Effects of a Single Dose of Ayahuasca in College Students With Harmful Alcohol Use: A Single-blind, Feasibility, Proof-of-Concept Trial.

BACKGROUND: Ayahuasca is a South American plant hallucinogen rich in the psychedelic N,N-dimethyltryptamine and ß-carbolines (mainly harmine). Preclinical and observational studies suggest that ayahuasca exerts beneficial effects in substance use disorders, but these potentials were never assessed in a clinical trial. METHODS: Single-center, single-blind, feasibility, proof-of-concept study, assessing the effects of one dose of ayahuasca accompanied by psychological support (without psychotherapy) on the drinking patterns (primary variable) of 11 college students with harmful alcohol consumption. Secondary variables included safety and tolerability, craving, personality, anxiety, impulsivity, self-esteem, and social cognition. FINDINGS: Ayahuasca was well tolerated (no serious adverse reactions were observed), while producing significant psychoactive effects. Significant reductions in days per week of alcohol consumption were found between weeks 2 and 3 (2.90 ± 0.28 vs 2.09 ± 0.41; P < 0.05, uncorrected), which were not statistically significant after Bonferroni correction. There were no statistically significant effects for other variables, except for a significant reduction in reaction time in an empathy task. CONCLUSIONS: A significant reduction in days of alcohol consumption was observed 2-3 weeks after ayahuasca intake, but this effect did not survive after Bonferroni correction. The lack of significant effects in alcohol use and other variables may be related to the small sample size and mild/moderate alcohol use at baseline. The present study shows the feasibility of our protocol, paving the way for future larger, controlled studies.

Mundo de Pólus serious game for people with bipolar disorder.

BACKGROUND: Serious games are play-based technologies designed to teach users a wide range of concepts and skills applicable in the non-virtual environment. OBJECTIVES: This paper describes the process of developing a serious game for people with bipolar disorder to promote symptom recognition and the safe use of medications. METHODS: This study was based on the User-Centered Design methodological model and the theoretical framework for Participatory Design. We conducted interviews with health professionals and discussion circles with people with bipolar disorder and their family members in order to identify the learning needs related to symptom recognition and safe medication use. A categorical analysis was completed of the participants' reports and the scientific literature and formed the basis for the design of Mundo de Pólus. RESULTS: The game development process had three pillars (detailed in this manuscript): missions, simulation, and journal. The serious game focuses on the users' perceptions about their experience with the disorder, their interpersonal relationships, coping strategies, use of medications, and non-pharmacological treatments. CONCLUSIONS: These scientific and technological outcomes are useful to promote literacy and safety in medication therapy for people with bipolar disorder.

Amyotrophic Lateral Sclerosis: An Analysis of the Electromyographic Fatigue of the Masticatory Muscles.

Amyotrophic lateral sclerosis is a chronic degenerative disease that affects motor neurons, thereby promoting functional changes in the human body. The study evaluated the electromyographic fatigue threshold of the masseter and temporal muscles of subjects with amyotrophic lateral sclerosis. A total of eighteen subjects were divided into two groups: amyotrophic lateral sclerosis (n=9) and disease-free control (n=9). The groups were equally divided according to gender (7 males, 2 females). The fatigue threshold was analysed using median frequencies obtained during the 5-second window (initial [IP], mid [MP], and final [FP] periods) of electromyographic signalling of the masseter and temporal muscles bilaterally, with reduction in muscle force during maximal voluntary dental clenching. Significant difference (p<0.05) in the left temporal muscle: IP (p=0.05) and MP (p=0.05) periods was demonstrated. The amyotrophic lateral sclerosis group showed a decrease in median frequency of the electromyographic signal of the masseter and temporal muscles compared to the control group. Amyotrophic lateral sclerosis promotes functional impairment of the stomatognathic system, especially at the electromyographic fatigue threshold of the masticatory muscles.

Ayahuasca, an ancient substance with traditional and contemporary use in neuropsychiatry and neuroscience.

Ayahuasca is a botanical hallucinogenic preparation traditionally used for ritual and therapeutic purposes by native populations of the Northwestern Amazon. In the last decades, ayahuasca use has spread to Europe, the United States, Asia, and Africa, and interest in the possible therapeutic uses of ayahuasca for treating anxiety and mood disorder and substance-use disorders has increased both among the general public and the scientific community. Indeed, preclinical, observational, and preliminary clinical studies have corroborated some of these findings. In the present article, we present an overview of these studies and highlight the current uses of ayahuasca in neuroscience, such as a tool in the investigation of the neural basis of introspection and other complex cognitive processes.

Does Systemic Arterial Hypertension Change the Function of the Stomatognathic System?

The aim of this study was to evaluate the stomatognathic system of individuals with controlled systemic hypertension through comparison with a disease-free control group. Seventy individuals (44 female and 26 male) were divided into two groups: a controlled systemic hypertension (n=35) and a disease-free control (n=35). The individuals were evaluated on the basis of masticatory cycle efficiency of the value of the ensemble-averaged integrated linear envelope to the electromyographic signal of the masseter and temporalis muscles in the habitual (peanuts and raisins) and non-habitual chewing (Parafilm M); molar bite force (right and left) and ultrasound images from the bilateral masseter and temporal muscles at rest and maximum voluntary contraction. The data obtained were tabulated and submitted to statistical analysis (p<0.05). There was a significant difference between groups in the habitual (peanuts and raisins) and non-habitual (Parafilm M) chewing with reduced muscle activity to controlled systemic hypertension group. Muscle thickness occurred significant difference between groups at rest and maximum voluntary contraction of the temporalis muscles. There was no significant difference between groups in maximum molar bite force. The present study findings indicate that the controlled systemic hypertension promotes functional changes of the masticatory system, especially with respect to its masticatory efficiency and muscle thickness.

Effects of Parkinson's disease on molar bite force, electromyographic activity and muscle thickness of the masseter, temporal and sternocleidomastoid muscles: A case-control study.

BACKGROUND: Parkinson's disease is a neurological disorder that promotes motor changes in the body. OBJECTIVE: The aim of this study was to investigate the impairment of the stomatognathic function regarding molar bite force, electromyographic activity and thickness of the craniocervical muscles in patients with Parkinson's disease in comparison with those in asymptomatic controls. METHODS: Twenty-four subjects were divided into two groups, a Parkinson's disease group (n = 12) and a control group (n = 12). The subjects were evaluated on the basis of molar bite force, electromyographic activity (rest, right and left laterality, protrusion, maximum voluntary contraction) and thickness (rest and maximum voluntary contraction) of the right and left temporal (anterior portion), masseter and sternocleidomastoid muscles. The results were submitted to a multivariate analysis of variance (MANOVA) to compare the means of the two independent groups, considering diagnosis of Parkinson's disease and craniocervical muscles as independent variables. For the post hoc comparisons, Bonferroni correction was used (P < 0.05). RESULTS: Parkinson's disease group presented lower mean values both sides for maximal molar bite force, significant increases in the electromyographic activities during mandibular tasks, lower mean thickness values of the masseter and sternocleidomastoid muscles, and higher mean thickness values of the temporalis muscles (anterior portion). CONCLUSION: The results suggest that patients with Parkinson's disease may present functional changes of the stomatognathic system, related to bite force, electromyographic activity and thickness of the craniocervical muscles. The greater temporal muscle thickness in Parkinson's disease patients may compromise their daily life activities, especially with respect to chewing and nutrition.

Effects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia.

BACKGROUND: Better treatments for schizophrenia are urgently needed. The therapeutic use of the nitric oxide (NO)-donor sodium nitroprusside (SNP) in patients with schizophrenia has shown promising results. The role of NO in schizophrenia is still unclear, and NO modulation is unexplored in ketamine (KET) animal models to date. In the present study, we compared the behavioral effects of pre- and post-treatment with SNP, glyceryl trinitrate (GTN), and methylene blue (MB) in the acute KET animal model of schizophrenia. The present study was designed to test whether acute SNP, GTN, and MB treatment taken after (therapeutic effect) or before (preventive effect) a single KET injection would influence the behavior of rats in the sucrose preference test, object recognition task and open field. RESULTS: The results showed that KET induced cognitive deficits and hyperlocomotion. Long- term memory improvement was seen with the therapeutic GTN and SNP treatment, but not with the preventive one. MB pretreatment resulted in long-term memory recovery. GTN pre-, but not post-treatment, tended to increase vertical and horizontal activity in the KET model. Therapeutic and preventive SNP treatment consistently decreased KET-induced hyperlocomotion. CONCLUSION: NO donors - especially SNP - are promising new pharmacological candidates in the treatment of schizophrenia. In addition, we showed that the potential impact of NO-related compounds on KET-induced behavioral changes may depend on the temporal window of drug administration.

Paliperidone palmitate for refractory and clozapine-resistant schizophrenia.

This is a report on two cases of refractory schizophrenia and two cases of clozapine-resistant schizophrenia successful treated with paliperidone palmitate. To the authors' knowledge, this is the first report of the successful use of paliperidone palmitate in such patients.

NMDA and AMPA/kainate glutamatergic receptors in the prelimbic medial prefrontal cortex modulate the elaborated defensive behavior and innate fear-induced antinociception elicited by GABAA receptor blockade in the medial hypothalamus.

The aim of the present study was to investigate the involvement of N-methyl-d-aspartate (NMDA) and amino-3-hydroxy-5-methyl-isoxazole-4-proprionate (AMPA)/kainate receptors of the prelimbic (PL) division of the medial prefrontal cortex (MPFC) on the panic attack-like reactions evoked by γ-aminobutyric acid-A receptor blockade in the medial hypothalamus (MH). Rats were pretreated with NaCl 0.9%, LY235959 (NMDA receptor antagonist), and NBQX (AMPA/kainate receptor antagonist) in the PL at 3 different concentrations. Ten minutes later, the MH was treated with bicuculline, and the defensive responses were recorded for 10 min. The antagonism of NMDA receptors in the PL decreased the frequency and duration of all defensive behaviors evoked by the stimulation of the MH and reduced the innate fear-induced antinociception. However, the pretreatment of the PL cortex with NBQX was able to decrease only part of defensive responses and innate fear-induced antinociception. The present findings suggest that the NMDA-glutamatergic system of the PL is critically involved in panic-like responses and innate fear-induced antinociception and those AMPA/kainate receptors are also recruited during the elaboration of fear-induced antinociception and in panic attack-related response. The activation of the glutamatergic neurotransmission of PL division of the MPFC during the elaboration of oriented behavioral reactions elicited by the chemical stimulation of the MH recruits mainly NMDA receptors in comparison with AMPA/kainate receptors.

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

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

Interventions for deficits in recognition of emotions in facial expressions in major depressive disorder: An updated systematic review of clinical trials.

The recognition of emotions in facial expressions (REFE) is a core construct of social cognition. In the last decades, studies have showed that REFE is altered in major depressive disorder (MDD), but the evidence is conflicting. Thus, we conducted a systematic review of clinical trials involving therapeutic interventions in MDD and any evaluation of REFE to update (2018-2023) and systematically evaluate the evidence derived from controlled clinical trials on the effects of therapeutic strategies to MDD on the REFE. Eleven studies were included in the final review. Some interventions, including drugs (ketamine, bupropion, psylocibin) and non-pharmacological strategies (psychotherapy) seem to be able to reduce pre-existing REFE biases in MDD patients. However, there was a high heterogeneity in the evaluated studies, in terms of sample, interventions, tasks and results. Further studies and more consistent evaluation tools are highly needed to better understand nuanced deficits and specific actions of different treatment options.

Sodium nitroprusside as an adjunctive treatment for schizophrenia reduces the Ndel1 oligopeptidase activity.

OBJECTIVE: Schizophrenia (SCZ) is a disabling disorder that continues to defy clinicians and researchers. We investigated the effects of sodium nitroprusside (sNP) in an animal model of SCZ and as an add-on therapy in patients and the relationship between treatment with sNP and activity of the nDel1 enzyme, whose involvement in the pathophysiology of the disorder has been suggested earlier. METHODS: Ndel1 activity was measured following sNP infusions in spontaneously hypertensive rats (SHR; 2.5 or 5.0 mg/kg) and in a double-blind trial with SCZ patients (0.5 µg/kg/min). RESULTS: Ndel1 activity was significantly reduced after sNP infusion in blood of SHR compared to controls, and in patients receiving sNP (t = 7.756, df = 97, p < 0.0001, dcohen = 1.44) compared to placebo. Reduced Ndel1 activity between baseline and the end of the infusion was only seen in patients after treatment with sNP. CONCLUSION: Our findings suggest that SCZ patients may benefit from adjunctive therapy with sNP and that the Ndel1 enzyme is a candidate biomarker of psychopathology in the disorder. Future research should look into the role of Ndel1 in SCZ and the potential effects of sNP and drugs with similar profiles of action in both animals and patients.

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

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

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

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

Stroke: An electromyographic approach to the masseter and temporal muscles, orofacial soft tissue pressure, and occlusal force.

Stroke is a cerebrovascular disease that triggers changes in the central and peripheral nervous systems, and can compromise human body function. This cross-sectional observational study aimed to analyze the electromyographic (EMG) activity of the masseter and temporal muscles, orofacial soft tissue pressure, and strength of occlusal contacts in patients who had suffered a stroke. Twenty-four patients were divided into two groups: stroke (n = 12) and control (n = 12). The EMG of the masseter and temporal muscles was evaluated during mandibular rest, protrusion, right laterality, left laterality, and maximal voluntary contraction. The Iowa Oral Pressure Instrument (IOPI) was used to measure pressure from the tongue, lips, and buccinator muscles. A computerized system for occlusal analysis (T-Scan III) was used to measure the occlusal contact points of the right and left hemiarches (upper and lower) and the upper and lower first molars. Data were subjected to Student's t-test (p < 0.05). The stroke group had lower normalized electromyographic activity, with a significant difference in the left temporal muscle during rest (p = 0.03) when compared to the control group. There was a significant difference between the groups in tongue pressure (p = 0.004) with a lower mean value in the stroke group. There was a significant difference between the groups in the evaluation of the occlusal contact points of the first permanent molars, with a lower mean percentage in the stroke group. The results indicate that stroke negatively affects functional performance of the stomatognathic system.

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.

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.

Validation of the Subjective Handicap of Epilepsy (SHE) in Brazilian patients with epilepsy.

The objectives of the study were to translate and adapt the Subjective Handicap of Epilepsy (SHE) instrument to Brazilian Portuguese and to determine its psychometric properties for the evaluation of quality of life in patients with epilepsy. A sample of 448 adult patients with epilepsy with different clinical profiles (investigation, preoperative period, postoperative period, and drug treatment follow-up) was evaluated with the SHE and the Epilepsy Surgery Inventory (ESI-55). Exploratory factorial analysis demonstrated that four factors explained 60.47% of the variance and were sensitive to discriminate the different clinical groups, with the preoperative group having the poorest quality of life. Internal consistency ranged from 0.92 to 0.96, and concurrent validity with the ESI-55 was moderate/strong (0.32-0.70). Test-retest reliability was confirmed, with an ICC value of 0.54 (2 days), 0.91 (7 days), and 0.97 (30 days). The SHE had satisfactory psychometric qualities for use in the Brazilian population, similar to those of the original version. The instrument seems to be more adequate in psychometric terms for the postoperative and drug treatment follow-up groups, and its use should be encouraged.

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.