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.

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.

Animal models of anxiety disorders and stress

Anxiety and stress-related disorders are severe psychiatric conditions that affect performance in daily tasks and represent a high cost to public health. The initial observation of Charles Darwin that animals and human beings share similar characteristics in the expression of emotion raise the possibility of studying the mechanisms of psychiatric disorders in other mammals (mainly rodents). The development of animal models of anxiety and stress has helped to identify the pharmacological mechanisms and potential clinical effects of several drugs. Animal models of anxiety are based on conflict situations that can generate opposite motivational states induced by approach-avoidance situations. The present review revisited the main rodent models of anxiety and stress responses used worldwide. Here we defined as “ethological” the tests that assess unlearned/unpunished responses (such as the elevated plus maze, light-dark box, and open field), whereas models that involve learned/punished responses are referred to as “conditioned operant conflict tests” (such as the Vogel conflict test). We also discussed models that involve mainly classical conditioning tests (fear conditioning). Finally, we addressed the main protocols used to induce stress responses in rodents, including psychosocial (social defeat and neonatal isolation stress), physical (restraint stress), and chronic unpredictable stress.

Mecanismos de ação dos antipsicóticos: hipóteses dopaminérgicas / Mechanisms of antipsychotic medications: dopaminergic hypotheses

Esta revisão discute algumas das principais hipóteses sobre os mecanismos de ação dos antipsicóticos no tratamento da esquizofrenia. São abordadas as teorias tentando diferenciar os antipsicóticos atípicos dos típicos, como a do antagonismo de receptores D2 de dopamina e 5-HT2 de serotonina, a da dissociação rápida do receptor D2 e, por fim, a teoria do agonismo parcial. Elas constituem um exemplo fascinante de como evoluem as idéias sobre os efeitos dos medicamentos. Além disso, mostram que há uma necessidade crescente de conceitose termos básicos da Farmacologia para que se compreendam as diferenças observadas entre os antipsicóticos. Daí a justificativa para um texto que aborde os aspectos farmacológicos e as suas respectivas implicações.

Does the panic attack activate the hypothalamic-pituitary-adrenal axis?

Realizou-se levantamento bibliográfico no indexadorMEDLINE, através das palavras-chave "cortisol" e "panic", sem limite de tempo, restringindo-se a sereshumanos e à localização das palavras-chave no título e no resumo. Foram excluídos artigos de revisão e relatos de caso, estudos sobre alterações ocorridas entre dois ataques, e os que tratavam de outras doenças psiquiátricas ou de sujeitos sadios, quando não comparados com pacientes de pânico. Os resultados mostraram que ataques de pânico naturais ou provocados pelos agentes panicogênicos seletivos, lactato de sódio e dióxido de carbono, não ativam o eixo hipotálamo-pituitária-adrenal (HPA). Agonistas do receptor de colecistocinina B elevam os hormônios de estresse, quer haja ataque de pânico ou não, parecendo ativar diretamente o eixo HPA. O antagonista benzodiazepínico flumazenil não eleva o nível dos hormônios de estresse, porém não induz ataques de pânico de modo consistente. Agentes farmacológicos que produzem ansiedade em pacientes de pânico e em voluntários saudáveis elevam o nível dos hormônios de estresse, entre estes o antagonista a2-adrenérgico ioimbina, os agentes serotonérgicos 1-(m-clorofenil) piperazina (mCPP) e fenfluramina, bem como o agente psicostimulante cafeína. Portanto, o ataque de pânico não parece ativar o eixo HPA, ao contrário da ansiedade antecipatória.

Papel dual da serotonina na ansiedade / Dual role of serotonin in anxiety

Os autores fazem revisäo crítica e seletiva das evidências pré-clínicas, experimentais no ser humano e clínicas, que implicam a serotonina (5HT) nos estados de ansiedade, enfatizando sua participaçäo no transtorno do pânico (TP) e no transtorno de ansiedade generalizada (TAG), e apresentam a teoria de DEAKIN e GRAEFF (1991), que procura integrar conhecimentos básicos e clínicos dentro de perspectiva evolutiva. Esta hipótese atribui dupla funçäo à 5HT na regulaçäo de comportamentos defensivos, cujos correlatos clínicos seriam diferentes transtornos de ansiedade. Assim, postula que a via serotoninérgica que se origina no núcleo dorsal da rafe (NDR) e inerva a amígdala intensifica o medo condicionado e, por extensäo, a ansiedade anticipatória e o TAG. Em contrapartida, a via que parte do mesmo núcleo e inerva a matéria cinzenta periaquedutal dorsal inibe comportamentos defensivos do tipo luta ou fuga e, na clínica, os ataques de pânico. A seguir, mostram os resultados de testes experimentais da referida teoria, realizados em modelo animal de ansiedade especialmente desenvolvido para este fim - o labirinto em T elevado, e em dois modelos de ansiedade experimental humana aplicados em voluntários sadios - o teste de simulaçäo de falar em público e o condicionamento das resposta de condutância de pele por estímulos sonoros. De modo geral, os resultados obtidos mostraram que os tratamentos farmacológicos que intensificam a funçäo das vias serotoninérgicas originárias do NDR aumentaram o medo condicionado e diminuíram o medo incondicionado. Tais resultados, portanto, säo compatíveis com as previsöes da teoria submetida à verificaçäo. Finalmente, discutem algumas das implicaçöes clínicas desses achados, especificamente no que se refere ao potencial terapêutico da d-fenfluramina no TP

Efeito da d-fenfluramina na ansiedade induzida por uma simulaçäo de falar em público / Effect of d-fenfluramine on anxiety induced by a simulated public speaking test

Com o intuito de continuar a investigaçäo sobre a funçäo da serotonina (5-HT) na ansiedade, 43 volunt rios sadios receberam, em condiçöes duplo-cegas, d-fenfluramina (15 a 30mg VO) ou placebo e foram submetidos a um teste de simulaçäo de falar em público, que consiste em falar em frente a uma videocâmara. O procedimento provocou aumento significativo da ansiedade subjetiva e da pressäo arterial sistólica. A droga atenuou esse aumento sem causar sedaçäo física ou mental. Além disso, a d-fenfluramina näo alterou de maneira significativa os parâmetros fisiológicos. A d-fenfluramina libera 5-Ht dos terminais nervosos e bloqueia sua recaptaçäo, estimulando indiretamente receptores 5-HT pós-sin pticos. Dessa forma, os resultados sugerem que a 5-HT inibe o substrato neural da ansiedade induzida pelo teste de simulaçäo de falar em público