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Antidepressant-Like and Anxiolytic-Like Effects of Cannabidiol: A Chemical Compound of Cannabis sativa
Abstract
Anxiety and depression are pathologies that affect human beings in many aspects of life, including social life, productivity and health. Cannabidiol (CBD) is a constituent non-psychotomimetic of Cannabis sativa with great psychiatric potential, including uses as an antidepressant-like and anxiolytic-like compound. The aim of this work is to review the animal study articles using CBD as an anxiolytic-like and antidepressant-like compound. Articles were identified using the major electronic databases, including the ISI Web of Knowledge, Scielo, PubMed and PsycINFO, combining the terms “cannabidiol”, “antidepressant-like” and “anxiolytic-like”. As languages for this search, we used Portuguese and English. Animal study articles were primarily included. Studies involving animal models, performing a variety of experiments on the above-mentioned disorders, such as the forced swimming test (FST), elevated plus maze (EPM) and Vogel conflict test (VCT), suggest that CBD exhibited an anti-anxiety and anti-depressant effects in animal models discussed. Experiments with CBD demonstrated non-activation of neuro-receptors CB1 and CB2. Most of the studies demonstrated a good interaction between CBD and the 5-HT1A neuro-receptor, except by on that it was not clear.
... Studies in various animal models have revealed that CBD is effective and has an anxiolytic-like impact at intermediate doses but not at low or high doses (García-Gutiérrez et al., 2020). CBD-associated anti-anxiety and antidepressant effects were proven by several tests, such as the elevated plus-maze (EPM), forced swimming test (FST), and Vogel conflict test (VCT) (de Mello Schier et al., 2014). The interaction of CBD with the 5-HT1A neuroreceptor was shown to be an underlying mechanism involved in the anxiolytic activity (de Mello Schier et al., 2014). ...
... CBD-associated anti-anxiety and antidepressant effects were proven by several tests, such as the elevated plus-maze (EPM), forced swimming test (FST), and Vogel conflict test (VCT) (de Mello Schier et al., 2014). The interaction of CBD with the 5-HT1A neuroreceptor was shown to be an underlying mechanism involved in the anxiolytic activity (de Mello Schier et al., 2014). Further experimental outcomes in animal models pointed out the decline in anxiety-and compulsive-like behaviors by CBD (Moreira et al., 2006;Nardo et al., 2014). ...
... Anxiety Disorders and Depression: Given CBD effects on serotonergic, GABAergic and other neurotransmitter systems, it may hold promise for treating disorders of generalized anxiety, social anxiety, panic, and post-traumatic stress [58]. Preclinical research shows that CBD may exert antidepressant effects by impacting serotonin pathways in the brain [59], and CBD may reduce anxiety through 5-HT 1A receptor activation in rats [60]. Thus, CBD may act as an antidepressant [61], and via its effects on specific GABA A receptor subtypes, as an anxiolytic agent [62]. ...
... Since CBD also increases the levels of naturally occurring endocannabinoids, such as anandamide, CBD may also hold promise for treating depression [59]. Since anxiety and depression occur in bipolar disorder, it has been suggested [65,66] that CBD may stabilize mood in bipolar disorder too. ...
Purpose of review
There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines.
Recent findings
Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity.
Summary
Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.
... • Kenevir, Kendir • Hemp, Marijuana 27): Anxiolytic, effective on the sleep-wake cycle of rats, antitumor effect through growth mechanism, appetizer for AIDS patients [199], antidepressant not active on, CB1 and CB2 receptors, but HT1A receptor [200], effective on seizures of Lennox-Gastaut syndrome, and Dravet syndrome for 2-year-old and older [201], anti-psychoactive [199], b) Δ 9 -Tetrahydrocannabinol (THC) (28): Psychoactive effect [199] 5.1.1.2. Other: a) Inflorescence of raw hemp of E., and decarboxylated E.: Neuroprotective, and trophic on SHSY5Y cell lines [202], CBD (27), and its synthetic analogs: Antioxidant, anticancer, and neuroprotective for epilepsy and Alzheimer's disease [203], phytocannabinoids: For nausea, and severe pain in chemotherapeutic patients, antiepileptic [204], b) Cannabis E., THC/CBD: Anticancer [205], c) E. includes 64.5% CBD (27), 4% THC (28), and less than 4% the other cannabinoids: Induce neuropathy, and alleviate neuropathic pain (STZ injection, GSH, GSSG, MDA, NGF assays) [206], d) α-Humulene, -caryophyllene, and caryophyllene oxide from n-hexane E: α-Humulene has significant antifungal activity against Cryptococcus neoforman, (α-Humulene > caryophyllene (low) > caryophyllene oxide (none)) [207] ...
... Cannabidiol is also effective on sleep-wake cycle, anxiety, but does not have psychoactive effect [199]. In addition, the compound has antidepressant activity via the HT1A receptor [200]. On the other hand, THC (28) has psychoactive effects, and can cause intoxicating effects on human bodies. ...
The increase of challenges in people's lives, daily problems as well as traumatic events could lead them to experience stress. Because of the side effects of current drugs, the recent medications are not sufficient to cure stress-related diseases; new approaches are needed in order to find more effective medications with fewer sideeffects. Ethnobotanical and ethnomedical research is increasingly recognized as a viable source of data and plausible pharmacological action of many plants. The review presents ethnobotanical information of the plants that have been used against stress-related diseases among local people of Turkey. In addition, a survey of the current literature on the topic aims to find new natural resources that will contribute to the development of drugs and bring them to the literature by scanning the scientific articles on the isolation and structure determination of the secondary metabolites of these medicinal plants, which have been already in use among the public for stressrelated disorders for centuries. This research is not only the first step in the research of promising new compounds against stress but it is also a presentation of data on medicinal plants of Turkey: Their medicinal parts, method of preparation, usage patterns and, if recorded, their dosages.
... 35 52-59 CBD is alleged to possess anxiolytic and antidepressant properties, as shown in several animal and human studies. [60][61][62][63][64][65][66] In addition, a well-controlled preliminary animal study showed that CBD, but not THC, enhanced the biomechanical properties of healing midfemoral fractures in rats, supporting a beneficial effect of CBD on bone healing. 67 Epidemiological studies have suggested a reduction in opioid use for pain coinciding with an increased use of medical cannabis, 30 a trend also documented in Canada. ...
Introduction Acute pain levels following orthopaedic injury (eg, fracture) are a predictor of the onset of chronic pain, which affects nearly 50% of fracture patients and impairs functional recovery. Among current pharmacological treatments for acute pain, non-steroidal anti-inflammatory drugs have been associated with delayed bone healing, while opioids inhibit effective bone remodelling, increase the risk of pseudarthrosis and carry a high risk of addiction. In light of this, the development of new pain treatments is essential. Cannabidiol (CBD), a non-addictive and non-psychotropic cannabis component stands out as a potential therapeutic agent, given its analgesic and anti-inflammatory properties as well as its potential benefits for bone healing. This randomised controlled trial aims to investigate the effect of acute CBD treatment, compared with placebo, on patients’ self-reported pain, inflammation and well-being following a fracture injury.
Methods and analysis This is a triple-blind, randomised, placebo-controlled clinical trial. A total of 225 adults aged 18–70 years, who have suffered a long bone fracture and were treated at the Hôpital du Sacré-Coeur de Montréal, will be randomly assigned within 1 week to one of three treatment arms (25 mg or 50 mg of CBD or placebo) for 1 month. The primary outcome will be the difference in the pain score between groups at 1-month follow-up. Secondary outcomes will include measures of persistent pain, inflammation, opioid usage, quality of life, sleep quality, depression, anxiety, cognition and orthopaedic function. Data will be collected at baseline, 1-month and 3-month follow-ups.
Ethics and dissemination This study obtained a Health Canada licence for use of cannabis products. It has also been approved by Health Canada and the Research Ethics Board of the CIUSSS du Nord-de-l’Île-de-Montréal (Project ID 2025-2105). The findings will be published in a peer-reviewed journal and presented at local, national and international conferences. The trial’s results will be made publicly available on the ClinicalTrials.gov database.
... CBD functions as a non-competitive antagonist and has a negative allosteric modulatory effect on cannabinoid type-1 and type-2 receptors [45,47]. Importantly, evidence has shown that CBD may be beneficial for METH abuse [48], Modifies behaviors connected to rewards, and reduces the intensity of desiring drugs in rodents [49,50]. Notably, CBD can improve addictive behaviors by making the reward system more responsive to natural incentives [51]. ...
Methamphetamine (METH), a stimulant that is extremely addictive, directly affects the central nervous system. METH's abuse and consumption are directly linked to mental illnesses, psychosis, and behavioral and cognitive impairments. It may disrupt the reward system and dopaminergic transmission. METH's rewarding qualities are associated with a rise in dopamine. Additionally, cannabidiol (CBD), one of the primary cannabinoid components of the cannabis plant, significantly affects dopaminergic transmission and may aid in reward- and addiction-related behaviors. To shed light on the role of the D2-like dopamine receptor (D2R) in the hippocampal dentate gyrus (DG), the present study examined the effects of CBD on the acquisition and expression of the conditioned place preference (CPP) induced by METH. The function of D2R was ascertained by delivering Sulpiride microinjections, as a D2R antagonist Sulpiride (0.25, 1, and 4 μg/0.5 μL DMSO12%) into the DG. Moreover, an intracerebroventricular injection of CBD at a dose of 10 μg/5 μL for CPP acquisition and 50 μg/5 μL for CPP expression was given to rats. According to the current research, CBD dramatically reduced the acquisition and expression of CPP resulting from METH. However, Sulpiride suppressed the effect of CBD on METH-induced CPP acquisition and expression, with a greater impact on expression experiments. Ultimately, this study proposed that the expression experiment of METH-induced CPP appears to be heavily dependent on D2R in the DG.
... CBD has shown an effect in treating the harshest two forms of childhood epilepsy; the Dravet syndrome and the Lennox-Gastaut syndrome), especially in patients who do not respond to other antiepileptic medications [26]. Many studies proved that CBD was able to reduce the number of daily seizures or stop seizures altogether [27]. The FDA has approved a CBD-based liquid medication (Epidiolex ® ) as the first cannabis-derived medicine for the treatment of these conditions [28]. ...
As presented in the previous chapters, the cannabis plant is rich in a variety of
constituents belonging to many different chemical classes. The most important and characteristic
class, specific to cannabis, is the cannabinoids. While a few naturally occurring cannabinoids are abundant in the plant materials, especially Δ9-tetrahydrocannabinol
and cannabidiol, other cannabinoids are present in small quantities. Synthesis of cannabinoids,
like most other natural products, has been one of the methods used for structure
elucidation. However, synthesis is also used to produce large supply of natural products
that might not be feasible by isolation from plant material. This chapter is dedicated to
methods used to synthesize the major cannabinoids that could be used for product development.
efforts of these cannabinoids. The synthetic routes offer alternative methods to
secure drug supply of these cannabinoids. Only examples of synthetic methods are given,
with no intention to provide exhaustive coverage of all literature procedures.
... The safety and tolerability of CBD have been investigated in healthy dogs, with reported adverse effects being mild gastrointestinal, neurological, or constitutional symptoms and an elevation of serum alkaline phosphatase (ALP) reported by some studies [98,99] (for a detailed review see [100]). It may also be a treatment option for cognitive impairment and behavioral comorbidities of canine epilepsy [101] and for mood or anxiety disorders [102,103]. While the mechanism of CBD's anticonvulsant effect has been investigated to a certain extent, it is currently unclear how exactly CBD acts as an anxiolytic [103]. ...
Simple Summary
Canine cognitive dysfunction is considered the canine equivalent to human Alzheimer’s disease. It is a growing concern in veterinary medicine, as it affects many aged dogs. Dietary intervention with different diets and supplements may improve clinical signs and prevent further degeneration. Using an online questionnaire, we found that even though few owners were willing to change their dog’s main diet, many of them added supplements such as oils and vitamins. Consulting a veterinary surgeon when using dietary supplements is important as it allows for evidence-based recommendations to be made.
Abstract
Canine cognitive dysfunction (CCD) is becoming increasingly recognized in veterinary medicine, as dogs live longer and with CCD being highly prevalent among the elderly dog population. Various studies have shown that diet and dietary supplementation can positively influence the clinical signs of CCD, especially if given at an early stage. The aim of this study was to investigate owner use of dietary supplements (DSs) in dogs with age-related behavioral changes. An observational study based on an online questionnaire for owners of dogs with age-related behavioral changes was performed. Out of a total of 394 owners who completed the survey, after noticing age-related behavioral changes, over half of the dogs received DSs (54%), whereas only 8% reported changing their dog’s base diet. The most used DS was fish oil (48%). The use of DSs should be discussed with and monitored by veterinary surgeons since many geriatric patients have multi-morbidities, may have specific nutritional requirements and receive multi-faceted medications.
... The authors of this very recent paper concluded that CBD may be a promising treatment for this condition, despite the fact that further research is needed to establish optimal dosing and assess the time course of CBD's anxiolytic effects [75]. Other reports describing the effects of CBD on anxiety can be found in the following papers [72,73,[76][77][78]. ...
The use of cannabinoids (substances contained specifically in hemp plants) for therapeutic purposes has received increased attention in recent years. Presently, attention is paid to two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). With respect to the psychotropic effects and dependence potential of THC (though it is very mild), its use is associated with certain restrictions, and thus the therapeutic properties of CBD are frequently emphasized because there are no limitations associated with the risk of dependence. Therefore, this review covers the main pharmacodynamic and pharmacokinetic features of CBD (including characteristics of endocannabinoidome) with respect to its possible beneficial effects on selected diseases in clinical practice. A substantial part of the text deals with the main effects of CBD on aging, including Alzheimer’s disease and related underlying mechanisms.
... The anxiolytic state with this compound is thought to be caused by the 5-HT1A receptor. It has been determined that this compound also reduces depression, fear, stress and trauma situations (53,54,55,56,57). ...
... On the other side, schizophrenia has appeared to be characterized by an enhanced endogenous cannabinoid production [39], which could be antagonised by the administration of cannabinoid anatagonists. At present, the only preliminary studies regard the therapeutic use of CBD, which has appeared to be effective in the treatment of anxiety and depression [40,41]. Moreover, it has been proven to reduce the hallucinatory experiences in patients with schizophrenia [41]. ...
The endocannabinoid system plays a physiological natural anti-inflammatory anticancer role and the pharmacological effects of cannabinoids from Cannabis plant simply reflect the action of the endogenous ones. Therefore, from a therapeutic point of view Cannabis plant cannot be understood without taking into consideration the physio-pathological role of the endocannabinoid system. Despite the great number of potentially therapeutic molecules with the Cannabis plant, they may be synthetized within four archetypic molecules, which consist of tetra-hydro-cannabinol (THC), cannabinol (CBN), cannabigerol (CBG) and cannabidiol (CBD). All molecules play a similar anticancer activity, whereas their psychological effects are different. THC is the only psychotropic sychedelic cannabinoid, whereas the other three cannabinoids have no psychotropic effect, but exert an important anxiolytic activity. Moreover, only THC acts as a direct enzyme responsible for annabinoid degradation, by enhancing the endogenous cannabinoid content. Unfortunately, despite the great number of experimental studies, the clinical use of cannabinoids in the treatment of systemic human diseases is still at the beginning.
... In contrast to THC being the most important psychoactive component of cannabis, CBD exhibits no state of euphoria [2]. Furthermore, CBD has the potential for several therapeutic options, e.g., showing spasmolytic [3,4], anxiolytic, antiinflammatory, and analgesic effects [5][6][7]. ...
Cannabidiol (CBD) products have ascribed an uprising trend for their health-promoting effects worldwide. In contrast to Δ⁹-tetrahydrocannabinol (THC), CBD exhibits no state of euphoria. Since conversion of CBD into THC in an acidic environment has been reported, it has not been proved whether this degradation will also occur in human gastric fluid. A total of 9 subjects ingested 400 mg CBD as a water-soluble liquid together with lecithin as an emulsifier and ethanol as a solubilizer. Blood samples were taken up to 4 h, and urine samples were submitted up to 48 h. THC, 11-hydroxy-Δ⁹-THC (THC-OH), 11-nor-9-carboxy-Δ⁹-THC (THC-COOH), CBD, 7-hydroxy cannabidiol (7-OH-CBD), and 7-carboxy cannabidiol (7-CBD-COOH) were determined in blood and THC-COOH and 7-CBD-COOH in urine by LC–MS/MS. Neither THC, THC-OH, nor THC-COOH were detectable in any serum specimen. Only two urine samples revealed THC-COOH values slightly above the threshold of 10 ng/ml, which could also be caused by trace amounts of THC being present in the CBD liquid. It can be concluded that negative consequences for participants of a drug testing program due to a conversion of CBD into THC in human gastric fluid appear unlikely, especially considering a single intake of dosages of less than 400 mg. Nevertheless, there is a reasonable risk for consumers of CBD products being tested positive for THC or THC metabolites. However, this is probably not caused by CBD cyclization into THC in human gastric fluid but is most likely due to THC being present as an impurity of CBD products.
... Anxiolytic effect -it has been shown that previous treatments with CBD significantly decreased the anxiety and restlessness. CBD blocked the anxiety induced by the THC and substantially reduced the anxiety in general in both animal models and humans (de Mello Schier et al. 2014;Masataka 2019). ...
In connection with the use of cannabinoids for therapeutic purposes in human medicine, there is increased attention for their use in veterinary medicine, particularly by the owners of companion animals and horses. Therefore, veterinarians are expected to face this interest and have the corresponding knowledge on these substances. Presently, it is not possible to use medical marijuana (in terms of the dried cannabis flowers) for veterinary purposes in many countries, but there is increasing evidence that isolated cannabinoids also have beneficial effects (namely cannabidiol – CBD). Thus, this review summarises the possible therapeutic implications of CBD within the scope of evidence-based medicine, particularly in dogs and horses in association with the treatment of pain, epilepsy and anxiety in order to provide veterinarians with a concise overview of scientific findings in this field.
... Indeed, CBD is a noncannabimimetic component that does not bind (i.e., has a very low affinity) CB 1 and CB 2 receptors, while it exerts inverse agonism at CB 2 receptors (Thomas et al., 2007) and negative allosteric modulatory activity at CB 1 receptors (Laprairie et al., 2015). Additional pharmacological features describe the CBD as a chemical compound able to inhibit, via FAAH, AEA hydrolysis and produce antipsychotic effects (Leweke et al., 2012), and a phytocannabinoid with agonistic activity at 5-HT1A receptor and desensitization activity of TRPV1 , thus providing anti-inflammatory, analgesic, anti-depressant and anxiolytic effects (Schier et al., 2014;Shannon et al., 2019;Atalay et al., 2020). Interestingly, CBD also binds the orphan G protein-coupled receptor 55 (GPR55), a recently included new member of the eCB family (Sharir and Abood, 2010), showing an involvement in several mechanisms accountable for the exacerbation of inflammatory processes . ...
The latest years have witnessed a growing interest towards the relationship between neuropsychiatric disease in children with autism spectrum disorders (ASD) and severe alterations in gut microbiota composition. In parallel, an increasing literature has focused the attention towards the association between derangement of the endocannabinoids machinery and some mechanisms and symptoms identified in ASD pathophysiology, such as alteration of neural development, immune system dysfunction, defective social interaction and stereotypic behavior. In this narrative review, we put together the vast ground of endocannabinoids and their partnership with gut microbiota, pursuing the hypothesis that the crosstalk between these two complex homeostatic systems (bioactive lipid mediators, receptors, biosynthetic and hydrolytic enzymes and the entire bacterial gut ecosystem, signaling molecules, metabolites and short chain fatty acids) may disclose new ideas and functional connections for the development of synergic treatments combining “gut-therapy,” nutritional intervention and pharmacological approaches. The two separate domains of the literature have been examined looking for all the plausible (and so far known) overlapping points, describing the mutual changes induced by acting either on the endocannabinoid system or on gut bacteria population and their relevance for the understanding of ASD pathophysiology. Both human pathology and symptoms relief in ASD subjects, as well as multiple ASD-like animal models, have been taken into consideration in order to provide evidence of the relevance of the endocannabinoids-microbiota crosstalk in this major neurodevelopmental disorder.
... This fit with non-veteran research that those with pre-existing mental health challenges may be having difficulties coping with the pandemic and are turning to substances to cope (Alonzi et al., 2020;Ettman et al., 2020;Rajkumar, 2020). In line with the self-medication hypothesis, veterans with preexisting anxiety may be consuming more alcohol and using more cannabis because of their anxiolytic effects (de Mello Schier et al., 2014;Knight et al., 2020). Further, acute doses of nicotine can also lead to anxiolytic effects (Anderson & Brunzell, 2015), which could also account for the higher levels of cigarette use seen in those with preexisting anxiety. ...
The COVID-19 pandemic has resulted in financial, employment, and mental health challenges. In general, American veterans report high rates of substance use, which may be influenced by the COVID-19 pandemic. Those with pre-existing mental health problems, employment disruptions, or financial stress may be particularly vulnerable. We examined the relationships between pre-existing self-report screens for a probable anxiety disorder, COVID-19-related financial stress, employment disruption (e.g., lost job, reduced hours), and alcohol, cannabis, and cigarette use during the pandemic among 1230 veterans ( M age = 34.5; 89% male). Participants were recruited through various social media sites and completed an online survey 1 month prior to implementation of the nationwide physical distancing guidelines in the United States (February 2020). Six months later (August 2020), they completed a follow-up survey. Compared to veterans who screened negative for anxiety prior to the pandemic, veterans who screened positive reported consuming more drinks per week ( b = 3.05), were more likely to use cannabis ( OR = 6.53), and smoked more cigarettes ( b = 2.06) during the first 6 months of the pandemic. Financial stress was positively associated with alcohol ( b = 1.09) and cannabis use ( OR = 1.90). Alcohol use was heaviest among veterans with a positive pre-existing anxiety screen and high financial stress. Moreover, veterans who experienced employment disruption due to the pandemic consumed less alcohol but were more likely to use cannabis during the pandemic. Veterans with pre-pandemic anxiety and pandemic-related financial stress may be using substances at higher rates and may benefit from intervention to mitigate negative substance use-related outcomes. Findings also enhance our understanding of veteran substance use behaviors following disruptions in employment due to the pandemic.
... Nevertheless, CBD, which is medically used in combination with Δ9-THC in cannabis-based drugs, contains a balanced content of both to manage the neuropathic symptoms related to multiple sclerosis (Fernandez, 2016). CBD is the single drug recently generating notable interest due to its useful antiepileptic (Wright et al., 2015), neuroprotective (Ibeas Bih et al., 2015), hypoxia-ischemia (Mori et al., 2017), anxiolytic (Schier et al., 2014), analgesic (Maione et al., 2011), anti-inflammatory (Burstein, 2015), anti-asthmatics (Vuolo et al., 2015), antipsychotic (Bhattacharyya et al., 2010), and antitumor activity (Massi et al., 2013) among others. ...
Recently, due to the valuable and high level of phytochemical compounds such as cannabinoids and other secondary metabolites, the cultivation of Cannabis sativa has increased in the world. The current study was conducted to evaluate the potential role of exogenous salicylic acid (control, 0.01, 0.1, and 1 M) on enhanced production of pharmaceutically important phytochemicals. The sprayed aerial parts were evaluated based on phenolic (TPC) and flavonoids (TFC) contents, antioxidant capacity (by FRAP and DPPH assay), photosynthetic pigments including chlorophyll a, b (Chl a and Chl b), total carotenoids (TCC), and cannabinoid compounds. Quantification of aerial parts metabolites was performed using gas chromatography. The results indicated that phytochemical compounds and antioxidant capacity in C. sativa were influenced by various concentrations of salicylic acid (SA). The highest TPC, TFC, TCC, Chl a, Chl b, and antioxidant capacity were obtained in 1 M treatment, whereas the lowest of them were found in control plants. The major cannabinoids in the analyzed extracts were CBD (19.91%–37.81%), followed by Δ⁹-THC (10.04%–22.84%), and CBL (nd-14.78%). The highest CBD (37.81%) and Δ⁹-THC (22.84%) were obtained in 1 M of SA. These results suggest that the elicitor SA (especially 1 M) was able to improve antioxidant capacity, phytochemicals, and cannabinoid compounds.
... Only two cannabinoidsthe psychoactive delta-9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD)-have been extensively studied for their potential therapeutic applications. Although CBD has potential to treat a wide range of clinical conditions like disorders of generalized anxiety, social anxiety, panic, and PTSD (Blessing et al. 2015), and depressive disorders via serotonergic pathways (de Mello et al. 2014) and endocannabinoid system (Ashton and Moore 2011), more clinical research from well-designed clinical trials is needed to support its use in treating anxiety and depressive disorders and bipolar disorders (Ashton et al. 2005). CBD also may be effective in promoting wakefulness, via triggering increased dopamine levels in either lateral hypothalamus or dorsal raphe nuclei, the areas of brain responsible for wakefulness, suggesting that CBD could treat sleeping disorders such as narcolepsy (Murillo-Rodriguez et al. 2008). ...
COVID-19 epidemic has resulted in devastating mortality and morbidity consisting of socioeconomic and health effects that have included respiratory/pulmonary, cardiovascular, mental health and neurological consequences such as anxiety, depression, and substance use. Several effective vaccines have been developed and extensive efforts are underway to develop therapeutics to treat COVID-19. Cannabis and/or its product-cannabidiol (CBD) are being advertised for the treatment of COVID-19 associated mental/neurological complications and substance use disorders. However, research reviewed shows that there is insufficient data from clinical studies to support the use of cannabis or CBD for the treatment of COVID-19 associated mental health and neurological complications. Additional basic and clinical research is suggested to develop cannabis or cannabidiol for the treatment of mental health problems associated with coronavirus infection and or substance use disorders. In the meantime, it is important that the addiction physician/psychiatrist must caution while prescribing or recommending cannabis or CBD for treating such clinical indications.
Graphical abstract
Research shows that currently there is no clinical evidence to support the use of cannabis or any of its compounds including CBD for treating any of the neuropsychiatric complications of COVID-19. Thus, it is important that the addiction physicians/psychiatrists caution their patients from using cannabis or cannabis products for treating any such complications.
Cannabis sativa L. is an important medicinal plant with high commercial value. In recent years, the research interest in cannabidiol (CBD) and terpene-rich cannabis has been rapidly expanding due to their high therapeutic potential. The present study aims to explore the phytocannabinoids and terpenes diversity in Cannabis sativa collected from different parts of northern India. Our findings revealed that the cannabinoids and terpenes synthesize together in capitate stalked and capitate sessile glandular trichomes, whereas bulbous glands synthesize only terpenes. The North Indian C. sativa is mainly dominated by tetrahydrocannabinol (THC). The CBD-rich plant diversity is nominal (1.11%) in studied north Indian C. sativa. The essential oil profiling reveals (E)-caryophyllene (10.30-36.80%) as the major constituent, followed by α-humulene (0.50-15.29%) and α-bisabolol (0.00-16.40%) in the North Indian population. The cannabinoids and terpenes content showed significant diversity among and within the five studied populations. The correlation analysis between cannabinoids and terpenes indicates that α-pinene, β-pinene, and limonene positively correlated with CBD content. Similarly, α- and β-selinene correlate positively with tetrahydrocannabinolic acid (THCA) content. This study could help to identify the key cultivars from India and establish a consistent chemotype for future breeding programs.
O Transtorno Obsessivo Compulsivo (TOC) é um distúrbio neuropsicológico caracterizado por obsessões e/ou compulsões que causam grande prejuízo na vida do indivíduo. Seu diagnóstico é realizado por meio de critérios dispostos pelo Manual Diagnóstico e Estatístico de Transtornos Mentais (DSM-5). A fisiopatologia desse transtorno ainda não está totalmente elucidada, contudo diversos avanços no estudo da área têm mostrado novos circuitos neuronais envolvidos na fisiopatologia do TOC e, com isso, novas possibilidades de tratamento. Um desses tratamentos é a utilização do composto canabidiol (CBD), presente na Cannabis Sativa, como farmacoterapia, já que o circuito do Eistema Endocanabinoide (SEC), segundo os estudos, tem se mostrado presente na fisiopatologia do TOC. Com isso, essa revisão integrativa de literatura tem como objetivo analisar a efetividade do uso da cannabis no tratamento desse transtorno, bem como analisar os avanços na área e as questões éticas envolvidas.
Los diferentes usos del cannabis han tenido un crecimiento en los últimos años, donde la producción mundial de cannabis con fines
medicinales incrementó de 100 toneladas en 2015 a 406 toneladas en 2017 (JIFE, 2018). Se estima que alrededor de 30 países han legalizado alguna de sus formas de producción y/o comercialización del cannabis, incluso con fines recreativos, en algunos de los casos (Global Markets - EY Knowledge, 2018). Así mismo, en la literatura se destacan los logros alcanzados en los desarrollos dentro de la industria del cannabis para uso medicinal que impacta positivamente en la economía de los países que han incursionado en el tema.
Respecto al ámbito local, en Colombia se observa un camino recorrido y las posibilidades de ahondar en los usos medicinales de cannabis que podrían situar al país en un lugar preponderante y de gran potencial en el desarrollo de esta industria y en su posicionamiento internacional. Para lo cual, existe un marco regulatorio colombiano que abre el acceso al cannabis con fines médicos y científicos.
Identification and development of pharmaceuticals for neurological disorders is associated with several unique challenges. The primary weakness of candidate neurological compounds is the poor penetration efficacy across the blood-brain barrier (BBB). The BBB is the bottleneck in nervous system drug development and is the paramount factor that limits success in neurotherapeutics. Findings suggest cannabinoids might overcome the limiting effects of the BBB and play a key role in improving neurological dysfunctions. This supports the therapeutic potential of cannabidiol for the treatment of ischemic and inflammatory diseases of the central nervous system (CNS). The potential application of cannabinoids for Parkinson’s disease, Autism, and childhood Epilepsy is explored in this chapter.
Background
There is limited evidence suggesting that osteoporosis might exacerbate depressive symptoms, while more studies demonstrate that depression negatively affects bone density and increases fracture risk.
Aims
To explore the relationship between major depressive disorder (MDD) and fracture risk.
Methods
We conducted a nested case-control analysis (32 670 patients with fracture and 397 017 individuals without fracture) and a matched cohort analysis (16 496 patients with MDD and 435 492 individuals without MDD) in the same prospective UK Biobank data set. Further, we investigated the shared genetic architecture between MDD and fracture with linkage disequilibrium score regression and the MiXeR statistical tools. We used the conditional/conjunctional false discovery rate approach to identify the specific shared loci. We calculated the weighted genetic risk score for individuals in the UK Biobank and logistic regression was used to confirm the association observed in the prospective study.
Results
We found that MDD was associated with a 14% increase in fracture risk (hazard ratio (HR) 1.14, 95% CI 1.14 to 1.15, p<0.001) in the nested case-control analysis, while fracture was associated with a 72% increase in MDD risk (HR 1.72, 95% CI 1.64 to 1.79, p<0.001) in the matched cohort analysis, suggesting a longitudinal and bidirectional relationship. Further, genetic summary data suggested a genetic overlap between MDD and fracture. Specifically, we identified four shared genomic loci, with the top signal (rs7554101) near SGIP1 . The protein encoded by SGIP1 is involved in cannabinoid receptor type 1 signalling. We found that genetically predicted MDD was associated with a higher risk of fracture and vice versa . In addition, we found that the higher expression level of SGIP1 in the spinal cord and muscle was associated with an increased risk of fracture and MDD.
Conclusions
The genetic pleiotropy between MDD and fracture highlights the bidirectional association observed in the epidemiological analysis. The shared genetic components (such as SGIP1 ) between the diseases suggest that modulating the endocannabinoid system could be a potential therapeutic strategy for both MDD and bone loss.
Cannabidiol (CBD), a component of Cannabis sativa, has been studied for its therapeutic properties in several medical conditions. Clinical indications include the treatment of refractory epilepsies, anxiety disorders, chronic pain of neuropathic or inflammatory origin, sleep disorders such as insomnia, and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. The use of CBD is considered when other therapeutic options fail, in patients intolerant to the adverse effects of conventional medications, or as an adjuvant therapy to enhance the effectiveness of other treatments.
Cannabidiol (CBD), nonpsychotropic cannabinoid found in Cannabis sativa, is a very promising drug candidate offering many differential effects such as sedative, antiinflammatory, antioxidant, and neuroprotective properties. Nevertheless, the therapeutic use of CBD is hindered by its lack of water solubility and relatively low bioavailability. Various carriers have been used to address the solubility issues of CBD and other highly lipophilic drugs so far. However, self-assembled peptide nanostructures as carrier have not been used to improve the water solubility of CBD yet. In this study, a self-assembling peptide micelle was demonstrated to be an effective vehicle for encapsulation of CBD and increased its aqueous solubility up to 2000-fold compared to CBD itself.
The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase inhibition while also inhibiting transient receptor potential vanilloid Type 1 channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor Type 1 agonist arachidonoyl-2′-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with seven daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA decreased rearing and decreased phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference, then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a conditioned place preference or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct cannabinoid receptor Type 1 agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism.
Background
Interest in the potential mental health effects of cannabidiol (CBD) has increased recently, with a surge in commercial and pharmaceutical development of CBD products and a concomitant rise in consumer use. However, despite the widespread and growing use of CBD products by adults and adolescents, the mental health effects of CBD remain largely unknown.
Objective
The goals of this review are: 1) to briefly review the evidence base for the mental health effects of CBD, using depression as an exemplar, and 2) to systematically outline complementary study designs needed to test CBD effects, together with challenges and special considerations related to each design.
Methods
This review integrates empirical findings related to CBD's effects on mental health outcomes with the literature on intervention trial design and current legal regulations pertaining to CBD.
Conclusion
Complementary controlled and observational studies of CBD are necessary to substantiate claims of mental health benefits, including for clinical depression and in pediatric populations. Investigators must consider challenges and opportunities specific to CBD as an intervention, including legal regulations, commercial or pharmaceutical product choice, dosing and bioavailability, and safety.
Cannabis enjoyed a “golden age” as a medicinal product in the late 19th, early 20th century, but the increased risk of overdose and abuse led to its criminalization. However, the 21st century have witnessed a resurgence of interest and a large body of literature regarding the benefits of cannabinoids have emerged. As legalization and decriminalization have spread around the world, cancer patients are increasingly interested in the potential utility of cannabinoids. Although eager to discuss cannabis use with their oncologist, patients often find them to be reluctant, mainly because clinicians are still not convinced by the existing evidence-based data to guide their treatment plans. Physicians should prescribe cannabis only if a careful explanation can be provided and follow up response evaluation ensured, making it mandatory for them to be up to date with the positive and also negative aspects of the cannabis in the case of cancer patients. Consequently, this article aims to bring some clarifications to clinicians regarding the sometimes-confusing various nomenclature under which this plant is mentioned, current legislation and the existing evidence (both preclinical and clinical) for the utility of cannabinoids in cancer patients, for either palliation of the associated symptoms or even the potential antitumor effects that cannabinoids may have.
Cannabidiol (CBD) is a non-psychoactive phytocannabinoid from Cannabis. It is already approved for treating some forms of epilepsy, and there is growing evidence suggesting the therapeutic potential of CBD in relation to many other diseases of the central nervous system. At the same time, at least in several countries use of CBD for medicinal and even research purposes is complicated or not possible due to legal restrictions that are mostly related to a source of CBD. Therefore, identification of alternative natural source of CBD may have important implications. In this context, the presence of CBD-like compound in fibers and seeds of flax (Styrczewska et al. 2012), with at least several characteristics similar to that of CBD, seems to be significant. Here some details/concerns regarding flax as a potential natural source of CBD are discussed.
It is concluded that addressing scientific questions related to occurrence of CBD-like compound in flax may have potentially important implications, including implications related to treatment of diseases of the central nervous system. For instance, given that CBD-like compound in flax is indeed CBD, it could be used for medicinal purposes in countries with legal restrictions on cannabis/hemp. Other potentially useful implications also cannot be excluded. For instance, given that the compound found in flax is CBD, its levels appear to be sufficient for CBD-containing dietary products. At the same time, before proceeding with these issues, exact nature of CBD-like compound in flax should be firmly determined.
Medicinal and aromatic plants have been one of the most important sources of medicine since the dawn of human civilization. Indigenous communities have used products from these plants in different conditions throughout history. Cannabis sativa L. is one of the most widely employed herbaceous medicinal plants for textiles, and fibers, in medicine, as a source of food, animal food, animal bedding, and agriculture for seeds. This paper highlights the traditional applications, botany, phytochemistry, and pharmacological properties of C. sativa. Extensive database retrieval, such as Google Scholar, Semantic Scholar, ResearchGate, Academia.edu, PubMed, SciFinder, ChemSpider, CNKI, PubFacts was performed using the keywords “Hemp” and “Cannabis,” as well as the scientific name of this plant species (Cannabis sativa). Besides, reviews of relevant textbooks, documents, and patents were also employed to collect sufficient information. This study revealed numerous pharmacological activities of C. sativa that could help with several health issues. Additionally, more than 565 bioactive constituents have been isolated and identified from diverse parts of C. sativa. This could help discover potential therapeutic effects and develop new medications to benefit human health.
Cannabis is one of the oldest crops grown, traditionally held religious attachments in various cultures for its medicinal use much before its introduction to Western medicine. Multiple preclinical and clinical investigations have explored the beneficial effects of cannabis in various neurocognitive and neurodegenerative diseases affecting the cognitive domains. Tetrahydrocannabinol (THC), the major psychoactive component, is responsible for cognition-related deficits, while cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been shown to elicit neuroprotective activity. In the present integrative review, the authors focus on the effects of cannabis on the different cognitive domains, including learning, consolidation, and retrieval. The present study is the first attempt in which significant focus has been imparted on all three aspects of cognition, thus linking to its usage. Furthermore, the investigators have also depicted the current legal position of cannabis in India and the requirement for reforms.
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Introdução: A ansiedade é caracterizada como uma emoção da vivência humana, sendo uma reação natural e fundamental à autopreservação, mesmo gerando sensações de apreensão e alterações físicas desagradáveis. A insônia, por sua vez, se caracteriza como um distúrbio do sono comum que pode se apresentar isoladamente ou em conjunto a outras condições médicas ou psiquiátricas. Tendo em vista estas comorbidades, o canabidiol (CBD) é um composto químico não alucinogênico, derivado da planta Cannabis sativa, com um novo papel no controle da ansiedade e insônia. Assim, tendo em vista a alta a prevalência dos transtornos de ansiedade e insônia, e nos prejuízos que esses quadros podem gerar na vida dos indivíduos, fazem-se necessárias investigações sobre o tema para a condução de tratamentos adequados. Logo, este estudo tem como premissa, discorrer sobre o uso de canabidiol no tratamento de ansiedade e insônia. Métodos: Trata de uma revisão de literatura com a finalidade de reunir e sintetizar o conteúdo acerca do uso terapêutico do canabidiol nos transtornos de ansiedade e insônia. Foram consideradas produções científicas realizadas com grupos de seres humanos e estudos de literaturas publicadas entre 2010 e 2020. O levantamento bibliográfico foi realizado nas seguintes bases de dados: Scientific Electronic Library Online (SciELO), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) e Medical Literature Analysis and Retrieval System Online (MEDLINE). Resultados: Foram selecionadas as publicações mais relevantes, restando apenas 32 artigos utilizados nesta revisão de literatura. Entre os artigos analisados, notou-se um grande número de publicações de países desenvolvidos e que já possuem há mais tempo a legalização do comércio e uso recreativo do canabidiol. Ressalta-se que boa parte dos estudos brasileiros são compostos de experiências regionais. Conclusão: O canabidiol é comumente considerado um auxílio para manejo da ansiedade e de distúrbios do sono, no entanto, não há estudos publicados até o momento avaliando seus efeitos sobre o sono em pessoas com transtorno de insônia crônica confirmado. Dado o crescente interesse do consumidor e a expansão da prescrição legal de CBD em todo o mundo, é importante compreender melhor como os medicamentos à base de canabidiol afetam a ansiedade e o sono, bem como a funcionalidade do paciente antes de se tornarem uma intervenção de rotina na prática clínica.
Introduction
A common side effect of cannabidiol is drowsiness, which could impact safe driving. This study's purpose was to determine feasibility and whether cannabidiol impacts simulated driving performance.
Methods
This was a randomized, parallel-group, sex-stratified, double-blind, pilot trial which consisted of a volunteer sample of healthy, currently driving, college students. Participants were randomized and allocated to receive placebo (N=19) or 300 mg cannabidiol (N=21) via oral syringe. Participants completed a ∼40-minute driving simulation. A post-test survey assessed acceptability. The primary outcomes were mean standard deviation of lateral position, total percent time the individual drove outside travel lanes, total collisions, time to initial collision, and mean brake reaction time. Outcomes were compared between groups using Student's T-tests and Cox proportional hazards models.
Results
None of the relationships were statistically significant, but the study was underpowered. Those receiving cannabidiol experienced slightly more collisions (0.90 vs 0.68, p=0.57), had slightly higher mean standard deviation of lateral position, and slower brake reaction times (0.60 vs. 0.58 seconds, p=0.61) compared to placebo. Participants were satisfied with their experience.
Conclusions
The design was feasible. Larger trials may be warranted as it is unclear whether the small differences in performance seen in CBD group were clinically relevant.
Objective
A single administration of cannabidiol (CBD) can reduce anxiety during social anxiety inductions. No study, however, has evaluated the impact of CBD on fear responding among humans.
Method
A double-blind, randomized, placebo-controlled trial was undertaken to address this gap in the literature. Specifically, the current study tested a single oral administration of CBD (either 150 mg, 300 mg, or 600 mg), compared to placebo, for reducing fear reactivity to a well-established 5-min administration of 10% carbon dioxide (CO2)-enriched air biological challenge. CBD was administered 90 min prior to the challenge. Participants were 61 healthy young adults who self-reported fear continuously during the challenge. Heart rate also was continuously monitored, and panic symptoms were self-reported using the Diagnostic Sensations Questionnaire immediately following the procedure.
Results
Results indicated no effect of condition on self-reported fear, panic symptoms, or heart rate.
Conclusion
This is the first study to document that CBD does not reduce fear reactivity in humans, thereby representing an important extension to research on the effects of CBD.
Neuropathic pain is experienced due to injury to the nerves, underlying disease conditions or toxicity induced by chemotherapeutics. Multiple factors can contribute to neuropathic pain such as central nervous system (CNS)-related autoimmune and metabolic disorders, nerve injury, multiple sclerosis and diabetes. Hence, development of pharmacological interventions to reduce the drawbacks of existing chemotherapeutics and counter neuropathic pain is an urgent unmet clinical need. Cannabinoid treatment has been reported to be beneficial for several disease conditions including neuropathic pain. Cannabinoids act by inhibiting the release of neurotransmitters from presynaptic nerve endings, modulating the excitation of postsynaptic neurons, activating descending inhibitory pain pathways, reducing neural inflammation and oxidative stress and also correcting autophagy defects. This review provides insights on the various preclinical and clinical therapeutic applications of cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) in various diseases and the ongoing clinical trials for the treatment of chronic and acute pain with cannabinoids. Pharmacological and genetic experimental strategies have well demonstrated the potential neuroprotective effects of cannabinoids and also elaborated their mechanism of action for the therapy of neuropathic pain.
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.
Depression and anxiety disorders are two of the most common and growing mental health concerns in adolescents. Consequently, antidepressant medication (AD) use has increased widely during the last decades. Several classes of antidepressants are used mainly to treat depression, anxiety, and obsessive-compulsive disorders by targeting relevant brain neurochemical pathways. Almost all randomized clinical trials of antidepressants examined patients with no concomitant medications or drugs. This does not address the expected course of therapy and outcome in cannabis users. Cannabis is the most commonly used illicit substance globally. Substantial changes in its regulation are recently taking place. Many countries and US states are becoming more permissive towards its medical and recreational use. The psychological and physiological effects of cannabis (mainly of its major components, tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been extensively characterized. Cannabis use can be a risk factor for depressive and anxiety symptoms, but some constituents or mixtures may have antidepressant and/or anxiolytic potential. The aim of this literature review is to explore whether simultaneous use of AD and cannabis in adolescence can affect AD treatment outcomes. Based on the current literature, it is reasonable to assume that antidepressants are less effective for adolescents with depression/anxiety who frequently use cannabis. The mechanisms of action of antidepressants and cannabis point to several similarities and conjunctions that merit future investigation regarding the potential effectiveness of antidepressants among adolescents who consume cannabis regularly.
Major depressive disorder is a high-impact, debilitating disease and it is currently considered the most prevalent mental illness. It is associated with disability, as well as increased morbidity and mortality. Despite its significant repercussions in our society, its exact pathophysiology remains unclear and therefore, available antidepressant treatment options are limited and, in some cases, ineffective. In the past years, research has focused on the development of a multifactorial theory of depression. Simultaneously, evidence supporting the role of the endocannabinoid system in the neurobiology of neuropsychiatric diseases has emerged. Studies have shown that the endocannabinoid system strongly impacts neurotransmission, and the neuroendocrine and neuroimmune systems, which are known to be dysfunctional in depressive patients. Accordingly, common antidepressants were shown to have a direct impact on the expression of cannabinoid receptors throughout the brain. Therefore, the relationship between the endocannabinoid system and major depressive disorder is worth consideration. Nevertheless, most studies focus on smaller pieces of what is undoubtedly a larger mosaic of interdependent processes. Therefore, the present review summarizes the existing literature regarding the role of the endocannabinoid system in depression aiming to integrate this information into a holistic picture for a better understanding of the relationship between the two.
The endocannabinoid system (ECS) is a widespread cell signaling network that maintains homeostasis in response to endogenous and exogenous stressors. This has made the ECS an attractive therapeutic target for various disease states. The ECS is a well-known target of exogenous phytocannabinoids derived from cannabis plants, the most well characterized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, the therapeutic efficacy of cannabis products comes with a risk of toxicity and high abuse potential due to the psychoactivity of THC. CBD, on the other hand, is reported to have beneficial medicinal properties including analgesic, neuroprotective, anxiolytic, anticonvulsant, and antipsychotic activities, while apparently lacking the toxicity of THC. Nevertheless, not only is the currently available scientific data concerning CBD’s efficacy insufficient, there is also ambiguity surrounding its regulatory status and safety in humans that brings inherent risks to manufacturers. There is a demand for alternative compounds combining similar effects with a robust safety profile and regulatory approval. Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator, primarily known for its anti-inflammatory, analgesic and neuroprotective properties. It appears to have a multi-modal mechanism of action, by primarily activating the nuclear receptor PPAR-α while also potentially working through the ECS, thus targeting similar pathways as CBD. With proven efficacy in several therapeutic areas, its safety and tolerability profile and the development of formulations that maximize its bioavailability, PEA is a promising alternative to CBD.
Background: Nearly one-third of American adults receive an anxiety disorder diagnosis in their lifetimes. Although evidence-based anxiety interventions exist, these treatments might have limited availability and efficacy. Though preliminary evidence supports the use of cannabidiol (CBD) to alleviate anxiety, no prior work investigates individuals’ expectancies about CBD’s impact on anxiety.
Methods: The present study examines relevant anxiety symptoms and expectancies about CBD’s effects in a sample of 455 CBD-using adults recruited from Amazon’s MTurk platform.
Results: Participants reported moderate anxiety without the influence of CBD. Moreover, they expected global and symptom-level anxiolytic effects of CBD. Anxiety scores positively covaried with usual cannabis intoxication, providing support for a self-medication hypothesis. Results revealed a positive relation between anxiety symptoms and expectancies about CBD’s anxiolytic properties; those who were most anxious expected more CBD-related relief. CBD consumption decreased as age increased, but showed little variation with other demographic variables.
Conclusions: Overall, individuals appear to hold positive expectancies about CBD’s anxiolytic potential. Results support placebo-controlled randomized clinical trials for CBD as an anxiolytic.
inner ear immunology in vestibular migraine and meniere disease, difrential proinflammatory profile
Introduction:
Cannabidiol (CBD) can be isolated from Cannabis sativa L. or synthetically produced. The aim of this study was to compare the in vitro effects of purified natural and synthetic CBD to establish any pharmacological differences or superiority between sources.
Methods:
Six purified samples of CBD were obtained, 4 of these were natural and 2 synthetic. The anticancer effects of CBD were assessed in a human ovarian cancer cell line (SKOV-3 cells). The neuroprotective effects of CBD were assessed in human pericytes in a model of stroke (oxygen glucose deprivation [OGD]). The ability of CBD to restore inflammation-induced intestinal permeability was assessed in differentiated human Caco-2 cells (a model of enterocytes).
Results:
(1) In proliferating and confluent SKOV-3 cells, all CBD samples similarly reduced resazurin metabolism as a marker of cell viability in a concentration-dependent manner (p < 0.001). (2) In pericytes exposed to OGD, all CBD samples similarly reduced cellular damage (measured by lactate dehydrogenase) at 24 h by 31-48% and reduced inflammation (measured by IL-6 secretion) by 30-53%. Attenuation of IL-6 was inhibited by 5HT1A receptor antagonism for all CBD sources. (3) In differentiated Caco-2 cells exposed to inflammation (TNFα and IFNγ, 10 ng/mL for 24 h), each CBD sample increased the speed of recovery of epithelial permeability compared to control (p < 0.05-0.001), which was inhibited by a CB1 receptor antagonist.
Conclusion:
Our results suggest that there is no pharmacological difference in vitro in the antiproliferative, anti-inflammatory, or permeability effects of purified natural versus synthetic CBD. The purity and reliability of CBD samples, as well as the ultimate pharmaceutical preparation, should all be considered above the starting source of CBD in the development of new CBD medicines.
Uncontrolled stress can lead to vascular injury, hypertension, arrhythmia, compromised immune system alteration in microbiota activity, and neurobehavioral changes, including depression. The gut microbiota has been recently developed, not only for major depressive disorders but also cardiovascular problems, as a therapeutic concern. Since then, >100 studies have studied the link between depression and cardiovascular disease (CVD), and have shown that depression is common (≈20%–35%) in patients with CVD, and seems to be indicative of negative heart effects in patients. Depressive symptoms patients have demonstrated an elevated platelet reactivity, reduced cardiac variability, and enhanced proinflammatory signals, which are all cardiovascular‐related risk factors. The pathophysiology of depression‐related CVD is nevertheless a challenge because of the heterogeneous depressive syndromes and the etiologies. The cardiovascular effects of tetrahydrocannabinol (THC) (the key psychotropic credential of cannabis) and endocannabinoids (THC endogenous equivalents which cause type 1 [CB1] and 2 [CB2] cannabinoids) have been extensively examined based on well‐documented effects of marijuana smoke on blood pressure (BP) and heart rate (HR). Therefore, the aim of the review article is to establish the relationship of abnormal cannabidiols system‐mediated cardiovascular protection in disrupted gut/brain axis associated depression to determine the translational potential of targeting abnormal cannabidiols receptors in clinical studies.
O objetivo do trabalho foi testar a hipótese de que a interpretação do tempo de imobilidade (desamparo aprendido ou adaptação) pode variar conforme o modelo utilizado (teste da natação forçada ou estresse por natação). Foram analisados o tempo de imobilidade (TI) e a mobilização de glicogênio de ratos submetidos à natação em dois protocolos: estresse por natação (EN) e teste da natação forçada (TNF). Também comparamos os efeitos da desipramina e diazepam. Os experimentos foram filmados para análise do TI. Os ratos, após a sessão de natação, foram sacrificados e amostras do fígado e músculos foram preparadas para quantificação do glicogênio. O TI foi menor no EN comparado ao TNF (p=0,001). As concentrações de glicogênio hepático dos grupos foram diferentes entre si (controle>EN>TNF; p<0,05). Nos músculos gastrocnêmio e sóleo, as concentrações de glicogênio foram menores no EN comparado ao controle e TNF (p<0,05). O TI do grupo tratado com desipramina e diazepam também foi mensurado. A desipramina diminuiu o TI no TNF, sem alterá-lo no EN. O diazepam aumentou o TI no EN sem alteração no TNF. Concluímos que o EN e o TNF induziram respostas fisiológicas e comportamentais distintas e representam situações diferentes para o animal.
This paper aimed to characterize psychological factors as anxiety and depression in a sample of patients classified as carring psychological factors that affect medical conditions. It was subjects of the investigation: 30 patients that sought a general hospital localized in the suburban area of São Paulo city south zone, of both sexes that was framed in classification above. It was utilized Factorial Scale of Emotional Adjustment/Neuroticism (EFN), developed by Hutz & Nunes (2001). As principal results it has been found: 36,67% of the subjects above the average and 16,67% much above the average, in sub-scale of anxiety, and 43,33% above the average and 36,67% much above the average, in sub-scale of depression.
The aim of this study was to investigate the as- sociation between depression and clinical illness among a group of elderly in the city of Salvador, Bahia, Brazil. The study population included 1,120 individuals over 60 years of age treated at a geriatric outpatient clinic. Crude and strati- fied prevalence ratios were calculated. Data were stratified by gender, age, and nutritional status. Ninety-five percent of the sample pre- sented at least one chronic disease, the most fre- quent being hypertension (62.2%), osteoarthritis (40%), and urinary incontinence (35%). Depres- sion was diagnosed in 23.4%, more commonly among women (PR = 1.28; 95%CI: 0.99-1.65) and those under 75 years (PR = 1.24; 95%CI: 1.00-1.53). There was an association between number of chronic diseases (> 3) and depres- sion (PR = 1.31; 95%CI: 1.04-1.66). Parkinson's disease was associated with depression, more evident among females (PR = 1.59; 95%CI: 1.05- 2.41) and in the 70-79-year age group (PR = 2.02; 95%CI: 1.28-3.20). The study demonstrates an association between depression and chronic co- morbidity. Since many elderly present multiple chronic diseases, health professionals should be alert to the possibility of depressive symptoms in these patients. Aged; Aging Health; Chronic Disease; Depression Introdução
O objetivo do trabalho foi testar a hipótese de que a interpretação do tempo de imobilidade (desamparo aprendido ou adaptação) pode variar conforme o modelo utilizado (teste da natação forçada ou estresse por natação). Foram analisados o tempo de imobilidade (TI) e a mobilização de glicogênio de ratos submetidos à natação em dois protocolos: estresse por natação (EN) e teste da natação forçada (TNF). Também comparamos os efeitos da desipramina e diazepam. Os experimentos foram filmados para análise do TI. Os ratos, após a sessão de natação, foram sacrificados e amostras do fígado e músculos foram preparadas para quantificação do glicogênio. O TI foi menor no EN comparado ao TNF (p=0,001). As concentrações de glicogênio hepático dos grupos foram diferentes entre si (controle>EN>TNF; p<0,05). Nos músculos gastrocnêmio e sóleo, as concentrações de glicogênio foram menores no EN comparado ao controle e TNF (p<0,05). O TI do grupo tratado com desipramina e diazepam também foi mensurado. A desipramina diminuiu o TI no TNF, sem alterá-lo no EN. O diazepam aumentou o TI no EN sem alteração no TNF. Concluímos que o EN e o TNF induziram respostas fisiológicas e comportamentais distintas e representam situações diferentes para o animal.
Rationale:
Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that promotes antianxiety and anti-panic effects in animal models after acute systemic or intra-dorsal periaqueductal gray (DPAG) administration. However, the effects of CBD repeated administration, and the possible mechanisms involved, in animal models of anxiety- and panic-related responses remain poorly understood.
Objective:
The present study evaluates the role of the serotonergic neurotransmission within the DPAG in the modulation of escape responses of rats chronically treated with CBD.
Methods:
Male Wistar rats received acute or repeated (5 mg/Kg/daily/21 days) administration of CBD and were submitted to the elevated T-maze (ETM). We also investigated if CBD effects on the ETM depend on facilitation of 5-HT1A-mediated neurotransmission in the DPAG. To this latter aim, we verified if these effects would be prevented by intra-DPAG injection of the 5-HT1A receptor antagonist WAY100635 (0.37 nmol/0.2 μL). Also, we verified, by in vivo microdialysis, if CBD chronic treatment increases serotonin (5-HT) release and, by quantitative polymerase chain reaction, if there are changes in 5HT-1A or 5HT-2C mRNA expression in DPAG.
Results:
The results showed that repeated but not acute peripheral administration of CBD decreases escape responses in the ETM, suggesting a panicolytic effect. This treatment did not change 5HT-1A or 5-HT-2C receptor mRNA expression nor modify serotonin extracellular concentrations in the DPAG. CBD effects were prevented by DPAG injection of the 5-HT1A receptor antagonist.
Conclusions:
Together, these findings suggest that repeated treatment with CBD induces anti-panic effects by acting on 5-HT1A receptors in DPAG.
Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.
To review and describe studies of the non-psychotomimetic constituent of Cannabis sativa, cannabidiol (CBD), as an anxiolytic drug and discuss its possible mechanisms of action.
The articles selected for the review were identified through searches in English, Portuguese, and Spanish in the electronic databases ISI Web of Knowledge, SciELO, PubMed, and PsycINFO, combining the search terms "cannabidiol and anxiolytic", "cannabidiol and anxiolytic-like", and "cannabidiol and anxiety". The reference lists of the publications included, review articles, and book chapters were handsearched for additional references. Experimental animal and human studies were included, with no time restraints.
Studies using animal models of anxiety and involving healthy volunteers clearly suggest an anxiolytic-like effect of CBD. Moreover, CBD was shown to reduce anxiety in patients with social anxiety disorder.
Future clinical trials involving patients with different anxiety disorders are warranted, especially of panic disorder, obsessive-compulsive disorder, social anxiety disorder, and post-traumatic stress disorders. The adequate therapeutic window of CBD and the precise mechanisms involved in its anxiolytic action remain to be determined.
Several pharmacological targets have been proposed as modulators of panic-like reactions. However, interest should be given to other potential therapeutic neurochemical agents. Recent attention has been given to the potential anxiolytic properties of cannabidiol, because of its complex actions on the endocannabinoid system together with its effects on other neurotransmitter systems. The aim of this study was to investigate the effects of cannabidiol on innate fear-related behaviors evoked by a prey vs predator paradigm. Male Swiss mice were submitted to habituation in an arena containing a burrow and subsequently pre-treated with intraperitoneal administrations of vehicle or cannabidiol. A constrictor snake was placed inside the arena, and defensive and non-defensive behaviors were recorded. Cannabidiol caused a clear anti-aversive effect, decreasing explosive escape and defensive immobility behaviors outside and inside the burrow. These results show that cannabidiol modulates defensive behaviors evoked by the presence of threatening stimuli, even in a potentially safe environment following a fear response, suggesting a panicolytic effect.
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.
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.
To perform an update on cannabis abuse by patients with psychiatric disorders.
A search was performed in the electronic databases Medline, The Cochrane Library Database, Lilacs, PubMed, and SciELO, using the keywords 'marijuana abuse', 'cannabis abuse', 'psychiatric disorders', and 'mental disorders'. Articles published until December 2009, dealing with cannabis abuse and dependence in association with other psychiatric disorders were included.
Cannabis abuse was found to be associated with increased risk for the onset of schizophrenia and chronic psychotic symptoms, although these findings require confirmation from additional research. Cannabis seems to be one of the drugs of choice of individuals with bipolar disorder, despite evidence that manic states can be induced by its use. Cannabis abuse also occurs frequently in individuals with anxiety disorders, but the relationship between the chronic nature of these conditions and the use of marijuana remains uncertain. In respect to depression, there is no clear evidence to date that depressive patients use cannabis as a form of self-medication. In individuals with psychiatric disorders, the use of cannabis has been associated with increased positive symptoms, additional negative symptoms in the course of illness, impaired treatment compliance, and more hospitalizations.
The abuse of cannabis by patients with psychiatric disorders such as schizophrenia and mood and anxious disorders has a negative impact both in the acute and advanced stages of these conditions, although further investigation on this association is still necessary.
Anxiety reactions and panic attacks are the acute symptoms most frequently associated with cannabis use. Understanding the relationship between cannabis and anxiety may clarify the mechanism of action of cannabis and the pathophysiology of anxiety. Aims of the present study were to review the nature of the relationship between cannabis use and anxiety, as well as the possible clinical, diagnostic and causal implications.
Systematic review of the Medline, PsycLIT and EMBASE literature.
Frequent cannabis users consistently have a high prevalence of anxiety disorders and patients with anxiety disorders have relatively high rates of cannabis use. However, it is unclear if cannabis use increases the risk of developing long-lasting anxiety disorders. Many hypotheses have been proposed in an attempt to explain these relationships, including neurobiological, environmental and social influences.
The precise relationship between cannabis use and anxiety has yet to be established. Research is needed to fully clarify the mechanisms of such the association.
Este artigo revê o conceito de depressão e a nosologia contemporânea dos estados depressivos e seus diferentes subtipos. São discutidos aspectos relativos ao curso (formas agudas vs crônicas da doença, padrão sazonal), características fenomenológicas (melancolia, quadros psicóticos, quadros atípicos, formas catatônicas) da doença, assim como a importância e o significado das alterações psicomotoras para o diagnóstico das chamadas depressões "endógenas" ou "vitais", de acordo com trabalhos contemporâneos (como os de Parker e Widlöcher). Este trabalho aborda também as fronteiras da depressão com o transtorno bipolar, os transtornos de personalidade, a desmoralização e os estados de luto normal, assim como os limites com outras doenças e estados induzidos por drogas.
The present study investigated the central effects of the eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid cannabidiol (CBD) on the extinction of contextual fear memories in rats. Rats were conditioned and 24 h later subjected to three consecutive 9-min non-reinforced exposures to the conditioning context (extinction sessions, 24 h intervals). AM404 or CBD was injected i.c.v. 5 min before each extinction session and a 3-min drug-free test of contextual memory was performed 24 h after the last extinction session. AM404 (1.0 microg/microl, i.c.v.) and CBD (2.0 microg/microl, i.c.v.) facilitated extinction of contextual fear memory, with persistent effects. These responses were antagonized by the CB1-selective antagonist SR141716A (0.2 mg/kg, i.p.), but not by the TRPV1-selective antagonist capsazepine (5.0 microg/microl, i.c.v.). The effect of the anxiolytic drug Diazepam (DZP) on the extinction of contextual fear memory was also investigated. In contrast with the CBD and AM404 results, DZP induced a general reduction in the expression of conditioned freezing. Both AM404 and CBD induced anti-anxiogenic effect in the fear-potentiated plus-maze test, whereas DZP was anxiolytic in conditioned and unconditioned rats. In conclusion, CBD, a non-psychoactive phytocannabinoid could be an interesting pharmacological approach to reduce the anxiogenic effects of stress and promote the extinction of fear memories.
In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.
The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.
Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB. Recent work has looked beyond hippocampus to other brain areas that are also likely involved. For example, nucleus accumbens, amygdala, and certain hypothalamic nuclei are critical in regulating motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed patients. A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome. These advances will fundamentally improve the treatment and prevention of depression.
The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of ∆9-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5mg/kg, i.p.), both ∆9-THC and ∆8-THC showed a U-shaped dose response with only ∆9-THC showing significant antidepressant-like effects at 2.5mg/kg (p
The medical properties of cannabis have been known for many centuries; its first documented use dates back to 2800 BC when it was described for its hallucinogenic and pain-relieving properties. In the first half of the twentieth century, a number of pharmaceutical companies marked cannabis for indications such as asthma and pain, but since then its use has sharply declined, mainly due to its unpredictable effects, but also for socio-political issues. Recently, great attention has been directed to the medical properties of phytocannabinoids present in the cannabis plant alongside the main constituent Δ9-Tetrahydrocannabinol (THC); these include cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). Evidence suggests an association between cannabis and schizophrenia: schizophrenics show a higher use of marijuana as compared to the healthy population. Additionally, the use of marijuana can trigger psychotic episodes in schizophrenic patients, and this has been ascribed to THC. Given the need to reduce the side effects of marketed antipsychotics, and their weak efficacy on some schizophrenic symptoms, cannabinoids have been suggested as a possible alternative treatment for schizophrenia. CBD, a non-psychoactive constituent of the Cannabis sativa plant, has been receiving growing attention for its anti-psychotic-like properties. Evidence suggests that CBD can ameliorate positive and negative symptoms of schizophrenia. Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia.
Posttraumatic stress disorder (PTSD) is an incapacitating syndrome that follows a traumatic experience. Predator exposure promotes long-lasting anxiogenic effect in rodents, an effect related to symptoms found in PTSD patients. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa with anxiolytic effects. The present study investigated the anti-anxiety actions of CBD administration in a model of PTSD. Male Wistar rats exposed to a predator (cat) received, 1 h later, singled or repeated i.p. administration of vehicle or CBD. Seven days after the stress animals were submitted to the elevated plus maze. To investigate the involvement of 5HT1A receptors in CBD effects animals were pre-treated with WAY100635, a 5HT1A receptor antagonist. To explore possible neurobiological mechanisms involved in these effects, 5HT1A receptor mRNA and BDNF protein expression were measured in the hippocampus, frontal cortex, amygdaloid complex and dorsal periaqueductal gray. Repeated administration of CBD prevented long-lasting anxiogenic effects promoted by a single predator exposure. Pretreatment with WAY100635 attenuated CBD effects. Seven days after predator exposure 5HT1A mRNA expression was up regulated in the frontal cortex and hippocampus. CBD and paroxetine failed to prevent this effect. No change in BDNF expression was found. In conclusion, predator exposure promotes long-lasting up-regulation of 5HT1A receptor gene expression in the hippocampus and frontal cortex. Repeated CBD administration prevents the long-lasting anxiogenic effects observed after predator exposure probably by facilitating 5HT1A receptors neurotransmission. Our results suggest that CBD has beneficial potential for PTSD treatment and that 5HT1A receptors could be a therapeutic target in this disorder.
Réus GZ, Stringari RB, Ribeiro KF, Luft T, Abelaira HM, Fries GR, Aguiar BW, Kapczinski F, Hallak JE, Zuardi AW, Crippa JA, Quevedo J. Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala.
Objective: Cannabidiol is a chemical constituent from Cannabis sativa and it has multiple mechanisms of action, including antidepressant effects. The main objective of the present study was to evaluate behavioural and molecular effects induced by administration of cannabidiol and imipramine in rats.
Methods: In the present study, rats were acutely or chronically treated for 14 days once a day with saline, cannabidiol (15, 30 and 60 mg/kg) or imipramine (30 mg/kg) and the animals behaviour was assessed in forced swimming and open-field tests. Afterwards, the prefrontal cortex, hippocampus and amygdala brain-derived neurotrophic factor (BDNF) levels were assessed by enzyme-linked immunosorbent sandwich assay.
Results: We observed that both acute and chronic treatments with imipramine at the dose of 30 mg/kg and cannabidiol at the dose of 30 mg/kg reduced immobility time and increased swimming time; climbing time was increased only with imipramine at the dose of 30 mg/kg, without affecting locomotor activity. In addition, chronic treatment with cannabidiol at the dose of 15 mg/kg and imipramine at the dose of 30 mg/kg increased BDNF levels in the rat amygdala.
Conclusion: In conclusion, our results indicate that cannabidiol has an antidepressant-like profile and could be a new pharmacological target for the treatment of major depression.
Objectives:
Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol (CBD), a non-psychotomimetic compound of the Cannabis sativa plant, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. The aim of this study is to evaluate the effects of CBD and rimonabant (CB1 receptor antagonist) on the contextual fear conditioning in SHR and Wistar rats (WR).
Methods:
Rats were submitted to CFC task after treatment with different doses of CBD (experiment 1) and rimonabant (experiment 2).
Results:
In experiment 1, SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg CBD. Moreover, all CBD-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant.
Discussion:
Our results suggest a potential therapeutical effect of CBD and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of CBD.
Several pre-clinical and human-based studies have shown that acutely administered cannabidiol (CBD) can produce anxiolytic-like effects
The present study investigated the effects of chronic administration of CBD on rat behaviour and on the expression of brain proteins.
Male Lister-hooded rats (150-200 g, n = 8 per group) received daily injections of CBD (10 mg/kg, i.p.) for 14 days. The rats were subjected to two behavioural tests: locomotor activity and conditioned emotional response (CER). The expression of brain-derived neurotrophic factor (BDNF), its receptor tyrosine kinase B (Trk B), extracellular signal-regulated kinases (ERK1/2) and phospho-ERK1/2 and the transcription factor cyclic AMP response element binding protein activation (CREB) and phospho-CREB were determined in brain regions such as the frontal cortex and hippocampus using Western immunoblotting.
CBD significantly increased the time spent freezing in the CER test with no effect on locomotor activity. CBD significantly reduced BDNF expression in the hippocampus and frontal cortex with no change in the striatum. In addition, CBD significantly reduced TrkB expression in the hippocampus with a strong trend towards reduction in the striatum but had no effect in the frontal cortex. In the hippocampus, CBD had no effect on ERK1/2 or phospho-ERK2, but in the frontal cortex, CBD significantly reduced phospho-ERK1/2 expression without affecting total ERK.
Chronic administration of CBD produced an anxiogenic-like effect in clear opposition to the acute anxiolytic profile previously reported. In addition, CBD decreased the expression of proteins that have been shown to be enhanced by chronic treatment with antidepressant/anxiolytic drugs.
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects in rodents and humans after systemic administration. Previous results from our group showed that CBD injection into the bed nucleus of the stria terminalis (BNST) attenuates conditioned aversive responses. The aim of this study was to further investigate the role of this region on the anxiolytic effects of the CBD. Moreover, considering that CBD can activate 5-HT1A receptors, we also verified a possible involvement of these receptors in those effects.
Male Wistar rats received injections of CBD (15, 30, or 60 nmol) into the BNST and were exposed to the elevated plus-maze (EPM) or to the Vogel conflict test (VCT), two widely used animal models of anxiety.
CBD increased open arms exploration in the EPM as well as the number of punished licks in the VCT, suggesting an anxiolytic-like effect. The drug did not change the number of entries into the enclosed arms of the EPM nor interfered with water consumption or nociceptive threshold, discarding potential confounding factors in the two tests. Moreover, pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.37 nmol) blocked the effects of CBD in both models.
These results give further support to the proposal that BNST is involved in the anxiolytic-like effects of CBD observed after systemic administration, probably by facilitating local 5-HT1A receptor-mediated neurotransmission.
Activation of 5-HT1A receptors in the dorsal periaqueductal gray (dPAG) impairs escape behavior, suggesting a panicolytic-like effect. Cannabidiol (CBD), a major non-psychotomimetic compound present in Cannabis sativa, causes anxiolytic-like effects after intra-dPAG microinjections by activating 5-HT1A receptors. In the present work we tested the hypothesis that CBD could also impair escape responses evoked by two proposed animal models of panic: the elevated T-maze (ETM) and electric stimulation of dPAG. In experiment 1 male Wistar rats with a single cannula implanted in the dPAG received a microinjection of CBD or vehicle and, 10 min later, were submitted to the ETM and open field tests. In experiment 2 escape electrical threshold was measured in rats with chemitrodes implanted in the dPAG before and 10 min after CBD microinjection. In experiment 3 similar to experiment 2 except that the animals received a previous intra-dPAG administration of WAY-100635, a 5-HT1A receptor antagonist, before CBD treatment. In the ETM microinjection of CBD into the dPAG impaired inhibitory avoidance acquisition, an anxiolytic-like effect, and inhibited escape response, a panicolytic-like effect. The drug also increased escape electrical threshold, an effect that was prevented by WAY-100635. Together, the results suggest that CBD causes panicolytic effects in the dPAG by activating 5-HT1A receptors.
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic- and antipsychotic-like effects in animal models. Effects of CBD may be mediated by the activation of 5-HT(1A) receptors. As 5-HT(1A) receptor activation may induce antidepressant-like effects, the aim of this work was to test the hypothesis that CBD would have antidepressant-like activity in mice as assessed by the forced swimming test. We also investigated if these responses depended on the activation of 5-HT(1A) receptors and on hippocampal expression of brain-derived neurotrophic factor (BDNF).
Male Swiss mice were given (i.p.) CBD (3, 10, 30, 100 mg*kg(-1)), imipramine (30 mg*kg(-1)) or vehicle and were submitted to the forced swimming test or to an open field arena, 30 min later. An additional group received WAY100635 (0.1 mg*kg(-1), i.p.), a 5-HT(1A) receptor antagonist, before CBD (30 mg*kg(-1)) and assessment by the forced swimming test. BDNF protein levels were measured in the hippocampus of another group of mice treated with CBD (30 mg*kg(-1)) and submitted to the forced swimming test.
CBD (30 mg*kg(-1)) treatment reduced immobility time in the forced swimming test, as did the prototype antidepressant imipramine, without changing exploratory behaviour in the open field arena. WAY100635 pretreatment blocked CBD-induced effect in the forced swimming test. CBD (30 mg*kg(-1)) treatment did not change hippocampal BDNF levels.
CBD induces antidepressant-like effects comparable to those of imipramine. These effects of CBD were probably mediated by activation of 5-HT(1A) receptors.
Several studies have shown anxiolytic effects of cannabinoids after systemic or central injections. The periaqueductal gray matter is a midbrain structure involved in the control of anxiety states. Intra-cerebral administration of cannabidiol, a phytocannabinoid, or anandamide, an endocannabinoid, into the dorsolateral portion of periaqueductal gray (dlPAG) promotes anxiolytic-like effects in several animal models of anxiety with bell-shaped dose-response curves. The reasons for these curves are still unclear, but since these drugs can also activate TRPV1 receptors and increase glutamate release, we hypothesized that, at high doses, cannabidiol and WIN 55,212-2, a CB1 receptor agonist, could activate TRPV1 receptors, facilitating glutamate neurotransmission and anxiety responses. To test this hypothesis male Wistar rats with cannulae aimed toward the dlPAG were submitted to the following intra-dlPAG treatments: Experiment 1. Vehicle (0.2 microL) or WIN 55,212-2 (3-30 pmol); Experiment 2. Capsazepine (CPZ, 10 nmol, a TRPV1 receptor antagonist) or vehicle followed, 5 min later, by vehicle or WIN 55, 212-2 (10 or 30 pmol); Experiment 3. CPZ (10 nmol) or vehicle followed, 5 min later, by cannabidiol (30 or 60 nmol). Ten minutes after the last injection the animals were tested in the elevated plus maze (EPM). WIN 55,212-2 and cannabidiol induced anxiolytic effects at lower doses that disappeared at the higher dose. Although CPZ+WIN 10 or CPZ+WIN 30 pmol groups were not different from control (CPZ+V), capsazepine prevented the decrease in open arm exploration caused by the higher of dose of WIN 55,212-2 (30 nmol) relative to the lower dose of WIN 55,212-2 (10 nmol) and, in the case of cannabidiol (60 nmol), increased open arm exploration (V+CBD 60 group versus CPZ+CBD 60 group). These results suggest that TRPV1 receptors in the dlPAG modulate anxiety and that activation of these receptors by high doses of cannabinoids could be involved in the bell-shaped dose-response curves observed with these compounds.
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa which induces anxiolytic- and antipsychotic-like effects in rodents. These effects could be mediated by facilitation of the endocannabinoid system or by the activation of 5-HT(1A) receptors. As either of these mechanisms could promote adaptation to inescapable stress, the aim of the present work was to test the hypothesis that CBD would attenuate the autonomic and behavioural consequences of restraint stress (RS). We also investigated if the responses to CBD depended on activation of 5-HT(1A) receptors.
Male Wistar rats received i.p. injections of vehicle or CBD (1, 10 or 20 mg kg(-1)) and 30 min later were submitted to 60 min of restraint where their cardiovascular responses were recorded. The protocol of the second experiment was similar to the first one except that animals received i.p. injections of the 5-HT(1A) receptor antagonist WAY100635 (0.1 mg kg(-1)) before CBD treatment and exposure to restraint. 24 h later they were also tested in the elevated plus-maze (EPM), an animal model of anxiety.
Exposure to RS increased blood pressure and heart rate and induced an anxiogenic response in the EPM 24 h later. These effects were attenuated by CBD. WAY100635 by itself did not change the cardiovascular and anxiogenic response to RS, but blocked the effects of CBD.
The results suggest that CBD can attenuate acute autonomic responses to stress and its delayed emotional consequences by facilitating 5-HT(1A) receptor-mediated neurotransmission.
The pharmacological profile of cannabidiol (CBD) has several characteristics in common with drugs known to benefit bipolar affective disorder (BAD), leading to the hypothesis that CBD may have therapeutic properties in BAD. Therefore, the aim of the present report was to directly investigate for the first time the efficacy and safety of CBD in two patients with BAD. Both patients met DSM IV criteria for bipolar I disorder experiencing a manic episode without comorbid conditions. This was an inpatient study, and the efficacy, tolerability and side effects were assessed. Both patients received placebo for the initial 5 days and CBD from the 6th to 30th day (initial oral dose of 600 mg reaching 1200 mg/ day). From the 6th to the 20th day, the first patient (a 34-year-old woman) received adjunctive olanzapine (oral dose of 10-15 mg). On day 31, CBD treatment was discontinued and replaced by placebo for 5 days. The first patient showed symptoms improvement while on olanzapine plus CBD, but showed no additional improvement during CBD monotherapy. The second patient (a 36-year-old woman) had no symptoms improvement with any dose of CBD during the trial. Both patients tolerated CBD very well and no side-effects were reported. These preliminary data suggest that CBD may not be effective for the manic episode of BAD.
This report will review the costs, risks, and benefits of potentially useful medications for the treatment of children and adolescents with anxiety disorders and will identify areas where data are limited and additional research is needed.
A Medline-assisted review of the literature was performed. Attention was given to dosage, response, and side effects of medications. Wherever possible, blinded, controlled medication trials in children with anxiety disorders (diagnosed by structured criteria) were targeted for use as the primary references. Relatively few systematic studies were found, so information from open trials and case reports also was included, as were controlled trials in adult populations.
The largest body of work supporting the use of medications for childhood anxiety came from studies of obsessive-compulsive disorder, where clomipramine and fluoxetine have been found effective in systematic studies. In other childhood anxiety disorders, there are conflicting data about the efficacy of medications, such as tricyclic antidepressants, benzodiazepines, serotonin reuptake inhibitors, beta-blockers, and monoamine oxidase inhibitors.
This review of the systematic pharmacological trials for childhood anxiety disorders revealed only 13 controlled studies: 5 for obsessive-compulsive disorder, 4 for school refusal/separation anxiety disorder, and 4 for avoidant/overanxious disorder or mixed diagnostic groups. Medications appear to be helpful for childhood anxiety disorders, although definitive pharmacotherapeutic data are lacking for many conditions. A systematic study of these medications is required to establish safety and efficacy in the pediatric age group. Evolving diagnostic criteria and terminology, the presence of comorbid diagnoses (especially affective disorders), and inadequate medication dosages may be factors hindering research in this field. Until additional research is done, clinicians must carefully consider the relative risk-to-benefit ratio when prescribing these medications.
To critically review the research on anxiety disorders in children and adolescents, focusing on new developments in the past 10 years.
This review includes recent articles which contribute to the conceptualization, assessment, and treatment of childhood anxiety disorders.
Information was organized into a developmental framework. Anxiety disorders research has shown steady progress.
More research is needed, particularly in the areas of neurobiological basis of anxiety disorders, longitudinal studies, and treatment.
Previous studies have shown that infusion of brain-derived neurotrophic factor (BDNF) into the midbrain, near the PAG and dorsal/median raphe nuclei, produced analgesia and increased activity in monoaminergic systems. Alterations in monoaminergic activity have also been implicated in the pathogenesis and treatment of depression. The present studies examined the ability of centrally administered BDNF to produce antidepressant-like activity in two animal models of depression, learned helplessness following exposure to inescapable shock and the forced swim test. In the learned helplessness paradigm, vehicle-infused rats pre-exposed to inescapable shock (veh/shock) showed severe impairments in escape behavior during subsequent conditioned avoidance trials, including a 47% decrease in the number of escapes and a 5 fold increase in escape latency, as compared to vehicle-infused rats which received no pre-shock treatment (veh/no shock). Midbrain BDNF infusion (12-24 micrograms/day) reversed these deficits, and in fact, BDNF-infused rats pre-exposed to inescapable shock (BDNF/shock) showed escape latencies similar to veh/no shock and BDNF/no shock rats. In the forced swim test, BDNF infusion decreased the immobility time by 70% as compared to vehicle-infused controls. Non-specific increases in activity could not account for these effects since general locomotor activity of BDNF- and vehicle-infused animals was not different. These findings demonstrate an antidepressant-like property of BDNF in two animal models of depression, which may be mediated by increased activity in monoaminergic systems.
Late life depression principally affects individuals with other medical and psychosocial problems, including cognitive dysfunction, disability, medical illnesses, and social isolation. The clinical associations of late life depression have guided the development of hypotheses on mechanisms predisposing, initiating, and perpetuating specific mood syndromes. Comorbidity studies have demonstrated a relationship between frontostriatal impairment and late life depression. Further research has the potential to identify dysfunctions of specific frontostriatal systems critical for antidepressant response and to lead to novel pharmacological treatments and targeted psychosocial interventions. The reciprocal interactions of depression with disability, medical illnesses, treatment adherence, and other psychosocial factors complicate the care of depressed older adults. Growing knowledge of the clinical complexity introduced by the comorbidity of late life depression can guide the development of comprehensive treatment models. Targeting the interacting clinical characteristics associated with poor outcomes has the potential to interrupt the spiral of deterioration of depressed elderly patients. Treatment models can be most effective if they focus on amelioration of depressive symptoms, but also on treatment adherence, prevention of relapse and recurrence, reduction of medical burden and disability, and improvement of the quality of life of patients and their families.
Current outcome measures for patients with Behçet's disease (BD) are impairment-focused and do not necessarily take account of the wider impact of the condition on the individual's lifestyle. Our aim was to develop a disease-specific measure of quality of life (QoL) for BD.
The content of the BD-QoL was derived from qualitative interviews with patients using a "needs-based" approach to identify items. A postal survey was used to test the scaling properties, reliability, internal consistency, and validity of the new questionnaire using Rasch analysis. A second postal survey was used to assess test-retest reliability and internal consistency and to provide further evidence of the validity of the questionnaire.
Main themes emerging from the qualitative interviews included relationships, emotions, limitations in day to day activities, and self-image. From these themes 71 statements were chosen as potential items for the BD-QoL. After analysis, 30 items of the BD-QoL emerged free of item bias for age and sex. Fit to the Rasch model was excellent. In the second postal survey test-retest reliability of the 30 item BD-QoL was 0.84.
The BD-QoL provides the clinician with a simple, reliable, and valid tool for assessing the influence of interventions for BD and for evaluating models of service delivery. It is well accepted by patients, and has excellent scaling and psychometric properties. The BD-QoL complements information obtained through BD-specific disease activity scales.
Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa that induces anxiolytic-like effects similar to diazepam in animal models of innate aversive behavior. However, the effects of CBD contextual conditioned fear have not been studied. Therefore, the aim of this work was to compare the behavioral and cardiovascular effects of CBD and diazepam, a prototype anxiolytic, in animals submitted to a contextual conditioned fear paradigm. Male Wistar rats were submitted to a 10min conditioning session (six footshocks, 2.5 mA, 3s, delivered at pseudo-random intervals). The behavioral and cardiovascular responses to the context were measured 24h later in a 10 min test session. Diazepam (2.5 mg/kg), FG-7142 (8 mg/kg), a benzodiazepine inverse agonist, or CBD (10 mg/kg) were administered i.p. before the test session. Conditioned rats submitted to the aversive context exhibited more freezing behavior and a larger increase in blood pressure and heart rate as compared to non-conditioned animals. These effects were attenuated by CBD and diazepam in the conditioned animals. These drugs did not have any effect in non-conditioned rats. FG-7142 treatment failed to change the behavioral and cardiovascular responses to the aversive context. In conclusion, the results suggest that CBD has anxiolytic-like properties similar to those of diazepam in a rat model of conditioned fear to context.
Over the course of the last 50 years many models of major depressive disorder have been developed on the basis of theoretical aspects of this disorder. These models and procedures have been crucial in the discovery and development of clinically-effective drugs. Notwithstanding, there is presently great concern about the discrepancy between positive outcomes of new candidate drugs in animal models and apparent lack of efficacy in humans i.e., the predictive validity of animal models. Some reasons for this concern lie in the over-reliance in the face value of behavioural models, design of clinical trials, placebo responses, genetic variations in response to drugs, species differences in bioavailability and toxicology, and not least, disinterest of pharmaceutical sponsors to continue developing certain drugs. Present model development is focusing on endophenotypic aspects of behaviours rather than trying to model whole syndromes. This essay traces the origins and theoretical bases of our animal models of depression or depressed-like behaviours in humans and indicates how they have evolved from behavioural assays used to measure the potency and efficacy of potential candidate drugs to tools by which endophenotypes of depression may be identified and verified pharmacologically. A cautionary note is included though to indicate that the true predictive validity of our models will not be fully assessed until we can determine the attrition rate of molecules discovered from new drug targets translating into clinically-effective drugs.
Cannabidiol (CBD) is a major constituent of the Cannabis sativa plant. It inhibits the anxiogenic activity of high doses of Delta9-tetrahydrocannabinol and induces anxiolytic-like effects. However, the mechanisms underlying the actions of CBD are unknown. Therefore, the aim of the present study was to test the effects of CBD in the Vogel test, a widely used animal model of anxiety. In addition, it was verified if these effects would depend on benzodiazepine-receptor activation. After 24 h of water deprivation, male Wistar rats were subjected to an initial 3-min non-punished (pre-test) drinking session. This was followed by an additional 24-h period of water deprivation followed by a 3-min punished-licking session (test). Diazepam (3 mg/kg) or CBD (2.5, 5 or 10 mg/kg) were intraperitoneally injected 30 min before the test session. CBD (10 mg/kg) and diazepam had similar anticonflict effects, increasing the number of punished licks. The effect of diazepam, but not of CBD, was prevented by the benzodiazepine-receptor antagonist flumazenil (10 mg/kg). To exclude that the anticonflict effects were reflecting non-specific drug effects, we checked the effects of CBD on water consumption and nociceptive response. The drug did not interfere on the former variable in a non-punished test session. Moreover, contrary to morphine (5 mg/kg), CBD was ineffective in the tail-flick test. In conclusion, CBD induced an anticonflict effect not mediated by benzodiazepine receptors or by non-specific drug interference on nociceptive threshold or water consumption. These results reinforce the hypothesis that this cannabinoid has anxiolytic properties.
Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa plant that induces anxiolytic effects. However, the brain sites and mechanisms of these effects remain poorly understood. The dorsolateral periaqueductal gray (dlPAG) is a midbrain structure related to anxiety that contains receptors proposed to interact with CBD such as 5HT1A. In addition, since CBD has been shown to inhibit anandamide metabolism, CB1 receptors could also be involved in the effects of this cannabinoid.
To investigate if the dlPAG could be a possible site of the anxiolytic effects induced by CBD and if these effects depend on CB1 or 5HT1A receptors.
Male Wistar rats with cannulae aimed at the dlPAG were tested in the elevated plus maze (EPM) and the Vogel conflict test (VCT).
CBD injected into the dlPAG produced anxiolytic-like effects in the EPM with a bell-shaped dose-response curve. The anxiolytic effect of CBD was confirmed in the VCT. These effects were prevented by WAY100635, a 5HT1A receptor antagonist, but not by AM251, an antagonist of CB1 receptors.
These results suggest the CBD interacts with 5HT1A receptors to produce anxiolytic effects in the dlPAG.
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