has been reported by studies to have antioxidant and anti‐inflammatory effects. In our study, we aimed to detect the effects of citrate‐coated silver nanoparticle‐loaded agomelatine application on neurodegeneration, endoplasmic reticulum stress, autophagic and apoptotic cell death, inflammation, and P2X7R expression in the cerebral ischemia–reperfusion model to facilitate the passage of blood–brain barrier. Forty two Sprague–Dawley rats in total were divided into six equal groups (n:7) and applications were performed. Acute cerebral injury in the ischemia–reperfusion model was created 2 h after internal carotid artery ligation in rats and then at the 2nd hour of reperfusion citrate‐coated silver nanoparticles loaded with Agomelatine were applied. Twenty four hours later, neurologic analysis on animals in experimental groups was performed, animals were decapitated and GSH, GPx, SOD, CAT, MDA, IL‐1β, and TNF‐α parameters were examined after taking blood and the cerebral tissue samples. As a result, it was determined that ischemia–reperfusion caused endoplasmic reticulum stress in the cerebral tissues and thus caused cellular injury. [ABSTRACT FROM AUTHOR]

A proportion of farmed salmon in seawater show a behaviorally inhibited, growth stunted profile known as a depression-like state (DLS). These DLS fish are characterized by chronically elevated serotonergic signaling and blood plasma cortisol levels and the inability to react further to acute stress, which is suggestive of chronic stress. In this study, we characterize the neuroendocrine profile of growth stunted freshwater parr and confirm that they show a DLS-like neuroendocrine profile with a blunted cortisol response and no serotonergic increase in response to acute stress. Furthermore, we attempted to reverse this DLS-like profile through pharmacological manipulation of the serotonin (5-HT) system with buspirone, an anxiolytic medication that acts as a serotonin receptor agonist (i.e., decreases serotonergic signaling). We found that while buspirone decreases anxiolytic-type behavior in healthy fish, no quantifiable behavioral change was found in DLS-like fish. However, there was a physiological effect of diminished basal serotonergic signaling. This suggests that at the physiological level, buspirone appears to reverse the neuroendocrine DLS profile. With a deeper understanding of what causes DLS profiles and growth stunting in juvenile fish, steps can be taken in terms of husbandry to prevent repeated stressors and the formation of the DLS profile, potentially reducing losses in aquaculture due to chronic stress. [ABSTRACT FROM AUTHOR]

Rationale: Several lines of evidence indicate that the neurosteroid dehydroepiandrosterone (DHEA) is involved in anxiety. BNN27 is a new DHEA derivative lacking steroidogenic effects. The beneficial effects exerted by BNN27 in preclinical models of schizophrenia and memory disorders have been recently reported. Objectives: The present study was designed to investigate the effects of this DHEA novel analog on anxiety-like behavior in rats. Methods: To this end, the light/dark box, the open field, the contextual fear conditioning, and the excessive self-grooming induced by the serotonin 5-HT2c receptor agonist mCPP tests were utilized. Results: Animals treated acutely with BNN27 (1, 3, and 6 mg/kg) dose dependently spent more time in the bright compartment of the light/dark box and in the central zone of the open field with respect to their vehicle-treated cohorts. Further, BNN27 reduced freezing behavior and weakened the mCPP-induced excessive self-grooming. Conclusions: Our data indicate that BNN27 is a highly potent anxiolytic agent, as in all studied paradigms it showed anxiolytic-like effects in male rats. [ABSTRACT FROM AUTHOR]

As serotonergic agonists, classical psychedelics, such as psilocybin, exert effects on the periphery as well as the brain. Disturbances in gut–brain axis function are reported in individuals with major depressive disorder, anxiety, substance use disorder, and anorexia nervosa, all conditions in which psilocybin is being trialled clinically. Activation of serotonin receptors in the gut by psilocybin could influence cortical neuroplasticity and mental health outcomes via direct stimulation of the vagus nerve. Indirect actions of psilocybin on vagus nerve stimulation could plausibly occur via alterations to the gut microbiome or immune system. The interactions between psilocybin, vagal nerve activity, and the gut microbiome can be rapidly disentangled using animal models to tailor the clinical application of psychedelic therapy to individuals most likely to respond with positive outcomes. The psychedelic compound psilocybin has recently emerged as a therapeutic intervention for various mental health conditions. Psilocybin is a potent agonist of serotonin (5-HT) receptors (5-HTRs), which are expressed in the brain and throughout peripheral tissues, with particularly high expression in the gastrointestinal (GI) tract. However, no studies have investigated the possibility that peripheral actions of psilocybin may contribute to improvements in mental health outcomes. This is despite strong evidence for disturbed gut–brain signalling in conditions in which psilocybin is being tested clinically. In this Opinion, we highlight the likely actions of psychedelics in the gut and provide initial support for the premise that peripheral actions may be involved in rapid and long-term therapeutic effects. A greater understanding of all sites and modes of action will guide more targeted approaches to drug development. [ABSTRACT FROM AUTHOR]

The role of serotonin 5-HT5A receptors in the modulation of miniature inhibitory synaptic activity was studied using intracellular recording of miniature glycinergic inhibitory postsynaptic potentials (glymIPSPs) in the lumbar motoneurons of the isolated spinal cord of the frog Rana ridibunda. In a medium containing TTx, CNQX, D-AP5, bicuculline, application of the serotonin receptor agonist 5-CT (10 µM) with high affinity for 5-HT5A led to a suppression of frequency by 86%, as well as the disappearance of high-amplitude glymIPSPs (200–500 µV) at preservation of rare potentials with an amplitude of about 100 µV. This effect indicates the possibility of pre- and postsynaptic action of 5-CT at such a concentration, not limited to its effect only on 5-HT5A receptors. The addition of methysergide, a blocker of 5-HT1,2 receptors, to the medium reduced the average frequency of glymIPSPs by 67%, the frequency of high-amplitude events by 5 times and their average amplitude by 20%, which may indicate the participation of 5-HT5A receptors in pre- and postsynaptic modulation in glymIPSPs of motoneurons. Application of 1 µM 5-CT led to a decrease in the frequency of glymIPSPs by 49% without a noticeable change in the amplitude of glymIPSPs, and the subsequent introduction of SB-699551, a selective antagonist of 5-HT5A receptors, into the solution increased the frequency of events by 41%, which confirms the involvement of 5-HT5A receptors in presynaptic modulation of glymIPSPs. Immunofluorescence study showed that supra- and intraspinal 5-HT+ ir neurons produce abundant branching in the lumbar region with the possibility of forming axosomatic contacts with labeled motoneurons and axodendritic contacts on the proximal and distal portions of their dendrites. It is also possible to form contacts in the perimedullary plexus, penetrated by the distal dendrites of motoneurons and astrocytic processes. This represents the structural basis for post-, pre- and extrasynaptic modulation of motoneuron activity by serotonin. The possibility of postsynaptic modulation of motoneuron activity through 5-HT5A receptors is confirmed by the point-like fluorescence of the 5-HT5ARlike+ signal on the dendrites and bodies of labeled motoneurons, which is present in the neuropil but absent in the perimedullary plexus. Double labeling with antibodies to the 5-HT5A receptor and the Ca2+-binding protein, parvalbumin, revealed 5-HT5ARlike+ localization in the myelin sheath of dorsal and ventromedial funiculi fibers. In preparations after long-term stimulation of the ventral roots through suction electrodes when labeling motor neurons with biocytin, a bright 5-HT5ARlike+ signal was detected in the myelin of motor axons, dorsal root fibers entering the brain in the region of the dorsal horn and individual fibers of the ventromedial funiculus. The participation of extrasynaptic 5-HT5A receptors in the functioning of feedback circuits of lumbar motoneuron activity, with the possible participation of glial elements in these circuits, is discussed. [ABSTRACT FROM AUTHOR]

Lasmiditan is an in vitro inhibitor of P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) efflux transporters. We aimed to confirm predictions from physiologically based pharmacokinetic models of lasmiditan, and assess the safety and tolerability of rosuvastatin and dabigatran co‐administered with lasmiditan. In this open‐label, post‐marketing drug–drug interaction, phase 1 clinical trial, eligible participants were adults aged 21‐70 years with a body mass index of 18.5‐35.0 kg/m2. Part 1 (P‐gp, 150 mg dabigatran etexilate with 200 mg lasmiditan) and part 2 (BCRP, 10 mg rosuvastatin with 200 mg lasmiditan) employed similar designs: a single dose of probe substrate administered on day −2 with pharmacokinetic evaluation; 1‐week washout; lasmiditan administered on days 8 and 9 alone; lasmiditan co‐administered with a single dose of probe substrate on day 10, with pharmacokinetic evaluation of probe substrate and lasmiditan. Sixty‐six participants were included in part 1 and 30 participants were included in part 2. Following dabigatran co‐administration with lasmiditan, versus dabigatran alone, 90% confidence intervals for geometric least‐squares (LS) mean ratios of area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and maximum observed drug concentration (Cmax) were not contained within the non‐effect boundaries (0.80 to 1.25). Dabigatran AUC0–∞ increased by 25% and Cmax increased by 22%. The median time of maximum observed drug concentration (tmax) for dabigatran was 2.0 to 3.0 hours. Following rosuvastatin co‐administration with lasmiditan, versus rosuvastatin alone, 90%CIs for geometric LS mean ratios of AUC0–∞ and Cmax were contained within non‐effect boundaries (0.80‐1.25). Rosuvastatin AUC0–∞ increased by 15% and Cmax increased by 7%. The median tmax for rosuvastatin was 4.0 hours. Results suggest that lasmiditan has a weak effect on P‐gp substrates and no clinically relevant effect on BCRP substrates. [ABSTRACT FROM AUTHOR]

Background: Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects (3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. Methods: We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. Results: MSI measures were confounded by CGRP’s effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. Conclusions: These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine [ABSTRACT FROM AUTHOR]

Plain Language Summary: A suicidal patient with Short‐lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) whose excruciating condition did not respond to various treatments discovered that ayahuasca, a psychoactive concoction used by indigenous populations of South America, caused his attacks to cease entirely. Inhaled N,N‐dimethyltryptamine (DMT), the principal psychoactive component of ayahuasca, also caused symptoms to disappear temporarily, as did a strong dose of lysergic acid diethylamide (LSD). This case study supports the potential of serotonergic psychedelics for the treatment of SUNCT and related headache disorders. [ABSTRACT FROM AUTHOR]

Background and Objectives: The renewed interest in psychedelic research provides growing evidence of potentially unique effects on various aspects of reward processing systems. Using the Research Domain Criteria (RDoC) framework, as proposed by the National Institute of Mental Health, we aim to synthesize the existing literature concerning the impact of lysergic acid diethylamide (LSD) on the RDoC's Positive Valence Systems (PVS) domain, and to identify potential avenues for further research. Methods: Two LSD-related terms (lysergic acid diethylamide and LSD) and 13 PVS-related terms (reward, happiness, bliss, motivation, reinforcement learning, operant, conditioning, satisfaction, decision making, habit, valence, affect, mood) were used to search electronic databases such as PubMed, Scopus, PsychINFO, and Web of Science for relevant articles. A manual search of the reference list resulted in nine additional articles. After screening, articles and data were evaluated and included based on their relevance to the objective of investigating the effects of LSD on the PVS. Articles and data were excluded if they did not provide information about the PVS, were observational in nature, lacked comparators or reference groups, or were duplicates. A risk of bias assessment was performed using the National Toxicology Program's Office of Health Assessment and Translation (NTP OHAT) risk of bias (RoB) tool. Data from the included articles were collected and structured based on the RDoC bio-behavioral matrix, specifically focusing on the PVS domain and its three constituent constructs: reward responsiveness, reward learning, and reward valuation. Results: We reviewed 28 clinical studies with 477 participants. Lysergic acid diethylamide, assessed at self-report (23 studies), molecular (5 studies), circuit (4 studies), and paradigm (3 studies) levels, exhibited dose-dependent mood improvement (20 short-term and 3 long-term studies). The subjective and neural effects of LSD were linked to the 5-HT2A receptor (molecular). Animal studies (14 studies) suggested LSD could mildly reinforce conditioned place preference without aversion and reduce responsiveness to other rewards. Findings on reward learning were inconsistent but hinted at potential associative learning enhancements. Reward valuation measures indicated potential reductions in effort expenditure for other reinforcers. Conclusion: Our findings are consistent with our previous work, which indicated classical psychedelics, primarily serotonin 2A receptor agonists, enhanced reward responsiveness in healthy individuals and patient populations. Lysergic acid diethylamide exhibits a unique profile in the reward learning and valuation constructs. Using the RDoC-based framework, we identified areas for future research, enhancing our understanding of the impact of LSD on reward processing. However, applying RDoC to psychedelic research faces limitations due to diverse study designs that were not initially RDoC-oriented. Limitations include subjective outcome measure selection aligned with RDoC constructs and potential bias in synthesizing varied studies. Additionally, some human studies were open-label, introducing potential bias compared to randomized, blinded studies. [ABSTRACT FROM AUTHOR]

Agonists of dopamine D2 receptors (D2R), 5‐hydroxytryptamine (5‐HT, serotonin) receptors (5‐HTR) and ghrelin receptors (GHSR) activate neurons in the lumbosacral defecation centre, and act as 'colokinetics', leading to increased propulsive colonic motility, in vivo. In the present study, we investigated which neurons in the lumbosacral defecation centre express the receptors and whether dopamine, serotonin and ghrelin receptor agonists act on the same lumbosacral preganglionic neurons (PGNs). We used whole cell electrophysiology to record responses from neurons in the lumbosacral defecation centre, following colokinetic application, and investigated their expression profiles and the chemistries of their neural inputs. Fluorescence in situ hybridisation revealed Drd2, Ghsr and Htr2C transcripts were colocalised in lumbosacral PGNs of mice, and immunohistochemistry showed that these neurons have closely associated tyrosine hydroxylase and 5‐HT boutons. Previous studies showed that they do not receive ghrelin inputs. Whole cell electrophysiology in adult mice spinal cord revealed that dopamine, serotonin, α‐methylserotonin and capromorelin each caused inward, excitatory currents in overlapping populations of lumbosacral PGNs. Furthermore, dopamine caused increased frequency of both IPSCs and EPSCs in a cohort of D2R neurons. Tetrodotoxin blocked the IPSCs and EPSCs, revealing a post‐synaptic excitatory action of dopamine. In lumbosacral PGNs of postnatal day 7–14 rats, only dopamine's postsynaptic effects were observed. Furthermore, inward, excitatory currents evoked by dopamine were reduced by the GHSR antagonist, YIL781. We conclude that lumbosacral PGNs are the site where the action of endogenous ligands of D2R and 5‐HT2R converge, and that GHSR act as a cis‐modulator of D2R expressed by the same neurons. Key points: Dopamine, 5‐hydroxytryptamine (5‐HT, serotonin) and ghrelin (GHSR) receptor agonists increase colorectal motility and have been postulated to act at receptors on parasympathetic preganglionic neurons (PGNs) in the lumbosacral spinal cord.We aimed to determine which neurons in the lumbosacral spinal cord express dopamine, serotonin and GHSR receptors, their neural inputs, and whether agonists at these receptors excite them.We show that dopamine, serotonin and ghrelin receptor transcripts are contained in the same PGNs and that these neurons have closely associated tyrosine hydroxylase and serotonin boutons.Whole cell electrophysiology revealed that dopamine, serotonin and GHSR receptor agonists induce an inward excitatory current in overlapping populations of lumbosacral PGNs. Dopamine‐induced excitation was reversed by GHSR antagonism.The present study demonstrates that lumbosacral PGNs are the site at which actions of endogenous ligands of dopamine D2 receptors and 5‐HT type 2 receptors converge. Ghrelin receptors are functional, but their role appears to be as modulators of dopamine effects at D2 receptors. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the effects of prucalopride, a prokinetic agent that acts as a potent serotonin agonist of 5-HT4 receptors, on gastric emptying and small bowel transit and assess its impact on the absorption of metronidazole. Methods: Six healthy volunteers, three men and three women, aged between 20 and 27 years, with a body weight ranging from 50 to 80 kg, were enrolled in this study. The pharmacokinetics and gastrointestinal transit parameters were evaluated simultaneously through pharmacomagnetography assessment, combining alternating current biosusceptometry and blood analysis. Key findings: The results showed that prucalopride enhances gastric emptying and small bowel transit when administered orally and significantly impacts the rate of metronidazole absorption, leading to enhanced bioavailability and rapid therapeutic response. Conclusion: Pharmacomagnetography assessment allows simultaneous tracking of transit by images and is a valuable method for analysing drug absorption using multiple instruments. [ABSTRACT FROM AUTHOR]

The neurotransmitter serotonin (5-HT) is involved in several key processes in the central nervous system. But the great majority of serotonin is produced by intestinal enterochromaffin cells of the gastrointestinal (GI) tract and circulating blood platelets, which work independently of the central nervous system. The mediating pathway through which serotonin transmits its effects is the 5-HT receptor (5-HTR) superfamily, which consists of at least 14 members with extensive characterizations. Having been discovered as the final member of the 5-HTR family, 5-HT7 receptors have specific roles in the neurological, GI, circulatory, and immune systems. Due to their extensive distribution, these receptors' stimulation and repression are of importance during the therapy process, even if their exact mechanism of action in disease has not been fully understood. This review establishes the functions of 5-HT7Rs in systems and discusses how these receptors may be used therapeutically to treat peripheral diseases. [ABSTRACT FROM AUTHOR]

Linezolid (LZD) has a longstanding reported association with the onset of serotonin toxicity (ST), secondary to drug–drug interactions with serotoninergic agents. There have been no conclusive data supporting the incidence or contributing risk factors to date. The study evaluated the incidence of ST in patients treated with LZD and serotonergic agents concomitantly versus LZD alone. The secondary objectives included a comparison of ST incidence in patients treated with one serotonergic agent + LZD versus two or more serotonergic agents + LZD. The studies used for this meta-analysis were retrieved from PubMed, Scopus, and Google Scholar. All studies including a comparison between LZD alone and LZD + a serotonergic agent published between 1 January 2000 and 1 October 2023 and meeting the quality standards were considered for inclusion. Fourteen studies were identified, with five meeting all inclusion and exclusion criteria with no significant heterogeneity. For the analysis of LZD monotherapy vs. SA combination therapy, four studies with 6025 patients total were analyzed and yielded an odds ratio of 1.78 (CI [1.04, 3.02]; I2 = 49%; GRADE certainty: low). Four studies and 2501 patients were included in the analysis of one versus more than one SA with an odds ratio of 5.18 (CI [1.05, 25.49]; I2 = 44.87; GRADE certainty: moderate). The Newcastle–Ottawa score, visual inspection of the funnel plot, and Egger's statistic were used to evaluate quality and heterogeneity. The Peto method was used to calculate the summary odds ratios. All analyses were performed using Comprehensive Meta-Analysis version 3.0 and R, while GRADE was used to evaluate the quality of the final recommendation. The number of concomitant serotonergic agents may play a role in the development of serotonin toxicity in patients prescribed linezolid. In patients requiring linezolid therapy and serotonergic agents, risk versus benefit analysis should pay attention to the number of interacting drugs. [ABSTRACT FROM AUTHOR]

Aim: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B‐receptor agonist) would alter glucose homeostasis in humans. Materials and Methods: We conducted a two‐visit random‐order double‐blinded placebo‐controlled cross‐over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60‐min intravenous glucose tolerance test, followed by a 120‐min hyperinsulinaemic euglycaemic clamp. Results: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0‐60 min 316 (268‐333) vs. 251 (197‐319) min/mmol/L p =.047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0‐10 min 1626 (1103‐2733) vs. 2336 (1702‐3269) min/pmol/L, p =.005], reduced insulin sensitivity [M/I‐value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p =.010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p =.027]. Conclusions: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness. [ABSTRACT FROM AUTHOR]

The article focuses on the potential of prucalopride, a serotonin 4 receptor agonist, to reduce depression risk, with topics including a cohort study comparing prucalopride to other anti-constipation medications and lower incidences of neuropsychiatric disorders among prucalopride users.

The article discusses the role of prokinetics in managing ineffective esophageal motility (IEM) and calls for a broader consideration of these drugs in treatment. While the effectiveness of prokinetics in improving esophageal symptoms is still debated, some studies suggest potential benefits, especially in patients with concomitant delayed gastric emptying. New prokinetic agents are being explored, with ongoing trials like Naronapride offering hope for new therapies. The authors advocate for a more detailed discussion on prokinetics as an alternative or adjunct to conservative care for managing this challenging condition. [Extracted from the article]

A call for papers on psychedelic-assisted treatment for substance use disorders is presented.

Background Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront. Methods We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein–coupled inward rectifier potassium channel activation assays. Results Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2. Conclusions Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds. [ABSTRACT FROM AUTHOR]

Background: New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. To uncover novel potentiators of T cell anti-tumor immunity, we carried out an ex vivo pharmacological screen and identified 5-Nonyloxytryptamine (5-NL), a serotonin agonist, as increasing the ability of T cells to target tumor cells. Methods: The pharmacological screen utilized lymphocytic choriomeningitis virus (LCMV)-primed splenic T cells and melanoma B16.F10 cells expressing the LCMV gp33 CTL epitope. In vivo tumor growth in C57BL/6 J and NSG mice, in vivo antibody depletion, flow cytometry, immunoblot, CRISPR/Cas9 knockout, histological and RNA-Seq analyses were used to decipher 5-NL's immunomodulatory effects in vitro and in vivo. Results: 5-NL delayed tumor growth in vivo and the phenotype was dependent on the hosts' immune system, specifically CD8+ T cells. 5-NL's pro-immune effects were not directly consequential to T cells. Rather, 5-NL upregulated antigen presenting machinery in melanoma and other tumor cells in vitro and in vivo without increasing PD-L1 expression. Mechanistic studies indicated that 5-NL's induced MHC-I expression was inhibited by pharmacologically preventing cAMP Response Element-Binding Protein (CREB) phosphorylation. Importantly, 5-NL combined with anti-PD1 therapy showed significant improvement when compared to single anti-PD-1 treatment. Conclusions: This study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common form of senile dementia, is poised to place an even greater societal and healthcare burden as the population ages. With few treatment options for the symptomatic relief of the disease and its unknown etiopathology, more research into AD is urgently needed. Psychedelic drugs target AD-related psychological pathology and symptoms such as depression. Using microdosing, psychedelic drugs may prove to help combat this devastating disease by eliciting psychiatric benefits via acting through various mechanisms of action such as serotonin and dopamine pathways. Herein, we review the studied benefits of a few psychedelic compounds that may show promise in treating AD and attenuating its related depressive symptoms. We used the listed keywords to search through PubMed for relevant preclinical, clinical research, and review articles. The putative mechanism of action (MOA) for psychedelics is that they act mainly as serotonin receptor agonists and induce potential beneficial effects for treating AD and related depression. [ABSTRACT FROM AUTHOR]

Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans — a group of selective serotonin 5-HT1F receptor agonists — has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency. Ditans are a recently developed drug class for the treatment of acute migraine. In this Review, the authors provide an overview of ditan development, from the initial rationale to the clinical studies that led to the recent FDA approval of the first ditan. Key points: Various animal studies have shown that selective agonists for the serotonin 5-HT1F receptor can reduce signals from an activated trigeminovascular system, thereby highlighting the receptor as an attractive target for symptomatic treatment of migraine. Long-term clinical studies involving two ditans — a group of 5-HT1F agonists — have provided class I evidence that lasmiditan, the first ditan, is both effective and safe in the symptomatic treatment of migraine. The 5-HT1F receptor is expressed by cells within the brain parenchyma, as well as by the trigeminal neurons, but not in vascular smooth muscle, suggesting that ditans act through neuropeptide release leading to acute headache relief, rather than via potential vasoactive properties, such as vasodilatation. Dizziness is the most common adverse event of lasmiditan; thus people should not drive for 8 h after taking lasmiditan. Development of novel ditans that do not cross the blood–brain barrier is expected to result in better tolerability and improved clinical use. [ABSTRACT FROM AUTHOR]

Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system areas and networks. A growing increase in the understanding of migraine pathophysiology in recent years has facilitated translation of that knowledge into novel treatments, which are currently becoming available to patients in many parts of the world and are substantially changing the clinical approach to the disease. In the first part of this review, we will provide an up to date overview of migraine pathophysiology by analyzing the anatomy and function of the main regions involved in the disease, focusing on how these give rise to the plethora of symptoms characterizing the attacks and overall disease. The second part of the paper will discuss the novel therapeutic agents that have emerged for the treatment of migraine, including molecules targeting calcitonin gene-related peptide (gepants and monoclonal antibodies), serotonin 5-HT1F receptor agonists (ditans) and non-invasive neuromodulation, as well as providing a brief overview of new evidence for classic migraine treatments. [ABSTRACT FROM AUTHOR]

A primary in vitro analysis of the anticholinesterase properties of substituted 1,3-dihydro-2-oxo-1H-benzimidazol-2-ones was performed along with in silico calculation of their oral toxicity. These compounds are analogs of BIMU-8, a well-known agonist of serotonin 5-HT4 receptors, and are supposed to combine the functions of cholinesterase inhibitors and serotonin receptor agonists. Biochemical analysis showed the ability of the obtained chemicals to inhibit acetyl- and butyrylcholinesterase. A compound with minimal toxicity, high inhibitory ability against butyrylcholinesterase, and low inhibitory ability against acetylcholinesterase has been identified, which is of greatest interest for further experimental development. [ABSTRACT FROM AUTHOR]

Although some clusters could not be mapped back to any mouse counterpart (H4 and H12 clusters), others showed resemblance to mouse (H1, H2, H5 clusters corresponded to mouse PEP1 C-polymodal subtypes; H8 to mouse TrpM8 SP high sp cold-sensing neurons; H9 to mouse PEP3; H10 to mouse NP1; H11 to mouse NP3; H13 to mouse A -LTMRs; H14 to mouse A -LTMRs; H15 to mouse proprioceptors; and C-LTMRs were not found), although some markers and inconsistencies were observed in the mouse-human comparison. Therefore, the molecular correlates between human neurons as identified by spatial transcriptomics and mouse or NHP neurons have not been extensively analyzed.[128] Nguyen et al.[90] identified 15 clusters based on snRNA-seq of human neurons (predicted neuron types, H1-H15) and identified mouse-human cell type counterparts based on some variably expressed genes and co-clustering. Low-threshold cold-sensitive fibers are largely unimodal consistent with the TrpM8 SP high sp neurons, while high-threshold cold nociceptors also respond to noxious heat and mechanical stimuli.[76] Among C-fiber neurons, the TrpM8 SP high sp neurons are the only nociceptors not expressing Scn10a (Na SB v sb 1.8). NP1, C-mechanopruriceptor neurons The nonpeptidergic NP1-type neurons are of small diameter, express Mrgprd in both mouse and NHP, and mostly innervate the superficial layer of the epidermis in the glabrous and hairy skin of the mouse.[156] They are polymodal C fibers representing about 25% to 32% of DRG neurons and are involved in pruriception and threshold detection to light punctate mechanical stimuli (von Frey). [Extracted from the article]

Agomelatine (AGM) is one of the latest atypical antidepressants, prescribed exclusively for the treatment of depression in adults. AGM belongs to the pharmaceutical class of melatonin agonist and selective serotonin antagonist ("MASS"), as it acts both as a selective agonist of melatonin receptors MT1 and MT2, and as a selective antagonist of 5-HT2C/5-HT2B receptors. AGM is involved in the resynchronization of interrupted circadian rhythms, with beneficial effects on sleep patterns, while antagonism on serotonin receptors increases the availability of norepinephrine and dopamine in the prefrontal cortex, with an antidepressant and nootropic effect. The use of AGM in the pediatric population is limited by the scarcity of data. In addition, few studies and case reports have been published on the use of AGM in patients with attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Considering this evidence, the purpose of this review is to report the potential role of AGM in neurological developmental disorders. AGM would increase the expression of the cytoskeleton-associated protein (ARC) in the prefrontal cortex, with optimization of learning, long-term memory consolidation, and improved survival of neurons. Another important feature of AGM is the ability to modulate glutamatergic neurotransmission in regions associated with mood and cognition. With its synergistic activity a melatoninergic agonist and an antagonist of 5-HT2C, AGM acts as an antidepressant, psychostimulant, and promoter of neuronal plasticity, regulating cognitive symptoms, resynchronizing circadian rhythms in patients with autism, ADHD, anxiety, and depression. Given its good tolerability and good compliance, it could potentially be administered to adolescents and children. [ABSTRACT FROM AUTHOR]

Classic psychedelics such as psilocybin, ketamine and lysergic acid diethylamide (LSD) are 5HT2A serotonin receptor agonists that produce individualised subjective affects. Today, public interest in psychedelic medicine has reached a fervour but the evidence for clinical benefit still lags. Psilocybin and psilocin are tryptophan based alkaloids found worldwide in mushrooms of the genera Psilocybe, Panaeolus, Conocybe, Gymnopilus, Stropharia, Pluteus and Panaeolina. This review addresses the current evidence base for psilocybin as a clinical medicine, the general chemistry and proposed mechanism of its therapeutic effect and future research directions for psilocybin based therapies. [ABSTRACT FROM AUTHOR]

This study aims to assess the therapeutic potentials of novel serotonergic compounds in treating alcohol use disorders by investigating the effects of SB242084 and buspirone on intermittent and continuous alcohol consumption in male and female mice. Adult male and female C57BL/6J mice were given two-bottle choice to 20% ethanol and water on an intermittent or continuous availability schedule. Drug testing consisted of intraperitoneal injections of 0.3, 1, 3 mg/kg SB242084 or 1, 3, 10 mg/kg buspirone, and subsequent alcohol and water consumption were measured. To monitor the drug effects on anxiety-like and locomotor behavior, the highest dose of each compound was administered before free activity in an open field. SB242084 dose-dependently attenuated alcohol drinking for intermittent alcohol drinking in male mice but did not significantly alter alcohol drinking in mice given continuous access. Two-hour and four-hour female drinking behavior was unaffected by SB242084. In comparison, buspirone not only suppressed intermittent and continuous alcohol drinking in both males and females but also reduced distance traveled in the open field test. Observed differences in responses to SB242084 between drinking groups may imply differing neural mechanisms between episodic and continuous drinking driven by serotonin. Reductions in drinking after buspirone treatment may be related to non-specific properties. These findings suggest the therapeutic potential of compounds blocking the 5-HT2C receptor for alcohol use disorders. [ABSTRACT FROM AUTHOR]