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.

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.

Evaluation of relationships between presence of adhesio interthalamica and cannabis use in first-episode psychosis: a magnetic resonance imaging investigation

ABSTRACT Recent studies suggested that cannabis use influences on the emergence of psychosis by disrupting neurodevelopmental processes that occur during adolescence and early adulthood and which are reflected on brain anatomical changes detectable with MRI. However, no MRI studies have investigated whether intrauterine neurodevelopmental abnormalities also interact with later cannabis use to influence on psychosis risk. We investigated differences between first-episode psychosis (FEP) patients with history of cannabis use (FEPC+, n=28), FEP subjects without cannabis use (FEPC-, n=78) and healthy controls (n=80) in regard to the frequency of absent or short Adhesio Interthalamica (AI), a well-established marker of intrauterine neurodevelopment. The FEPC+ subgroup had a significantly lower prevalence of absent AI than FEPC- subjects, as well as a lack of a significantly shorter AI length compared to controls (as found in FEPC- subjects). These preliminary results show that psychosis subjects with cannabis use present a low rather than high frequency of absent AI, suggesting that fixed intrauterine neurodevelopmental abnormalities may not be associated with cannabis use later in life to influence on the emergence of psychosis. This is consistent with a view that multiple different etiological processes may lead to similar clinical presentations in patients with FEP.

Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload.

Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats. In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction. Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed. Male rats received vehicle or iron carbonyl (30 mg/kg) from the 12th to the 14th postnatal days and were treated with vehicle or CBD (10 mg/kg) for 14 days in adulthood. Iron increased Caspase 9, Cytochrome c, APAF1, Caspase 3 and cleaved PARP, without affecting cleaved Caspase 8 levels. CBD reversed iron-induced effects, recovering apoptotic proteins Caspase 9, APAF1, Caspase 3 and cleaved PARP to the levels found in controls. These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action.

Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: Reversal by cannabidiol.

Evidence has demonstrated iron accumulation in specific brain regions of patients suffering from neurodegenerative disorders, and this metal has been recognized as a contributing factor for neurodegeneration. Using an experimental model of brain iron accumulation, we have shown that iron induces severe memory deficits that are accompanied by oxidative stress, increased apoptotic markers, and decreased synaptophysin in the hippocampus of rats. The present study aims to characterize iron loading effects as well as to determine the molecular targets of cannabidiol (CBD), the main non-psychomimetic compound of Cannabis sativa, on mitochondria. Rats received iron in the neonatal period and CBD for 14 days in adulthood. Iron induced mitochondrial DNA (mtDNA) deletions, decreased epigenetic modulation of mtDNA, mitochondrial ferritin levels, and succinate dehydrogenase activity. CBD rescued mitochondrial ferritin and epigenetic modulation of mtDNA, and restored succinate dehydrogenase activity in iron-treated rats. These findings provide new insights into molecular targets of iron neurotoxicity and give support for the use of CBD as a disease modifying agent in the treatment of neurodegenerative diseases.

Can anxiety increase tremors in patients with Parkinson's disease? An experimental model

Abstract Background Among non-motor symptoms of Parkinson's disease (PD), anxiety occurs in up to 67% of patients. Clinically, PD patients report worsening of tremors in anxiogenic situations. Objective The aim of this study was to evaluate the association between motor symptoms and anxiety in PD patients and compare their performances with those of healthy volunteers. Methods Fifteen volunteers with PD and 15 healthy volunteers without clinically significant psychiatric disorders were evaluated. Both groups were subjected to a simulated public speaking test (SPST). The following parameters were measured: visual analog mood scale (VAMS), items related to tremors of UPDRS, bradykinesia tests, blood pressure, and heart rate. Results Results of repeated measures ANOVA indicated a significant effect on group × phase interaction (F3.7,105.6 = 2.56; p = 0.046) for VAMS anxiety factor. Regarding tremors, ANOVA indicated significant differences in group × phase interaction (F4.5,121 = 2.88; p = 0.021) and between the groups (F1,27 = 45.88, p < 0.001), with differences in the anticipatory phase, performance, and post-speech, compared with those in the baseline. There were no significant differences between the groups with regard to other factors of VAMS, physiological measurements, and bradykinesia. Discussion Worsening of tremors occurred during SPST, particularly in phases with higher anxiety scores.

Early interventions for the prevention of PTSD in adults: a systematic literature review

Abstract Background Secondary interventions are implemented within a short interval following the occurrence of traumatic events with the purpose of preventing the onset of PTSD. Objective Analyze the results of studies that assessed post-trauma interventions in adults aimed at preventing the onset of PTSD or symptoms related to PTSD. Methods We performed literature searches using the search expression [(Early intervention OR secondary prevention) AND (Post traumatic stress disorder OR PTSD)] for articles published until October 2016. Among the references found, 29 fulfilled the selection criteria established for the review. Data were divided and analyzed according to the type of intervention: pharmacological or psychological. Results Psychological measures used in the studies lack homogeneity regarding the type of intervention and the assessment of intervention outcomes. Pharmacological interventions were less frequent and findings require replication, together with an expansion in the types of substances investigated. In general, many of the studies reviewed suggest that both pharmacological and psychological interventions are effective in the prevention of PTSD. Discussion Future trials should be focused on determining the best interventions for the secondary prevention of PTSD. The combination of psychological and pharmacological interventions for post-trauma patients poses opportunities and challenges that remain unexplored.

Heritability of social anxiety disorder: a systematic review of methodological designs

Abstract Background The investigation of heritability stands out as an important means to establish the weight of genetic and environmental factors in the development of social anxiety disorder. Objective This study aims to make a critical review of methodological designs used in the investigation of the social anxiety disorder (SAD) heritability. Methods We reviewed 31 research articles published until October 2015 and found through the electronic search bases PubMed, Web of Science, and Scopus and manual searches in the reference lists of the selected references. Most of the investigations involved adult samples and twins to assess heritability. Results There was great variability in the screening and diagnostic instruments used in the studies, leading to different outcomes. Structural equation models proved to be the most adequate to assess SAD heritability, allowing better estimates of this aspect of the disorder. SAD heritability rates varied between 13% and 76% in the articles reviewed. Discussion We discuss methodological aspects that may affect the quality and the development of improved studies to investigate SAD heritability such as sample size, quality of screening instruments, and use of diagnostic interviews. More homogeneous investigations involving larger samples and standardized instruments and methods are desirable and opportune.

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.

Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

Objective: To conduct a systematic literature review of animal and human studies reporting anxiolytic or antidepressive effects of ayahuasca or some of its isolated alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, and harmaline). Methods: Papers published until 3 April 2015 were retrieved from the PubMed, LILACS and SciELO databases following a comprehensive search strategy and using a predetermined set of criteria for article selection. Results: Five hundred and fourteen studies were identified, of which 21 met the established criteria. Studies in animals have shown anxiolytic and antidepressive effects of ayahuasca, harmine, and harmaline, and experimental studies in humans and mental health assessments of experienced ayahuasca consumers also suggest that ayahuasca is associated with reductions in anxiety and depressive symptoms. A pilot study reported rapid antidepressive effects of a single ayahuasca dose in six patients with recurrent depression. Conclusion: Considering the need for new drugs that produce fewer adverse effects and are more effective in reducing anxiety and depression symptomatology, the described effects of ayahuasca and its alkaloids should be further investigated.

Reprint of "Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio)".

Cannabidiol (CBD) has been investigated in a wide spectrum of clinical approaches due to its psychopharmacological properties. CBD has low affinity for cannabinoid neuroreceptors and agonistic properties to 5-HT receptors. An interaction between cannabinoid and purinergic receptor systems has been proposed. The purpose of this study is to evaluate CBD properties on memory behavioral and locomotor parameters and the effects of pre-treatment of adenosine receptor blockers on CBD impacts on memory using adult zebrafish. CBD (0.1, 0.5, 5, and 10mg/kg) was tested in the avoidance inhibitory paradigm and anxiety task. We analyzed the effect of a long-term caffeine pre-treatment (~20mg/L - four months). Also, acute block of adenosine receptors was performed in co-administration with CBD exposure in the memory assessment. CBD promoted an inverted U-shaped dose-response curve in the anxiety task; in the memory assessment, CBD in the dose of 5mg/Kg promoted the strongest effects without interfering with social and aggressive behavior. Caffeine treatment was able to prevent CBD (5mg/kg) effects on memory when CBD was given after the training session. CBD effects on memory were partially prevented by co-treatment with a specific A2A adenosine receptor antagonist when given prior to or after the training session, while CBD effects after the training session were fully prevented by adenosine A1 receptor antagonist. These results indicated that zebrafish have responses to CBD anxiolytic properties that are comparable to other animal models, and high doses changed memory retention in a way dependent on adenosine.

Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio).

Cannabidiol (CBD) has been investigated in a wide spectrum of clinical approaches due to its psychopharmacological properties. CBD has low affinity for cannabinoid neuroreceptors and agonistic properties to 5-HT receptors. An interaction between cannabinoid and purinergic receptor systems has been proposed. The purpose of this study is to evaluate CBD properties on memory behavioral and locomotor parameters and the effects of pre-treatment of adenosine receptor blockers on CBD impacts on memory using adult zebrafish. CBD (0.1, 0.5, 5, and 10mg/kg) was tested in the avoidance inhibitory paradigm and anxiety task. We analyzed the effect of a long-term caffeine pre-treatment (~20mg/L - four months). Also, acute block of adenosine receptors was performed in co-administration with CBD exposure in the memory assessment. CBD promoted an inverted U-shaped dose-response curve in the anxiety task; in the memory assessment, CBD in the dose of 5mg/Kg promoted the strongest effects without interfering with social and aggressive behavior. Caffeine treatment was able to prevent CBD (5mg/kg) effects on memory when CBD was given after the training session. CBD effects on memory were partially prevented by co-treatment with a specific A2A adenosine receptor antagonist when given prior to or after the training session, while CBD effects after the training session were fully prevented by adenosine A1 receptor antagonist. These results indicated that zebrafish have responses to CBD anxiolytic properties that are comparable to other animal models, and high doses changed memory retention in a way dependent on adenosine.

Cannabidiol Exposure During Neuronal Differentiation Sensitizes Cells Against Redox-Active Neurotoxins.

Cannabidiol (CBD), one of the most abundant Cannabis sativa-derived compounds, has been implicated with neuroprotective effect in several human pathologies. Until now, no undesired side effects have been associated with CBD. In this study, we evaluated CBD's neuroprotective effect in terminal differentiation (mature) and during neuronal differentiation (neuronal developmental toxicity model) of the human neuroblastoma SH-SY5Y cell line. A dose-response curve was performed to establish a sublethal dose of CBD with antioxidant activity (2.5 µM). In terminally differentiated SH-SY5Y cells, incubation with 2.5 µM CBD was unable to protect cells against the neurotoxic effect of glycolaldehyde, methylglyoxal, 6-hydroxydopamine, and hydrogen peroxide (H2O2). Moreover, no difference in antioxidant potential and neurite density was observed. When SH-SY5Y cells undergoing neuronal differentiation were exposed to CBD, no differences in antioxidant potential and neurite density were observed. However, CBD potentiated the neurotoxicity induced by all redox-active drugs tested. Our data indicate that 2.5 µM of CBD, the higher dose tolerated by differentiated SH-SY5Y neuronal cells, does not provide neuroprotection for terminally differentiated cells and shows, for the first time, that exposure of CBD during neuronal differentiation could sensitize immature cells to future challenges with neurotoxins.

Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection.

We have recently shown that chronic treatment with cannabidiol (CBD) was able to recover memory deficits induced by brain iron loading in a dose-dependent manner in rats. Brain iron accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's and Alzheimer's, and has been related to cognitive deficits in animals and human subjects. Deficits in synaptic energy supply have been linked to neurodegenerative diseases, evidencing the key role played by mitochondria in maintaining viable neural cells and functional circuits. It has also been shown that brains of patients suffering from neurodegenerative diseases have increased expression of apoptosisrelated proteins and specific DNA fragmentation. Here, we have analyzed the expression level of brain proteins involved with mitochondrial fusion and fission mechanisms (DNM1L and OPA1), the main integral transmembrane protein of synaptic vesicles (synaptophysin), and caspase 3, an apoptosis-related protein, to gain a better understanding of the potential of CBD in restoring the damage caused by iron loading in rats. We found that CBD rescued iron-induced effects, bringing hippocampal DNM1L, caspase 3, and synaptophysin levels back to values comparable to the control group. Our results suggest that iron affects mitochondrial dynamics, possibly trigging synaptic loss and apoptotic cell death and indicate that CBD should be considered as a potential molecule with memory-rescuing and neuroprotective properties to be used in the treatment of cognitive deficits observed in neurodegenerative disorders.

A motivational profile for smoking among adolescents.

OBJECTIVES: To characterize a motivational profile of reasons for smoking among teenagers. To investigate the influence of clinical and social elements on observed scores. METHODS: High school students who smoked in the past month (n = 226; age, 16.4 ± 10 years; 46.5% male) answered a questionnaire during school time. The instrument included the University of São Paulo Reasons for Smoking Scale (USP-RSS), the Fagerström Test for Nicotine Dependence, and clinical and social information. The USP-RSS scores from 307 healthy adult smokers (67.5% male; age, 37.9 ± 11.2 years) were also used for comparisons. RESULTS: Most of the adolescents (90.2%) exhibited low or very low levels of nicotine addiction (median Fagerström Test for Nicotine Dependence score 0, range 0 to 8). The mean scores of the USP-RSS subscales were as follows: Addiction, 1.9 ± 1.1; Pleasure From Smoking, 3.0 ± 1.3; Tension Reduction, 2.4 ± 1.3; Stimulation, 1.9 ± 0.9; Automatism, 1.3 ± 0.6; Handling, 2.3 ± 1.1; Social Smoking, 1.9 ± 1.0; Weight Control, 1.4 ± 1.0; and Affiliative Attachment, 1.6 ± 0.9. In comparison with adults, teenagers exhibited lower scores for Addiction, Pleasure From Smoking, Tension Reduction, Automatism, Weight Control, and Affiliative Attachment and higher scores for Social Smoking (P < 0.05). Older age, past school failure, illicit drugs use, alcohol abuse, high levels of perceived stress, and the death of at least one parent were associated with high scores for all subscales. CONCLUSIONS: The USP-RSS subscales Addiction, Pleasure From Smoking, and Social Smoking were important factors for adolescent smoking. Comparisons with adult smokers stressed the importance of the component of Social Smoking. The identification of distinctive factors that drive teenagers to smoke might help in making decisions dealing with interventions aimed at smoking cessation and control.

Higher prevalence of major depressive symptoms in Brazilians aged 14 and older

Objective: Depression is a highly prevalent condition and is considered a major public health issue. The aim of the present study was to estimate the prevalence of depressive symptoms in the Brazilian population and establish their sociodemographic correlates. Method: A cross-sectional study was conducted between November 2005 and April 2006. Data were collected in face-to-face interviews using a standardized questionnaire. The sample consisted of 3,007 interviews with individuals aged 14 years and older and followed a probabilistic design covering the Brazilian national territory. Depressive symptoms were assessed according to the Center for Epidemiologic Studies Depression Scale. Results: The observed prevalence of depressive symptoms was 28.3% (13% mild/moderate; 15.3% major/severe; p < 0.01). Increased depressive symptom rates were associated with being a female, being 45 years of age and older, having lower educational attainment, being single, having family income of up to 2.5 times minimum wage, and living in the northern region of Brazil (p < 0.05). Conclusions: The prevalence of depressive symptoms in Brazil is high, with major depressive symptoms being the most frequent form of this symptomatology. Considering the biopsychosocial model of mental disorders, this survey points to the involvement of psychosocial factors in the prevalence of depressive symptoms in Brazil. .

Validation of the state version of the Self-Statement during Public Speaking Scale

OBJECTIVE: To adapt the trait version of the Self Statements during Public Speaking (SSPS) scale to a state version (SSPS-S) and to assess its discriminative validity for use in the Simulated Public Speaking Test (SPST). METHOD: Subjects with and without social anxiety disorder (n = 45) were assessed while performing the SPST, a clinical-experimental model of anxiety with seven different phases. RESULTS: Alterations in negative self-assessment occurred with significant changes throughout the different phases of the procedure (p = .05). Non-cases presented significantly higher mean values of the SSPS-S in all phases of the procedure than cases (p < .01). CONCLUSION: Cases assessed themselves in a less positive and more negative manner during the SPST than did non-cases. SSPS-S is adequate for this assessment, especially its negative subscale, and shows good psychometric qualities.