cannabidiol and Schizophrenia

Cannabidiol (CBD) is one of the major phytocannabinoids present in the cannabis plant, with no acute psychotropic effects and a favorable safety and abuse liability profile. Animal and limited controlled human studies have demonstrated CBD to have analgesic, anxiolytic, anti-inflammatory, antipsychotic, and anticonvulsant effects, to name a few possible indications. There is growing evidence for the use of CBD to treat neurological disorders such as epilepsy, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. It has been suggested that CBD improves cognition and neurogenesis. Cognitive impairment is associated with numerous disorders and can involve deficits in learning, memory, executive functioning, and attention. The purpose of this review will be to evaluate the available preclinical and clinical data on CBD for the treatment of the cognitive impairment associated with several disorders including schizophrenia, epilepsy, Alzheimer's disease, and others. Preclinical, but not clinical, studies found evidence for an improvement in cognitive performance after treatment with CBD. More research is needed to determine whether CBD can be effectively used as a monotherapy to treat cognitive dysfunction. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Topics: Alzheimer Disease; Animals; Cannabidiol; Cognitive Dysfunction; Epilepsy; Humans; Schizophrenia

Owing to its psychotropic effects, Cannabis has been stigmatized by its recreational use leading to a dramatic decline in the experimentations about its medical use in the twentieth century. The medical properties of the plant - known since ancient times - have received increased attention over recent years; yet, the research on its potential application in the field of psychiatry is still nascent. In this connection, the non-psychotropic cannabidiol (CBD) has emerged as a phytocannabinoid compound with promising antipsychotic effects. In addition, advances in our understanding of the endocannabinoid system, along with accumulating evidence implicating this system in the pathophysiology of schizophrenia, have stimulated research by the pharmaceutical industry to explore whether alteration of this system can be of medical benefit. This review examines the current state of evidence regarding the clinical potential of cannabinoid-based drugs as a treatment for schizophrenia, while discussing various limitations with the therapeutic approaches considered so far. In the second part, the author highlights the most promising strategies, as well as the most interesting directions one could follow, in the emerging field of cannabinoid therapies for schizophrenia.

Topics: Animals; Antipsychotic Agents; Cannabidiol; Endocannabinoids; Humans; Schizophrenia

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

Medicinal use of

Topics: Alzheimer Disease; Anxiety; Bicyclic Monoterpenes; Cannabidiol; Cannabinoid Receptor Agonists; Cannabis; Cognitive Dysfunction; Dronabinol; Humans; Inflammatory Bowel Diseases; Neuralgia; Neuroprotective Agents; Nootropic Agents; Schizophrenia; Sesquiterpenes; Terpenes

The purpose of the present meta-analysis was to assess the efficacy of cannabidiol (CBD) oil in patients with schizophrenia. A search was conducted in EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) up to April 24th, 2020. Randomized clinical trials (RCTs), which used CBD oil treatment versus placebo or any other antipsychotic in schizophrenia patients either as monotherapy or add-on therapy, were included. Data were pooled using a random-effects model. The primary outcomes were efficacy as measured by total symptoms of schizophrenia and improvement in cognition. The meta-analysis was registered with PROSPERO [number: CRD42020157146]. Three double-blind RCTs were included. In one study, CBD oil was compared with amisulpride as monotherapy treatment, but no statistically significant difference in overall efficacy was detected between them. No data were available for cognition. The other two studies estimated the effects of CBD oil as add-on treatment compared to placebo; no significant difference was found either in overall efficacy or in cognition. Altogether, insufficient evidence exists on the efficacy and safety of CBD oil in schizophrenia patients. More RCTs, comparing CBD oil with placebo and other antipsychotics are warranted.

Topics: Amisulpride; Antipsychotic Agents; Cannabidiol; Double-Blind Method; Humans; Plant Oils; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Cannabidiol (CBD) represents a new promising drug due to a wide spectrum of pharmacological actions. In order to relate CBD clinical efficacy to its pharmacological mechanisms of action, we performed a bibliographic search on PUBMED about all clinical studies investigating the use of CBD as a treatment of psychiatric symptoms. Findings to date suggest that (a) CBD may exert antipsychotic effects in schizophrenia mainly through facilitation of endocannabinoid signalling and cannabinoid receptor type 1 antagonism; (b) CBD administration may exhibit acute anxiolytic effects in patients with generalised social anxiety disorder through modification of cerebral blood flow in specific brain sites and serotonin 1A receptor agonism; (c) CBD may reduce withdrawal symptoms and cannabis/tobacco dependence through modulation of endocannabinoid, serotoninergic and glutamatergic systems; (d) the preclinical pro-cognitive effects of CBD still lack significant results in psychiatric disorders. In conclusion, current evidences suggest that CBD has the ability to reduce psychotic, anxiety and withdrawal symptoms by means of several hypothesised pharmacological properties. However, further studies should include larger randomised controlled samples and investigate the impact of CBD on biological measures in order to correlate CBD's clinical effects to potential modifications of neurotransmitters signalling and structural and functional cerebral changes.

Topics: Anti-Anxiety Agents; Antipsychotic Agents; Anxiety Disorders; Brain; Cannabidiol; Clinical Trials as Topic; Humans; Psychopharmacology; Schizophrenia

Prepulse inhibition (PPI) of acoustic startle reflex is a well-established behavior paradigm to measure sensorimotor gating deficits. PPI is disrupted in several neuropsychiatric disorders, including schizophrenia. PPI tests can be used to screen new drugs for treatment of such disorders. In this review, we discuss how PPI paradigm can help in screening the therapeutic effects of cannabidiol (CBD). We look into recent literature about CBD effects on PPI response in animal models, especially in nonhuman primates. CBD has been shown to modify PPI in N-methyl d-aspartate receptor antagonist models for schizophrenia, both in rodents and in nonhuman primates. These results show CBD as a potential drug for the treatment of neurologic disorders that present alterations in sensorimotor system, such as schizophrenia. Moreover, the PPI paradigm seems to be a useful and relative simple paradigm to test the efficacy of CBD as a potential therapeutic drug.

Topics: Animals; Cannabidiol; Humans; Neural Inhibition; Prepulse Inhibition; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia

Cannabidiol has recently been proposed as an antipsychotic for schizophrenia. However, its clinical use and safety is controversial. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified six systematic reviews incorporating four primary studies overall, including two randomized trials. We extracted data from the systematic reviews, reanalyzed data from primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded cannabidiol probably does not improve symptoms in schizophrenia and leads to frequent side effects.. Recientemente se ha propuesto el uso de cannabidiol como antipsicótico para la esquizofrenia. Sin embargo, su utilidad clínica y seguridad genera controversia. Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Identificamos seis revisiones sistemáticas que en conjunto incluyen cuatro estudios, entre ellos dos ensayos controlados aleatorizados. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE. Concluimos que el cannabidiol probablemente no disminuye la sintomatología en pacientes con esquizofrenia, y está asociado a efectos adversos frecuentes.

Topics: Antipsychotic Agents; Cannabidiol; Humans; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Cognitive impairment is a core symptom domain of schizophrenia, neurological disorders and substance abuse. It is characterised by deficits in learning, memory, attention and executive functioning and can severely impact daily living. Antipsychotic drugs prescribed to treat schizophrenia provide limited cognitive benefits and novel therapeutic targets are required. Cannabidiol (CBD), a component of the cannabis plant, has anti-inflammatory and antipsychotic-like properties; however, its ability to improve cognitive impairment has not been thoroughly explored. The aim of this systematic review was to evaluate preclinical and clinical literature on the effects of CBD in cognitive domains relevant to schizophrenia.. A systematic literature search was performed across numerous electronic databases for English language articles (January 1990-March 2016), with 27 articles (18 preclinical and 9 clinical studies) included in the present review.. CBD improves cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric (schizophrenia), neurodegenerative (Alzheimer's disease), neuro-inflammatory (meningitis, sepsis and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia). To date, there is one clinical investigation into the effects of CBD on cognition in schizophrenia patients, with negative results for the Stroop test. CBD attenuates Δ. The efficacy of CBD to improve cognition in schizophrenia cannot be elucidated due to lack of clinical evidence; however, given the ability of CBD to restore cognition in multiple studies of impairment, further investigation into its efficacy in schizophrenia is warranted. Potential mechanisms underlying the efficacy of CBD to improve cognition are discussed.

Topics: Antipsychotic Agents; Cannabidiol; Cognition; Dronabinol; Humans; Schizophrenia

Growing clinical and pre-clinical evidence points to a critical role for cannabidiol (CBD), the largest phytochemical component of cannabis, as a potential pharmacotherapy for various neuropsychiatric disorders. In contrast to delta-9-tetrahydrocannabinol (THC), which is associated with acute and neurodevelopmental pro-psychotic side-effects, CBD possesses no known psychoactive or dependence-producing properties. However, evidence has demonstrated that CBD strongly modulates the mesolimbic dopamine (DA) system and may possess promising anti-psychotic properties. Despite the psychotropic differences between CBD and THC, little is known regarding their molecular and neuronal effects on the mesolimbic DA system, nor how these differential effects may relate to their potential pro vs. anti-psychotic properties. This review summarizes clinical and pre-clinical evidence demonstrating CBD's modulatory effects on DA activity states within the mesolimbic pathway, functional interactions with the serotonin 5-HT

Topics: Cannabidiol; Dopamine; Dronabinol; Humans; Schizophrenia

Schizophrenia is a debilitating psychiatric disorder which places a significant emotional and economic strain on the individual and society-at-large. Unfortunately, currently available therapeutic strategies do not provide adequate relief and some patients are treatment-resistant. In this regard, cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, has shown significant promise as a potential antipsychotic for the treatment of schizophrenia. However, there is still considerable uncertainty about the mechanism of action of CBD as well as the brain regions which are thought to mediate its putative antipsychotic effects. We argue that further research on CBD is required to fast-track its progress to the clinic and in doing so, we may generate novel insights into the neurobiology of schizophrenia.

Topics: Animals; Antipsychotic Agents; Cannabidiol; Humans; Schizophrenia

Schizophrenia is a frequent disorder, which substantially impairs patients' quality of life. Moreover, the burden of illness for patients, their families and for the society, in general, is substantial. Nevertheless, the understanding of the pathophysiology of this syndrome, concise diagnostic methods and more effective and tolerable treatments are still lacking. Thus, innovative approaches and the exploration of new territories are required.. An overview of repurposed drugs and emerging treatments for schizophrenia is presented, focusing on randomized, controlled trials and meta-analyses.. Despite many years of drug research, several needs in the treatment of schizophrenia including the safety and tolerability, stage-dependent and personalized approaches, as well as drug delivery and sustainability have not been addressed sufficiently. Given the current failure of a number of mechanistically new drugs, repurposed compounds may serve as alternative and/or adjunctive agents for schizophrenic patients and for treatment refractory patients in particular. Anti-inflammatory drugs (e.g., acetylsalicylic acid, celecoxib and minocycline), as well as N-acetylcysteine, a precursor of the major antioxidant glutathione, hormones (e.g., estrogen, raloxifene and oxytocin), glutamatergic (e.g., glycine and d-serine) and nicotinergic compounds, 'nutraceuticals' (e.g., ω-3 fatty acids) and cannabidiol, an endocannabinoidmodulator, represent promising agents in this field.

Topics: Acetylcysteine; Anti-Inflammatory Agents, Non-Steroidal; Antipsychotic Agents; Cannabidiol; Dietary Supplements; Drug Repositioning; Drug Therapy, Combination; Fatty Acids, Omega-3; Hormones; Humans; Meta-Analysis as Topic; Quality of Life; Randomized Controlled Trials as Topic; Schizophrenia

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

The endocannabinoid (EC) system is widely distributed throughout the brain and modulates many functions. It is involved in mood and related disorders, and its activity may be modified by exogenous cannabinoids. This article examines the therapeutic potential of cannabinoids in psychiatric disorders.. An overview is presented of the literature focussed on the functions of the EC system, its dysfunction in mood disorders and the therapeutic potential of exogenous cannabinoids.. We propose (hypothesize) that the EC system, which is homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders. Anandamide, tetrahydrocannabinol (THC) and cannabidiol (CBD) variously combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, suggesting a therapeutic potential in mood and related disorders. Currently, cannabinoids find a role in pain control. Post mortem and other studies report EC system abnormalities in depression, schizophrenia and suicide. Abnormalities in the cannabinoid-1 receptor (CNR1) gene that codes for cannabinoid-1 (CB1) receptors are reported in psychiatric disorders. However, efficacy trials of cannabinoids in psychiatric disorders are limited but offer some encouragement.. Research is needed to elucidate the role of the EC system in psychiatric disorders and for clinical trials with THC, CBD and synthetic cannabinoids to assess their therapeutic potential.

Topics: Anxiety; Bipolar Disorder; Cannabidiol; Cannabinoid Receptor Modulators; Cannabinoids; Cerebral Cortex; Depression; Dronabinol; Electroencephalography; Endocannabinoids; Humans; Mood Disorders; Pain; Receptors, Cannabinoid; Schizophrenia; Suicide

There is a high comorbidity between cannabis use and schizophrenia. Several factors contribute to this comorbidity: secondary development of addiction, cannabis-related induction of psychosis and shared neurobiological alterations. Meanwhile, there is evidence that cannabis use is associated with an increased risk of schizophrenia. Prospective epidemiological studies have shown that a frequent cannabis use doubles the risk for schizophrenia. Interestingly, schizophrenic patients with comorbid cannabis use often show significantly better performances in neuropsychological tests than patients without cannabis use. This is nevertheless not due to a positive effect of cannabis, but a sign of cannabis-related psychosis induction in subjects with a higher level of function and less cognitive impairment. Whether cannabis use leads to schizophrenia is determined by the individual vulnerability.

Topics: Brain; Cannabidiol; Causality; Comorbidity; Cross-Sectional Studies; Diagnosis, Dual (Psychiatry); Dopamine; Dronabinol; Humans; Marijuana Abuse; Neuropsychological Tests; Psychoses, Substance-Induced; Risk; Schizophrenia; Switzerland

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.

Topics: Animals; Antipsychotic Agents; Arachidonic Acids; Cannabidiol; Endocannabinoids; Humans; Memory; Piperidines; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-fos; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Schizophrenia; Sensory Gating

The aim of this review is to describe the historical development of research on cannabidiol.. This review was carried out on reports drawn from Medline, Web of Science and SciELO.. After the elucidation of the chemical structure of cannabidiol in 1963, the initial studies showed that cannabidiol was unable to mimic the effects of Cannabis. In the 1970's the number of publications on cannabidiol reached a first peak, having the research focused mainly on the interaction with delta9-THC and its antiepileptic and sedative effects. The following two decades showed lower degree of interest, and the potential therapeutic properties of cannabidiol investigated were mainly the anxiolytic, antipsychotic and on motor diseases effects. The last five years have shown a remarkable increase in publications on cannabidiol mainly stimulated by the discovery of its anti-inflammatory, anti-oxidative and neuroprotective effects. These studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson's disease, Alzheimer's disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer.. In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials.

Topics: Anti-Anxiety Agents; Anti-Inflammatory Agents; Antiemetics; Antineoplastic Agents; Antioxidants; Antipsychotic Agents; Biomedical Research; Cannabidiol; Cannabis; Diabetes Mellitus; Humans; Mental Disorders; Neuroprotective Agents; Parkinson Disease; Schizophrenia

Cannabis use has increased greatly over the last three decades. The various types of cannabis differ in their concentration of the main psychoactive component, Delta-9-tetrahydrocannabinol (THC), and the other major ingredient, cannabidiol (CBD). Plant engineering has maximized levels of THC, thus increasing the potency of street cannabis. It is well known that cannabis intoxication can cause brief psychotic symptoms like paranoia, whilst recent evidence demonstrates that heavy use of cannabis increases the risk of chronic psychoses like schizophrenia; genetic vulnerability seems to predispose some people to a higher risk. This paper starts to consider the neurochemical mechanisms whereby cannabis use increases the risk of psychosis.

Topics: Abnormalities, Drug-Induced; Cannabidiol; Cannabinoid Receptor Modulators; Dopamine; Dronabinol; Humans; Marijuana Smoking; Paranoid Disorders; Psychoses, Substance-Induced; Receptor, Cannabinoid, CB1; Risk Factors; Schizophrenia

A high dose of delta9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of delta9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Cannabidiol; Cannabis; Clinical Trials as Topic; Disease Models, Animal; Humans; Mental Disorders; Mice; Rats; Schizophrenia

Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia.. In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S).. After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=-1.4, 95% CI=-2.5, -0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=-0.5, 95% CI=-0.8, -0.1) and as not severely unwell (CGI-S: treatment difference=-0.3, 95% CI=-0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=-0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=-0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups.. These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD's effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder.

Topics: Adult; Antipsychotic Agents; Cannabidiol; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia

Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS).. This study compared the cognitive, symptomatic, and side effects of CBD versus placebo in a clinical trial.. This study was a 6-week, randomized, placebo-controlled, parallel group, fixed-dose study of oral CBD (600 mg/day) or placebo augmentation in 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. All subjects completed the MATRICS Consensus Cognitive Battery (MCCB) at baseline and at end of 6 weeks of treatment. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and biweekly.. There was no main effect of time or drug on MCCB Composite score, but a significant drug × time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo-treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS Total scores over time (p < 0. 0001) but there was no significant drug × time interaction (p = 0.18). Side effects were similar between CBD and placebo, with the one exception being sedation, which was more prevalent in the CBD group.. At the dose studied, CBD augmentation was not associated with an improvement in MCCB or PANSS scores in stable antipsychotic-treated outpatients with schizophrenia. Overall, CBD was well tolerated with no worsening of mood, suicidality, or movement side effects.. https://clinicaltrials.gov/ct2/show/NCT00588731.

Topics: Administration, Oral; Adult; Affect; Antipsychotic Agents; Cannabidiol; Chronic Disease; Cognition; Cognitive Dysfunction; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Outpatients; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

Topics: Acute Disease; Adult; Amides; Amisulpride; Antipsychotic Agents; Arachidonic Acids; Cannabidiol; Double-Blind Method; Drug Therapy, Combination; Endocannabinoids; Ethanolamines; Female; Humans; Male; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Signal Transduction; Sulpiride; Young Adult

Cannabidiol (CBD), one of the major products of the marijuana plant, is devoid of marijuana's typical psychological effects. In contrast, potential antipsychotic efficacy has been suggested based on preclinical and clinical data (Zuardi et al., 2002). In this report, we further investigated the efficacy and safety of CBD monotherapy in three patients with treatment-resistant schizophrenia (TRS). This was an in-patient study. All patients were given placebo for the initial 5 days, and from the 6th to 35th day (inclusive) they received CBD (initial oral dose of 40 mg reaching 1280 mg/day). On the 36th day, CBD treatment was discontinued and replaced by placebo for 5 days, which was subsequently switched to olanzapine for over 15 days. Efficacy, tolerability and side effects were assessed. One patient showed mild improvement, but two patients didn't show any improvement during CBD monotherapy. All patients tolerated CBD very well and no side effects were reported. These preliminary data suggest that CBD monotherapy may not be effective for TRS.

Topics: Adult; Aggression; Antipsychotic Agents; Behavior; Cannabidiol; Drug Resistance; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Substance Withdrawal Syndrome

Schizophrenia is a chronic mental disorder that disturbs feelings and behavior. The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive. Cognitive symptoms are characterized by memory loss or attentional deficits, and are especially difficult to treat. Thus, there is intense research into the development of new treatments for schizophrenia-related responses. One of the possible strategies is connected with cannabidiol (CBD), a cannabinoid compound. This research focuses on the role of CBD in different stages of memory (acquisition, consolidation, retrieval) connected with fear conditioning in the passive avoidance (PA) learning task in mice, as well as in the memory impairment typical of cognitive symptoms of schizophrenia. Memory impairment was provoked by an acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (animal model of schizophrenia). Our results revealed that an acute injection of CBD (30 mg/kg; intraperitoneally (i.p.) improved all phases of long-term fear memory in the PA test in mice. Moreover, the acute injection of non-effective doses of CBD (1 or 5 mg/kg; i.p.) attenuated the memory impairment provoked by MK-801 (0.6 mg/kg; i.p.) in the consolidation and retrieval stages of fear memory, but not in the acquisition of memory. The present findings confirm that CBD has a positive influence on memory and learning processes in mice, and reveals that this cannabinoid compound is able to attenuate memory impairment connected with hypofunction of glutamate transmission in a murine model of schizophrenia.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cannabidiol; Disease Models, Animal; Dizocilpine Maleate; Locomotion; Male; Memory; Memory Disorders; Mice; Schizophrenia

Cannabidiol (CBD) is a non-addictive ingredient of cannabis with antipsychotic potential, while ketamine (KET), an uncompetitive NMDA receptor inhibitor, has been extensively used as a psychotomimetic. Only few studies have focused on the role of CBD on the KET-induced motor profile, while no study has investigated the impact of CBD on KET-induced alterations in NMDA receptor subunit expression and ERK phosphorylation state, in brain regions related to the neurobiology and treatment of schizophrenia. Therefore, the aim of the present study is to evaluate the role of CBD on KET-induced motor response and relevant glutamatergic signaling in the prefrontal cortex, the nucleus accumbens, the dorsal and ventral hippocampus. The present study demonstrated that CBD pre-administration did not reverse KET-induced short-lasting hyperactivity, but it prolonged it over time. CBD alone decreased motor activity at the highest dose tested (30 mg/kg) while KET increased motor activity at the higher doses (30, 60 mg/kg). Moreover, KET induced regionally-dependent alterations in NR1 and NR2B expression and ERK phosphorylation that were reversed by CBD pre-administration. Interestingly, in the nucleus accumbens KET per se reduced NR2B and p-ERK levels, while the CBD/KET combination increased NR2B and p-ERK levels, as compared to control. This study is the first to show that CBD prolongs KET-induced motor stimulation and restores KET-induced effects on glutamatergic signaling and neuroplasticity-related markers. These findings contribute to the understanding of CBD effects on the behavioral and neurobiological profiles of psychotogenic KET.

Topics: Antipsychotic Agents; Cannabidiol; Humans; Ketamine; Receptors, N-Methyl-D-Aspartate; Schizophrenia

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

Cannabidiol (CBD), a major non-psychotomimetic component of the Cannabis sativa plant, shows therapeutic potential in several psychiatric disorders, including schizophrenia. The molecular mechanisms underlying the antipsychotic-like effects of CBD are not fully understood. Schizophrenia and antipsychotic treatment can modulate DNA methylation in the blood and brain, resulting in altered expression of diverse genes associated with this complex disorder. However, to date, the possible involvement of DNA methylation in the antipsychotic-like effects of CBD has not been investigated. Therefore, this study aimed at evaluating in mice submitted to the prepulse inhibition (PPI) model: i) the effects of a single injection of CBD or clozapine followed by AMPH or MK-801 on PPI and global DNA methylation changes in the ventral striatum and prefrontal cortex (PFC); and ii). if the acute antipsychotic-like effects of CBD would last for 24-h. AMPH (5 mg/kg) and MK-801 (0.5 mg/kg) impaired PPI. CBD (30 and 60 mg/kg), similar to clozapine (5 mg/kg), attenuated AMPH- and MK801-induced PPI disruption. AMPH, but not MK-801, increased global DNA methylation in the ventral striatum, an effect prevented by CBD. CBD and clozapine increased, by themselves, DNA methylation in the prefrontal cortex. The acute effects of CBD (30 or 60 mg/kg) on the PPI impairment induced by AMPH or MK-801 was also detectable 24 h later. Altogether, the results show that CBD induces acute antipsychotic-like effects that last for 24-h. It also modulates DNA methylation in the ventral striatum, suggesting a new potential mechanism for its antipsychotic-like effects.

Topics: Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Cannabidiol; Clozapine; Dizocilpine Maleate; DNA Methylation; Epigenesis, Genetic; Hallucinogens; Male; Mice; Neuroprotective Agents; Prefrontal Cortex; Prepulse Inhibition; Reflex, Startle; Schizophrenia; Sensory Gating; Time Factors; Ventral Striatum

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ.

Topics: Animals; Animals, Newborn; Antipsychotic Agents; Cannabidiol; Cell Culture Techniques; Cerebral Cortex; Disease Models, Animal; Female; Isoxazoles; Male; Neurons; Piperidines; Rats; Rats, Sprague-Dawley; Schizophrenia; Sex Characteristics

Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies. Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics. We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg). Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFβ1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC. The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.

Topics: Animals; Antipsychotic Agents; Cannabidiol; Cognitive Dysfunction; Disease Models, Animal; Ketamine; Prefrontal Cortex; Rats, Sprague-Dawley; Schizophrenia

Preclinical and clinical data indicate that cannabidiol (CBD), a non-psychotomimetic compound from the Cannabis sativa plant, can induce antipsychotic-like effects. In an animal model of schizophrenia based on the antagonism of NMDA receptors, the behavioral and molecular changes induced by repeated treatment with the NMDA receptor antagonist MK-801 were prevented when CBD was co-administered with MK-801. It is unknown, however, if CBD would reverse these changes once they have been established. Thus, in the present study we used male C57BL/6J mice, 6 weeks old, to evaluate whether daily CBD injection for seven days, starting after the end of the repeated treatment with MK-801 for 14 days, would reverse MK-801-induced deficits in the social interaction (SI) and novel object recognition (NOR) tests, which have been used to investigate the negative and cognitive symptoms of schizophrenia, respectively. We also assessed whether CBD effects would be blocked by pretreatment with AM251, a CB1 receptor antagonist, AM630, a CB2 receptor antagonist, or WAY100635, a 5-HT1A receptor antagonist. CBD and the second-generation antipsychotic clozapine, used as a positive control, attenuated the impairments in the SI and NOR tests induced by repeated administered MK-801. CBD effects were blocked by WAY100635, but not by AM251 or AM630. These data suggest that CBD induces antipsychotic-like effects by activating 5-HT1A receptors and indicate that this compound could be an interesting alternative for the treatment of negative and cognitive symptoms of schizophrenia.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Brain; Cannabidiol; Disease Models, Animal; Male; Mice, Inbred C57BL; Open Field Test; Receptor, Serotonin, 5-HT1A; Schizophrenia; Schizophrenic Psychology; Serotonin 5-HT1 Receptor Agonists; Signal Transduction; Social Behavior

Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.

Topics: Animals; Antipsychotic Agents; Brain; Cannabidiol; Cerebrovascular Circulation; Disease Models, Animal; Female; Gene Expression Regulation; Haloperidol; Magnetic Resonance Imaging; Male; Methylazoxymethanol Acetate; Models, Molecular; Molecular Dynamics Simulation; Pregnancy; Prenatal Exposure Delayed Effects; Puberty; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia

Patients with psychiatric conditions are increasingly using cannabinoids, particularly cannabidiol (CBD), to treat their own symptoms. After reviewing the mechanism of action of CBD, the current article examines the existing evidence for CBD in the treatment of schizophrenia, anxiety, autism, posttraumatic stress disorder, and insomnia, and discusses the challenges in translating these studies, often using very high doses of CBD, into clinical practice. Until additional, well-designed studies that examine the more common practice of lower doses of CBD are performed, a harm-reduction, patient-centered, empiric approach is encouraged to optimize symptom reduction while at the same time avoiding the known risks of cannabis. [Journal of Psychosocial Nursing and Mental Health Services, 57(10), 7-11.].

Topics: Anxiety Disorders; Cannabidiol; Cannabis; Humans; Mental Health; Schizophrenia; Sleep Initiation and Maintenance Disorders; Stress Disorders, Post-Traumatic

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.

Topics: Amides; Animals; Arachidonic Acids; Cannabidiol; Disease Models, Animal; Endocannabinoids; Ethanolamines; Female; Glycerides; Hippocampus; Interpersonal Relations; Male; Methylazoxymethanol Acetate; Motor Activity; Oleic Acids; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Puberty; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Recognition, Psychology; RNA, Messenger; Schizophrenia

Topics: Antipsychotic Agents; Cannabidiol; Combined Modality Therapy; Humans; Schizophrenia

Topics: Cannabidiol; Humans; Schizophrenia; Suicide, Attempted

Topics: Acetylcholinesterase; Animals; Cannabidiol; Choline O-Acetyltransferase; Down-Regulation; Female; Hippocampus; Male; Poly I-C; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Receptor, Muscarinic M1; Receptor, Muscarinic M4; Schizophrenia; Sex Characteristics; Synaptic Transmission

The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits. We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown. An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R). This study investigated the effects of chronic CBD treatment on markers of glutamatergic, GABAergic and endocannabinoid signalling in brain regions implicated in social behaviour and cognitive function, including the prefrontal cortex (PFC) and hippocampus (HPC). Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg, i.v.) or saline (control) on gestational day 15. Male offspring were injected with CBD (10 mg/kg, i.p.) or vehicle twice daily from postnatal day 56 for 3 weeks. The prefrontal cortex (PFC) and hippocampus (HPC) were collected for post-mortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:C-induced deficits in cannabinoid CB1 receptor binding in the PFC and glutamate decarboxylase 67, the enzyme that converts glutamate to GABA, in the HPC. CBD treatment increased parvalbumin levels in the HPC, regardless of whether offspring were exposed to poly I:C in utero. Conversely, CBD did not affect N-methyl-d-aspartate receptor and gamma-aminobutyric acid (GABA) A receptor binding or protein levels of fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid, anandamide. Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure. These findings provide novel evidence for the potential mechanisms underlying the therapeutic effects of CBD treatment in the poly I:C model.

Topics: Animals; Cannabidiol; Disease Models, Animal; Endocannabinoids; Female; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Male; Neurons; Poly I-C; Prefrontal Cortex; Pregnancy; Rats; Rats, Sprague-Dawley; Schizophrenia; Signal Transduction

Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain. Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties. We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment. Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring. Time-mated pregnant Sprague-Dawley rats (n = 16) were administered poly I:C (4 mg/kg; i.v.) or saline (control) on gestational day 15. From postnatal day 56, female offspring received CBD (10 mg/kg, i.p.) or vehicle treatment for approximately 3 weeks. Following 2 weeks of CBD treatment, offspring underwent behavioural testing, including the novel object recognition, rewarded alternation T-maze and social interaction tests to assess recognition memory, working memory and sociability, respectively. After 3 weeks of CBD treatment, the prefrontal cortex (PFC) and hippocampus (HPC) were collected to assess effects on endocannabinoid, glutamatergic and gamma-aminobutyric acid (GABA) signalling markers. CBD attenuated poly I:C-induced deficits in recognition memory, social interaction and glutamatergic N-methyl-d-aspartate receptor (NMDAR) binding in the PFC of poly I:C offspring. Working memory performance was similar between treatment groups. CBD also increased glutamate decarboxylase 67, the rate-limiting enzyme that converts glutamate to GABA, and parvalbumin protein levels in the HPC. In contrast to the CBD treatment effects observed in poly I:C offspring, CBD administration to control rats reduced social interaction, cannabinoid CB1 receptor and NMDAR binding density in the PFC, suggesting that CBD administration to healthy rats may have negative consequences on social behaviour and brain maturation in adulthood. Overall, the findings of this study support the therapeutic benefits of CBD on recognition memory and sociability in female poly I:C

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Brain; Cannabidiol; Cognition; Cognitive Dysfunction; Female; Hippocampus; Memory, Short-Term; Neurodevelopmental Disorders; Poly I-C; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recognition, Psychology; Schizophrenia

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

Topics: Antipsychotic Agents; Cannabidiol; Humans; Schizophrenia

Cannabis use represents a major public health issue throughout the globe. Yet, we still lack the most fundamental knowledge on long-term effects of cannabis on neural, cognitive, and behavioral function. Part of this stems from how cannabis has been measured historically. To this end, most empirical examinations of cannabis have consolidated all types of cannabis collectively. However, this approach obscures differences in how cannabinoids operate. In this commentary, we address the contrasting properties of tetrahydrocannabinol (THC) and cannabidiol (CBD) and their opposing effects on cognitive function. In addition, we address the increase in cannabis potency throughout the past two decades and how that impacts generalizability of early data to evaluations of contemporary public health. We underscore the urgent need for future research to disaggregate examination of THC from CBD, along with the importance of measuring cannabis potency to more effectively unravel its influence on cognitive function and other health issues.

Topics: Brain; Cannabidiol; Cannabis; Cognition; Dronabinol; Humans; 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

Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4'-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Anxiety; Anxiety Disorders; Behavior, Animal; Cannabidiol; Depression; Depressive Disorder; Disease Models, Animal; Male; Mice; Motor Activity; Schizophrenia

Although all current antipsychotics act by interfering with the action of dopamine at dopamine D2 receptors, two recent reports showed that 800 to 1000 mg of cannabidiol per day alleviated the signs and symptoms of schizophrenia, although cannabidiol is not known to act on dopamine receptors. Because these recent clinical findings may indicate an important exception to the general rule that all antipsychotics interfere with dopamine at dopamine D2 receptors, the present study examined whether cannabidiol acted directly on D2 receptors, using tritiated domperidone to label rat brain striatal D2 receptors. It was found that cannabidiol inhibited the binding of radio-domperidone with dissociation constants of 11 nm at dopamine D2High receptors and 2800 nm at dopamine D2Low receptors, in the same biphasic manner as a dopamine partial agonist antipsychotic drug such as aripiprazole. The clinical doses of cannabidiol are sufficient to occupy the functional D2High sites. it is concluded that the dopamine partial agonist action of cannabidiol may account for its clinical antipsychotic effects.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Brain; Cannabidiol; Domperidone; Dose-Response Relationship, Drug; Humans; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology

Topics: Antipsychotic Agents; Brain; Cannabidiol; Cannabis; Cerebral Cortex; Gene-Environment Interaction; Humans; Marijuana Abuse; Risk Factors; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

Topics: Cannabidiol; Cannabis; Causality; Dronabinol; Humans; Marijuana Abuse; Psychoses, Substance-Induced; Risk Factors; Schizophrenia; Schizophrenic Psychology

Topics: Cannabidiol; Cannabis; Dronabinol; Humans; Marijuana Abuse; Psychoses, Substance-Induced; Schizophrenia; Schizophrenic Psychology

Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801.. Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine.. MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment.. These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties.

Topics: Animals; Behavior, Animal; Cannabidiol; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; GABAergic Neurons; Hippocampus; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Parvalbumins; Prefrontal Cortex; Prepulse Inhibition; Proto-Oncogene Proteins c-fos; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Schizophrenia; Sensory Gating; Treatment Outcome

The medical properties of cannabis have been known for many centuries; its first documented use dates back to 2800 BC when it was described for its hallucinogenic and pain-relieving properties. In the first half of the twentieth century, a number of pharmaceutical companies marked cannabis for indications such as asthma and pain, but since then its use has sharply declined, mainly due to its unpredictable effects, but also for socio-political issues. Recently, great attention has been directed to the medical properties of phytocannabinoids present in the cannabis plant alongside the main constituent Δ⁹-Tetrahydrocannabinol (THC); these include cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). Evidence suggests an association between cannabis and schizophrenia: schizophrenics show a higher use of marijuana as compared to the healthy population. Additionally, the use of marijuana can trigger psychotic episodes in schizophrenic patients, and this has been ascribed to THC. Given the need to reduce the side effects of marketed antipsychotics, and their weak efficacy on some schizophrenic symptoms, cannabinoids have been suggested as a possible alternative treatment for schizophrenia. CBD, a non-psychoactive constituent of the Cannabis sativa plant, has been receiving growing attention for its anti-psychotic-like properties. Evidence suggests that CBD can ameliorate positive and negative symptoms of schizophrenia. Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia.

Topics: Animals; Antipsychotic Agents; Cannabidiol; Cannabis; Dronabinol; Humans; Marijuana Abuse; Psychoses, Substance-Induced; Schizophrenia; Schizophrenic Psychology

Recently, a novel paradigm has been designed to assess social investigative behaviour in pairs of Sprague-Dawley rats, which involves physical separation whilst ensuring they are able to maintain contact through other social cues. We have modified this set-up in order to assess not just social behaviour but also locomotor activity of the rats. Results showed that the MK-801- (0.3 mg/kg) treated rats displayed reduced social investigative behaviour, hyperactivity as well as reduced attention span. Pretreatment with the phytocannabinoid cannabidiol (3 mg/kg) not only normalised social investigative behaviour but increased it beyond control levels. Pretreatment with clozapine (1, 3 mg/kg) also normalised social investigative behaviour. Both cannabidiol and clozapine inhibited MK-801-induced hyperactivity. However, there were no effects of pretreatment on impairments to attention span. Our findings reinforce several aspects of the validity of the MK-801-induced model of social withdrawal and hyperactivity and also support the use of this novel set-up for further investigations to assess the antipsychotic potential of novel compounds.

Topics: Animals; Antipsychotic Agents; Attention; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Motor Activity; Psychomotor Agitation; Psychotropic Drugs; Rats; Rats, Sprague-Dawley; Schizophrenia; Social Behavior; Social Behavior Disorders

The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophrenia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. the ABC transporter, P-glycoprotein).

Topics: Animals; Animals, Newborn; Cannabidiol; Disease Models, Animal; Dronabinol; Humans; Marijuana Abuse; Mice; Psychoses, Substance-Induced; Rats; Schizophrenia

Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR).. Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2).. In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant.. Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD.

Topics: Animals; Cannabidiol; Cannabinoid Receptor Antagonists; Disease Models, Animal; Emotions; Male; Piperidines; Pyrazoles; Rats, Wistar; Rimonabant; Schizophrenia; Schizophrenic Psychology

Cannabidiol is a non-psychoactive phytocannabinoid which, based on several previous preclinical and clinical reports, is purported to have antipsychotic potential. The purpose of this investigation was to further investigate if these effects would be seen using an MK-801-induced rat model of aspects of schizophrenia. MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviours which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. Following a 4-day acclimatisation to the holding room, rats were acclimatised to startle chambers on day 5 and their prepulse inhibition (PPI) determined on day 6 following treatment with cannabidiol or vehicle and MK-801 or vehicle. On day 9, rats were acclimatised to the social interaction testing arena and on day 10, were tested for social interaction and locomotor activity following the same treatments. Cannabidiol treatment alone disrupted PPI and produced hyperactivity but had no effect on social behaviour. Cannabidiol had no effect on MK-801-induced disruption of PPI or hyperactivity but showed potential towards inhibiting MK-801-induced social withdrawal. As a comparator, we also tested the effect of the atypical antipsychotic clozapine which only partially reversed MK-801-induced disruption of PPI but was able to reverse MK-801-induced hyperactivity and social withdrawal. In conclusion, cannabidiol showed both propsychotic activity and partial antipsychotic activity in an MK-801-induced model of aspects of schizophrenia. Further behavioural studies would be required using a range of species, strains, animal models and testing paradigms to conclusively establish the antipsychotic potential of cannabidiol.

Topics: Animals; Antipsychotic Agents; Cannabidiol; Clozapine; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Inhibition, Psychological; Interpersonal Relations; Male; Motor Activity; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia

Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9-THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open-field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic-like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats.

Topics: Animals; Anti-Anxiety Agents; Antipsychotic Agents; Anxiety; Behavior, Animal; Cannabidiol; Catalepsy; Dronabinol; Hypothermia; Interpersonal Relations; Male; Mice; Mice, Inbred C57BL; Motor Activity; Pain Measurement; Photoperiod; Psychotropic Drugs; Rats; Rats, Wistar; Schizophrenia; Schizophrenic Psychology; Sensory Gating; Time Factors

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

Topics: Adult; Cannabidiol; Diazepam; Drug Therapy, Combination; Female; Haloperidol; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology