Category Archives: Schizophrenia

Oromucosal as an Alternative Method for Administration of Cannabis Products in Rodents

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“Oral administration of drugs in laboratory rodents such as rats is conventionally performed using the gavage technique. Despite effectiveness, gavage can induce distress associated with restraint, especially following repeated animal handling.

To mitigate these adverse effects and reduce morbidity associated with traditional methods, we explored oromucosal/buccal administration of cannabidiol (CBD)-enriched Cannabis extract.

In this method, male rats were treated daily for 15 days with medium-chain triglycerides (TCM) derived from coconut oil or CBD-enriched Cannabis extract. Each treatment was administered individually while animals were gently immobilized using an affectionate touch technique. The administration involved the use of a micropipette to apply the oily formulation directly into the oral mucosa. The dosage was calculated based on the CBD concentration in the Cannabis extract, standardized at 3 mg/kg/day. To ensure accuracy, animals were weighed daily, allowing for dose adjustments in accordance with weight changes over the treatment period. This method offers non-invasive and stress-reducing treatment, potentially improving animal welfare in experimental settings.

The treatment with CBD-enriched Cannabis extract was safe, and the analysis of the hippocampus of these animals’ showed alterations in the expression levels of GluA1 and GFAP proteins, which are directly associated with glutamatergic receptor functionality and neuroinflammation, respectively. This suggests that Cannabis extract could be applied in pathological conditions where glutamatergic excitotoxicity and astrogliosis are observed.”

https://pubmed.ncbi.nlm.nih.gov/40920655/

https://app.jove.com/t/68104/oromucosal-as-an-alternative-method-for-administration-cannabis

Cannabidiol reverses microglia activation and loss of parvalbumin interneurons and perineuronal nets in a mouse model of schizophrenia

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“Cannabidiol (CBD) has shown potential for treating schizophrenia (SCZ) by targeting its positive and negative cognitive symptoms. In this study, we investigated if CBD could reverse the memory impairment observed after chronic administration of the NMDA receptor antagonist MK-801.

Chronic treatment with MK-801 (0.5 mg/kg i.p., twice a day, for 14 days) resulted in short- and long-term memory deficits and decreased relative power of γ oscillations in freely moving animals. CBD administration (30 mg/kg i.p. daily for seven days after the MK-801 treatment period) reversed these changes. The cognitive effects of CBD were prevented by blocking 5-HT1A but not CB2 receptors.

At the cellular level, the depletion of parvalbumin-positive neurons and their associated perineuronal nets in the prelimbic medial prefrontal cortex (mPFC) and ventral hippocampus (vHip) induced by MK-801 was reversed by CBD. This neuroprotective effect was mediated by 5-HT1A and CB2 receptors in the vHip but was independent of these receptors in the mPFC. Additionally, CBD reversed MK-801-induced microglial activation in both mPFC and vHip, again through 5-HT1A and CB2 receptors.

These findings suggest that CBD modulates multiple pathways affected in SCZ-like conditions, offering a promising therapeutic avenue for SCZ treatment.”

https://pubmed.ncbi.nlm.nih.gov/40484109/

https://www.sciencedirect.com/science/article/abs/pii/S0006899325003336?via%3Dihub

Cannabidiol reverses myeloperoxidase hyperactivity in the prefrontal cortex and striatum, and reduces protein carbonyls in the hippocampus in a ketamine-induced schizophrenia rat model

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“Background: Schizophrenia (SCZ) has limited treatment options, often with significant side effects. Cannabidiol (CBD), a non-euphoric phytocannabinoid, has shown potential as a novel therapeutic option in SCZ due to antipsychotic-like, anti-inflammatory, and antioxidant properties. We compared the therapeutic effects of CBD and risperidone (RISP) in a rat model of SCZ induced by sub-chronic ketamine (KET), focusing on inflammatory and oxidative stress, and behavioral phenotypes.

Methods: Rats were pre-treated with KET or saline (SAL) for 10 days followed by CBD or RISP for 8 days. Locomotion, anxiety- and anhedonia-like behavior, and recognition memory were assessed. Oxidative damage as measured by protein carbonyls, thiobarbituric acid reactive substances, and catalase activity, and the inflammation markers myeloperoxidase (MPO) activity and nitrite/nitrate (N/N) concentration ratio were assessed in the prefrontal cortex (PFC), hypothalamus (HYP), hippocampus (HPC), and striatum, brain areas relevant to SCZ.

Results: CBD restored the KET-induced decreased rearing behavior in the OFT, while RISP further decreased rearing. RISP treatment in control rats decreased rearing and elicited an anhedonic-like phenotype, while CBD did not. CBD, but not RISP restored the KET-induced increased levels of MPO activity in the PFC and the striatum, and protein carbonyls in the HPC. Post-KET treatment with RISP but not CBD decreased protein carbonyls in the PFC, and decreased the N/N concentration ratio in the HYP.

Conclusion: CBD restored the KET-induced decrease in rearing behavior without inducing an anhedonic-like phenotype as observed with RISP. CBD, and to a lesser extent RISP restored the oxidative stress and neuroinflammation elicited by KET in the striatum, HPC, and PFC. These findings support the possibility that the antipsychotic effects of CBD might be mediated by its antioxidant and anti-inflammatory effects.”

https://pubmed.ncbi.nlm.nih.gov/40132281/

https://www.sciencedirect.com/science/article/abs/pii/S0920996425000908?via%3Dihub

Therapeutic potential of cannabidiol polypharmacology in neuropsychiatric disorders

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“Cannabidiol (CBD), the primary non-intoxicating compound in cannabis, is currently approved for treating rare, treatment-resistant seizures.

Recent preclinical research suggests that CBD’s multifaceted mechanisms of action in the brain, which involve multiple molecular targets, underlie its neuroprotective, anti-inflammatory, anxiolytic, and antipsychotic effects. Clinical trials are also exploring CBD’s therapeutic potential beyond its current uses.

This review focuses on CBD’s polypharmacological profile and discusses the latest preclinical and clinical findings regarding its efficacy in neuropsychiatric disorders.

Existing evidence suggests that CBD’s ability to modulate multiple signaling pathways may benefit neuropsychiatric disorders, and we propose further research areas to clarify its mechanisms, address data gaps, and refine its therapeutic indications.”

https://pubmed.ncbi.nlm.nih.gov/39837749/

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(24)00271-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0165614724002712%3Fshowall%3Dtrue

CBD and the 5-HT1A receptor: A medicinal and pharmacological review

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“Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms.

It has the ability to bind multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD’s pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated.

This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling.

A comprehensive survey of the literature underscores CBD’s multifaceted neurotherapeutic effects, encompassing antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR.

Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.”

https://pubmed.ncbi.nlm.nih.gov/39778776/

“Cannabis was one of the first inhaled drugs utilized by humans, with evidence of use for gout, rheumatism, and malaria dating to 2737 BCE”

“The concurrent literature revealed that CBD produces several therapeutic effects through its complex pharmacodynamic interactions with 5-HT1AR. Therapeutic applications of CBD, including its anxiolytic, antidepressant, antipsychotic, anti-degenerative, neuroprotective, anti-epileptic, and anti-addictive properties were mediated, at least in part, by its binding to 5-HT1AR.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225000048?via%3Dihub

Therapeutic potential of minor cannabinoids in psychiatric disorders: A systematic review

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“Interest in cannabinoids’ therapeutic potential in mental health is growing, supported by evidence of the involvement of the endocannabinoid system in psychiatric disorders such as anxiety, depression, and addiction.

While the major cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have been more extensively researched, approximately 120 minor cannabinoids from the cannabis plant have been identified. Although some displayed promising pharmacological profiles, research on their application for psychiatric disorders is fragmented.

This systematic review evaluates, for the first time, both preclinical and clinical studies exploring minor cannabinoids’ therapeutic potential in psychiatric disorders. 22 preclinical studies and one clinical study were included, investigating various minor cannabinoids in substance use disorders, anxiety disorders, depressive disorders, trauma and stressor-related disorders, psychotic disorders, neurodevelopmental disorders, and eating disorders. Despite the heterogeneous results and the moderate to high risk of bias in several articles, certain compounds demonstrate promise for further investigation.

Δ8-tetrahydrocannabidivarin (Δ8-THCV) exhibited potential for nicotine addiction; Δ9-tetrahydrocannabidivarin (Δ9-THCV) for psychotic-like symptoms; cannabidiolic acid methyl ester (CBDA-ME) alleviated anxiety and depression-like symptoms, and cannabidivarin (CBDV) autism spectrum disorder-like symptoms.”

https://pubmed.ncbi.nlm.nih.gov/39541799/

https://www.sciencedirect.com/science/article/pii/S0924977X24007508?via%3Dihub

Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring

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“Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited.

We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams.

Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma.

CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females.

These findings underscore the persistent influence of maternal obesity on the offspring’s health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.”

https://pubmed.ncbi.nlm.nih.gov/39447736/

“Treatment with cannabidiol rescues anxiety and social disturbances in the offspring.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390824003654?via%3Dihub


Cannabidiol, a plant-derived compound, is an emerging strategy for treating cognitive impairments: comprehensive review of randomized trials

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“Background: Finding new strategies to treat cognitive disorders is a challenging task. Medication must defeat the blood-brain barrier. Cannabidiol (CBD), a non-intoxicating compound of the cannabis plant, has gained recognition as a nutraceutical for its potential effectiveness in treating anxiety, oxidative stress, convulsions, and inflammation. However, the dose, tolerable upper intake, formulation, administration routes, comorbidities, diet, and demographic factors to reverse cognitive impairments have not been completely explored. Trials using CBD as a primary intervention have been conducted to alleviate cognitive issues. This review evaluates the benefits of CBD supplementation, research design, formulations, and outcomes reported in randomized clinical trials.

Methods: An evidence-based systematic literature review was conducted using PUBMED and the Florida International University Research Library resources. Fourteen randomized trials were selected for review, and their designs and outcomes were compared conceptually and in the form of resume tables.

Results: CBD showed improvement in anxiety and cognitive impairments in 9 out of 16 analyzed trials. However, the variability could be justified due to the diversity of the trial designs, underpowered studies, assayed population, uncontrolled results for comorbidities, medications, severity of drug dependence, compliances, and adherences. Overall, oral single doses of 200 mg-1,500 mg or vaporized 13.75 mg of CBD were shown to be effective at treating anxiety and cognition with a good safety profile and no drug addiction behaviors. Conversely, results that did not have a significant effect on treating cognitive impairments can be explained by various factors such as THC or other abuse drugs masking effect, low dose, and unknown purity of CBD. Furthermore, CBD shows potential properties that can be tested in the future for Alzheimer’s disease.

Conclusion: As medical cannabis becomes more accessible, it is essential to understand whether medication rich in CBD exerts a beneficial effect on cognitive disorders. Our study concludes that CBD is a promising candidate for treating neurocognitive disorders; however, more studies are required to define CBD as a therapeutic candidate for managing cognitive disorders.”

https://pubmed.ncbi.nlm.nih.gov/39323633/

“Cannabidiol (CBD), a phytocannabinoid, is derived from the cannabis plant.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1403147/full

Multi-level therapeutic actions of cannabidiol in ketamine-induced schizophrenia psychopathology in male rats

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“Repeated administration of ketamine (KET) has been used to model schizophrenia-like symptomatology in rodents, but the psychotomimetic neurobiological and neuroanatomical underpinnings remain elusive. In parallel, the unmet need for a better treatment of schizophrenia requires the development of novel therapeutic strategies.

Cannabidiol (CBD), a major non-addictive phytocannabinoid has been linked to antipsychotic effects with unclear mechanistic basis. Therefore, this study aims to clarify the neurobiological substrate of repeated KET administration model and to evaluate CBD’s antipsychotic potential and neurobiological basis.

CBD-treated male rats with and without prior repeated KET administration underwent behavioral analyses, followed by multilevel analysis of different brain areas including dopaminergic and glutamatergic activity, synaptic signaling, as well as electrophysiological recordings for the assessment of corticohippocampal and corticostriatal network activity.

Repeated KET model is characterized by schizophrenia-like symptomatology and alterations in glutamatergic and dopaminergic activity mainly in the PFC and the dorsomedial striatum (DMS), through a bi-directional pattern. These observations are accompanied by glutamatergic/GABAergic deviations paralleled to impaired function of parvalbumin- and cholecystokinin-positive interneurons, indicative of excitation/inhibition (E/I) imbalance.

Moreover, CBD counteracted the schizophrenia-like behavioral phenotype as well as reverted prefrontal abnormalities and ventral hippocampal E/I deficits, while partially modulated dorsostriatal dysregulations.

This study adds novel insights to our understanding of the KET-induced schizophrenia-related brain pathology, as well as the CBD antipsychotic action through a region-specific set of modulations in the corticohippocampal and costicostrtiatal circuitry of KET-induced profile contributing to the development of novel therapeutic strategies focused on the ECS and E/I imbalance restoration.”

https://pubmed.ncbi.nlm.nih.gov/39242923/

https://www.nature.com/articles/s41386-024-01977-1


Occasional cannabis use is associated with higher premorbid functioning and IQ in youth at clinical high-risk (CHR) for psychosis: Parallel findings to psychosis cohorts

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“Background: Neurocognitive deficits have been widely reported in clinical high-risk for psychosis (CHR) populations. Additionally, rates of cannabis use are high among CHR youth and are associated with greater symptom severity. Cannabis use has been sometimes shown to be associated with better neurocognition in more progressed psychosis cohorts, therefore in this study we aimed to determine whether a similar pattern was present in CHR.

Methods: CHR participants ages 12-30 from the North American Prodromal Longitudinal Study (NAPLS-3) (N = 698) were grouped according to: “minimal to no cannabis use” (n = 406), “occasional use” (n = 127), or “frequent use” (n = 165). At baseline, cannabis use groups were compared on neurocognitive tests, clinical, and functional measures. Follow-up analyses were used to model relationships between cannabis use frequency, neurocognition, premorbid, and social functioning.

Results: Occasional cannabis users performed significantly better than other use-groups on measures of IQ, with similar trend-level patterns observed across neurocognitive domains. Occasional cannabis users demonstrated better social, global, and premorbid functioning compared to the other use-groups and less severe symptoms compared to the frequent use group. Follow-up structural equation modeling/path analyses found significant positive associations between premorbid functioning, social functioning, and IQ, which in turn was associated with occasional cannabis use frequency.

Discussion: Better premorbid functioning positively predicts both better social functioning and higher IQ which in turn is associated with a moderate cannabis use pattern in CHR, similar to reports in first-episode and chronic psychosis samples. Better premorbid functioning likely represents a protective factor in the CHR population and predicts a better functional outcome.”

https://pubmed.ncbi.nlm.nih.gov/39084107/

“This study contributed to emerging studies in CHR and provided parallel findings to existing evidence from both FEP and chronic psychosis populations of better neurocognitive performance among those who use cannabis”

https://www.sciencedirect.com/science/article/pii/S0920996424003384?via%3Dihub