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Cannabidiol decreases body weight gain in rats: Involvement of CB2 receptors
... Another possible anti-obesity target is the CB2 receptor. Ignatowska-Jankowska and colleagues [14] demonstrated that the anorexigenic effect following CBD administration could depend on the activation of the hypothalamic CB2 pool. Therefore, the anorexigenic effect exerted by the CBD could be the result of a multitarget mechanism, involving the whole endocannabinoid receptor system, particularly in the hypothalamus. ...
... Nevertheless, the study performed by Merroun and colleagues [33] suggested the lateral hypothalamus-derived orexin A as a mediator of the anorexigenic effects induced by CB1 antagonist AM251 as well [33]. The anorexigenic effects of CBD were also related to CB2 receptor activation [14], whilst the cannabigerol proved to challenge brain α2-adrenoceptor [34], whose activation is well known to be related to a feeding stimulating effect [35]. Another parameter investigated after CBD and CBG treatment was the gene expression of FAAH, a key enzyme known for being able to stimulate food intake and notoriously involved in the degradation of endocannabinoids such as anandamide [7]. ...
... In a previous study, the RVD-hemopressin-α, an endogenous anorexigenic peptide, proved to be a negative allosteric modulator of CB1 [43] and to inhibit hypothalamic NE levels following peripheral administration despite being ineffective against DA and 5-HT levels [30]. The two terpenophenols objects of this study were also ineffective against the DA level, whereas the sole CBD stimulated 5-HT levels, and this could explain, albeit partially, the aforementioned anorexigenic effects [14]. The evaluation of the biogenic amine steady state level is currently considered a useful tool to predict the effect of a drug on the activity in the brain, particularly in in vivo studies [44,45]. ...
Tanacetum parthenium (feverfew) has traditionally been employed as a phytotherapeutic remedy in the treatment of migraine. In this study, a commercial T. parthenium water extract was investigated to explore its anti-inflammatory and neuromodulatory effects. Isolated mouse cortexes were exposed to a K+ 60 mM Krebs-Ringer buffer and treated with T. parthenium water extract. The prostaglandin E2 (PGE2) level, brain-derived neurotrophic factor (BDNF), interleukin-10 (IL-10), and IL-1β gene expression were evaluated in the cortex. The effects on dopamine (DA) release and dopamine transporter (DAT) gene expression were assayed in hypothalamic HypoE22 cells. A bioinformatics analysis was conducted to further investigate the mechanism of action. The extract was effective in reducing cortex PGE2 release and IL-1β gene expression. In the same experimental system, IL-10 and BDNF gene expressions increased, and in HypoE22 cells, the extract decreased the extracellular dopamine level and increased the DAT gene expression due to the direct interaction of parthenolide with the DAT. Overall, the present findings highlight the efficacy of T. parthenium water extract in controlling the inflammatory pathways that occur during cortical-spreading depression. Additionally, the inhibition of the hypothalamic DA release observed in this study further supports the role of dopaminergic pathways as key targets for novel pharmacological approaches in the management of migraine attacks.
... An adequate intake of energy and nutrients is essential to support optimal athletic training, recovery, and performance [173]. Various preclinical studies have investigated the effect of CBD on feeding behaviour in rodents [58,93,155,159,195], with results suggesting that higher doses may influence food intake several hours post-treatment. Indeed, while CBD, at doses of 3-100 mg·kg −1 , i.p. (IRC mice) [195] and 1-20 mg·kg −1 , i.p. (Wistar rats) [155], failed to influence food intake during a 1 h ad libitum feeding period, moderate to high doses of CBD (4.4 mg·kg −1 , i.p. [58]. ...
... 4-6 h). In line with these results, Ignatowska-Jankowska et al. [93] found that chronic CBD treatment (2.5 and 5 mg·kg −1 ·day −1 , i.p. 14 days) attenuated BM gains in growing Wistar rats. A recent systematic review of human trials also reported that individuals with epilepsy receiving CBD (5-20 mg·kg −1 ·day −1 ) were more likely to experience decreased appetite than those receiving placebo (i.e.~20 vs. 5% of patients) [107]. ...
... Δ 9 -THC, AEA, cannabinol) reliably induce hyperphagia when administered exogenously [58,197,198]; but CBD lacks such an effect. Ignatowska-Jankowska et al. [93] did report that the selective CB 2 R antagonist, AM630, prevented CBD-induced BM changes; however, CB 2 R has not generally been linked to feeding behaviour, and if CBD is indirectly increasing endocannabinoid tone (i.e. via AEA) [92], this might be expected to promote feeding behaviour (via indirect CB 1 R agonist effects) [197]. A role for GI side effects in affecting appetite therefore cannot be ruled out [107]. ...
Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.
... Paradoxically, several epidemiological studies have established the association between cannabis exposure and reduced risk of obesity and metabolic diseases [9][10][11][12]. Moreover, cannabis extracts, as well as THC and CBD, have been shown to exert anti-obesity properties in animal models [13][14][15]. ...
... Previous studies have investigated the anti-obesity properties of treatment with single cannabinoids or cannabis extracts [13][14][15]. However, to our knowledge, we are the first to incorporate a noninvasive oral route of administration method to compare the prolonged treatment of THC and CBD in an animal model of obesity. ...
Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.
... Although the antitumor effects of CBD have been widely focused on in oncology fields (12), the antitumor effect was increased when used CBD in combination with THC compared to a single compound use. Moreover, this combination showed better tolerated than the separate use (13). There are several studies that evaluated the antitumor effects of cannabinoids in animal models of cancers. ...
... The active components of cannabis are called cannabinoids composed of CBD and THC. In addition, the antitumor effect was increased when used CBD in combination with THC compared to single use of CBD or THC alone and their combination showed better tolerance than separate use (13). Tumor cells xenografts transplanted subcutaneously into the immunodeficiency mice have been widely tested in the preclinical studies for identifying or developing the new anticancer drugs (19). ...
Background
Pancreatic cancer is considered a rare type of cancer, but the mortality rate is high. Cannabinoids extracted from the cannabis plant have been interested as an alternative treatment in cancer patients. Only a few studies are available on the antitumor effects of cannabinoids in pancreatic cancer. Therefore, this study aims to evaluate the antitumor effects of cannabinoids in pancreatic cancer xenografted mouse model.
Materials and Methods
Twenty-five nude mice were subcutaneously transplanted with a human pancreatic ductal adenocarcinoma cell line (Capan-2). All mice were randomly assigned into 5 groups including negative control (gavage with sesame oil), positive control (5 mg/kg 5-fluorouracil intraperitoneal administration), and cannabinoids groups that daily received THC:CBD, 1:6 at 1, 5, or 10 mg/kg body weight for 30 days, respectively. Xenograft tumors and internal organs were collected for histopathological examination and immunohistochemistry.
Results
The average tumor volume was increased in all groups with no significant difference. The average apoptotic cells and caspase-3 positive cells were significantly increased in cannabinoid groups compared with the negative control group. The expression score of proliferating cell nuclear antigen in positive control and cannabinoids groups was decreased compared with the negative control group.
Conclusions
Cannabinoids have an antitumor effect on the Capan-2-derived xenograft mouse model though induce apoptosis and inhibit proliferation of tumor cells in a dose-dependent manner.
... CB2Rs are involved in modulating a variety of behavioral effects in the CNS. It has been reported that CB2Rs modulate food intake, body weight [51,52], depression and anxiety [12,53], drug addiction [54,55], and schizophrenia-like behavior [56]. Brain CB2Rs are expressed at low levels under physiological conditions; however, in pathological conditions, such as neuropathic pain [57], stroke [58], traumatic brain injury [59], neurodegenerative diseases [54,60,61], or drug addiction [62,63], their expression is enhanced and up-regulated. ...
... CB2Rs are involved in modulating a variety of behavioral effects in the CNS. It has been reported that CB2Rs modulate food intake, body weight [51,52], depression and anxiety [12,53], drug addiction [54,55], and schizophrenialike behavior [56]. Brain CB2Rs are expressed at low levels under physiological conditions; however, in pathological conditions, such as neuropathic pain [57], stroke [58], traumatic brain injury [59], neurodegenerative diseases [54,60,61], or drug addiction [62,63], their expression is enhanced and up-regulated. ...
The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 and CB2 cannabinoid receptors (CB1R, CB2R), endocannabinoids (eCBs), and the metabolic enzyme machinery for their synthesis and catabolism. The activation of CB1R is associated with adverse effects on the central nervous system (CNS), which has limited the therapeutic use of drugs that bind this receptor. The discovery of the functional neuronal CB2R raised new possibilities for the potential and safe targeting of the ECS for the treatment of CNS disorders. Previous studies were not able to detect CB2R mRNA transcripts in brain tissue and suggested that CB2Rs were absent in the brain and were considered peripheral receptors. Studies done on the role of CB2Rs as a potential therapeutic target for treating different disorders revealed the important putative role of CB2Rs in certain CNS disorders, which requires further clinical validation. This review addresses recent advances on the role of CB2Rs in neuropsychiatric and neurodegenerative disorders, including, but not limited to, anxiety, depression, schizophrenia, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and addiction.
... In summary, we identified CBD as a selective OX1R antagonist and such effect could contribute to explaining, for example, the anorexigenic effect exerted by CBD reported in some studies [45], since OX1R is localized in appetite-regulating neurons in the hypothal- In fact, among the contacting residues in the OX1R binding site, CBD formed stable interactions with the only two non-conserved residues between OX1R and OX2R, that is OX1R Ser103 2.61 (pose I) and OX1R Ala127 3.33 (pose III), both replaced by a bulkier threonine residue in OX2R, which contributed to the destabilization of the CBD-OX2R complex during MD simulations, in agreement with the results from the binding assays. Furthermore, the docking/MD study identified a protein-ligand interaction network involving OX1R residues reported to be critical for antagonist binding, in agreement with the experimental validation. ...
... In summary, we identified CBD as a selective OX1R antagonist and such effect could contribute to explaining, for example, the anorexigenic effect exerted by CBD reported in some studies [45], since OX1R is localized in appetite-regulating neurons in the hypothalamus [46] and it has been demonstrated that the hyperphagia induced by the centrally administrated OX-A is mediated by OX1Rs [47,48]. Moreover, the selective OX1R antagonist SB-334867 attenuates orexin-A induced feeding and has anorectic effects inducing satiety without nausea [49]. ...
The potential, multifaceted therapeutic profile of cannabidiol (CBD), a major constituent derived from the Cannabis sativa plant, covers a wide range of neurological and psychiatric disorders, ranging from anxiety to pediatric epilepsy and drug addiction. However, the molecular targets responsible for these effects have been only partially identified. In this view, the involvement of the orexin system, the key regulator in arousal and the sleep/wake cycle, and in motivation and reward processes, including drug addiction, prompted us to explore, using computational and experimental approaches, the possibility that CBD could act as a ligand of orexin receptors, orexin 1 receptor of type 1 (OX1R) and type 2 (OX2R). Ligand-binding assays showed that CBD is a selective ligand of OX1R in the low micromolar range (Ki 1.58 ± 0.2 μM) while in vitro functional assays, carried out by intracellular calcium imaging and mobilization assays, showed that CBD acts as an antagonist at this receptor. Finally, the putative binding mode of CBD has been inferred by molecular docking and molecular dynamics simulations and its selectivity toward the OX1R subtype rationalized at the molecular level. This study provides the first evidence that CBD acts as an OX1R antagonist, supporting its potential use in addictive disorders and/or body weight regulation.
... Conversely, CBD unexpectedly exhibited a high affinity for the CB2 receptor, for which it could act as an agonist. 177 An interesting result of studies is the fact that CBD has a greater affinity for several receptors, including 5-HT1A, TRPV, and PPARc channels. 110,153,178 Activation of the 5-HT1A receptor can act as an antioxidant by capturing ROS preventing membrane oxidation. ...
... These data suggest the possible roles of CBD in the darkening of white adipocytes, increased lipolysis, thermogenesis, and reduced lipogenesis. 184 In a study by Ignatowska-Jankowska et al., 177 the effects of repeated administration of CBD on body weight gain in rats were investigated. The animals received intraperitoneal injections of CBD at doses of 2.5 and 5 mg/kg per day for 14 consecutive days and body weight gain was monitored. ...
Introduction: Obesity is defined as an excess of accumulation of fat that can be harmful to health. Storage of excess fat in the adipose tissue triggers an inflammatory process, which makes obesity a low-grade chronic inflammatory disease. Obesity is considered a complex and multifactorial disease; hence, no intervention strategy appears to be an ideal treatment for all individuals. Therefore, new therapeutic alternatives are often studied for the treatment of this disease. Currently, herbal medicines are gaining ground in the treatment of obesity and its comorbidities. In this context, much attention is being paid to Cannabis sativa derivatives, and their therapeutic functions are being widely studied, including in treating obesity. Objective: Highlight the pharmacological properties of Δ9-tetrahydrocannabivarin (THCV), Δ9-tetrahydrocannabidinol (THC), and cannabidiol (CBD), the predominant isolated components of Cannabis sativa, as well as its therapeutic potential in the treatment of obesity. Methods: This is a narrative review that shows the existing scientific evidence on the clinical application of Cannabis sativa as a possible treatment for obesity. Data collection was performed in the PubMed electronic database. The following word combinations were used: Cannabis and obesity, Cannabis sativa and obesity, THCV and obesity, THC and obesity, CBD and obesity, and Cannabis sativa and inflammation. Results: Evidence shows that Cannabis sativa derivatives have therapeutic potential due to their anti-inflammatory properties. In addition, people who use cannabis have a lower body mass index than those who do not, making the plant an option to reduce and reverse inflammation and comorbidities in obesity. Conclusion: It is concluded that phytocannabinoids derived from Cannabis sativa have therapeutic potential due to its anti-inflammatory, antioxidant, and neuroprotective properties, making the plant a study option to reduce and reverse inflammation and comorbidities associated with obesity.
... Human Obesity Rimonabant (SR141716) CB 1 inverse agonist ↓ food intake ↓ waist circumference improve metabolic parameters [192,193] BPR0912 CB 1 antagonist ↓ body weight ↑ β-oxydation and thermogenesis [196] Monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity AM6545 CB 1 antagonist ↓ body weight no effect on food intake ↑ circulating adipokine ↓ inflammation [197] DIO Pregnenolone Allosteric inhibitor ↓ body weight ↓ food intake [198] DIO ∆ 9 -THC Cannabinoid receptor agonist ↓ AMPK activity ↑ adipogenesis [199] DIO 2-AG CB 1 and CB 2 agonist ↑ insulin sensitivity ↑ AKT phosphorylation and GLUT4 translocation [200] ob/ob JWH-133 CB 2 agonist ↑ adipose tissue inflammation ↑ insulin resistance [201] Rats DIO AM630 CB 2 antagonist weight gain blockage [202] DIO Cannabidiol CB 1 and CB 2 agonist ↓ weight loss [202] DIO and chow-fed rats PSNCBAM-1 Allosteric inhibitor ↓ body weight ↓ food intake [203] Zucker rats Diet enriched in n-3 PUFA FA ↓ level of endocannabinoid in adipose tissue, liver ↓ ectopic fat ↓ inflammation [204] Cold exposure Rimonabant (SR141716) CB 1 inverse agonist ↑ 1.5 to 5 • C of body temperature ↓ Body weight [205] ...
... Human Obesity Rimonabant (SR141716) CB 1 inverse agonist ↓ food intake ↓ waist circumference improve metabolic parameters [192,193] BPR0912 CB 1 antagonist ↓ body weight ↑ β-oxydation and thermogenesis [196] Monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity AM6545 CB 1 antagonist ↓ body weight no effect on food intake ↑ circulating adipokine ↓ inflammation [197] DIO Pregnenolone Allosteric inhibitor ↓ body weight ↓ food intake [198] DIO ∆ 9 -THC Cannabinoid receptor agonist ↓ AMPK activity ↑ adipogenesis [199] DIO 2-AG CB 1 and CB 2 agonist ↑ insulin sensitivity ↑ AKT phosphorylation and GLUT4 translocation [200] ob/ob JWH-133 CB 2 agonist ↑ adipose tissue inflammation ↑ insulin resistance [201] Rats DIO AM630 CB 2 antagonist weight gain blockage [202] DIO Cannabidiol CB 1 and CB 2 agonist ↓ weight loss [202] DIO and chow-fed rats PSNCBAM-1 Allosteric inhibitor ↓ body weight ↓ food intake [203] Zucker rats Diet enriched in n-3 PUFA FA ↓ level of endocannabinoid in adipose tissue, liver ↓ ectopic fat ↓ inflammation [204] Cold exposure Rimonabant (SR141716) CB 1 inverse agonist ↑ 1.5 to 5 • C of body temperature ↓ Body weight [205] ...
The endocannabinoid system is involved in a wide range of processes including the control of energy acquisition and expenditure. Endocannabinoids and their receptors are present in the central nervous system but also in peripheral tissues, notably the adipose tissues. The endocannabinoid system interacts with two main hormones regulating appetite, namely leptin and ghrelin. The inhibitory effect of the cannabinoid receptor 1 (CB1) antagonist rimonabant on fat mass suggested that the endocannabinoid system can also have a peripheral action in addition to its effect on appetite reduction. Thus, several investigations have focused on the peripheral role of the endocannabinoid system in the regulation of metabolism. The white adipose tissue stores energy as triglycerides while the brown adipose tissue helps to dissipate energy as heat. The endocannabinoid system regulates several functions of the adipose tissues to favor energy accumulation. In this review we will describe the presence of the endocannabinoid system in the adipose tissue. We will survey the role of the endocannabinoid system in the regulation of white and brown adipose tissue metabolism and how the eCB system participates in obesity and metabolic diseases.
... A mild mean reduction in body weight was observed across all treatment groups in the present study, including the placebo group; however, a greater reduction was observed across the 4 CBD dose groups (2.3% to 5.7%), compared with the reduction in the placebo group (0.7%), that was not explained by changes in food consumption or daily activity or the sporadic occurrence of gastrointestinal AEs. Whereas MCT oil has been shown to affect body weight in rodents, 29 MCT oil was not a major constituent of the dogs' diets in the present study, and not all dogs in the placebo group had a body weight reduction. Nonetheless, it remains unclear whether the MCT oil contributed to mild variations in observed body weights. ...
... Interestingly, in rodents, coadministration of CBD with an antagonist of cannabinoid-2 receptors prevented the observed decreases in weight produced by CBD alone. 29 Also in rodents, oral administration of CBD (4.4 mg/kg) induced a significant reduction in total food consumption over a 4-hour test period, compared with that for vehicle-treated control animals 30 ; however, when administered IP (3 to 100 mg/kg), no effects on food consumption were observed. 31,32 The effects of CBD on food consumption and body weight in dogs remain inconclusive and require further investigation. ...
Objective:
To determine the safety and pharmacokinetics of various doses of plant-derived cannabidiol (CBD) versus placebo following repeated oral administration.
Animals:
20 healthy adult Beagles.
Procedures:
In a randomized, blinded, placebo-controlled trial, dogs were randomized to 5 groups balanced in body weight and sex (n = 4 dogs/group) and received a CBD (1, 2, 4, or 12 mg/kg; from cannabis extract) or placebo oil formulation PO once daily for 28 days. Outcome variables were assessed through daily health observations, veterinary examinations, CBC, and serum biochemical analysis. Blood samples were collected at various time points to estimate 24-hour pharmacokinetic profiles of CBD and selected metabolites (7-carboxy-CBD and 7-hydroxy-CBD).
Results:
Repeated CBD administration was well tolerated by dogs, with no clinically important changes in measured safety outcomes. Veterinary examinations revealed no clinically important abnormal findings. Adverse events were mild in severity. Relative to placebo administration, CBD administration at 12 mg/kg/d resulted in more gastrointestinal adverse events (mainly hypersalivation) and significantly higher serum alkaline phosphatase activity. Total systemic exposure to CBD increased on a dose-dependent basis following both acute (first dose) and chronic (28 days) administration. Within each CBD dose group, repeated administration increased total systemic exposure to CBD 1.6- to 3.3-fold. The 24-hour trough plasma CBD concentrations were also dose dependent, with a steady state reached following 2 weeks of administration.
Conclusions and clinical relevance:
Repeated, daily oral administration of the CBD formulation led to dose-dependent increases in total systemic exposure to CBD and 24-hour trough plasma concentrations in healthy dogs. These findings could help guide dose selection.
... A selective CB2 receptor antagonist was also used and found to have no effect on body weight on its own, but when administered with CBD, it reversed its effect on body weight. It can therefore be assumed that the effect of cannabidiol on body weight is due to its effect on the CB2 receptor [61]. However, the results of the other studies do not allow us to define an unambiguous position. ...
Cannabis-derived therapies are gaining popularity in the medical world. More and more perfect forms of cannabinoids are sought, which could be used in the treatment of many common diseases, including metabolic syndrome, whose occurrence is also increasing. The purpose of this review was to investigate the usefulness of cannabinoids, mainly cannabidiol (CBD), in individuals with obesity, impaired glucose and lipid metabolism, high blood pressure, and non-alcoholic fatty liver disease (NAFLD). We summarised the most recent research on the broad topic of cannabis-derived influence on metabolic syndrome components. Since there is a lot of work on the effects of Δ9-THC (Δ9-tetrahydrocannabinol) on metabolism and far less on cannabidiol, we felt it needed to be sorted out and summarised in this review. The research results on the use of cannabidiol in obesity are contraindicatory. When it comes to glucose homeostasis, it appears that CBD maintains it, sensitises adipose tissue to insulin, and reduces fasting glucose levels, so it seems to be a potential target in this kind of metabolic disorder, but some research results are inconclusive. CBD shows some promising results in the treatment of various lipid disorders. Some studies have proven its positive effect by decreasing LDL and increasing HDL as well. Despite their probable efficacy, CBD and its derivatives will likely remain an adjunctive treatment rather than a mainstay of therapy. Studies have also shown that CBD in patients with hypertension has positive effects, even though the hypotensive properties of cannabidiol are small. However, CBD can be used to prevent blood pressure surges, stabilise them, and have a protective effect on blood vessels. Results from preclinical studies have shown that the effect of cannabidiol on NAFLD may be potentially beneficial in the treatment of the metabolic syndrome and its components. Nevertheless, there is limited data on CBD and NAFLD in human studies. Because of the numerous confounding factors, the conclusions are unclear, and more research in this field is required.
... This phytocannabinoid interacts with several molecular targets, including CB receptors, but whether CBD acts as an agonist or an allosteric modulator is unknown. Although some studies report a lack of CBD effects on food consumption, CBD appears to inhibit food intake [45][46][47] as well as responding for food or sweetened water in rats and monkeys [48,49]. A recent study has also shown that CBD inhibits oral sucrose self-administration through CB1 and CB2 mechanisms [50]. ...
Eating disorders are multifactorial disorders that involve maladaptive feeding behaviors. Binge eating disorder (BED), the most prevalent of these in both men and women, is characterized by recurrent episodes of eating large amounts of food in a short period of time, with a subjective loss of control over eating behavior. BED modulates the brain reward circuit in humans and animal models, which involves the dynamic regulation of the dopamine circuitry. The endocannabinoid system plays a major role in the regulation of food intake, both centrally and in the periphery. Pharmacological approaches together with research using genetically modified animals have strongly highlighted a predominant role of the endocannabinoid system in feeding behaviors, with the specific modulation of addictive-like eating behaviors. The purpose of the present review is to summarize our current knowledge on the neurobiology of BED in humans and animal models and to highlight the specific role of the endocannabinoid system in the development and maintenance of BED. A proposed model for a better understanding of the underlying mechanisms involving the endocannabinoid system is discussed. Future research will be necessary to develop more specific treatment strategies to reduce BED symptoms.
... THC administered orally at a dose of 2 mg/kg, increased appetite 1 h after administration although the animals subsequently compensated for their hyperphagia, so that 24-h intakes were similar to controls [21]. On the other hand, Ignatowska-Jankowska et al. demonstrated that CBD (2.5 and 5 mg/kg) induced a decrease in body weight gain in rats, while other studies have shown no significant impact on food intake and body weight in mice and rats, respectively [22][23][24]. This contradiction may be explained by the concentrations of cannabinoids (i.e., THC and/or CBD) administered, time and route of administration used in the experiments. ...
Objective: The aim of the present study was to analyse the effects of cannabis oil on cannabinoid-induced tetrad, blood pressure, and metabolic parameters in rats normal fed a sucrose-rich diet (SRD). Methods: Male Wistar rats were fed the following diets for 21 days: Reference Diet (RD): standard commercial laboratory diet, SRD and SRD+Cannabis oil (SRD+Ca): the oral administration of 1 mg/kg of body weight of cannabis oil daily. Cannabis oil present a total cannabinoids CBD:THC 2:1 ratio. During the experimental period, body weight, food intake, blood pressure, body temperature, locomotion, catalepsy and analgesia were evaluated. At the end of the experimental period, levels of glucose, triglycerides, cholesterol, uric acid, AST, ALT and AP in serum were evaluated. In liver were determined AST, ALT and AP enzymes and triglycerides and cholesterol content. Results: A cannabis oil administration significantly increased (P<0.05) analgesia, and locomotion was also significantly decreased, which was found to be increased in the SRD group. Systolic and diastolic blood pressure decreased during the experiment. In the SRD+Ca group, serum triglycerides and cholesterol levels significantly decreased, reaching values similar to RD group, without changes in glucose levels. In addition, serum uric acid and AP levels significantly decreased, although did not obtain reference values. AST and ALT levels in serum and liver significantly decreased, reaching reference values. At the liver, the triglycerides and cholesterol content significantly decreased with the administration of cannabis oil, although not reaching to reference values. Conclusions: Our results suggest that cannabis oil could be useful as a therapeutic strategy to prevent some of the alterations present in Metabolic Syndrome, including hypertension, dyslipidemia and liver damage. In addition, the analgesic effect of cannabis oil could be observed in SRD-fed rats.
... Simultaneously, intraperitoneal (i.p.) injections of CBD or its vehicle were given to the animals, starting from the fifth week. Daily injections with synthetic CBD (10 mg/kg, purity ≥ 99%; THC Pharm GmbH, Frankfurt, Germany) or its solvent for control and HFD groups (3:1:16, ethanol, Tween-80, and 0.9% NaCl) lasted for two weeks 56,57 . Then, at the end of the 7th week of the experiment and 24 h after the last dose of CBD or its vehicle, rats from all experimental groups were anesthetized i.p. with pentobarbital (80 mg/kg). ...
Obesity is one of the principal public health concerns leading to disturbances in glucose and lipid metabolism, which is a risk factor for several chronic diseases, including insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. In recent years, it turned out that cannabidiol (CBD) is a potential therapeutic agent in the treatment of obesity and its complications. Therefore, in the present study, we used CBD therapy (intraperitoneal injections in a dose of 10 mg/kg of body mass for 14 days) in a rat model of obesity induced by a high-fat diet (HFD). Gas–liquid chromatography and Western blotting were applied in order to determine the intramuscular lipid content and total expression of selected proteins in the white and red gastrocnemius muscle, respectively. Based on fatty acid composition, we calculated de novo lipogenesis ratio (16:0/18:2n-6), desaturation ratio (18:1n-9/18:0), and elongation ratios (18:0/16:0, 20:0/18:0, 22:0/20:0 and 24:0/22:0), in the selected lipid fractions. Two-week CBD administration significantly reduced the intramuscular fatty acids (FAs) accumulation and inhibited de novo lipogenesis in different lipid pools (in the free fatty acid, diacylglycerol, and triacylglycerol fractions) in both muscle types, which coincided with a decrease in the expression of membrane fatty acid transporters (fatty acid translocase, membrane-associated fatty acid binding protein, and fatty acid transport proteins 1 and 4). Moreover, CBD application profoundly improved the elongation and desaturation ratios, which was in line with downregulated expression of enzymes from the family of elongases and desaturases regardless of the metabolism presented by the muscle type. To our knowledge, this study is the first that outlines the novel effects of CBD action on skeletal muscle with different types of metabolism (oxidative vs. glycolytic).
... CBD on Weight or Appetite CBD has been thought to play important roles in energy balance, food intake, and body weight control. A 2-week CBD treatment (2.5 or 5 mg/kg i.p.) decreased the body weight gain by 10 g compared to vehicle-treated rats [123]. Decreased appetite had also been reported as a side effect in some human studies after oral CBD administration [3,4,52,67]. ...
The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.
... The high dose of cannabis 8mg/kg after two weeks showed a lesser relative body weight when compared with control. This finding agree with previous study that reported that cannabis reduces body weight in rats [11] The result shows a reduction in the semen volume, sperm motility, sperm morphology and sperm count in the high dose 8mg/kg cannabis treatment groups when compared with the low dose 4mg/kg cannabis treatment group. More so, semen volume, sperm motility and morphology showed an increase in the low dose 4mg/kg cannabis group when compared with the control rats and the high dose 8mg/kg cannabis group. ...
Cannabis is one of the most commonly used psychoactive drug worldwide, and it is the single most popular illegal drug. The aim of this study is to evaluate the effect of Cannabis sativa on sperm quality and testis histology in male Wistar rat. Thirty rats were randomly divided into 3 groups. Group 1 was the control group and was administered with and water and rat chaw, Group 2 was administered with 4mg/kg body weight of Cannabis Sativa, while Group 3 was administered with 8mg/kg body weight of Cannabis Sativa. At the end of 14days of the experiment, the experimental animals were euthanized by cervical dislocation, sperm parameters were obtained and the testes were harvested for histological analysis. Using a light microscope with H&E staining techniques and x400 lens resolution, the histological sections were observed and observations were recorded and interpreted. Findings from this study revealed that the relative body weight of rats treated with Cannabis at both doses had a lesser weight gain compared to control group. The study recorded a significant (p<0.05) reduction in the semen volume, sperm motility, sperm morphology and sperm count of rats treated with high dose 8mg/kg Cannabis extract when compared with the low dose 4mg/kg cannabis treatment group, however, the semen volume, sperm motility and morphology of the rats were significant (p<0.05) increased in the low dose treated group when compared with control and 8mg/kg groups respectively. Similarly, our result revealed that there was no observable difference in the histology of testis for both the control group and experimental test groups administered with low and high doses of Cannabis sativa. In conclusion, administration of higher doses of Cannabis sativa affected the relative body weights, semen volume, morphology, motility and sperm count but not the testis histoarchitecture of the male Wistar rats.
... Risperidone-induced weight gain may be associated with histamine H 1 receptor antagonism, leptin resistance, and consequent disinhibition of food intake 73 . CBD has also been shown to decrease weight in animal studies 74 , but other studies contradict these observations 75,76 . ...
Atypical antipsychotics, despite their rapid dissociation from dopamine receptors and reduced tendency to induce oxidative stress, have been associated with difficult-to-manage movement disorders, including tardive dyskinesia (TD). The study set out to investigate the effects of cannabidiol (CBD), a potent antioxidant, on risperidone-induced behavioural and motor disturbances; namely vacuous chewing movements (VCM), and oxidative stress markers (e.g. superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), malondialdehyde (MDA), Nitric oxide (NO), and DPPH (2,2-diphenyl-1-picrylhydrazyl)). Oral risperidone (10 mg/kg) or oral CBD (5 mg/kg) were administered to six experimental groups. While risperidone alone was administered for 28 days, CBD concomitantly or in sequential order with risperidone, was administered for 28 days; and CBD alone was administered for 21 days. Behavioural, motor, and specific biochemical parameters, which included VCM, muscle tone, fasting blood sugar (FBS), and oxidative stress markers were assessed at different time points after the last dose of medication. Oral CBD (5 mg/kg) significantly reduced risperidone-induced elevated FBS when given after the administration of risperidone. Oral CBD also had effects on VCM when administered before risperidone and similarly, attenuated risperidone-induced increased muscle tone. It was also established that concomitant or sequential administration of CBD and risperidone did not have any adverse effects on cognition or locomotion. Both CBD and risperidone increased the activity of antioxidant enzymes and decreased the activity of pro-oxidant enzymes. This study suggests CBD could mitigate metabolic dysregulation and extrapyramidal side effects associated with risperidone without producing cognitive impairments.
... CBD can also affect food intake and body weight gain 33,45 . However, juvenile males of Nile tilapia supplemented with different CBD doses did not alter food intake or any of the measured growth response variables. ...
Cannabidiol (CBD) is a substance derived from Cannabis sativa, widely studied in medicine for controlling neural diseases in humans. Besides the positive effects on humans, it also presents anxiolytic proprieties and decreases aggressiveness and stress in mammals. Therefore, CBD has the potential to increase welfare in reared animals, as it seems to reduce negative states commonly experienced in artificial environments. Here, we tested the effect of different CBD doses (0, 1, 10 and 20 mg/kg) on aggressiveness, stress and reproductive development of the Nile tilapia (Oreochromis niloticus) a fish reared worldwide for farming and research purposes. CBD mixed with fish food was offered to isolated fish for 5 weeks. The 10 mg/kg dose decreased fish’s aggressiveness over time, whereas 20 mg/kg attenuated non-social stress. Both doses decreased the baseline cortisol level of fish and increased the gonadosomatic index. However, CBD 1 and 10 mg/kg doses decreased the spermatozoa number. No CBD dose affected feeding ingestion and growth variables, showing that it is not harmful to meat production amount. Despite the effect on spermatozoa, CBD supplementation exhibits high potential to benefit animals’ lives in artificial environments. Therefore, we showed for the first time that CBD could be used as a tool to increase non-mammal welfare, presenting a great potential to be explored in other husbandry and captivity species.
... Finally, as to the mechanisms that mediate CBDinduced loss of appetite, very little is known. In addition to the CB 1 -mediated anorexigenic effect mentioned above, the anti-obesity effect of CBD was mentioned to be CB 2 -mediated [32] or dependent on the induction of β-adrenergic receptors [38]. Moreover, some preclinical animal and in vitro data using cell cultures have identified some mechanisms of action that may contribute to these effects of CBD, including an increase in lipolysis [39,40], an increase in thermogenesis, a decrease in lipogenesis and an increase in browning of white adipocytes [41], and an increase in insulin secretion [42]. ...
Background and objective:
Cannabidiol, one of the main components of the Cannabis sativa plant, is a non-psychotropic cannabinoid that has recently drawn the attention of researchers and clinicians for its potential therapeutic applications. In this systematic review, we aim to describe the possible effects of cannabidiol in appetite and body weight.
Methods:
Both authors independently ran a thorough search in both PubMed and Cochrane databases up to 31 July, 2022 and included every peer-reviewed, original randomized controlled clinical trial that reported data on either of the said outcomes. Risk of assessment bias was performed with Cochrane's risk of bias tool and results were summarized in tables.
Results:
A total of 11 trials were included in this review. Of these, the majority reported on cannabidiol reducing appetite and/or body weight whilst some have found no significant changes and one trial described an increase in appetite.
Conclusions:
This systematic review suggests that cannabidiol has an anorexigenic effect, correlated with a decrease in body weight. However, most of the studies included in the present review raised some concerns in terms of risk of bias. We believe further research is needed in order to clarify potential mechanisms involved in the effect of cannabidiol on feeding/appetite.
... Moreover, our results demonstrated that the impact of THC on HC11 cell differentiation may be mediated via CB2. When co-treated with THC, AM630 (a selective antagonist of CB2 [75]) restored the levels of CSN2, HK2 and FABP4, which had decreased upon THC treatment. In contrast to THC, CBD has been reported to be a potent inverse agonist of CB2 [76]. ...
Pregnant and lactating women have been discouraged from using cannabis by Health Can-ada. However, the increasing rate of cannabis use among pregnant women has presented an urgent need to investigate its physiological effects during the perinatal period. During pregnancy, the mammary gland (MG) undergoes remodeling, which involves alveolar differentiation of mammary epithelial cells (MECs), which is essential for breast milk production and secretion. Limited evidence has been reported on the impact of cannabis or its components , delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), on MG development or MEC differentiation. In this study, we investigated the effects of THC and CBD on the differentiation of MECs by assessing changes in cellular viability, lipid accumulation, and gene and protein expression of major milk protein and lipid synthesizing markers. using the HC11 cells as a model. We hypothesized that THC and CBD will negatively impact the synthesis of milk proteins and lipids, as well as lipid markers in HC11 cells. Our results demonstrated that THC and CBD reduced cellular viability at concentrations above 30μM and 20μM, respectively. Relative to control, 10μM THC and 10μM CBD reduced mRNA levels of milk proteins (CSN2 and WAP), lipid synthesizing and glucose transport markers (GLUT 1, HK2, FASN, FABP4, PLIN2 and LPL), as well as whey acidic protein and lipid levels. In addition, co-treatment of a CB2 antagonist with THC, and a CB2 agonist with CBD, reversed the impact of THC and CBD on the mRNA levels of key markers, respectively. In conclusion, 10μM THC and CBD altered the differentiation of HC11 cells, in part via the CB2 receptor.
... CBD may have ameliorated these effects in the subchronic haloperidol group because the dopaminergic hypofunction in the VTA and hyperprolactinemia induced by dopamine receptor occupation may not have been severe enough compared to that induced by chronic and persistence receptor occupation. The endocannabinoid system (ECS) is critical in maintaining energy balance, intake, metabolism, and storage of calories; cannabinoid receptor types 1 and 2 are the two main receptors in the ECS [34][35][36]. CBD has been reported to reduce body weight gain in rats through its effect on CB 2 receptors [37]. Other investigators have documented CB 2 receptors to be important in feeding behaviour, body weight and metabolic disorders associated with obesity [38,39]. ...
Objectives
The duration of administration (e.g., subchronic or chronic) of haloperidol may influence its adverse effects. We studied the effects of duration of administration of haloperidol on body weight and fasting blood sugar (FBS). In addition, we examined whether orally administered cannabidiol (CBD) had any putative mitigating influence on haloperidol-induced body weight changes and FBS elevation.
Methods
Haloperidol (5 mg/kg/day) was administered for 21 days (subchronic administration), via the intraperitoneal (IP) route, or monthly (50 mg/kg monthly) for 3 months (chronic administration), via the intramuscular (IM) route, either alone or before CBD (5 mg/kg/day). Oral CBD (5 mg/kg/day) alone and distilled water alone were administered for 21 days. Weight and FBS were measured before administration of pharmacological agents (distilled water in the control group) and post-administration.
Results
Group differences in average weight across time were significant. Pairwise comparisons showed that mean weight of the subchronic (IP) haloperidol alone group (Group A) and the chronic (IM) haloperidol before CBD group (Group F) increased significantly over time. Post medications, there was a significant increase in mean FBS in the subchronic (IP) haloperidol group compared to the subchronic (IP) haloperidol before CBD group. There was also a significant reduction in mean FBS from the baseline for the control group only.
Conclusion
We demonstrated that the duration of administration of haloperidol influenced weight and FBS in rats, suggesting that metabolic side effects, may be influenced by duration of administration. CBD ameliorated the increase in weight and FBS observed in the subchronic (IP) haloperidol groups.
... A large body of evidence signifies the possible agonistic activity of CBD on CB2 receptors applying anti-inflammatory consequences in various tissues. 51 Of great note, the anti-inflammatory properties of CBD seem to be orchestrated by regulating the proinflammatory agents, including interleukins and TNF-α, confirmed by a recent study on allergic contact dermatitis. 52 Additionally, clinical studies have affirmed that CBD reduces the levels of proinflammatory cytokines, hinders T-cell proliferation, triggers T-cell apoptosis and abolishes the immunomodulatory cascade. ...
Background One of the major complications associated with random-pattern skin flaps is distal necrosis. Cannabidiol (CBD) has recently gained much attention as a therapeutic anti-inflammatory agent. We aimed to evaluate the efficacy of CBD on the random-pattern skin flap survival (SFS) in rats and to explore the possible involvement of cannabinoid type-2 (CB2) receptors.
Methods In this controlled experimental study, we randomly divided male Wistar rats into seven study groups (six rats each). We performed a random-pattern skin flap model in each rat following pretreatment with vehicle (control) or multiple doses of CBD (0.3, 1, 5, or 10 mg/kg). In a separate group, we injected SR144528 (2 mg/kg), a high affinity and selective CB2 inverse agonist, before the most effective dose of CBD (1 mg/kg). A sham nontreated and nonoperated group was also included. Seven days after surgeries, the percentage of necrotic area (PNA) was calculated. Histopathological microscopy, CB2 expression level, and interleukin (IL)-1β and tumor necrosis factor (TNF)-α concentrations were also investigated in the flap tissue samples.
Results A PNA of 72.7 ± 7.5 (95% confidence interval [CI]: 64.8–80.6) was captured in the control group. Following treatment with CBD 0.3, 1, 5, and 10 mg/kg, a dose-dependent effect was observed with PNAs of 51.0 ± 10.0 (95% CI: 40.5–61.5; p <0.05), 15.4 ± 5.8 (95% CI: 9.3–21.5; p <0.001), 37.1 ± 10.2 (95% CI: 26.3–47.8; p <0.001), and 46.4 ± 14.0 (95% CI: 31.7–61.1; p <0.001), respectively. Histopathologically, tissues enhanced significantly. Besides, CB2 expression surged remarkably, IL-1β and TNF-α concentrations decreased considerably after treatment with CBD of 1 mg/kg compared with the control (p <0.05 and <0.001, respectively). Administering SR144528 reversed the favorable effects of CBD of 1 mg/kg, both macroscopically and microscopically.
Conclusion Pretreatment with CBD of 1 mg/kg improved SFS considerably in rats and exerted desirable anti-inflammatory effects which were possibly mediated by CB2 receptors.
... CB2Rs are mainly expressed postsynaptically and their activation inhibits postsynaptic neuronal function through membrane potential hyperpolarization (53), and also reported presynaptically in some terminals. Thus, CB2Rs are involved in modulating a variety of behavioral effects in the CNS with reports that CB2Rs modulate food intake, body weight (54,55), depression and anxiety (14,56), drug addiction (57,58) and schizophrenia-like behavior (59). Brain CB2Rs are expressed at low levels under physiological conditions; however, in pathological conditions, such as neuropathic pain (60), stroke (61), traumatic brain injury (TBI) (62), neurodegenerative diseases (57,63,64) or drug addiction (65,66), their expression is enhanced and up-regulated. ...
The endocannabinoid system (ECS) is composed of the two canonical receptor subtypes; type-1 cannabinoid (CB1R) and type 2 receptor (CB2R), endocannabinoids (eCBs) and enzymes responsible for the synthesis and degradation of eCBs. Recently, with the identification of additional lipid mediators, enzymes and receptors, the expanded ECS called the endocannabinoidome (eCBome) has been identified and recognized. Activation of CB1R is associated with a plethora of physiological effects and some central nervous system (CNS) side effects, whereas, CB2R activation is devoid of such effects and hence CB2Rs might be utilized as potential new targets for the treatment of different disorders including neuropsychiatric disorders. Previous studies suggested that CB2Rs were absent in the brain and they were considered as peripheral receptors, however, recent studies confirmed the presence of CB2Rs in different brain regions. Several studies have now focused on the characterization of its physiological and pathological roles. Studies done on the role of CB2Rs as a therapeutic target for treating different disorders revealed important putative role of CB2R in neuropsychiatric disorders that requires further clinical validation. Here we provide current insights and knowledge on the potential role of targeting CB2Rs in neuropsychiatric and neurodegenerative disorders. Its non-psychoactive effect makes the CB2R a potential target for treating CNS disorders; however, a better understanding of the fundamental pharmacology of CB2R activation is essential for the design of novel therapeutic strategies.
... Different studies demonstrated the positive effects of CBD on various obesity-related mechanisms. For instance, CBD was found to reduce body weight [22] and to prevent hyperphagia [23] in rat models. Moreover, a clinical study investigating CBD administration for epilepsy reported loss of appetite as a common side effect [24]. ...
Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader–Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD). Whereas the anti-obesity properties of CBD have been reasonably identified, our knowledge of the pharmacology of CBDA is more limited due to its instability. To stabilize CBDA, a new derivative, CBDA-O-methyl ester (HU-580, EPM301), was synthesized. The therapeutic potential of EPM301 in appetite reduction, weight loss, and metabolic improvements in DIO and GIO was tested in vivo. EPM301 (40 mg/kg/d, i.p.) successfully resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in DIO mice. Additionally, EPM301 ameliorated DIO-induced hepatic dysfunction and steatosis. Importantly, EPM301 (20 and 40 mg/kg/d, i.p.) effectively reduced body weight and hyperphagia in a high-fat diet-fed Magel2null mouse model for PWS. In addition, when given to standard-diet-fed Magel2null mice as a preventive treatment, EPM301 completely inhibited weight gain and adiposity. Lastly, EPM301 increased the oxidation of different nutrients in each strain. All together, EPM301 ameliorated obesity and its metabolic abnormalities in both DIO and GIO. These results support the idea to further promote this synthetic CBDA derivative toward clinical evaluation in humans.
... The current study demonstrates for the first time that the CB2 inverse agonist SMM-189 can restore body weight and suppress colitis symptoms. It has been shown that the neutral CB receptor antagonists AM4113 and AM630 reduce body weight by reducing food intake [35,36]. The data at our disposal does not support the previous findings, because we did not measure the food intake in these mice. ...
The causes of Crohn’s disease (CD) and ulcerative colitis (UC), the two most common forms of inflammatory bowel disease (IBD), are multi-factorial and include dysregulation of immune cells in the intestine. Cannabinoids mediate protection against intestinal inflammation by binding to the G-protein coupled cannabinoid receptors 1 and 2 (CB1 and CB2). Here, we investigate the effects of the CB2 inverse agonist SMM-189 on dextran sodium sulfate (DSS)-induced experimental colitis. We observed that SMM-189 effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis, and increased both body weight and colon length. Treatment with SMM-189 also increased the expression of CB2 and protein kinase A (PKA) in colon lamina propria lymphocytes (LPLs). We noticed alterations in the percentage of Th17, neutrophils, and natural killer T (NKT) cells in the spleen, mesenteric lymph nodes (MLNs), and LPLs of mice with DSS-induced colitis after treatment with SMM-189 relative to DSS alone. Further, myeloid-derived suppressor cells (MDSCs) during colitis progression increased with SMM-189 treatment as compared to DSS alone or with control cohorts. These findings suggest that SMM-189 may ameliorate experimental colitis by inducing the expression of endogenous CB2 and PKA in LPLs, increasing numbers of MDSCs in the spleen, and reducing numbers of Th17 cells and neutrophils in the spleen, MLNs, and LPLs. Taken together, these data support the idea that SMM-189 may be developed as a safe novel therapeutic target for IBD.
... Furthermore, studies involving the administration of CBD within male rats found similar results with regard to food intake [115,191], with others observing a significant decrease in sucrose self-administration as well [192]. Not only has CBD been seen to affect food intake, but the authors of [189] suggested that chronic administration of a 2.5 or 5 mg/kg dose of CBD resulted in a significant decrease in body weight within a group of male Wistar rats. While the mechanism of the CB2Rs' responsibility in regulating body weight is not well understood, the researchers in [207] explained CB2Rs as having a role in improving both glucose tolerance and metabolism. ...
The Cannabis sativa plant has historically been used for both recreational and medical purposes. With the recent surge in recreational use of cannabis among adolescents and adults in particular, there is an increased obligation to determine the short- and long-term effects that consuming this plant may have on several aspects of the human psyche and body. The goal of this article was to examine the negative effects of obesity, and how the use of Δ9-tetrahydrocannibinol (THC) or cannabidiol (CBD) can impact rates of this global pandemic at different timepoints of life. Conflicting studies have been reported between adult and adolescents, as there are reports of THC use leading to increased weight due to elevated appetite and consumption of food, while others observed a decrease in overall body weight due to the regulation of omega-6/omega-3 endocannabinoid precursors and a decrease in energy expenditure. Studies supported a positive correlation between prenatal cannabis use and obesity rates in the children as they matured. The data did not indicate a direct connection between prenatal THC levels in cannabis and obesity rates, but that this development may occur due to prenatal THC consumption leading to low birthweight, and subsequent obesity. Due to the fact that there are not many studies that directly measured the effects that prenatal THC administration has on obesity risks within offspring, this could potentially be a topic of interest to investigate closer in the future.
... This suggests a possibility that CB 2 R expression not only exists in peripheral tissues but also in the brain. As mentioned previously, CB 2 Rs mediate a variety of important modulations in DAassociated behaviors [91], including food intake, body weight [92][93][94][95], depression [96], anxiety [84,97], and schizophrenia-like behavior [85,98]. Recent reports emerging from several labs, including ours, have shown that brain CB 2 Rs play a pivotal role in the elimination of cocaine, alcohol, and nicotine addiction [99][100][101]. ...
Cannabinoids are compounds that were initially isolated from cannabis marihuana and are also widely present in both nervous and immune systems of animals. In recent years, with in-depth research on cannabinoids, their clinical medicinal value has been evaluated, and many exciting achievements have been continuously accumulating, especially in the field of neurodegenerative disease. Alzheimer's disease is the most common type of neurodegenerative disease that causes dementia and has become a global health problem that seriously impacts human health today. In this review, we discuss the therapeutic potential of cannabinoids for the treatment of Alzheimer's disease. How cannabinoids act on different endocannabinoid receptor subtypes to regulate Alzheimer's disease, the roles of the endocannabinoid system in Alzheimer's disease are outlined, and the underlying mechanisms are discussed. Finally, we summarize the most relevant opportunities of cannabinoid pharmacology related to Alzheimer's disease and discuss the potential usefulness of cannabinoids in the clinical treatment of Alzheimer's disease.
... CBD may have the converse action. Studies in mice show increased metabolism and decreased appetite leading to weight loss with high doses of CBD on CB1R and CB2R [5][6][7]. Patients may use different amounts of THC versus CBD, which may ultimately affect weight loss after bariatric surgery. ...
IntroductionMarijuana use has been legalized in several states. It is unclear if marijuana use affects weight loss outcomes or complication rates following bariatric surgery. The purpose of this study was to determine if patients who use marijuana had higher complication rates or lower weight loss compared with non-users.Methods
All patients at a single institution who underwent primary bariatric surgery between July 2015 and July 2020 at a single institution after the legalization of marijuana within the jurisdiction were included. Data regarding marijuana use, weight and complications were abstracted retrospectively. Differences between groups were evaluated with Wilcoxon Rank-Sum tests and Fisher Freeman Halton test. Trends for marijuana use over time was evaluated with simple linear regression on summary data.Results1107 patients met inclusion criteria. 798 (73.3%) were never users, 225 (19.4%) were previous users, and 84 (7.2%) were active users. The proportion of active users and previous users increased over time, with significantly more prior marijuana use reported in more recent years (p = 0.014). Active users had significantly higher pre-procedural BMIs than never users: 48.7 vs. 46.3 (p = 0.03). Any marijuana use (active and previous users) was associated with higher preoperative weight compared to never: 136.4 kg vs. 130.6 kg (p = 0.001). Overall complication rate was low in all groups, and there was no difference in the rates of any complications. Active and previous users tended to lose less weight than never users, but this was not statistically significant (p = 0.17).Conclusions
Active and prior marijuana users tend to have higher BMIs on presentation, but use was not associated with complications or percent weight loss. The incidence of patient reported marijuana use is increasing in the study population. More studies on the effects of marijuana use in this patient population are warranted.
... Previous studies reported that CBD has opposite impacts to those triggered by THC, as it has anti-anxiolytic, anti-epileptic, and antipsychotic properties 60 . While there is conflicting evidence regarding the effects of CBD on food intake and appetite, the meta-analysis suggests that CBD has decreased appetite, although no CBD biological mechanism was fully deciphered [61][62][63] . ...
Despite the increased use of medical cannabinoids, the efficacy and safety of the treatment among children remain uncertain. The objective was to study the efficacy and safety of medical cannabinoids in children. The search included studies through 11-May-2020. Selection criteria included studies evaluating efficacy and safety outcomes of medical cannabinoids (tetrahydrocannabinol, cannabidiol and other cannabis derivatives) versus control in children, independently assessed by two reviewers. Eight studies were included, all of which are randomized controlled trials. Cannabidiol is associated with 50% reduction in seizures rate (Relative Risk (RR) = 1.69, 95% CI [1.20–2.36]) and caregiver global impression of change (Median Estimated difference = (− 1), 95%CI [− 1.39–(− 0.60)]) in Dravet syndrome, compared to placebo. While cannabidiol was associated with a reduction in reported seizure events (RR = 0.59, 95% CI [0.36–0.97]), no association was found in products contained also tetrahydrocannabinol (RR = 1.35, 95% CI [0.46–4.03]). Higher dose of cannabidiol was associated with decreased appetite (RR = 2.40, 95% CI [1.39–4.15]). A qualitative assessment suggests that medical cannabinoids might be associated with adverse mental events. In conclusion, cannabidiol is associated with clinical improvement in Dravet syndrome. However, cannabidiol is also associated with decreased appetite. Adverse mental events were reported as well, however, more research should be performed to assess well this outcome.
... This suggests the possibility that CB 2 R expression not only exists in peripheral tissues, but also in the brain. It has been reported that CB 2 Rs modulate a variety of important processes in dopamine (DA)-related behaviors [38], including food intake [39][40][41][42], anxiety [33,43], depression [44], and schizophrenia-like behavior [34,45]. Recent evidences emerging from several laboratories, including ours, have indicated that brain CB 2 Rs play a pivotal role in the reduction of cocaine, alcohol, and nicotine addiction [46][47][48]. ...
Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non-selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB2 receptors and seizures and emphasize the potential mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia cells. The unique features of CB2Rs, such as lower expression levels under physiological conditions and high inducibility under epileptic conditions, make it an important target for future research on drug-resistant epilepsy.
... Pretreatment with AM630 blocked JWH133-induced reduction in sucrose self-administration. These findings are consistent with previous reports that CB2R antagonism attenuates CBD-induced reductions in food intake, body weight and obesity [61][62][63], and attenuates CBD-produced neuroprotection [64] (Table 2). Table 2. Receptor mechanism studies in vivo in reward-related behaviors in experimental animals. ...
Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT1A receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.
... In seeming contrast to THC effects on food intake, chronic THC administration causes reductions in body weight in rats (Nelson et al., 2019) and analogously, rates of obesity are lower in cannabis users (Smit and Crespo, 2001;Hayatbakhsh et al., 2010). The mechanism of cannabis and cannabinoids effects on energy expenditure, metabolism, and body weight are not yet well understood and are an active area of research (Pagotto et al., 2006;Ignatowska-Jankowska et al., 2011;Ruiz de Azua et al., 2017). ...
Cannabis is one of the most frequently used psychoactive substances in the world. The most common route of administration for cannabis and cannabinoid constituents such as Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is via smoking or vapor inhalation. Preclinical vapor models have been developed, although the vaporization devices and delivery methods vary widely across laboratories. This review examines the emerging field of preclinical vapor models with a focus on cannabinoid exposure in order to (1) summarize vapor exposure parameters and other methodological details across studies; (2) discuss the pharmacological and behavioral effects produced by exposure to vaporized cannabinoids; and (3) compare behavioral effects of cannabinoid vapor administration with those of other routes of administration. This review will serve as a guide for past and current vapor delivery methods in animals, synergize findings across studies, and propose future directions for this area of research.
... Our data are also in line with those obtained by Laprairie et al., since they demonstrated that CBD is a negative allosteric modulator of the CB 1 receptor [50]. On the other hand, in the case of the CBD effect on CB 2 receptors, several studies showed contradictory data, describing its activity as an agonist or inverse agonist of these receptors [51,52]. Our research reported that CBD significantly increased total CB 2 expression in both control and high-fat diet-fed animals. ...
Numerous studies showed that sustained obesity results in accumulation of bioactive lipid derivatives in several tissues, including skeletal muscle, which further contributes to the development of metabolic disturbances and insulin resistance (IR). The latest data indicate that a potential factor regulating lipid and glucose metabolism is a phytocannabinoid—cannabidiol (CBD), a component of medical marijuana (Cannabis). Therefore, we aimed to investigate whether chronic CBD administration influences bioactive lipid content (e.g., ceramide (CER)), as well as glucose metabolism, in the red skeletal muscle (musculus gastrocnemius) with predominant oxidative metabolism. All experiments were conducted on an animal model of obesity, i.e., Wistar rats fed a high-fat diet (HFD) or standard rodent chow, and subsequently injected with CBD in a dose of 10 mg/kg or its solvent for two weeks. The sphingolipid content was assessed using high-performance liquid chromatography (HPLC), while, in order to determine insulin and glucose concentrations, immunoenzymatic and colorimetric methods were used. The protein expression from sphingolipid and insulin signaling pathways, as well as endocannabinoidome components, was evaluated by immunoblotting. Unexpectedly, our experimental model revealed that the significantly intensified intramuscular de novo CER synthesis pathway in the HFD group was attenuated by chronic CBD treatment. Additionally, due to CBD administration, the content of other sphingolipid derivatives, i.e., sphingosine-1-phosphate (S1P) was restored in the high-fat feeding state, which coincided with an improvement in skeletal muscle insulin signal transduction and glycogen recovery.
... Body weight loss, as an auxiliary indicator of depression was significantly attenuated in the CBD-treated group compared to control rats. This could seem to contradict previous results in which CBD was shown to reduce body weight gain in rats [51] and induce the browning of white adipocytes promoting thermogenesis and lipolysis [52]. However, CBD at 10 mg/kg dose did not decrease the body weight of juvenile rats after a three-week treatment [53]. ...
Several neuropharmacological actions of cannabidiol (CBD) due to the modulation of the endocannabinoid system as well as direct serotonergic and gamma-aminobutyric acidergic actions have recently been identified. The current study aimed to reveal the effect of a long-term CBD treatment in the chronic unpredictable mild stress (CUMS) model of depression. Adult male Wistar rats (n = 24) were exposed to various stressors on a daily basis in order to induce anhedonia and anxiety-like behaviors. CBD (10 mg/kg body weight) was administered by daily intraperitoneal injections for 28 days (n = 12). The effects of the treatment were assessed on body weight, sucrose preference, and exploratory and anxiety-related behavior in the open field (OF) and elevated plus maze (EPM) tests. Hair corticosterone was also assayed by liquid chromatography–mass spectrometry. At the end of the experiment, CBD-treated rats showed a higher rate of body weight gain (5.94% vs. 0.67%) and sucrose preference compared to controls. A significant increase in vertical exploration and a trend of increase in distance traveled in the OF test were observed in the CBD-treated group compared to the vehicle-treated group. The EPM test did not reveal any differences between the groups. Hair corticosterone levels increased in the CBD-treated group, while they decreased in controls compared to baseline (+36.01% vs. −45.91%). In conclusion, CBD exerted a prohedonic effect in rats subjected to CUMS, demonstrated by the increased sucrose preference after three weeks of treatment. The reversal of the effect of CUMS on hair corticosterone concentrations might also point toward an anxiolytic or antidepressant-like effect of CBD, but this needs further confirmation.
O canabidiol (CBD) tem sido utilizado para tratar inúmeras condições patológicas principalmente doenças que afetam o sistema nervoso central como epilepsia, esquizofrenia e doenças neurodegenerativas crônicas como Alzheimer e Parkinson. A liberação das formulações com CBD, no Brasil, limita em 0,2% a presença de D9-tetrahidrocanabinol, a substância psicoativa da Cannabis sativa. O neurotransmissor dopamina está relacionado com o sistema de recompensa cerebral e com a doença de Parkinson, entre outras funções. O objetivo deste estudo foi administrar cronicamente CBD, em ratos, via gavage, para avaliar o impacto sobre os níveis de dopamina e no desempenho neuromotor. O estudo foi aprovado pela Comissão de Ética em Uso de Animais institucional (protocolo 173/2020). Ratos Wistar, machos (n=8), receberam via gavage 50 μL completado até 1 mL água/dia de CBD (200 mg/mL). Grupo controle recebeu pela mesma via, 1 mL de água/dia (n=8). Os animais foram pesados mensalmente. Findo o período de 90 dias, os animais foram eutanasiados em câmara de CO2 para a coleta de tecido cerebral e isolamento da preparação neuromuscular. A dosagem neuroquímica foi realizada via HPLC/MS-MS após realização de curva de calibração com 1 mg/mL de dopamina e seus metabólitos 3,4-di-hidroxifenilacetico (DOPAC) e ácido homovanílico (HVA), utilizando como padrão interno, 3,4-di-hidroxibenzilamina. O desempenho neuromotor foi avaliado por técnica miográfica convencional e análise histológica dos músculos por procedimentos de rotina. Os resultados foram expressos em média ± EPM ou ± DP, analisados por Anova One way seguido de Tukey, com p<0,05 indicando significância. Não houve diferença significativa na concentração de dopamina e seus metabólitos entre os grupos experimental e controle, CBD não afetou o desempenho neuromotor e as células musculares esqueléticas. Conclui-se que o CBD administrado cronicamente na concentração eleita mostrou-se seguro, sem causar alterações em nível neuroquímico, nem no desempenho neuromotor, além de preservar a célula muscular esquelética.
The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
Background
The phytocannabinoid cannabidiol (CBD) has been demonstrated to possess anti-inflammatory, anti-seizure, anti-oxidant, and proposed anti-obesity effects. Therapeutic modalities that improve the size of existing adipocytes through a reduction in hypertrophy, or result in increased hyperplasia (increased cell number) and decreased hypertrophy (enlarged cell size) during adipogenesis can result in smaller adipocytes that maintain insulin sensitivity, reducing the incidence of dysfunctional adipose tissue. The effect of timing CBD treatment to the proliferation (mitotic expansion) phase or the differentiation phase of pre-adipocytes on hyperplasia, hypertrophy, and expression of genes involved in triacylglycerol synthesis has not been investigated. We aimed to determine how exposing 3T3-L1 pre-adipocytes to CBD during the expansion or differentiation phase affected proliferation, cell size, and expression of enzymes involved in triacylglycerol synthesis.
Methods
Cells were treated with CBD at doses of 0.2 µM (low [CBD]) or 20 µM (high [CBD]) for measurement of cell viability and proliferation. Additionally, pre-adipocytes were exposed to CBD during proliferation and before stimulation of differentiation (expansion phase) or during the differentiation protocol (differentiation phase) and cell size, total lipid deposition and gene expression of acylglycerophosphate acyltransferase-2 (AGPAT2), diacylglycerol acyltransferase-2 (DGAT2), and glycerol-3-phosphate acyltransferase-3 (GPAT3) were quantified in the mature, lipid-storing adipocytes.
Results
The high CBD dose reduced cell viability and completely inhibited differentiation of pre-adipocytes into mature adipocytes when cells were treated during the differentiation period. Treatment of cells with the high CBD dose during the mitotic clonal expansion period significantly reduced but did not inhibit differentiation of the cells into the mature phenotype. The low CBD dose did not affect cell viability and resulted in increased proliferation and smaller mature adipocytes that did not differ from control cells with regards to lipid droplet deposition but that exhibited changes in gene expression of AGPAT and GPAT.
Conclusions
Our results suggest that a low (0.2 µM), physiologically achievable dose of CBD affects mature adipocyte cell size and gene expression of acyltransferases involved in triacylglycerol synthesis and that these effects are dependent on timing the CBD exposure to the cell’s mitotic clonal expansion phase.
Abstract Metabolic syndrome (MetS), an epidemic defined as a group of interconnected physiological, biochemistry, clinical, and metabolic factors, directly increases the risk of cardiovascular disease, atherosclerosis, type 2 diabetes, and death. MetS therapy includes diet, physical exercise, and a poly-pharmacological intervention. Cannabis is mainly recognized for its recreational uses and has several medical applications for neurological diseases, due to its hypnotic, anxiolytic, antinociceptive, anti-inflammatory, and anticonvulsant activities. Although several clinical observations in Cannabis smokers suggest metabolic effects, its utility in metabolic disorders is unclear. This review aims to determine under what conditions Cannabis might be useful in the treatment of MetS. Cannabis contains 120 phytocannabinoids, of which Δ9-THC mediates its psychoactive effects. Cannabinoids exert biological effects through interactions with the endocannabinoid system, which modulates several physiologic and metabolic pathways through cannabinoid receptors (CB1/CB2). Signaling through both receptors inhibits neurotransmitter release. In general, endocannabinoid system stimulation in Cannabis smokers and Δ9-THC signaling through CB1 have been implicated in MetS development, obesity, and type 2 diabetes. In contrast, CB1 antagonists and non-psychotropic phytocannabinoids like cannabidiol reduce these effects through interactions with both cannabinoid and non-cannabinoid receptors. These pharmacological approaches represent a source of new therapeutic agents for MetS. However, more studies are necessary to support the therapeutic potential of Cannabis and cannabinoids in metabolic abnormalities.
The excessive consumption of ultra-processed foods and the development of obesity has been associated with several comorbidities, including psychiatric disorders. Excess fat tissue promotes a low-intensity inflammatory state, mainly in the white tissue, which is essential in developing metabolic alterations and influences brain homeostasis. In this scenario, Cannabidiol (CBD), a compound from Cannabis sativa, has presented anxiolytic and anti-inflammatory effects in murine models. This study verified whether CBD treatment would ameliorate the compulsive-like and anxiety-like behaviors observed after mice’s chronic consumption of a high-refined carbohydrate (HC) diet. BALB/c male mice received a control or HC diet for 12 weeks followed by vehicle and CBD (30 mg/Kg, i.p.) administration, and their behavior was evaluated in the Marble Burying test (MB) and Novel Suppressing Feeding test (NSF). The sub-chronic, but not acute, treatment with CBD attenuated the compulsive-like and anxiogenic-like behavior induced by the HC diet. Our data reinforced the harmful effects of the HC diet’s chronic consumption on compulsive and anxious behaviors and the potential of CBD as a drug treatment for psychiatric disorders associated with obesity.
Aging predisposes to late-life depression and since antidepressants are known to change their efficacy with age, novel treatment options are needed for our increased aged population. In this context, the goal of the present study was to evaluate the potential antidepressant-like effect of cannabidiol in aged rats. For this purpose, 19–21-month-old Sprague–Dawley rats were treated for 7 days with cannabidiol (dose range: 3–30 mg/kg) and scored under the stress of the forced-swim test. Hippocampal cannabinoid receptors and cell proliferation were evaluated as potential molecular markers underlying cannabidiol’s actions. The main results of the present study demonstrated that cannabidiol exerted a dose-dependent antidepressant-like effect in aged rats (U-shaped, effective at the intermediate dose of 10 mg/kg as compared to the other doses tested), without affecting body weight. None of the molecular markers analyzed in the hippocampus were altered by cannabidiol’s treatment. Overall, this study demonstrated a dose-dependent antidepressant-like response for cannabidiol at this age-window (aged rats up to 21 months old) and in line with other studies suggesting a beneficial role for this drug in age-related behavioral deficits.
Cannabidiol (CBD) is a substance derived from Cannabis sativa, widely studied in medicine for controlling neural diseases in humans. Besides the positive effects on humans, it also presents anxiolytic proprieties and decreases aggressiveness and stress in mammals. Therefore, CBD has the potential to increase welfare in reared animals, as it seems to reduce negative states commonly experienced in artificial environments. Here, we tested the effect of different CBD doses (0,1,10, and 20 mg/kg) on aggressiveness, stress, and reproductive development of the Nile tilapia ( Oreochromis niloticus ) a worldwide fish reared for farming and research purposes. CBD mixed with fish food was offered to isolated fish for 5 weeks. The 10 mg/kg dose decreased fish’s aggressiveness over time, whereas 20 mg/kg attenuated non-social stress. Both doses decreased the baseline cortisol level of fish and increased the gonadosomatic index. However, CBD 1 and 10 mg/kg doses decreased the spermatozoa number. All CBD doses did not affect feeding ingestion and growth variables, showing that it is not harmful to meat production amount. Despite the effect on spermatozoa, CBD supplementation exhibits high potential to benefit animals’ lives on an integrative-based welfare approach. Therefore, we showed for the first time that CBD could be used as a tool to increase non-mammal welfare, presenting a great potential to be explored in other husbandry and captivity species.
Reduced glucose uptake and utilization, with concomitant lipolysis in adipose tissues has been linked to the pathogenesis of obesity and its complications. The present study investigated the effect of cannabinoid-stimulated glucose uptake on redox imbalance, glucose and lipid metabolisms, as well as cholinergic and purinergic dysfunctions in isolated rats' adipose tissues. Freshly Isolated rats' adipose tissues were incubated with glucose and different concentrations of cannabidiol for 2 h at 37 • C. The negative control consisted of incubation without cannabidiol, while normal control consisted of incubations without glucose and/or cannabidiol and Metformin served as the standard drug. Cannabidiol caused an increase in adipose-glucose uptake, with concomitant elevation of glutathione, triglyceride level, superoxide dismutase, catalase and 5 ′ nucleotidase activities. It also caused suppression in malondialdehyde and cholesterol levels, acetylcholinesterase, ENTPDase, fructose-1,6-biphosphatase, glucose 6-phosphatase, glycogen phosphorylase, and lipase activities. In silico studies revealed a strong molecular interaction of cannabidiol with adipose triglyceride lipase, hormone-sensitive lipase, and monoglyceride lipase. These results indicate that cannabidiol-enhanced glucose uptake in adipose tissues is associated with enhanced antioxidative activities, concomitant modulation of cholinergic and purinergic dys-functions, and improved glucose-lipid homeostasis.
Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) share the pathological hallmark of intracellular neurofibrillary tangles, which result from the hyperphosphorylation of microtubule associated protein tau. The P301S mutation in human tau carried by TAU58/2 transgenic mice results in brain pathology and behavioural deficits relevant to FTD and AD.
The phytocannabinoid cannabidiol (CBD) exhibits properties beneficial for multiple pathological processes evident in dementia. Therefore, 14-month-old female TAU58/2 transgenic and wild type-like (WT) littermates were treated with 100 mg/kg CBD or vehicle i.p. starting three weeks prior to conducting behavioural paradigms relevant to FTD and AD.
TAU58/2 females exhibited impaired motor function, reduced bodyweight and less anxiety behaviour compared to WT. An impaired spatial reference memory of vehicle-treated transgenic mice were restored by chronic CBD treatment. Chronic CBD also reduced anxiety-like behaviors and decreased contextual fear-associated freezing in all mice.
Chronic remedial CBD treatment ameliorated several disease-relevant phenotypes in 14-month-old TAU58/2 transgenic mice, suggesting potential for the treatment of tauopathy-related behavioural impairments including cognitive deficits.
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.
Cannabidiol (CBD) is a non-intoxicating phytocannabinoid whose purported therapeutic benefits and impression of a high safety profile has promoted its increasing popularity. CBD’s popularity is also increasing among children and adolescents who are being administered CBD, off label, for the treatment of numerous symptoms associated with autism spectrum disorder, attention deficit hyperactivity disorder, anxiety, and depression. The relative recency of its use in the adolescent population has precluded investigation of its impact on the developing brain and the potential consequences that may present in adulthood. Therefore, there’s an urgency to identify whether prolonged adolescent CBD exposure has substantive impacts on the developing brain that impact behavioral and cognitive processes in adulthood. Here, we tested the effect of twice-daily intraperitoneal administrations of CBD (20 mg/kg) in male and female C57BL/6J mice during the adolescent period of 25–45 days on weight gain, and assays for locomotor behavior, anxiety, and spatial memory. Prolonged adolescent CBD exposure had no detrimental effects on locomotor activity in the open field, anxiety behavior on the elevated plus maze, or spatial memory in the Barnes Maze compared to vehicle-treated mice. Interestingly, CBD-treated mice had a faster rate of learning in the Barnes Maze. However, CBD-treated females had reduced weight gain during the exposure period. We conclude that prolonged adolescent CBD exposure in mice does not have substantive negative impacts on a range of behaviors in adulthood, may improve the rate of learning under certain conditions, and impacts weight gain in a sex-specific manner.
The non-psychoactive component of Cannabis Sativa, cannabidiol (CBD), has centered the attention of a large body of research in the last years. Recent clinical trials have led to the FDA approval of CBD for the treatment of children with drug-resistant epilepsy. Even though it is not yet in clinical phases, its use in sleep-wake pathological alterations has been widely demonstrated.Despite the outstanding current knowledge on CBD therapeutic effects in numerous in vitro and in vivo disease models, diverse questions still arise from its molecular pharmacology. CBD has been shown to modulate a wide variety of targets including the cannabinoid receptors, orphan GPCRs such as GPR55 and GPR18, serotonin, adenosine, and opioid receptors as well as ligand-gated ion channels among others. Its pharmacology is rather puzzling and needs to be further explored in the disease context.Also, the metabolism and interactions of this phytocannabinoid with other commercialized drugs need to be further considered to elucidate its clinical potential for the treatment of specific pathologies.Besides CBD, natural and synthetic derivatives of this chemotype have also been reported exhibiting diverse functional profiles and providing a deeper understanding of the potential of this scaffold.In this chapter, we analyze the knowledge gained so far on CBD and its analogs specially focusing on its molecular targets and metabolic implications. Phytogenic and synthetic CBD derivatives may provide novel approaches to improve the therapeutic prospects offered by this promising chemotype.
Vagal afferent neurons abundantly express excitatory transient receptor potential (TRP) channels which strongly influence afferent signaling. Cannabinoids have been identified as direct agonists of TRP channels, including TRPA1 and TRPV1, suggesting exogenous cannabinoids may influence vagal signaling via TRP channel activation. The diverse therapeutic effects of electrical vagus nerve stimulation also result from administration of the non-psychotropic cannabinoid cannabidiol (CBD); however, the direct effects of CBD on vagal afferent signaling remain unknown. We investigated actions of CBD on vagal afferent neurons using calcium imaging and electrophysiology. CBD produced strong excitatory effects in neurons expressing TRPA1. CBD responses were prevented by removal of bath calcium, ruthenium red, and the TRPA1 antagonist A967079; but not the TRPV1 antagonist SB366791; suggesting an essential role for TRPA1. These pharmacological experiments were confirmed using genetic knockouts where TRPA1 KO mice lacked CBD responses while TRPV1 KO mice exhibited CBD-induced activation. We also characterized CBD-provoked inward currents at resting potentials in vagal afferents expressing TRPA1 that were absent in TRPA1 KO mice, but persisted in TRPV1 KO mice. CBD also inhibited voltage-activated sodium conductances in A-fiber, but not C-fiber afferents. To simulate adaptation resulting from chronic cannabis use, we administered cannabis extract vapor daily for three weeks. Cannabis exposure reduced the magnitude of CBD responses likely due to a loss of TRPA1 signaling. Together these findings detail a novel excitatory action of CBD at vagal afferent neurons which requires TRPA1 and may contribute to the vagal mimetic effects of CBD and adaptation following chronic cannabis use.
Chronic hepatitis C virus (HCV) infection is a risk factor of insulin resistance, and HCV‐infected patients are at a high risk of developing diabetes. In the general population, research has shown the potential benefit of cannabis use for the prevention of diabetes and related metabolic disorders. We aimed to test whether cannabis use is associated with a lower risk of diabetes in chronic HCV‐infected patients.Chronic HCV‐infected patients (n=10,445) were selected from the French national, multicenter, observational ANRS CO22 Hepather cohort. Cross‐sectional data collected at cohort enrolment were used to assess the association between patients’ clinical and behavioral characteristics and the risk of diabetes. Logistic regression model was performed with cannabis use as the main independent variable and a significance level set at 5%. A similar model stratified by the presence of advanced liver fibrosis (FIB‐4>3.25) was also run. After multivariable adjustment, current (AOR [95%CI]: 0.49 [0.38‐0.63]) and former (0.81 [0.67‐0.98], p<.001) cannabis use were both associated with a reduced odds of diabetes. Conversely, male gender, tobacco use, elevated BMI, poverty, being a migrant and advanced fibrosis were associated with increased odds of diabetes. The association between cannabis use and diabetes was maintained in the stratified analysis. In this large cross‐sectional study of chronic HCV‐infected patients, cannabis use was associated with a lower risk of diabetes independently of clinical and socio‐behavioral factors. Further studies are needed to elucidate a potential causal link and shed light on cannabis compounds and mechanisms involved in this relationship.
Objectives: Tardive dyskinesia (TD) unlike acute dystonia may be irreversible. This study investigated the effects of oral cannabidiol (CBD) on haloperidol induced vacuous chewing movement (VCM) model of TD.
Methods: There were six experimental groups with different combinations of oral cannabidiol with 5mg/kg of haloperidol given orally. Behavioural assays and FBS were measured. Vacuous chewing movements were assessed after the last dose of medication. Blood for oxidative stress assay was collected on the 8th day after the administration of the last dose of medication.
Results: This study found that CBD co-administration with haloperidol attenuated the vacuous chewing movements and increased motor tone produced by haloperidol. CBD alone at 5 mg/kg appears to have anxiolytic properties but may not be as effective as haloperidol which exhibited a greater anxiolytic effect at 5 mg/kg. Treatment with CBD alone at 5mg/kg also appeared to enhance brain DPPH scavenging activity.
Conclusions: We confirmed that CBD can ameliorate motor impairments produced by haloperidol. Our data suggest that CBD can be combined with haloperidol to prevent the emergent of extrapyramidal side effects and long-term movement disorders, such as acute dystonic disorder and tardive dyskinesia.
Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver.
Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-).
In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice.
These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorders.
Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence implicates the CB(1) receptor in the production of antinociception. However, the capacity of CB(2) receptors, which are located outside the central nervous system (CNS), to produce antinociception is not known. Using AM1241, a CB(2) receptor-selective agonist, we demonstrate that CB(2) receptors produce antinociception to thermal stimuli. Injection of AM1241 in the hindpaw produced antinociception to a stimulus applied to the same paw. Injection of an equivalent dose of AM1241 into the paw contralateral to the side of testing did not. The antinociceptive actions of AM1241 were blocked by the CB(2) receptor-selective antagonist AM630, but not by the CB(1) receptor-selective antagonist AM251. AM1241 also produced antinociception when injected systemically (intraperitoneally). The antinociceptive actions of systemic AM1241 were blocked by injection of AM630 into the paw where the thermal stimulus was applied, but not the contralateral paw. These findings demonstrate the local, peripheral nature of CB(2) cannabinoid antinociception. AM1241 did not produce the CNS cannabinoid effects of hypothermia, catalepsy, inhibition of activity or impaired ambulation, while this tetrad of effects was produced by the mixed CB(1)/CB(2) receptor agonist WIN55,212-2. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB(2) receptors. CB(2) receptor agonists may have promise clinically for the treatment of pain without CNS cannabinoid side effects.
This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.
Endocannabinoids were first defined in 1995 as 'endogenous substances capable of binding to and functionally activating the cannabinoid receptors'. To date, two well-established endocannabinoids, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as a few other putative ligands, all derived from long-chain polyunsaturated fatty acids, have been identified in animal tissues. The biosynthetic and metabolic pathways for anandamide and 2-AG have been elucidated, and most of the enzymes therein involved have been cloned. We now know that CB1 receptors, and endocannabinoids in tissue concentrations sufficient to activate them, are more widely distributed than originally thought, and are found in brain and peripheral organs involved in the control of energy intake and processing, including the hypothalamus, nucleus accumbens, brainstem, vagus nerve, gastrointestinal tract, adipose tissue and liver. Endocannabinoid biosynthetic and inactivating pathways are under the regulation of neuropeptides and hormones involved in energy homeostasis, and endocannabinoid levels are directly affected by the diet. Endocannabinoids, in turn, regulate the expression and action of mediators involved in nutrient intake and processing. These cross-talks are at the basis of the proposed role of endocannabinoid signalling in the control of food intake, from invertebrates to lower vertebrates and mammals, and their perturbation appears to contribute to the development of eating disorders.
The link between excess intra-abdominal adiposity (IAA) and metabolic complications leading to type 2 diabetes and cardiovascular disease is well recognized. Blockade of endocannabinoid action at cannabinoid CB(1) receptors was shown to reduce these complications. Here, we investigated the relationship between IAA, circulating endocannabinoid levels and markers of cardiometabolic risk in male obese subjects.
Fasting plasma levels of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), were measured by liquid chromatography-mass spectrometry in a study sample of 62 untreated asymptomatic men with body mass index (BMI) from 18.7 to 35.2 kg/m(2).
Plasma 2-AG, but not AEA, levels correlated positively with BMI, waist girth, IAA measured by computed tomography, and fasting plasma triglyceride and insulin levels, and negatively with high-density lipoprotein cholesterol and adiponectin levels. Obese men with similar BMI values (> or =30 kg/m(2)) but who markedly differed in their amount of IAA (< vs > or = 130 cm(2), n=17) exhibited higher 2-AG levels in the presence of high IAA. No difference in 2-AG concentrations was observed between obese men with low levels of IAA vs nonobese controls.
These results provide evidence for a relationship in men between a key endocannabinoid, 2-AG, and cardiometabolic risk factors, including IAA.
The aim of this review is to present some of the recent publications on cannabidiol (CBD; 2), a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms. The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity.
Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown.
In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain.
Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.
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.
(−)-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
To investigate the mechanisms involved in cannabidiol (CBD)-induced neuroprotection in hypoxic-ischemic (HI) immature brain, forebrain slices from newborn mice underwent oxygen and glucose deprivation in the presence of vehicle, or CBD alone or with selective antagonists of cannabinoid CB(1) and CB(2), and adenosine A(1) and A(2) receptors. CBD reduced acute (LDH efflux to the incubation medium) and apoptotic (caspase-9 concentration in tissue) HI brain damage by reducing glutamate and IL-6 concentration, and TNFalpha, COX-2, and iNOS expression. CBD effects were reversed by the CB(2) antagonist AM630 and by the A(2A) antagonist SCH58261. The A(1A) antagonist DPCPX only counteracted the CBD reduction of glutamate release, while the CB(1) antagonist SR141716 did not modify any effect of CBD. In conclusion, CBD induces robust neuroprotection in immature brain, by acting on some of the major mechanisms underlying HI cell death; these effects are mediated by CB(2) and adenosine, mainly A(2A), receptors.
Marijuana use activates cannabinoid receptors (CB-Rs) producing several behavioral effects related to addiction, mood, and appetite. We investigated the association between CNR2 gene, which encodes cannabinoid CB2 receptor (CB2-R) and eating disorders in 204 subjects with eating disorders and 1876 healthy volunteers in Japanese population. The effect of treatment with CB2-R ligands on mouse food consumption was also determined. The CB2-R ligands used suppressed food intake in a time- and strain-dependent manner when food was available ad libitum and during the 12-h fast except, AM 630-the CB2-R antagonist that stimulated food consumption in food-deprived mice. There is an association between the R63Q polymorphism of the CNR2 gene and eating disorders (P = 0.04; Odds ratio 1.24, 95% CI, (1.01-1.53). These results suggest that cannabinoid CB2-R is involved in the endocannabinoid signaling mechanisms associated with the regulation of food intake and in eating disorders.
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)-tetrahydrocannabinol, 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)-tetrahydrocannabinol. 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.
Obesity is a severe health problem in the modernized world and understanding the central nervous mechanisms underlying food-seeking behaviour and reward are at the forefront of medical research. Cannabinoid receptors have proven an efficient target to suppress hunger and weight gain by their pharmacological inactivation.
A standard fasted protocol and a novel long-term home-cage observation system with free-feeding animals were used to assess the feeding behaviour of mice treated with the CB1 antagonist AM251. Similarly, the effects of the phytocannabinoid Delta9-tetrahydrocannabivarin (Delta9-THCV), which behaves like a CB1 antagonist, were also determined in free-feeding animals.
AM251 suppressed food intake and weight gain in fasted and non-fasted animals. The suppression of food intake by AM251 (10 mg.kg-1) endured for a period of 6-8 h when administered acutely, and was continuous when injected for four consecutive days. Pure Delta9-THCV also induced hypophagia and weight reduction at doses as low as 3 mg.kg-1. No rebound was observed on the following day with all drug groups returning to normal activity and feeding regimes. However, a Delta9-THCV-rich cannabis-extract failed to suppress food intake and weight gain, possibly due to residual Delta9-tetrahydrocannabinol (Delta9-THC) in the extract. This Delta9-THC effect was overcome by the co-administration of cannabidiol.
The data strongly suggest (i) the long-term home-cage observation system is a sensitive and obesity-relevant tool, and (ii) the phytocannabinoid Delta9-THCV is a novel compound with hypophagic properties and a potential treatment for obesity
Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed.
Cannabidiol is the main nonpsychoactive component of marijuana. We examined the ability of in vivo and in vitro cannabidiol to interfere with the production of interleukin (IL)-12 and IL-10 by murine macrophages and to modulate macrophage chemotaxis. Cannabidiol added in vitro to peritoneal macrophages significantly increased IL-12 and decreased IL-10 production. The CB1 and CB2 receptor antagonists prevented this modulation. Macrophages from animals treated with cannabidiol at the dose of 30 mg kg(-1) either orally or i.p. produced higher levels of IL-12 and lower levels of IL-10 in comparison to controls, and the CB receptor antagonists did not prevent these effects. Cannabidiol dose-dependently decreased fMLP-induced chemotaxis of macrophages, and the CB2 receptor antagonist prevented this decrease.
1 Marijuana's appetite-increasing effects have long been known. Recent research suggests that the CB(1) cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB(1) cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food-restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB(1) antagonist SR141716A dose-dependently decreased food consumption at doses that did not affect motor activity, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased food consumption at doses that had no effect on motor activity. O-3259 and O-3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB(2) cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild-type mice, but lacked pharmacological activity in CB(1) knockout mice; however, basal food intake was lower in CB(1) knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB(1) receptors may play a role in regulation of feeding behavior.
Marijuana and its major psychotropic component, Delta(9)-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB(1) cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes.
Brain expression of CB2 cannabinoid receptors has been much less well established and characterized in comparison to the expression of brain CB1 receptors. Since CB2 receptors are intensely expressed in peripheral and immune tissues, expression in brain microglia has been anticipated. Nevertheless, we now describe expression of CB2-receptor-like immunoreactivity in brain in neuronal patterns that support broader CNS roles for this receptor. Two anti-CB2 affinity purified polyclonal antibodies were raised in rabbits immunized with peptide conjugates that corresponded to amino acids 1-33 and 20-33. Western blot analyses revealed specific bands that were identified using these sera and were absent when the sera were preadsorbed with 8.3 mug/ml of the immunizing peptides. These studies, and initial RT-PCR analyses of brain CB1 and CB2 mRNAs, also support the expression of brain CB2 receptor transcripts at levels much lower than those of CB1 receptors. CB2 cannabinoid receptor mRNA was clearly expressed in the cerebellum of wild type but not in CB2 knockout mice. CB2 immunostaining was detected in the interpolar part of spinal 5th nucleus of wild type but not in CB2 knockout mice, using a mouse C-terminal CB2 receptor antibody. Immunohistochemical analyses revealed abundant immunostaining for CB2 receptors in apparent neuronal and glial processes in a number of rat brain areas. Cerebellar Purkinje cells and hippocampal pyramidal cells revealed substantial immunoreactivity that was absent when sections were stained with preadsorbed sera. CB2 immunoreactivity was also observed in olfactory tubercle, islands of Calleja, cerebral cortex, striatum, thalamic nuclei, hippocampus, amygdala, substantia nigra, periaqueductal gray, paratrochlear nucleus, paralemniscal nucleus, red nucleus, pontine nuclei, inferior colliculus and the parvocellular portion of the medial vestibular nucleus. In-vitro, CB2 immunoreactivity was also present in hippocampal cell cultures. The multifocal expression of CB2 immunoreactivity in glial and neuronal patterns in a number of brain regions suggests reevaluation of the possible roles that CB2 receptors may play in the brain.
Mammalian tissues express the cannabinoid 1 (CB(1)) receptor and the cannabinoid 2 (CB(2)) receptor, the latter being involved in inflammation and pain. In somatic nerve pathways, the analgesic effects of CB(2) agonism are well documented. Two papers published in the Journal have provided evidence that CB(2) receptor activation inhibits visceral afferent nerve activity in rodents. These exciting findings are discussed in the context of recent data highlighting the emerging role of CB(2) receptor as a critical target able to counteract hypermotility in pathophysiological states, gut inflammation and possibly colon cancer.
As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment.
Molecular targets for cannabid-iol and its synthetic analogues: effects on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide
- J B Moriello
- R Davis
- V Mechoulam
- Di
Moriello, J.B. Davis, R. Mechoulam, V. Di Marzo, Molecular targets for cannabid-iol and its synthetic analogues: effects on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide, Br. J. Pharmacol. 134 (2001) 845–852.
Targeting the endocannabinoid system: to enhance or to reduce?
- Di Marzo
V. Di Marzo, Targeting the endocannabinoid system: to enhance or to reduce?
Nat. Rev. Drug Discov. 7 (2008) 438-455.