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Abstract

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ9-Tetrahydrocannabinol (Δ9-THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ9-THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ9-THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ9-THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

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... CBD is not thought to significantly activate CB1 and CB2 receptors as THC does (Devinsky et al. 2014) and may reduce the psychoactive effects of THC by negative allosteric modulation at CB1 (Laprairie et al. 2015). However, it is thought to have other molecular targets including equilibrative nucleoside transporters (ENT), GPR55 receptors, TRPM8 channels, 5HT1a receptors, alpha1 and 3 glycine receptors, and TRPV1 and TRPV2 channels and an indirect effect on adenosine A1 receptor and has a bidirectional effect on intracellular calcium (Devinsky et al. 2014). ...
... CBD is not thought to significantly activate CB1 and CB2 receptors as THC does (Devinsky et al. 2014) and may reduce the psychoactive effects of THC by negative allosteric modulation at CB1 (Laprairie et al. 2015). However, it is thought to have other molecular targets including equilibrative nucleoside transporters (ENT), GPR55 receptors, TRPM8 channels, 5HT1a receptors, alpha1 and 3 glycine receptors, and TRPV1 and TRPV2 channels and an indirect effect on adenosine A1 receptor and has a bidirectional effect on intracellular calcium (Devinsky et al. 2014). Some of the actions in these areas are thought to include reduction of THC psychoactive activity and anti-spasticity effects in multiple sclerosis; though there is also a high degree of uncertainty around the effects and mechanism of these actions (Devinsky et al. 2014). ...
... However, it is thought to have other molecular targets including equilibrative nucleoside transporters (ENT), GPR55 receptors, TRPM8 channels, 5HT1a receptors, alpha1 and 3 glycine receptors, and TRPV1 and TRPV2 channels and an indirect effect on adenosine A1 receptor and has a bidirectional effect on intracellular calcium (Devinsky et al. 2014). Some of the actions in these areas are thought to include reduction of THC psychoactive activity and anti-spasticity effects in multiple sclerosis; though there is also a high degree of uncertainty around the effects and mechanism of these actions (Devinsky et al. 2014). ...
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Introduction Cannabidiol (CBD) is now a legal substance in Europe and is available in ‘high street shops’, usually as CBD oil. However, in the United Kingdom (UK), there is no clear consensus among healthcare professionals and organisations over how to manage CBD use in their patients. This is an important issue as CBD is a constituent of ‘medicinal and recreational cannabis’ and is gaining support in the scientific literature and lay media for use in physical and mental health problems. Given the aforementioned, this study is an exploration of healthcare professionals’ beliefs and attitudes with regard to CBD. Methods In July 2018, we sent requests by email to approximately 2000 clinical staff (including 319 physicians) at a mental health trust in South West London to answer 8 questions in a single survey using Surveyplanet.com , about their beliefs regarding CBD. There was no specific method of choosing the staff, and the aim was to get the email request sent to as many staff as possible on each service line. We did an analysis to see how the attitudes and beliefs of different staff member groups compared. We also gave them space to offer free text responses to illustrate their ideas and concerns. We used chi-squared tests for comparison across groups and used odds ratio for pairwise group comparisons. Results One hundred ninety surveys were received in response, and of these, 180 were included in the final sample. The physician response rate was 17.2% (55/319); the response rate for non-physicians could not be estimated as their total number was not known at outset. 32.2% of the responders had the right to prescribe (58/180) and 52.8% had an experience of working in addiction services (95/180). We found that staff members who can prescribe were 1.99 times as likely to believe CBD has potential therapeutic properties compared to those who do not ( OR = 1.99, CI = 1.03, 3.82; p = 0.038) and 2.94 times less likely to think it had dangerous side effects ( OR = 0.34, CI = 0.15, 0.75; p = 0.006). Prescribing healthcare professionals were 2.3 times as likely to believe that CBD reduces the likelihood of psychosis ( OR = 2.30, CI = 1.10, 4.78; p = 0.024). However, prescribing healthcare professionals with the ability to prescribe were 2.12 times as likely to believe that CBD should be prescription only ( OR = 2.12, CI = 1.12, 4.01; p = 0.02). Individuals experienced in addiction services were 2.22 times as likely to be associated with a belief that CBD has therapeutic properties ( OR = 2.22, CI = 1.22, 4.04; p = 0.009). Staff in general reported a lack of knowledge about CBD in their free text responses. Conclusions With almost 95% of prescribers being physicians, they appear to demonstrate awareness of potential therapeutic benefit, reduced likelihood of psychosis and seeming lack of dangerous side effects with CBD. However, their higher stringency about the need for prescription implies an attitude of caution. There was also a suggestion that biases about cannabis were influencing responses to questions as well. The external validity of this study could be diminished by sampling bias and limitation to a single mental health trust. Nonetheless, some of the results drew a reasonable comparison with similar studies.
... Data shown as mean ± SEM. ANOVA (C, D, E, F) and Mann-Whitney test (G, H): *p < 0.05, ***p < 0.001 between them had no significant main effects, indicating that neither footshock experiences nor administration of HU210 affected motor ability (treatment F (1,32) = 0.862, p = 0.360; stress F (1,32) = 0.165, p = 0.687; treatment × stress F (1,32) = 0.60, p = 0.443; Fig. 1D). Moreover, the results of plantar Hargreaves test (PHT) suggested that HU210 at the dose of 15 μg/kg had no significant impact on the algesthesia (treatment F (1,16) = 0.316, p = 0.582; session F (1,16) = 1.980, p = 0.179; treatment × session F (1,16) = 0.668, p = 0.425; Fig. 1F), indicating the impairment of learning may not be due to the sensorimotor deficits. ...
... Data shown as mean ± SEM. ANOVA (C, D, E, F) and Mann-Whitney test (G, H): *p < 0.05, ***p < 0.001 between them had no significant main effects, indicating that neither footshock experiences nor administration of HU210 affected motor ability (treatment F (1,32) = 0.862, p = 0.360; stress F (1,32) = 0.165, p = 0.687; treatment × stress F (1,32) = 0.60, p = 0.443; Fig. 1D). Moreover, the results of plantar Hargreaves test (PHT) suggested that HU210 at the dose of 15 μg/kg had no significant impact on the algesthesia (treatment F (1,16) = 0.316, p = 0.582; session F (1,16) = 1.980, p = 0.179; treatment × session F (1,16) = 0.668, p = 0.425; Fig. 1F), indicating the impairment of learning may not be due to the sensorimotor deficits. ...
... Data shown as mean ± SEM. ANOVA (C, D, E, F) and Mann-Whitney test (G, H): *p < 0.05, ***p < 0.001 between them had no significant main effects, indicating that neither footshock experiences nor administration of HU210 affected motor ability (treatment F (1,32) = 0.862, p = 0.360; stress F (1,32) = 0.165, p = 0.687; treatment × stress F (1,32) = 0.60, p = 0.443; Fig. 1D). Moreover, the results of plantar Hargreaves test (PHT) suggested that HU210 at the dose of 15 μg/kg had no significant impact on the algesthesia (treatment F (1,16) = 0.316, p = 0.582; session F (1,16) = 1.980, p = 0.179; treatment × session F (1,16) = 0.668, p = 0.425; Fig. 1F), indicating the impairment of learning may not be due to the sensorimotor deficits. ...
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Background Cannabinoids and their derivatives attract strong interest due to the tremendous potential of their psychoactive effects for treating psychiatric disorders and symptoms. However, their clinical application is restricted by various side-effects such as impaired coordination, anxiety, and learning and memory disability. Adverse impact on dorsal striatum-dependent learning is an important side-effect of cannabinoids. As one of the most important forms of learning mediated by the dorsal striatum, reinforcement learning is characterized by an initial association learning phase, followed by habit learning. While the effects of cannabinoids on habit learning have been well-studied, little is known about how cannabinoids influence the initial phase of reinforcement learning. Results We found that acute activation of cannabinoid receptor type 1 (CB1R) by the synthetic cannabinoid HU210 induced dose-dependent impairment of association learning, which could be alleviated by intra-dorsomedial striatum (DMS) injection of CB1R antagonist. Moreover, acute exposure to HU210 elicited enhanced synaptic transmission in striatonigral “direct” pathway medium spiny neurons (MSNs) but not indirect pathway neurons in DMS. Intriguingly, enhancement of synaptic transmission that is also observed after learning was abolished by HU210, indicating cannabinoid system might disrupt reinforcement learning by confounding synaptic plasticity normally required for learning. Remarkably, the impaired response-reinforcer learning was also induced by selectively enhancing the D1-MSN (MSN that selectively expresses the dopamine receptor type 1) activity by virally expressing excitatory hM3Dq DREADD (designer receptor exclusively activated by a designer drug), which could be rescued by specifically silencing the D1-MSN activity via hM4Di DREADD. Conclusion Our findings demonstrate dose-dependent deleterious effects of cannabinoids on association learning by disrupting plasticity change required for learning associated with the striatal direct pathway, which furthers our understanding of the side-effects of cannabinoids and the underlying mechanisms.
... Given the sparsity of effective and accessible treatments, people with FND may seek alternative treatments and selfmanagement strategies, including legal and illicit substances, despite potential risks. Although legal psychoactive drugs, such as alcohol, caffeine, nicotine, and cannabidiol (CBD; a constituent of the cannabis plant), have no proven efficacy in the treatment of FND, their psychopharmacological effects on the central nervous system (CNS) may aid in symptom management, either directly or via an effect on common comorbidities such as anxiety (10). As an example, the health supplement CBD has been suggested as having promise in the attenuation of symptoms in psychological and neuropsychiatric illnesses (10). ...
... Although legal psychoactive drugs, such as alcohol, caffeine, nicotine, and cannabidiol (CBD; a constituent of the cannabis plant), have no proven efficacy in the treatment of FND, their psychopharmacological effects on the central nervous system (CNS) may aid in symptom management, either directly or via an effect on common comorbidities such as anxiety (10). As an example, the health supplement CBD has been suggested as having promise in the attenuation of symptoms in psychological and neuropsychiatric illnesses (10). ...
Article
Objective: Functional neurological disorder (FND) causes a high burden of disability and distress. Although it is a common disorder, there is a pressing need for improved access to evidence-based treatments. With difficulties in finding effective treatment, some people with FND may seek alternative means of symptom relief, such as legal and illicit psychoactive substances, although the prevalence and nature of such self-management strategies are currently unclear. Additionally, psychoactive substances may represent novel treatment research opportunities, particularly for those with suboptimal improvement. The investigators examined the use of self-management techniques, as well as perspectives on novel therapies, in this patient population. Methods: An online survey was created to assess self-management strategies and views on novel treatments for FND, including psychedelic therapy. The survey was accessible for 1 month, and respondents were recruited internationally through social media and patient groups. A total of 1,048 respondents from 16 countries completed the survey. Results: Almost half (46%) of 980 respondents reported having tried legal psychoactive substances for the management of their FND symptoms and, on average, nicotine, alcohol, and cannabidiol were reported as modestly effective. Additionally, 15% of respondents reported having used illicit substances, mostly cannabis, to manage FND, with the majority reporting moderate effectiveness and experiencing no or minimal physical (90%) and psychological (95%) sequelae. Many respondents (46%) reported that they would be willing to try medically supervised psychedelic therapy (with 19% of respondents ambivalent) if it were found to be safe and effective. Conclusions: Many people with FND seek alternative means of symptom management outside usual medical care, including legal and illicit psychoactive substances. Further research exploring novel treatment options, such as psychedelics, in FND may be warranted.
... THC is the primary psychoactive ingredient (5) and has shown therapeutic benefit for pain, nausea, and sleep (1). CBD is non-intoxicating at medically relevant doses (4); and when combined with THC, may counterbalance the psychoactivity of THC (6), while increasing THC tolerance (7). Cannabidiol has antiinflammatory, neuroprotective, antipsychotic, anxiolytic, and antidepressant properties (8). ...
... Although the UK has begun to develop a registry of medical cannabis patients (9), rigorous observational studies and prospective clinical trials have yet to be undertaken and most of the available data is derived from surveys of cooperating users. These surveys are usually limited in scope, retrospective, and rarely collect data on variables beyond basic demographic elements, comorbidities, modes of consumption, and overall satisfaction (2,(6)(7)(8)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). ...
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Background Despite the absence of rigorous prospective studies, there has been an increase in the use of cannabis-based medicinal products. During the study period, the use of medical cannabis in Israel was tightly regulated by national policy. Through a prospective study of approximately 10,000 patients, we aimed to characterize the medical cannabis patient population as well as to identify treatment adherence, safety, and effectiveness. Methods and Findings In this study of prescribed medical cannabis patients, adherence, safety, and effectiveness were assessed at 6 months. Treatment adherence was assessed by the proportion of patients purchasing the medication out of the total number of patients (excluding deceased cases and patients transferred to another cannabis clinic). Safety was assessed by the frequency of the side-effects, while effectiveness was defined as at least moderate improvement in the patient condition without treatment cessation or serious side-effects. The most frequent primary indications requiring therapy were cancer (49.1%), followed by non-specific pain (29.3%). The average age was 54.6 ± 20.9 years, 51.1% males; 30.2% of the patients reported prior experience with cannabis. During the study follow-up, 1,938 patients died (19.4%) and 1,735 stopped treatment (17.3%). Common side-effects, reported by 1,675 patients (34.2%), were: dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%), and psychoactive effect (4.3%). Overall, 70.6% patients had treatment success at 6 months. Multivariable logistic regression analysis revealed that the following factors were associated with treatment success: cigarette smoking, prior experience with cannabis, active driving, working, and a young age. The main limitation of this study was the lack of data on safety and effectiveness of the treatment for patients who refused to undergo medical assessment even at baseline or died within the first 6 months. Conclusions We observed that supervised medical-cannabis treatment is associated with high adherence, improvement in quality of life, and a decrease in pain level with a low incidence of serious adverse events.
... Thus, it is postulated that TRPV1 antagonists penetrating the blood-brain barrier may be promising ASD candidates, which adds to their potent central and peripheral antinociceptive properties. It should be emphasized herein that cannabidiol (CBD) which is one of the newest ASDs effective in DRE (i.e., Dravet and Lennox-Gastaut syndromes in children), has a multi-target mechanism of action and causes desensitization of the TRPV1, besides the inhibition of sodium and calcium conductance [27,28]. Therefore, it is suggested that a multimodal mechanism of action underlines a broad spectrum of antiseizure activity of CBD that was demonstrated in preclinical studies [29]. ...
... Unfortunately, none of the aforementioned compounds showed satisfactory activity in this test (only 53 and 60 provided weak 25% protection, Table S1). The lack or very weak activity in the aforementioned chemically-induced seizures proves that the pyrrolidine-2,5-dione ring seems to be crucial for activity in the scPTZ test, as it was observed for structurally-related succinimide analogues that were described by our team in the previous studies [28]. ...
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In the present study, a focused combinatorial chemistry approach was applied to merge structural fragments of well-known TRPV1 antagonists with a potent anticonvulsant lead compound, KA-104, that was previously discovered by our group. Consequently, a series of 22 original compounds has been designed, synthesized, and characterized in the in vivo and in vitro assays. The obtained compounds showed robust in vivo antiseizure activity in the maximal electroshock (MES) test and in the 6 Hz seizure model (using both 32 and 44 mA current intensities). The most potent compounds 53 and 60 displayed the following pharmacological profile: ED50 = 89.7 mg/kg (MES), ED50 = 29.9 mg/kg (6 Hz, 32 mA), ED50 = 68.0 mg/kg (6 Hz, 44 mA), and ED50 = 73.6 mg/kg (MES), ED50 = 24.6 mg/kg (6 Hz, 32 mA), and ED50 = 56.3 mg/kg (6 Hz, 44 mA), respectively. Additionally, 53 and 60 were effective in the ivPTZ seizure threshold and had no influence on the grip strength and body temperature in mice. The in vitro binding and functional assays indicated a multimodal mechanism of action for 53 and 60. These molecules, beyond TRPV1 antagonism, inhibited calcium currents and fast sodium currents in patch-clamp assays. Further studies proved beneficial in vitro ADME-Tox properties for 53 and 60 (i.e., high metabolic stability, weak influence on CYPs, no neurotoxicity, etc.). Overall, 53 and 60 seem to be interesting candidates for future preclinical development in epilepsy and pain indications due to their interaction with the TRPV1 channel.
... Their target, the endocannabinoid system, is composed primarily of CB1 receptors, expressed mainly by central and peripheral neurons, and CB2 receptors, expressed mainly by immune cells (14)(15)(16), suggesting a therapeutic value of CBD for numerous medical conditions in humans because of its potential neural (2,17) and immunomodulatory properties (18). Therapeutic applications of CBD in humans include epilepsy (1,(19)(20)(21), Alzheimer's disease (22) and multiple sclerosis (23,24). In the veterinary medicine, therapeutic applications of CBD in dogs include osteoarthritis-associated pain (6,25,26), aggressive behavior (27), and epilepsy (7,28). ...
... In the veterinary medicine, therapeutic applications of CBD in dogs include osteoarthritis-associated pain (6,25,26), aggressive behavior (27), and epilepsy (7,28). CBD is generally administered orally, but its low bioavailability, which is estimated to be <10% in humans (19,29), continues to be a main issue in clinical trials (30). In healthy dogs, it has been shown that administration of oral CBD is associated with a low bioavailability as well, ranging from 13 to 19%, most likely due to its first-pass phenomenon in the liver (31). ...
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The therapeutic potential of cannabidiol (CBD), a non-psychtropic component of the Cannabis sativa plant, is substantiated more and more. We aimed to determine the pharmacokinetic behavior of CBD after a single dose via intranasal (IN) and intrarectal (IR) administration in six healthy Beagle dogs age 3-8 years old, and compare to the oral administration route (PO). Standardized dosages applied for IN, IR and PO were 20, 100, and 100 mg, respectively. Each dog underwent the same protocol but received CBD through a different administration route. CBD plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry before and at fixed time points after administration. Non-compartmental analysis was performed on the plasma concentration-time profiles. Plasma CBD concentrations after IR administration were below the limit of quantification. The mean area under the curve (AUC) after IN and PO CBD administration was 61 and 1,376 ng/mL * h, respectively. The maximal plasma CBD concentration (C max) after IN and PO CBD administration was 28 and 217 ng/mL reached after 0.5 and 3.5 h (T max), respectively. Significant differences between IN and PO administration were found in the T max (p = 0.04). Higher AUC and C max were achieved with 100 mg PO compared to 20 mg IN, but no significant differences were found when AUC (p = 0.09) and C max (p = 0.44) were normalized to 1 mg dosages. IN administration of CBD resulted in faster absorption when compared to PO administration. However, PO remains the most favorable route for CBD delivery due to its more feasible administration. The IR administration route is not advised for clinical application.
... Cannabidiol (CBD), the most abundant phytocannabinoid of cannabis after Δ 9 -tetrahydrocannabinol (THC), has generated significant hope in treating drug addiction (Calpe-López et al., 2019;Chye et al., 2019;Hurd, 2017). In the past two decades, a large body of basic and clinical research has revealed that CBD can be beneficial for treating neurological disorders such as epilepsy (Devinsky et al., 2014;Samanta, 2019), multiple sclerosis (Kozela et al., 2011), Parkinson's disease (Chagas et al., 2014;Zuardi et al., 2009), and Alzheimer's disease (Cheng et al., 2014;Martín-Moreno et al., 2011). Moreover, a substantial body of work has suggested that CBD improves cognition (Razavi et al., 2020) with anxiolytic (Gasparyan et al., 2020;Hahn, 2018), antidepressant (Linge et al., 2016;Zanelati et al., 2010), and antipsychotic-like effects (Elsaid et al., 2019;Scuderi et al., 2009), supporting its potential for the treatment of neuropsychiatric disorders including schizophrenia (Leweke et al., 2012;McGuire et al., 2018;Schoevers et al., 2020), mood disorders (Bartoli et al., 2021;Bonaccorso et al., 2019), anxiety disorders (Blessing et al., 2015;Skelley et al., 2020), and drug addiction (Elsaid et al., 2019). ...
... CBD is not associated with adverse cognitive effects, presents good safety and tolerability profiles in humans, and has a broad pharmacological spectrum of action (Zhornitsky and Potvin, 2012;niesink & van laar, 2013). As noted in this review: CBD has sedative, anti-craving, antidepressant, mood-stabilizing, and anxiolytic properties (Schier et al., 2012;Zhornitsky and Potvin, 2012;niesink & van laar, 2013;Robson, 2014). Moreover, CBD could effectively reduce the rewarding and reinforcing effects of some addictive drugs. ...
Article
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Background Cannabidiol (CBD) is one of the major constituents of Cannabis sativa L. that lacks psychotomimetic and rewarding properties and inhibits the rewarding and reinforcing effects of addictive drugs such as cocaine, methamphetamine (METH), and morphine. Additionally, CBD's safety profile and therapeutic potential are currently evaluated in several medical conditions, including pain, depression, movement disorders, epilepsy, multiple sclerosis, Alzheimer's disease, ischemia, and substance use disorder. There is no effective treatment for substance use disorders such as addiction, and this review aims to describe preclinical and clinical investigations into the effects of CBD in various models of opioid, psychostimulant, cannabis, alcohol, and nicotine abuse. Furthermore, the possible mechanisms underlying the therapeutic potential of CBD on drug abuse disorders are reviewed. Methods The current review considers and summarizes the preclinical and clinical investigations into CBD's effects in various models of drug abuse include opioids, psychostimulants, cannabis, alcohol, and nicotine. Results Several preclinical and clinical studies have proposed that CBD may be a reliable agent to inhibit the reinforcing and rewarding impact of drugs. Conclusions While the currently available evidence converges to suggest that CBD could effectively reduce the rewarding and reinforcing effects of addictive drugs, more preclinical and clinical studies are needed before CBD can be added to the therapeutic arsenal for treating addiction.
... It is possible that differences between the RL/+ mutants and WT littermates in the expression of other CBD target receptors, CBD metabolism, or network excitability may have contributed to the altered response to CBD. Previous studies have identified several potential mechanisms by which CBD decreases neuronal excitability, including acting upon TRPV1 and blocking the orphan receptor GPR55 (Devinsky et al., 2014;Kaplan et al., 2017). At physiologically relevant concentrations, CBD does not directly bind to the endocannabinoid receptors CB1 or CB2 (Devinsky et al., 2014;Mcpartland et al., 2015). ...
... Previous studies have identified several potential mechanisms by which CBD decreases neuronal excitability, including acting upon TRPV1 and blocking the orphan receptor GPR55 (Devinsky et al., 2014;Kaplan et al., 2017). At physiologically relevant concentrations, CBD does not directly bind to the endocannabinoid receptors CB1 or CB2 (Devinsky et al., 2014;Mcpartland et al., 2015). However, CBD has been shown to inhibit human and mouse Na v 1.6 currents at therapeutically relevant concentrations (Ghovanloo et al., 2018). ...
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Voltage-gated sodium channel genes are an important family of human epilepsy genes. De novo missense mutations in SCN8A (encoding Na v 1.6) are associated with a spectrum of clinical presentation, including multiple seizure types, movement disorders, intellectual disability, and behavioral abnormalities such as autism. Patients with SCN8A mutations are often treated with multiple antiepileptic drugs, the most common being sodium channel blockers. Cannabidiol (CBD) has been included as a component of treatment regimens for some SCN8A patients; however, to date, there are no clinical trials that have evaluated the therapeutic potential of CBD in patients with SCN8A mutations. In the current manuscript, we demonstrated a dose-dependent increase in seizure resistance following CBD treatment in mice expressing the human SCN8A mutation R1620L (RL/+). We also found that CBD treatment improved social behavior and reduced hyperactivity in the RL/+ mutants. Our findings suggest that CBD may be beneficial in patients with SCN8A- associated disease.
... CBD can also activate the TRPV1 channel, serotonin 1A (5-HT 1A ) receptors, and opioid receptors [24,172]. CBD has anti-inflammatory, anti-oxidative, anti-epileptic, analgesic, anti-neoplastic, sedative, neuroprotective, and anti-anxiety activities [173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188]. Moreover, CBD inhibits sebocyte lipogenesis by activating the TRPV4 ion channel that interferes with the pro-lipogenic ERK1/2 MAPK pathway [189]. ...
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Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
... Cannabidiol (CBD), a major nonpsychotropic ingredient of phytocannabinoids present in the medical cannabis plant and approved by the FDA for the treatment of Dravet syndrome, has been shown to possess broad-spectrum pharmacological activities in many neurological diseases, such as epilepsy and multiple sclerosis [12,13]. A growing body of evidence suggests that CBD may be an effective and safe antidepressant agent; however, the underlying mechanisms of the antidepressive effect of CBD are unclear [14][15][16]. ...
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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.
... When seizures are induced by chemoconvulsants or electrical stimulation, pro-inflammatory cytokines are elevated, along with other inflammatory mediators, in brain areas associated with epileptic activity [21,22]. The beneficial effects of CBD appear to be related to neuroprotective mechanisms that inhibit excessive inflammatory responses and reduce proinflammatory cytokines, such as IL1-b, which in turn reduces seizure severity [12,[23][24][25][26]. ...
Article
Approximately 70% of women with epilepsy experience additional challenges in seizure exacerbation due to hormonal changes, particularly during fluctuations of estrogen-progesterone levels in the menstrual cycle, which is known as catamenial epilepsy. In animal models of epilepsy, a sustained increase in seizure frequency has been observed in female rats during the proestrus-estrus transition when estrogen levels are high and progesterone levels are low resembling catamenial epilepsy. Cannabidiol (CBD) has been proposed to have anticonvulsant and anti-inflammatory effects, able to decrease seizure duration and increase seizure threshold in rats with epilepsy. However, most studies have used males to investigate the pharmacological effects of CBD on seizures, and the neuroprotective effects of CBD against seizures exacerbated by hormonal fluctuations in females are still little explored. Given this scenario, the aim of the present study was to investigate whether CBD would protect against acute seizures induced by pentylenetetrazole (PTZ) in female rats during a pro-convulsant hormonal phase. Therefore, CBD (50 mg/kg) or saline was administered during the proestrus-estrus transition phase, 1 h prior to induction of seizures with PTZ (60 mg/kg), and the following parameters were recorded: duration, latency to first seizure, as well as percentage of convulsing animals (incidence), mortality, and severity of seizures. Brains were processed for immunohistochemistry for microglial cells (Iba-1), and blood was collected for the analysis of cytokines (IL-1b, IL-6, IL-10, and TNF-a). Cannabidiol pre-treated rats showed a significant reduction in duration and severity of seizures, and IL-1b levels, although the latency, incidence of seizures , and mortality rate remained unchanged as well the quantification of microglia in the selected areas. Therefore, acute administration of CBD in a single dose prior to seizure induction showed a partial neuroprotective effect against seizure severity and inflammation, suggesting that female rats in the pro-convulsant phase of proestrus-estrus have a low seizure threshold and are more resistant to the anticon-vulsant effects of CBD. It appears that other doses or administration windows of CBD may be required to achieve a full protective effect against seizures, suggesting that CBD could be used as an adjunctive therapy during fluctuations of estrogen-progesterone levels. In this sense, considering the hormonal fluctuation as a seizure-potentiating factor, our study contributes to understand the anticonvulsant activity of CBD in females in a pro-convulsant hormonal phase, similar to catamenial seizures in humans.
... The CB 1 receptor is principally expressed in the central nervous system, whereas CB 2 is the predominant cannabinoid receptor within the immune system's cells [38]. Cannabidiol is known to interact with various complex signaling systems involved in eCBome; however, it has a very low affinity to cannabinoid receptors [39]. We can distinguish two endocannabinoids (eCBs) that are endogenous agonists of CB 1 and CB 2 receptors-anandamide (AEA) and 2-arachidonoylglycerol (2-AG), [40]. ...
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It is known that metabolic disturbances, including obesity, predispose to an increased incidence of cardiovascular diseases. Elevated consumption of dietary fat results in intramyocardial accumulation of lipids and their biologically active derivatives, which can disrupt the contractile function of the heart, its metabolism, and intracellular signaling pathways. Therefore, alternative methods, such as phytocannabinoids, are being sought for the treatment of obesity-related effects. In a model of rodent obesity (seven weeks of high-fat-diet (HFD) regime), we used cannabidiol—CBD therapy (intraperitoneal injections for 14 days; 10 mg/kg). High-performance and gas-liquid chromatographies were applied in order to determine sphingolipids in the heart and plasma as well as Western blotting for protein expression. Two-week CBD administration significantly inhibited the de novo ceramide synthesis pathway in the heart of HFD fed rats by lowering sphinganine and sphinganine-1-phosphate contents. The above reductions were accompanied by markedly diminished expressions of myocardial serine palmitoyltransferase 1 and 2 as well as ceramide synthase 5 and 6 in the HFD group with 2-week CBD treatment. To our knowledge, this research is the first that reveals unknown effects of CBD treatment on the heart, i.e., amelioration of de novo ceramide synthesis pathway in obese rats.
... Despite the utilization of cannabis for the treatment of epilepsy since antiquity, only over the last decade, focused research in cannabis-based therapies has gained momentum [6][7][8][9]. Highly purified cannabidiol (CBD) formulation, the principal nonpsychoactive constituent of the Cannabis sativa plant, had been used in clinical trials to mitigate the concern related to inconsistency of the unregulated crude CBD extracts (artisanal CBD) [10]. Following 4 phase III, randomized controlled trials (RCTs) of CBD in the treatment of Lennox-Gastaut (LGS) and Dravet syndromes (DS), a pharmaceutical-grade product (Epidiolex Ò / Epidyolex Ò ) was approved by the US Food and Drug Administration (FDA) in 2018 and by the European Medicines Agency (EMA) in 2019 for the treatment of seizures associated with patients with DS and LGS aged !2 years [7,[9][10][11]. ...
Article
Cannabidiol (CBD) has recently been approved as an add-on therapy by various regulatory agencies for tuberous sclerosis complex (TSC)-associated seizures based on its short-term efficacy and safety in a pivotal randomized controlled trial. However, critical information about which patients with TSC and seizure types respond best to CBD (clinical, electrophysiological, and genetic predictors of responsiveness), when to use CBD in the treatment algorithm, and how CBD can be combined with other antiseizure medications (ASMs) in the form of a rational polypharmacy therapy is still lacking. In general, there is a limited in-depth critical review of CBD for the treatment of TSC to facilitate its optimal use in a clinical context. Here, we utilized a scoping review approach to report the current evidence of efficacy and safety of pharmaceutical-grade CBD in patients with TSC, including relevant mechanism of action and drug–drug interactions with other ASMs. We also discussed emerging information about CBD’s long-term efficacy and safety data in patients with TSC. Finally, we discussed some critical unanswered questions in several domains related to effective clinical management of TSC using CBD, including barriers to early and aggressive treatment in infants, difficulty with universal access to CBD, a lack of studies to understand CBD’s impact on seizure severity and specific seizure types, insufficient exploration of CBD in TSC-related cognitive and behavioral issues, and the need for more research into CBD’s effects on various biomarkers.
... Both THC and CBD have gained an important role in therapeutical, medical, and recreational usage due to their physiological and psychotropic effects [4]. The efficacy of THC and CBD has been assessed for treating symptoms of: multiple sclerosis [5], epilepsy [6,7], chronic pain [8,9], chemotherapyrelated symptoms [10], appetite stimulation in cancer and AIDS patients [11,12], and in the treatment of Tourette syndrome [13,14]. ...
Article
Cannabis is widely recognized as a medicinal plant owing to bioactive cannabinoids. However, it is still considered a narcotic plant, making it hard to be accessed. Since the biosynthetic pathway of cannabinoids is disclosed, biotechnological methods can be employed to produce cannabinoids in heterologous systems. This would pave the way toward biosynthesizing any cannabinoid compound of interest, especially minor substances that are less produced by a plant but have a high medicinal value. In this context, microalgae have attracted increasing scientific interest given their unique potential for biopharmaceutical production. In the present review, the current knowledge on cannabinoid production in different hosts is summarized and the biotechnological potential of microalgae as an emerging platform for synthetic production is put in perspective. A critical survey of genetic requirements and various transformation approaches are also discussed.
... GPCRs are potential targets of anxiolytic drug involving in 7-transmembrane, metabotropic receptors and modulate neurotransmitters. For instance, the anxiolytic effects of SSRIs and norepinephrine reuptake inhibitors (NRI) are produced by GPCRs to stimulate serotonin (5-HT) and norepinephrine (NE) indirectly (Devinsky et al. 2014). Orphan GPCRs (oGPCRs) are subfamily of GPCRs and also considered as potential anxiolytic targets via genome wide association studies (GWAS) and post-mor tem transcr iptomic analysis in patients (Watkins and Orlandi 2020). ...
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Bupleurum chinense DC. (Chaihu) is a traditional Chinese medicine (TCM) used in the treatment of anxiety. But the anxiolytic mechanisms of bupleurum are still unclear. Therefore, this unknown is predicted by network pharmacology study with molecular docking in the present study. The components of bupleurum were obtained from the databases. Genes associated with components and disease were also provided by databases. Overlapping genes between components and disease were analyzed. The network of medicine-components-targets-disease was constructed, visualized, and analyzed. Protein-protein interaction (PPI), gene ontology (GO), pathway enrichment (KEGG) and molecular docking were conducted to predict the potential mechanisms of bupleurum on anxiety. A total of 9 bioactive components derived from bupleurum with 80 target genes were involved in anxiety. Neurotransmitter receptor activity, G protein-coupled amine receptor activity, regulation of blood circulation, neuroactive ligand-receptor interaction, calcium signaling pathway and salivary secretion may play significant roles in the anxiolytic of bupleurum. Molecular docking implicated that ACHE and MAOA showed high affinity for stigmasterol. Based on network pharmacology study with molecular docking, multi-component-multi-target-multi-pathway action mode of bupleurum on anxiety was elaborated. Stigmasterol might be the core bioactive component, while ACHE and MAOA might be the core target genes in the pharmacological profile of bupleurum on anxiety.
... CBD is responsible for neurologic and bioactive reactions, but not for psychoactivity. It has the potential to treat epilepsy, inflammation, migraine, and psychiatric disorders [19]. THC, the main psychoactive component of cannabis, is responsible for the drug's mind-altering effects and has a potential effect in treating glaucoma, muscle spasticity, low appetite, and insomnia [18]. ...
Article
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Objective To examine the efficacy and safety of medical cannabis in benign essential blepharospasm (BEB). Methods This is a prospective, double-blind, placebo-controlled study. All consecutive adult BEB patients who had been treated with BTX-A injections without success between 3/2019 and 2/2020 were recruited. The study patients were randomly allocated into a treatment and a control (placebo) group in a 1:1 ratio. The treatment group used cannabis drops and the control group used cannabis oil drops during the first 6 weeks of the study, and both groups were treated with the medical cannabis drops during the second 6 weeks. The cannabis dose was gradually increased for each patient depending upon effect and tolerability. Results Three patients were included in each group (treatment and control groups). The mean duration of spasm attack during the first 6 weeks was 4.29 min in the treatment group and 73.9 min in the placebo group (P < 0.01). During the last 6 weeks, the treatment group used an average of 6.27 drops and the placebo group used an average of 5.36 drops (P = 0.478). There were 61 spasm events in the treatment group and 94 spasm events in the placebo group (P = 0.05). The mean duration of spasm attack was 1.77 and 8.96 min, respectively (P < 0.01). The side effects were mild, and they included general fatigue, dry mouth, and insomnia. Conclusions Medical cannabis can be an effective and safe treatment for BEB as a second line after BTX-A injections when used for 3 months. No significant ocular or systemic side effects was associated with the treatment.
... Cannabis was used for the treatment of epilepsy for centuries [203][204][205]. Cannabis, cannabinoids, and endocannabinoids have been extensively studied and found to have antiseizure activities [206][207][208]. ...
Article
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Autism spectrum disorder (ASD) is a group of disabilities with impairments in physical, verbal, and behavior areas. Regardless the growing frequency of autism, no medicine has been formed for the management of the ASD primary symptoms. The most frequently prescribed drugs are off-label. Therefore, there is necessity for an advance tactic for the treatment of autism. The endocannabinoid system has a central role in ruling emotion and social behaviors. Dysfunctions of the system donate to the behavioral deficits in autism. Therefore, the endocannabinoid system represents a potential target for the development of a novel autism therapy. Cannabis and associated compounds have produced substantial research attention as a capable therapy in neurobehavioral and neurological syndromes. In this review we examine the potential benefits of medical cannabis and related compounds in the treatment of ASD and concurrent disorders
... These findings support the idea of both medical and recreation motives for cannabis use during pregnancy. However, given that studies of motives for cannabis use among clinical populations [30][31][32] have largely excluded pregnant women; this remains an important, understudied area of investigation. ...
Article
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In utero cannabis exposure can disrupt fetal development and increase risk for various behavioral disruptions, including hyperactivity, inattention, delinquent behaviors, and later substance abuse, among others. This review summarizes the findings from contemporary investigations linking prenatal cannabis exposure to the development of psychopathology and identifies the limitations within the literature, which constrain our interpretations and generalizability. These limitations include a lack of genetic/familial control for confounding and limited data examining real world products, the full range of cannabinoids, and motives for use specifically in pregnant women. Taken together, our review reveals the need to continue to improve upon study designs in order to allow researchers to accurately draw conclusions about the development of behavioral consequences of prenatal cannabis exposure. Findings from such studies would inform policy and practices regarding cannabis use during pregnancy and move the field toward developing a comprehensive teratogenic profile of cannabis similar to what is characterized in the prenatal alcohol and tobacco literature.
... CBD also exhibits a sedative-hypnotic effect in rodent models after oral administration [14][15][16][17][18]. In animal models and human experiments, fortunately, there has only been limited data for its beneficial effects [19][20][21][22][23]. CBD was expected to lower seizure frequency in patients with DS and other treatment-resistant epilepsies in recent human research [22,24]. ...
Article
The focus of this research was to implement a new RP-HPLC-PDA method for determining cannabidiol (CBD), which has been established with the help of Quality by Design (QbD). Design expert (version 12) software was used to conduct the factor screening studies. The mobile phase ratio, flow rate, and temperature conditions were used as independent variables, while retention time, peak area, and peak tailing were used as dependent variables in a Box-Behnken design. The best separation was obtained with acetonitrile and water as mobile phase in the ratio of 45:55 % (v/v), a flow rate of 1.0 ml/min, and an oven temperature of 30 °C with PDA detection at 210 nm. The newly optimized method showed the concentration linearity range in µg/ml (1187.57 - 5997.83) of CBD with an excellent correlation coefficient R2 = 0.9951. The % recovery of the CBD was obtained between 97.84 to 99.34 %, and the % RSD was not more than 2 %, thus clearly confirming the high level of accuracy for analysis. The technique was assessed under the ICH guidelines, which revealed excellent linearity, precision, and robustness. Consequently, the approach was used to determine the retention time of the drug in its nanoemulsion formulation, which revealed no substantial change in retention time.
... 6)). In addition, CBD interacts with other non-cannabinoid receptors such as serotonin (5-HT) receptors, orphan G protein-coupled receptors (GPCRs), adenosine A1 receptors, nuclear receptors activated by peroxisome proliferators type γ (PPARγs), transient receptors potential cation channel subfamily V member 1 (TRPV1s) and also α1 and α3 glycine receptors ( [26,27] (p. 4), (p. ...
Article
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Translational research made with Cannabis sativa L. and its biocompounds provides data for some targeted diseases, as also symptoms associated with Autism Spectrum Disorders (ASDs). The main compounds ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are capable of modulating the endocannabinoid system since its dysregulation interferes with the pathophysiology of ASDs there are clinical evidence for its potential use in the treatment of the disease. Conventional therapy still has limitations, as it does not always treat the central symptoms, and there are many patients who do not respond to treatment, which demands more research on new therapies. Through the analysis of published literature on this topic, it is verified that cannabinoids, in particular CBD, improves symptoms associated with common comorbidities in ASDs. Some studies also demonstrate the therapeutic potential of these compounds in the treatment of central symptoms of autism. In addition, cannabinoid therapy to ASDs is associated with low adverse effects and a reduction in concomitant medication. Although it appears to be promising, it is essential to do the translation of this data into clinical research and some of its potential and critical gaps are discussed in this review pointing to large-scale and long-term clinical trials that should include more patients and homogeneous samples.
... 2-AG hydrolysis is known to initiate prostaglandin pathways, and high concentrations of prostaglandins promote vasoconstriction. 7 As both rodents and humans have previously been shown to be susceptible to hypoxic episodes postictally, 8,9 the experimenters explored whether there was a link between 2-AG induced neuro-inflammation and postictal hypoxia. To test this, they implemented a series of pharmacological interventions that inhibited specific enzymes involved in the 2-AGprostaglandin pathway. ...
... µM) (Guy and Flint, 2004;Guy and Robson, 2004). Anticonvulsant effects of THC and CBD have an ED 50 ∼120 mg/kg (Devinsky et al., 2014). Depending on the mode of administration, 120 mg/kg of CBD leads to concentrations of 7 µM in serum and 1.3 µg/g in the brain; increased with IP administration to 45 µM in serum and 6.9 µg/g in the brain (Deiana et al., 2012). ...
Article
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Cannabinoids are a broad class of molecules that act primarily on neurons, affecting pain sensation, appetite, mood, learning, and memory. In addition to interacting with specific cannabinoid receptors (CBRs), cannabinoids can directly modulate the function of various ion channels. Here, we examine whether cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the most prevalent phytocannabinoids in Cannabis sativa, can regulate the function of hyperpolarization-activated cyclic-nucleotide-gated (HCN1) channels independently of CBRs. HCN1 channels were expressed in Xenopus oocytes since they do not express CBRs, and the effects of cannabinoid treatment on HCN1 currents were examined by a two-electrode voltage clamp. We observe opposing effects of CBD and THC on HCN1 current, with CBD acting to stimulate HCN1 function, while THC inhibited current. These effects persist in HCN1 channels lacking the cyclic-nucleotide binding domain (HCN1ΔCNBD). However, changes to membrane fluidity, examined by treating cells with TX-100, inhibited HCN1 current had more pronounced effects on the voltage-dependence and kinetics of activation than THC, suggesting this is not the primary mechanism of HCN1 regulation by cannabinoids. Our findings may contribute to the overall understanding of how cannabinoids may act as promising therapeutic molecules for the treatment of several neurological disorders in which HCN function is disturbed.
... Recently, a promising substance that has a great potential to increase the welfare of farm animals is one of the major cannabinoids from the Cannabis sativa plant, the cannabidiol (CBD) 18 . The CBD presents many pharmacological properties and great medicinal potential, assisting the treatment of many human diseases and psychiatric disorders 19 . In non-human mammals, the CBD shows anxiolytic-like 20,21 and antidepressant-like effects 22,23 , decreases the aggressiveness 24,25 and the stress 26,27 , has anti-in ammatory effects 28 , bene ts the food intake and weight gain 29 , and regulates the fertility 30 . ...
Preprint
Cannabidiol (CBD) is a substance derived from Cannabis sativa, widely studied in medicine for controlling neural diseases in humans. Besides the positive effects on humans, it also presents anxiolytic proprieties and decreases aggressiveness and stress in mammals. Therefore, CBD has the potential to increase welfare in reared animals, as it seems to reduce negative states commonly experienced in artificial environments. Here, we tested the effect of different CBD doses (0,1,10, and 20 mg/kg) on aggressiveness, stress, and reproductive development of the Nile tilapia ( Oreochromis niloticus ) a worldwide fish reared for farming and research purposes. CBD mixed with fish food was offered to isolated fish for 5 weeks. The 10 mg/kg dose decreased fish’s aggressiveness over time, whereas 20 mg/kg attenuated non-social stress. Both doses decreased the baseline cortisol level of fish and increased the gonadosomatic index. However, CBD 1 and 10 mg/kg doses decreased the spermatozoa number. All CBD doses did not affect feeding ingestion and growth variables, showing that it is not harmful to meat production amount. Despite the effect on spermatozoa, CBD supplementation exhibits high potential to benefit animals’ lives on an integrative-based welfare approach. Therefore, we showed for the first time that CBD could be used as a tool to increase non-mammal welfare, presenting a great potential to be explored in other husbandry and captivity species.
... Instead, it appears to indirectly modulate the endocannabinoid system (and other molecular systems) through the orphan G protein-coupled receptor 55 (GPR55), the serotonin 1A (5-HT 1a ) receptors, and glycine receptor subtypes, as well as inhibiting adenosine uptake (increasing its endogenous availability). 16 Anandamide and 2-arachidonoylglycerol (2-AG) are the most widely known endocannabinoids. Anandamide is a partial agonist of CB1 receptors and a very low agonist of CB2 receptors, whereas 2-AG acts as a full agonist at both receptors. ...
Article
Objective To provide health care providers with the best evidence on cannabis use and women’s health. Areas of focus include screening, dependence, and withdrawal; communication and documentation; pregnancy (including maternal and fetal outcomes); maternal pain control; postpartum care (including second-hand smoking and parenting); and breastfeeding. Target Population The target population includes women who are planning a pregnancy, pregnant, or breastfeeding. Benefits, Harms, and Costs Discussing cannabis use with women who are planning a pregnancy, pregnant, or breastfeeding allows them to make informed choices about their cannabis use. Based on the limited evidence, cannabis use in pregnancy or while breastfeeding should be avoided, or reduced as much as possible if abstaining is not feasible, given the absence of safety and long-term follow up data on cannabis-exposed pregnancies and infants. Evidence PubMed and Cochrane Library databases were searched for articles relevant to cannabis use during pregnancy and breastfeeding published between January 1, 2018, and February 5, 2021. The search terms were developed using the MeSH terms and keywords and their variants, including cannabis, cannabinoids, cannabidiol, CBD, THC, marijuana, edible, pregnancy, pregnant, prenatal, perinatal, postnatal, breastfeed, breastfed, lactation, nursing, fetus, fetal, neonatal, newborn, and child. In terms of publication type, all clinical trials, observational studies, reviews (including systematic reviews and meta-analyses), guidelines, and conference consensus statements were included. The main inclusion criteria were pregnant and breastfeeding women as the target population, and exposure to cannabis as the intervention of interest. Validation Methods The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). Intended Audience All health care providers who care for women of reproductive age. SUMMARY STATEMENTS 1.Screening, brief intervention, and referral for treatment can be used to identify and treat cannabis use in women during pregnancy (low). 2.The effectiveness of cannabis for treatment of nausea and vomiting in pregnancy is unclear (very low). 3.Prenatal cannabis exposure is associated with mild fetal growth restriction (low). 4.The effects of prenatal cannabis exposure on long-term outcomes through to childhood, adolescence, and adulthood have not been conclusively defined, but recent data suggest that there are persistent neurocognitive effects into adulthood (moderate). 5.Although cannabis is commonly used to treat pain, there is no evidence for its use in alleviating pain during pregnancy, intrapartum and/or postpartum periods (very low). 6.There is little data available to inform decisions about cannabis use during breastfeeding (low). 7.Given the evidence, the safest option is to avoid cannabis use during pregnancy and breastfeeding (moderate). 8.In cases where women are unable to abstain, given the apparent dose–response relationship between prenatal cannabis exposure and persistent neurocognitive effects on the fetus and/or neonate, decreasing cannabis use during pregnancy and breastfeeding can mitigate the adverse effects (moderate). RECOMMENDATIONS 1.All women should be screened for cannabis use, including during pregnancy, using a validated screening tool (strong, low). 2.Women with at-risk cannabis use or cannabis use disorder should be offered brief intervention, and, if appropriate, referral for treatment (strong, low). 3.If possible, health care providers should document cannabis use in pregnancy, both in the prenatal record and in the infant’s medical record (strong, low). 4.Cannabis should not be used during pregnancy because prenatal exposure can increase the risk of neurobehavioural abnormalities in the child (strong, moderate). 5.Health care providers should monitor women who regularly (near daily or more than twice weekly) use cannabis during pregnancy for potential intrapartum and/or postpartum withdrawal (or cannabis withdrawal syndrome) (strong, moderate). 6.Health care providers should recommend that women abstain from cannabis use during breastfeeding (strong, low).
... Instead, it appears to indirectly modulate the endocannabinoid system (and other molecular systems) through the orphan G protein-coupled receptor 55 (GPR55), the serotonin 1A (5-HT 1a ) receptors, and glycine receptor subtypes, as well as inhibiting adenosine uptake (increasing its endogenous availability). 16 Anandamide and 2-arachidonoylglycerol (2-AG) are the most widely known endocannabinoids. Anandamide is a partial agonist of CB1 receptors and a very low agonist of CB2 receptors, whereas 2-AG acts as a full agonist at both receptors. ...
Article
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Objective To provide health care providers with the best evidence on cannabis use with respect to women’s health. Areas of focus include general patterns of cannabis use as well as safety of use; care for women who use cannabis; stigma; screening, brief intervention, and referral to treatment; impact on hormonal regulation; reproductive health, including contraception and fertility; sexual function; effects on perimenopausal and menopausal symptoms; and use in chronic pelvic pain syndromes. Target Population The target population includes all women currently using or contemplating using cannabis. Outcomes Open, evidence-informed dialogue about cannabis use, which will lead to improvement in patient care. Benefits, Harms, and Costs Exploring cannabis use through a trauma-informed approach provides the health care provider and patient with an opportunity to build a strong, collaborative, therapeutic alliance. This alliance empowers women to make informed choices about their own care. It also allows for the diagnosis and possible treatment of cannabis use disorders. Use should not be stigmatized, as stigma leads to poor “partnered care” (i.e., the partnership between the patient and care provider). Multiple side effects of cannabis use may be mistaken for other disorders. Currently, use of cannabis to treat women’s health issues is not covered by public funding; as a result, individual users must pay the direct cost. The indirect costs of cannabis use are unknown. Thus, health care providers and patients must understand the role of cannabis in women’s health issues, so that women can make knowledgeable decisions. Evidence PubMed, EMBASE, and grey literature were searched to identify studies of “cannabis use and effect on infertility, contraception, perimenopause and menopausal symptoms, and pelvic pain” published between January 1, 2018 and February 18, 2021. All clinical trials, observational studies, reviews (including systematic reviews and meta-analyses), guidelines, and conference consensus statements were included. Publications were screened for relevance. The search terms were developed using the Medical Subject Headings (MeSH) terms and keywords (and variants), including cannabis, cannabinoids, marijuana, dexanabinol, dronabinol, tetrahydrocannabinol; the specific terms to capture women’s health were estrogen, estradiol, medroxyprogesterone acetate, vaginal contraception, oral contraceptives, fertilization, amenorrhea, oligomenorrhea, pelvic pain, dysmenorrhea, endometriosis, interstitial cystitis, vulvodynia, and menopause. Validation Methods The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). Intended Audience All heath care providers who care for women. SUMMARY STATEMENTS 1.Cannabis use is increasing, and women are commonly using cannabis for recreational and medical reasons (high). 2.Use of cannabis, especially products containing tetrahydrocannabinol, can induce or worsen psychosis and worsen depression (high). 3.Study results concerning the association between cannabis and anxiety are conflicting, and this association requires further evaluation (high). 4.Use of cannabis, similar to use of other intoxicating substances, may be associated with high-risk sexual activity (low). 5.There is no evidence that contraceptive methods are altered by cannabis use (low). 6.There is limited evidence that frequent cannabis use may affect female fertility (moderate), but frequent use can diminish male fertility (moderate). 7.There is no evidence for cannabis use for management of perimenopausal symptoms (very low). 8.There is no evidence that cannabis products improve chronic pelvic pain (low). RECOMMENDATIONS 1.Women should be screened for cannabis use, as they are for other substance use (strong, moderate), and further exploration of its impact should be initiated (strong, moderate). 2.Cannabis use can be screened for using appropriate screening tools (conditional, moderate) 3.A trauma-informed care approach and harm reduction should be used when inquiring about cannabis use (strong, low). 4.The fact that a woman uses cannabis should not influence her choice of contraceptive method (strong, moderate). 5.Couples should be counselled that cannabis use appears to affect male fertility and may have an impact on female fertility (conditional, moderate). 6.Sleep disturbances in the perimenopausal period should be characterized and other management modalities trialed before women consider using any cannabis product for this indication (strong, moderate). 7.Women should be counselled about the lack of evidence for using cannabis products to treat chronic pelvic pain (strong, moderate).
... In preclinical studies, it was suggested that CBD attenuates seizures, improves survival, and behavioral comorbidities of Dravet syndrome in mice [19,20]. Similarly, CBD exerts anticonvulsant activities in a wide variety of acute seizure models, such as the audiogenic seizure, maximal electroshock, and 6 Hz-seizure models [21,22], or other models in which seizures are induced by isoniazid, cocaine, or gamma-aminobutyric acid type A (GABA A ) receptor antagonists [23][24][25]. Additionally, CBD seems to display anti-ictal activities in rodents when administered prior to the pilocarpine or penicillin-induced seizures [26,27]. ...
Article
Full-text available
We evaluated the effects of cannabidiol (CBD) on seizures and peroxisome proliferator activated receptor gamma (PPAR) levels in an animal model of temporal lobe epilepsy (TLE). Adult male Sprague-Dawley rats were continuously monitored by video-electrocorticography up to 10 weeks after an intraperitoneal kainic acid (15 mg/kg) injection. Sixty-seven days after the induction of status epilepticus and the appearance of spontaneous recurrent seizures in all rats, CBD was dissolved in medium-chain triglyceride (MCT) oil and administered subcutaneously at 120 mg/kg (n = 10) or 12 mg/kg (n = 10), twice a day for three days. Similarly, the vehicle was administered to ten epileptic rats. Brain levels of PPARgamma immunoreactivity were compared to those of six healthy controls. CBD at 120 mg/kg abolished the seizures in 50% of rats (p = 0.033 vs. pretreatment, Fisher’s exact test) and reduced total seizure duration (p < 0.05, Tukey Test) and occurrence (p < 0.05). PPARgamma levels increased with CBD in the hippocampal CA1 subfield and subiculum (p < 0.05 vs. controls, Holm–Šidák test), but only the highest dose increased the immunoreactivity in the hippocampal CA3 subfield (p < 0.001), perirhinal cortex, and amygdala (p < 0.05). Overall, these results suggest that the antiseizure effects of CBD are associated with upregulation of PPARgamma in the hippocampal CA3 region.
... Cannabis, also known as marijuana, is the dried and processed leaves, flowers and body of the genus Cannabis. The oldest mention of it dates back to China in the year 2,120 B.C. (Devinsky et al., 2014;Russo, 2007). Cannabis contains substances called cannabinoids of which two cannabinoids, namely Tetrahydrocannabinol (THC) and Cannabidiol (CBD), are the ones with the highest level of medical potential. ...
Article
Full-text available
Cannabis, or hemp, is a plant with a huge medical and economic potential. Known since ancient times, Cannabis is rich in cannabinoids of which cannabidiol (CBD) is the most biologically active compound with almost none of the negative aspects of its fellow cannabinoids. Since the 19th century, Cannabis has been used as an analgesic, anesthetic, antidepressant, sedative and even antibiotic. However, its bio-industrial potential has not yet been fully explored and given that Cannabis plants are harvested for hemp, animal feed and various agricultural purposes, their potential effects as fertilizer or herbicide have not yet been identified. This paper presents the effects of C. sativa hydroextract on Triticum aestivum seedlings. During this study it was observed that Triticum aestivum seedlings treated with 100%, 10% and 5% C. sativa extracts showed lower levels of Chlorophyll A and B than the control sample. The seedlings treated with 50% and 25% C. sativa extracts showed higher levels of Chlorophyll A and lower content of Chlorophyll B when compared to the control. There was an increase in the carotenoids detected in all samples, with 50% and 25% showing the highest levels. This suggests that C. sativa extracts have the ability to increase the carotenoids levels in T. aestivum seedlings and modify the amount of Chlorophyll A and Chlorophyll B extract in a dose-dependent manner.
... Instead, it appears to indirectly modulate the endocannabinoid system (and other molecular systems) through the orphan G protein-coupled receptor 55 (GPR55), the serotonin 1A (5-HT 1a ) receptors, and glycine receptor subtypes, as well as inhibiting adenosine uptake (increasing its endogenous availability). 16 Anandamide and 2-arachidonoylglycerol (2-AG) are the most widely known endocannabinoids. Anandamide is a partial agonist of CB1 receptors and a very low agonist of CB2 receptors, whereas 2-AG acts as a full agonist at both receptors. ...
Article
Résumé Objectif Fournir aux fournisseurs de soins de santé les meilleures données probantes sur l’utilisation de cannabis et la santé des femmes. Les domaines d’intérêt sont : les profils généraux d’utilisation du cannabis ainsi que la sécurité de la consommation; les soins aux femmes qui utilisent le cannabis; la stigmatisation; le dépistage, l’intervention brève et l’orientation vers le traitement; les effets sur la régulation hormonale; la santé reproductive, y compris la contraception et la fertilité; la fonction sexuelle; les effets sur les symptômes périménopausiques et postménopausiques; et l’utilisation dans le traitement des syndromes de douleur pelvienne chronique. Population cible La population cible comprend toutes les femmes qui consomment ou utilisent du cannabis ou qui envisagent de le faire. Résultats Un dialogue ouvert et fondé sur des données probantes relativement à l’utilisation et la consommation de cannabis, dialogue qui mènera à l’amélioration des soins aux patientes. Bénéfices, risques et coûts L’exploration de l’utilisation et de la consommation de cannabis par une approche basée sur la connaissance des traumatismes donne l’occasion au fournisseur de soins et à la patiente de créer une solide alliance thérapeutique collaborative. Cette alliance permet aux femmes de faire des choix éclairés sur leurs propres soins. Elle facilite également le diagnostic et le traitement possible des troubles de l’usage du cannabis. Il ne faut pas stigmatiser la consommation, car la stigmatisation nuit à l’alliance thérapeutique (c’est-à-dire le partenariat entre la patiente et le fournisseur de soins). Plusieurs effets indésirables de la consommation de cannabis peuvent être confondus avec d’autres problèmes de santé. À l’heure actuelle, l’utilisation du cannabis pour traiter les problèmes de santé féminine n’est pas financée par le secteur public; par conséquent, les utilisatrices doivent assumer les coûts directs. Les coûts indirects de l’utilisation de cannabis sont inconnus. Ainsi, les fournisseurs de soins et les patientes doivent comprendre le rôle du cannabis dans les problèmes de santé féminine de sorte que les femmes puissent prendre des décisions éclairées. Données probantes Des recherches ont été effectuées dans PubMed, Embase et la littérature grise pour recenser des études publiées entre le 1er janvier 2018 et le 18 février 2021 concernant l’utilisation du cannabis et ses effets sur l’infertilité, la contraception, les symptômes périménopausiques et postménopausiques et la douleur pelvienne. Toutes les publications des types suivants ont été incluses : essais cliniques, études observationnelles, revues (y compris les revues systématiques et les méta-analyses), directives cliniques et déclarations de conférences de consensus. Un survol des publications a été effectué pour en confirmer la pertinence. Les termes de recherche ont été définis à l’aide des termes MeSH (Medical Subject Headings) et mots clés (et variantes) suivants : cannabis, cannabinoids, marijuana, dexanabinol, dronabinol et tetrahydrocannabinol. À ces termes ont été combinés les termes suivants afin de cerner la santé des femmes : estrogen, estradiol, medroxyprogesterone acetate, vaginal contraception, oral contraceptives, fertilization, amenorrhea, oligomenorrhea, pelvic pain, dysmenorrhea, endometriosis, interstitial cystitis, vulvodynia et menopause. Méthodes de validation Les auteurs ont évalué la qualité des données probantes et la force des recommandations en utilisant l’approche d’évaluation, de développement et d’évaluation (GRADE). Voir l’annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l’interprétation des recommandations fortes et faibles). Professionnels concernés Tous les fournisseurs de soins de santé qui prodiguent des soins aux femmes. DÉCLARATIONS SOMMAIRES 1.Le cannabis est de plus en plus utilisé, et les femmes l’utilisent couramment pour des raisons récréatives et médicales (élevée). 2.L’utilisation de cannabis, en particulier des produits contenant du tétrahydrocannabinol, peut provoquer ou exacerber une psychose et aggraver une dépression (élevée). 3.Les résultats des études sur l’association entre le cannabis et l’anxiété sont contradictoires; par conséquent, cette association nécessite des recherches plus approfondies (élevée). 4.L’utilisation de cannabis, semblable à celle d’autres substances psychoactives, peut être associée à des comportements sexuels à risque élevé (faible). 5.Il n’existe aucunes données probantes indiquant que le cannabis altère l’efficacité des méthodes contraceptives (faible). 6.Les données probantes sont limitées concernant l’effet nocif de l’utilisation fréquente de cannabis sur la fertilité féminine (moyenne), mais l’utilisation fréquente peut diminuer la fertilité masculine (moyenne). 7.Il n’existe aucune donnée probante concernant l’utilisation de cannabis pour le traitement des symptômes périménopausiques (très faible). 8.Il n’existe aucune donnée probante indiquant que les produits de cannabis soulagent la douleur pelvienne chronique (faible). RECOMMANDATIONS 1.Il faut dépister l’utilisation de cannabis chez les femmes au même titre que pour toute autre consommation de substances psychoactives (forte, moyenne) et amorcer une exploration plus poussée de ses effets (forte, moyenne). 2.Il est possible de dépister l’utilisation de cannabis à l’aide d’outils de dépistage appropriés (conditionnelle, moyenne). 3.Il y a lieu d’adopter une approche de soins tenant compte des traumatismes et de miser sur la réduction des méfaits lorsqu’il s’agit de poser des questions sur l’utilisation de cannabis (forte, faible). 4.Le fait qu’une femme utilise du cannabis ne devrait pas influencer son choix de méthode contraceptive (forte, moyenne). 5.Les couples doivent être informés que l’utilisation de cannabis semble nuire à la fertilité masculine et pourrait avoir un effet nocif sur la fertilité féminine (conditionnelle, moyenne). 6.On doit caractériser les troubles du sommeil se manifestant en période périménopausique et essayer d’autres modes de traitement avant que les femmes ne puissent envisager l’utilisation de produits de cannabis pour cette indication (forte, moyenne). 7.Il y a lieu d’informer les femmes du manque de données probantes sur l’utilisation de produits de cannabis pour traiter la douleur pelvienne chronique (forte, moyenne).
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The subject of this article is an overview of legal regulations in the cultivation and processing of cannabis other than industrial cannabis (hemp) in selected countries and a comparison of them with the law currently in force in Poland. The article is an attempt to initiate a discussion on the legitimacy of conducting the legislative process, with due caution and all necessary safety measures, as a result of which legal solutions allowing legal cultivation of cannabis for the pharmaceutical industry in Poland could be created
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Epilepsy is a neurological disorder with a high prevalence worldwide. Several studies carried out during the last decades indicate that the administration of cannabinoids as well as the activation of the endocannabinoid system (ECS) represent a therapeutic strategy to control epilepsy. However, there are controversial studies indicating that activation of ECS results in cell damage, inflammation and neurotoxicity, conditions that facilitate the seizure activity. The present review is focused to present findings supporting this issue. According to the current discrepancies, it is relevant to elucidate the different effects induced by the activation of ECS and determine the conditions under which it facilitates the seizure activity.
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Methamphetamine (MA) abuse is a major global public health problem, with cardiovascular issues becoming an increasingly recognized complication. Cannabidiol (CBD) has gained recent attention, due to its various pharmacological properties. However, whether CBD has therapeutic effects on MA-induced cardiotoxicity remains unknown. In the present study, we investigated whether CBD has a protective or therapeutic effect on MA-induced cardiac damage in rats via the protein kinase A (PKA)/cyclic adenosine monophosphate response element-binding (CREB) signaling pathway. Thirty rats were randomly divided into five groups. The rats were administered MA by intraperitoneal injection (IP) once a day for 4 weeks, with CBD (40 or 80 mg/kg, IP) treatment 1 h prior to the MA injections. Body and heart weights were measured, and morphological changes were determined using hematoxylin & eosin and Masson’s trichrome staining. The serum levels of interleukin-6 (IL-6) and IL-10 were detected using enzyme linked immunosorbent assay (ELISA) kits. The protein expression levels of PKA, phospho-PKA (p-PKA), CREB, phospho-CREB (p-CREB) and cardiac troponin I (cTnI) in the myocardium were detected by western blot analysis. Results showed that the heart-to-body weight ratio increased significantly following MA administration but decreased with CBD treatment. Chronic administration of MA resulted in a cardiac inflammatory response and progressive development of fibrosis, while CBD treatment attenuated these lesions in a dose-dependent manner. MA administration increased IL-6 but decreased IL-10 levels, which were reversed by CBD pretreatment. Moreover, MA significantly increased the cTnI level, but this was decreased by CBD treatment at 80 mg/kg. The protein expression levels of PKA, p-PKA, CREB, and p-CREB increased following MA administration, but significantly decreased with CBD treatment. Overall, these results indicate that chronic MA administration leads to cardiotoxicity, including cardiac inflammatory response, fibrosis, and myocardial necrosis, but these effects can be attenuated by CBD pretreatment. Our research suggests a potential application of CBD for MA-induced cardiotoxicity, which may attenuate inflammatory response and necrosis through the PKA/CREB signaling pathway.
Chapter
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Chapter
Full-text available
A obra intitulada “Fudamentos e práticas nas ciências da saúde vol. 2”, publicada pela Brazilian Journals Publicações de Periódicos e Editora, apresenta um conjunto de dezessete capítulos que visa abordar diversos assuntos do conhecimento da área da saúde. Logo, os capítulos apresentam os seguintes temas: análise da correlação entre a taxa de internações por Condições Sensíveis à Atenção Primária em menores de cinco anos e a cobertura da Estratégia Saúde da Família, no estado de Mato Grosso do Sul, no período de 2008 a 2017. Também é discorrido sobre a identificação dos critérios diagnósticos da síndrome metabólica revertidos em pacientes após um ano de cirurgia, analisar a prevalência dos perfisclínico-laboratoriais relacionados à idade, sexo, circunferência abdominal, pressão arterial, HDL-colesterol, glicemia em jejum e triglicerídeos. O livro traz um estudo, com o objetivo de aperfeiçoar técnicas endovasculares, especialmente angioplastia de artérias carótidas, angiografias e angioplastias de outras artériasperiféricas através de um simulador endovascular (Mentice VIST® G5 – um simulador endovascular de alta fidelidade que permite o treinamento prático de procedimentos para profissionais médicos). Será apresentado também um trabalho que tem como objetivo, analisar o uso do canabidiol (CBD) no tratamento das epilepsias refratárias comparando aos tratamentos com drogas antiepilépticas, observando a eficácia dos métodos de tratamentos e possíveis feitos colaterais relacionado do CBD, através de revisão em artigos, entre outros. Dessa forma, agradecemos aos autores por todo esforço e dedicação que contribuíram para a construção dessa obra, e esperamos que este livro possa colaborar para a discussão e entendimento de temas relevantes para a área da saúde, orientando docentes, estudantes, gestores e pesquisadores à reflexão sobre os assuntos aqui apresentados.
Chapter
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The proposed detoxifying herbal formulation contains the following ingredients: Flores Calendulae, Radices Glycyrrhizae, Folia Urticae dioicae, Folia Betulae, Folia Juglandis. The herbal mixture might be applied as a nutritional supplement for detoxification and cleansing of the body; protection of the liver and other systems by removal of toxins, alcohol, heavy metals, pesticides and other toxic chemicals in states of intoxication; prevention of chronic toxicity due to prolonged administration of some groups of medicines (antibiotics, NSAIDs, immunosuppressants); reduction of symptoms of nausea, diarrhea and intestinal infections; improvement of liver and kidney function. The presented outcomes of the performed investigation on herbal substances with accessible resource base, possessing detoxifying, gastro- and hepatoprotective and some other related properties, comprise the basis for their incorporation into the developed detoxifying herbal formulation.
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Chapter
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Cannabidiol (CBD), as a major phytocannabinoid of Cannabis sativa, has emerged as a promising natural compound in the treatment of diseases. Its diverse pharmacological effects with limited side effects have promoted researchers to pursue new therapeutic applications. It has little affinity for classical cannabinoid receptors (CB1 and CB2). Considering this and its diverse pharmacological effects, it is logical to set up studies for finding its putative potential targets other than CB1 and CB2. A class of ion channels, namely transient potential channels (TRP), has been identified during two recent decades. More than 30 members of this family have been studied, so far. They mediate diverse physiological functions and are associated with various pathological conditions. Some have been recognized as key targets for natural compounds such as capsaicin, menthol, and CBD. Studies show that CBD has agonistic effects for TRPV1-4 and TRPA1 channels with antagonistic effects on the TRPM8 channel. In this article, we reviewed the recent findings considering the interaction of CBD with these channels. The review indicated that TRP channels mediate, at least in part, the effects of CBD on seizure, inflammation, cancer, pain, acne, and vasorelaxation. This highlights the role of TRP channels in CBD-mediated effects, and binding to these channels may justify part of its paradoxical effects in comparison to classical phytocannabinoids.
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The occurrence and development of HIV-associated neurocognitive disorders (HAND) is related to synaptic injury and neuron loss, which gradually reduces the ability of learning and memory, and eventually leads to cognitive dysfunction. Human immunodeficiency virus type 1 (HIV-1) enveloped glycoprotein 120 (GP120) is the principal etiological agent of HIV-1-induced nerve damage and HAND. Our previous study demonstrated that GP120 can induce neuronal damage by increasing N-methyl-D-aspartic acid receptor (NMDAR) mediated excitatory postsynaptic currents (EPSCsNMDAR), In addition to neuroexcitotoxicity, the inflammatory response, oxidative stress, and neuronal apoptosis mediated by NMDAR overactivation are also involved in HAND. Because cannabinoids have known effects against neuroinflammation, stress response, and oxidative effects, we researched the effects of the cannabinoid receptor agonist Win55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3 [(4-morpholinyl) methyl] pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt] on synaptic changes induced by GP120. In this study, we discovered that Win55,212-2 prevents GP120-induced neurological injury and cognitive dysfunction, and these effects are consistent with the neuroprotective effect of NMDAR blockers. In the Morris water maze (MWM) test, the results revealed that GP120 could induce learning and memory impairment in rats, while antagonizing NMDARs or activating CB2R could counteract GP120-induced cognitive dysfunction in rats; The results of TUNEL staining were consistent with the above results of MWM behavioral experiments. GP120 damaged hippocampal neurons in the CA1 region, while the NMDAR antagonist and cannabinoid 2 receptor (CB2R) agonist prevented GP120-induced effects. In molecular biology experiments, Our results showed that GP120 significantly upregulated the mRNA expressions of inflammatory factors IL-1β, IL-6, TNF-α and CXCL10; Furthermore, GP120 significantly upregulated the protein expression level of pro-inflammatory cytokine IL-1β and decreased the protein expression level of anti-inflammatory cytokine IL-10 as measured by ELISA. Additionally, in the GP120 group, the mRNA expression levels of pro-apoptosis factors such as Bax, CytC, and caspase-3, -8 and -9 were significantly increased while the expression level of anti-apoptotic factors Bcl-2 was significantly decreased (P < 0.05). Our studie also demonstrated that the mRNA expression levels of apoptotic pathway factors could be regulated by the p38 JNK MAPK pathway. But pretreatment with NMDAR antagonist memantine or CB2R agonist Win55,212-2 significantly reduced the expression levels of inflammatory factors and apoptotic factors. And the effects aroused by Win55,212-2 could be reversed by the CB2R antagonist AM630. These data suggest that the activation of the CB2R is neuroprotective against GP120-induced neurotoxicity, and CB2R agonist might play a potential therapeutic role in HAND.
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Of the 37.9 million individuals infected with human immunodeficiency virus type 1 (HIV-1), approximately 50% exhibit HIV-associated neurocognitive disorders (HAND). We and others previously showed that HIV-1 viral RNAs, such as trans-activating response (TAR) RNA, are incorporated into extracellular vesicles (EVs) and elicit an inflammatory response in recipient naïve cells. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the primary cannabinoids present in cannabis, are effective in reducing inflammation. Studies show that cannabis use in people living with HIV-1 is associated with lower viral load, lower circulating CD16+ monocytes and high CD4+ T-cell counts, suggesting a potentially therapeutic application. Here, HIV-1 infected U1 monocytes and primary macrophages were used to assess the effects of CBD. Post-CBD treatment, EV concentrations were analyzed using nanoparticle tracking analysis. Changes in intracellular and EV-associated viral RNA were quantified using RT-qPCR, and changes in viral proteins, EV markers, and autophagy proteins were assessed by Western blot. Our data suggest that CBD significantly reduces the number of EVs released from infected cells and that this may be mediated by reducing viral transcription and autophagy activation. Therefore, CBD may exert a protective effect by alleviating the pathogenic effects of EVs in HIV-1 and CNS-related infections.
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The knowledge of compounds stability in the process of sample preparation for analysis and during analysis itself helps assess the accuracy and precision of estimating their concentration in tested samples. The present paper shows that a significant amount of CBD present in the blood/plasma sample analyzed by means of GC transforms in the hot GC injector not only to 9α-hydroxyhexahydrocannabinol, 8-hydroxy-iso-hexahydrocannabinol, delta-9-tetrahydrocannabinol, Δ8-tetrahydrocannabinol, and cannabinol but also to the trifluoroacetic esters of Δ9-THC and Δ8-THC, when trifuoroacetic acid is used as protein precipitation agent. The amount of those newly revealed CBD transformation products depends on the GC injector temperature and on the extrahent type when extracts of the supernatants centrifuged from human plasma samples are analyzed after their preliminary protein precipitation by trifuoroacetic acid. Although trifuoroacetic acid as a protein precipitating agent has many disadvantages, it is quite often used for this purpose due to its very high protein precipitation efficiency. The results presented in the study demonstrate why the use of trifuoroacetic acid for plasma samples deproteinization should be avoided when CBD is determined by GC.
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Patient-generated health data provide a great opportunity for more detailed ambulatory monitoring and more personalized treatments in many diseases. In epilepsy, robust diagnostics applicable to the ambulatory setting are needed as diagnosis and treatment decisions in current clinical practice are primarily reliant on patient self-reports, which are often inaccurate. Recent work using wearable devices has focused on methods to detect and forecast epileptic seizures. Whether wearable device signals may also contain information about the effect of antiseizure medications (ASMs), which may ultimately help to better monitor their efficacy, has not been evaluated yet. Here we systematically investigated the effect of ASMs on different data modalities (electrodermal activity, EDA, heart rate, HR, and heart rate variability, HRV) simultaneously recorded by a wearable device in 48 patients with epilepsy over several days in the epilepsy long-term monitoring unit at a tertiary hospital. All signals exhibited characteristic diurnal variations. HRV, but not HR or EDA-based metrics, were reduced by ASMs. By assessing multiple signals related to the autonomic nervous system simultaneously, our results provide novel insights into the effects of ASMs on the sympathetic and parasympathetic interplay in the setting of epilepsy and indicate the potential of easy-to-wear wearable devices for monitoring ASM action. Future work using longer data may investigate these metrics on multidien cycles and their utility for detecting seizures, assessing seizure risk, or informing treatment interventions.
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Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD. Cell Death and Disease (2013) 4, e949; doi:10.1038/cddis.2013.471; published online 5 December 2013
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The mechanisms underlying the neuroprotective effects of cannabidiol (CBD) were studied in vivo using a hypoxic-ischemic (HI) brain injury model in newborn pigs. One- to two-day-old piglets were exposed to HI for 30 min by interrupting carotid blood flow and reducing the fraction of inspired oxygen to 10%. Thirty minutes after HI, the piglets were treated with vehicle (HV) or 1 mg/kg CBD, alone (HC) or in combination with 1 mg/kg of a CB2 receptor antagonist (AM630) or a serotonin 5HT1A receptor antagonist (WAY100635). HI decreased the number of viable neurons and affected the amplitude-integrated EEG background activity as well as different prognostic proton-magnetic-resonance-spectroscopy (H±-MRS)-detectable biomarkers (lactate/N-acetylaspartate and N-acetylaspartate/choline ratios). HI brain damage was also associated with increases in excitotoxicity (increased glutamate/N-acetylaspartate ratio), oxidative stress (decreased glutathione/creatine ratio and increased protein carbonylation) and inflammation (increased brain IL-1 levels). CBD administration after HI prevented all these alterations, although this CBD-mediated neuroprotection was reversed by co-administration of either WAY100635 or AM630, suggesting the involvement of CB2 and 5HT1A receptors. The involvement of CB2 receptors was not dependent on a CBD-mediated increase in endocannabinoids. Finally, bioluminescence resonance energy transfer studies indicated that CB2 and 5HT1A receptors may form heteromers in living HEK-293T cells. In conclusion, our findings demonstrate that CBD exerts robust neuroprotective effects in vivo in HI piglets, modulating excitotoxicity, oxidative stress and inflammation, and that both CB2 and 5HT1A receptors are implicated in these effects.
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This Phase I, open label, four-way crossover study pertains to pharmacokinetic parameters of four cannabis based medicine extracts (CBME). Sublingual, buccal and oro-pharyngeal test treatments (GW-1000-02) consisted of 25 mg cannabidiol (CBD) + 25 mg Δ-tetra-hydrocannabinol (THC) per ml formulated in ethanol (eth):propylene glycol (PG) (50:50), with peppermint flavouring with a 100 μl actuation volume (total dose 10 mg CBD + 10 mg THC in 4 actuations). An oral capsule contained 2.5 mg CBD + 2.5 mg THC sprayed onto granulated lactose and encapsulated in soft gelatin capsules (total dose of 10 mg CBD + 10 mg THC 4 capsules). This study was performed in healthy volunteers in an open label, 4 period, 3-way randomised crossover followed by a nonrandomised oral dose using single doses of 20 mg of CBME (10 mg CBD + 10 mg THC). In Periods 1 to 3, the test treatment was administered as a liquid spray according to the randomisation scheme (i.e., sublingually, buccally, oro-pharyngeally). In Period 4 the test treatment was delivered as an oral capsule. There was a six-day washout between each dose.Primary objectives were to compare the pharmacokinetic profiles of cannabis based medicine extract (CBME) when administered on different areas of the buccal mucosa. Secondary objectives were to investigate the pharmacokinetic profile of CBME when administered as an oral capsule.Concentrations of THC were higher than the corresponding levels of CBD at most time points. Concentrations of 11-hydroxy-THC exceeded the corresponding concentration of THC at most time points. By 720 min (12 h) post-dose, mean concentrations of each cannabinoid were still above the lower limit of quantification (LLOQ). There was a high degree of inter-subject and intra-subject variability in the plasma concentrations achieved.Tmax of CBD and THC occurred earlier following sublingual administration than oro-pharyngeal or buccal although only the difference in Tmax of CBD compared with buccal was statistically significant. Cmax of both CBD and THC was greatest following buccal administration although this was not statistically significant. AUC was greatest following oro-pharyngeal and was statistically significantly greater than buccal. The lower bioavailability, as measured by AUC, following buccal administration when compared to the sublingual and oro-pharyngeal routes may be related to the difficulty of spraying onto the inside of the cheek reported during the study and could be due to some loss of spray. Buccal administration of the pump action sublingual spray (PASS) test treatment resulted in a later Tmax but greater Cmax when compared to the sublingual and oro-pharyngeal routes. Comparison of the sublingual and oro-pharyngeal routes showed no statistically significant difference in THC or CBD pharmacokinetic parameters other than an earlier Tmax following sublingual dosing. The oral capsule appeared to show an early Tmax of both CBD and THC. Mean Cmax of THC and 11-hydroxy-THC were greater, but in contrast the Cmax of CBD was lower, than following the PASS treatments. Relative to THC, the plasma level AUC of 11-hydroxy-THC was proportionally greatest following oral capsules which could be a reflection of greater metabolism by this route. Of the PASS treatments the ratio of 11-hydroxy-THC to THC was greatest following sublingual and least following oro-pharyngeal. There was very wide inter-and to a lesser extent intra-subject variability in pharmacokinetics. Differences in mean values between the routes of administration, even when statistically significant, are small relative to the very wide range of values between subjects. The sublingual and oro-pharyngeal routes of administration appear to have the same pharmacokinetic results. The buccal pharmacokinetic parameters are lower when compared to the sublingual and oro-pharyngeal routes.A total of 146 adverse events (AEs) occurred in 12 subjects. Two events were classified as moderate (flu-like illness and pharyngeal irritation) and the remaining 144 were classified as mild. All routes of administration were well tolerated by all subjects with no serious AEs and no withdrawals due to AEs.The overall results indicate that administration of the liquid spray (GW-1000-02) need not be limited to sublingual administration. The oral capsule, has good bioavailability, and provided, as is the case here the formulation is not oil based, may be a viable formulation when self-titration is not necessary.
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Community-based studies suggest that cannabis products that are high in Δ(9)-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ(2)=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6±18.9%) compared with the CBD group (-0.4%±9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.
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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.
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This paper aims to evaluate the anti-emetic efficacy of cannabinoids in cancer patients receiving chemotherapy using a systematic review of literature searched within electronic databases such as PUBMED, EMBASE, PSYCINFO, LILACS, and ‘The Cochrane Collaboration Controlled Trials Register’. Studies chosen were randomized clinical trials comprising all publications of each database until December 2006. From 12 749 initially identified papers, 30 fulfilled the inclusion criteria for this review, with demonstration of superiority of the anti-emetic efficacy of cannabinoids compared with conventional drugs and placebo. The adverse effects were more intense and occurred more often among patients who used cannabinoids. Five meta-analyses were carried out: (1) dronabinol versus placebo [n = 185; relative risk (RR) = 0.47; confidence interval (CI) = 0.19–1.16]; (2) Dronabinol versus neuroleptics [n = 325; RR = 0.67; CI = 0.47–0.96; number needed to treat (NNT) = 3.4]; (3) nabilone versus neuroleptics (n = 277; RR = 0.88; CI = 0.72–1.08); (4) levonantradol versus neuroleptics (n = 194; RR = 0.94; CI = 0.75–1.18); and (5) patients' preference for cannabis or other drugs (n = 1138; RR = 0.33; CI = 0.24–0.44; NNT = 1.8). The superiority of the anti-emetic efficacy of cannabinoids was demonstrated through meta-analysis.
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Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazole-induced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (≥ 10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic-clonic seizures. These results extend the anti-convulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.
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Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.
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The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ(9)tetrahydrocannabivarin (Δ(9)-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ(9)-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ(9)-THC pCB-based medicines.
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Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo. A total of 24 never-treated patients with SAD were allocated to receive either CBD (600 mg; n=12) or placebo (placebo; n=12) in a double-blind randomized design 1 h and a half before the test. The same number of HC (n=12) performed the SPST without receiving any medication. Each volunteer participated in only one experimental session in a double-blind procedure. Subjective ratings on the Visual Analogue Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) were measured at six different time points during the SPST. The results were submitted to a repeated-measures analysis of variance. Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group as assessed with the VAMS. The SSPS-N scores evidenced significant increases during the testing of placebo group that was almost abolished in the CBD group. No significant differences were observed between CBD and HC in SSPS-N scores or in the cognitive impairment, discomfort, and alert factors of VAMS. The increase in anxiety induced by the SPST on subjects with SAD was reduced with the use of CBD, resulting in a similar response as the HC.
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Background: Significant pain from HIV-associated sensory neuropathy (HIV-SN) affects ∼40% of HIV infected individuals treated with antiretroviral therapy (ART). The prevalence of HIV-SN has increased despite the more widespread use of ART. With the global HIV prevalence estimated at 33 million, and with infected individuals gaining increased access to ART, painful HIV-SN represents a large and expanding world health problem. There is an urgent need to develop effective pain management strategies for this condition. Method and findings: Objective: To evaluate the clinical effectiveness of analgesics in treating painful HIV-SN. Design: Systematic review and meta-analysis. Data sources: Medline, Cochrane central register of controlled trials, www.clinicaltrials.gov, www.controlled-trials.com and the reference lists of retrieved articles. Selection criteria: Prospective, double-blinded, randomised controlled trials (RCTs) investigating the pharmacological treatment of painful HIV-SN with sufficient quality assessed using a modified Jadad scoring method. Review methods: Four authors assessed the eligibility of articles for inclusion. Agreement of inclusion was reached by consensus and arbitration. Two authors conducted data extraction and analysis. Dichotomous outcome measures (≥ 30% and ≥ 50% pain reduction) were sought from RCTs reporting interventions with statistically significant efficacies greater than placebo. These data were used to calculate RR and NNT values. Results: Of 44 studies identified, 19 were RCTs. Of these, 14 fulfilled the inclusion criteria. Interventions demonstrating greater efficacy than placebo were smoked cannabis NNT 3.38 95%CI(1.38 to 4.10), topical capsaicin 8%, and recombinant human nerve growth factor (rhNGF). No superiority over placebo was reported in RCTs that examined amitriptyline (100mg/day), gabapentin (2.4 g/day), pregabalin (1200 mg/day), prosaptide (16 mg/day), peptide-T (6 mg/day), acetyl-L-carnitine (1g/day), mexilitine (600 mg/day), lamotrigine (600 mg/day) and topical capsaicin (0.075% q.d.s.). Conclusions: Evidence of efficacy exists only for capsaicin 8%, smoked cannabis and rhNGF. However,rhNGF is clinically unavailable and smoked cannabis cannot be recommended as routine therapy. Evaluation of novel management strategies for painful HIV-SN is urgently needed.
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Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis.
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The two main constituents of cannabis, cannabidiol and Δ(9)-tetrahydrocannabinol (THC), have opposing effects both pharmacologically and behaviourally when administered in the laboratory. Street cannabis is known to contain varying levels of each cannabinoid. To study how the varying levels of cannabidiol and THC have an impact on the acute effects of the drug in naturalistic settings. Cannabis users (n = 134) were tested 7 days apart on measures of memory and psychotomimetic symptoms, once while they were drug free and once while acutely intoxicated by their own chosen smoked cannabis. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analysed for levels of cannabinoids. On the basis of highest and lowest cannabidiol content of cannabis, two groups of individuals were directly compared. Groups did not differ in the THC content of the cannabis they smoked. Unlike the marked impairment in prose recall of individuals who smoked cannabis low in cannabidiol, participants smoking cannabis high in cannabidiol showed no memory impairment. Cannabidiol content did not affect psychotomimetic symptoms, which were elevated in both groups when intoxicated. The antagonistic effects of cannabidiol at the CB(1) receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like 'skunk' and encouraged to use strains containing higher levels of cannabidiol.
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Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.
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We assessed the anticonvulsant potential of the phytocannabinoid Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) by investigating its effects in an in vitro piriform cortex (PC) brain slice model of epileptiform activity, on cannabinoid CB1 receptor radioligand-binding assays and in a generalized seizure model in rats. Δ⁹-THCV was applied before (10 μm Δ⁹-THCV) or during (10-50 μm Δ⁹-THCV) epileptiform activity induced by Mg²(+) -free extracellular media in adult rat PC slices and measured using multielectrode array (MEA) extracellular electrophysiologic techniques. The actions of Δ⁹-THCV on CB1 receptors were examined using [³H]SR141716A competition binding and [³⁵S]GTPγS assays in rat cortical membranes. Effects of Δ⁹-HCV (0.025-2.5 mg/kg) on pentylenetetrazole (PTZ)-induced seizures in adult rats were also assessed. After induction of stable spontaneous epileptiform activity, acute Δ⁹ -THCV application (≥ 20 μm) significantly reduced burst complex incidence and the amplitude and frequency of paroxysmal depolarizing shifts (PDSs). Furthermore, slices pretreated with 10 μm Δ⁹-THCV prior to induction of epileptiform activity exhibited significantly reduced burst complex incidence and PDS peak amplitude. In radioligand-binding experiments, Δ⁹-THCV acted as a CB1 receptor ligand, displacing 0.5 nm [³H]SR141716A with a Ki∼290 nm, but exerted no agonist stimulation of [³⁵S]GTPγS binding. In PTZ-induced seizures in vivo, 0.25 mg/kg Δ⁹-THCV significantly reduced seizure incidence. These data demonstrate that Δ⁹-THCV exerts antiepileptiform and anticonvulsant properties, actions that are consistent with a CB1 receptor-mediated mechanism and suggest possible therapeutic application in the treatment of pathophysiologic hyperexcitability states.
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Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC. Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol. Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.
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Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.
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Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca(2+) homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca(2+) regulation is bidirectional, depending on the excitability of cells. Under physiological K(+)/Ca(2+) levels, CBD caused a subtle rise in [Ca(2+)](i), whereas CBD reduced [Ca(2+)](i) and prevented Ca(2+) oscillations under high-excitability conditions (high K(+) or exposure to the K(+) channel antagonist 4AP). Regulation of [Ca(2+)](i) was not primarily mediated by interactions with ryanodine or IP(3) receptors of the endoplasmic reticulum. Instead, dual-calcium imaging experiments with a cytosolic (fura-2 AM) and a mitochondrial (Rhod-FF, AM) fluorophore implied that mitochondria act as sinks and sources for CBD's [Ca(2+)](i) regulation. Application of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and the mitochondrial Na(+)/Ca(2+) exchange inhibitor, CGP 37157, but not the mitochondrial permeability transition pore inhibitor cyclosporin A, prevented subsequent CBD-induced Ca(2+) responses. In established human neuroblastoma cell lines (SH-SY5Y) treated with mitochondrial toxins, CBD (0.1 and 1 microm) was neuroprotective against the uncoupler FCCP (53% protection), and modestly protective against hydrogen peroxide- (16%) and oligomycin- (15%) mediated cell death, a pattern also confirmed in cultured hippocampal neurons. Thus, under pathological conditions involving mitochondrial dysfunction and Ca(2+) dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca(2+) homeostasis.
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