cannabidiol and Psychotic-Disorders

Psychotic disorders are considered chronic mental health issues. Although it has been demonstrated that these disorders can present with a wide range of symptoms, pharmacological treatment is based on the use of typical and atypical antipsychotics, whose main mechanism of action is dopaminergic blockade, limiting their effect to the improvement of positive symptoms, without improving the rest of the symptoms and giving rise to a large number of serious adverse effects. For this reason, new therapeutic targets other than the dopaminergic system are being studied. The main objective of this review is to test whether these psychoactive substances used in clinical practice could provide additional benefits as an adjunctive treatment for people with psychotic disorders.. For this systematic review, a literature search was conducted in the databases PsycINFO, Medline, Psicodoc, PubMed and Google Scholar. Altogether 28 articles were included in the review. One of the main findings is that cannabidiol is more effective for improving positive symptoms and psychopathology; modafinil, for cognitive symptoms, motor and emotional functioning and quality of life; and ketamine, for negative symptoms. In addition, all the substances showed a good tolerability and safety profile, especially in comparison to antipsychotics.. The results obtained open up the possibility of having a guideline for clinicians/health professionals on the use of cannabidiol, modafinil and ketamine as adjunctive treatment for patients with psychotic conditions.. Uso de sustancias psicoactivas como tratamiento de la psicosis.. Introducción. Los trastornos psicóticos se consideran problemas crónicos de salud mental. Aunque se ha demostrado que estos trastornos pueden presentarse con sintomatologías muy heterogéneas, el tratamiento farmacológico se basa en el uso de antipsicóticos típicos y atípicos, cuyo mecanismo de acción principal es el bloqueo dopaminérgico, limitando su efecto a la mejora de los síntomas positivos, sin mejorar el resto de la sintomatología y presentando una gran cantidad de efectos adversos graves. Por este motivo se están estudiando nuevas dianas terapéuticas distintas al sistema dopaminérgico. El objetivo principal de esta revisión es comprobar si estas sustancias psicoactivas utilizadas en la práctica clínica podrían aportar beneficios adicionales como tratamiento complementario para personas con trastornos psicóticos. Desarrollo. Para esta revisión sistemática se realizó una búsqueda bibliográfica en las bases de datos PsycINFO, Medline, Psicodoc, PubMed y Google Scholar. Se incluyeron 28 artículos en la revisión. Entre los principales resultados encontramos que el cannabidiol es más efectivo para mejorar los síntomas positivos y la psicopatología; el modafinilo, para los síntomas cognitivos, el funcionamiento motor y emocional y la calidad de vida; y la ketamina, para los síntomas negativos. Además, todas las sustancias presentaron un buen perfil de tolerabilidad y seguridad, especialmente en comparación con los antipsicóticos. Conclusión. Con los resultados obtenidos, se abre la posibilidad de tener una guía de actuación para los clínicos/profesionales de la salud sobre el uso del cannabidiol, el modafinilo y la ketamina como tratamiento adyuvante para pacientes con cuadros psicóticos.

Topics: Antipsychotic Agents; Cannabidiol; Humans; Ketamine; Modafinil; Psychotic Disorders; Quality of Life

Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing.. We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine.. This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis RESULTS: There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC.. There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.

Topics: Antipsychotic Agents; Cannabidiol; Cannabinoids; Dopamine; Dronabinol; Humans; Psychotic Disorders; Reward

The pharmacological interventions available for individuals in the early stages of psychosis are extremely limited. For those at clinical high risk for psychosis, there is no licensed treatment available. For those with first-episode psychosis, all licensed antipsychotic medications act via dopamine D

Topics: Antipsychotic Agents; Cannabidiol; Cannabinoids; Cannabis; Humans; Psychotic Disorders

Amidst a rapidly changing legal landscape, cannabis use in the United States has become increasingly common in the past several years. There is strong evidence to suggest that chronic and early cannabis use increases the risk of developing a psychotic disorder, and there is at least moderate evidence that suggests ongoing cannabis use among individuals with a psychotic disorder worsens clinical outcomes (eg, decreased psychiatric medication adherence, more frequent psychiatric hospitalizations). In this Review Article, we provide a focused, clinically oriented overview of the epidemiology and characteristics of cannabis use among individuals with first-episode psychosis; evaluation of cannabis use; and treatment modalities, focusing on behavioral interventions suitable for outpatient primary care settings. We discuss the limited data supporting pharmacologic interventions for cannabis use disorder, specifically among individuals with first-episode psychosis, and the unique potential of cannabidiol to serve as a harm-reduction strategy for individuals who are not able or willing to achieve abstinence for cannabis.

Topics: Analgesics; Cannabidiol; Cannabis; Humans; Marijuana Abuse; Psychotic Disorders

Acute exposure to cannabis has been associated with an array of cognitive alterations, increased risk for neuropsychiatric illness, and other neuropsychiatric sequelae including the emergence of acute psychotic symptoms. However, the brain alterations associating cannabis use and these behavioral and clinical phenotypes remains disputed. To this end, neuroimaging can be a powerful technique to non-invasively study the impact of cannabis exposure on brain structure and function in both humans and animal models. While chronic exposure studies provide insight into how use may be related to long-term outcomes, acute exposure may reveal interesting information regarding the immediate impact of use and abuse on brain circuits. Understanding these alterations could reveal the connection with symptom dimensions in neuropsychiatric disorders and, more specifically with psychosis. The purpose of the present review is to: 1) provide an update on the findings of pharmacological neuroimaging studies examining the effects of administered cannabinoids and 2) focus the discussion on studies that examine the sensitive window for the emergence of psychosis. Current literature indicates that cannabis exposure has varied effects on the brain, with the principal compounds in cannabis (delta-9-tetrahydrocannabinol and cannabidiol) altering activity across different brain regions. Importantly, we also discovered critical gaps in the literature, particularly regarding sex-dependent responses and long-term effects of chronic exposure. Certain networks often characterized as dysregulated in psychosis, like the default mode network and limbic system, were also impacted by THC exposure, identifying areas of particular interest for future work investigating the potential relationship between the two.

Topics: Animals; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Humans; Neuroimaging; Psychotic Disorders

The most recent studies published or initiated in the last 18 months, investigating cannabidiol in the treatment of symptoms of schizophrenia and related conditions are summarized, including observed tolerability and reported side-effects.. Recent studies focused on patients with sub-acute psychotic syndromes of schizophrenia, clinical high-risk state for psychosis (CHR-P), or frequent cannabis users, as well as cognitive functioning in chronic schizophrenia. There is further, although not consistent evidence for cannabidiol-reducing positive symptoms, but not negative symptoms. Evidence for improvement of cognition was weaker, with one study reporting a worsening. Regarding side effects and tolerability, cannabidiol induced sedation in one study, with the other studies indicating good tolerability, even at high doses.. Recent clinical trials added further evidence for an antipsychotic potential of cannabidiol. In general, studies following trial designs as suggested by regulators in schizophrenia are needed in sufficient numbers to clarify the safety and efficacy of cannabidiol herein. In addition, such studies will further elucidate its ability to target specific aspects of the syndrome, such as negative or cognitive symptoms. Furthermore, aiming for an add-on treatment with cannabidiol will require further studies to identify potentially useful or even harmful combinations.

Topics: Antipsychotic Agents; Cannabidiol; Cognition; Humans; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

The potential therapeutic use of some

Topics: Animals; Anxiety; Cannabidiol; Depression; Dose-Response Relationship, Drug; Drug Administration Routes; Humans; Psychotic Disorders; Treatment Outcome

Cannabidiol (CBD) is a cannabis-derived medicinal product with potential application in a wide-variety of contexts; however, its effective dose in different disease states remains unclear. This review aimed to investigate what doses have been applied in clinical populations, in order to understand the active range of CBD in a variety of medical contexts.. Publications involving administration of CBD alone were collected by searching PubMed, EMBASE and ClinicalTrials.gov.. A total of 1038 articles were retrieved, of which 35 studies met inclusion criteria covering 13 medical contexts. Twenty-three studies reported a significant improvement in primary outcomes (e.g. psychotic symptoms, anxiety, seizures), with doses ranging between <1 and 50 mg/kg/d. Plasma concentrations were not provided in any publication. CBD was reported as well tolerated and epilepsy was the most frequently studied medical condition, with all 11 studies demonstrating positive effects of CBD on reducing seizure frequency or severity (average 15 mg/kg/d within randomised controlled trials). There was no signal of positive activity of CBD in small randomised controlled trials (range n = 6-62) assessing diabetes, Crohn's disease, ocular hypertension, fatty liver disease or chronic pain. However, low doses (average 2.4 mg/kg/d) were used in these studies.. This review highlights that CBD has a potential wide range of activity in several pathologies. Pharmacokinetic studies as well as conclusive phase III trials to elucidate effective plasma concentrations within medical contexts are severely lacking and highly encouraged.

Topics: Anxiety; Cannabidiol; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Humans; Psychotic Disorders; Randomized Controlled Trials as Topic; Seizures; Severity of Illness Index; Treatment Outcome

A major factor associated with poor prognostic outcome after a first psychotic break is cannabis misuse, which is prevalent in schizophrenia and particularly common in individuals with recent-onset psychosis. Behavioral interventions aimed at reducing cannabis use have been unsuccessful in this population. Cannabidiol (CBD) is a phytocannabinoid found in cannabis, although at low concentrations in modern-day strains. CBD has a broad pharmacological profile, but contrary to ∆9-tetrahydrocannabinol (THC), CBD does not activate CB1 or CB2 receptors and has at most subtle subjective effects. Growing evidence indicates that CBD acts as an antipsychotic and anxiolytic, and several reports suggest neuroprotective effects. Moreover, CBD attenuates THC's detrimental effects, both acutely and chronically, including psychotogenic, anxiogenic, and deleterious cognitive effects. This suggests that CBD may improve the disease trajectory of individuals with early psychosis and comorbid cannabis misuse in particular-a population with currently poor prognostic outcome and no specialized effective intervention.

Topics: Anti-Anxiety Agents; Antipsychotic Agents; Cannabidiol; Comorbidity; Humans; Marijuana Abuse; Psychotic Disorders

Topics: Animals; Anxiety; Brazil; Cannabidiol; Cannabis; Clinical Trials as Topic; Epilepsy; Humans; Neuroprotective Agents; Parkinson Disease; Psychotic Disorders; Translational Research, Biomedical

Despite extensive study over the past decades, available treatments for schizophrenia are only modestly effective and cause serious metabolic and neurological side effects. Therefore, there is an urgent need for novel therapeutic targets for the treatment of schizophrenia. A highly promising new pharmacological target in the context of schizophrenia is the endocannabinoid system. Modulation of this system by the main psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), induces acute psychotic effects and cognitive impairment. However, the non-psychotropic, plant-derived cannabinoid agent cannabidiol (CBD) may have antipsychotic properties, and thus may be a promising new agent in the treatment of schizophrenia. Here we review studies that investigated the antipsychotic properties of CBD in human subjects. Results show the ability of CBD to counteract psychotic symptoms and cognitive impairment associated with cannabis use as well as with acute THC administration. In addition, CBD may lower the risk for developing psychosis that is related to cannabis use. These effects are possibly mediated by opposite effects of CBD and THC on brain activity patterns in key regions implicated in the pathophysiology of schizophrenia, such as the striatum, hippocampus and prefrontal cortex. The first small-scale clinical studies with CBD treatment of patients with psychotic symptoms further confirm the potential of CBD as an effective, safe and well-tolerated antipsychotic compound, although large randomised clinical trials will be needed before this novel therapy can be introduced into clinical practice.

Topics: Antipsychotic Agents; Brain; Cannabidiol; Humans; Psychotic Disorders

Cannabis sativa is the most widely used illicit drug in the world. There is concern about its harmful effects, especially because of increasing potency, which has been reported globally. These effects seem to result from the relationship among its components, notably delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which have opposite effects. THC is considered responsible for the main psychotropic effects of the drug, while CBD seems to antagonize these effects, particularly those that induce psychosis.. We performed a PubMed literature review of research discussing the association of cannabidiol and psychosis published from 2006 to July 2014.. The effects of Cannabis seem to depend on several variables related to the type of plant, its strength, usage patterns, and intersubjective variations. CBD could be used to treat several conditions, including psychosis, when the current treatment is associated with significant side effects.. Because of the complexity of the subject, including limitations and contradictions in studies available to date, further research involving the possible antipsychotic effect and other potential positive effects of Cannabis are needed. There also are noteworthy differences between the research design parameters and recreational use of Cannabis.

Topics: Cannabidiol; Humans; Psychotic Disorders

Since most patients with schizophrenia do not respond properly to treatment, scientific effort has been driven to the development of new compounds acting on pharmacological targets beyond the dopaminergic system. Therefore, the aim is to review basic and clinical research findings from studies evaluating the effects of cannabidiol (CBD), an inhibitor of the reuptake and metabolism of anandamide and several other effects on nervous system, and sodium nitroprusside, a nitric oxide donor, on the prevention and treatment of psychosis. Animal and human research supports that CBD and sodium nitroprusside might be effective in the prevention and treatment of psychosis in general and especially in schizophrenia. The evidence available to date shows that CBD and sodium nitroprusside act in pathways associated with psychotic symptoms and that they may be important agents in the management of prodromal psychotic states and psychosis. This underscores the relevance of further research on the effects of these agents and others that mediate the activity of the cannabinoid system and of nitric oxide, as well as comparative studies of their antipsychotic effects and those of other antipsychotic drugs currently used to treat schizophrenia.

Topics: Animals; Antipsychotic Agents; Brain; Cannabidiol; Humans; Nitroprusside; Psychotic Disorders; Schizophrenia

Although cannabis use is associated with an increased risk of developing psychosis, the cannabis constituent cannabidiol (CBD) may have antipsychotic properties. This review concisely describes the role of the endocannabinoid system in the development of psychosis and provides an overview of currently available animal, human experimental, imaging, epidemiological and clinical studies that investigated the antipsychotic properties of CBD. In this targeted literature review we performed a search for English articles using Medline and EMBASE. Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved the use of CBD as intervention. Evidence from several research domains suggests that CBD shows potential for antipsychotic treatment.

Topics: Animals; Antipsychotic Agents; Cannabidiol; Databases, Bibliographic; Humans; Psychotic Disorders

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety Disorders; Arachidonic Acids; Cannabidiol; Clinical Trials as Topic; Depression; Dose-Response Relationship, Drug; Endocannabinoids; Humans; Neurogenesis; Phytotherapy; Polyunsaturated Alkamides; Psychotic Disorders; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT1A; Synaptic Transmission; TRPV Cation Channels

The first clinical trials with cannabidiol (CBD) as treatment for psychotic disorders have shown its potential as an effective and well-tolerated antipsychotic agent. However, the neurobiological mechanisms underlying the antipsychotic profile of CBD are currently unclear. Here we investigated the impact of 28-day adjunctive CBD or placebo treatment (600 mg daily) on brain function and metabolism in 31 stable recent-onset psychosis patients (<5 years after diagnosis). Before and after treatment, patients underwent a Magnetic Resonance Imaging (MRI) session including resting state functional MRI, proton Magnetic Resonance Spectroscopy (

Topics: Antipsychotic Agents; Brain; Cannabidiol; Humans; Magnetic Resonance Imaging; Psychotic Disorders

Psychotic disorders are a leading cause of disability in young adults. Antipsychotics have been the primary intervention for psychosis for over 60 years, and yet, we have made little progress in treating negative symptoms, neurocognition, and functional disability. There is growing evidence that cannabidiol (CBD) is effective in treating positive psychotic symptoms, possibly also negative and neurocognitive symptoms, and moreover is well tolerated compared to other psychotropic medications. Anecdotally, patients participating in the Cognitive Assessment and Risk Evaluation (CARE) Early Psychosis Treatment Program at the University of California, San Diego, are self-administering CBD and report subjective improvement in stress, anxiety, and ability to cope with symptoms. The overarching aim of the trial is to explore the effectiveness of CBD augmentation on symptoms and neurocognition in early psychosis while also exploring the mechanism of action of CBD and predictors of response to treatment. The mechanism by which cannabidiol has a therapeutic effect on psychosis is poorly understood. Recent evidence has suggested that CBD may reduce stress and pro-inflammatory biomarker levels. Endocannabinoids also have powerful roles in eating behavior, reward, and mood, indicating these neurotransmitters may play a role in reducing hyperphagia and metabolic abnormalities that are present early in the course of psychotic illness and exacerbated by antipsychotic medication. The neurophysiological effects of CBD have been studied in animal models of psychosis that show improvements in information processing in response to CBD, but there are no studies in individuals with early psychosis.. A total of 120 individuals in the early stages of psychosis will be randomized to 1000 mg of CBD versus placebo as an adjunct to existing treatment in a 8-week, double-blind superiority randomized control trial. The primary outcome measures are symptoms and neurocognition.. We hypothesized that CBD will improve symptoms and neurocognition as well as secondary outcome measures of neurohormones, inflammation, eating behaviors, and information processing. Importantly, predictors, moderators, and mediators of the CBD effects will be examined. A better understanding of which individuals are likely to respond to CBD can inform treatment planning and personalize treatment.. ClinicalTrials.gov NCT04411225. Registered on June 2, 2020.

Topics: Affect; Antipsychotic Agents; Anxiety; Cannabidiol; Humans; Psychotic Disorders; Randomized Controlled Trials as Topic; Young Adult

Evidence suggests that people at Clinical High Risk for Psychosis (CHR) have a blunted cortisol response to stress and altered mediotemporal activation during fear processing, which may be neuroendocrine-neuronal signatures of maladaptive threat responses. However, whether these facets are associated with each other and how this relationship is affected by cannabidiol treatment is unknown. We examined the relationship between cortisol response to social stress and mediotemporal function during fear processing in healthy people and in CHR patients. In exploratory analyses, we investigated whether treatment with cannabidiol in CHR individuals could normalise any putative alterations in cortisol-mediotemporal coupling. 33 CHR patients were randomised to 600 mg cannabidiol or placebo treatment. Healthy controls (n = 19) did not receive any drug. Mediotemporal function was assessed using a fearful face-processing functional magnetic resonance imaging paradigm. Serum cortisol and anxiety were measured immediately following the Trier Social Stress Test. The relationship between cortisol and mediotemporal blood-oxygen-level-dependent haemodynamic response was investigated using linear regression. In healthy controls, there was a significant negative relationship between cortisol and parahippocampal activation (p = 0.023), such that the higher the cortisol levels induced by social stress, the lower the parahippocampal activation (greater deactivation) during fear processing. This relationship differed significantly between the control and placebo groups (p = 0.033), but not between the placebo and cannabidiol groups (p = 0.67). Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine (cortisol) response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis.

Topics: Cannabidiol; Fear; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Psychotic Disorders; Stress, Psychological

No biological treatment has been firmly established for the at-risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non-psychoactive compound of the plant Cannabis sativa. The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra-high risk (UHR) for psychosis group.. Three-arm randomized controlled trial of 405 patients (135 per arm) aged 12-25 years who meet UHR for psychosis criteria. The study includes a 6-week lead-in phase during which 10% of UHR individuals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At-Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained.. This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder.

Topics: Administration, Oral; Adolescent; Adult; Cannabidiol; Child; Humans; Psychotic Disorders; Young Adult

Recent evidence suggests that cannabidiol (CBD), a non-intoxicating ingredient present in cannabis extract, has an antipsychotic effect in people with established psychosis. However, the effect of CBD on the neurocognitive mechanisms underlying psychosis is unknown.. Patients with established psychosis on standard antipsychotic treatment were studied on separate days at least one week apart, to investigate the effects of a single dose of orally administered CBD (600 mg) compared to a matched placebo (PLB), using a double-blind, randomized, PLB-controlled, repeated-measures, within-subject cross-over design. Three hours after taking the study drug participants were scanned using a block design functional magnetic resonance imaging (fMRI) paradigm, while performing a verbal paired associate learning task. Fifteen psychosis patients completed both study days, 13 completed both scanning sessions. Nineteen healthy controls (HC) were also scanned using the same fMRI paradigm under identical conditions, but without any drug administration. Effects of CBD on brain activation measured using the blood oxygen level-dependent hemodynamic response fMRI signal were studied in the mediotemporal, prefrontal, and striatal regions of interest.. Compared to HC, psychosis patients under PLB had altered prefrontal activation during verbal encoding, as well as altered mediotemporal and prefrontal activation and greater mediotemporal-striatal functional connectivity during verbal recall. CBD attenuated dysfunction in these regions such that activation under its influence was intermediate between the PLB condition and HC. CBD also attenuated hippocampal-striatal functional connectivity and caused trend-level symptom reduction in psychosis patients.. This suggests that normalization of mediotemporal and prefrontal dysfunction and mediotemporal-striatal functional connectivity may underlie the antipsychotic effects of CBD.

Topics: Adult; Antipsychotic Agents; Attention; Brain; Cannabidiol; Corpus Striatum; Double-Blind Method; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Mental Recall; Prefrontal Cortex; Psychotic Disorders; Young Adult

Cannabis use is an important risk factor for development of psychosis and further transition to schizophrenia. The prevalence of patients with psychosis and comorbid cannabis use (dual diagnosis) is rising with no approved specialized pharmacological treatment option. Cannabidiol, a constituent of the Cannabis sativa plant, has potential both as an antipsychotic and as a cannabis substituting agent. The aim of this study is to evaluate the efficacy of cannabidiol versus a first-choice second-generation antipsychotic (risperidone) in patients with early psychosis and comorbid cannabis use.. The study is a phase II randomized, double-blinded, parallel-group, active-comparator clinical trial. We plan to include 130 patients aged between 18 and 64 years with a recent diagnosis of psychosis, comorbid cannabis use, and currently not treated with antipsychotics. The participants will be randomized to seven weeks of treatment with either cannabidiol 600 mg (300 mg BID) or risperidone 4 mg (2 mg BID). Participants will undergo clinical assessment after 1, 3, 5 and 7 weeks, telephone assessment the weeks in between, and a safety visit two weeks after end of treatment. The primary outcomes are cessation of cannabis use (self-reported) and psychotic symptom severity. The secondary outcomes include frequency and quantity of cannabis use, global illness severity, psychosocial functioning, subjective well-being, cognition, sleep, circadian rhythmicity, and metabolomics.. The results of this trial can potentially contribute with a new treatment paradigm for patients suffering from dual diagnosis.. ClinicalTrials.gov , NCT04105231 , registered April 23rd, 2021.

Topics: Adolescent; Adult; Antipsychotic Agents; Cannabidiol; Cannabis; Humans; Middle Aged; Psychotic Disorders; Randomized Controlled Trials as Topic; Risperidone; Young Adult

Stress is a risk factor for psychosis and treatments which mitigate its harmful effects are needed. Cannabidiol (CBD) has antipsychotic and anxiolytic effects.. We investigated whether CBD would normalise the neuroendocrine and anxiety responses to stress in clinical high risk for psychosis (CHR) patients.. Thirty-two CHR patients and 26 healthy controls (HC) took part in the Trier Social Stress Test (TSST) and their serum cortisol, anxiety and stress associated with public speaking were estimated. Half of the CHR participants were on 600 mg/day of CBD (CHR-CBD) and half were on placebo (CHR-P) for 1 week.. One-way analysis of variance (ANOVA) revealed a significant effect of group (HC, CHR-P, CHR-CBD (p = .005) on cortisol reactivity as well as a significant (p = .003) linear decrease. The change in cortisol associated with experimental stress exposure was greatest in HC controls and least in CHR-P patients, with CHR-CBD patients exhibiting an intermediate response. Planned contrasts revealed that the cortisol reactivity was significantly different in HC compared with CHR-P (p = .003), and in HC compared with CHR-CBD (p = .014), but was not different between CHR-P and CHR-CBD (p = .70). Across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p's < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change.. Our findings show that it is worthwhile to design further well powered studies which investigate whether CBD may be used to affect cortisol response in clinical high risk for psychosis patients and any effect this may have on symptoms.

Topics: Adolescent; Adult; Anti-Anxiety Agents; Antipsychotic Agents; Anxiety; Cannabidiol; Double-Blind Method; Female; Humans; Hydrocortisone; Male; Psychotic Disorders; Risk Factors; Social Behavior; Speech; Stress, Psychological; Treatment Outcome; Young Adult

Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent.

Topics: Brain; Brain Mapping; Cannabidiol; Corpus Striatum; Double-Blind Method; Fear; Humans; Magnetic Resonance Imaging; Psychotic Disorders

Accumulating evidence points towards the antipsychotic potential of cannabidiol. However, the neurocognitive mechanisms underlying the antipsychotic effect of cannabidiol remain unclear. We investigated this in a double-blind, placebo-controlled, parallel-arm study. We investigated 33 antipsychotic-naïve subjects at clinical high risk for psychosis (CHR) randomised to 600 mg oral cannabidiol or placebo and compared them with 19 healthy controls. We used the monetary incentive delay task while participants underwent fMRI to study reward processing, known to be abnormal in psychosis. Reward and loss anticipation phases were combined to examine a motivational salience condition and compared with neutral condition. We observed abnormal activation in the left insula/parietal operculum in CHR participants given placebo compared to healthy controls associated with premature action initiation. Insular activation correlated with both positive psychotic symptoms and salience perception, as indexed by difference in reaction time between salient and neutral stimuli conditions. CBD attenuated the increased activation in the left insula/parietal operculum and was associated with overall slowing of reaction time, suggesting a possible mechanism for its putative antipsychotic effect by normalising motivational salience and moderating motor response.

Topics: Adolescent; Adult; Brain Mapping; Cannabidiol; Cerebral Cortex; Double-Blind Method; Female; Humans; Magnetic Resonance Imaging; Male; Motivation; Psychotic Disorders; Reaction Time; Young Adult

Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear.. To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis.. In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication-naive participants at clinical high risk (CHR) of psychosis and 19 healthy control participants were studied. Data were collected from July 2013 to October 2016 and analyzed from November 2016 to October 2017.. A total of 16 participants at CHR of psychosis received a single oral dose of 600 mg of CBD, and 17 participants at CHR received a placebo. Control participants were not given any drug. All participants were then studied using functional magnetic resonance imaging (fMRI) while performing a verbal learning task.. Brain activation during verbal encoding and recall, indexed using the blood oxygen level-dependent hemodynamic response fMRI signal.. Of the 16 participants in the CBD group, 6 (38%) were female, and the mean (SD) age was 22.43 (4.95) years; of 17 in the placebo group, 10 (59%) were female, and the mean (SD) age was 25.35 (5.24) years; and of 19 in the control group, 8 (42%) were female, and the mean (SD) age was 23.89 (4.14) years. Brain activation (indexed using the median sum of squares ratio of the blood oxygen level-dependent hemodynamic response effects model component to the residual sum of squares) was analyzed in 15 participants in the CBD group, 16 in the placebo group, and 19 in the control group. Participants receiving placebo had reduced activation relative to controls in the right caudate during encoding (placebo: median, -0.027; interquartile range [IQR], -0.041 to -0.016; control: median, 0.020; IQR, -0.022 to 0.056; P < .001) and in the parahippocampal gyrus and midbrain during recall (placebo: median, 0.002; IQR, -0.016 to 0.010; control: median, 0.035; IQR, 0.015 to 0.039; P < .001). Within these 3 regions, activation in the CBD group was greater than in the placebo group but lower than in the control group (parahippocampal gyrus/midbrain: CBD: median, -0.013; IQR, -0.027 to 0.002; placebo: median, -0.007; IQR, -0.019 to 0.008; control: median, 0.034; IQR, 0.005 to 0.059); the level of activation in the CBD group was thus intermediate to that in the other 2 groups. There were no significant group differences in task performance.. Cannabidiol may partially normalize alterations in parahippocampal, striatal, and midbrain function associated with the CHR state. As these regions are critical to the pathophysiology of psychosis, the influence of CBD at these sites could underlie its therapeutic effects on psychotic symptoms.. isrctn.org Identifier: ISRCTN46322781.

Topics: Adult; Cannabidiol; Corpus Striatum; Double-Blind Method; Female; Humans; Least-Squares Analysis; Magnetic Resonance Imaging; Male; Mental Recall; Mesencephalon; Parahippocampal Gyrus; Psychotic Disorders; Young Adult

The mechanisms underlying the antipsychotic potential of cannabidiol (CBD) remain unclear but growing evidence indicates that dysfunction in the insula, a key brain region involved in the processing of motivationally salient stimuli, may have a role in the pathophysiology of psychosis. Here, we investigate whether the antipsychotic mechanisms of CBD are underpinned by their effects on insular activation, known to be involved in salience processing.. A within-subject, crossover, double-blind, placebo-controlled investigation of 19 healthy controls and 15 participants with early psychosis was conducted. Administration of a single dose of CBD was compared with placebo in psychosis participants while performing the monetary incentive delay task, an fMRI paradigm. Anticipation of reward and loss were used to contrast motivationally salient stimuli against a neutral control condition.. No group differences in brain activation between psychosis patients compared with healthy controls were observed. Attenuation of insula activation was observed following CBD, compared to placebo. Sensitivity analyses controlling for current cannabis use history did not affect the main results.. Our findings are in accordance with existing evidence suggesting that CBD modulates brain regions involved in salience processing. Whether such effects underlie the putative antipsychotic effects of CBD remains to be investigated.

Topics: Antipsychotic Agents; Brain; Cannabidiol; Double-Blind Method; Humans; Magnetic Resonance Imaging; Motivation; Psychotic Disorders

Topics: Adult; Antipsychotic Agents; Cannabidiol; Cannabinoid Receptor Modulators; Comorbidity; Harm Reduction; Humans; Male; Marijuana Abuse; Patient Education as Topic; Psychoses, Substance-Induced; Psychotic Disorders; Young Adult

Emerging evidence supports the antipsychotic effect of cannabidiol, a non-intoxicating component of cannabis, in people with psychosis. Preclinical findings suggest that this antipsychotic effect may be related to cannabidiol modulating glutamatergic signalling in the brain.. The purpose of this study was to investigate the effects of cannabidiol on the neurochemical mechanisms underlying psychosis.. We investigated the effects of a single oral dose of cannabidiol (600 mg) in patients with psychosis, using a double-blind, randomised, placebo-controlled, repeated-measures, within-subject cross-over design. After drug administration, 13 patients were scanned using proton magnetic resonance spectroscopy to measure left hippocampal glutamate levels. Symptom severity was rated using the Positive and Negative Syndrome Scale 60 min before drug administration (pre-scan), and 270 min after drug administration (post-scan). Effects of cannabidiol on hippocampal glutamate levels, symptom severity, and correlations between hippocampal glutamate and symptoms were investigated.. Compared to placebo, there was a significant increase in hippocampal glutamate (. These findings may suggest a link between the increase in glutamate levels and concomitant decrease in symptom severity under cannabidiol treatment observed in psychosis patients. Furthermore, the findings provide novel insight into the potential neurochemical mechanisms underlying the antipsychotic effects of cannabidiol.

Topics: Adult; Antipsychotic Agents; Cannabidiol; Female; Glutamic Acid; Hippocampus; Humans; Male; Outcome Assessment, Health Care; Proton Magnetic Resonance Spectroscopy; Psychotic Disorders; Schizophrenia; Severity of Illness Index; Young Adult

To investigate the biological mechanisms underlying the higher risk for psychosis in those that use cannabis, we conducted a genome-wide environment-interaction study (GWEIS). In a sample of individuals without a psychiatric disorder (N = 1262), we analyzed the interactions between regular cannabis use and genotype with psychotic-like experiences (PLE) as outcome. PLE were measured using the Community Assessment of Psychic Experiences (CAPE). The sample was enriched for those at the extremes of both cannabis use and PLE to increase power. A single nucleotide polymorphism in the P2RX7 gene (rs7958311) was associated with risk for a high level of psychotic experiences in regular cannabis users (p = 1.10 x10

Topics: Cannabidiol; Cannabinoids; Dronabinol; Humans; Psychotic Disorders; Receptors, Purinergic P2X; Receptors, Purinergic P2X7

Anxiety disorders in young people are frequently comorbid with other mental disorders and respond unsatisfactorily to first-line treatment in many cases. Here, we report the case of a 20-year-old man with severe social anxiety disorder, major depressive disorder, insomnia and attenuated psychotic symptoms despite ongoing treatment with cognitive behavioural therapy and mirtazapine who was treated with adjunctive cannabidiol (CBD) in doses between 200 and 800 mg/day for 6 months. During treatment with CBD, he experienced subjective benefits to his anxiety, depression and positive symptoms during treatment that were confirmed by clinicians and by standardised research instruments. Findings from this case study add to existing evidence in support of the safety of CBD and suggest that it may be useful for young people with treatment refractory anxiety and for attenuated psychotic symptoms.

Topics: Adult; Cannabidiol; Cognitive Behavioral Therapy; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Male; Mirtazapine; Phobia, Social; Psychiatric Status Rating Scales; Psychotic Disorders; Psychotropic Drugs; Sleep Initiation and Maintenance Disorders; Treatment Outcome

Cannabis use disorders are frequently comorbid in patients with a psychotic disorder and are associated with worse outcomes. To date there are no proven effective strategies to achieve cannabis abstinence in this population. An alternative for abstinence might be harm reduction, i.e. replacing the use of street cannabis with high tetrahydrocannabinol and low cannabidiol levels by medicinal cannabis variants with relatively low tetrahydrocannabinol and relatively high cannabidiol levels, thereby reducing the psychosis inducing effects of cannabis and enhancing the antipsychotic effects of cannabis. Here we present the data of a case series with seven inpatients diagnosed with a psychotic disorder and a treatment-resistant cannabis use disorder who received substitution therapy with a low tetrahydrocannabinol medicinal cannabis variant (Bedrolite). The results suggest that the low tetrahydrocannabinol medicinal cannabis variant Bedrolite is not effective in the treatment of inpatients with a psychotic disorder and comorbid cannabis use disorder. Bedrolite is thus not very likely to become an effective harm reduction strategy in these patients.

Topics: Adult; Antipsychotic Agents; Cannabidiol; Cannabis; Comorbidity; Dronabinol; Female; Humans; Inpatients; Male; Marijuana Abuse; Marijuana Smoking; Medical Marijuana; Middle Aged; Psychotic Disorders; Young Adult

Topics: Cannabidiol; Cannabinoids; Cannabis; Humans; Psychotic Disorders; Schizophrenia

Topics: Aging; Animals; Antipsychotic Agents; Cannabidiol; Disease Models, Animal; Exploratory Behavior; Mice, Inbred C57BL; Motor Activity; Poly I-C; Psychological Tests; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Social Behavior; Treatment Outcome

NMDA receptor hypofunction could be involved, in addition to the positive, also to the negative symptoms and cognitive deficits found in schizophrenia patients. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and glial cells, such as microglia and astrocytes, have been related to the pathogenesis of schizophrenia. Cannabidiol (CBD), a major non-psychotomimetic constituent of Cannabis sativa with anti-inflammatory and neuroprotective properties induces antipsychotic-like effects. The present study evaluated if repeated treatment with CBD (30 and 60 mg/kg) would attenuate the behavioral and glial changes observed in an animal model of schizophrenia based on the NMDA receptor hypofunction (chronic administration of MK-801, an NMDA receptor antagonist, for 28 days). The behavioral alterations were evaluated in the social interaction and novel object recognition (NOR) tests. These tests have been widely used to study changes related to negative symptoms and cognitive deficits of schizophrenia, respectively. We also evaluated changes in NeuN (a neuronal marker), Iba-1 (a microglia marker) and GFAP (an astrocyte marker) expression in the medial prefrontal cortex (mPFC), dorsal striatum, nucleus accumbens core and shell, and dorsal hippocampus by immunohistochemistry. CBD effects were compared to those induced by the atypical antipsychotic clozapine. Repeated MK-801 administration impaired performance in the social interaction and NOR tests. It also increased the number of GFAP-positive astrocytes in the mPFC and the percentage of Iba-1-positive microglia cells with a reactive phenotype in the mPFC and dorsal hippocampus without changing the number of Iba-1-positive cells. No change in the number of NeuN-positive cells was observed. Both the behavioral disruptions and the changes in expression of glial markers induced by MK-801 treatment were attenuated by repeated treatment with CBD or clozapine. These data reinforces the proposal that CBD may induce antipsychotic-like effects. Although the possible mechanism of action of these effects is still unknown, it may involve CBD anti-inflammatory and neuroprotective properties. Furthermore, our data support the view that inhibition of microglial activation may improve schizophrenia symptoms.

Topics: Animals; Antipsychotic Agents; Brain; Calcium-Binding Proteins; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Male; Maze Learning; Mice; Mice, Inbred C57BL; Microfilament Proteins; Neuroglia; Phosphopyruvate Hydratase; Psychotic Disorders; Recognition, Psychology

The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing.. To examine the effects of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) on regional brain function during salience processing.. Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Δ9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli.. University center.. Fifteen healthy men with minimal previous cannabis use.. Symptom ratings, task performance, and regional brain activation.. During the processing of oddball stimuli, relative to placebo, Δ9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Δ9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Δ9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Δ9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation.. Δ9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.

Topics: Adult; Attention; Cannabidiol; Corpus Striatum; Dronabinol; Hallucinogens; Humans; Male; Prefrontal Cortex; Psychotic Disorders; Reaction Time; Space Perception; Young Adult

The last decade has seen increasing evidence of dysfunctions in the endogenous cannabinoid system in schizophrenia and of its relationship with the typical cognitive impairment of the disorder. Studies in animal models, healthy volunteers, and psychotic patients clearly suggest an antipsychotic-like effect of cannabidiol. This study investigated the effects of cannabidiol on selective attention in 28 schizophrenic patients using the Stroop Color Word Test and on these patients' electrodermal responsiveness to auditive stimuli.. The subjects attended two experimental sessions, the first one without the administration of drugs. In the second session the subjects were divided into three groups that received either a single dose of cannabidiol 300 mg or cannabidiol 600 mg or placebo.. The three groups did not differ significantly with respect to electrodermal measures in the two experimental sessions. When the first and second sessions were compared improved performance was found in all three groups, with patients who received placebo and cannabidiol 300 mg performing better than those who received cannabidiol 600 mg.. The single, acute administration of cannabidiol seems to have no beneficial effects on the performance of schizophrenic patients in the Stroop Color Word Test, although the hypothesis that chronic administration may lead to improvement cannot be disregarded.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Cannabidiol; Cognition; Dose-Response Relationship, Drug; Female; Galvanic Skin Response; Humans; Male; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Stroop Test

The management of psychosis in Parkinson's disease (PD) has been considered a great challenge for clinicians and there is a need for new pharmacological intervention. Previously an antipsychotic and neuroprotective effect of Cannabidiol (CBD) has been suggested. Therefore, the aim of the present study was to directly evaluate for the first time, the efficacy, tolerability and safety of CBD on PD patients with psychotic symptoms. This was an open-label pilot study. Six consecutive outpatients (four men and two women) with the diagnosis of PD and who had psychosis for at least 3 months were selected for the study. All patients received CBD in flexible dose (started with an oral dose of 150 mg/day) for 4 weeks, in addition to their usual therapy. The psychotic symptoms evaluated by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire showed a significant decrease under CBD treatment. CBD did not worsen the motor function and decreased the total scores of the Unified Parkinson's Disease Rating Scale. No adverse effect was observed during the treatment. These preliminary data suggest that CBD may be effective, safe and well tolerated for the treatment of the psychosis in PD.

Topics: Adult; Aged; Cannabidiol; Female; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects; Psychotic Disorders