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| Animal studies evaluating the effects of cannabidiol (CBD) on social behavior. 

| Animal studies evaluating the effects of cannabidiol (CBD) on social behavior. 

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There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds. The endocannabinoid system has been suggested to represent a potential new target in this indication. While the chronic use of cannabis itself has been considered a risk factor contributing to the development of schizophrenia, t...

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... withdrawal is a key negative symptom of schizophrenia. Thus, several studies investigated the effects of cannabidiol on social behavior in different rodent animal models for schizophrenia ( Table 1). ...

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There are several lines of evidence indicating a possible therapeutic action of cannabidiol (CBD) in schizophrenia treatment. Studies with rodents have demonstrated that CBD reverses MK-801 effects in prepulse inhibition (PPI) disruption, which may indicate that CBD acts by improving sensorimotor gating deficits. In the present study, we investigat...

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... Finally, scarce evidence suggests the CBD might be useful for the treatment of other neurological and psychiatric disorders, such as schizophrenia and anxiety (Black et al., 2019). Although there is little clinical evidence for these indications (Crippa et al., 2018;Rohleder et al., 2016), anxiety is mentioned by a significant number of webpages. ...
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Background There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis. Methods We searched “medical cannabis” on June 2019 using google.com and downloaded the first 243 websites. After excluding dead links or websites with no information about cannabis, 176 websites were included. They were then classified for their typology (e.g., commercial, government, news outlets). As an indicator of trustworthiness, we used the Journal of American Medical Association (JAMA) score, which assesses the indication of date, author, ownership of the website, and the presence of references. We also considered if a website is certified by Health-On-the-Net (HON), an independent organization, by displaying a HONCode symbol. Subsequently, we performed a content analysis to assess both the medical cannabis indications mentioned by webpages and the completeness of the information provided (whether they mentioned potential side effects and legal/regulatory issues or not). Results Analyzing 176 webpages returned by a search engine, we found that 52% of them were news websites. Pain, epilepsy, and multiple sclerosis were the most frequently mentioned therapeutic areas (cited in 92, 84 and 80 webpages, respectively), which did not always match those for which there is regulatory approval. Information was also incomplete, with only 22% of the webpages mentioning potential side effects. Health portal websites provided the most complete information, with all of them ( n = 7) reporting side effects. On average, 80% of webpages had a neutral stance on the potential benefits of medical cannabis, with commercial websites having more frequently a positive stance (67%). Conclusions We conclude that the information that can be found online is not always aligned in terms of the therapeutic areas for which science-based evidence is often still weak.
... 28 This suggests that CBDs antipsychotic properties are mediated through FAAH inhibition or blockade of fatty acid-binding proteins (FABPs), which act as intracellular carriers. 30,31 The lipophilic nature of these eCBs and NAEs also allows them to modulate and readily cross the blood-brain barrier, 32-34 making them promising biomarker candidates and therapeutic targets. 35,36 Quantification of eCBs and NAEs relies on mass spectrometry as their concentrations are often found at trace levels under physiological conditions, making their detection difficult. ...
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Introduction: The primary compounds of Cannabis sativa, delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), inflict a direct influence on the endocannabinoid system-a complex lipid signaling network with a central role in neurotransmission and control of inhibitory and excitatory synapses. These phytocannabinoids often interact with endogenously produced endocannabinoids (eCBs), as well as their structurally related N-acylethanolamines (NAEs), to drive neurobiological, nociceptive, and inflammatory responses. Identifying and quantifying changes in these lipid neuromodulators can be challenging owing to their low abundance in complex matrices. Materials and Methods: This article describes a robust liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the extraction and quantification of the eCBs anandamide and 2-arachidonoylglycerol, along with their congener NAEs oleoylethanolamine and palmitoylethanolamine, and phytocannabinoids CBD, Δ9-THC, and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol, a major metabolite of Δ9-THC. Our method was applied to explore pharmacokinetic and pharmacodynamic effects from intraperitoneal injections of Δ9-THC and CBD on circulating levels of eCBs and NAEs in rodent serum. Results: Detection limits ranged from low nanomolar to picomolar in concentration for eCBs (0.012-0.24 pmol/mL), NAEs (0.059 pmol/mL), and phytocannabinoids (0.24-0.73 pmol/mL). Our method displayed good linearity for calibration curves of all analytes (R2>0.99) as well as acceptable accuracy and precision, with quality controls not deviating >15% from their nominal value. Our LC-MS/MS method reliably identified changes to these endogenous lipid mediators that followed a causal relationship, which was dependent on both the type of phytocannabinoid administered and its pharmaceutical preparation. Conclusion: We present a rapid and reliable method for the simultaneous quantification of phytocannabinoids, eCBs, and NAEs in serum using LC-MS/MS. The accuracy and sensitivity of our assay infer it can routinely monitor endogenous levels of these lipid neuromodulators in serum and their response to external stimuli, including cannabimimetic agents.
... Therefore, research into new therapeutics with fewer adverse effects is of immense importance. Cannabidiol (CBD) is being considered as a viable candidate for a next-generation antipsychotic, owing to its promising efficacy in SCZ and moderate side effects (93)(94)(95)(96). Although underlying mechanisms remain still conjectural, growing evidence suggests CBD may exert its antipsychotic properties, at least in part, via lipid signaling in the ECS (93)(94)(95)(96). ...
... Cannabidiol (CBD) is being considered as a viable candidate for a next-generation antipsychotic, owing to its promising efficacy in SCZ and moderate side effects (93)(94)(95)(96). Although underlying mechanisms remain still conjectural, growing evidence suggests CBD may exert its antipsychotic properties, at least in part, via lipid signaling in the ECS (93)(94)(95)(96). A systematic examination of lipids in response to CBD might shed light on their physiological relevance to CBD efficacy, particularly given recent dynamics investigating the consequence of phospholipidomic shifts on altered ECS function (75). ...
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Schizophrenia spectrum disorders (SSD) are traditionally diagnosed and categorized through clinical assessment, owing to their complex heterogeneity and an insufficient understanding of their underlying pathology. However, disease progression and accurate clinical diagnosis become problematic when differentiating shared aspects amongst mental health conditions. Hence, there is a need for widely accessible biomarkers to identify and track the neurobiological and pathophysiological development of mental health conditions, including SSD. High-throughput omics applications involving the use of liquid chromatography-mass spectrometry (LC-MS) are driving a surge in biological data generation, providing systems-level insight into physiological and pathogenic conditions. Lipidomics is an emerging subset of metabolomics, largely underexplored amongst the omics systems. Lipid profiles in the brain are highly enriched with well-established functions, including maintenance, support, and signal transduction of neuronal signaling pathways, making them a prospective and exciting source of biological material for neuropsychiatric research. Importantly, changes in the lipid composition of the brain appear to extend into the periphery, as there is evidence that circulating lipid alterations correlate with alterations of psychiatric condition(s). The relative accessibility of fluid lipids offers a unique source to acquire a lipidomic “footprint” of molecular changes, which may support reliable diagnostics even at early disease stages, prediction of treatment response and monitoring of treatment success (theranostics). Here, we summarize the latest fluid lipidomics discoveries in SSD-related research, examining the latest strategies to integrate information into multi-systems overviews that generate new perspectives of SSD-related psychosis identification, development, and treatment.
... Clinical studies have shown that cannabidiol (CBD), a nonaddictive cannabis compound, ameliorates schizophrenia symptoms (Leweke et al., 2012;Leweke et al., 2016;Rohleder et al., 2016;McGuire et al., 2018). Several experimental studies support the anti-psychotic properties of CBD by investigating its potential to counteract/reverse behavioral and neurobiological abnormalities that mirror psychosis and schizophrenia (Long et al., 2012;Rohleder et al., 2016;Osborne et al., 2017;Hudson et al., 2019;Rodrigues da Silva et al., 2020). ...
... Clinical studies have shown that cannabidiol (CBD), a nonaddictive cannabis compound, ameliorates schizophrenia symptoms (Leweke et al., 2012;Leweke et al., 2016;Rohleder et al., 2016;McGuire et al., 2018). Several experimental studies support the anti-psychotic properties of CBD by investigating its potential to counteract/reverse behavioral and neurobiological abnormalities that mirror psychosis and schizophrenia (Long et al., 2012;Rohleder et al., 2016;Osborne et al., 2017;Hudson et al., 2019;Rodrigues da Silva et al., 2020). CBD has been also reported to modulate acute KET-induced effects on neurobiological neuroplastic indices , while limited data have been published regarding the effect of CBD on KET-induced schizophrenia-like impairments (Kozela et al., 2020). ...
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Clinical evidence and experimental studies have shown the psychotomimetic properties induced by ketamine. Moreover, acute or chronic ketamine (KET) administration has been widely used for modeling schizophrenia-like symptomatology and pathophysiology. Several studies have reported the antipsychotic potential of cannabidiol (CBD), while there is limited information on the cannabidiol effect on KET-induced schizophrenia-like impairments. Therefore, the goal of the present study was to evaluate neuroplastic changes induced by repeated KET administration, which is used as an experimental model of schizophrenia—with a behavioral focus on positive-like symptomatology– and to assess the modulatory role of CBD treatment. The present findings have shown a robust increase in motor activity in KET-treated rats, following a 10-day period of chronic administration at the sub-anesthetic dose of 30 mg/kg (i.p), that was reversed to normal by subsequent chronic CBD treatment. Concerning the expression of glutamate receptors, the current findings have shown region-dependent KET-induced constitutional alterations in NMDA and AMPA receptors that were modified by subsequent CBD treatment. Additionally, repeated KET administration increased ERK1/2 phosphorylation state in all regions examined, apart from the ventral hippocampus that was modulated by subsequent CBD treatment. The present results show, for the first time, a stimulated motor output coupled with a specific glutamatergic-related status and ERK1/2 activation following chronic KET administration that were attenuated by CBD treatment, in a region-dependent manner. These findings provide novel information concerning the antipsychotic potential of CBD using a specific design of chronic KET administration, thus contributing to experimental approaches that mirror the symptomatology and pathophysiology of schizophrenia.
... Especially drug-drug interactions precipitated by CBD have gained interest as CBD is being employed in the treatment of refractory epilepsia [29,30]. There is further evidence for CBDs efficacy as an antipsychotic [31][32][33][34] and its usefulness in the treatment of non-motor symptoms in Parkinson's disease [35]. CYP3A4 inhibition by CBD may explain the increased buprenorphine levels observed. ...
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Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug-drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring.
... O Brasil vem apresentando papel relevante no cenário mundial nesta área do conhecimento. Grupos de pesquisadores brasileiros demonstraram o papel do CBD no tratamento de sintomas não motores chave, como os distúrbios do sono e a psicose 10,6 . Um estudo realizado na USP de Ribeirão Preto demonstrou melhora dos escores de qualidade de vida dos pacientes com doses de 300mg/dia de CBD purificado 24 . ...
... Brazil has been presenting a relevant role in the world scenario in this area of knowledge. Groups of Brazilian researchers demonstrated the role of cannabidiol (CBD) in the treatment of non-motor symptoms, such as sleep disorders and psychosis 10,11 . A study conducted at Ribeirão Preto University showed improved patients' quality of life scores with doses of 300mg/day of purified CBD 12 . ...
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This is a personal view about the role of cannabinoids in the management of PD non-motors symptoms. The author briefly reviewed the history of James Parkinson's original description and landmarks. In the light of research carried out in Brazil, the author comments on the main studies conducted in Brazilian universities. Finally, presents how the knowledge about the therapeutic class of cannabinoids should be explained to patients and developed in the Brazilian medical community.
... We report that early embryonic exposure to THC and CBD (until 10 h post-fertilization) impacts neural activity later in larval development (at 4 and 5 days post-fertilization (dpf)). The concentrations of THC and CBD used mimic plasma levels of human subjects with high cannabis consumption [35][36][37] , though complexity arises from estimating diffusion through multiple barriers (e.g. incubation media through the chorion and then into the plasma and tissues of the zebrafish embryo). ...
... Here, the doses of CBD and THC aligned with our previous work 13 , reflecting high cannabis consumption in humans. Comparisons of our dosage to humans requires various considerations: (1) blood plasma concentrations of THC can peak up to 0.25 mg/l while smoking a single cigarette 35 ; (2) the content of THC in cannabis has increased in the past 20 years; and (3) doses of intraperitoneally administered medical CBD can vary greatly, from 5 to 100 mg/kg, with a daily maximum of 1500 mg/ kg 36,37 . The current study uses up to 6 µg/mL of THC and 3 µg/mL of CBD and absorption studies using Liquid Chromatography-Tandem Mass Spectrometry suggest that an estimated 0.1-10% of toxic compounds will pass through the chorion to reach the embryo 40,41 . ...
Article
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In light of legislative changes and the widespread use of cannabis as a recreational and medicinal drug, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. Here, zebrafish embryos were exposed to cannabidiol (CBD) and Δ ⁹ -tetrahydrocannabinol (THC) until the end of gastrulation (1–10 h post-fertilization) and analyzed later in development (4–5 days post-fertilization). In order to measure neural activity, we implemented Calcium-Modulated Photoactivatable Ratiometric Integrator (CaMPARI) and optimized the protocol for a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses, both cannabinoids could dramatically reduce neural activity and locomotor activity. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using cannabinoid type 1 and 2 receptor inhibitors. Overall, we report that CBD toxicity occurs via two cannabinoid receptors and is synergistically enhanced by THC exposure to negatively impact neural activity late in larval development. Future studies are warranted to reveal other cannabinoids and their receptors to understand the implications of cannabis consumption on fetal development.
... Therefore, novel compounds with a different mechanism of action are currently investigated, such as cholinergic agents, dopamine D 1 agonists, glutamatergic agents (Buchanan et al., 2007), and CBD (Boggs et al., 2018). CBD seems to mediate its antipsychotic effects by modulating the endocannabinoid system Rohleder et al., 2016;Leweke et al., 2018). More precisely, its antipsychotic actions have been found to be related to increased levels of the endocannabinoid anandamide , e.g., by blocking the anandamide degrading enzyme fatty acid amide hydrolase (FAAH) or the fatty amide binding proteins (FABPs) that transport anandamide to the FAAH enzyme (Elmes et al., 2015). ...
Article
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Cannabidiol (CBD), a principal phytocannabinoid constituent, has demonstrated antipsychotic properties in recent clinical trials. While it has also been suggested a promising candidate for the treatment of neurodegenerative disorders, it failed to demonstrate efficacy in cognitive impairments associated with schizophrenia as an add-on treatment (600 mg/day for 6 weeks) in 18 chronically ill patients co-treated with a variety of psychopharmacologic drugs. Here, we report on the results of parallel-group, active-controlled, mono-therapeutic, double-blind, randomized clinical trial (CBD-CT1; ClinicalTrials.gov identifier: NCT00628290) in 42 acute paranoid schizophrenic patients receiving either CBD (up to 800 mg/day) or amisulpride (AMI, up to 800 mg/day) for four weeks in an inpatient setting with neurocognition as a secondary objective. Twentynine patients (15 and 14 in the CBD and AMI group, respectively) completed two cognitive assessments at baseline and the end of the treatment period. We investigated the following cognitive domains: pattern recognition, attention, working memory, verbal and visual memory and learning, processing speed, and verbal executive functions. When applying the Bonferroni correction for multiple testing, p < 0.0004 would indicate statistical significance. There was no relevant difference in neurocognitive performance between the CBD and the AMI group at baseline, and we observed no post-treatment differences between both groups. However, we observed improvements within both groups from pre-to post-treatment (standardized differences reported as Cohen’s d ) in visual memory (CBD: 0.49, p = 0.015 vs. AMI: 0.63, p = 0.018) and processing speed (CBD: 0.41, p = 0.004 vs. AMI: 0.57, p = 0.023). Furthermore, CBD improved sustained attention (CBD: 0.47, p = 0.013, vs. AMI: 0.52, p = 0.085), and visuomotor coordination (CBD: 0.32, p = 0.010 vs. AMI: 0.63, p = 0.088) while AMI led to enhanced working memory performance in two different paradigms (Subject Ordered Pointing Task–AMI: 0.53, p = 0.043 vs. CBD: 0.03, p = 0.932 and Letter Number Sequencing–AMI: 0.67, p = 0.017 vs. CBD: 0.08 p = 0.755). There was no relevant correlation between changes in neurocognitive parameters and psychotic symptoms or anandamide serum levels. This study shows that both CBD and AMI improve neurocognitive functioning with comparable efficacy in young and acutely ill schizophrenia patients via an anandamide-independent mechanism.
... Some clinical and preclinical evidence suggests the antipsychotic property of CBD (Zuardi et al., 2012;Saito et al., 2013;Rohleder et al., 2016;Schoevers et al., 2020). Furthermore, CBD does not promote the side effects commonly induced by the traditional antipsychotic drugs (Briles et al., 2012;Leweke et al., 2012;Gomes et al., 2013;Dos-Santos-Pereira et al., 2016;Park et al., 2018). ...
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Schizophrenia and autism spectrum disorders (ASD) are psychiatric neurodevelopmental disorders that cause high levels of functional disabilities. Also, the currently available therapies for these disorders are limited. Therefore, the search for treatments that could be beneficial for the altered course of the neurodevelopment associated with these disorders is paramount. Preclinical and clinical evidence points to cannabidiol (CBD) as a promising strategy. In this review, we discuss clinical and preclinical studies on schizophrenia and ASD investigating the behavioral, molecular, and functional effects of chronic treatment with CBD (and with cannabidivarin for ASD) during neurodevelopment. In summary, the results point to CBD's beneficial potential for the progression of these disorders supporting further investigations to strengthen its use.