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Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior. Despite extensive research, effective pharmacological interventions for ASD remain limited. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has potential therapeutic effects on several neurological and psychiatric disorders. CBD interacts with the endocannabinoid system, a complex cell-signaling system that plays a crucial role in regulating various physiological processes, maintaining homeostasis, participating in social and behavioral processing, and neuronal development and maturation with great relevance to ASD. Furthermore, preliminary findings from clinical trials indicate that CBD may have a modulatory effect on specific ASD symptoms and comorbidities in humans. Interestingly, emerging evidence suggests that CBD may influence the gut microbiota, with implications for the bidirectional communication between the gut and the central nervous system. CBD is a safe drug with low induction of side effects. As it has a multi-target pharmacological profile, it becomes a candidate compound for treating the central symptoms and comorbidities of ASD.
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Trastorno del Espectro Autista , Cannabidiol , Humanos , Trastorno del Espectro Autista/tratamiento farmacológico , Cannabidiol/uso terapéutico , Cannabidiol/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacosRESUMEN
About one-third of major depressive disorder (MDD) patients demonstrate unresponsiveness to classic antidepressants, and even the clinical efficacy of fast-acting drugs such as ketamine varies significantly among patients with treatment-resistant depression. Nevertheless, the lack of suitable animal models that mimic a possible ketamine-resistant phenotype challenges the understanding of resistance to drug treatment. In this study, we showed that PI3Kγ knock-out (KO) mice do not respond to classical doses of ketamine and classical antidepressants. PI3Kγ KO mice were unresponsive to both the rapid and sustained antidepressant-like effects of a single dose of ketamine in the forced swimming test. Additionally, they were unresponsive to the antidepressant-like effects induced by the tricyclic antidepressant imipramine and the selective serotonin reuptake inhibitor fluoxetine. However, acute pharmacological inhibition of PI3Kγ did not block the antidepressant-like effect of ketamine, showing that a chronic deficiency of the PI3Kγ-mediated pathway is necessary for the effects of classic doses of ketamine and antidepressants. Therefore, we propose that PI3Kγ participates in the antidepressant activity and is likely implicated in the neurobiology and phenotype observed in patients with MDD who demonstrate treatment resistance.
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BACKGROUND: Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days. METHODS: C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis. RESULTS: The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways. CONCLUSION: This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.
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Chronic neuropathic pain (CNP) is a vast world health problem often associated with the somatosensory domain. This conceptualization is problematic because, unlike most other sensations that are usually affectively neutral and may present emotional, affective, and cognitive impairments. Neuronal circuits that modulate pain can increase or decrease painful sensitivity based on several factors, including context and expectation. The objective of this study was to evaluate whether subchronic treatment with Cannabidiol (CBD; 0.3, 3, and 10 mg/kg intraperitoneal route - i.p., once a day for 3 days) could promote pain-conditioned reversal, in the conditioned place preference (CPP) test, in male Wistar rats submitted to chronic constriction injury (CCI) of the sciatic nerve. Then, we evaluated the expression of astrocytes and microglia in animals treated with CBD through the immunofluorescence technique. Our results demonstrated that CBD promoted the reversal of CPP at 3 and 10 mg/kg. In CCI animals, CBD was able to attenuate the increase in neuronal hyperactivity, measured by FosB protein expression, in the regions of the corticolimbic circuit: anterior cingulate cortex (ACC), complex basolateral amygdala (BLA), granular layer of the dentate gyrus (GrDG), and dorsal hippocampus (DH) - adjacent to subiculum (CA1). CBD also prevented the increased expression of GFAP and IBA-1 in CCI animals. We concluded that CBD effects on CNP are linked to the modulation of the aversive component of pain. These effects decrease chronic neuronal activation and inflammatory markers in regions of the corticolimbic circuit.
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Cannabidiol , Neuralgia , Ratas , Animales , Masculino , Ratas Wistar , Cannabidiol/farmacología , Reacción de Prevención , Enfermedades Neuroinflamatorias , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismoRESUMEN
Studies have shown high comorbidity of anxiety disorder and chronic pain; generalized anxiety disorder (GAD) and neuropathic pain are among these pathologies. Cannabidiol (CBD) has been considered a promising treatment for these conditions. This study investigated whether chronic systemic treatment with CBD alters pain in high- (CHF) and low-freezing (CLF) Carioca rats (GAD model) and control rats (CTL) submitted to chronic neuropathic pain. The rats were evaluated in the sensory aspects (von Frey, acetone, and hot plate tests) before the chronic constriction injury of the ischiatic nerve (CCI) or not (SHAM) and on days 13 and 23 after surgery. Chronic treatment with CBD (5 mg/kg daily) was used for ten days, starting the 14th day after surgery. The open field test on the 22nd also evaluated locomotion and anxiety-like behavior. CBD treatment had an anti-allodynic effect on the mechanical and thermal threshold in all lineages; however, these effects were lower in the CHF and CLF lineages. Considering emotional evaluation, we observed an anxiolytic effect in CTL+CCI and CHF+CCI after CBD treatment and increased mobility in CLF+SHAM rats. These results suggest that the CBD mechanical anti-allodynic and emotional effects can depend on anxiety level.
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BACKGROUND: The FKBP5 and NR3C1 genes play an important role in stress response, thus impacting mental health. Stress factor exposure in early life, such as maternal depression, may contribute to epigenetic modifications in stress response genes, increasing the susceptibility to different psychopathologies. The present study aimed to evaluate the DNA methylation profile in maternal-infant depression in regulatory regions of the FKBP5 gene and the alternative promoter of the NR3C1 gene. METHODS: We evaluated 60 mother-infant pairs. The levels of DNA methylation were analyzed by the MSRED-qPCR technique. RESULTS: We observed an increased DNA methylation profile in the NR3C1 gene promoter in children with depression and children exposed to maternal depression (p < 0.05). In addition, we observed a correlation of DNA methylation between mothers and offspring exposed to maternal depression. This correlation shows a possible intergenerational effect of maternal MDD exposure on the offspring. For FKBP5, we found a decrease in DNA methylation at intron 7 in children exposed to maternal MDD during pregnancy and a correlation of DNA methylation between mothers and children exposed to maternal MDD (p < 0.05). LIMITATIONS: Although the individuals of this study are a rare group, the sample size of the study was small, and we evaluated the DNA methylation of only one CpG site for each region. CONCLUSION: These results indicate changes in DNA methylation levels in regulatory regions of FKBP5 and NR3C1 in the mother-child MDD context and represent a potential target of studies to understand the depression etiology and how it occurs between generations.
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Metilación de ADN , Depresión , Receptores de Glucocorticoides , Proteínas de Unión a Tacrolimus , Femenino , Humanos , Lactante , Embarazo , Depresión/genética , Metilación de ADN/genética , Epigénesis Genética , Regiones Promotoras Genéticas , Receptores de Glucocorticoides/genética , Proteínas de Unión a Tacrolimus/genéticaRESUMEN
RATIONALE: Cannabidiol (CBD), the major non-psychoactive constituent of cannabis, has therapeutic potential for the treatment of anxiety. Most preclinical studies investigate only acute effects of CBD and only in males, yet the drug is most likely to be used over a sustained period in clinical practice. OBJECTIVES: The objectives of this study were to investigate the anxiolytic-like effect of CBD in female rats compared to males and to determine whether the responsiveness of females was influenced by the stage of the estrous cycle. METHODS: We carried out experiments to compare the effect of CBD in male and female rats in the elevated plus maze (EPM) in response to acute and short-term (4 days) administration through a complete cycle in females. RESULTS: Male and female rats behaved in a similar manner in the EPM, but females in the late diestrus (LD) phase exhibited more anxiety-like behavior than at other stages, the difference reaching statistical significance compared to proestrus stages. CBD produced anxiolytic-like effects in both sexes, but female rats were responsive only in LD and 10-fold lower dose than males. After sub-chronic (4 days) treatment, responsiveness to CBD was maintained in females in LD, but females in proestrus remained unresponsive to CBD treatment. CONCLUSIONS: We suggest that there are sex differences in the anxiolytic-like effects of CBD in rats that reflect different underlying mechanisms: based on literature data, gonadal hormone status linked to GABAA receptor expression in females, and 5-HT1A receptor activation in males.
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Ansiolíticos , Cannabidiol , Femenino , Masculino , Ratas , Animales , Ansiolíticos/farmacología , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Prueba de Laberinto Elevado , Caracteres Sexuales , Ratas Wistar , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Receptores de GABA-ARESUMEN
RATIONALE: Autism spectrum disorder (ASD) is defined as a group of neurodevelopmental disorders whose symptoms include impaired communication and social interaction, restricted and repetitive patterns of behavior, and varying levels of intellectual disability. ASD is observed in early childhood and is one of the most severe chronic childhood disorders in prevalence, morbidity, and impact on society. It is usually accompanied by attention deficit hyperactivity disorder, anxiety, depression, sleep disorders, and epilepsy. The treatment of ASD has low efficacy, possibly because it has a heterogeneous nature, and its neurobiological basis is not clearly understood. Drugs such as risperidone and aripiprazole are the only two drugs available that are recognized by the Food and Drug Administration, primarily for treating the behavioral symptoms of this disorder. These drugs have limited efficacy and a high potential for inducing undesirable effects, compromising treatment adherence. Therefore, there is great interest in exploring the endocannabinoid system, which modulates the activity of other neurotransmitters, has actions in social behavior and seems to be altered in patients with ASD. Thus, cannabidiol (CBD) emerges as a possible strategy for treating ASD symptoms since it has relevant pharmacological actions on the endocannabinoid system and shows promising results in studies related to disorders in the central nervous system. OBJECTIVES: Review the preclinical and clinical data supporting CBD's potential as a treatment for the symptoms and comorbidities associated with ASD, as well as discuss and provide information with the purpose of not trivializing the use of this drug.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Cannabidiol , Aripiprazol/uso terapéutico , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Trastorno del Espectro Autista/tratamiento farmacológico , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Preescolar , Endocannabinoides , HumanosRESUMEN
Cannabinoid signaling, mainly via CB1 and CB2 receptors, plays an essential role in oligodendrocyte health and functions. However, the specific molecular signals associated with the activation or blockade of CB1 and CB2 receptors in this glial cell have yet to be elucidated. Mass spectrometry-based shotgun proteomics and in silico biology tools were used to determine which signaling pathways and molecular mechanisms are triggered in a human oligodendrocytic cell line (MO3.13) by several pharmacological stimuli: the phytocannabinoid cannabidiol (CBD); CB1 and CB2 agonists ACEA, HU308, and WIN55, 212-2; CB1 and CB2 antagonists AM251 and AM630; and endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The modulation of cannabinoid signaling in MO3.13 was found to affect pathways linked to cell proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Additionally, we found that carbohydrate and lipid metabolism, as well as mitochondrial function, were modulated by these compounds. Comparing the proteome changes and upstream regulators among treatments, the highest overlap was between the CB1 and CB2 antagonists, followed by overlaps between AEA and 2-AG. Our study opens new windows of opportunities, suggesting that cannabinoid signaling in oligodendrocytes might be relevant in the context of demyelinating and neurodegenerative diseases. Proteomics data are available at ProteomeXchange (PXD031923).
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Cannabidiol , Cannabinoides , Cannabidiol/farmacología , Cannabinoides/farmacología , Carbohidratos , Proliferación Celular/fisiología , Endocannabinoides/metabolismo , Endocannabinoides/farmacología , Humanos , Oligodendroglía/metabolismo , Proteoma , Transducción de SeñalRESUMEN
This study aimed to assess the ultrapure cannabidiol (CBD) antibacterial activity and to investigate the antibacterial activity of the combination CBD + polymyxin B (PB) against Gram-negative (GN) bacteria, including PB-resistant Gram-negative bacilli (GNB). We used the standard broth microdilution method, checkerboard assay, and time-kill assay. CBD exhibited antibacterial activity against Gram-positive bacteria, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis), and Mycobacterium tuberculosis, but not against GNB. For most of the GNB studied, our results showed that low concentrations of PB (≤ 2 µg/mL) allow CBD (≤ 4 µg/mL) to exert antibacterial activity against GNB (e.g., Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii), including PB-resistant GNB. CBD + PB also showed additive and/or synergistic effect against LOS-expressing GND. Time-kill assays results showed that the combination CBD + PB leads to a greater reduction in the number of colony forming units per milliliter compared to CBD and PB alone, at the same concentration used in combination, and the combination CBD + PB was synergistic for all four PB-resistant K. pneumoniae isolates evaluated. Our results show that CBD has translational potential and should be further explored as a repurposed antibacterial agent in clinical trials. The antibacterial efficacy of the combination CBD + PB against multidrug-resistant and extensively drug-resistant GNB, especially PB-resistant K. pneumoniae, is particularly promising.
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Cannabidiol , Polimixina B , Antibacterianos/farmacología , Cannabidiol/farmacología , Reposicionamiento de Medicamentos , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Bacterias Gramnegativas , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana , Polimixina B/farmacologíaRESUMEN
Objective: To compare plasma concentrations of cannabidiol (CBD) following oral administration of two formulations of the drug (powder and dissolved in oil), and to evaluate the effects of these distinct formulations on responses to emotional stimuli in healthy human volunteers. Methods: In a randomized, double-blind, placebo-controlled, parallel-group design, 45 healthy male volunteers were randomly assigned to three groups of 15 subjects that received either 150 mg of CBD powder; 150 mg of CBD dissolved in corn oil; or placebo. Blood samples were collected at different times after administration, and a facial emotion recognition task was completed after 150 min. Results: There were no significant differences across groups in the subjective and physiological measures, nor in the facial emotion recognition task. However, groups that received the drug showed statistically significant differences in baseline measures of plasma CBD, with a significantly greater difference in favor of the oil formulation. Conclusion: When administered as a single 150-mg dose, neither formulation of oral CBD altered responses to emotional stimuli in healthy subjects. The oil-based CBD formulation resulted in more rapid achievement of peak plasma level, with an approximate fourfold increase in oral bioavailability.
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OBJECTIVE: To compare plasma concentrations of cannabidiol (CBD) following oral administration of two formulations of the drug (powder and dissolved in oil), and to evaluate the effects of these distinct formulations on responses to emotional stimuli in healthy human volunteers. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group design, 45 healthy male volunteers were randomly assigned to three groups of 15 subjects that received either 150 mg of CBD powder; 150 mg of CBD dissolved in corn oil; or placebo. Blood samples were collected at different times after administration, and a facial emotion recognition task was completed after 150 min. RESULTS: There were no significant differences across groups in the subjective and physiological measures, nor in the facial emotion recognition task. However, groups that received the drug showed statistically significant differences in baseline measures of plasma CBD, with a significantly greater difference in favor of the oil formulation. CONCLUSION: When administered as a single 150-mg dose, neither formulation of oral CBD altered responses to emotional stimuli in healthy subjects. The oil-based CBD formulation resulted in more rapid achievement of peak plasma level, with an approximate fourfold increase in oral bioavailability.
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Cannabidiol , Emociones , Reconocimiento Facial , Vehículos Farmacéuticos , Administración Oral , Cannabidiol/química , Cannabidiol/farmacología , Método Doble Ciego , Composición de Medicamentos , Humanos , MasculinoRESUMEN
The interest in psychedelic substances as potential treatments for psychiatric disorders is increasing. The ß-carboline harmine, an Ayahuasca component, presents hallucinogenic and antidepressant effects. Although Ayuahuasca-and consequently harmine-is usually consumed in rituals, the role of social contexts in the behavioral effects of harmine has not been investigated yet. In this sense, affective states may modulate cohabitants' behavior, including learning/memory. This work investigates the effects of harmine on the learning/memory performance of rats evaluated on the contextual and tone fear conditioning (CFC and TFC) and on the plus-maze discriminative avoidance (PMDAT) tasks. The possible influence of a harmine-treated cohabitant was assessed by evaluating rats housed in homogeneous cages-where all the animals were acutely administered with the same treatment (vehicle, 5, 10, or 15 mg/kg harmine), and in heterogeneous cages-where each animal received a different drug treatment. The main results are: (a) harmine impaired CFC (10 mg/kg) and PMDAT discrimination (all doses); and (b) harmine caused a memory deficit in CFC, TFC, and PMDAT of untreated rats kept in heterogeneous cages. Our results show that harmine induces a memory deficit in tasks with emotional contexts. Further, the cohabitation with animals treated with this drug also seems to impair memory performance of untreated animals. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Emociones , Harmina , Ratas , Animales , Harmina/farmacología , Cognición , Miedo , Trastornos de la MemoriaRESUMEN
[This corrects the article DOI: 10.3389/fnmol.2021.673144.].
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Objective: The aim of the present study was to analyze the body sway response in specific phobia (SP) patients and healthy controls while viewing neutral, phobic, and disgusting images. Methods: The participants' heart rate (HR) and skin conductance were also recorded during the procedure. Nineteen patients with arachnophobia and 19 healthy volunteers matched by age, gender, and years of education underwent a postural control test on a stabilometric platform. Results: The platform recorded increased body sway in the SP group when exposed to spider images (SPI). The SP group presented increases in most parameters (SD, velocity, frequency, area, p ≤ 0.05) when viewing pictures of the SPI category. Psychometric measures of subjective anxiety (State-Trait Anxiety Inventory, STAI) and physiological states (HR; skin conductance responses; spontaneous fluctuations in skin conductance) showed increased anxiety (p ≤ 0.05) in the SP group compared to healthy volunteers. High anxiety levels were observed throughout the assessment, including the task of exposure to SPI (p ≤ 0.05). No significant effect or correlation was found between skin conductance and body sway measures (p > 0.05). Conclusions: The results of the postural control test suggest the occurrence of a defensive escape response in SP, in agreement with previous evidence.
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Trastornos Fóbicos , Arañas , Ansiedad , Trastornos de Ansiedad , Frecuencia CardíacaRESUMEN
Objective: To assess the efficacy of cannabidiol (CBD) in the management of crack-cocaine craving and the treatment of frequent withdrawal symptoms. Methods: Thirty-one men with a diagnosis of crack-cocaine dependence were enrolled in a randomized, double-blind, placebo-controlled trial. We applied neuropsychological tests and assessed craving intensity, anxiety and depression symptoms, and substance use patterns at baseline and at the end of the trial. The participants were treated with CBD 300 mg/day or placebo for 10 days. During this period, we used a technique to induce craving and assessed the intensity of symptoms before and after the induction procedure. Results: Craving levels reduced significantly over the 10 days of the trial, although no differences were found between the CBD and placebo groups. Craving induction was successful in both groups, with no significant differences between them. Indicators of anxiety, depression, and sleep alterations before and after treatment also did not differ across groups. Conclusion: Under the conditions of this trial, CBD was unable to interfere with symptoms of crack-cocaine withdrawal. Further studies with larger outpatient samples involving different doses and treatment periods would be desirable and timely to elucidate the potential of CBD to induce reductions in crack-cocaine self-administration.
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Humanos , Masculino , Cannabidiol , Cocaína Crack , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Método Doble Ciego , AnsiaRESUMEN
The incidence of chronic pain is high in the general population and it is closely related to anxiety disorders, which promote negative effects on the quality of life. The cannabinoid system has essential participation in the pain sensitivity circuit. In this perspective, cannabidiol (CBD) is considered a promising strategy for treating neuropathic pain. Our study aimed to evaluate the effects of sub-chronic systemic treatment with CBD (0.3, 3, 10, or 30 mg/kg, i.p.) in male in rats submitted to chronic constriction injury of the sciatic nerve (CCI) or not (SHAM) and assessed in nociceptive tests (von Frey, acetone, and hot plate, three days CBD's treatment) and in the open field test (OFT, two days CBD's treatment). We performed a screening immunoreactivity of CB1 and TRPV1 receptors in cortical and limbic regions tissues, which were collected after 1.5 h of behavioral tests on the 24th experimental day. This study presents a dose-response curve to understand better the effects of low doses (3 mg/kg) on CBD's antiallodynic and anxiolytic effects. Also, low doses of CBD were able to (1) reverse mechanical and thermal allodynia (cold) and hyperalgesia, (2) reverse anxious behaviors (reduction of the % of grooming and freezing time, and increase of the % of center time in the OFT) induced by chronic pain. The peripheral neuropathy promoted the increase in the expression of CB1 and TRPV1 receptors in the anterior cingulate cortex (ACC), anterior insular cortex (AIC), basolateral amygdala (BLA), dorsal hippocampus (DH), and ventral hippocampus (VH). CBD potentiated this effect in the ACC, AIC, BLA, DH, and VH regions. These results provide substantial evidence of the role of the ACC-AIC-BLA corticolimbic circuit, and BLA-VH for pain regulation. These results can be clinically relevant since they contribute to the evidence of CBD's beneficial effects on treating chronic pain and associated comorbidities such as anxiety.
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Ansiedad/tratamiento farmacológico , Cannabidiol/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Receptor Cannabinoide CB1/efectos de los fármacos , Canales Catiónicos TRPV/efectos de los fármacos , Animales , Ansiedad/psicología , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Calor , Sistema Límbico/efectos de los fármacos , Masculino , Red Nerviosa/efectos de los fármacos , Neuralgia/metabolismo , Neuralgia/psicología , Dimensión del Dolor/efectos de los fármacos , Estimulación Física , Ratas , Ratas Wistar , Ciática/tratamiento farmacológicoRESUMEN
Cannabidiol, a compound of Cannabis sativa, has been proposed as an alternative treatment of schizophrenia. Preclinical and clinical data have suggested that cannabidiol shares more similarity with atypical antipsychotics than typical, both of which are customarily used to manage schizophrenia symptoms. While oligodendrocytes are known to be relevant targets of antipsychotics, the biochemical knowledge in this regard is still limited. Here we evaluated the molecular pathways modulated by cannabidiol compared to the antipsychotics clozapine (atypical) and haloperidol (typical), additionally evaluating the effects of benztropine, a muscarinic receptor antagonist that displays a protective effect in oligodendrocytes and myelination. For this purpose, we employed nano-chromatography coupled with mass spectrometry to investigate the proteomic response to these drugs both in healthy oligodendrocytic cells and in a cuprizone-based toxicity model, using the human oligodendrocyte precursor cell line MO3.13. Cannabidiol shares similarities of biochemical pathways with clozapine and benztropine, in agreement with other studies that indicated an atypical antipsychotic profile. All drugs tested affected metabolic and gene expression pathways and cannabidiol, benztropine, and clozapine modulated cell proliferation and apoptosis when administered after cuprizone-induced toxicity. These general pathways are associated with cuprizone-induced cytotoxicity in MO3.13 cells, indicating a possible proteomic approach when acting against the toxic effects of cuprizone. In conclusion, although modeling oligodendrocytic cytotoxicity with cuprizone does not represent the entirety of the pathophysiology of oligodendrocyte impairments, these results provide insight into the mechanisms associated with the effects of cannabidiol and antipsychotics against cuprizone toxicity, offering new directions of study for myelin-related processes and deficits.