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Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were "cannabinoids", "cannabidiol" and "side effects". Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.
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... In contrast, CBD, the other primary cannabinoid in cannabis, is generally considered non-impairing at low and moderate doses (See Figure 1) (18). Current evidence suggests CBD may cause sedation in some individuals at higher doses (19,20). However, evidence is inconclusive and dose ranges are unclear. ...
... However, evidence is inconclusive and dose ranges are unclear. Some studies and reviews report no sedation at higher doses of 1,000-1,500 mg of CBD (11,19,21,22), while others, primarily in pediatric epilepsy populations, report sedation at more moderate doses of 5-10 mg/kg/day CBD (20,23,24). Further investigation is needed to assess if there is a true dose-dependent effect or if sedation is due to the coadministration of other drugs such as antiepileptics or CNS depressants, which may lead to drug interactions resulting in increased sedation (20,25,26). ...
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Clinicians play an important role in promoting safe and responsible medical cannabis use. One essential component to safe use is considering a patient's risk of neurocognitive impairment. However, there remains a lack of practical guidance on how clinicians can evaluate this risk for medical cannabis patients. Here, a practical framework is presented for clinicians to assess and stratify cannabis-associated impairment risk. The proposed framework is intended to practically guide healthcare providers in gaining a more comprehensive review of a patient's impairment-related factors. This framework can be used to assess impairment risk for patients currently using or considering medical cannabis and is recommended for all patients who perform safety-sensitive duties. Healthcare providers (HCP) managing patient's medical cannabis or those conducting assessments to determine risk of impairment for safety-sensitive workplaces can utilize this framework to stratify patients' risk of impairment. Such assessments can inform patient-specific needs for support, education, and guidance, to ensure cannabis is used safely and responsibly.
... An average CBD dose of 15 mg/kg/day showed positive significant reductions of seizure while CBD between 150 and 600 mg/day produced therapeutic effects in social anxiety disorder and insomnia. The maximum tolerated dose for CBD in humans is 1500 mg/day [30]. This data shows that CBD-dominant products have a higher therapeutic index than THCdominant products. ...
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Cannabis medicines are in demand from the public for treating a range of diseases and symptoms; however, clinicians are reluctant to prescribe these products because of limited evidence and prescribing information. To generate this evidence , quality clinical trials of cannabis medicines must be undertaken, yet their design is a complex, often uncharted territory, and involves the cooperation and sharing of knowledge of multiple stakeholders. Before designing a clinical trial, researchers require a clear understanding of the potential therapeutic benefit cannabis medicines may have, the form and formulation of the product, and the dose to be investigated. Researchers must also be aware of the applicable pharmaceutical regulations in the country or jurisdiction where the research is to be undertaken, as well as manufacturing or licensing regulations that may be imposed at the source of the cannabis product. Importantly, collaborations with industry are a key to the successful outcome of cannabis medicines clinical trials. Without funding and sponsorship of clinical trials, the ability to generate quality data will be limited and the evidence for cannabis medicines to be registered as therapeutics lacking. Collaborations between researchers, industry, and regulators, working together in sharing knowledge, are therefore critical to generate high quality cannabis medicines research.
... CBD, a non-psychotropic phytocannabinoid derived from the industrial hemp plant (Cannabis sativa L.), has displayed diverse pharmacological activities relevant to postmenopause including antioxidant and anti-inflammatory activities (De Filippis et al., 2011;Atalay et al., 2019;Nichols and Kaplan, 2020), improved gut barrier (Cocetta et al., 2021), protection from collageninduced arthritis (Malfait et al., 2000), and reduced bone loss (Napimoga et al., 2009;Raphael-Mizrahi and Gabet, 2020). CBD (Epidiolex ® ) is currently FDA-approved for treatment of epilepsy-related disorders in children and adults with a favorable safety profile (Bergamaschi et al., 2011;Iffland and Grotenhermen, 2017;Larsen and Shahinas, 2020;Gaston et al., 2021). CBD is highly lipophilic and reported to have relatively low bioavailability (~6%) if consumed during fasting but can increase 4-fold if consumed with a high fat meal (Millar et al., 2018;Perucca and Bialer, 2020). ...
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Loss of ovarian 17β-estradiol (E2) in postmenopause is associated with gut dysbiosis, inflammation, and increased risk of cardiometabolic disease and osteoporosis. The risk-benefit profile of hormone replacement therapy is not favorable in postmenopausal women therefore better treatment options are needed. Cannabidiol (CBD), a non-psychotropic phytocannabinoid extracted from hemp, has shown pharmacological activities suggesting it has therapeutic value for postmenopause, which can be modeled in ovariectomized (OVX) mice. We evaluated the efficacy of cannabidiol (25 mg/kg) administered perorally to OVX and sham surgery mice for 18 weeks. Compared to VEH-treated OVX mice, CBD-treated OVX mice had improved oral glucose tolerance, increased energy expenditure, improved whole body areal bone mineral density (aBMD) and bone mineral content as well as increased femoral bone volume fraction, trabecular thickness, and volumetric bone mineral density. Compared to VEH-treated OVX mice, CBD-treated OVX mice had increased relative abundance of fecal Lactobacillus species and several gene expression changes in the intestine and femur consistent with reduced inflammation and less bone resorption. These data provide preclinical evidence supporting further investigation of CBD as a therapeutic for postmenopause-related disorders.
... The pharmacologic effects they each exude are quite distinct. For instance, CBD does not produce acute intoxication, has been proven to treat refractory epileptic syndromes in children, and may have anti-inflammatory, anxiolytic, and antipsychotic indications (Zuardi et al., 1993;Bergamaschi et al., 2011a;Bergamaschi et al., 2011b;Leweke et al., 2012;Iseger and Bossong, 2015;Devinsky et al., 2017). Yet, there is currently no substantial evidence that CBD alone has analgesic efficacy in humans-the primary indication for which patients seek out cannabis in the United States (U.S.) . ...
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Background and aims: The effects exuded by cannabis are a result of the cannabinoids trans-Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD), and is dependent upon their pharmacological interaction and linked to the two cannabinoids’ concentrations and ratios. Based on current literature and trends of increasing cannabis potency, we postulate that most medical cannabis products with THC and CBD have ratios capable of producing significant acute intoxication and are similar to recreational products. We will test this by organizing products into clinically distinct categories according to TCH:CBD ratios, evaluating the data in terms of therapeutic potential, and comparing the data obtained from medical and recreational programs and from states with differing market policies. Methods: We utilized data encompassing online herbal dispensary product offerings from nine U.S. states. The products were analyzed after being divided into four clinically significant THC:CBD ratio categories identified based on the literature: CBD can enhance THC effects (THC:CBD ratios ≥1:1), CBD has no significant effect on THC effects (ratios ∼ 1:2), CBD can either have no effect or can mitigate THC effects (ratios 1:>2 < 6), or CBD is protective against THC effects (ratios ≤1:6). Results: A significant number of products (58.5%) did not contain any information on CBD content. Across all states sampled, the majority (72–100%) of both medical and recreational products with CBD (>0%) fall into the most intoxicating ratio category (≥1:1 THC:CBD), with CBD likely enhancing THC’s acute effects. The least intoxicating categories (1:>2 < 6 and ≤1:6 THC:CBD) provided the smallest number of products. Similarly, the majority of products without CBD (0%) contained highly potent amounts of THC (>15%). These results were consistent, regardless of differing market policies in place. Conclusions: Despite the distinct goals of medical and recreational cannabis users, medical and recreational program product offerings are nearly identical. Patients seeking therapeutic benefits from herbal cannabis products are therefore at a substantial risk of unwanted side effects, regardless of whether they obtain products from medical or recreational programs. Efforts are needed to better inform patients of the risks associated with high potency cannabis and the interaction between THC and CBD, and to help shape policies that promote more therapeutic options.
... To date, CBD appears to carry a very low risk of toxicity (23)(24)(25). The main reported side effects at high doses in studies evaluating CBD in epilepsy were diarrhea, sedation, nausea, headache and changes to appetite. ...
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Introduction: Cannabidiol (CBD), the second most prevalent cannabinoid found in cannabis, is considered to be safe for use. Studies suggest that CBD may be of benefit in treating cannabis use disorder (CUD). In clinical practice, CBD is already being used by patients who are trying to reduce or stop their cannabis consumption. The aim of this study was to assess the potential of CBD inhaled using a vaping device in CUD. Methods: This was an exploratory, observational, non-randomized, open-label study conducted at an Addiction Support and Prevention Center in Paris. The primary endpoint was a reduction of at least 50% in the reported number of joints consumed daily at 12 weeks. The participants were given an electronic cigarette along with liquid containing CBD. Nicotine at 6 mg/ml could be added in case of co-consumption of tobacco. They were assessed once a week and the CBD liquid dose was adjusted based on withdrawal signs and cravings (33.3, 66.6 or 100 mg/mL). Results: Between November 2020 and May 2021, 20 patients were included and 9 (45%) completed the follow-up. All of the participants used tobacco, and were provided a liquid with nicotine. At 12 weeks, 6 patients (30%) had reduced their daily cannabis consumption by at least 50%. The mean number of joints per day was 3, compared to 6.7 at baseline. The mean amount of CBD inhaled per day was 215.8 mg. No symptomatic treatment for cannabis withdrawal was prescribed. Mild adverse effects attributable to CBD and not requiring the prescription of any medicines were reported in a few patients. Conclusion: This research provides evidence in favor of the use of CBD in CUD. It also highlights the benefits of inhalation as the route of CBD administration in patients who use cannabis: inhalation can allow users to self-titrate CBD based on their withdrawal symptoms and cravings. This study illustrates the interest of proposing an addictological intervention targeting at the same time tobacco and cannabis dependence in users who are co-consumers. A double-blind, randomized, placebo-controlled clinical trial is needed to assess the efficacy of inhaled CBD in CUD.Study registration number (IDRCB) issued by the ANSM (Agence nationale de sécurité du médicament et des produits de santé-French National Agency for Medicines and Health Products Safety): 2018-A03256-49. This study received IEC approval from the CPP Sud-Ouest et Outre-Mer 1 (South-West and Overseas 1 IEC) on 15/06/2020 (CPP 1-19-041/ID 3012).
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Following injury, the endocannabinoid system is activated in the brain suggesting a strategic role in the self-repair mechanisms. Indeed endocannabinoid system manipulation ameliorates traumatic brain injury (TBI) symptoms. Cannabidiol (CBD), together with △⁹-tetrahydrocannabinol (THC), is the main phytocannabinoid extracted from the plant Cannabis sativa, and it plays anti-inflammatory, antioxidant, neuroprotective, anticonvulsant, hypnotic, and antiemetic effects and has proven to be useful in neuropsychiatric, neurodegenerative, post-traumatic stress, and ischemic disorders. Unlike THC, CBD is not psychoactive and enhances the beneficial and reduces the side effects of THC. CBD has negligible action on cannabinoid receptors and modulates the endocannabinoid system throughout the inhibition of endocannabinoid degradation and reuptake. It also stimulates serotonin 1A (5-HT1A), adenosine 2A (A2A), transient receptor potential vanilloid subtype 1 (TRPV1), and nuclear peroxisome proliferator-activated receptor γ (PPARγ). We collect in this chapter all the preclinical and clinical evidence on the beneficial effects of CBD in the TBI considering it important for two main reasons: the lack of effective therapy for the TBI and the good tolerability of the CBD.
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Introduction: This systematic review aimed to assess efficacy and safety for skin-applied formulations containing CBD. Methods: Bibliographic and clinical trial registries were searched for interventional human trials using cutaneously administered CBD or reported plasma CBD concentrations (any species). Results: Eight of 544 articles fitted the selection criteria: 3 placebo-controlled randomized and 5 single-arm trials. Eleven more studies were found in clinical trial databases but not accessible. Symptoms targeted were dermatopathologies or safety (two studies), pain (two), and behavior (one). Doses were 50-250 mg or 0.075-1.0% CBD, but coformulated with other ingredients. Risk of bias was high and reporting deficiencies further compromised data reliability. Diverse methodologies and formulations hampered syntheses for CBD dose, efficacy, and safety. Plasma CBD levels in dogs and rodents were 0.01-5 μM translating to <100 nM free, unbound CBD in humans. Adverse events were uncommon and mild, but meaningless without CBD's contribution to efficacy data. Achievable free CBD plasma concentrations ∼100 nM can interact predominantly with high-affinity CBD targets, for example, TRPA1 and TRPM8 membrane channels that are abundantly expressed in pathological conditions. Even if reached, higher CBD concentrations on less susceptible targets risk complex and unsafe CBD therapy. A conceptual framework is proposed where dermal capillary loops create sinking for topical CBD demonstrating parallels between topical and transdermal CBD administration. Conclusions: Users risk generalizing inadequately designed trials to all CBD preparations. New clinical trials are urgently needed: they must demonstrate that outcomes are solely from CBD pharmacology, are reliable, unbiased, safe, and comparable. Measurements of sustained plasma CBD levels are mandatory, irrespective of administration route for successful translation from in vitro systems that express human molecular targets. Placebos must be appropriate. Transcutaneous and topical formulations need preliminary in vitro studies to optimize CBD skin penetration. Then, users can rationally balance efficacy against potential harms and cost-effectiveness of CBD formulations.
Article
Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (β = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (β = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens.
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The development of medications or cosmetics from botanicals such as the cannabis plant is the current major topic of interest in the pharmaceutical and cosmetic industry. Currently, several countries have legalized the use and dispensing of cannabis products. Cannabis is one of the most commonly abused or used addictive natural products after alcohol and tobacco. Concerning the cosmetic world, cannabis-based products are used extensively in various formulations. The most common personal care products are the skin, hair, eye, nails, or face formulations which are generally used to improve the appearance and prevent aging or risk of other diseases. This chapter deals with various cannabis-based cosmetic products and their uses.
Article
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
Article
Cannabidiol and other cannabinoids were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate. The psychotropic cannabinoid receptor agonist Δ9-tetrahydrocannabinol (THC) and cannabidiol, (a non-psychoactive constituent of marijuana), both reduced NMDA, AMPA and kainate receptor mediated neurotoxicities. Neuroprotection was not affected by cannabinoid receptor antagonist, indicating a (cannabinoid) receptor-independent mechanism of action. Glutamate toxicity can be reduced by antioxidants. Using cyclic voltametry and a fenton reaction based system, it was demonstrated that Cannabidiol, THC and other cannabinoids are potent antioxidants. As evidence that cannabinoids can act as an antioxidants in neuronal cultures, cannabidiol was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, cannabidiol was superior to both a-tocopherol and ascorbate in protective capacity. Recent preliminary studies in a rat model of focal cerebral ischemia suggest that cannabidiol may be at least as effective in vivo as seen in these in vitro studies.
Article
(−)-Cannabidiol (CBD) is a non-psychotropic component of Cannabis with possible therapeutic use as an anti-inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)-CBD, together with seven analogues, obtained by exchanging the C-7 methyl group of CBD with a hydroxy-methyl or a carboxyl function and/or the C-5′ pentyl group with a di-methyl-heptyl (DMH) group, were tested on: (a) VR1-mediated increase in cytosolic Ca2+ concentrations in cells over-expressing human VR1; (b) [14C]-AEA uptake by RBL-2H3 cells, which is facilitated by a selective membrane transporter; and (c) [14C]-AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)-CBD, but not the other analogues, stimulated VR1 with EC50=3.2 – 3.5 μM, and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μM). CBD (10 μM) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)-5′-DMH-CBD and (+)-7-hydroxy-5′-DMH-CBD inhibited [14C]-AEA uptake (IC50=10.0 and 7.0 μM); the (−)-enantiomers were slightly less active (IC50=14.0 and 12.5 μM). CBD and (+)-CBD were also active (IC50=22.0 and 17.0 μM). CBD (IC50=27.5 μM), (+)-CBD (IC50=63.5 μM) and (−)-7-hydroxy-CBD (IC50=34 μM), but not the other analogues (IC50>100 μM), weakly inhibited [14C]-AEA hydrolysis. Only the (+)-isomers exhibited high affinity for CB1 and/or CB2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB1 and CB2 receptors, (−)-5′-DMH-CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. British Journal of Pharmacology (2001) 134, 845–852; doi:10.1038/sj.bjp.0704327