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.

Pharmacological Interaction Between Cannabidiol and Tramadol on Experimental Diabetic Neuropathic Pain: An Isobolographic Analysis.

Introduction: Diabetic neuropathies are the most prevalent chronic complications of diabetes, characterized by pain and substantial morbidity. Although many drugs have been approved for the treatment of this type of pain, including gabapentin, tramadol (TMD), and classical opioids, it is common to report short-term results or potentially severe side effects. TMD, recommended as a second-line treatment can lead to unwanted side effects. Cannabidiol (CBD) has been gaining attention recently due to its therapeutic properties, including pain management. This study aimed to characterize the pharmacological interaction between CBD and TMD over the mechanical allodynia associated with experimental diabetes using isobolographic analysis. Materials and Methods: After diabetes induction by streptozotocin (STZ), diabetic rats were systemically treated with CBD or TMD alone or in combination (doses calculated based on linear regression of effective dose 40% [ED40]) and had the mechanical threshold evaluated using the electronic Von Frey apparatus. Both experimental and theoretical additive ED40 values (Zmix and Zadd, respectively) were determined for the combination of CBD plus TMD in this model. Results: Acute treatment with CBD (3 or 10 mg/kg) or TMD (2.5, 5, 10, or 20 mg/kg) alone or in combination (0.38+1.65 or 1.14+4.95 mg/kg) significantly improved the mechanical allodynia in STZ-diabetic rats. Isobolographic analysis revealed that experimental ED40 of the combination (Zmix) was 1.9 mg/kg (95% confidence interval [CI]=1.2-2.9) and did not differ from the theoretical additive ED40 2.0 mg/kg (95% CI=1.5-2.8; Zadd), suggesting an additive antinociceptive effect in this model. Conclusions: Using an isobolographic analysis, these results provide evidence of additive pharmacological interaction between CBD and TMD over the neuropathic pain associated with experimental diabetes induced by STZ.

Mental health trajectories of Brazilian health workers during two waves of the COVID-19 pandemic (2020-2021).

This study aimed to: (a) monitor the progression of symptoms of mental health burden among frontline workers caring for COVID-19 patients in Brazil during the two waves of the pandemic, considering the number of new cases and deaths, and; (b) to verify the different mental health outcomes and potential associations with current burnout symptoms. A non-probabilistic sample of health professionals was assessed as the pandemic progressed in Brazil (May/2020 August/2021). Standardized instruments focusing on anxiety, depression, insomnia, post-traumatic stress, and burnout symptoms were applied online. The results indicate a decrease in anxiety levels, what was related to when the number of new cases declined (end 1th-wave); symptoms returned to higher levels later. Emotional exhaustion increased when there was a higher incidence of cases, returning to the baseline levels at the end of the second wave. Depersonalization symptoms increased in this phase, characterized by a further decrease in new cases, while professional accomplishment decreased during the follow-up. The highest number of new cases was associated with a higher frequency of anxiety (OR = 1.467;95%CI = 1.109-1.941; p = 0.007) and professional accomplishment (OR = 1.490;95%CI = 1.098-2.023; p = 0.011). The subjects with trajectory of resilience against anxiety presented the lowest level of emotional exhaustion and depersonalization (p < 0.05). The conclusion is that the pressure experienced by healthcare professionals throughout the pandemic caused different impacts on their mental health, emphasizing the dynamic nature of this condition and the need for constant monitoring and care. This finding directly affects mental health prevention and intervention measures, which remain a priority and require continuous reinforcement, especially among the most vulnerable groups.

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.

Workplace Protections and Burnout Among Brazilian Frontline Health Care Professionals During the COVID-19 Pandemic.

Health care workers from low- and middle-income countries have been playing a critical role in overcoming the challenges related to the COVID-19 pandemic; yet little is known about the relationship between workplace protections and wellbeing of Brazilian health care workers during the pandemic. This study aimed to evaluate whether Brazilian health care workers were satisfied with their workplace measures to protect their physical and mental health during the pandemic, and to assess the associations of such levels of satisfaction with indicators of burnout. Licensed Brazilian health care professionals were recruited via popular media between 5/19/2020 and 8/23/2020 to complete an online survey including questions about their demographic/professional characteristics, satisfaction with their workplace protective measures during the pandemic, and validated questionnaires assessing neuroticism, resilient coping, and symptoms of burnout. Most participants reported being dissatisfied with their workplace measures to protect their physical (516, 56.3%) and mental health (756, 82.5%). In multivariable analysis adjusted for personal and environmental factors, dissatisfaction with workplace physical health protections was significantly associated with higher levels of emotional exhaustion (B = 1.08, 95% CI = 0.47-1.69) and depersonalization (B = 0.61, 95% CI = 0.10-1.12), and dissatisfaction with workplace mental health protections significantly associated with higher levels emotional exhaustion (B = 1.17, 95% CI = 0.40-1.95). Efforts to improve both physical and mental health protective measures are critical to guarantee that health care workers continue to provide care at their maximum capacity.

The anxiolytic effect of cannabidiol depends on the nature of the trauma when patients with post-traumatic stress disorder recall their trigger event

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.

Monitoring the Mental Health and Professional Overload of Health Workers in Brazil: A Longitudinal Study Considering the First Wave of the COVID-19 Pandemic.

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.

The anxiolytic effect of cannabidiol depends on the nature of the trauma when patients with post-traumatic stress disorder recall their trigger event.

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.

Effects of cannabidiol on symptoms induced by the recall of traumatic events in patients with posttraumatic stress disorder.

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.

Cannabidiol reverses memory impairments and activates components of the Akt/GSK3ß pathway in an experimental model of estrogen depletion.

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/GSK3ß 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/GSK3ß pathway's activation by decreasing the phosphorylation levels of Akt and GSK3ß and Bcl2 levels, which were ameliorated by CBD. The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3ß survival pathway's activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance.

Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors.

Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.

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.

Oral Cannabidiol Does Not Convert to Δ8-THC or Δ9-THC in Humans: A Pharmacokinetic Study in Healthy Subjects.

Introduction: Recent studies have suggested that cannabidiol (CBD) could interconvert into Delta-8- and Delta-9- tetrahydrocannabinol. Materials and Methods: Thus, we tested the plasma samples of 120 healthy human subjects (60 male and 60 female), 60 in fasting and the other 60 under normal feeding conditions after acute administration of an oral solution containing CBD 300 mg. To do this, we developed a bioanalytical method to determine CBD and the presence of THC in plasma samples by Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry. Results: The results showed that THC was not detected in plasma after the administration of CBD, and those study participants did not present psychotomimetic effects. Conclusions: The findings presented here are consistent with previous evidence suggesting that the oral administration of CBD in a corn oil formulation is a safe route for the administration of the active substance without bioconversion to THC in humans.

Is Cannabidiol During Neurodevelopment a Promising Therapy for Schizophrenia and Autism Spectrum Disorders?

Schizophrenia and autism spectrum disorders (ASD) are psychiatric neurodevelopmental disorders that cause high levels of functional disabilities. Also, the currently available therapies for these disorders are limited. Therefore, the search for treatments that could be beneficial for the altered course of the neurodevelopment associated with these disorders is paramount. Preclinical and clinical evidence points to cannabidiol (CBD) as a promising strategy. In this review, we discuss clinical and preclinical studies on schizophrenia and ASD investigating the behavioral, molecular, and functional effects of chronic treatment with CBD (and with cannabidivarin for ASD) during neurodevelopment. In summary, the results point to CBD's beneficial potential for the progression of these disorders supporting further investigations to strengthen its use.

Pharmacological interventions during the process of reconsolidation of aversive memories: A systematic review.

Reconsolidation is the return of a memory to a transient state of lability, following memory consolidation, that can occur when memories are evoked. During the process of reconsolidation, memories may be modified by different means, including the administration of drugs, during a period called the "reconsolidation window". This process has been widely studied in animals, but human studies are limited and include several methodological pitfalls. Our objective was to conducte a systematic review of the literature that utilizes pharmacological interventions during the process of reconsolidation of aversive memories in humans, with a critical analysis of the methodologies used. Searches were made in the electronic databases PubMed, Scopus, Web of Science and SciELO using the following search terms: (memory) AND (consolidation OR reconsolidation) AND (pharmacological manipulation OR pharmacological intervention). We found 294 references and ten (3.4%) were included in the review, based on preestablished eligibility criteria. All studies were randomized, double-blind clinical trials. The most commonly studied drug was propranolol. Two studies used a protocol involving autobiographical aversive memories, while in the remaining aversive memories were produced in the laboratory. The timing of pharmacological interventions is a controversial issue in the field, as drug activity must occur within the reconsolidation window. The small number of studies and some methodological difficulties of this type of research highlights the need for studies that individually evaluate some of the issues discussed, particularly the timing of pharmacological interventions and the duration of reconsolidation windows.