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Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.
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... CBD does not cause the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and antinociception) that is considered a good predictor of THC-like pharmacological activity, thus confirming that CBD lacks direct CB1 agonist properties (Martin et al. 1991). However, some of the CBD effects (e.g., increased hippocampal neurogenesis) are prevented by CB1 or CB2 receptor antagonists, indicating they depend on the facilitation of endocannabinoid signaling (Campos et al. 2013;Fogaça et al. 2018). Regarding the endocannabinoidome, CBD presents pharmacological targets that may be relevant to ASD. ...
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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.
... These effects are mediated by 5HT 1A R (De Gregorio et al., 2019;de Almeida and Devi, 2020). At 100 mg/kg, CBD can increase 5HT concentration in rat brain (Abame et al., 2021), but at 5 mg/kg, the antipanic effect of CBD is reversed by 5HT 1A R antagonists, and it is not associated with changes in the concentration of 5HT (Campos et al., 2013). In our case, the CBD dose was even lower than that. ...
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Background: Hypoxic–ischemic (HI) insults have important deleterious consequences in newborns, including short-term morbidity with neuromotor and cognitive disturbances. Cannabidiol (CBD) has demonstrated robust neuroprotective effects and shows anxiolytic/antidepressant effects as well. These effects are thought to be related to serotonin 5-HT 1A receptor (5HT 1A R) activation. We hereby aimed to study the role of 5HT 1A R in the neuroprotective and behavioral effects of CBD in HI newborn piglets. Methods: 1-day-old piglets submitted to 30 min of hypoxia (FiO2 10%) and bilateral carotid occlusion were then treated daily with vehicle, CBD 1 mg/kg, or CBD with the 5HT 1A R antagonist WAY 100635 1 mg/kg 72 h post-HI piglets were studied using amplitude-integrated EEG to detect seizures and a neurobehavioral test to detect neuromotor impairments. In addition, behavioral performance including social interaction, playful activity, hyperlocomotion, and motionless periods was assessed. Then, brain damage was assessed using histology (Nissl and TUNEL staining) and biochemistry (proton magnetic resonance spectroscopy studies. Results: HI led to brain damage as assessed by histologic and biochemistry studies, associated with neuromotor impairment and increased seizures. These effects were not observed in HI piglets treated with CBD. These beneficial effects of CBD were not reversed by the 5HT 1A R antagonist, which is in contrast with previous studies demonstrating that 5HT 1A R antagonists eliminated CBD neuroprotection as assessed 6 h after HI in piglets. HI led to mood disturbances, with decreased social interaction and playfulness and increased hyperlocomotion. Mood disturbances were not observed in piglets treated with CBD, but in this case, coadministration of the 5HT 1A R antagonist eliminates the beneficial effects of CBD. Conclusion: CBD prevented HI-induced mood disturbances in newborn piglets by acting on 5HT 1A R. However, 5HT 1A R activation seems to be necessary for CBD neuroprotection only in the first hours after HI.
... Clinically, CBD does antagonize some actions of THC. However, CBD has different clinical effects to recombinant and other antagonists of CB 1/2 (McPartland et al. 2015), and the overall clinical effect of CBD is to increase CB 1/2 signaling (Blessing et al. 2015;Campos et al. 2013;Fogaça et al. 2018). CBD is also an antagonist of GPR55, which is an endocannabinoid receptor with multiple putative clinical actions (de Almeida and Devi 2020). ...
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Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells. The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain. THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.
... In the pursuit of alternative pharmacotherapies for depression, preclinical evidence suggests that pharmacological enhancement of the endogenous cannabinoid system (ECS) promotes antidepressant and anxiolytic effects [2,8,[12][13][14][15][16][17][18][19][20][21][22]. The fundamental elements of the ECS consist of the cannabinoid one receptor (CB1R), the cannabinoid two receptor (CB2R), the endogenous cannabinoid (eCB) arachidonoyl-ethanolamide (i.e., anandamide) (AEA), the eCB 2-arachidonoyl glycerol , and the enzymes involved in eCB synthesis and catabolism [23]. ...
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Neuroscience research presents contradictory evidence in support of both the protective and destructive effects of cannabinoids in depression. Therefore, this systematic review and meta-analysis summarizes the existing preclinical literature on the effects of cannabinoid administration in the chronic unpredictable stress model of depression in order to evaluate the effects of cannabinoids and identify gaps in the literature. After protocol registration (PROSPERO #CRD42020219986), we systematically searched Scopus, Embase, Psychology & Behavioral Sciences Collection, APA PsychINFO, PubMed, CINAHL Complete, and ProQuest Dissertations & Theses Global from the earliest record of the databases, February 1964, to November 2020 for articles that met inclusion criteria (e.g., rodent subjects and administration of a cannabinoid. A total of 26 articles were included representing a sample size estimate of 1132 rodents with the majority of articles administering daily intraperitoneal injections during chronic unpredictable stress. These articles were evaluated using a modified SYRCLE’s risk-of-bias tool. For each continuous behavioral measure, the standardized mean difference was calculated between cannabinoid and vehicle groups in rodents subjected to chronic unpredictable stress. The effects of cannabinoids on depressive-like behavior was evaluated using a multilevel mixed-effects model with effect size weights nested within control groups. Cannabinoid administration moderately improved the pooled negative effects of chronic unpredictable stress on anhedonia, learned helplessness, novelty suppressed feeding, time in the anxiogenic context, and entries into the anxiogenic context. Although the interpretations are limited, these findings suggest that with further investigation, cannabinoids may be a viable long-term treatment for stress-related psychopathologies such as depression.
... Another potential caveat of this study involves the lack of a dose range. More concentrations of the compounds employed here may reveal more information since cannabinoids commonly produce inverted U-shaped dose-response curves in vitro [84] and similarly affect behavior tasks [85][86][87]. ...
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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).
... Preclinical literature regarding CBD in rodent models of generalized anxiety suggest CBD's efficacy in minimizing anxiety associated behaviors relevant in GAD, SAD, PTSD, and OCD. Studies utilizing CBD in elevated plus and elevated T mazes with rodents have observed anxiolytic effects following both acute systemic administration (Campos et al., 2012;Campos et al., 2013a;Campos et al., 2013b) and acute local administrations in areas such as the amygdala central nucleus (Hsiao et al., 2012), bed nucleus of the stria terminalis (Gomes et al., 2011), and the intra-dorsal periaqueductal gray (Soares et al., 2010). Anxiolytic effects of CBD in these models are presented as a bell-shaped dose-response curve, with anxiolytic effects generally observed at moderate doses; 2.5-10.0 ...
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Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.
... CBD is a multi-target ligand with a poor affinity for CB1R and CB2R and behaves as a modulator of eCB levels [53]. For example, CBD enhances neurogenesis, possibly by increasing AEA levels [54], suggesting mechanisms via an indirect stimulation of the ECS. CBD reduces the negative effects of NMDAR overactivity (see below, entourage effect). ...
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The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory. The advent of novel genomic, optogenetic, and viral tracing and imaging techniques will help to further detail therapeutically relevant functional and structural features. An evolutionarily highly conserved group of neuromodulatory lipids, their receptors, and anabolic and catabolic enzymes are involved in a remarkable variety of physiological and pathological processes and has been termed the endocannabinoid system (ECS). A large body of data has emerged in recent years, pointing to a crucial role of this system in the regulation of the behavioral domains of acquired fear, anxiety, and stress-coping. Besides neurons, also glia cells and components of the immune system can differentially fine-tune patterns of neuronal activity. Dysregulation of ECS signaling can lead to a lowering of stress resilience and increased incidence of psychiatric disorders. Chronic pain may be understood as a disease process evoked by fear-conditioned nociceptive input and appears as the dark side of neuronal plasticity. By taking a toll on every part of your life, this abnormal persistent memory of an aversive state can be more damaging than its initial experience. All strategies for the treatment of chronic pain conditions must consider stress-related comorbid conditions since cognitive factors such as beliefs, expectations, and prior experience (memory of pain) are key modulators of the perception of pain. The anxiolytic and anti-stress effects of medical cannabinoids can substantially modulate the efficacy and tolerability of therapeutic interventions and will help to pave the way to a successful multimodal therapy. Why some individuals are more susceptible to the effects of stress remains to be uncovered. The development of personalized prevention or treatment strategies for anxiety and depression related to chronic pain must also consider gender differences. An emotional basis of chronic pain opens a new horizon of opportunities for developing treatment strategies beyond the repeated sole use of acutely acting analgesics. A phase I trial to determine the pharmacokinetics, psychotropic effects, and safety profile of a novel nanoparticle-based cannabinoid spray for oromucosal delivery highlights a remarkable innovation in galenic technology and urges clinical studies further detailing the huge therapeutic potential of medical cannabis (Lorenzl et al.; this issue).
... The hypothesis that abnormal AHN is involved in the pathology of depression is partly supported by the decrease in AHN and the loss of hippocampal volume observed in patients with major depression and in depressive-like animal models [32,33]. Consistent with previous reports on other depression models [34][35][36], we found that the numbers of nestin-positive and BrdU/NeuN-double-positive cells were significantly decreased in the CRS model, confirming the impairment of AHN under stress conditions. Intriguingly, our results also revealed a significant increase in the number of BrdU/GFAP-double-labeled cells in CRS mice, indicating that rNSCs underwent activation-dependent differentiation into astrocytes. ...
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Chronic stress impairs radial neural stem cell (rNSC) differentiation and adult hippocampal neurogenesis (AHN), whereas promoting AHN can increase stress resilience against depression. Therefore, investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs. The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against depression. However, whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown. Here, by using the chronic restraint stress (CRS) mouse model, we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions. Moreover, transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process. The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte, which was partly mediated by the modulation of the FoxO signaling pathway. These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.
Chapter
Cannabinoids are ligands that are either plant derived, synthetic, or semisynthetic, and have affinity for and activity at cannabinoid receptors. The biological effects of phytocannabinoids or synthetic cannabinoids, like endogenous cannabinoids, occur through interactions with the endocannabinoid system (ECS). This system is essential for a diverse range of brain functions including mood balance, energy balance, learning and memory and has been implicated in multiple psychiatric, neurological, neurodegenerative, and neuroinflammatory related diseases. The increasing societal and medical interest in the recreational and therapeutic use of cannabinoid drugs raises concern for unwanted adverse effects of exposure during critical life-stages or over the long-term as occurs with modification of the endocannabinoid system. Understanding the role of the ECS in various aspects of brain development and function is a critical basis for understanding the potential for adverse effects of usage on the nervous system upon recreational usage or therapeutic intervention. This chapter presents a background on the ECS and how interactions with this system may alter nervous system function. It presents information on the role of two mechanistic targets of the ECS, the GABAergic neurotransmitter system and the brain immune cell and considers how knowledge of these systems can advance our understanding of the effects of cannabinoids on the nervous system.
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Adult hippocampal neurogenesis has been implicated in cognitive and emotional processes, as well as in response to antidepressant treatment. However, little is known about how the adult stem cell lineage contributes to hippocampal structure and function and how this process is modulated by the animal's experience. Here we perform an indelible lineage analysis and report that neural stem cells can produce expanding and persisting populations of not only neurons, but also stem cells in the adult hippocampus. Furthermore, the ratio of stem cells to neurons depends on experiences of the animal or the location of the stem cell. Surprisingly, social isolation facilitated accumulation of stem cells, but not neurons. These results show that neural stem cells accumulate in the adult hippocampus and that the stem cell-lineage relationship is under control of anatomic and experiential niches. Our findings suggest that, in the hippocampus, fate specification may act as a form of cellular plasticity for adapting to environmental changes.