Please use this link to access this publication. Abstract The phytocannabinoid Δ9-tetrahydrocannabinol (THC) was isolated and synthesized in the 1960s. Since then, two synthetic cannabinoids (SCBs) targeting the cannabinoid 1 (CB1R) and 2 (CB2R) receptors were approved for medical use based on clinical safety and efficacy data: dronabinol (synthetic THC) and nabilone (synthetic THC analog). To probe the function of the endocannabinoid system further, hundreds of investigational compounds were developed; in particular, agonists with (1) greater CB1/2R affinity relative to THC and (2) full CB1/2R agonist activity. This pharmacological profile may pose greater risks for misuse and adverse effects relative to THC, and these SCBs proliferated in retail markets as legal alternatives to cannabis (e.g., novel psychoactive substances...

Please use this link to access this publication. Abstract Background Evidence regarding the role of cannabinoids in managing acute postoperative pain is conflicting. The purpose of this systematic review and meta-analysis was to determine the analgesic efficacy of perioperative cannabinoid compounds for acute pain management after surgery. Methods Original research articles evaluating the addition of cannabinoids to standard opioid-based systemic analgesia (Control) in the postoperative period were sought. Our primary outcomes were cumulative oral morphine equivalent consumption and rest pain severity at 24 hours postoperatively. We also assessed analgesic consumption in the postanesthesia care unit (PACU), pain scores in PACU, 6 and 12 hours postoperatively, and opioid-related and...

Please use this link to access this publication. Abstract Background and Objectives Cannabis use is common in people with and mood and anxiety disorders (ADs), and rates of problematic use are higher than in the general population. Given recent policy changes in favor of cannabis legalization, it is important to understand how cannabis and cannabinoids may impact people with these disorders. We aimed to assess the effects of cannabis on the onset and course of depression, bipolar disorder, ADs, and post-traumatic stress disorder (PTSD), and also to explore the therapeutic potential of cannabis and cannabinoids for these disorders. Methods A systematic review of the...

Summary Intestinal disequilibrium leads to inflammatory bowel disease (IBD), and chronic inflammation predisposes to oncogenesis. Antigen-presenting dendritic cells (DCs) and macrophages can tip the equilibrium toward tolerance or pathology. Here we show that delta-9-tetrahydrocannabinol (THC) attenuates colitis-associated colon cancer and colitis induced by anti-CD40. Working through cannabinoid receptor 2 (CB2), THC increases CD103 expression on DCs and macrophages and upregulates TGF-β1 to increase T regulatory cells (Tregs). THC-induced Tregs are necessary to remedy systemic IFNγ and TNFα caused by anti-CD40, but CB2-mediated suppression of APCs by THC quenches pathogenic release of IL-22 and IL-17A in the colon. By examining tissues from multiple sites, we...

Please use this link to access this publication. Abstract Tolerance to the antinociceptive effects of cannabinoids represents a significant limitation to their clinical use in managing chronic pain. Tolerance likely results from desensitization and down-regulation of the cannabinoid type 1 receptor (CB1R), with CB1R desensitization occurring via phosphorylation of CB1Rs by a G protein-coupled receptor kinase and subsequent association with an arrestin protein. Previous studies have shown that (1) desensitization-resistant S426A/S430A mice exhibit a modest delay in tolerance for Δ9-THC and (-)-CP55,940 but a more pronounced disruption in tolerance for WIN 55,212-2 and (2) that c-Jun N-terminal kinase (JNK) signaling may selectively mediate antinociceptive tolerance to morphine compared to other opioid...

Abstract Objective. Colorectal cancer represents a heavy burden for health systems worldwide, being the third most common cancer worldwide. Despite the breakthroughs in medicine, current chemotherapeutic options continue to have important side effects and may not be effective in preventing disease progression. Cannabinoids might be substances with possible therapeutic potential for cancer because they can attenuate the side effects of chemotherapy and have antiproliferative and antimetastatic effects. We aim to determine, through a systematic review of experimental studies performed on animal CRC models, if cannabinoids can reduce the formation of preneoplastic lesions (aberrant crypt foci), number, and volume of neoplastic lesions. Materials and Methods. A...

Please use this link to access this publication. Abstract Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder linked to various converging toxic mechanisms. Evidence suggests that hyperglycemia induces oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity, all of which play important roles in the onset and progression of AD pathogenesis. The endocannabinoid system (ECS) orchestrates major physiological responses, including neuronal plasticity, neuroprotection, and redox homeostasis, to name a few. The multi-targeted effectiveness of the ECS emerges as a potential approach to treat AD. Here we characterized the protective properties of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), the synthetic cannabinoids CP 55–940 and WIN 55,212–2, and the fatty acid amide hydrolase (FAAH) inhibitor URB597, on a combined hyperglycemia + oligomeric amyloid β peptide (Aβ1-42) neurotoxic model in primary hippocampal neurons...

Abstract Background Cannabis benefits patients with inflammatory bowel disease (IBD). Cannabinoid receptors are expressed in gut immune cells and in epithelial cells of inflamed guts. Mucosal healing (MH) requires epithelial layer restoration. Objective To analyze the effects of CB2 agonist on parameters implicated in gut inflammation and MH. Methods Mucosal samples from areas of inflamed/uninflamed colon from 16 patients with IBD were cultured without/with cannabinoid receptor 2 (CB2) agonist (JWH-133, 10 µM, 6 hours (hr)), and analyzed for epithelial/stromal cell proliferation, apoptosis (secretome matrix metalloproteinase 9 (MMP9) activity, which impairs epithelial permeability) and interleukin-8 (IL-8) levels (n = 5–9). In addition, Caco-2 (colon carcinoma epithelial cells) were...

Abstract The last decades have seen a major gain in understanding the action of cannabinoids and the endocannabinoid system in reward processing and the development of addictive behavior. Cannabis-derived psychoactive compounds such as Δ9-tetrahydrocannabinol and synthetic cannabinoids directly interact with the reward system and thereby have addictive properties. Cannabinoids induce their reinforcing properties by an increase in tonic dopamine levels through a cannabinoid type 1 (CB1) receptor–dependent mechanism within the ventral tegmental area. Cues that are conditioned to cannabis smoking can induce drug-seeking responses (ie, craving) by eliciting phasic dopamine events. A dopamine-independent mechanism involved in drug-seeking responses involves an endocannabinoid/glutamate interaction within the...

Abstract Mental disorders represent a significant public health burden worldwide due to their high prevalence, chronically disabling nature, and substantial impact on quality of life. Despite growing knowledge of the pathological mechanisms that underlie the development of these disorders, a high percentage of patients do not respond to first-line clinical treatments; thus, there is a strong need for alternative therapeutic approaches. During the past half-century, after the identification of the endocannabinoid system and its role in multiple physiological processes, both natural and synthetic cannabinoids have attracted considerable interest as putative medications in pathological conditions such as, but not exclusive to, mental disorders. Here, we...