Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer's Disease Rat Model: A Proof-of-Concept Study.

An early and persistent sign of Alzheimer's disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in an AD model. Intracerebroventricular (icv) injection of streptozotocin (STZ) is a validated model for hypometabolism observed in AD. This proof-of-concept study evaluated the effect of cannabidiol treatment in the brain glucose metabolism of an icv-STZ AD model by PET imaging. Wistar male rats received 3 mg/kg of STZ and [18F]FDG PET images were acquired before and 7 days after STZ injection. Animals were treated with intraperitoneal cannabidiol (20 mg/kg-STZ-cannabidiol) or saline (STZ-saline) for one week. Novel object recognition was performed to evaluate short-term and long-term memory. [18F]FDG uptake in the whole brain was significantly lower in the STZ-saline group. Voxel-based analysis revealed a hypometabolism cluster close to the lateral ventricle, which was smaller in STZ-cannabidiol animals. The brain regions with more evident hypometabolism were the striatum, motor cortex, hippocampus, and thalamus, which was not observed in STZ-cannabidiol animals. In addition, STZ-cannabidiol animals revealed no changes in memory index. Thus, this study suggests that cannabidiol could be an early treatment for the neurodegenerative process observed in AD.

Antinociceptive action of cannabidiol on thermal sensitivity and post-operative pain in male and female rats.

This study investigated the antinociceptive potential of cannabidiol (CBD) in male and female Wistar rats. The assessment and analysis included tail withdrawal to thermal stimulation (tail flick test) and mechanical allodynia induced by plantar incision injury (von Frey test). CBD reduced acute thermal sensitivity in uninjured animals and post-operative mechanical allodynia in males and females. In the tail flick test, CBD 30 mg/kg i.p. was required to induce antinociception in males. During the proestrus phase, females did not show a statistically significant antinociceptive response to CBD treatment despite a noticeable trend. In contrast, in a separate group of rats tested during the late diestrus phase, antinociception varied with CBD dosage and time. In the post-operative pain model, CBD at 3 mg/kg decreased mechanical allodynia in males. Similarly, this dose reduced allodynia in females during proestrus. However, in females during late diestrus, the lower dose of CBD (0.3 mg/kg) reduced mechanical allodynia, although the latency to onset of the effect was slower (90 min). The effectiveness of a 10-fold lower dose of CBD during the late diestrus stage in females suggests that ovarian hormones can influence the action of CBD. While CBD has potential for alleviating pain in humans, personalized dosing regimens may need to be developed to treat pain in women.

Cannabidiol in anxiety disorders: Current and future perspectives.

Anxiety disorders are highly prevalent psychiatric disorders, characterized by a chronic course and often accompanied by comorbid symptoms that impair functionality and decrease quality of life. Despite advances in basic and clinical research in our understanding of these disorders, currently available pharmacological options are associated with limited clinical benefits and side effects that frequently lead to treatment discontinuation. Importantly, a significant number of patients do not achieve remission and live with lifelong residual symptoms that limit daily functioning. Since the 1970s, basic and clinical research on cannabidiol (CBD), a non-psychotomimetic compound found in the Cannabis sativa plant, has indicated relevant anxiolytic effects, garnering attention for its therapeutic potential as an option in anxiety disorder treatment. This chapter aims to review the history of these studies on the anxiolytic effects of CBD within the current understanding of anxiety disorders. It highlights the most compelling current evidence supporting its anxiolytic effects and explores future perspectives for its clinical use in anxiety disorders.

Involvement of prelimbic medial prefrontal cortex in panic-like elaborated defensive behaviour and innate fear-induced antinociception elicited by GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei: role of the endocannabinoid CB1 receptor.

It has been shown that GABAA receptor blockade in the dorsomedial and ventromedial hypothalamic nuclei (DMH and VMH, respectively) induces elaborated defensive behavioural responses accompanied by antinociception, which has been utilized as an experimental model of panic attack. Furthermore, the prelimbic (PL) division of the medial prefrontal cortex (MPFC) has been related to emotional reactions and the processing of nociceptive information. The aim of the present study was to investigate the possible involvement of the PL cortex and the participation of local cannabinoid CB1 receptors in the elaboration of panic-like reactions and in innate fear-induced antinociception. Elaborated fear-induced responses were analysed during a 10-min period in an open-field test arena. Microinjection of the GABAA receptor antagonist bicuculline into the DMH/VMH evoked panic-like behaviour and fear-induced antinociception, which was decreased by microinjection of the non-selective synaptic contact blocker cobalt chloride in the PL cortex. Moreover, microinjection of AM251 (25, 100 or 400 pmol), an endocannabinoid CB1 receptor antagonist, into the PL cortex also attenuated the defensive behavioural responses and the antinociception that follows innate fear behaviour elaborated by DMH/VMH. These data suggest that the PL cortex plays an important role in the organization of elaborated forward escape behaviour and that this cortical area is also involved in the elaboration of innate fear-induced antinociception. Additionally, CB1 receptors in the PL cortex modulate both panic-like behaviours and fear-induced antinociception elicited by disinhibition of the DMH/VMH through microinjection of bicuculline.

Progression of the COVID-19 pandemic, Brazilian healthcare workers' emotional burden and the effects on professional fulfillment at the end of the third wave: a longitudinal study.

Introduction: Even though the long-term effects of the COVID-19 pandemic on healthcare workers' mental health remain unknown, such effects might negatively impact health services and patient safety, especially in countries like Brazil, where there is little investment in public health policies. Objectives: To assess how the mental health indicators of Brazilian healthcare workers progressed between the beginning and 2 years after the pandemic (at the end of the third wave when there was a significant decrease in the number of new cases and deaths). Methods: The sample comprised healthcare workers whose mental health indicators have been monitored since the beginning of the pandemic in Brazil. The potential participants were addressed via social media and contacted through class councils and health institutions across Brazil. A total of 165 participants answered instruments at the baseline and 2 years after the pandemic. Data were collected online using the Redcap platform and addressed symptoms of anxiety, depression, post-traumatic stress, insomnia, and burnout (emotional exhaustion, depersonalization, and professional fulfillment). Results: Brazilian healthcare workers faced three periods of intensified incidence of new cases and deaths due to COVID-19 for 2 years. Approximately one-third of the sample still experiences high levels of anxiety, depression, and post-traumatic stress. Insomnia indicators remained the most prevalent compared to the baseline assessment, while post-traumatic stress symptoms (p = 0.04) and professional fulfillment (p = 0.005) decreased. Conclusion: The lack of positive changes in mental health indicators coupled with decreased professional fulfillment over time highlights the pandemic's chronic effects and the need for organizations to monitor these workers' mental health, especially in developing countries like Brazil, where there is a high demand for health services and public policies are poorly structured and unstable.

The Effect of Cannabidiol for Restless Legs Syndrome/Willis-Ekbom Disease in Parkinson's Disease Patients with REM Sleep Behavior Disorder: A Post Hoc Exploratory Analysis of Phase 2/3 Clinical Trial.

Background: Cannabidiol (CBD) is one of the main nonpsychoactive components of Cannabis sativa and may represent an alternative treatment for Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) in patients with Parkinson's disease (PD) and REM (Rapid Eye Movement) sleep behavior disorder (RBD). Objective: Our purpose was a post hoc exploratory analysis to evaluate the CBD's efficacy to improve the severity of RLS/WED symptoms in patients with PD and RBD. Methods: A post hoc exploratory analysis of a phase II/III, a parallel, double-blind, placebo-controlled clinical trial was conducted in 18 patients with RLS/WED and PD plus RBD associated. Six patients were randomized to the CBD group in doses of 75-300 mg, and twelve received placebo capsules. They were followed up for 14 weeks. The primary outcome was the severity of RLS/WED by Restless Legs Syndrome Rating Scale of the International Restless Legs Syndrome Study Group (IRLSSG). Results: CBD showed no difference in relationship to placebo for primary and secondary outcomes. Conclusion: CBD showed no reduction in the severity of RLS/WED manifestation in patients with PD and RBD.

Memory bias and personality characteristics in college students with social anxiety disorder.

INTRODUCTION: Some individuals are more susceptible to recalling false information about events that never happened in their life. Nevertheless, there are several factors, such as personality characteristics, that appear to be related to memory performance. Social anxiety also provokes memory deficits for events that happen to other people, because these individuals tend to focus on their own inner selves rather than on external signs. OBJECTIVE: To investigate the influence of the personality characteristics of individuals with social anxiety disorder (SAD) on memory performance. METHODS: In this study, 183 university students had their memory tested using a complex emotional story about a mother and her son. Only subjects without clinical symptoms of depression and general anxiety (N = 148; 61 with SAD) were included in the study. Participants were compared for differences in personality characteristics using the Factorial Inventory of Personality and for SAD using the Social Phobia Inventory. RESULTS: The main results showed that memory performance of individuals with low percentile ranks in the personality characteristic dominance, i.e., those with low self-esteem, remembered more true information about the story than those with high scores when they did not have SAD. CONCLUSION: The results are helpful to foster better understanding of the personality characteristics related to SAD, such as low dominance, which implies low self-esteem and difficulties with trust and with imposing themselves on others. The results could help development and improvement of techniques for therapeutic intervention.

Magnetic restricted-access carbon nanotubes for SPME to determine cannabinoids in plasma samples by UHPLC-MS/MS.

This manuscript describes the development of magnetic restricted-access carbon nanotubes (M-RACNTs) for use as SPME sorbent to determine cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) in human plasma samples by UHPLC-MS/MS. The adsorptive phase was immobilized on an SPME device by electromagnetic interactions between the M-RACNTs and a cylindrical neodymium magnet (3-mm diameter x 8-mm height) attached to a stainless-steel rod (3-mm diameter x 40-mm height). The M-RACNTs were synthesized by incorporating Fe3O4 magnetic nanoparticles (MNPs) into commercial carbon nanotubes (CNTs); then the surface of the resulting sorbent was further coated with a layer of bovine serum albumin (BSA). Characterization techniques (SEM, FTIR, and Zeta potential) confirmed the presence of both MNPs and BSA layer dispersed through the structure of the CNTs. The M-RACNTs presented adequate sorption capacity, stable physical/chemical characteristics, and appropriate magnetic properties. Protein exclusion capacity (about 98.5%) was attributed to the chemical diffusion barrier created by the BSA network at the outer surface of the sorbent. The SPME parameters (sample pH, equilibrium time, and desorption conditions) were optimized by design of experiments (fraction factorial planning). The method (validated according to the FDA guidelines) presented adequate selectivity and linearity (coefficient of determination higher than 0.99) at concentrations ranging from the lower limit of quantification (LLOQ) (10 ng mL-1) to the upper limit of quantification (ULOQ) (300 ng mL-1) for both CBD and THC. Precision and accuracy varied from 4.47 to 19.84% (LLOQ) and -6.90 to 17.78% (LLOQ), respectively. Carry-over and matrix effect were not significant. The method was successfully applied to determine plasmatic CBD levels in healthy volunteers attending a single session of oral drug administration and THC levels in frequent cannabis smokers.

Cannabidiol enhances the antinociceptive effects of morphine and attenuates opioid-induced tolerance in the chronic constriction injury model.

Neuropathic pain (NP) is a complex health problem that includes sensorial manifestations such as evoked and ongoing pain. Cannabidiol (CBD) has shown potential in the treatment of NP and the combination between opioids and cannabinoids has provided promising results on pain relief. Thus, our study aimed to investigate the effect of treatment combination between CBD and morphine on evoked and ongoing pain, and the effect of CBD on morphine-induced tolerance in the model of chronic constriction injury (CCI) of the sciatic nerve in rats. Mechanical thresholds (i.e., evoked pain) were evaluated before and 7 days after surgery. We also employed a 4-day conditioned place preference (CPP) protocol, to evaluate relief of ongoing pain (6-9 days after surgery). Treatment with morphine (2 and 4 mg/kg) or CBD (30 mg/kg) induced a significant antinociceptive effect on evoked pain. The combination of CBD (30 mg/kg) and morphine (1 mg/kg) produced an enhanced antinociceptive effect, when compared to morphine alone (1 mg/Kg). Treatment with morphine (1 and 2 mg/kg) or CBD (30 mg/kg) alone failed to induce significant scores in the CPP test. However, combined treatment of CBD (30 mg/kg) and morphine (1 mg/kg) provided significant positive scores, increased the number of entrances in the drug-paired chamber in the CPP test and did not alter locomotor activity in rats. Lastly, treatment with CBD partially attenuated morphine-induced tolerance. In summary, our results support the indication of CBD as an adjuvant to opioid therapy for the attenuation of NP and opioid-induced analgesic tolerance.

Circulating Endocannabinoids in Huntington's Disease: An Exploratory Cross-Sectional Study.

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive and behavioral deficits. Some evidence suggests that the endocannabinoid system participates in the pathophysiology of HD. We conducted a cross-sectional study comparing plasma levels of anandamide and 2-arachidonoylglycerol in manifest HD gene-expansion carriers (HDGEC) and healthy controls, finding no difference in endocannabinoid levels between the groups. Correlations between endocannabinoid levels and clinical scales (Mini-Mental State Examination, Hospital Anxiety and Depression Scale, Unified Huntington Disease Rating Scale) were non-significant. We found a significant association between body mass index and anandamide levels in healthy controls but not in HDGEC.

Risk and Protective Factors for the Mental Health of Brazilian Healthcare Workers in the Frontline of COVID-19 Pandemic.

The objective was to compare the mental health indicators of health workers providing care to individuals with COVID-19 in Brazil, considering sociodemographic and occupational variables and the risk perception of contamination by the Sars-CoV-2 of workers from different professions, identifying risk and protective factors. A sample of 916 health workers was assessed: physicians, nursing workers, and workers from other professions (psychologists, physical therapists, nutritionists, speech therapists, occupational therapists, dentists, pharmacists, and social workers). REDCAP software was used to collect data online, using standardized instruments to assess anxiety, depression, posttraumatic stress, and insomnia, and one questionnaire addressed risk and protective variables. Statistical techniques for comparing groups were used along with logistic regression analysis. The results revealed that all the groups presented indicators of significant mental health problems (>36%), especially the nursing group. A larger percentage of participants, regardless of the profession, presented a high rate of insomnia disorders, while posttraumatic stress was the least expressive. Occupational variables stand out as risk factors for mental health, with specificities among the different groups. A protective factor for all the groups was having positive professional prospects. The protective factors for the physicians group included support provided by co-workers, being older and a man, while being satisfied with physical protective measures implemented by the employing institution was a protective factor for the groups composed of nursing workers and other professionals. These findings are relevant for devising mental health care strategies.

The prevalence and clinical correlates of cannabis use and cannabis use disorder among patients with bipolar disorder: A systematic review with meta-analysis and meta-regression.

Bipolar disorder (BD) is commonly associated with comorbidities, especially substance use disorders. In light of this, the present review aimed to investigate the prevalence and clinical correlates of cannabis use in BD. Studies evaluating the prevalence of cannabis use among patients with BD and studies reporting a dichotomous sample of patients with cannabis use compared to those without the use were included. Meta-analyses using random-effects models were performed, and sources of heterogeneity were explored using meta-regression. The search resulted in 2918 publications, of which 53 were included. The prevalence of cannabis use was 24% (95%CI:18-29; k = 35; n = 51,756). Cannabis use was significantly associated with being younger, male, and single; having fewer years of education and an earlier onset of affective symptoms; and lifetime psychotic symptoms, suicide attempts, and use of tobacco, alcohol, and other substances. In conclusion, cannabis use present in almost one-quarter of patients with BD and is associated with factors that are highly relevant for both clinical practice and public health.

Personality Inventory for DSM-5 (PID-5): cross-cultural adaptation and content validity in the Brazilian context.

OBJECTIVE: To describe the process of cross-cultural adaptation of the Personality Inventory for DSM-5 (PID-5) to the Brazilian context. METHODS: Cross-cultural adaptation involved the steps of independent translation of the instrument, synthesis version, and back-translation. Analysis of content validity was conducted by a multidisciplinary expert committee and consisted of quantitative assessment of agreement indicators. The test was then applied to a target population. RESULTS: All the steps required for a cross-cultural adaptation were followed and satisfactory agreement values (≥ 4.75) were reached for most of the structures assessed. Most of the changes suggested by the experts were followed; these changes consisted primarily of adjustments to verb tense and agreement and the inclusion of letters and words to allow gender inflection. In the pre-test, no suggestions were made and the instrument was considered comprehensible. CONCLUSION: The Brazilian version of the PID-5 was found to be adequate to the Brazilian context from semantic, idiomatic, cultural, and conceptual perspectives. The Brazilian version assessed here can be freely used, was approved by the publishers who hold the copyright on the instrument, and is considered the official version of the instrument. New studies are underway to determine the validity and reliability of the PID-5.

Memory bias and personality characteristics in college students with social anxiety disorder

Abstract Introduction Some individuals are more susceptible to recalling false information about events that never happened in their life. Nevertheless, there are several factors, such as personality characteristics, that appear to be related to memory performance. Social anxiety also provokes memory deficits for events that happen to other people, because these individuals tend to focus on their own inner selves rather than on external signs. Objective To investigate the influence of the personality characteristics of individuals with social anxiety disorder (SAD) on memory performance. Methods In this study, 183 university students had their memory tested using a complex emotional story about a mother and her son. Only subjects without clinical symptoms of depression and general anxiety (N = 148; 61 with SAD) were included in the study. Participants were compared for differences in personality characteristics using the Factorial Inventory of Personality and for SAD using the Social Phobia Inventory. Results The main results showed that memory performance of individuals with low percentile ranks in the personality characteristic dominance, i.e., those with low self-esteem, remembered more true information about the story than those with high scores when they did not have SAD. Conclusion The results are helpful to foster better understanding of the personality characteristics related to SAD, such as low dominance, which implies low self-esteem and difficulties with trust and with imposing themselves on others. The results could help development and improvement of techniques for therapeutic intervention.

Cross-cultural validation of the Brief Social Phobia Scale for use in Portuguese and the development of a structured interview guide.

OBJECTIVE: To present the translation and validation of the Brief Social Phobia Scale for use in Brazilian Portuguese, to develop a structured interview guide in order to systemize its use and to perform a preliminary study of inter-rater reliability. METHOD: The instrument was translated and adapted to Portuguese by specialists in anxiety disorders and rating scales. A structured interview guide was created with the aim of covering all of the items of the instrument and grouping them into six categories. Specialists in mental health evaluated the guide. These professionals also watched the videotaped interviews of patients with and without social anxiety disorders, and, based on the interview guide, they rated the scale to evaluate its reliability. RESULTS: No semantic or linguistic adjustments were needed. For the complete scale, the general evaluation showed a percentage of agreement of 0.84 and intraclass coefficient of 0.91. The mean inter-rater correlation was 0.84. CONCLUSIONS: The Portuguese-language version of the Brief Social Phobia Scale is available for use in the Brazilian population, with rather acceptable indicators of inter-rater reliability. The interview guide was useful in providing these values. Further studies are needed in order to improve the reliability and to study other psychometric properties of the instrument.

Determination of Drugs in Plasma Samples by High-Performance Liquid Chromatography-Tandem Mass Spectrometry for Therapeutic Drug Monitoring of Schizophrenic Patients.

This work describes the development of a simple, sensitive and selective method based on high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) to determine antipsychotics (olanzapine, quetiapine, clozapine, haloperidol and chlorpromazine) along with antidepressants (mirtazapine, paroxetine, citalopram, sertraline, imipramine, clomipramine and fluoxetine), anticonvulsants (carbamazepine and lamotrigine) and anxiolytics (diazepam and clonazepam) in plasma samples obtained from schizophrenic patients. The samples were prepared by protein precipitation. The target drugs were separated on an XSelect SCH C18 column (100 mm × 2.1 mm × 2.5 µm) within 8.0 min by means of gradient elution. The drugs were then detected on a quadrupole tandem mass spectrometer equipped with an electrospray ionization source, operating in the multiple reactions monitoring mode and in the positive ionization mode. The LC-MS-MS method was linear range from subtherapeutic to toxic concentrations with lower limit of quantification values ranged from 0.2 to 5.0 ng mL(-1), precision with coefficient of variation values lower than 12%, and accuracy ranged from 90 to 108%. The developed method enabled successful analysis of the target drugs in plasma samples obtained from 51 schizophrenic patients. Therapeutic drug monitoring revealed that many of the evaluated schizophrenic patients presented altered plasma concentrations of the analyzed drugs. These altered concentrations resulted from pharmacokinetic interactions among the medications prescribed to treat schizophrenia.

Evaluation of the role of the cannabidiol system in an animal model of ischemia/reperfusion kidney injury.

OBJECTIVE: This work aimed to investigate the effects of the administration of cannabidiol in a kidney ischemia/reperfusion animal model. METHODS: Kidney injury was induced by 45 minutes of renal ischemia followed by reperfusion. Cannabidiol (5mg/kg) was administered immediately after reperfusion. RESULTS: Ischemia/reperfusion increased the IL-1 and TNF levels, and these levels were attenuated by cannabidiol treatment. Additionally, cannabidiol was able to decrease lipid and protein oxidative damage, but not the nitrite/nitrate levels. Kidney injury after ischemia/reperfusion seemed to be independent of the cannabidiol receptor 1 and cannabidiol receptor 2 (CB1 and CB2) expression levels, as there was no significant increase in these receptors after reperfusion. CONCLUSION: The cannabidiol treatment had a protective effect against inflammation and oxidative damage in the kidney ischemia/reperfusion model. These effects seemed to be independent of CB1/CB2 receptor activation.

Effects of cannabidiol (CBD) on regional cerebral blood flow.

Animal and human studies have suggested that cannabidiol (CBD) may possess anxiolytic properties, but how these effects are mediated centrally is unknown. The aim of the present study was to investigate this using functional neuroimaging. Regional cerebral blood flow (rCBF) was measured at rest using (99m)Tc-ECD SPECT in 10 healthy male volunteers, randomly divided into two groups of five subjects. Each subject was studied on two occasions, 1 week apart. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. SPECT images were acquired 90 min after drug ingestion. The Visual Analogue Mood Scale was applied to assess subjective states. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping (SPM). CBD significantly decreased subjective anxiety and increased mental sedation, while placebo did not induce significant changes. Assessment of brain regions where anxiolytic effects of CBD were predicted a priori revealed two voxel clusters of significantly decreased ECD uptake in the CBD relative to the placebo condition (p<0.001, uncorrected for multiple comparisons). These included a medial temporal cluster encompassing the left amygdala-hippocampal complex, extending into the hypothalamus, and a second cluster in the left posterior cingulate gyrus. There was also a cluster of greater activity with CBD than placebo in the left parahippocampal gyrus (p<0.001). These results suggest that CBD has anxiolytic properties, and that these effects are mediated by an action on limbic and paralimbic brain areas.

Electrodermically nonresponsive schizophrenia patients make more errors in the Stroop Color Word Test, indicating selective attention deficit.

This study investigated whether skin conductance responsivity is associated with selective attention assessed by the Stroop Color Word Test (SCWT) in schizophrenia patients. The subjects (31 schizophrenia patients and 20 patients with other psychotic diagnoses) were selected from among inpatients of a general hospital psychiatric ward or day hospital attendees. They were matched with 31 healthy volunteers. The patients began experimental sessions immediately after remission of an acute episode. The three groups of participants were subdivided according to electrodermal responsivity into nonresponsive (NR) and responsive (R) groups. After the psychophysiological recording, the SCWT was applied. Results indicated that on the SCWT, the error interference of the NR schizophrenia group was significantly higher than that of all the other groups. Furthermore, the NR schizophrenia patients had significantly more negative symptoms than the R schizophrenia patients. These results suggest that there is a homogeneous subgroup of schizophrenia patients characterized by low neurovegetative responsiveness to external stimuli, predominance of negative symptoms, and selective attention deficit.