Natural products of pharmaceutical interest often do not reach the drug market due to the associated low yields and difficult extraction. Knowledge of biosynthetic pathways is a key element in the development of biotechnological strategies for plant specialized metabolite production. Erythrina species are mainly used as central nervous system depressants in folk medicine and are important sources of bioactive tetracyclic benzylisoquinoline alkaloids (BIAs), which can act on several pathology-related biological targets.

In older patients, timely recognition and treatment of medication misuse and dependence are crucial to secure medication safety and to avoid increasing health expenditure. Nonetheless, the detection of this condition remains challenging due to the paucity of screening instruments validated for older people. This study assesses diagnostic accuracy, reliability, validity and the factor structure of the Severity of Dependence Scale (SDS) in detecting medication misuse and dependence among hospitalized older patients, focusing on prescribed central nervous system depressants (CNSDs): opioid analgesics, benzodiazepines and z-hypnotics.

Background and Purpose: Sedation and somnolence remain serious adverse effects of the existing analgesics (e.g., pregabalin, duloxetine) for neuropathic pain. The available evidence indicates that serotonin (5-HT), noradrenaline (NE), and dopamine (DA) play important roles in modulating the descending inhibitory pain pathway and sleep-wake cycle. The aim of this work was to test the hypothesis that LPM580098, a novel triple reuptake inhibitor (TRI) of 5-HT, NE, and DA, has analgesic effect, and does not induce significant adverse effects associated with central inhibition, such as sedation and somnolence. Methods: The analgesic activity of LPM580098 was assessed on formalin test and spinal nerve ligation (SNL)-induced neuropathic pain model. Locomotor activity, pentobarbital sodium-induced sleeping and rota-rod tests were also conducted. In vitro binding and uptake assays, and Western blotting were performed to examine the potential mechanisms. Results: LPM580098 suppressed the nocifensive behaviors during phase II of the formalin test in mice. In SNL rats, LPM580098 (16 mg kg-1) inhibited mechanical allodynia, thermal hyperalgesia and hyperexcitation of wide-dynamic range (WDR) neurons, in which the effect of LPM580098 was similar to pregabalin (30 mg kg-1). However, pregabalin altered the spontaneous locomotion, affected pentobarbital sodium-induced sleep, and showed a trend to perform motor dysfunction, which were not induced by LPM580098. Mechanistically, LPM580098 inhibited the uptake of 5-HT, NE, and DA, improved pain-induced changes of the synaptic functional plasticity and structural plasticity possibly via downregulating the NR2B/CaMKIIα/GluR1 and Rac1/RhoA signaling pathways. Conclusion: Our results suggest that LPM580098, a novel TRI, is effective in attenuating neuropathic pain without producing unwanted sedation and somnolence associated with central nervous system (CNS) depressants.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish.

The present study aimed to assess the quality and risks involved in the consumption of psychoactive herbal products (PHs) that are available through informal commerce in the city of Diadema, SP, Brazil. Methods of ethnography were used to conduct the fieldwork during which four dealers were selected to record the collection, handling, packaging, types of PHs marketed, and their therapeutic purposes. In addition, lots of the PHs selected were purchased from the dealers and analyzed using microbiology and pharmacognosy techniques. 217 PHs were recorded and categorized into two main groups: stimulants (67%) and depressants (27%) of the central nervous system; sixteen of them were selected, and their 52 lots were acquired. The deficiencies observed in handling and packaging these lots by dealers were confirmed by microbiological analysis; 80.8% of them presented risk according to the indicators defined by the Brazilian Pharmacopoeia. The pharmacognostic analysis confirmed the authenticity of only 9 to 16 PHs analyzed. In addition, descriptions of contraindications, adverse reactions, and drug interactions were found in the literature for the PHs. The results of this study allow the observation of the priorities for the sanitary adequacy of the popular trade of herbs.

Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy, and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti-depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD.

Barbiturates potentiate GABA actions at the GABA(A) receptor and act as central nervous system depressants that can induce effects ranging from sedation to general anesthesia. No structural information has been available about how barbiturates are recognized by their protein targets. For this reason, we tested whether these drugs were able to bind specifically to horse spleen apoferritin, a model protein that has previously been shown to bind many anesthetic agents with affinities that are closely correlated with anesthetic potency. Thiopental, pentobarbital, and phenobarbital were all found to bind to apoferritin with affinities ranging from 10-500 µM, approximately matching the concentrations required to produce anesthetic and GABAergic responses. X-ray crystal structures were determined for the complexes of apoferritin with thiopental and pentobarbital at resolutions of 1.9 and 2.0 Å, respectively. These structures reveal that the barbiturates bind to a cavity in the apoferritin shell that also binds haloalkanes, halogenated ethers, and propofol. Unlike these other general anesthetics, however, which rely entirely upon van der Waals interactions and the hydrophobic effect for recognition, the barbiturates are recognized in the apoferritin site using a mixture of both polar and nonpolar interactions. These results suggest that any protein binding site that is able to recognize and respond to the chemically and structurally diverse set of compounds used as general anesthetics is likely to include a versatile mixture of both polar and hydrophobic elements.

About one-third of adult life is spent in the workplace. The use of psychoactive substances is a major preventable cause of morbidity and mortality. The consumption of psychoactive substances during or outside working hours greatly increases the frequency and severity of labor accidents, as well as the workers' poor general state of health and productivity, implying higher costs for enterprises. It is the responsibility of organizations to ensure the safety and health of their workers. These cannot be limited to traditional routine clinical exams, as other aspects also have an impact on health. Thus, prevention and intervention in the consumption of psychoactive substances (e.g., ethanol, opioids, central nervous system stimulants or depressants, hallucinogens, Cannabis derivatives, dissociative substances, and inhalants) in labor activity should be considered as an investment of organizations and not as a cost, in view of the professional, personal, and family advantages for workers and employers, with a potential impact on productivity, security, health, and quality of life at work. Despite the extensive literature on the subject, each article generally focuses on one or another aspect of a very specific nature, not tackling the problem in a holistic way by confronting clinical, safety, and legal issues. This article presents a reflection on the legal, laboratorial, clinical, ethical, forensic, and safety concerns related to the consumption of psychoactive substances in the workplace, and can be a cross-cutting contribution to occupational medicine, forensic medicine, and insurance medicine, as well as for entrepreneurs, lawyers, judges, workers, and technicians from the public and private sectors that develop projects in this area. This discussion is based on general principles established internationally and highlights the role of the occupational healthcare system and other decision-making actors in the prevention and supervision of workplace psychoactive consumption.

Neuropsychiatric symptoms (NPS) in dementia impact profoundly on the quality of life of people living with dementia and their care givers. Evidence for the effectiveness and safety of current therapeutic options is varied. Cannabinoids have been proposed as an alternative therapy, mainly due to their activity on CB1 receptors in the central nervous system. However, little is known regarding the safety and effectiveness of cannabinoid therapy in people with dementia. A literature review was undertaken to identify, describe and critically appraise studies investigating cannabinoid use in treating NPS in dementia.

Inflammatory insult to the central nervous system (CNS) can lead to development of depression, and subsequently depression is the most frequent psychiatric comorbidity following ischemic stroke, often limiting recovery and rehabilitation in patients. The initiators of inflammatory pathways in the CNS are microglia activated in response to acute ischemic stress, and anti-depressants have been shown to have anti-inflammatory effects in the CNS, promoting neuronal survival following ischemic insult. We have previously shown that the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and citalopram promote neuronal survival after oxygen-glucose deprivation, an in vitro model of ischemia, by attenuating the release of glutamate and D-serine from activated microglia. Interestingly, we found that fluoxetine-treated microglial cultures contained fewer numbers of cells compared to other groups and hypothesized that fluoxetine and citalopram attenuated the release of glutamate and D-serine by promoting the apoptosis of microglia. The present study aimed to test and compare antidepressants from three distinct classes (tricyclics, monoamine oxidase inhibitors, and SSRIs) on microglial apoptosis. Primary microglia were treated with 1 μg/mL lipopolysaccharide and/or 10 μM antidepressants, and various apoptotic markers were assayed. Fluoxetine and its metabolite norfluoxetine decreased protein levels in cell lysates, decreased cell viability of microglia, and increased the expression of the apoptotic marker cleaved-caspase 3 in microglia. Live/dead nuclear staining also showed that fluoxetine- or norfluoxetine-treated cultures contained greater numbers of dying microglial cells compared to vehicle-treated cultures. Cultures treated with citalopram, phenelzine, or imipramine showed no evidence of inducing microglial apoptosis. Our results demonstrate that fluoxetine and norfluoxetine induce the apoptotic death of microglia, which may serve as a mechanism to attenuate the release of glutamate and D-serine from activated microglia. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.