Background and objectives 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. Methods 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. Results 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 9 -THCinduced cognitive deficits. Conclusions 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.

Neuropsychiatric disorders such as schizophrenia are associated with cognitive impairment, including learning, memory and attention deficits. Antipsychotic drugs are limited in their efficacy to improve cognition; therefore, new therapeutic agents are required. Cannabidiol (CBD), the non-intoxicating component of cannabis, has anti-inflammatory, neuroprotective and antipsychotic-like properties; however, its ability to improve the cognitive deficits of schizophrenia remains unclear. Using a prenatal infection model, we examined the effect of chronic CBD treatment on cognition and social interaction. Time-mated pregnant Sprague-Dawley rats (n=16) were administered polyinosinic-polycytidilic acid (poly I:C) (POLY; 4 mg/kg) or saline (CONT) at gestation day 15. Male offspring (PN56) were injected twice daily with 10 mg/kg CBD (CONT+CBD, POLY+CBD; n=12 per group) or vehicle (VEH; CONT+VEH, POLY+VEH; n=12 per group) for 3 weeks. Body weight, food and water intake was measured weekly. The Novel Object Recognition and rewarded T-maze alternation tests assessed recognition and working memory, respectively, and the social interaction test assessed sociability. POLY+VEH offspring exhibited impaired recognition and working memory, and reduced social interaction compared to CONT+VEH offspring (p<0.01). CBD treatment significantly improved recognition, working memory and social interaction deficits in the poly I:C model (p<0.01 vs POLY+VEH), did not affect total body weight gain, food or water intake, and had no effect in control animals (all p>0.05). In conclusion, chronic CBD administration can attenuate the social interaction and cognitive deficits induced by prenatal poly I:C infection. These novel findings present interesting implications for potential use of CBD in treating the cognitive deficits and social withdrawal of schizophrenia.

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). Timemated 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 postmortem receptor binding and Western blot analyses (n = 8 per group). CBD treatment attenuated poly I:Cinduced 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 Nmethyl-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.

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 (polyinosinicpolycytidilic 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 Nmethyl-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 offspring, and provide insight into the neurochemical changes that may underlie the therapeutic benefits of CBD in the poly I:C model.

Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs.

Cognitive impairment is a core symptom of schizophrenia; however, current antipsychotic drugs have limited efficacy to treat these symptoms and can cause serious side-effects, highlighting a need for novel therapeutics. Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has demonstrated pro-cognitive effects in multiple disease states, including a maternal immune activation (poly I:C) model of schizophrenia, but the mechanisms underlying the efficacy of CBD require investigation. Muscarinic neurotransmission is highly implicated in the cognitive impairments of schizophrenia; however, the effect of CBD on this system is unknown. We examined alterations in markers of muscarinic neurotransmission in the pre-frontal cortex (PFC) and hippocampus (HPC) following CBD treatment. Pregnant Sprague-Dawley rats (n=16) were administered poly I:C (4 mg/kg) or saline. Adult offspring were treated (3-weeks) with CBD (10 mg/kg) or vehicle. Receptor autoradiography (using [ 3 H]pirenzepine) was used to examine changes in muscarinic M1/ M4 receptor (M1/M4R) binding density. Levels of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) protein expression were examined using Western blot. M1/M4R binding density was downregulated in the PFC and CA1/CA2 and CA3 subregions in male poly I:C offspring. M1/ M4R deficits were normalised after CBD treatment. ChAT protein expression was reduced in the HPC of male poly I:C offspring, while CBD treated poly I:C offspring exhibited control-like ChAT levels. AChE levels were unaltered in any of the groups. There were also no changes in muscarinic signalling in female offspring. These findings demonstrate that CBD can normalise muscarinic neurotransmission imbalances in male poly I:C offspring in regions of the brain implicated in cognition.

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