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Cannabidiol decreases body weight gain in rats: Involvement of CB2 receptors
... Furthermore, it has been reported that CBD may have therapeutic potential in controlling food intake and preventing obesity. A number of studies indicate that CBD can inhibit food consumption [20][21][22] and responding for food or sweetened water in rats and monkeys. 23,24 In contrast, a lack of CBD effects on food-related behaviors in rats or mice has also been reported. ...
... The present finding is consistent with previous reports that CBD is effective and useful at controlling food intake and body weight and in preventing the development of obesity. [20][21][22]51 It is also consistent with previous reports that CBD may have a therapeutic value to treat substance use disorders and obesity as it has the ability to reduce rewarding effects of alcohol 28 , cocaine, and methamphetamine. 29,30,52 Although CBD failed to alter heroin self-administration, it reduced cue-induced reinstatement of drug seeking 53 and facilitated the extinction of psychostimulant-induced conditioned place preference (CPP). ...
... First, deletion of CB2Rs abolished CBD action; second, pretreatment with AM630, a selective CB2R antagonist, prevented CBD action; third, JWH133, a selective CB2R agonist, produced a similar effect as CBD; and fourth, pretreatment with AM630 blocked JWH133 action on sucrose self-administration. These findings are consistent with previous reports indicating that a CB2R-dependent mechanism is closely associated with CBD-induced reduction in food intake, body weight, and obesity 21,69,70 and with CBD-produced neuroprotection. 50,71 The molecular mechanisms through which CBD modulates CB2R function are still not fully understood. ...
A growing number of studies suggest therapeutic applications of cannabidiol (CBD), a recently U.S. Food and Drug Administration (FDA)–approved medication for epilepsy, in treatment of many other neuropsychological disorders. However, pharmacological action and the mechanisms by which CBD exerts its effects are not fully understood. Here, we examined the effects of CBD on oral sucrose self‐administration in rodents and explored the receptor mechanisms underlying CBD‐induced behavioral effects using pharmacological and transgenic approaches. Systemic administration of CBD (10, 20, and 40 mg/kg, ip) produced a dose‐dependent reduction in sucrose self‐administration in rats and in wild‐type (WT) and CB1−/− mice but not in CB2−/− mice. CBD appeared to be more efficacious in CB1−/− mice than in WT mice. Similarly, pretreatment with AM251, a CB1R antagonist, potentiated, while AM630, a selective CB2R antagonist, blocked CBD‐induced reduction in sucrose self‐administration, suggesting the involvement of CB1 and CB2 receptors. Furthermore, systemic administration of JWH133, a selective CB2R agonist, also produced a dose‐dependent reduction in sucrose self‐administration in WT and CB1−/− mice, but not in CB2−/− mice. Pretreatment with AM251 enhanced, while AM630 blocked JWH133‐induced reduction in sucrose self‐administration in WT mice, suggesting that CBD inhibits sucrose self‐administration likely by CB1 receptor antagonism and CB2 receptor agonism. Taken together, the present findings suggest that CBD may have therapeutic potential in reducing binge eating and the development of obesity. Cannabidiol is a recently U.S. FDA approved medication for the treatment of epilepsy. In this study, we found that it is also effective in controlling food‐taking behavior in rats and mice largely by activation of cannabinoid CB2 receptor.
... 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]. ...
Background:
Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic terpenophenols isolated from Cannabis sativa, which, besides their anti-inflammatory/antioxidant effects, are able to inhibit, the first, and to stimulate, the second, the appetite although there are no studies elucidating their role in the hypothalamic appetite-regulating network. Consequently, the aim of the present research is to investigate the role of CBD and CBG in regulating hypothalamic neuromodulators. Comparative evaluations between oxidative stress and food intake-modulating mediators were also performed.
Methods:
Rat hypothalamic Hypo-E22 cells and isolated tissues were exposed to either CBD or CBG, and the gene expressions of neuropeptide (NP)Y, pro-opiomelanocortin (POMC) and fatty acid amide hydrolase were assessed. In parallel, the influence of CBD on the synthesis and release of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) was evaluated. The 3-hydroxykinurenine/kinurenic acid (3-HK/KA) ratio was also determined.
Results:
Both CBD and CBG inhibited NPY and POMC gene expression and decreased the 3-HK/KA ratio in the hypothalamus. The same compounds also reduced hypothalamic NE synthesis and DA release, whereas the sole CBD inhibited 5-HT synthesis.
Conclusion:
The CBD modulates hypothalamic neuromodulators consistently with its anorexigenic role, whereas the CBG effect on the same mediators suggests alternative mechanisms, possibly involving peripheral pathways.
... 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.
... 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.
... 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.
... Moreover, cannabidiol (15 and 30 mg/kg, oral administration during 34 days, PND 21-55) did not alter body weight in mice (Carvalho et al. 2018). Interestingly, when revising the current literature exploring the effects of cannabidiol in adult rats, some prior studies suggested that while acute cannabidiol did not affect body weight (de Morais et al. 2018), its repeated treatment decreased body weight in rodents (e.g., Ignatowska-Jankowska et al. 2011;Santiago et al. 2019), an effect that was prevented by a CB 2 receptor antagonist (Ignatowska-Jankowska et al. 2011). There is a broad literature suggesting a potential role for endocannabinoids in controlling body weight by regulating circuits that coordinate energy homeostasis (e.g., Di Di Marzo and Matias 2005;Horn et al. 2018), mainly through drugs that function as an antagonist or inverse agonist over CB 1 receptors (e.g., rimonabant; Horn et al. 2018). ...
... Moreover, cannabidiol (15 and 30 mg/kg, oral administration during 34 days, PND 21-55) did not alter body weight in mice (Carvalho et al. 2018). Interestingly, when revising the current literature exploring the effects of cannabidiol in adult rats, some prior studies suggested that while acute cannabidiol did not affect body weight (de Morais et al. 2018), its repeated treatment decreased body weight in rodents (e.g., Ignatowska-Jankowska et al. 2011;Santiago et al. 2019), an effect that was prevented by a CB 2 receptor antagonist (Ignatowska-Jankowska et al. 2011). There is a broad literature suggesting a potential role for endocannabinoids in controlling body weight by regulating circuits that coordinate energy homeostasis (e.g., Di Di Marzo and Matias 2005;Horn et al. 2018), mainly through drugs that function as an antagonist or inverse agonist over CB 1 receptors (e.g., rimonabant; Horn et al. 2018). ...
RationaleCannabidiol is a non-psychoactive phytocannabinoid with great therapeutic potential in diverse psychiatric disorders; however, its antidepressant potential has been mainly ascertained in adult rats.Objectives
To compare the antidepressant-like response induced by cannabidiol in adolescent and adult rats and the possible parallel modulation of hippocampal neurogenesis.Methods
Male Sprague-Dawley rats were repeatedly treated with cannabidiol (3, 10, and 30 mg/kg) or vehicle (1 mL/kg) during adolescence (postnatal days, PND 27-33) or adulthood (PND 141-147) and exposed to 3 consecutive tests (forced swim, open field, two-bottle choice) that quantified behavioral despair, anxiety, and sucrose intake respectively.ResultsCannabidiol induced differential effects depending on the age and dose administered, with a decreased sensitivity observed in adolescent rats: (1) cannabidiol (30 mg/kg) decreased body weight only in adult rats; (2) cannabidiol ameliorated behavioral despair in adolescent and adult rats, but with a different dose sensitivity (10 vs. 30 mg/kg), and with a different extent (2 vs. 21 days post-treatment); (3) cannabidiol did not modulate anxiety-like behavior at any dose tested in adolescent or adult rats; and (4) cannabidiol increased sucrose intake in adult rats.Conclusions
Our findings support the notion that cannabidiol exerts antidepressant- and anorexigenic-like effects in adult rats and demonstrate a decreased potential when administered in adolescent rats. Moreover, since cannabidiol did not modulate hippocampal neurogenesis (cell proliferation and early neuronal survival) in adolescent or adult rats, the results revealed potential antidepressant-like effects induced by cannabidiol without the need of regulating hippocampal neurogenesis.
... Furthermore, it was indicated that CBD is able to block CB 1 receptor, thereby producing anti-obesity effects. Otherwise, CBD unexpectedly exhibited a high affinity for CB 2 receptor as an agonist or inverse agonist depending on the research model (in vitro or in vivo) (54,55). An interesting result of the latest studies was the fact that CBD has greater affinity for various eCBome receptors, including GPR55, α1adrenoreceptors, 5-HT 1A , TRPV channels and PPARγ (Figure 2) (19,26,42,56,57). ...
... Additionally, recent research has shown that CBD inhibited weight gain in rats subjected to high fat diet (HFD) for 14 days and this effect was probably mediated by CB 2 receptor (54). The authors confirmed the above effect by using a selective CB 2 antagonist-AM630, which prevented the reduction in weight gain due to CBD treatment (54). However, additional studies are required to uncover the mechanisms by which CBD induces the above metabolic changes in adipocytes. ...
Currently, an increasing number of diseases related to insulin resistance and obesity is an alarming problem worldwide. It is well-known that the above states can lead to the development of type 2 diabetes, hypertension, and cardiovascular diseases. An excessive amount of triacylglycerols (TAGs) in a diet also evokes adipocyte hyperplasia and subsequent accumulation of lipids in peripheral organs (liver, cardiac muscle). Therefore, new therapeutic methods are constantly sought for the prevention, treatment and alleviation of symptoms of the above mentioned diseases. Currently, much attention is paid to Cannabis derivatives—phytocannabinoids, which interact with the endocannabinoid system (ECS) constituents. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant compounds of Cannabis plants and their therapeutic application has been suggested. CBD is considered as a potential therapeutic agent due to its anti-inflammatory, anti-oxidant, anti-tumor, neuroprotective, and potential anti-obesity properties. Therefore, in this review, we especially highlight pharmacological properties of CBD as well as its impact on obesity in different tissues.
... 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.
... 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.
... 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.
... In some in vitro assays, CBD action has been linked to CB 2 Rs activation because some in vivo effects were blocked by the administration of a CB 2 R antagonist. Thus, Ignatowska-Jankowska et al. (2011), using AM630 as antagonist, reported that the weight gain-reducing effect of CBD apparently 1 www.guidetopharmacology.org involved CB 2 Rs. In addition, the well-substantiated protective role of CBD in newborn hypoxia-ischemia correlates with CB 2 R expression (Castillo et al., 2007;Alvarez et al., 2008;Lafuente et al., 2011;Pazos et al., 2013). ...
The mechanism of action of cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa L., is not completely understood. First assumed that the compound was acting via cannabinoid CB2 receptors (CB2Rs) it is now suggested that it interacts with non-cannabinoid G-protein-coupled receptors (GPCRs); however, CBD does not bind with high affinity to the orthosteric site of any GPCR. To search for alternative explanations, we tested CBD as a potential allosteric ligand of CB2R. Radioligand and non-radioactive homogeneous binding, intracellular cAMP determination and ERK1/2 phosphorylation assays were undertaken in heterologous systems expressing the human version of CB2R. Using membrane preparations from CB2R-expressing HEK-293T (human embryonic kidney 293T) cells, we confirmed that CBD does not bind with high affinity to the orthosteric site of the human CB2R where the synthetic cannabinoid, [3H]-WIN 55,212-2, binds. CBD was, however, able to produce minor but consistent reduction in the homogeneous binding assays in living cells using the fluorophore-conjugated CB2R-selective compound, CM-157. The effect on binding to CB2R-expressing living cells was different to that exerted by the orthosteric antagonist, SR144528, which decreased the maximum binding without changing the KD. CBD at nanomolar concentrations was also able to significantly reduce the effect of the selective CB2R agonist, JWH133, on forskolin-induced intracellular cAMP levels and on activation of the MAP kinase pathway. These results may help to understand CBD mode of action and may serve to revisit its therapeutic possibilities.
... 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.
... 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.
... Actually, repeated CBD administration in rats decreases body weight. This effect was prevented by a CB 2 receptor antagonist (Ignatowska-Jankowska et al. 2011). However, CBD also acts through non-cannabinoid receptors, including 5-HT1A (Campos and Guimaraes 2008), G proteincoupled receptor-55 (GPR55; Pertwee 2008b), and GPR18 (Matouk et al. 2018). ...
Diabetes and aging are risk factors for cognitive impairments after chronic cerebral hypoperfusion (CCH). Cannabidiol (CBD) is a phytocannabinoid present in the Cannabis sativa plant. It has beneficial effects on both cerebral ischemic diseases and diabetes. We have recently reported that diabetes interacted synergistically with aging to increase neuroinflammation and memory deficits in rats subjected to CCH. The present study investigated whether CBD would alleviate cognitive decline and affect markers of inflammation and neuroplasticity in the hippocampus in middle-aged diabetic rats submitted to CCH. Diabetes was induced in middle-aged rats (14 months old) by intravenous streptozotocin (SZT) administration. Thirty days later, the diabetic animals were subjected to sham or CCH surgeries and treated with CBD (10 mg/kg, once a day) during 30 days. Diabetes exacerbated cognitive deficits induced by CCH in middle-aged rats. Repeated CBD treatment decreased body weight in both sham- and CCH-operated animals. Cannabidiol improved memory performance and reduced hippocampal levels of inflammation markers (inducible nitric oxide synthase, ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and arginase 1). Cannabidiol attenuated the decrease in hippocampal levels of brain-derived neurotrophic factor induced by CCH in diabetic animals, but it did not affect the levels of neuroplasticity markers (growth-associated protein-43 and synaptophysin) in middle-aged diabetic rats. These results suggest that the neuroprotective effects of CBD in middle-aged diabetic rats subjected to CCH are related to a reduction in neuroinflammation. However, they seemed to occur independently of hippocampal neuroplasticity changes.
... Additionally, reduced growth could have been caused by a significant change in development or behavior that affected food intake. Exposure to CBD significantly reduced body weight gain in rats, which was completely blocked when co-treated with a cannabinoid receptor type 2 CB2 receptor antagonist (Ignatowska-Jankowska et al. 2011). This result in rats is surprising because CBD displays very weak affinity for both cannabinoid receptor type 1 (CB1) and CB2 receptors (Zou and Kumar 2018), although it is possible that CBD influences CB2 signaling by increasing endocannabinoid tone and its associated agonism of CB2 (Bisogno et al. 2001). ...
Consumption of cannabinoid-containing products is on the rise, even during pregnancy. Unfortunately, the long-term, age-related consequences of developmental cannabidiol (CBD) exposure remain largely unknown. This is a critical gap given the established Developmental Origins of Health and Disease (DOHaD) paradigm which emphasizes that stressors, like drug exposure, early in life can instigate molecular and cellular changes that ultimately lead to adverse outcomes later in life. Thus, we exposed zebrafish (Danio rerio) to varying concentrations of CBD (0.02, 0.1, 0.5 μM) during larval development and assessed aging in both the F0 (exposed generation) and their F1 offspring 30 months later. F0 exposure to CBD significantly increased survival (~ 20%) and reduced size (wet weight and length) of female fish. While survival was increased, the age-related loss of locomotor function was unaffected and the effects on fecundity varied by sex and dose. Treatment with 0.5 μM CBD significantly reduced sperm concentration in males, but 0.1 μM increased egg production in females. Similar to other model systems, control aged zebrafish exhibited increased kyphosis as well as increased expression markers of senescence, and inflammation (p16ink4ab, tnfα, il1b, il6, and pparγ) in the liver. Exposure to CBD significantly reduced the expression of several of these genes in a dose-dependent manner relative to the age-matched controls. The effects of CBD on size, gene expression, and reproduction were not reproduced in the F1 generation, suggesting the influence on aging was not cross-generational. Together, our results demonstrate that developmental exposure to CBD causes significant effects on the health and longevity of zebrafish.
... Although Abn-CBD did not impact either body weight or the lipid profile, it increased leptin levels. CBD has been described to decrease food intake in acute tests (29,30) but its impact on body weight is poorly investigated and controversial (31,32). Previous data using a streptozotocin (STZ)-induced diabetic mouse model showed that Abn-CBD lowered food intake (15), which was associated with restored plasma insulin levels. ...
Background and Aims: The synthetic atypical cannabinoid Abn-CBD, a cannabidiol (CBD) derivative, has been recently shown to modulate the immune system in different organs, but its impact in obesity-related meta-inflammation remains unstudied. We investigated the effects of Abn-CBD on metabolic and inflammatory parameters utilizing a diet-induced obese (DIO) mouse model of prediabetes and non-alcoholic fatty liver disease (NAFLD). Materials and Methods: Ten-week-old C57Bl/6J mice were fed a high-fat diet for 15 weeks, following a 2-week treatment of daily intraperitoneal injections with Abn-CBD or vehicle. At week 15 mice were obese, prediabetic and developed NAFLD. Body weight and glucose homeostasis were monitored. Mice were euthanized and blood, liver, adipose tissue and pancreas were collected and processed for metabolic and inflammatory analysis. Results: Body weight and triglycerides profiles in blood and liver were comparable between vehicle- and Abn-CBD-treated DIO mice. However, treatment with Abn-CBD reduced hyperinsulinemia and markers of systemic low-grade inflammation in plasma and fat, also promoting white adipose tissue browning. Pancreatic islets from Abn-CBD-treated mice showed lower apoptosis, inflammation and oxidative stress than vehicle-treated DIO mice, and beta cell proliferation was induced. Furthermore, Abn-CBD lowered hepatic fibrosis, inflammation and macrophage infiltration in the liver when compared to vehicle-treated DIO mice. Importantly, the balance between hepatocyte proliferation and apoptosis was improved in Abn-CBD-treated compared to vehicle-treated DIO mice. Conclusions: These results suggest that Abn-CBD exerts beneficial immunomodulatory actions in the liver, pancreas and adipose tissue of DIO prediabetic mice with NAFLD, thus protecting tissues. Therefore, Abn-CBD and related compounds could represent novel pharmacological strategies for managing obesity-related metabolic disorders.
... This is consistent with our recent report indicating that pharmacological blockade or genetic deletion of CB2R blocked CBD-induced reduction in oral sucrose self-administration . Blockade of CB2R also attenuated CBD-induced reduction in food intake, body weight and obesity (Ignatowska-Jankowska et al., 2011;Ishiguro et al., 2010) and attenuated CBDproduced neuroprotection (Castillo et al., 2010). Our findings also correspond with previous reports that stimulation of CB2Rs by JWH133 inhibited cocaine self-administration and cocaine-induced CPP and locomotor sensitization (Delis et al., 2017;Xi et al., 2011). ...
Cocaine abuse continues to be a serious health problem worldwide. Despite intense research there is currently no FDA-approved medication to treat cocaine use disorder. The recent search has been focused on agents targeting primarily the dopamine system, while limited success has been achieved at the clinical level. Cannabidiol (CBD) is a U.S. FDA-approved cannabinoid for the treatment of epilepsy and recently was reported to have therapeutic potential for other disorders. Here we systemically evaluated its potential utility for the treatment of cocaine use disorder and explored the underlying receptor mechanisms in experimental animals. Systemic administration (10-40 mg/kg) of CBD dose-dependently inhibited cocaine self-administration, shifted a cocaine dose-response curve downward, and lowered break-points for cocaine self-administration under a progressive-ratio schedule of reinforcement. CBD inhibited cocaine self-administration maintained by low, but not high, doses of cocaine. In addition, CBD (3-20 mg/kg) dose-dependently attenuated cocaine-enhanced brain-stimulation reward (BSR) in rats. Strikingly, this reduction in both cocaine self-administration and BSR was blocked by AM630 (a cannabinoid CB2 receptor antagonist), WAY100135 (a 5-HT1A receptor antagonist), or capsazepine (a TRPV1 channel blocker), but not by AM251 (a CB1 receptor antagonist), CID16020046 (a GPR55 antagonist), or naloxone (an opioid receptor antagonist), suggesting the involvement of CB2, 5-HT1A, and TRPV1 receptors in CBD action. In vivo microdialysis indicated that pretreatment with CBD (10-20 mg/kg) attenuated cocaine-induced increases in extracellular dopamine (DA) in the nucleus accumbens, while CBD alone failed to alter extracellular DA. These findings suggest that CBD may have certain therapeutic utility by blunting the acute rewarding effects of cocaine via a DA-dependent mechanism.
... Our findings that the CB 2 R-mediated reduction of VTA DA neuronal excitability, the underlying intracellular signaling (cAMP) and target (M-channels) have translational significance. Accumulating lines of evidence demonstrate that CB 2 Rs mediate a variety of important modulations in DA-associated behaviors [76] including food intake, body weight [77][78][79][80], depression [81], anxiety [14,82], and schizophrenialike behavior [15,83]. Recent reports emerging from several labs, including ours, have shown brain CB 2 Rs play a pivotal role in the elimination of cocaine, alcohol and nicotine addiction [84][85][86]. ...
Background:
We have recently reported that activation of cannabinoid type 2 receptors (CB2Rs) reduces dopamine (DA) neuron excitability in mouse ventral tegmental area (VTA). Here, we elucidate the underlying mechanisms.
Methods:
Patch-clamp recordings were performed in mouse VTA slices and dissociated single VTA DA neurons.
Findings:
Using cell-attached recording in VTA slices, bath-application of CB2R agonists (JWH133 or five other CB2R agonists) significantly reduced VTA DA neuron action potential (AP) firing rate. Under the patch-clamp whole-cell recording model, JWH133 (10 μM) mildly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) but not miniature inhibitory postsynaptic currents (mIPSCs). JWH133 also did not alter evoked EPSCs or IPSCs. In freshly dissociated VTA DA neurons, JWH133 reduced AP firing rate, delayed AP initiation and enhanced AP after-hyperpolarization. In voltage-clamp recordings, JWH133 (1 μM) enhanced M-type K+ currents and this effect was absent in CB2-/- mice and abolished by co-administration of a selective CB2R antagonist (10 μM, AM630). CB2R-mediated inhibition in VTA DA neuron firing can be mimicked by M-current opener (10 μM retigabine) and blocked by M-current blocker (30 μM XE991). In addition, enhancement of neuronal cAMP by forskolin (10 μM) reduced M-current and increased DA neuron firing rate. Finally, pharmacological block of synaptic transmission by NBQX (10 μM), D-APV (50 μM) and picrotoxin (100 μM) in VTA slices failed to prevent CB2R-mediated inhibition, while intracellular infusion of guanosine 5'-O-2-thiodiphosphate (600 μM, GDP-β-S) through recording electrode to block postsynaptic G-protein function prevented JWH133-induced reduction in AP firing.
Interpretation:
Our results suggest that CB2Rs modulate VTA DA neuron excitability mainly through an intrinsic mechanism, including a CB2R-mediated reduction of intracellular cAMP, and in turn enhancement of M-type K+ currents. FUND: This research was supported by the Barrow Neuroscience Foundation, the BNI-BMS Seed Fund, and CNSF (81771437).
... 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.
... It was proposed that this effect may be mediated by the modulation of TRPV1 (transient receptor potential vanilloid type 1), also known as the capsaicin receptor ( Costa et al., 2007). On the contrary, in an experimental study that assessed the effects of repeated CBD administration on body weight gains in Wistar rats, it was observed that daily administration of CBD at doses of 2.5 and 5 mg/kg for 13 days significantly slowed body weight gain (Ignatowska-Jankowska, Jankowski, & Swiergiel, 2011). However, we did not find significant differences in body weight variation in CBD- treated animals versus control. ...
... 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.
... 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.
... post-drug use), as these can result in very different effects on body weight. Despite the lack of consensus in human studies (Nolan 2013;Sansone and Sansone 2013;Meule 2014), in animal models active substance abuse is more commonly associated with low body weight in comparison to controls for many drug types including opioids (Thornhill et al. 1976), cocaine (Planeta and Marin 2002), nicotine (Grebenstein et al. 2013), methamphetamine (Williams et al. 2004), marijuana (Rahminiwati and Nishimura 1999;Ignatowska-Jankowska et al. 2011), and 3,4-methylenedioxymethamphetamine (MDMA) (Piper et al. 2005). However, findings on body weight are inconsistent in animal models of alcohol consumption (Larue-Achagiotis et al. 1990;Vetter et al. 2007). ...
Background: Substance abuse can cause a range of harmful secondary health consequences, including body weight changes. These remain poorly understood but can lead to metabolic disorders including obesity and diabetes. Energy balance is a function of the equation: energy balance = energy intake – energy expenditure; an imbalance to this equation results in body weight changes. Currently, in the clinical setting, changes to food intake (energy intake) are considered as the primary mediator of body weight changes related to substance abuse, reflected in the current treatment focus on nutritional intervention. The influence of substance abuse on energy expenditure receives less attention. The aim of this think-piece is to consider potential causes of body weight changes during active substance abuse and abstinence, by focussing on the components of the energy balance equation.
Methods: We discuss both human and animal studies on the effects of substance abuse on energy balance, with particular focus on animal models utilising pair-feeding, which enable investigation of energy balance whilst controlling for the effects of altered food intake.
Results: We demonstrate that whilst some drugs of abuse affect food intake, this effect is inconsistent. Furthermore, body weight changes do not match food intake changes.
Conclusion: We provide evidence that drugs of abuse can affect both energy intake and energy expenditure; contributing to the observed body weight changes. This think-piece highlights that treatment strategies for body weight changes related to substance abuse cannot focus solely on nutritional interventions, but should consider the impact of broader disruptions to energy balance.
... 20,21 The effects of THC's (CB1 agonists) action in the brain has been revealed to be responsible for the addictive and psychotic effects of cannabis. [22][23][24] Despite these detrimental effects of CB-1 activation, activation of CB-2 receptors by CBD has demonstrated potent antiinflammatory effects in some tissues, which has been reported to be related to a reduction in obesity in rats 25 and diabetes mellitus in mice 26 and humans. 27 A classical hallmark of ALD includes dysregulated innate immune cell activation as a direct effect of alcohol, alcohol metabolites and gut-derived endotoxins resulting in increased/sustained hepatic and systemic inflammation. ...
Background:
Abusive alcohol use has well-established health risks including causing liver disease (ALD) characterized by alcoholic steatosis (AS), steatohepatitis (AH), fibrosis, cirrhosis (AC) and hepatocellular carcinoma (HCC). Strikingly, a significant number of individuals who abuse alcohol also use Cannabis, which has seen increased legalization globally. While cannabis has demonstrated anti-inflammatory properties, its combined use with alcohol and the development of liver disease remains unclear.
Aim:
To determine the effects of cannabis use on the incidence of liver disease in individuals who abuse alcohol.
Methods:
We analyzed the 2014 Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (NIS) discharge records of patients 18years and older, who had a past or current history of abusive alcohol use(n=319,514). Using the International Classification of Disease, Ninth Edition codes, we studied the four distinct phases of progressive ALD with respect to three cannabis exposure groups: non-cannabis-users (90.39%), non-dependent-cannabis-users (8.26%) and dependent cannabis users (1.36%). We accounted for the complex survey sampling methodology and estimated the adjusted odds ratio (AOR) for developing AS, AH, AC and HCC with respect to cannabis use (SAS 9.4).
Results:
Our study revealed that among alcohol users, individuals who additionally use cannabis (dependent and non-dependent cannabis use) showed significantly lower odds of developing AS, AH, AC and HCC (AOR: 0.55[0.48-0.64], 0.57[0.53-0.61], 0.45[0.43-0.48] & 0.62[0.51-0.76]). Further, dependent users had significantly lower odds than non-dependent users for developing liver disease.
Conclusions:
Our findings suggest that cannabis use is associated with reduced incidence of liver disease in alcoholics. This article is protected by copyright. All rights reserved.
... 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.
... 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.
... 20,21 The effects of THC's (CB1 agonists) action in the brain has been revealed to be responsible for the addictive and psychotic effects of cannabis. [22][23][24] Despite these detrimental effects of CB-1 activation, activation of CB-2 receptors by CBD has demonstrated potent antiinflammatory effects in some tissues, which has been reported to be related to a reduction in obesity in rats 25 and diabetes mellitus in mice 26 and humans. 27 A classical hallmark of ALD includes dysregulated innate immune cell activation as a direct effect of alcohol, alcohol metabolites and gut-derived endotoxins resulting in increased/sustained hepatic and systemic inflammation. ...
A growing body of evidence demonstrates that GLUT1-mediated erythrocyte sugar transport is more complex than widely assumed and that contemporary interpretations of emergent GLUT1 structural data are incompatible with the available transport and biochemical data. This study examines the kinetic basis of one such incompatibility—transport allostery—and in doing so suggests how the results of studies examining GLUT1 structure and function may be reconciled. Three types of allostery are observed in GLUT1-mediated, human erythrocyte sugar transport: (1) exofacial cis-allostery in which low concentrations of extracellular inhibitors stimulate sugar uptake while high concentrations inhibit transport; (2) endofacial cis-allostery in which low concentrations of intracellular inhibitors enhance cytochalasin B binding to GLUT1 while high concentrations inhibit binding, and (3) trans-allostery in which low concentrations of ligands acting at one cell surface stimulate ligand binding at or sugar transport from the other surface while high concentrations inhibit these processes. We consider several kinetic models to account for these phenomena. Our results show that an inhibitor can only stimulate then inhibit sugar uptake if (1) the transporter binds two or more molecules of inhibitor; (2) high-affinity binding to the first site stimulates transport, and (3) low-affinity binding to the second site inhibits transport. Reviewing the available structural, transport, and ligand binding data, we propose that exofacial cis-allostery results from cross-talk between multiple, co-existent ligand interaction sites present in the exofacial cavity of each GLUT1 protein, whereas trans-allostery and endofacial cis-allostery require ligand-induced subunit–subunit interactions.
... 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.
... 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.
... 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.
... 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.
... These results are in contrast with previous findings from Riedel and colleges who reported that acute CBD treatment (10 mg/kg, one injection) induced a small although non-significant reduction in food intake and weight gain (Riedel et al., 2009). Furthermore, CBD treatment was shown to decrease the weight gain in rats (5 mg/kg for 14 days; Ignatowska-Jankowska et al., 2011). In adult male rats, oral administration of CBD (4.4 mg/kg) induced a significant reduction in total food intake over 4 h of test time (Farrimond et al., 2012). ...
The Cannabis plant contains more than 100 currently known phytocannabinoids. Regarding the rising consumption of the non-psychotropic phytocannabinoid cannabidiol (CBD) in people’s everyday life (e.g., beauty products, food and beverages), the importance of studies on the influence of CBD on healthy humans and rodents is evident. Therefore, the behavioral profile of CBD was investigated with a battery of behavioral tests, including motor, anxiety, and memory tests after prolonged CBD treatment. Adult C57Bl/6J wildtype (WT) mice were daily intraperitoneally injected with 20 mg/kg CBD for 6 weeks starting at two different points of ages (3 months and 5 months) to compare the influence of prolonged CBD treatment with a washout period (former group) to the effects of long term CBD treatment (current group). Our results show that CBD treatment does not influence motor performance on an accelerating Rotarod test, while it also results in a lower locomotor activity in the open field (OF). No influence of CBD on spatial learning and long term memory in the Morris Water Maze (MWM) was observed. Memory in the Novel Object Recognition test (NORT) was unaffected by CBD treatment. Two different anxiety tests revealed that CBD does not affect anxiety behavior in the Dark-Light Box (DLB) and OF test. Although, anxiety is altered by current CBD treatment in the Elevated Plus Maze (EPM). Moreover, CBD-treated C57Bl/6J mice showed an unaltered acoustic startle response (ASR) compared to vehicle-treated mice. However, current CBD treatment impairs prepulse inhibition (PPI), a test to analyze sensorimotor gating. Furthermore, prolonged CBD treatment did not affect the hippocampal neuron number. Our results demonstrate that prolonged CBD treatment has no negative effect on the behavior of adult C57Bl/6J mice.
Background.—Comprehensive literature reviews of
historical perspectives and evidence supporting cannabis/
cannabinoids in the treatment of pain, including migraine
and headache, with associated neurobiological mechanisms
of pain modulation have been well described. Most of the
existing literature reports on the cannabinoids Δ9
-tetrahydrocannabinol (THC) and cannabidiol (CBD), or
cannabis in general. There are many cannabis strains that
vary widely in the composition of cannabinoids, terpenes,
flavonoids, and other compounds. These components work
synergistically to produce wide variations in benefits, side
effects, and strain characteristics. Knowledge of the individual
medicinal properties of the cannabinoids, terpenes, and
flavonoids is necessary to cross-breed strains to obtain
optimal standardized synergistic compositions. This will
enable targeting individual symptoms and/or diseases,
including migraine, headache, and pain.
Objective.—Review the medical literature for the use of
cannabis/cannabinoids in the treatment of migraine,
headache, facial pain, and other chronic pain syndromes, and
for supporting evidence of a potential role in combatting the
opioid epidemic. Review the medical literature involving
major and minor cannabinoids, primary and secondary
terpenes, and flavonoids that underlie the synergistic
entourage effects of cannabis. Summarize the individual
medicinal benefits of these substances, including analgesic
and anti-inflammatory properties.
Conclusion.—There is accumulating evidence for various
therapeutic benefits of cannabis/cannabinoids, especially in
the treatment of pain, which may also apply to the treatment
of migraine and headache. There is also supporting evidence
that cannabis may assist in opioid detoxification and weaning,
thus making it a potential weapon in battling the opioid
epidemic. Cannabis science is a rapidly evolving medical
sector and industry with increasingly regulated production
standards. Further research is anticipated to optimize
breeding of strain-specific synergistic ratios of cannabinoids,
terpenes, and other phytochemicals for predictable user
effects, characteristics, and improved symptom and diseasetargeted
therapies.
BACKGROUND
Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp . It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ ⁹ -tetrahydrocannabinol (THC) in vivo . How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.
EXPERIMENTAL APPROACH
AtT20 cells stably expressing HA-tagged human CB1 and CB2 receptors were used. Assays of cellular membrane potential and loss of cell surface receptors were performed.
KEY RESULTS
CBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. Activation of CB2 receptors was antagonised by the CB2 antagonist AM630 and sensitive to pertussis toxin. Co-application of CBC reduced activation of CB2 receptors CP55,940, a potent CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.
CONCLUSIONS AND IMPLICATIONS
Cannabichromene is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.
The herb Cannabis sativa has been traditionally used in many cultures and all over the world for thousands of years as medicine and recreation. However, because it was brought to the Western world in the late 19th century, its use has been a source of controversy with respect to its physiological effects as well as the generation of specific behaviors. In this regard, the CB1 receptor represents the most relevant target molecule of cannabinoid components on nervous system and whole-body energy homeostasis. Thus, the promotion of CB1 signaling can increase appetite and stimulate feeding, whereas blockade of CB1 suppresses hunger and induces hypophagia. Taste and flavor are sensory experiences involving the oral perception of food-derived chemicals and drive a primal sense of acceptable or unacceptable for what is sampled. Therefore, research within the last decades focused on deciphering the effect of cannabinoids on the chemical senses involved in food perception and consequently in the pattern of feeding. In this review, we summarize the data on the effect of cannabinoids on chemical senses and their influences on food intake control and feeding behavior.
La marihuana es uno de los psicoactivos más consumidos en Colombia y el mundo. Se ha observado que tiene efectos sobre el sistema nervioso central y, en consecuencia, podría afectar al metabolismo y el estado nutricional de los individuos consumidores. Este artículo pretende evaluar si el consumo de marihuana y la activación del sistema cannabinoide tienen la capacidad de activar mecanismos fisiológicos mediante los cuales se afecte la ingesta de alimentos, el metabolismo de los nutrientes y el estado nutricional de los adultos adictos. Como resultado se encuentra que el consumo de la marihuana puede incrementar los estímulos orexigénicos y disminuir los anorexigénicos, incidiendo en el aumento de la ingesta y en cambios sobre la producción de enzimas importantes para el metabolismo de las grasas. Además, influye en la aparición de alteraciones del estado nutricional de los consumidores relacionadas con una disminución del índice de masa corporal (IMC), lo cual contrasta con los resultados observados a nivel de la ingesta, por lo tanto se resalta la importancia de efectuar estudios profundos que expliquen este cuestionamiento.
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.
Background:
Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ9 - tetrahydrocannabinol (THC) in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.
Experimental approach:
AtT20 cells stably expressing HA-tagged human CB1 and CB2 receptors were used. Assays of cellular membrane potential and loss of cell surface receptors were performed.
Key results:
CBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. This activation was inhibited by a CB2 antagonist AM630, and sensitive to pertussis toxin. Application of CBC reduced activation of CB2 receptors (but not CB1 receptors) by subsequent co-application of CP55,940, an efficacious CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.
Conclusions and implications:
CBC is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC can also recruit CB2 receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.
Background. As the survival of preterm infants has increased significantly, germinal matrix hemorrhage (GMH) has become an important public health issue. Nevertheless, treatment strategies for the direct neuronal injury are still scarce. The present study aims to analyze the neuroprotective properties of cannabidiol in germinal matrix hemorrhage.
Methods. 112 Wistar rat pups (P7) were submitted to an experimental collagenase induced model of GMH. Inflammatory response and neuronal death were analyzed both at the perilesional area as at the distant ipsilateral CA1 hippocampal area. Immunohistochemistry for GFAP and caspase 3 was used. The ipsilateral free water content was assessed for stimation of cerebral edema, and neurodevelopment and neurofunctional tests were conducted.
Results. Reduction of reactive astrocytosis was observed both in the perilesional area 24 hours and 14 days after the hemorrhage lesion (p < 0.001) and in the Stratum oriens of the ipsilateral hippocampal CA1 14 days after the hemorrhage lesion (p < 0.05) in the treated groups. Similarly, there was a reduction in the number of Caspase 3-positive astrocytes in the perilesional area in the treated groups 24 hours after the hemorrhage lesion (p < 0.001). Finally, we found a significant increase in the weight of the rats treated with cannabidiol.
Conclusion. The treatment of GMH with cannabidiol significantly reduced the number of apoptotic cells and reactive astrocytes in the perilesional area and the ipsilateral hippocampus. In addition, this response was sustained 14 days after the hemorrhage. These results corroborate our hypothesis that cannabidiol is a potential neuroprotective agent in the treatment of germinal matrix hemorrhage.
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.
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.
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.
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.
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 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.
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.
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.
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.
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.