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The objective of this article is to present a critical analysis of the research outlines used in empirical studies published between the years 2000 and March of 2007 about social anxiety disorder and its associations with social skills. Seventeen papers were identified and grouped into two classes for analysis, namely: Characterization of Social Skills Repertoire (N = 10) and Therapeutical Modalities -- Application and Comparison of Clinical Intervention (N = 7). The critical analysis of the research outlines pointed to the necessity of new studies with clinical and non-clinical samples, with random allocation of individuals, with the proposition of contextualized interaction tasks, in order to support the generalization as to the association of the social skills and social anxiety disorder, and to demonstrate the functionality and process by which anxiety interferes with social performance. [ABSTRACT FROM AUTHOR]

PURPOSE. This article evaluates the comparability of the telephone and in-person Structured Clinical Interview for DSM-IV (SCID) interviews in assessing patients with social anxiety disorder (SAD) as an independent anxiety diagnosis. DESIGN AND METHODS. One hundred subjects were randomly selected and interviewed with the SCID, once by telephone and once in person (1-3 months later). FINDINGS. The prevalence of SAD assessed with the telephone interviews was 56%, whereas the in-person prevalence was 52%, with no statistically significant difference. The test-retest kappa for the 200 interviews was .84, indication of excellent agreement. PRACTICE IMPLICATIONS. These findings, along with the existing evidence of their validity, should encourage the use of SCID by telephone for SAD diagnostic interviews. [ABSTRACT FROM AUTHOR]

Background: The concept of an "entourage" effect in the cannabis and cannabinoids' field was first introduced in the late 1990s, during a period when most research on medical cannabinoids focused on the effects of isolated cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol. Over the past decade, however, with the increased understanding of the endocannabinoid system, the discovery of other phytocannabinoids and their potential therapeutic uses, the term has gained widespread use in scientific reviews and marketing campaigns. Objective: Critically review the application of the term "entourage effect (EE)" in the literature and its endorsement by certain sectors of the cannabis market. Also, explore the perspectives for further interpretation and elaboration of the term based on current evidence, aiming to contribute to a more nuanced understanding of the concept and its implications for cannabinoid-based medicine. Methods: A comprehensive review of the literature was conducted to evaluate the current state of knowledge regarding the entourage effect. Relevant studies and scientific reviews were analyzed to assess the evidence of clinical efficacy and safety, as well as the regulation of cannabinoid-containing product production. Results: The EE is now recognized as a synergistic phenomenon in which multiple components of cannabis interact to modulate the therapeutic actions of the plant. However, the literature provides limited evidence to support it as a stable and predictable phenomenon. Hence, there is also limited evidence to support clinical efficacy, safety, and appropriate regulation for cannabinoid-containing products based on a "entourage" hypothesis. Conclusion: The EE has significant implications for the medical use of cannabinoid-containing products and their prescription. Nevertheless, a critical evaluation of the term's application is necessary. Further research and evidence are needed to establish the clinical efficacy, safety, and regulatory framework for these products. It's crucial that regulators, the pharmaceutical industry, the media, and health care providers exercise caution and avoid prematurely promoting the entourage effect hypothesis as a scientific proven phenomenon for cannabinoids and other cannabis-derived compound combinations.

Background: Agomelatine is an antidepressant drug that acts as an agonist of melatoninergic MT1/2 receptors and an antagonist of serotonergic 5-HT2C receptors. Studies suggest that agomelatine has anxiolytic properties in social anxiety, but there are no studies that assessed the effects of this compound in human experimental anxiety induced by a public speaking test. The objective of our investigation was to assess the effects of agomelatine on human experimental anxiety using the Simulation Public Speaking Test (SPST)., Methods: Agomelatine (25 mg, n = 14), citalopram (20 mg, n = 14), venlafaxine (75 mg, n = 14), or placebo (n = 14) were administered in single doses to healthy volunteers in a double-blind study. Subjective anxiety was assessed with the Visual Analogue Mood Scale. Arterial blood pressure, heart rate, and blood levels of prolactin and cortisol were also recorded, as well as plasma levels of the 3 drugs., Results: The SPST induced significant subjective, physiological, and hormonal effects in all groups. The SPST also increased the anxiety and decreased mental sedation Visual Analogue Mood Scale factors during the anticipatory and performance phases of the test. Citalopram increased anxiety during the test in females, whereas agomelatine and venlafaxine were not different from placebo., Conclusions: Confirming previous results, a serotonin selective reuptake inhibitor, citalopram, caused an anxiogenic effect in the SPST only in females. Acute administration of a low dose of agomelatine failed to modify the behavioral and physiological changes caused by this test. Future studies using higher doses and repeated administration should investigate if agomelatine behavioral and physiological effects could be detected in human experimental anxiety models., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The treatment of bipolar depression remains challenging due to the limited effective and safe therapeutic options available; thus, developing newer treatments that are effective and well tolerable is an urgent unmet need. The objective of the present trial was to test 150 to 300 mg/day of cannabidiol as an adjunctive treatment for bipolar depression., Method: A randomized, double-blind, placebo-controlled pilot study to assess the efficacy of adjunctive cannabidiol in bipolar depression was used. Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 8. Secondary outcomes included response and remission rates, changes in anxiety and psychotic symptoms, and changes in functioning. Patients continued double-blind treatment until week 12 to monitor for adverse effects, laboratory analysis, and manic symptoms. Study registry: NCT03310593., Results: A total of 35 participants were included. MADRS scores significantly decreased from baseline to the endpoint (placebo, -14.56; cannabidiol, -15.38), but there was no significant difference between the groups. Similarly, there were no other significant effects on the secondary outcomes. However, an exploratory analysis showed a significant effect of cannabidiol 300 mg/day in reducing MADRS scores from week 2 to week 8 (placebo, -6.64; cannabidiol, -13.72). There were no significant differences in the development of manic symptoms or any other adverse effects., Conclusion: Cannabidiol did not show significantly higher adverse effects than placebo. Despite the negative finding on the primary outcome, an exploratory analysis suggested that cannabidiol should be further studied in bipolar depression in higher doses of at least 300 mg/day and under research designs that could better control for high placebo response., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JAC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE)—National Health and Medical Research Council (NHMRC). JAC and JEH have received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm in the past. JAC, JEH, FK, FSG, and AWZ are coinventors of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; 29 July 2015; INPI on 19 August 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC, JEH, FSG, ACC, and AWZ are coinventors of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on 16 September 2016 (BR 112018005423-2). MKS reports research grants from SMRI, from the National Council for Scientific and Technological Development, Ministry of Science and Technology, Brazil (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq), and Coordination of Superior Level Staff Improvement (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES), and personal fees from SHIRE and Daichii-Sankyo, from FIPE-HCPA (Fundo de Incentivo à Pesquisa e Eventos – HCPA), and from CNPq Produtividade em Pesquisa outside of the submitted work. LNY is a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding from Abbvie, Alkermes, Allergan, Canadian Network for Mood and Anxiety Treatments (CANMAT), Canadian Institutes of Health Research (CIHR), Dainippon Sumitomo Pharma, Gedeon Richter, Intracellular Therapies, Lundbeck, Merck, Otsuka, Sanofi and Sunovion over the past 3 years. All other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: Conflict of Interest JA Crippa is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) – National Health and Medical Research Council (NHMRC). JA Crippa has received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JA Crippa is a coinventor of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JA, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JAC is a coinventor of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on September 16th, 2016 (BR 112018005423-2). The other authors declare that they have no conflicts of interest. JA Crippa is a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding from Janssen-Cilag, Torrent Pharm, Prati-Donaduzzi, PurMed Global, and BSPG Pharm over the past 3 years., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The effects of cannabidiol (CBD) on cognition has been investigated in recent years to determine the therapeutic potential of this cannabinoid for a broad gamut of medical conditions, including neuropsychiatric disorders. The aim of the present study was to perform a systematic review of studies that analyzed the effects of the acute and chronic administration of CBD on cognition in humans and animals both to assess the cognitive safety of CBD and to determine a beneficial potential of CBD on cognition. Methods: The PubMed, Web of Science, PsycINFO, and Scopus databases were searched in December of 2022 for relevant articles using the following combinations of keywords: ("cannabidiol" OR "CBD") AND ("cognition" OR "processing cognitive" OR "memory" OR "language" OR "attention" OR "executive function" OR "social cognition" OR "perceptual motor ability" OR "processing speed"). Results: Fifty-nine articles were included in the present review (36 preclinical and 23 clinical trials). CBD seems not to have any negative effect on cognitive processing in rats. The clinical trials confirmed these findings in humans. One study found that repeated dosing with CBD may improve cognitive in people who use cannabis heavily but not individuals with neuropsychiatric disorders. Considering the context of neuropsychiatric disorders in animal models, CBD seems to reverse the harm caused by the experimental paradigms, such that the performance of these animals becomes similar to that of control animals. Conclusions: The results demonstrate that the chronic and acute administration of CBD seems not to impair cognition in humans without neuropsychiatric disorders. In addition, preclinical studies report promising results regarding the effects of CBD on the cognitive processing of animals. Future double-blind, placebo-controlled, randomized clinical trials with larger, less selective samples, with standardized tests, and using different doses of CBD in outpatients are of particular interest to elucidate the cognitive effects of CBD.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Loureiro, Zuardi, Silveira, Crippa, Hallak and Osório.)

Background: Serotonergic hallucinogens and cannabinoids may alter the recognition of emotions in facial expressions (REFE). Cannabidiol (CBD) attenuates the psychoactive effects of the cannabinoid-1 agonist tetrahydrocannabinol. Ayahuasca is a dimethyltryptamine-containing hallucinogenic decoction. It is unknown if CBD may moderate and attenuate the effects of ayahuasca on REFE., Procedures: Seventeen healthy volunteers participated in a 1-week preliminary parallel-arm, randomized controlled trial for 18 months. Volunteers received a placebo or 600 mg of oral CBD followed by oral ayahuasca (1 mL/kg) 90 minutes later. Primary outcomes included REFE and empathy tasks (coprimary outcome). Tasks were performed at baseline and 6.5 hours, 1 and 7 days after the interventions. Secondary outcome measures included subjective effects, tolerability, and biochemical assessments., Results: Significant reductions (all P values <0.05) only in reaction times were observed in the 2 tasks in both groups, without between-group differences. Furthermore, significant reductions in anxiety, sedation, cognitive deterioration, and discomfort were observed in both groups, without between-group differences. Ayahuasca, with or without CBD, was well tolerated, producing mainly nausea and gastrointestinal discomfort. No clinically significant effects were observed on cardiovascular measurements and liver enzymes., Conclusions: There was no evidence of interactive effects between ayahuasca and CBD. The safety of separate and concomitant drug intake suggests that both drugs could be applied to clinical populations with anxiety disorders and in further trials with larger samples to confirm findings., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The FKBP5 and NR3C1 genes play an important role in stress response, thus impacting mental health. Stress factor exposure in early life, such as maternal depression, may contribute to epigenetic modifications in stress response genes, increasing the susceptibility to different psychopathologies. The present study aimed to evaluate the DNA methylation profile in maternal-infant depression in regulatory regions of the FKBP5 gene and the alternative promoter of the NR3C1 gene., Methods: We evaluated 60 mother-infant pairs. The levels of DNA methylation were analyzed by the MSRED-qPCR technique., Results: We observed an increased DNA methylation profile in the NR3C1 gene promoter in children with depression and children exposed to maternal depression (p < 0.05). In addition, we observed a correlation of DNA methylation between mothers and offspring exposed to maternal depression. This correlation shows a possible intergenerational effect of maternal MDD exposure on the offspring. For FKBP5, we found a decrease in DNA methylation at intron 7 in children exposed to maternal MDD during pregnancy and a correlation of DNA methylation between mothers and children exposed to maternal MDD (p < 0.05)., Limitations: Although the individuals of this study are a rare group, the sample size of the study was small, and we evaluated the DNA methylation of only one CpG site for each region., Conclusion: These results indicate changes in DNA methylation levels in regulatory regions of FKBP5 and NR3C1 in the mother-child MDD context and represent a potential target of studies to understand the depression etiology and how it occurs between generations., Competing Interests: Declaration of competing interest JAC and JECH are co-inventors (Mechoulam R, Crippa JA, Guimaraes FS, Zuardi A, Hallak, JE, and Breuer A) of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023” Def. US no. Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927). The University of São Paulo has licensed the patent to Phytecs Pharm (USP Resolution 15.1.130002.1.1). USP has an agreement with Prati-Donaduzzi (Toledo, Brazil) to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson's disease, and anxiety disorders.” JAC has received travel support from and is a medical advisor of the SCBD Centre, and has a grant from the University Global Partnership Network (UGPN) – “Global priorities in cannabinoid research excellence.” JAC is member of the international advisory board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE; funded by the National Health and Medical Research Council through the Centre of Research Excellence). The other authors report no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.

Child sexual abuse (CSA) is a frequent phenomenon, and women who report it are at a higher risk of mental disorders and sexual dysfunction. The application of a brief questionnaire could help gynecologists assessment of CSA history in women. This study was carried out including women ( n  = 593) who had been victims of CSA before the age of 18 years. We used the Early Trauma Inventory Self Report-Short Form (ETISR-SF) Part 4, the Female Sexual Function Index (FSFI), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), the Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), and a semi-structured instrument to assess CSA. Among the 593 women included, 77 agreed to answer the questionnaires, 62(80.5%) had traumatic sexual events, 53(68.8%) had a total FSFI score ≤ 26.55, and 64(84.2%) considered themselves victims of CSA. There was an association regarding the belief that CSA influenced their sex life and their being at risk for GAD ( p  = 0.001), PTSD ( p  = 0.02), and sexual abuse by a family member ( p  = 0.01). The risk factors were the presence of risk for GAD (OR = 5.88[1.3-27.03]) and CSA by a family member (OR = 5.78[1.57-21.28]). This methodology can assist gynecologists in assessing a patient's history of CSA.

The interest in psychedelic substances as potential treatments for psychiatric disorders is increasing. The β-carboline harmine, an Ayahuasca component, presents hallucinogenic and antidepressant effects. Although Ayuahuasca-and consequently harmine-is usually consumed in rituals, the role of social contexts in the behavioral effects of harmine has not been investigated yet. In this sense, affective states may modulate cohabitants' behavior, including learning/memory. This work investigates the effects of harmine on the learning/memory performance of rats evaluated on the contextual and tone fear conditioning (CFC and TFC) and on the plus-maze discriminative avoidance (PMDAT) tasks. The possible influence of a harmine-treated cohabitant was assessed by evaluating rats housed in homogeneous cages-where all the animals were acutely administered with the same treatment (vehicle, 5, 10, or 15 mg/kg harmine), and in heterogeneous cages-where each animal received a different drug treatment. The main results are: (a) harmine impaired CFC (10 mg/kg) and PMDAT discrimination (all doses); and (b) harmine caused a memory deficit in CFC, TFC, and PMDAT of untreated rats kept in heterogeneous cages. Our results show that harmine induces a memory deficit in tasks with emotional contexts. Further, the cohabitation with animals treated with this drug also seems to impair memory performance of untreated animals. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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., Competing Interests: Conflict of interest JASC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) – National Health and Medical Research Council (NHMRC). JASC has received travel support to attend scientific meetings and personal consultation fees from BSPG-Pharm. JASC is a coinventor of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” JASC is a coinventor of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on September 16th, 2016 (BR 112018005423–2). The other authors declare that they have no conflicts of interest. JASC is a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding from Janssen-Cilag, Torrent Pharm, Prati-Donaduzzi, PurMed Global, and BSPG Pharm over the past 3 years., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: No conflicts of interest declared concerning the publication of this article.

Objective: To assess whether the effects of oral administration of 300 mg of Cannabidiol (CBD) for 28 days on mental health are maintained for a period after the medication discontinuation. Methods: This is a 3-month follow-up observational and clinical trial study. The data were obtained from two studies performed simultaneously by the same team in the same period and region with Brazilian frontline healthcare workers during the COVID-19 pandemic. Scales to assess emotional symptoms were applied weekly, in the first month, and at weeks eight and 12. Results: The primary outcome was that, compared to the control group, a significant reduction in General Anxiety Disorder-7 Questionnaire (GAD-7) from baseline values was observed in the CBD group on weeks two, four, and eight (Within-Subjects Contrasts, time-group interactions: F 1-125 = 7.67; p = 0.006; η p 2 = 0.06; F 1-125 = 6.58; p = 0.01; η p 2 = 0.05; F 1-125 = 4.28; p = 0.04; η p 2 = 0.03, respectively) after the end of the treatment. Conclusions: The anxiolytic effects of CBD in frontline health care professionals during the COVID-19 pandemic were maintained up to 1 month after the treatment discontinuation, suggesting a persistent decrease in anxiety in this group in the real world. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings and weigh the benefits of CBD therapy against potential undesired or adverse effects., Competing Interests: AZ reported receiving grants from the National Institute of Translational Science and Technology in Medicine and personal fees from the National Council for Scientific and Technological Development during the conduct of the study, being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs), and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. FG reported receiving grants from Prati-Donaduzzi, being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs), and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. AC reported having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. JH reported receiving grants from Prati-Donaduzzi, travel support and personal fees from BioSynthesis Pharma Group, being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs), and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. RD Santos reported receiving grants from the National Council for Scientific and Technological Development during the conduct of the study. RM reported being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs) outside the submitted work. FK reported receiving grants from the Canada Foundation for Innovation, the National Council for Scientific and Technological Development, Mitacs, and the Stanley Medical Research Institute; personal fees from Aché Laboratorios Farmaceuticos, Daiichi Sankyo, and Janssen-Cilag; and being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs) outside the submitted work. MA reported receiving technical support from Salomao Zoppi Serviços Médicos e Participações during the conduct of the study and personal fees from Laboratório Chromatox outside the submitted work. JC reported receiving grants from the São Paulo Research Foundation and the National Institute of Translational Science and Technology in Medicine and personal fees from the National Council for Scientific and Technological Development and Salomão e Zoppi Serviços Médicos e Participações during the conduct of the study and receiving travel support and personal fees from BioSynthesis Pharma Group; serving as a member of the international advisory board of the Australian Centre for Cannabinoid Clinical and Research Excellence, National Health and Medical Research Council; being a co-owner of a patent for fluorinated cannabidiol compounds (licensed to Phytecs); and having a patent pending for a cannabinoid-containing oral pharmaceutical composition outside the submitted work. No other disclosures were reported., (Copyright © 2022 Souza, Zuardi, Guimarães, Osório, Loureiro, Campos, Hallak, Dos Santos, Machado Silveira, Pereira-Lima, Pacheco, Ushirohira, Ferreira, Costa, Scomparin, Scarante, Pires-Dos-Santos, Mechoulam, Kapczinski, Fonseca, Esposito, Andraus and Crippa.)

Importance: Owing to its anti-inflammatory properties and antiviral "in vitro" effect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cannabidiol (CBD) has been proposed as a potential treatment for coronavirus disease 2019 (COVID-19). Objective: To investigate the safety and efficacy of CBD for treating patients with mild to moderate COVID-19. Design: Randomized, parallel-group, double-blind, placebo-controlled clinical trial conducted between July 7 and October 16, 2020, in two sites in Brazil. Setting: Patients were recruited in an emergency room. Participants: Block randomized patients (1:1 allocation ratio-by a researcher not directly involved in data collection) with mild and moderate COVID-19 living in Ribeirão Preto, Brazil, seeking medical consultation, and those who voluntarily agreed to participate in the study. Interventions: Patients received 300 mg of CBD or placebo added to standard symptomatic care during 14 days. Main Outcome and Measure: The primary outcome was reduction or prevention of the deterioration in clinical status from mild/moderate to severe/critical measured with the COVID-19 Scale or the natural course of the resolution of typical clinical symptoms. Primary study outcome was assessed on days 14, 21, and 28 after enrollment. Results: A total of 321 patients were recruited and assessed for eligibility, and 105 were randomly allocated either in CBD ( n =49) or in placebo ( n =42) group. Ninety-one participants were included in the analysis of efficacy. There were no baseline between-group differences regarding disease severity (χ 2 =0.025, p =0.988) and median time to symptom resolution (12 days [95% confidence interval, CI, 6.5-17.5] in the CBD group, 9 days [95% CI, 4.8-13.2] in the placebo group [χ 2 =1.6, p =0.205 by log-rank test]). By day 28, 83.3% in the CBD group and 90.2% in the placebo group had resolved symptoms. There were no between-group differences on secondary measures. CBD was well tolerated, producing mostly mild and transient side effects (e.g., somnolence, fatigue, changes in appetite, lethargy, nausea, diarrhea, and fever), with no significant differences between CBD and placebo treatment groups. Conclusions and Relevance: Daily administration of 300 mg CBD for 14 days failed to alter the clinical evolution of COVID-19. Further trials should explore the therapeutic effect of CBD in patients with severe COVID-19, possibly trying higher doses than the used in our study. Trial Registration: ClinicalTrials.gov identifier NCT04467918 (date of registration: July 13, 2020).

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 Fe 3 O 4 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Crippa, JC is a member of the International Advisory Board of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE)—National Health and Medical Research Council (NHMRC). JAC has received personal consultation fees from BSPG-Pharm and PurMed Global. He received speaking fees from Torrent, and Janssen. Crippa, JC is coinventor of the patent “Fluorinated CBD compounds, compositions and uses thereof. Pub. No.: WO/2014/108899. International Application No.: PCT/IL2014/050023,” Def. US number Reg. 62193296; July 29, 2015; INPI on August 19, 2015 (BR1120150164927; Mechoulam R, Zuardi AW, Kapczinski F, Hallak JEC, Guimarães FS, Crippa JAS, Breuer A). Universidade de São Paulo (USP) has licensed this patent to Phytecs Pharm (USP Resolution No. 15.1.130002.1.1) and has an agreement with Prati-Donaduzzi to “develop a pharmaceutical product containing synthetic CBD and prove its safety and therapeutic efficacy in the treatment of epilepsy, schizophrenia, Parkinson’s disease, and anxiety disorders.” Crippa, JC is coinventor of the patent “Cannabinoid-containing oral pharmaceutical composition, method for preparing and using same,” INPI on September 16, 2016 (BR 112018005423-2). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Rationale: Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellectual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence, morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression, sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder. These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence. Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotransmitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system and shows promising results in studies related to disorders in the central nervous system., Objectives: Review the preclinical and clinical data supporting CBD's potential as a treatment for the symptoms and comorbidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this drug., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Studies with cannabidiol (CBD) suggest that this compound has anxiolytic properties and may mediate the reconsolidation and extinction of aversive memories. The objective of this study was to test whether the administration of CBD 300 mg before the recall of traumatic events attenuated symptoms usually induced by recall in subjects diagnosed with posttraumatic stress disorder (PTSD) and if its potential effects interfere with the reconsolidation of aversive memories. The double-blind trial included 33 participants of both sexes, aged between 18 and 60 years, diagnosed with PTSD according to the SCID-5 and randomly allocated to two groups treated with CBD (n = 17) and placebo (n = 16). In the first experimental section, participants were matched by sex, age, body mass index (BMI), and PTSD symptoms as assessed with the Posttraumatic Stress Disorder Checklist (PCL-5). On the same day, participants prepared the behavior test, recording accounts of their traumas in digital audio for a minute and a half and then imagining the trauma for 30 s. After 7 days, participants received CBD (300 mg) or placebo and performed the behavioral test, listening to the trauma account and imagining themselves in that situation. Before and after the behavioral test, subjective changes in mood and anxiety were recorded (Visual and Analogical Mood Scale - VAMS and STAI-state), along with physiological correlates of anxiety blood pressure (BP), heart rate (HR), and salivary cortisol (SC). Seven days later, participants underwent the same procedures as the previous session, but without the pharmacological intervention, to assess the effect on reconsolidation of traumatic memories. We found that CBD significantly attenuated the increase in the VAMS scale cognitive impairment factor scores, under the CBD's effect, with this effect remaining 1 week after drug administration. No significant differences between the effects of CBD and placebo on anxiety, alertness, and discomfort induced by the recall of the traumatic event during the pharmacological intervention and in the subsequent week, in the absence of it. There were no significant differences between the CBD and placebo groups regarding physiological data (BP, HR, and SC). The attenuation of cognitive impairments during trauma recall under the effect of CBD may have interfered with the reconsolidation of traumatic memories concerning its association with cognitive impairments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We assessed whether administering cannabidiol (CBD) before recalling the traumatic event that triggered their disorder attenuates anxiety in patients with post-traumatic stress disorder (PTSD). As an exploratory pilot analysis, we also investigated whether this effect depends on the nature of the event (sexual vs. nonsexual trauma)., Methods: Thirty-three patients of both sexes with PTSD were recruited and randomized 1:1 into two groups. One group received oral CBD (300 mg), and the other received a placebo before listening to a digital audio playback of their previously recorded report of the trigger event. Subjective and physiological measurements were taken before and after recall. We analyzed the data in two subsamples: trigger events involving sexual and nonsexual trauma., Results: In the nonsexual trauma group, the differences between measurements before and after recall were significantly smaller with CBD than placebo; this held true for anxiety and cognitive impairment. However, in the sexual trauma group, the differences were non-significant for both measurements., Conclusion: A single dose of CBD (300mg) attenuated the increased anxiety and cognitive impairment induced by recalling a traumatic event in patients with PTSD when the event involved nonsexual trauma.

Competing Interests: None to declare.

This study aimed to assess the ultrapure cannabidiol (CBD) antibacterial activity and to investigate the antibacterial activity of the combination CBD + polymyxin B (PB) against Gram-negative (GN) bacteria, including PB-resistant Gram-negative bacilli (GNB). We used the standard broth microdilution method, checkerboard assay, and time-kill assay. CBD exhibited antibacterial activity against Gram-positive bacteria, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis), and Mycobacterium tuberculosis, but not against GNB. For most of the GNB studied, our results showed that low concentrations of PB (≤ 2 µg/mL) allow CBD (≤ 4 µg/mL) to exert antibacterial activity against GNB (e.g., Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii), including PB-resistant GNB. CBD + PB also showed additive and/or synergistic effect against LOS-expressing GND. Time-kill assays results showed that the combination CBD + PB leads to a greater reduction in the number of colony forming units per milliliter compared to CBD and PB alone, at the same concentration used in combination, and the combination CBD + PB was synergistic for all four PB-resistant K. pneumoniae isolates evaluated. Our results show that CBD has translational potential and should be further explored as a repurposed antibacterial agent in clinical trials. The antibacterial efficacy of the combination CBD + PB against multidrug-resistant and extensively drug-resistant GNB, especially PB-resistant K. pneumoniae, is particularly promising., (© 2022. The Author(s).)

Few longitudinal studies assessed the less immediate consequences of the COVID-19 pandemic on health workers' mental health, especially in less developed countries. The objective was to assess the evolution of mental health indicators of Brazilian health workers providing care to COVID-19 patients, considering the beginning and first wave of the pandemic, identifying risk and protective factors. A non-probabilistic sample of health professionals was assessed for 6 months at seven different points in time using standardized instruments to measure anxiety, depression, insomnia, posttraumatic stress, and burnout symptoms. Risk and protective factors were assessed using a questionnaire addressing socio-demographic, clinical, occupational variables, and COVID-19 risk perception. The results indicate high rates for all the indicators (>30%) throughout the follow-up; only anxiety symptoms decreased in the different phases compared to the baseline. Depression and insomnia symptoms showed a significant drop in isolated points of the assessment, which were not maintained at the final follow-up. Burnout indicators concerning emotional exhaustion and depersonalization remained stable (40 and 20%), while professional achievement decreased by approximately 19%. Occupational and personal characteristics (profession and work setting), perceptions regarding protective measures imposed by the institutions, and future professional prospects stood out as risk/protective factors in mental health. Unlike European and Asian countries, where mental distress symptoms tended to decrease over the pandemic, this study's results suggest alarming indicators of mental health problems remaining stable with burnout symptoms on the rise. Hence, the different contexts across countries, with different management resources and investments in health actions, seem to influence workers' mental health differently, demanding constant attention and monitoring and measures to minimize the impacts on individuals and collectives, especially in less developed countries like Brazil., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewers SP and Y-PW declared a shared affiliation with the authors FO, AZ, IS, JC, JH, KP-L, and SL at the time of review., (Copyright © 2022 Osório, Zuardi, Silveira, Crippa, Hallak, Pereira-Lima and Loureiro.)

Clinical and preclinical evidence has indicated that estrogen depletion leads to memory impairments and increases the susceptibility to neural damage. Here, we have sought to investigate the effects of Cannabidiol (CBD) a non-psychotomimetic compound from Cannabis sativa, on memory deficits induced by estrogen depletion in rats, and its underlying mechanisms. Adult rats were subjected to bilateral ovariectomy, an established estrogen depletion model in rodents, or sham surgery and allowed to recover for three weeks. After that, they received daily injections of CBD (10 mg/kg) for fourteen days. Rats were tested in the inhibitory avoidance task, a type of emotionally-motivated memory. After behavioral testing they were euthanized, and their hippocampi were isolated for analysis of components of the Akt/GSK3β survival pathway and the antiapoptotic protein Bcl2. Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment. Ovariectomy also reduced Akt/GSK3β pathway's activation by decreasing the phosphorylation levels of Akt and GSK3β and Bcl2 levels, which were ameliorated by CBD. The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3β survival pathway's activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance., (Copyright © 2021. Published by Elsevier B.V.)

An early and persistent sign of Alzheimer's disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18 F-2-fluoro-2-deoxy-D-glucose ([ 18 F]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 [ 18 F]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. [ 18 F]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.

Cannabidiol (CBD), a major non-psychotomimetic component of the Cannabis sativa plant, shows therapeutic potential in several psychiatric disorders, including schizophrenia. The molecular mechanisms underlying the antipsychotic-like effects of CBD are not fully understood. Schizophrenia and antipsychotic treatment can modulate DNA methylation in the blood and brain, resulting in altered expression of diverse genes associated with this complex disorder. However, to date, the possible involvement of DNA methylation in the antipsychotic-like effects of CBD has not been investigated. Therefore, this study aimed at evaluating in mice submitted to the prepulse inhibition (PPI) model: i) the effects of a single injection of CBD or clozapine followed by AMPH or MK-801 on PPI and global DNA methylation changes in the ventral striatum and prefrontal cortex (PFC); and ii). if the acute antipsychotic-like effects of CBD would last for 24-h. AMPH (5 mg/kg) and MK-801 (0.5 mg/kg) impaired PPI. CBD (30 and 60 mg/kg), similar to clozapine (5 mg/kg), attenuated AMPH- and MK801-induced PPI disruption. AMPH, but not MK-801, increased global DNA methylation in the ventral striatum, an effect prevented by CBD. CBD and clozapine increased, by themselves, DNA methylation in the prefrontal cortex. The acute effects of CBD (30 or 60 mg/kg) on the PPI impairment induced by AMPH or MK-801 was also detectable 24 h later. Altogether, the results show that CBD induces acute antipsychotic-like effects that last for 24-h. It also modulates DNA methylation in the ventral striatum, suggesting a new potential mechanism for its antipsychotic-like effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Brain magnetic resonance imaging studies have not investigated the cortical surface comprehensively in schizophrenia subjects by assessing thickness, surface area and gyrification separately during the first-episode of psychosis (FEP) or chronic schizophrenia (ChSch)., Methods: We investigated cortical surface abnormalities in 137 FEP patients and 240 ChSch subjects compared to 297 Healthy Controls (HC) contributed by five cohorts. Maps showing results of vertexwise between-group comparisons of cortical thickness, area, and gyrification were produced using T1-weighted datasets processed using FreeSurfer 5.3, followed by validated quality control protocols., Results: FEP subjects showed large clusters of increased area and gyrification relative to HC in prefrontal and insuli cortices (Cohen's d: 0.049 to 0.28). These between-group differences occurred partially beyond the effect of sample. ChSch subjects displayed reduced cortical thickness relative to HC in smaller fronto-temporal foci (d: -0.73 to -0.35), but not beyond the effect of sample. Differences between FEP and HC subjects were associated with male gender, younger age, and earlier illness onset, while differences between ChSch and HC were associated with treatment-resistance and first-generation antipsychotic (FGA) intake independently of sample effect., Conclusions: Separate assessments of FEP and ChSch revealed abnormalities that differed in regional distribution, phenotypes affected and effect size. In FEP, associations of greater cortical area and gyrification abnormalities with earlier age of onset suggest an origin on anomalous neurodevelopment, while thickness reductions in ChSch are at least partially explained by treatment-resistance and FGA intake. Associations of between-group differences with clinical variables retained statistical significance beyond the effect of sample., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Importance: Frontline health care professionals who work with patients with COVID-19 have an increased incidence of burnout symptoms. Cannabidiol (CBD) has anxiolytic and antidepressant properties and may be capable of reducing emotional exhaustion and burnout symptoms., Objective: To investigate the safety and efficacy of CBD therapy for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19., Design, Setting, and Participants: This prospective open-label single-site randomized clinical trial used a 1:1 block randomization design to examine emotional exhaustion and burnout symptoms among frontline health care professionals (physicians, nurses, and physical therapists) working with patients with COVID-19 at the Ribeirão Preto Medical School University Hospital in São Paulo, Brazil. Participants were enrolled between June 12 and November 12, 2020. A total of 214 health care professionals were recruited and assessed for eligibility, and 120 participants were randomized in a 1:1 ratio by a researcher who was not directly involved with data collection., Interventions: Cannabidiol, 300 mg (150 mg twice per day), plus standard care or standard care alone for 28 days., Main Outcomes and Measures: The primary outcome was emotional exhaustion and burnout symptoms, which were assessed for 28 days using the emotional exhaustion subscale of the Brazilian version of the Maslach Burnout Inventory-Human Services Survey for Medical Personnel., Results: A total of 120 participants were randomized to receive either CBD, 300 mg, plus standard care (treatment arm; n = 61) or standard care alone (control arm; n = 59) for 28 days. Of those, 118 participants (59 participants in each arm; 79 women [66.9%]; mean age, 33.6 years [95% CI, 32.3-34.9 years]) received the intervention and were included in the efficacy analysis. In the treatment arm, scores on the emotional exhaustion subscale of the Maslach Burnout Inventory significantly decreased at day 14 (mean difference, 4.14 points; 95% CI, 1.47-6.80 points; partial eta squared [ηp2] = 0.08), day 21 (mean difference, 4.34 points; 95% CI, 0.94-7.73 points; ηp2 = 0.05), and day 28 (mean difference, 4.01 points; 95% CI, 0.43-7.59 points; ηp2 = 0.04). However, 5 participants, all of whom were in the treatment group, experienced serious adverse events: 4 cases of elevated liver enzymes (1 critical and 3 mild, with the mild elevations reported at the final 28-day assessment) and 1 case of severe pharmacodermia. In 2 of those cases (1 with critical elevation of liver enzymes and 1 with severe pharmacodermia), CBD therapy was discontinued, and the participants had a full recovery., Conclusions and Relevance: In this study, CBD therapy reduced symptoms of burnout and emotional exhaustion among health care professionals working with patients during the COVID-19 pandemic. However, it is necessary to balance the benefits of CBD therapy with potential undesired or adverse effects. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings., Trial Registration: ClinicalTrials.gov Identifier: NCT04504877.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Osório, Silveira, Pereira-Lima, Crippa, Hallak, Zuardi and Loureiro.)

Background: REM sleep behaviour disorder (RBD) is a common non-motor feature of Parkinson's disease (PD). Cannabidiol (CBD) is one of the main non-psychoactive components of Cannabis sativa and may represent an alternative route for treating RBD., Objective: This study assessed the efficacy and safety of CBD for RBD in PD., Methods: We conducted a phase II/III, double-blind, placebo-controlled clinical trial in 33 patients with RBD and PD. Patients were randomized 1:1 to CBD in doses of 75 to 300mg or matched capsules placebo and were followed up for 14 weeks. The primary outcomes were the frequency of nights with RBD, CGI-I, and CGI-S., Results: CBD showed no difference to placebo for primary outcomes. Regarding secondary outcomes, we observed a significant improvement in average sleep satisfaction from the 4th to 8th week in the CBD versus placebo group with P = 0.049 and P = 0.038, respectively., Conclusion: CBD, as an adjunct therapy, showed no reduction in RBD manifestations in PD patients. A transient improvement in sleep satisfaction with a dose of 300mg has been noted. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Schizophrenia is a complex disabling mental disorder, and many patients present poor response to available treatments. Accumulating evidence about the role of the glutamate/nitric oxide pathway in mediating the positive and negative symptoms of schizophrenia suggests potential benefits of drugs that modulate this system. The aim of this study was to test the efficacy of isosorbide mononitrate (ISMN) as an adjunctive therapy for symptomatic outpatients with schizophrenia., Methods: This was a 2-month randomized, double-blind, placebo-controlled trial with 24 schizophrenia patients. Participants were treated with ISMN 50 mg for 1 month and placebo for another month in a crossover design. The Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, Global Assessment of Functioning, and MATRICS Cognitive Consensual Battery were used for symptom assessment and arterial spin labeling was used to assess brain activation patterns., Results: We found significant differences in the total, general, and positive subscales of the PANSS, Global Assessment of Functioning scores, and Clinical Global Impression scores during treatment with ISMN relative to placebo. No treatment effects were found comparing scores in the MATRICS Cognitive Consensual Battery and the negative subscale of the PANSS between the active and placebo conditions. A post hoc analysis of neuroimaging data showed reduced activity in the thalamus in subgroup of patients with severe psychopathology., Conclusions: Schizophrenia patients with persistent symptoms showed significant improvement after 4 weeks of treatment with ISMN 50 mg/d compared with placebo. Isosorbide mononitrate added beneficial effects to antipsychotic treatment in terms of positive symptoms and functioning., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Essential tremor (ET) is a common clinical syndrome characterized by action tremors affecting both upper limbs that can compromise manual tasks' execution and impair functional and social performance. The primary pharmacological treatment is symptomatic, but effective medicines are somewhat limited. There is a clear need to find new effective therapies for the treatment of ET. Cannabidiol (CBD) is a modulator of CB1 receptor and CB1 agonists can reduce tremors in experimental models. We hypothesized that a single acute CBD intake would reduce tremors in ET patients. We performed a randomized, controlled, double-blind, crossover study on 19 patients with ET. They were 10 males and 9 females, had mean 63 years of age, and mean 23 years of disease duration and had insufficient control of their tremors with the usual pharmacological treatment. They ingested a single oral dose of CBD (300 mg) or placebo in two experimental sessions performed 2-weeks apart. Patients were evaluated immediately before and after oral ingestion (60 min and 210 min), using the Fahn-Tolosa-Marin clinical scale. There was no carryover effect. There were no significant differences in upper limb tremors score, specific motor task tremor scores (writing and drawing/pouring) or clinical impression of change after treatment with placebo or CBD. In conclusion, a single 300 mg oral dose of CBD had no significant effect on the severity of upper limb tremors of ET patients. Our findings did not exclude the possibility that chronic treatment with CBD could have a symptomatic effect., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Cannabis can synthetize more than 400 compounds, including terpenes, flavonoids, and more than 100 phytocannabinoids. The main phytocannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabis-based products are used as medicines in several countries. In this text, we present an overview of the main neurochemical mechanisms of action of the phytocannabinoids, especially THC and CBD. We also reviewed the indications and adverse effects of the main cannabis-based medicinal products. THC acts as a partial agonist at cannabinoid 1/2 receptors (CB 1/2 ). It is responsible for the characteristic effects of cannabis, such as euphoria, relaxation, and changes in perceptions. THC can also produce dysphoria, anxiety, and psychotic symptoms. THC is used therapeutically in nausea and vomiting due to chemotherapy, as an appetite stimulant, and in chronic pain. CBD acts as a noncompetitive negative allosteric modulator of the CB 1 receptor, as an inverse agonist of the CB 2 receptor, and as an inhibitor of the reuptake of the endocannabinoid anandamide. Moreover, CBD also activates 5-HT 1A serotonergic receptors and vanilloid receptors. Its use in treatment-resistant epilepsy syndromes is approved in some countries. CBD does not produce the typical effects associated with THC and has anxiolytic and antipsychotic effects. Some of the most common adverse effects of CBD are diarrhea, somnolence, nausea, and transaminase elevations (with concomitant use of antiepileptics). The mechanisms of action involved in both the therapeutic and adverse effects of the phytocannabinoids are not fully understood, involving not only the endocannabinoid system. This "promiscuous" pharmacology could be responsible for their wide therapeutic spectrum.

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are phytocannabinoids being linked with modulation of anxiety and depression. The recognition of emotions in facial expressions (REFE) is impaired in these disorders. Both drugs could modulate anxiety and mood by interfering with REFE. Thus, a systematic review of controlled trials assessing the effects of THC and CBD on REFE was performed. Ten studies describing seven distinct experiments were found (n = 170). THC (7.5-15 mg) did not alter REFE in three experiments, but reduced task performance in other three experiments. CBD did not alter REFE in two experiments, but improved task performance and counteracted the effects of THC in one experiment. THC (≥ 10 mg) and CBD (600 mg) showed opposite effects on brain activation, skin conductance, and anxiety measures with negative/threatening faces. The limited number of studies precludes firm conclusions on the effects of these substances on REFE. Further controlled trials are needed to elucidate the effects of THC and CBD on REFE. The PROSPERO ID for this study is CRD42019135085., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) are frequent complications, and the endocannabinoid system has a role on its pathophysiology. To test the hypothesis that the functioning of the endocannabinoid system would be altered in PD and in LID by measuring plasma and CSF levels of α-N-arachidonoylethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in patients with PD with and without LID and in healthy controls. Blood and CSF samples were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. The levels of AEA and 2-AG were measured using a highly sensitive column switching ultrahigh-performance liquid chromatography-tandem mass spectrometry method. When pooled together, patients with PD had lower plasma and CSF levels of 2-AG and higher CSF levels of AEA compared to healthy controls (Mann-Whitney statistics = 303.0, p = 0.02). Patients with PD without LID had lower CSF levels of 2-AG (Kruskal-Wallis statistics = 7.76, p = 0.02) and higher CSF levels of AEA levels than healthy controls (Kruskal-Wallis statistics = 8.81, p = 0.01). The findings suggest that the endocannabinoid system participates in the pathophysiology of PD symptoms, but its role in the pathophysiology of LID is still unclear.