Systemic Chronic Treatment with Cannabidiol in Carioca High- and Low-Conditioned Freezing Rats in the Neuropathic Pain Model: Evaluation of Pain Sensitivity.

Studies have shown high comorbidity of anxiety disorder and chronic pain; generalized anxiety disorder (GAD) and neuropathic pain are among these pathologies. Cannabidiol (CBD) has been considered a promising treatment for these conditions. This study investigated whether chronic systemic treatment with CBD alters pain in high- (CHF) and low-freezing (CLF) Carioca rats (GAD model) and control rats (CTL) submitted to chronic neuropathic pain. The rats were evaluated in the sensory aspects (von Frey, acetone, and hot plate tests) before the chronic constriction injury of the ischiatic nerve (CCI) or not (SHAM) and on days 13 and 23 after surgery. Chronic treatment with CBD (5 mg/kg daily) was used for ten days, starting the 14th day after surgery. The open field test on the 22nd also evaluated locomotion and anxiety-like behavior. CBD treatment had an anti-allodynic effect on the mechanical and thermal threshold in all lineages; however, these effects were lower in the CHF and CLF lineages. Considering emotional evaluation, we observed an anxiolytic effect in CTL+CCI and CHF+CCI after CBD treatment and increased mobility in CLF+SHAM rats. These results suggest that the CBD mechanical anti-allodynic and emotional effects can depend on anxiety level.

Effect of two oral formulations of cannabidiol on responses to emotional stimuli in healthy human volunteers: pharmaceutical vehicle matters

Objective: To compare plasma concentrations of cannabidiol (CBD) following oral administration of two formulations of the drug (powder and dissolved in oil), and to evaluate the effects of these distinct formulations on responses to emotional stimuli in healthy human volunteers. Methods: In a randomized, double-blind, placebo-controlled, parallel-group design, 45 healthy male volunteers were randomly assigned to three groups of 15 subjects that received either 150 mg of CBD powder; 150 mg of CBD dissolved in corn oil; or placebo. Blood samples were collected at different times after administration, and a facial emotion recognition task was completed after 150 min. Results: There were no significant differences across groups in the subjective and physiological measures, nor in the facial emotion recognition task. However, groups that received the drug showed statistically significant differences in baseline measures of plasma CBD, with a significantly greater difference in favor of the oil formulation. Conclusion: When administered as a single 150-mg dose, neither formulation of oral CBD altered responses to emotional stimuli in healthy subjects. The oil-based CBD formulation resulted in more rapid achievement of peak plasma level, with an approximate fourfold increase in oral bioavailability.

Increased body sway in phobic patients exposed to images of spiders

Objective: The aim of the present study was to analyze the body sway response in specific phobia (SP) patients and healthy controls while viewing neutral, phobic, and disgusting images. Methods: The participants' heart rate (HR) and skin conductance were also recorded during the procedure. Nineteen patients with arachnophobia and 19 healthy volunteers matched by age, gender, and years of education underwent a postural control test on a stabilometric platform. Results: The platform recorded increased body sway in the SP group when exposed to spider images (SPI). The SP group presented increases in most parameters (SD, velocity, frequency, area, p ≤ 0.05) when viewing pictures of the SPI category. Psychometric measures of subjective anxiety (State-Trait Anxiety Inventory, STAI) and physiological states (HR; skin conductance responses; spontaneous fluctuations in skin conductance) showed increased anxiety (p ≤ 0.05) in the SP group compared to healthy volunteers. High anxiety levels were observed throughout the assessment, including the task of exposure to SPI (p ≤ 0.05). No significant effect or correlation was found between skin conductance and body sway measures (p > 0.05). Conclusions: The results of the postural control test suggest the occurrence of a defensive escape response in SP, in agreement with previous evidence.

Cannabidiol for the treatment of crack-cocaine craving: an exploratory double-blind study

Objective: To assess the efficacy of cannabidiol (CBD) in the management of crack-cocaine craving and the treatment of frequent withdrawal symptoms. Methods: Thirty-one men with a diagnosis of crack-cocaine dependence were enrolled in a randomized, double-blind, placebo-controlled trial. We applied neuropsychological tests and assessed craving intensity, anxiety and depression symptoms, and substance use patterns at baseline and at the end of the trial. The participants were treated with CBD 300 mg/day or placebo for 10 days. During this period, we used a technique to induce craving and assessed the intensity of symptoms before and after the induction procedure. Results: Craving levels reduced significantly over the 10 days of the trial, although no differences were found between the CBD and placebo groups. Craving induction was successful in both groups, with no significant differences between them. Indicators of anxiety, depression, and sleep alterations before and after treatment also did not differ across groups. Conclusion: Under the conditions of this trial, CBD was unable to interfere with symptoms of crack-cocaine withdrawal. Further studies with larger outpatient samples involving different doses and treatment periods would be desirable and timely to elucidate the potential of CBD to induce reductions in crack-cocaine self-administration.

Cannabidiol induces autophagy via ERK1/2 activation in neural cells.

Autophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

Associations between primary health care strategies and outcomes of mental disorders

Objective: To investigate associations between the percentage and severity of mental disorders (MD) and three different primary health care (PHC) strategies in Brazil: traditional care (TC), the Family Health Strategy (FHS), and FHS with shared mental health care (FHS+SC). Methods: Random samples were selected from three different areas of a Brazilian city. Each area was served by a different PHC strategy (TC, FHS, or FHS+SC). Five mental health professionals, blinded to the type of PHC strategy delivered in each area, conducted interviews using the Mini International Neuropsychiatric Interview (MINI) and other specific instruments to assess the prevalence and severity of MD. Results: 530 subjects were interviewed. The TC strategy was significantly associated with a higher percentage of MD when compared to FHS and FHS+SC. These results were not affected by adjustment for sociodemographic variables. The difference in prevalence of MD between the two FHS areas (with and without SC) was not statistically significant. No significant differences in MD severity were observed across the three PHC strategies. Conclusion: Areas covered by FHS showed a lower percentage of MD than those covered by TC. Presence of SC did not influence the prevalence of MD, suggesting that mental-health training of FHS teams may have minimized the influence of SC.

Biological bases for a possible effect of cannabidiol in Parkinson's disease

Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.

Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test

Objective: Cannabidiol (CBD), one of the non-psychotomimetic compounds of Cannabis sativa, causes anxiolytic-like effects in animals, with typical bell-shaped dose-response curves. No study, however, has investigated whether increasing doses of this drug would also cause similar curves in humans. The objective of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers performing a simulated public speaking test (SPST), a well-tested anxiety-inducing method. Method: A total of 57 healthy male subjects were allocated to receive oral CBD at doses of 150 mg (n=15), 300 mg (n=15), 600 mg (n=12) or placebo (n=15) in a double-blind procedure. During the SPST, subjective ratings on the Visual Analogue Mood Scale (VAMS) and physiological measures (systolic and diastolic blood pressure, heart rate) were obtained at six different time points. Results: Compared to placebo, pretreatment with 300 mg of CBD significantly reduced anxiety during the speech. No significant differences in VAMS scores were observed between groups receiving CBD 150 mg, 600 mg and placebo. Conclusion: Our findings confirm the anxiolytic-like properties of CBD and are consonant with results of animal studies describing bell-shaped dose-response curves. Optimal therapeutic doses of CBD should be rigorously determined so that research findings can be adequately translated into clinical practice.

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine - A translational double-blind study

Abstract Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38) were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min). First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

Características básicas do transtorno do pânico / Basic features of panic disorder

O objetivo é caracterizar o Transtorno do Pânico (TP) com ênfase em seu diagnóstico e tratamento. O TP é um dos transtornos de ansiedade, caracterizado por ataques de pânico recorrentes acompanhados por uma persistente preocupação com ataques adicionais e alterações mal adaptativas do comportamento (Associação Americana de Psiquiatria - DSM-V). Sua etiologia ainda não é conhecida, mas deve envolver uma interação de fatores genéticos, de desenvolvimento e ambientais que resultam em altera- ções no funcionamento de algumas áreas cerebrais. O tratamento farmacológico de primeira escolha é com o uso de antidepressivos inibidores seletivos da recaptação de serotonina, os quais apresentam uma latência de 20 a 30 dias para o início do efeito. (AU)

The aim of this paper is to characterize the Panic Disorder (PD) with an emphasis on diagnosis and treatment. PD is one of the anxiety disorders, characterized by recurrent panic attacks accompanied by a persistent preoccupation with additional attacks and maladaptive behavioral changes (American Psychiatric Association ­ DSM-V). Its etiology is not known, but should involve an interaction of genetic, developmental and environmental factors that result in changes in the functioning of some brain areas. The pharmacological treatment of choice is with the use of selective serotonin reuptake inhibitors, which has a latency of 20 for 30 days for the beginning of the therapeutic effect. (AU)

Características básicas do transtorno de ansiedade generalizada / Basic features of generalized anxiety disorder

Este texto é dirigido à alunos de graduação com o objetivo de caracterizar o Transtorno de Ansiedade Generalizada (TAG) com ênfase em seu diagnóstico e tratamento. O TAG é um dos transtornos psiquiá- tricos mais subdiagnosticados. Caracteriza-se por preocupação persistente e excessiva acompanhada de sintomas físicos relacionados a hiperatividade autonômica e a tensão muscular. Apresenta comorbidade frequente com depressão e outros transtornos de ansiedade. A abordagem psicoterápica, num sentido amplo, deve ser prioritária no tratamento desse distúrbio e o tratamento farmacológico, quando indicado, não deve ser a única opção terapêutica. (AU)

This text is addressed to medical undergraduate students with aim to characterize Generalized Anxiety Disorder (GAD) with emphasis on diagnosis and treatment. GAD is one of the most psychiatric disorders under-diagnosed. The main characteristic of GAD is persistent and excessive worry accompanied by physical symptoms related to autonomic hyperactivity and muscle tension. The comorbidity with depression and other anxiety disorders is frequently. The psychotherapeutic approach, in a wide sense, must be a priority in the treatment of this disease and, when indicated, the pharmacological treatment should not be the only therapeutic option. (AU)

Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol.

Animal studies and preliminary clinical trials have shown that cannabidiol (CBD)-enriched extracts may have beneficial effects for children with treatment-resistant epilepsy. However, these compounds are not yet registered as medicines by regulatory agencies. We describe the cases of two children with treatment-resistant epilepsy (Case A with left frontal dysplasia and Case B with Dravet Syndrome) with initial symptom improvement after the introduction of CBD extracts followed by seizure worsening after a short time. The children presented typical signs of intoxication by Δ9-THC (inappropriate laughter, ataxia, reduced attention, and eye redness) after using a CBD-enriched extract. The extract was replaced by the same dose of purified CBD with no Δ9-THC in both cases, which led to improvement in intoxication signs and seizure remission. These cases support pre-clinical and preliminary clinical evidence suggesting that CBD may be effective for some patients with epilepsy. Moreover, the cases highlight the need for randomized clinical trials using high-quality and reliable substances to ascertain the safety and efficacy of cannabinoids as medicines.

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years.

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.

Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia.

Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12months of a randomized double-blind, placebo-controlled clinical trial of minocycline add-on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12months of adjuvant treatment with minocycline (200mg/d) or placebo. MRI (1.5T) and [(99m)Tc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel-based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.

Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain

Objective: To investigate the effects of cannabidiol (CBD) on mitochondrial complex and creatine kinase (CK) activity in the rat brain using spectrophotometry. Method: Male adult Wistar rats were given intraperitoneal injections of vehicle or CBD (15, 30, or 60 mg/kg) in an acute (single dose) or chronic (once daily for 14 consecutive days) regimen. The activities of mitochondrial complexes and CK were measured in the hippocampus, striatum, and prefrontal cortex. Results: Both acute and chronic injection of CBD increased the activity of the mitochondrial complexes (I, II, II-III, and IV) and CK in the rat brain. Conclusions: Considering that metabolism impairment is certainly involved in the pathophysiology of mood disorders, the modulation of energy metabolism (e.g., by increased mitochondrial complex and CK activity) by CBD could be an important mechanism implicated in the action of CBD. .

Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: role for the adenosine A(2A) receptor.

Acute lung injury is an inflammatory condition for which treatment is mainly supportive because effective therapies have not been developed. Cannabidiol, a non-psychotropic cannabinoid component of marijuana (Cannabis sativa), has potent immunosuppressive and anti-inflammatory properties. Therefore, we investigated the possible anti-inflammatory effect of cannabidiol in a murine model of acute lung injury. Analysis of total inflammatory cells and differential in bronchoalveolar lavage fluid was used to characterize leukocyte migration into the lungs; myeloperoxidase activity of lung tissue and albumin concentration in the bronchoalveolar lavage fluid were analyzed by colorimetric assays; cytokine/chemokine production in the bronchoalveolar lavage fluid was also analyzed by Cytometric Bead Arrays and Enzyme-Linked Immunosorbent Assay (ELISA). A single dose of cannabidiol (20mg/kg) administered prior to the induction of LPS (lipopolysaccharide)-induced acute lung injury decreases leukocyte (specifically neutrophil) migration into the lungs, albumin concentration in the bronchoalveolar lavage fluid, myeloperoxidase activity in the lung tissue, and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) 1, 2, and 4days after the induction of LPS-induced acute lung injury. Additionally, adenosine A(2A) receptor is involved in the anti-inflammatory effects of cannabidiol on LPS-induced acute lung injury because ZM241385 (4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (a highly selective antagonist of adenosine A(2A) receptor) abrogated all of the anti-inflammatory effects of cannabidiol previously described. Thus, we show that cannabidiol has anti-inflammatory effects in a murine model of acute lung injury and that this effect is most likely associated with an increase in the extracellular adenosine offer and signaling through adenosine A(2A) receptor.

Psychometric qualities of the Brazilian versions of the Fagerström Test for Nicotine Dependence and the Heaviness of Smoking Index.

INTRODUCTION: This study examined the psychometric properties of the Brazilian versions of the Fagerström Test for Nicotine Dependence (FTND) and the Heaviness of Smoking Index (HSI). METHODS: The test-retest reliability of the FTND was assessed in a sample of 61 smoking university students, with a 15-day interval between assessments. The interrater reliability was examined in 30 smoking patients of a psychosocial care center for alcohol and drug users (PCC-AD). The reliability coefficient was estimated by the kappa and intraclass correlation coefficients. The predictive validity, internal consistency, and factor structure of the FTND and the HSI were evaluated by factor analysis in 271 smokers treated at an emergency unit and at the PCC-AD. The gold standard was the nicotine dependence criteria of DSM-IV, as assessed by the Structured Clinical Interview for DSM-IV. RESULTS: The FTND showed high reliability, with correlation coefficients of .92 for test-retest reliability and .99 for interrater reliability. Both the FTND and the HSI presented high levels of sensitivity and specificity. The internal consistency evaluation yielded a Cronbach's alpha coefficient of .83 for the FTND and of .56 for the HSI. An exploratory factor analysis found 2 factors in the FTND, which were validated by a confirmatory factor analysis. DISCUSSION: The results obtained in this study confirm the validity and reliability of the Brazilian versions of the FTND and the HSI.

A Faculdade de Medicina de Ribeirão Preto e a Reforma Universitária: o sonho de 1968 / The School of Medicine of Ribeirão Preto and the university reform: the dream of 1968

O objetivo dessa revisão é descrever a participação de docentes e discentes da Faculdade de Medicina de Ribeirão Preto (FMRP) nas discussões sobre a reforma da Universidade de São Paulo (USP), que ocorreram no ano de 1968. Essas discussões ocorreram em comissões compostas por igual número de docentes e discentes (comissões paritárias) e resultaram numa proposta de reforma aprovada por uma assembléia da FMRP, especialmente criada com essa finalidade. O artigo discute, também, o contexto e a influência dessas discussões na reforma aprovada pelo Conselho Universitário da USP, no início de 1969 e que ficou conhecido como Estatuto Hélio Lourenço.

The objective of this review is to describe the participation of the lecturers and students of the School of Medicine of Ribeirão Preto (FMRP) in discussions on reform of the University of São Paulo (USP), which occurred in the year 1968. These discussions occurred in committees composed of equal numbers of lecturers and students (parity committees) and resulted in a proposal for reform adopted by an assemblyof the FMRP, specially created for this purpose. The paper discuss also the context and influence of these discussions in the reform approved by the University Council at the beginning of 1969 and that became known as Hélio Lourenço's statute.

Cannabidiol increases Fos expression in the nucleus accumbens but not in the dorsal striatum.

Preclinical and clinical studies suggest that cannabidiol (CBD), a major component of Cannabis sativa, could produce antipsychotic effects without causing extra-pyramidal side-effects. In the present paper we employed the detection of Fos protein to investigate neuronal activation in the dorsal striatum and nucleus accumbens of male Wistar rats after systemic administration of CBD (120 mg/kg), haloperidol (1 mg/kg) or clozapine (20 mg/kg). Only haloperidol was able to increase the number of Fos immunoreactive neurons (FIr) in the dorsal striatum (vehicle: 0.07 +/- 0.07/0.1 mm(2), haloperidol: 28.3 +/- 8.9/0.1 mm(2), p < 0.01). In contrast, both haloperidol and CBD significantly increased FIr in the nucleus accumbens (Vehicle: 0 +/- 0/0.1 mm(2), haloperidol: 7.2 +/- 2.7/0.1 mm(2), CBD: 4.0 +/- 1.9/0.1 mm(2), p < 0.05). Clozapine also produced a barely significant increase in FIr (3.0 +/- 1.7/0.1 mm(2), p = 0.062). These results show that CBD is able to induce FIr in a limbic- but not in a motor-related area.