The Safety and Efficacy of Remimazolam Compared to Dexmedetomidine for Awake Tracheal Intubation by Flexible Bronchoscopy: A Randomized, Double-Blind, Controlled Trial.

Background: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that has the potential to be an alternative for procedural sedation due to its rapid sedation and recovery, no accumulation effect, stable hemodynamics, minimal respiratory depression, anterograde amnesia effect, and specific antagonist. Here, we aimed to compare the safety and efficacy of remimazolam with dexmedetomidine for awake tracheal intubation by flexible bronchoscopy (ATI-FB). Methods: Ninety patients scheduled for ATI-FB were randomly divided into three groups, each consisting of 30 cases: dexmedetomidine 0.6 µg/kg + sufentanil (group DS), remimazolam 0.073 mg/kg + sufentanil (group R1S), or remimazolam 0.093 mg/kg + sufentanil (group R2S). The primary outcome was the success rate of sedation. Secondary outcomes were MOAA/S scores, hemodynamic and respiratory parameters, intubation conditions, intubation time, tracheal intubation amnesia, and adverse events. Results: The success rates of sedation in groups R2S and DS were higher than that in group R1S (93.3%, 86.7%, respectively, vs 58.6%; P = 0.002), and intubation conditions were better than those in group R1S (P < 0.05). Group R2S had shorter intubation times than groups R1S and DS (P = 0.003), and a higher incidence of tracheal intubation amnesia than group DS (P = 0.006). No patient in the three groups developed hypoxemia or hypotension, and there were no significant differences in oligopnea, PetCO2, or bradycardia (P > 0.05). Conclusion: In conclusion, both DS and R2S had higher success rates of sedation, better intubation conditions, and minor respiratory depression, but R2S, with its shorter intubation time, higher incidence of anterograde amnesia, and ability to be antagonized by specific antagonists, may be a good alternative sedation regimen for patients undergoing ATI-FB.

Seizures and memory impairment induced by patient-derived anti-N-methyl-D-aspartate receptor antibodies in mice are attenuated by anakinra, an interleukin-1 receptor antagonist.

OBJECTIVE: Neuroinflammation associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti-NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)-1-mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL-1 by anakinra, a selective IL-1 receptor antagonist, blunts antibody-induced seizures. METHODS: We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti-NMDAR encephalitis or monoclonal anti-NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6-day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4-day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adapter molecule [Iba]-1) activation. RESULTS: Of 31 mice infused with purified patient NMDAR-IgG (n = 17) or monoclonal NMDAR-IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p = .04). Anakinra improved novel object recognition in mice with antibody-induced seizures (p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba-1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation. SIGNIFICANCE: Our evidence supports a role for IL-1 in the pathogenesis of seizures in anti-NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL-1 receptor-mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures.

A reappraisal of acute doses of benzodiazepines as a model of anterograde amnesia.

OBJECTIVE: Acute administration of benzodiazepines is considered a pharmacological model of general organic anterograde amnesias (OAA). We sought to determine which type of amnesia these drugs best model by comparing the effects of diazepam with those reported in amnesiacs regarding working memory capacity (WMC), susceptibility to retroactive interference (RI), and accelerated forgetting. METHODS: In this double-blind, parallel-group design study, 30 undergraduates were randomly allocated to acute oral treatments with 15 mg diazepam or placebo. WMC and story recall were assessed pre- and post-treatment. Story presentation was succeeded by 10 min of RI (spotting differences in pictures) or minimal RI (doing nothing in a darkened room). Delayed story recall was assessed under diazepam and 7 days later in a drug-free session to assess accelerated forgetting. RESULTS: Recall of stories encoded under diazepam, whether reactivated or not, was severely impaired (anterograde amnesia). However, diazepam did not impair WMC, increase susceptibility to RI, or accelerate forgetting. CONCLUSIONS: Diazepam's amnestic effects mirror those in patients with probable severe medial temporal damage, mostly restricted to initial consolidation and differ from other OAA (Korsakoff syndrome, frontal, transient epileptic, posttraumatic amnesia, and most progressive amnesias) in terms of WMC, susceptibility to RI and accelerated forgetting.

Development and initial validation of the alcohol-induced blackout measure.

BACKGROUND: Blackouts are common among young adults and predict alcohol-related harm. However, existing measures do not capture the range of alcohol-induced memory impairment involved in blackout experiences and do not differentiate between fragmentary and en bloc blackouts. This study aimed to develop and validate a brief, reliable measure of alcohol-induced blackouts among young adults. METHODS: College students reporting alcohol-induced memory impairment in the past year were recruited via Qualtrics to participate in an online survey (N = 350, 56% female). A subsample (n = 109, 67% female) completed a one-month follow-up. Principal component analysis was used to determine the structure of the Alcohol-Induced Blackout Measure (ABOM), which was designed to reflect two components (fragmentary and en bloc blackouts). The reliability and validity of the total ABOM score was assessed. RESULTS: The final five items fit in a two-component scale structure; however, a single principal component accounted for 73% of variance in blackout items, all of which demonstrated high component loadings and communalities. The total blackout score demonstrated strong internal consistency, test-retest reliability, and convergent and incremental validity. ABOM scores predicted alcohol-related consequences at baseline and one-month follow-up. CONCLUSIONS: The ABOM is a brief and reliable, self-report measure that quantifies the frequency of a range of blackout experiences in the past 30 days. Accounting for this range of experiences improved predictive validity over single-item blackout measures. Blackout frequency is a strong, unique predictor of alcohol-related problems.

Anterograde Amnesia Induced by Disruption of Consolidation or Reconsolidation of Long-Term Memory.

Mechanisms of amnesia caused by impairment of consolidation or reconsolidation of conditioned food aversion memory with protein synthesis inhibitor cycloheximide were studied in Helix lucorum. Cycloheximide injection during training or memory reconsolidation in trained snails produced amnesia. In both cases, repeated training 10 days after amnesia induction led to short-term memory formation, while long-term memory was not formed, despite the fact that the number of conditioned and reinforcing stimuli combinations was higher than during initial training. The possibility of formation of short-term memory not transforming into long-term memory is one of the key characteristics of anterograde amnesia. Our findings data and experimental model can be used for analysis of specific molecular mechanisms of anterograde amnesia.

What is the level of evidence for the amnestic effects of sedatives in pediatric patients? A systematic review and meta-analyses.

BACKGROUND: Studies have suggested that benzodiazepines are amnestic drug par excellence, but when taken together, what level of evidence do they generate? Are other sedatives as amnestic as benzodiazepines? The aim of this study was to assess the level of scientific evidence for the amnestic effect of sedatives in pediatric patients who undergo health procedures. METHODS: The literature was searched to identify randomized controlled trials that evaluated anterograde and retrograde amnesia in 1-19-year-olds who received sedative drugs during health procedures. Electronic databases, including PubMed, Scopus and Cochrane Library besides clinical trial registries and grey literature were searched. Two independent reviewers performed data extraction and risk of bias assessment using the Cochrane Collaboration's Tool. The meta-analyses were performed by calculating relative risk (RR) to 95% confidence intervals (CI). The quality of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS: Fifty-four studies were included (4,168 participants). A higher occurrence of anterograde amnesia was observed when benzodiazepines, the most well-studied sedatives (n = 47), were used than when placebo was used (n = 12) (RR = 3.10; 95% CI: 2.30-4.19, P<0.001; I2 = 14%), with a moderate level of evidence. Higher doses of alpha2-adrenergic agonists (clonidine/dexmedetomidine) produced more anterograde amnesia than lower doses (n = 2) (RR = 1.83; 95% CI: 1.03-3.25; P = 0.038; I2 = 0%), with a low level of evidence; benzodiazepines' amnestic effects were not dose-dependent (n = 3) (RR = 1.54; 95% CI: 0.96-2.49; P = 0.07; I2 = 12%) but the evidence was low. A qualitative analysis showed that retrograde amnesia did not occur in 8 out of 10 studies. CONCLUSIONS: In children, moderate evidence support that benzodiazepines induce anterograde amnesia, whereas the evidence for other sedatives is weak and based on isolated and small studies. Further clinical trials focused on the amnesia associated with non-benzodiazepine sedatives are therefore needed. TRIAL REGISTRATION: PROSPERO CRD42015017559.

Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing.

The Glasgow Coma Scale (GCS) only assesses orientation after traumatic brain injury (TBI). 'Post-traumatic amnesia' (PTA) comprises orientation, anterograde amnesia (AA) and retrograde amnesia (RA). However, RA is often disregarded in formalized PTA assessment. Drugs can potentially confound PTA assessment: e.g. midazolam can cause AA. However, potential drug confounders are also often disregarded in formalized PTA testing. One study of medium-stay elective-surgery orthopaedic patients (without TBI) demonstrated AA in 80% taking opiates after general anesthesia. However, RA was not assessed. Opiates/opioids are frequently administered after TBI. We compared AA and RA in short-stay orthopaedic surgery in-patients (without TBI) taking post-operative opioids after opiate/opioid/benzodiazepine-free spinal anesthesia. In a prospective cohort, the Westmead PTA Scale (WPTAS) was used to assess AA (WPTAS<12), whilst RA was assessed using the Galveston Orientation and Amnesia Test RA item. Results were obtained in n=25 (60±14yrs, M:F 17:8). Surgery was uncomplicated: all were discharged by Day-4. All were taking regular oxycodone as a new post-operative prescription. Only one co-administered non-opioid was potentially confounding (temezepam, n=4). Of 25, 14 (56%) demonstrated AA: five (20%) were simultaneously disorientated. Mean WPTAS was 11.08±1.22. RA occurred in 0%. CONCLUSIONS: AA and disorientation, but not RA, were associated with in-patients (without TBI) taking opioids. Caution should therefore be applied in assessing AA/orientation in TBI in-patients taking opioids. By contrast, retrograde memory was robust and more reliable: even in older patients with iatrogenic AA and disorientation. RA assessment should therefore be integral to assessing TBI severity in all formalized PTA and GCS testing.

Systemic or intra-amygdala infusion of an endocannabinoid CB1 receptor antagonist AM251 blocked propofol-induced anterograde amnesia.

Propofol is well-known for its anterograde amnesic actions. However, a recent experiment showed that propofol can also produce retrograde memory enhancement effects via an interaction with the endocannabinoid CB1 system. Therefore, the authors hypothesized that the regulating effect of propofol on the endocannabinoid CB1 system might also decrease the anterograde amnesic effect of propofol under some conditions, which might be a risk factor for intraoperative awareness. Since, the basolateral amygdala (BLA) has been confirmed to mediate propofol-induced anterograde amnesia and the BLA contains a high concentration of CB1 receptors, the authors investigated whether and how the endocannabinoid system, particularly the CB1 receptor within BLA, influences propofol-induced anterograde amnesia. Male Sprague-Dawley rats trained with inhibitory avoidance (IA) were systematically pre-trained using a memory-impairing dose of propofol (25 mg/kg). Before propofol administration, rats received an intraperitoneal injection of a CB1 receptor antagonist AM251 (1 mg/kg or 2 mg/kg) or a bilateral intra-BLA injection of AM251 (0.6 ng or 6 ng per 0.5 µl). Twenty-four hours after IA training, the IA retention latency was tested. It was found that systemic or intra-BLA injection of a non-regulating dose of AM251 (2 mg/kg or 6 ng per 0.5 µl, respectively) blocked the memory-impairing effect of propofol. These results indicate that the anterograde amnesic effect of propofol is mediated, in part, by activation of the CB1 cannabinoid receptors in the BLA.

Chemical submission to commit robbery: a series of involuntary intoxications with flunitrazepam in Asian travellers in Brussels.

Between January 17, 2003 and August 29, 2003, the Emergency Department admitted a patient who had been surreptitiously intoxicated and robbed of his valuables every Friday. The first cases were considered anecdotal, but criminal activity was rapidly suspected. The cohort includes 16 male Asian patients aged 28-50 years. All the victims had just arrived in Brussels through one of the main rail station of the town and were admitted via the emergency ambulance service from different locations in the centre of Brussels around the CHU Saint-Pierre Hospital. Haemodynamic parameters upon admission were within normal limits. The Glasgow Coma Scale was equal or higher than 9/15 in 14 of the 16 victims. Toxicology screening obtained in 12 patients revealed the presence of flunitrazepam, which was further quantified at levels ranging from 21 to 75 µg/l. One of the Japanese patients, who returned to Belgium afterwards for professional reasons, was approached by the police and accepted to press charges. This allowed the police to investigate and send undercover agents to the railway station on Friday afternoons and evenings. They found a person who was offering welcome cookies to Asian travellers. He arrived from Amsterdam and returned once his crime was committed. Flunitrazepam is well known as a rape drug. We report a series of victims in whom flunitrazepam was used to facilitate robbery.

Prevalence and clinical characteristics of unremembered nocturnal eating in diabetic subjects: Kurume sleep trouble in obesity and metabolic disorders (KUSTOMED) study.

Nighttime food intake is associated with weight gain and higher HbA1c levels. We experienced night eaters who have no memory of their nocturnal eating in the morning. In this study, the curious night eating behavior was designated as "unremembered nocturnal eating syndrome (UNES)". We screened 1,169 patients with diabetes for sleep quality and abnormal eating behavior at night using the Pittsburgh Sleep Quality Index questionnaire with an additional question regarding UNES. When abnormal nocturnal eating behavior was noted, detailed clinical information was extracted from interviews with the patients. We identified 9 patients who experienced UNES. They had a higher BMI compared with subjects who reported no such episodes. Among them, 6 patients who consumed food at night without memory 2-5 times per month or more had significantly higher HbA1c levels. Continuous glucose monitoring in a patient with type 1 diabetes revealed an abrupt elevation of glucose levels from midnight when some foods were consumed. Eight of the 9 patients were taking benzodiazepine and/or non-benzodiazepine hypnotic agents when they experienced the episodes. The prevalence of UNES was 0.8% in all subjects and 4% in those taking hypnotic drugs. The ratio of hypnotic drug use in subjects with UNES was significantly higher than for individuals without UNES (89% vs. 17%, p<0.0001). Although UNES seems to be etiologically heterogeneous, hypnotics-induced parasomnia and/or anterograde amnesia may be associated with the behavior. UNES is not rare in diabetic patients on hypnotic medicine and may be a hidden cause of unexpected morning hyperglycemia.

Comparison by means of bispectral index score, between anxiolysis induced by diazepam and sedation induced by midazolam.

AIM: Bispectral Index Score (BIS) is an objective tool to assess sedation depth. Benzodiazepines have different pharmacological profiles and diazepam may be safer than midazolam in this setting. The aim of this study was to compare BIS values observed during anxiolysis after diazepam versus sedation after midazolam. METHODS: Thirty-six patients were randomly assigned to 3 groups: group 1 was treated with i.v. diazepam, groups 2 and 3 with iv midazolam 1 and 3 mg, respectively. Sedation was monitored clinically and by means of BIS. BIS values were evaluated as area under the curve (AUC) and compared by variance analysis. The statistical comparison of other data was performed by variance analysis or, alternatively, the χ2 according to Yates. The statistical significance was indicated by P values <0.05. RESULTS: AUC values were significantly lower after midazolam when compared to AUC values registered in diazepam treated patients; 22.6% of the group 3 patients showed BIS values <80, versus 0.4% of group 1 patients. CONCLUSION: Diazepam has a safer profile, with BIS values and clinical conditions according to the definition of minimal and/or moderate sedation. Diazepam represents the safer drug for anxiety management in dentistry, because regularly produces a state of sedation during which verbal contact with the patient is maintained and carry a margin of safety wide enough to render loss of consciousness unlikely.

Salvianolic acid A exerts antiamnesic effect on diazepam-induced anterograde amnesia in mice.

Benzodiazepine was known to produce amnesia. Salvianolic acid A extracted from Salvia miltiorrhiza was an effective antioxidant. The objective of the study was to evaluate the effect of salvianolic acid A on diazepam-induced amnesia in mice. C57BL/6 mice were treated with salvianolic acid A at doses of 10, 20 and 40 mg/kg following administration with diazepam at a dose of 3 mg/kg. Morris water maze was performed to evaluate the effect of salvianolic acid A on amnesia. The antioxidative parameters in hippocampus were measured. The results showed that salvianolic acid A decreased the mean escape latency and increased the percentage of time spent in target quadrant. Salvianolic acid A reduced the content of malondialdehyde and increased the activities of superoxide dismutase, catalase and glutathione peroxidase in hippocampus. The findings demonstrated that salvianolic acid A had antiamnesic effects on diazepam-induced anterograde amnesia in mice, by augmenting the antioxidative capacity of hippocampus.

Slowing of the hippocampal θ rhythm correlates with anesthetic-induced amnesia.

BACKGROUND: Temporary, antegrade amnesia is one of the core desirable endpoints of general anesthesia. Multiple lines of evidence support a role for the hippocampal θ rhythm, a synchronized rhythmic oscillation of field potentials at 4-12 Hz, in memory formation. Previous studies have revealed a disruption of the θ rhythm at surgical levels of anesthesia. We hypothesized that θ-rhythm modulation would also occur at subhypnotic but amnestic concentrations. Therefore, we examined the effect of three inhaled agents on properties of the θ rhythm considered critical for the formation of hippocampus-dependent memories. METHODS: We studied the effects of halothane and nitrous oxide, two agents known to modulate different molecular targets (GABAergic [γ-aminobutyric acid] vs. non-GABAergic, respectively) and isoflurane (GABAergic and non-GABAergic targets) on fear-conditioned learning and θ oscillations in freely behaving rats. RESULTS: All three anesthetics slowed θ peak frequency in proportion to their inhibition of fear conditioning (by 1, 0.7, and 0.5 Hz for 0.32% isoflurane, 60% N2O, and 0.24% halothane, respectively). Anesthetics inconsistently affected other characteristics of θ oscillations. CONCLUSIONS: At subhypnotic amnestic concentrations, θ-oscillation frequency was the parameter most consistently affected by these three anesthetics. These results are consistent with the hypothesis that modulation of the θ rhythm contributes to anesthetic-induced amnesia.

Anti-amnesic effect of Ficus religiosa in scopolamine-induced anterograde and retrograde amnesia.

CONTEXT: Ficus religiosa Linn (Moraceae) is a variety of fig tree. Its figs are known to contain a high serotonergic content, and modulation of serotonergic neurotransmission plays a crucial role in the pathogenesis of amnesia. Thus, the present study was envisaged. OBJECTIVE: To investigate the effect of the methanol extract of figs of Ficus religiosa (FRFE) on scopolamine-induced anterograde and retrograde amnesia in mice. MATERIALS AND METHODS: Transfer latency (TL) to the preferred niche in the elevated plus-maze (EPM) and learning avoidance of passive behavior to avoid punishment in the modified passive avoidance paradigm (MPA) served as behavioral models for the assessment of memory. Scopolamine (1 mg/kg, i.p.) was administered before training for induction of anterograde amnesia and before retrieval for induction of retrograde amnesia in both models. TL in the EPM, step down latency (SDL), number of trials, and number of mistakes in the MPA were determined in vehicle control, FRFE treated (10, 50, and 100 mg/kg, i.p.), and standard groups (piracetam 200 mg/kg, i.p.). Cyproheptadine, a non-selective 5-HT(1/2) blocker (4 mg/kg, i.p.), was administered along with the FRFE to investigate the involvement of serotonergic pathways in the anti-amnesic effect of FRFE. RESULTS AND DISCUSSION: FRFE resulted in a significant improvement of memory, as its treatment attenuated the scopolamine-induced anterograde and retrograde amnesia dose-dependently. Further, cyproheptadine pretreatment significantly reversed the anti-amnesic effect of FRFE. CONCLUSION: FRFE has anti-amnesic activity against scopolamine-induced amnesia, in a dose-dependent manner. Inhibition of the anti-amnesic effect of FRFE by cyproheptadine substantiates the involvement of serotonergic pathways for its activity.

Scopolamine induced amnesia is reversed by Bacopa monniera through participation of kinase-CREB pathway.

Scopolamine, an anticholinergic drug, is reported to produce amnesia by interference of long term potentiation and has been used for discerning the efficacy of various antiamnesic drugs. The intoxication with anticholinergics and benzodiazepines tend to produce neurodegeneration which cause memory deficits. Our earlier reports have shown the antiamnesic drug, B. monniera to be capable of alleviating diazepam induced memory deficits. We have now tested how scopolamine affects downstream signaling molecules of long term potentiation and if B. monniera can also modulate the scopolamine induced amnesia. We used Morris water maze scale to test the amnesic effect of scopolamine and its reversal by B. monniera. Rota-rod test was used to screen muscle coordination activity of mice before water maze investigations were carried out. The results showed that scopolamine downregulated protein kinase C and iNOS without affecting cAMP, protein kinase A, calmodulin, MAP kinase, nitrite, CREB and pCREB. B. monniera reversed the scopolamine induced amnesia by significantly improving calmodulin and by partially attenuating protein kinase C and pCREB. These observations suggest involvement of calmodulin in evoking antiamnesic effects of B. monniera.

Memory loss caused by beta-amyloid protein is rescued by a beta(3)-adrenoceptor agonist.

Accumulation of the neurotoxic beta-amyloid protein (Abeta) in the brain is a key step in the pathogenesis of Alzheimer's disease (AD). Although transgenic mouse models of AD have been developed, there is a clear need for a validated animal model of Abeta-induced amnesia which can be used for toxicity testing and drug development. Intracranial injections of Abeta(1-42) impaired memory in a single trial discriminative avoidance learning task in chicks. Memory inhibition was closely associated with the state of aggregation of the Abeta peptide, and a scrambled-sequence of Abeta(1-42) peptide failed to impair memory. Abeta had little effect on labile (short-term and intermediate) memory, but blocked consolidation of memory into long-term storage mimicking the type of anterograde amnesia that occurs in early AD. Since noradrenaline exerts a modulatory influence on labile memory in the chick, we examined the effects of two beta-adrenoceptor (AR) agonists on Abeta-induced amnesia. A beta(3)-AR agonist (CL316243), but not a beta(2)-AR agonist, rescued Abeta-induced memory loss, suggesting the need for further studies on the role of beta(3)-ARs in AD.

Nootropic activity of lipid-based extract of Bacopa monniera Linn. compared with traditional preparation and extracts.

OBJECTIVES: The aim was to design an alternative solvent-free extraction method using the hydrophilic lipid Gelucire (polyethylene glycol glycerides) for herbal extraction and to confirm the efficacy of extraction using biological screening. METHODS: Bacopa monniera Linn. (BM) was selected for the study. Conventional methanolic extract (MEBM), Ayurvedic ghrita (AGBM) and lipid extracts (LEBM) were prepared and standardised by high-performance thin-layer chromatography (HPTLC). Nootropic activity in rats was evaluated using the two-trial Y-maze test and the anterograde amnesia induced by scopolamine (1 mg/kg i.p.) determined by the conditioned avoidance response. The extracts were administered daily at doses of 100, 200 and 400 mg/kg orally. At the end of the conditioned avoidance response test, brain monoamine levels were estimated by HPLC. KEY FINDINGS: The LEBM, MEBM and AGBM contained 3.56%, 4.10% and 0.005% bacoside A, respectively. Significantly greater spatial recognition was observed with LEBM (P < 0.001 at 400 and 200 mg/kg) and MEBM (P < 0.001 at 400 mg/kg, P < 0.01 at 200 mg/kg) than AGBM. The conditioned avoidance response was significantly higher in the groups treated with high doses of LEBM and MEBM than AGBM. There were significant decreases in brain noradrenaline (P < 0.001) and 5-hydroxytryptamine (P < 0.01) levels and an increase in dopamine levels (P < 0.05) in the LEBM-treated groups compared with the stress control group. CONCLUSIONS: The proposed LEBM is solvent free, does not have the shortcomings associated with conventional extraction, and had comparable nootropic activity to the MEBM.