Platelet factors attenuate inflammation and rescue cognition in ageing.

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.

Lecanemab in Early Alzheimer's Disease.

BACKGROUND: The accumulation of soluble and insoluble aggregated amyloid-beta (Aß) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aß soluble protofibrils, is being tested in persons with early Alzheimer's disease. METHODS: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment). RESULTS: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%. CONCLUSIONS: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.).

Cognitive-Enhancing Effects of Acetylcholine Receptor Agonists in Group-Housed Cynomolgus Monkeys Who Drink Ethanol.

The cognitive impairments that are often observed in patients with alcohol use disorder (AUD) partially contribute to the extremely low rates of treatment initiation and adherence. Brain acetylcholine receptors (AChR) mediate and modulate cognitive and reward-related behavior, and their distribution can be altered by long-term heavy drinking. Therefore, AChRs are promising pharmacotherapeutic targets for treating the cognitive symptoms of AUD. In the present study, the procognitive efficacy of two AChR agonists, xanomeline and varenicline, were evaluated in group-housed monkeys who self-administered ethanol for more than 1 year. The muscarinic AChR antagonist scopolamine was used to disrupt performance of a serial stimulus discrimination and reversal (SDR) task designed to probe cognitive flexibility, defined as the ability to modify a previously learned behavior in response to a change in reinforcement contingencies. The ability of xanomeline and varenicline to remediate the disruptive effects of scopolamine was compared between socially dominant and subordinate monkeys, with lighter and heavier drinking histories, respectively. We hypothesized that subordinate monkeys would be more sensitive to all three drugs. Scopolamine dose-dependently impaired performance on the serial SDR task in all monkeys at doses lower than those that produced nonspecific impairments (e.g., sedation); its potency did not differ between dominant and subordinate monkeys. However, both AChR agonists were effective in remediating the scopolamine-induced deficit in subordinate monkeys but not in dominant monkeys. These findings suggest xanomeline and varenicline may be effective for enhancing cognitive flexibility in individuals with a history of heavy drinking. SIGNIFICANCE STATEMENT: Procognitive effects of two acetylcholine (ACh) receptor agonists were assessed in group-housed monkeys who had several years' experience drinking ethanol. The muscarinic ACh receptor agonist xanomeline and the nicotinic ACh receptor agonist varenicline reversed a cognitive deficit induced by the muscarinic ACh receptor antagonist scopolamine. However, this effect was observed only in lower-ranking (subordinate) monkeys and not higher-ranking (dominant monkeys). Results suggest that ACh agonists may effectively remediate alcohol-induced cognitive deficits in a subpopulation of those with alcohol use disorder.

Update on Cognitive Enhancers Among the Older Adult Population: A Clinical Review.

PURPOSE OF REVIEW: The purpose of this review is to identify key classes of medications that are used for the treatment of older adults with neurocognitive disorders. RECENT FINDINGS: Clinical factors play a critical role in the prescribing of these medication classes for the treatment of dementia. The variation in prescribing trends is determined by the presence of medical and psychiatric comorbidities commonly occurring in older adults and is based on the consideration of potential interactions between pharmacotherapies for the comorbidities and for the dementia. Six medication classes currently exist to address the neurocognitive aspect of dementia, with varying pharmacokinetic and pharmacodynamic profiles. We review these six classes in this report and provide a provision of clinical insights regarding the use of these agents. While literature exists on the safety and efficacy of individual medication options for the treatment of dementia in the older adult population, further research is needed to provide clearer guidance regarding the specific use of these agents in clinical practice.

Trends of use and characterisation of anti-dementia drugs users: a large multinational-network population-based study.

BACKGROUND: An updated time-trend analysis of anti-dementia drugs (ADDs) is lacking. The aim of this study is to assess the incident rate (IR) of ADD in individuals with dementia using real-world data. SETTING: Primary care data (country/database) from the UK/CPRD-GOLD (2007-20), Spain/SIDIAP (2010-20) and the Netherlands/IPCI (2008-20), standardised to a common data model. METHODS: Cohort study. Participants: dementia patients ≥40 years old with ≥1 year of previous data. Follow-up: until the end of the study period, transfer out of the catchment area, death or incident prescription of rivastigmine, galantamine, donepezil or memantine. Other variables: age/sex, type of dementia, comorbidities. Statistics: overall and yearly age/sex IR, with 95% confidence interval, per 100,000 person-years (IR per 105 PY (95%CI)). RESULTS: We identified a total of (incident anti-dementia users/dementia patients) 41,024/110,642 in UK/CPRD-GOLD, 51,667/134,927 in Spain/SIDIAP and 2,088/17,559 in the Netherlands/IPCI.In the UK, IR (per 105 PY (95%CI)) of ADD decreased from 2007 (30,829 (28,891-32,862)) to 2010 (17,793 (17,083-18,524)), then increased up to 2019 (31,601 (30,483 to 32,749)) and decrease in 2020 (24,067 (23,021-25,148)). In Spain, IR (per 105 PY (95%CI)) of ADD decreased by 72% from 2010 (51,003 (49,199-52,855)) to 2020 (14,571 (14,109-15,043)). In the Netherlands, IR (per 105 PY (95%CI)) of ADD decreased by 77% from 2009 (21,151 (14,967-29,031)) to 2020 (4763 (4176-5409)). Subjects aged ≥65-79 years and men (in the UK and the Netherlands) initiated more frequently an ADD. CONCLUSIONS: Treatment of dementia remains highly heterogeneous. Further consensus in the pharmacological management of patients living with dementia is urgently needed.

Exploring the understanding, source of availability and level of access of cognitive enhancers among university students in the United Arab Emirates: A qualitative study.

OBJECTIVE: The use of prescription stimulants for cognitive enhancement by healthy university students, identified as the largest cohort of cognitive enhancer (CE) users, is of growing interest. The purpose of this study was to look at the understanding, perception, experience, and level of access of CEs among healthy university students in the United Arab Emirates (UAE). METHODS: The study was conducted in six highly competitive university programmes. Semi-structured interviews were conducted with 18 university students to discuss their own experiences and those of their friends and peers regarding the use of prescription stimulants. In addition, semi-structured interviews were conducted with seven teaching faculty staff members (registered pharmacists and medical doctors) to explore their views on the use of CEs in their university. RESULTS: Data were analysed thematically for the identification of themes and subthemes within the data using coding. It was found that, 'Adderall' was the most common prescribed CE drug and caffeine super strength pills were the most common non-prescribed CE drug, both reported to enhance concentration, motivation, and meet academic deadlines. CONCLUSIONS: It is expected that the findings of this study will be of interest to a wide range of services in UAE universities. This will enable them to raise awareness about the use of CEs among students.

Dexmedetomidine administration as a possible cognitive enhancer through increasing the level of brain-derived neurotrophic factors in surgical patients: a systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aimed to investigate the effect of dexmedetomidine on brain-derived neurotrophic factor (BDNF) levels in individuals undergoing various medical procedures. We systematically searched electronic databases and manually identified relevant articles to assess the impact of dexmedetomidine on BDNF levels in surgical patients. METHODS: A comprehensive literature search was conducted in PubMed, Scopus, Embase, and Web of Science databases with no language restrictions. Studies that examined the effects of dexmedetomidine administration on BDNF levels in surgical patients were included. RESULTS: The overall analysis revealed a statistically significant increase in BDNF levels in individuals receiving dexmedetomidine compared to controls (Standardized Mean Difference SMD = 1.65, 95% CI: 1.02 to 2.28; I2: 89%). Subgroup analyses based on the anesthesia method (p < 0.01), and the type of surgery (p < 0.01) showed significant between-group differences (Fig. 3). The results of the sensitivity analyses indicated that individual studies did not significantly affect the overall results. CONCLUSION: This meta-analysis indicates that dexmedetomidine administration is associated with a significant increase in BDNF levels in individuals undergoing surgical procedures. These findings highlight the potential role of dexmedetomidine in modulating BDNF levels, which may have implications for optimizing perioperative neuroprotective strategies and improving patient outcomes.

From functional neuroimaging to neurostimulation: fNIRS devices as cognitive enhancers.

Functional near-infrared spectroscopy (fNIRS) relies on near-infrared (NIR) light for changes in tissue oxygenation. For decades, this technique has been used in neuroscience to measure cortical activity. However, recent research suggests that NIR light directed to neural populations can modulate their activity through "photobiomodulation" (PBM). Yet, fNIRS is being used exclusively as a measurement tool. By adopting cognitive tests sensitive to prefrontal functioning, we show that a 'classical' fNIRS device, placed in correspondence of the prefrontal cortices of healthy participants, induces faster RTs and better accuracy in some of the indexes considered. A well-matched control group, wearing the same but inactive device, did not show any improvement. Hence, our findings indicate that the 'standard' use of fNIRS devices generates PBM impacting cognition. The neuromodulatory power intrinsic in that technique has been so far completely overlooked, and future studies will need to take this into account.

Efficacy and safety of donepezil in patients with dementia with Lewy bodies: results from a 12-week multicentre, randomised, double-blind, and placebo-controlled phase IV study.

BACKGROUND: Donepezil has been approved in Japan for the treatment of dementia with Lewy bodies (DLB) based on clinical trials showing its beneficial effects on cognitive impairment. This phase IV study evaluated the efficacy of donepezil by focusing on global clinical status during a 12-week double-blind phase. METHODS: Patients with probable DLB were randomly assigned to the placebo (n = 79) or 10 mg donepezil (n = 81) groups. The primary endpoint was changes in global clinical status, assessed using the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). We also assessed four CIBIC-plus domains (general condition, cognitive function, behaviour, and activities of daily living) and changes in cognitive impairment and behavioural and neuropsychiatric symptoms measured using the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI), respectively. RESULTS: Although donepezil's superiority was not shown in the global clinical status, a significant favourable effect was detected in the cognitive domain (P = 0.006). MMSE scores improved in the donepezil group after adjustments in post hoc analysis (MMSE mean difference, 1.4 (95% confidence interval (CI), 0.42-2.30), P = 0.004). Improvements in NPIs were similar between the groups (NPI-2: -0.2 (95% CI, -1.48 to 1.01), P = 0.710; NPI-10: 0.1 (95% CI, -3.28 to 3.55), P = 0.937). CONCLUSION: The results support the observation that the efficacy of 10 mg donepezil in improving cognitive function is clinically meaningful in DLB patients. The evaluation of global clinical status might be affected by mild to moderate DLB patients enrolled in this study. No new safety concerns were detected.

Effect of Neurotropic and Immunotropic Drugs on Leukocyte Elastase Activity In Vitro.

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.

Donepezil for dementia with Lewy bodies: meta-analysis of multicentre, randomised, double-blind, placebo-controlled phase II, III, and, IV studies.

BACKGROUND: Current evidence for the management of symptoms associated with dementia with Lewy bodies (DLB) using donepezil is limited. We conducted a meta-analysis of three randomised controlled trials of donepezil in patients with DLB to investigate the overall efficacy of donepezil on Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). METHODS: A meta-analysis was performed using the data of 312 patients administered placebo or 10 mg donepezil. Overall mean score differences for MMSE, NPI-2, and NPI-10 from baseline to week 12 and their 95% confidence intervals (CI) were estimated. For CIBIC-plus, which was transformed from a seven-point grade to a dichotomous outcome (improvements/no improvements), odds ratio (OR) and its 95% CI were estimated. Random-effects models were used, and heterogeneity was evaluated using the Cochrane's Q test and I2 statistic. RESULTS: Heterogeneity was suspected for NPI-2 (P < 0.05; I2 = 87.2%) and NPI-10 (P < 0.05; I2 = 67.7%) while it was not suspected for MMSE (P = 0.23; I2 = 32.4%) and CIBIC-plus (P = 0.26; I2 = 19.8%). The overall mean MMSE score difference (mean difference: 1.50; 95% CI, 0.67-2.34) and the overall odds of improving CIBIC-plus (OR: 2.20; 95% CI, 1.13-4.26) from baseline to week 12 were higher in the donepezil group than in the placebo group. CONCLUSION: Results of our meta-analysis indicated overall efficacy of donepezil on cognitive impairment and global clinical status in patients with DLB.

The Impact of Combined Application of Donepezil and Nimodipine on Patients with Comorbid Cerebral Small Vessel Disease and Cognitive Dysfunction: Efficacy and Influence on Nutritional Status.

BACKGROUND AND OBJECTIVE: Cerebral small vessel disease (CSVD) often coexists with cognitive dysfunction in patients, leading to significant challenges in treatment and management. This study aimed to examine the efficacy of combined application of donepezil and nimodipine on patients with comorbid CSVD and cognitive dysfunction and the effects on patients' albumin and prealbumin levels. METHODS: The records of 112 patients with comorbid CSVD and cognitive dysfunction treated at the People's Hospital of Suzhou New District from January 2019 to December 2022 were analysed retrospectively. A total of 50 patients receiving donepezil were allocated to the control group, and 62 patients receiving both nimodipine and donepezil to the study group. Outcomes compared between the two groups included serum homocysteine (Hcy), high sensitivity C-reactive protein (hs-CRP), albumin, and prealbumin before and after therapy, efficacy, and adverse reactions. Additionally, logistic regression was performed to analyze the risk factors impacting patient prognosis. RESULTS: Prior to therapy, the two groups did not differ significantly in Hcy and hs-CRP levels (p > 0.05), whereas after therapy, the levels in both groups dropped significantly (p < 0.01), with more obvious lower levels in the study group (p < 0.05). After treatment, the study group presented significantly higher albumin and prealbumin levels than the control group (p < 0.001). An obvious higher overall response rate was observed in the study group compared to the control group (p = 0.012). No significant inter-group discrepancy was found regarding the total incidence of adverse reactions (p = 0.752). Univariate analysis identified age, course of disease, heart rate (HR), Montreal Cognitive Assessment (MoCA) score, diastolic blood pressure (DBP), systolic blood pressure (SBP), drinking history, as well as medication regimen as risk factors impacting patient prognosis. Multivariate logistic regression analysis identified SBP, DBP, and medication regimen as the independent risk factors. CONCLUSION: Combined application of donepezil and nimodipine can effectively treat patients with comorbid CSVD and cognitive dysfunction. It can significantly lower the Hcy and hs-CRP levels and improve the nutritional status without increasing the frequency of adverse reactions. In addition, for CSVD patients with cognitive dysfunction, age, course of disease, MoCA score, HR, SBP, DBP, drinking history, and medication regimen are risk factors impacting patient prognosis, while SBP, DBP, and medication regimen are independent risk factors.

Latest research in nootropic therapy of patients with chronic cerebral circulation insufficiency.

OBJECTIVE: Aim: To analyze latest research on the usage of choline alfoscerate and ethylmethylhydroxypyridine succinate (EMHPS) as nootropic therapy for patients with chronic cerebral circulation insufficiency (CCCI). PATIENTS AND METHODS: Materials and Methods: Bibliosemantic, comparative and system analysis methods were used in the study. The proposed recommendations are developed on the basis of the analysis of modern literature, the results of randomized studies and meta-analyses, authoritative studies devoted to the study of the CCCI problem. CONCLUSION: Conclusions: The combination of EMHPS with choline alfoscerate for the complex treatment of CCCI and associated syndromes improves the functions of the endothelium, leads to asthenic syndrome, indicators of stress, depression and anxiety decreasing has a positive effect on the cognitive impairment and complications' progress reduction.

Neuroprotective effect of herbal extracts inhibiting soluble epoxide hydrolase (sEH) and cyclooxygenase (COX) against chemotherapy-induced cognitive impairment in mice.

Chemotherapy-induced cognitive impairment (CICI) is a novel clinical condition characterized by memory, learning, and motor function deficits. Oxidative stress and inflammation are potential factors contributing to chemotherapy's adverse effects on the brain. Inhibition of soluble epoxide hydrolase (sEH) has been proven effective in neuroinflammation and reversal of memory impairment. The research aims to evaluate the memory protective effect of sEH inhibitor and dual inhibitor of sEH and COX and compare its impact with herbal extracts with known nootropic activity in an animal model of CICI. In vitro sEH, the inhibitory activity of hydroalcoholic extracts of Sizygium aromaticum, Nigella sativa, and Mesua ferrea was tested on murine and human sEH enzyme as per the protocol, and IC50 was determined. Cyclophosphamide (50 mg/kg), methotrexate (5 mg/kg), and fluorouracil (5 mg/kg) combination (CMF) were administered intraperitoneally to induce CICI. The known herbal sEH inhibitor, Lepidium meyenii and the dual inhibitor of COX and sEH (PTUPB) were tested for their protective effect in the CICI model. The herbal formulation with known nootropic activity viz Bacopa monnieri and commercial formulation (Mentat) were also used to compare the efficacy in the CICI model. Behavioral parameter such as cognitive function was assessed by Morris Water Maze besides investigating oxidative stress (GSH and LPO) and inflammatory (TNFα, IL-6, BDNF and COX-2) markers in the brain. CMF-induced CICI, which was associated with increased oxidative stress and inflammation in the brain. However, treatment with PTUPB or herbal extracts inhibiting sEH preserved spatial memory via ameliorating oxidative stress and inflammation. S. aromaticum and N. sativa inhibited COX2, but M. Ferrea did not affect COX2 activity. Lepidium meyenii was the least effective, and mentat showed superior activity over Bacopa monnieri in preserving memory. Compared to untreated animals, the mice treated with PTUPB or hydroalcoholic extracts showed a discernible improvement in cognitive function in CICI.

A comprehensive review on tissue culture studies and secondary metabolite production in Bacopa monnieri L. Pennell: a nootropic plant.

Bacopa monnieri L. Pennell, commonly known as Brahmi, is an important medicinal plant that belongs to the family Plantaginaceae. Brahmi is rich in innumerable bioactive secondary metabolites, especially bacosides that can be employed to reduce many health issues. This plant is used as a neuro-tonic and treatment for mental health, depression, and cognitive performance. Brahmi is also known for its antioxidant, anti-inflammatory, and anti-hepatotoxic activities. There is a huge demand for its raw materials, particularly for the extraction of bioactive molecules. The conventional mode of propagation could not meet the required commercial demand. To overcome this, biotechnological approaches, such as plant tissue culture techniques have been established for the production of important secondary metabolites through various culture techniques, such as callus and cell suspension cultures and organ cultures, to allow for rapid propagation and conservation of medicinally important plants with increased production of bioactive compounds. It has been found that a bioreactor-based technology can also enhance the multiplication rate of cell and organ cultures for commercial propagation of medicinally important bioactive molecules. The present review focuses on the propagation and production of bacoside A by cell and organ cultures of Bacopa monnieri, a nootropic plant. The review also focuses on the biosynthesis of bacoside A, different elicitation strategies, and the over-expression of genes for the production of bacoside-A. It also identifies research gaps that need to be addressed in future studies for the sustainable production of bioactive molecules from B. monnieri.

Toxidrome of an Easily Obtainable Nootropic: A Case Report of Phenibut Intoxication and Withdrawal Delirium.

PURPOSE/BACKGROUND: Phenibut (4-amino-3-phenyl-butyric acid) is a structural analog of GABA with central nervous system depressant and anxiolytic properties, developed in the former Soviet Union for anxiety, insomnia, and alcohol withdrawal. Its primary mechanism of action is believed to be a GABA-B receptor agonist-with high affinity at the α 2 δ subunit-containing voltage-dependent calcium channels and therefore gabapentinoid activity-as well as, to a lesser extent, GABA-A agonist activity. While not approved or regulated by the FDA, phenibut is easily obtainable online, where it is marketed as a nootropic, or cognitive enhancer. However, phenibut can lead to problems related to intoxication, dependency, and withdrawal, similar to other sedatives. METHODS/PROCEDURES: We present a case of phenibut intoxication and withdrawal delirium that provided diagnostic and management challenges because of a patient that was initially not forthcoming about his phenibut use which resulted in five presentations to the hospital including two admissions. FINDINGS/RESULTS: Initial differential including adrenergic, serotonergic or anticholinergic toxidrome based on clinical picture and history reported at that time, however phenibut use of 50 g daily was eventually revealed, an amount exceeding the highest reported cases in our review of the English literature. IMPLICATIONS/CONCLUSIONS: High-dose phenibut intoxication and withdrawal can appear as dramatic and dangerous as high-dose sedative withdrawal, however given its specified receptor affinity and binding profile we found that a pharmacotherapeutic approach targeting GABA-B, GABA-A, and gabapentenoid receptors were effective in stabilizing this patient, eventually leading to the patient's full and sustained recovery.

Plant-derived nootropics and human cognition: A systematic review.

Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2021137.

Efficacy of the nootropic supplement Mind Lab Pro on memory in adults: Double blind, placebo-controlled study.

OBJECTIVES: This study aimed to investigate the efficacy of taking Mind Lab Pro, a plant-based nootropic on memory in a group of healthy adults. Auditory, visual, visual working memory, immediate and delayed recall (DR) were assessed. METHODS: The study employed a pseudo randomised, double blinded, placebo-controlled design. A total of 49 healthy individuals completed the study with 36 in the experimental group and 13 in the control group. Participants ranged between 20 and 68 years with a mean age of 31.4 ± 14.4 years. Pre and post taking either the Mind Lab Pro supplement or placebo for 30 days. All participants completed the Wechsler Memory Scale Fourth UK Edition (WSM-IV UK). RESULTS: We found that the experimental group significantly improved in all memory subtests assessed (p < 0.05) whilst the control group only significantly improved in auditory memory and immediate recall (p = 0.004 and p = 0.014 respectively). A significant difference in immediate and DR was also found between the control and experimental group (p = 0.005 and 0.034 respectively). CONCLUSION: The use of Mind Lab Pro for 4 weeks improves memory with the experimental group significantly improving in all sub areas of memory as assessed by the WSM-IV UK.

Methylphenidate use and misuse among medical residents in Israel: a cross-sectional study.

BACKGROUND: Methylphenidate (MPH) and other stimulants may be misused, mainly as cognitive enhancers and recreational drugs. Data regarding misuse among medical residents are scarce. This study aimed to evaluate the prevalence of and main reasons for methylphenidate (MPH) use and misuse among Israeli medical residents. METHODS: In this cross-sectional study, we sent an online questionnaire to medical residents who had completed their first residency exam and specialists with up to 2 years of experience. We asked about the use of MPH before and during residency and attitudes toward the use of MPH as a cognitive enhancer. We also added the Adult ADHD Self-Report Scale (ASRS) questionnaire, a validated tool used to screen for the presence of attention deficit hyperactivity disorder (ADHD). Users and misusers were classified based on self-report of use and formal ADHD diagnosis. Logistic regression analysis was used to evaluate factors associated with MPH misuse. RESULTS: From March 2021 to August 2021, 370 physicians responded to our questionnaire (response rate 26.4%). Twenty-eight met the exclusion criteria and were not included. The respondents' average age was 36.5 years. Women comprised 63.5% of the respondents. Of the participants, 16.4% were classified as users and 35.1% as misusers. The prevalence of misusers was 45.6% among surgery and OB/GYN physicians, 39.4% among pediatricians and internists, and 24% among family physicians (P < 0.001). Misusers had a more liberal approach than others to MPH use as a cognitive enhancer. Factors associated with misuse of MPH included not being a native-born Israeli (OR-1.99, 95% CI 1.08, 3.67) and type of residency (OR-2.33, 95% CI 1.22, 4.44 and OR-4.08, 95% CI 2.06, 8.07 for pediatrics and internal medicine and surgery, respectively). CONCLUSION: Very high levels of MPH misuse during residency may be related to stress, long working hours, night shifts, and the academic burden of the residency period. We believe that our findings should be considered by healthcare policymakers as they make decisions regarding the conditions of medical residencies. The use of MPH as a cognitive enhancer should be further studied and discussed.

Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

PURPOSE: Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. METHODS: Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. RESULTS: Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). CONCLUSIONS: The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.