Acomplia (rimonabant) / Sanofi - LARVOL DELTA

RIMOHANDOPEN: Effect of Rimonabant on Hand Function in Patients With Spinal Cord Injury (clinicaltrials.gov) - P1/2 | N=8 | Active, not recruiting | Sponsor: Sinfatin S.L

New P1/2 trial • CNS Disorders • Orthopedics

Anxiety-like behaviors induced by chronic administration of the synthetic cannabinoid 4F-ABUTINACA in rats and the underlying mechanisms (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "4F-ABUTINACA produces THC-like discriminative stimulus effects via CB1 receptor activation, suggesting that it has abuse liability. Chronic 4F-ABUTINACA administration induces anxiety-like behaviors in rats, and the underlying mechanism may involve sustained hippocampal glial activation and impaired synaptic plasticity."

Journal • Preclinical • Mood Disorders • Psychiatry • CA3

Tolerance, physical dependence, and Δ9-THC-like interoceptive effects of cannabinol in mice. (PubMed, Drug Alcohol Depend) - "These data indicate that repeated CBN administration induces tolerance and physical dependence and that CBN reduces THC's psychoactive effects."

Journal • Preclinical • CNS Disorders • Movement Disorders • Psychiatry • Substance Abuse

Acetaminophen alters endogenous lipid signaling and attenuates pathological pain through a mechanism requiring diacylglycerol lipase, monoacylglycerol lipase and cannabinoid CB1 receptors in mice. (PubMed, Neuropharmacology) - "Global (rimonabant, AM251) but not peripherally restricted (AM6545) cannabinoid receptor antagonists prevented APAP-induced analgesia. In addition, APAP reduced up to 39% of signaling lipids detected in the targeted screen in CFA-treated subjects in a tissue-dependent manner. These observations suggest that APAP plays a wider role in endogenous lipid signaling than previously hypothesized and provides novel insight into mechanisms of action."

Journal • Preclinical • Immunology • Pain

Enhancement of 2-arachidonoylglycerol but not anandamide signaling in the ventral tegmental area selectively increases the choice to respond to reward-predictive incentive cues in male rats. (PubMed, Neuropharmacology) - "We microinfused MJN110 or PF3845, a fatty acid amide hydrolase (FAAH) inhibitor, into the VTA to increase 2-AG and anandamide, respectively in male rats...Further, the intra-VTA MJN110 enhancement of responding to ICs was blocked by the CB1 receptor antagonist rimonabant. Our results suggest that increasing 2-AG, but not anandamide, in the VTA selectively enhances the choice to respond to cues predicting a reward. However, the effects of systemic MJN110 in enhancing the vigor of responding cannot be attributed to VTA 2-AG signaling."

Journal • Preclinical

Peripheral cannabinoid-1 receptor antagonists in clinical development: therapeutic potential for the management of obesity and related metabolic disorders for the management of obesity and related metabolic disorders. (PubMed, Expert Opin Investig Drugs) - "Peripherally restricted CB1R antagonists aim to deliver the metabolic benefits of CB1R blockade while avoiding the toxicity that ended development of centrally acting agents such as rimonabant. Recent phase 2 data with monlunabant demonstrated dose-dependent psychiatric adverse events and high discontinuation rates. Nimacimab, an antibody-based approach, has shown only marginal efficacy. The future of this drug class will therefore likely depend on rigorous long-term safety evaluation, biased CB1R pharmacology, and multitarget strategies including combinations with incretin-based therapies."

Journal • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry

Rimonabant reveals reward- and anxiety-related behavioral effects of N-arachidonoyl dopamine (N-ADA) in mice. (PubMed, Physiol Behav) - "These findings indicate that prior exposure to N-ADA can influence reward- and anxiety-related behaviors specifically under conditions of CB1 blockade/GPR55 modulation. The results support the modulatory role of N-ADA on reward- and anxiety-related behaviors at the dose tested, indicating an interaction with endocannabinoid signaling (or other rimonabant-sensitive mechanisms)."

Journal • Preclinical • Inflammation • Mood Disorders • Psychiatry • GPR55

Cannabinoid (CB) 1 receptor antagonists block fentanyl conditioned place preference but not fentanyl antinociception. (PubMed, Drug Alcohol Depend) - "These results add to a growing body of evidence that CB1 neutral antagonists can attenuate the rewarding properties of opioids while sparing their therapeutically desirable antinociceptive effects, providing support for further investigation of CB1 neutral antagonists as possible treatments for OUD."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry • Substance Abuse

Double dissociation in the involvement of noradrenergic and endocannabinoid systems in classical and higher-order conditioning in newborn rabbits. (PubMed, Neurobiol Learn Mem) - "Intraperitoneal injections of Propranolol, an antagonist of beta-adrenergic receptors, blocked classical conditioning promoted by the mammary pheromone in newborn rabbits but had no effect on sensory preconditioning or second-order conditioning. Conversely, intraperitoneal injections of Rimonabant, an antagonist of the main cannabinoid receptor CB1, had no effect on classical conditioning but blocked sensory preconditioning and second-order conditioning, indicating a specific impact on unreinforced association...Whereas our results indicate the noradrenergic system specifically promotes reinforced association in pups, they also establish that the endocannabinoid system selectively mediates higher-order conditioning by regulating unreinforced association in newborns. This also highlights that the rabbit is an excellent model for further investigating the neurobiology of neonatal first- and higher-order memory."

Journal • Preclinical

Methodological comparisons for benefit-risk assessment in complex decision-making: applications and insights from a case study. (PubMed, Front Drug Saf Regul) - "Eight BRA methodologies were evaluated using data from European Public Assessment Reports, randomized controlled trials, and published literature on rimonabant, including two descriptive frameworks, two quantitative frameworks, and four metrics and estimation techniques...Metrics enabled comparison of individual benefit and risk criteria, offering straightforward numerical evaluations. A combination of descriptive and quantitative frameworks allows for a comprehensive BRA, accommodating multiple criteria, stakeholder's preferences, and uncertainties."

Benefit-risk assessment • Journal

Long-term effects of weight-reducing drugs in people with hypertension. (PubMed, Cochrane Database Syst Rev) - "There have been multiple developments in the domain of medications for long-term weight reduction in recent years. Several pharmaceutical products have been removed from the market due to safety concerns, whilst new drugs have been introduced. Our critical outcomes of death and cardiovascular complications were not the focus of the trials included in this review but were sometimes presented as part of an 'adverse events' outcome, with the resultant data providing only very low certainty evidence. Overall, the evidence for people with hypertension remains insufficient to draw conclusions regarding the benefits of pharmacological weight loss in terms of reducing the risk of mortality or cardiovascular morbidity. Further trials are needed. Moreover, separate results for participants with hypertension should be made available from any completed trials involving both normotensive and hypertensive people."

Clinical • Journal • Review • Cardiovascular • Hypertension • Obesity

Modulatory Effects of CB1 Receptors on Cognitive Performance in Rat Model of Empathic Pain. (PubMed, Basic Clin Neurosci) - "One sibling received formalin injection into the hind paw five times within nine days (demonstrator), and the other siblings reported pain (observer) while being treated with dimethyl sulfoxide (DMSO), the CB1R agonist WIN 55,212-2 (WIN; 3 mg/kg, intraperitoneal), or the CB1R antagonist rimonabant (1 mg/kg intraperitoneal)...CB1Rs play a modulatory role in social contagion. This modulation may provide new therapeutic targets for conditions, such as autism spectrum disorder, schizophrenia, and other psychological disorders characterized by impaired empathy and dysregulated social behavior associated with the CB1 signaling pathway."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Genetic Disorders • Mood Disorders • Pain • Psychiatry • Schizophrenia

Exploratory study on the effect of Rimonabant on hand function in patients with spinal cord injury (RIMOHANDOPEN) (clinicaltrialsregister.eu) - P1/2 | N=8 | Recruiting | Sponsor: Sinfatin S.L. | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Orthopedics

Activating endocannabinoid pathways in epidermolysis bullosa to manage pain (SID 2026) - "Rimonabant, a CB1 receptor inverse agonist, increased pain 3-fold (p=0.004), underscoring the critical role of CB1 receptor signaling in modulating pain. PF-3845, a fatty acid amide hydrolase (FAAH) inhibitor, did not impact pain, suggesting that signaling through anandamide (AEA, a partial CB1 receptor agonist) is not involved. 2-AG/CB1 is the primary endocannabinoid pathway affecting pain in RDEB, suggesting increasing cannabinoid signaling through 2-AG enhancement as a potential therapeutic strategy for managing acute pain in RDEB."

Inflammation • Pain • CNR1 • COL7A1 • TRPV1

A Scoping Review of Preclinical Paradigms for Clinically Tested Medications in Alcohol Use Disorder. (PubMed, Alcohol Clin Exp Res (Hoboken)) - "For 2BC consumption, the largest effects were observed for medications with limited studies, such as levetiracetam (d = -4.58), while more extensively tested medications showed moderate effects, including prazosin (d = -0.74) and naltrexone (d = -0.63)...In reinstatement models, rimonabant showed the largest effect (d = -3.11), while naltrexone (d = -0.70), baclofen (d = -1.05), and varenicline (d = -0.72) had moderate effects...Medications with moderate, replicable preclinical effects, especially those tested across both 2BC and reinstatement models, may hold greater translational promise. These findings offer key opportunities for enhancing the translational alignment of preclinical AUD pharmacotherapy research."

Journal • Preclinical • Review • Addiction (Opioid and Alcohol)

Therapeutically relevant rimonabant exposure drives epigenetic remodeling in neuronal cells and rat brain tissue. (PubMed, Arch Toxicol) - "Collectively, these findings demonstrate that rimonabant disrupts key epigenetic regulatory mechanisms in the brain and support the hypothesis that epigenetic dysregulation contributes to its psychiatric liabilities. This work strengthens the value of incorporating epigenetic endpoints into neuropharmacological safety assessments."

Journal • Preclinical • CNS Disorders • Depression • Genetic Disorders • Metabolic Disorders • Mood Disorders • Neuroblastoma • Obesity • Oncology • Psychiatry • Schizophrenia • Solid Tumor

Synthesis of Acrylamide Analogs of Rimonabant and Evaluation of Anti-Inflammatory Activities by Inhibiting NF-κB and MAPK Signaling Pathways in Lipopolysaccharide-Induced BV2 Cells. (PubMed, ChemMedChem) - "In addition, 7n inhibited the expression of iNOS, COX-2, and proinflammatory cytokines and attenuated LPS-induced activation of nuclear factor-kappa B (NF-κB) and MAPK phosphorylation in BV2 cells. These results demonstrated that 7n exerted anti-inflammatory effects by NF-κB and the JNK and p38 MAPK pathways in BV2 cells and could become a prospective candidate for treatment of neuroinflammation-related disorders."

Journal • Inflammation • PTGS2

Exploratory study on the effect of Rimonabant on hand function in patients with spinal cord injury (RIMOHANDOPEN) (clinicaltrialsregister.eu) - P1/2 | N=8 | Not yet recruiting | Sponsor: Sinfatin S.L.

New P1/2 trial • CNS Disorders • Orthopedics

Pharmacokinetic and pharmacodynamic properties of cannabigerol in male mice. (PubMed, J Pharmacol Exp Ther) - "This response was not affected by the CB1 cannabinoid receptor inverse agonist, rimonabant (3 mg/kg, i.p.), indicating a mechanism independent of CB1 signaling...SIGNIFICANCE STATEMENT: Application of a new liquid chromatography-tandem mass spectrometry method to quantify cannabigerol reveals key pharmacokinetic properties of this phytocannabinoid in mice, including unexpectedly high brain accumulation of its metabolite cyclo-cannabigerol, which was accompanied by anxiogenic-like effects. The results offer valuable tools for advancing preclinical and clinical investigations into cannabigerol pharmacology."

Journal • PK/PD data • Preclinical • Mood Disorders • Psychiatry

Neuroprotective Role of Cannabinoid CB1 and GPR55 Receptors in a Cell Model of Multiple Sclerosis. (PubMed, Mol Neurobiol) - "In serum-free conditions, selective activation of CB1R with arachidonyl-2'-chloroethylamide (ACEA) or GPR55 with CID1792197 enhanced cell survival, while the CB1R antagonist SR141716 blocked both ACEA- and CID1792197-induced protection. These cross-antagonistic interactions support the presence of heteromer-dependent signaling. Altogether, our findings identify CB1R/GPR55 heteromers as novel modulators of OLG resilience and highlight their potential as therapeutic targets for promoting neuroprotection and remyelination in demyelinating diseases such as MS."

Journal • CNS Disorders • Inflammation • Multiple Sclerosis • Solid Tumor • GPR55

Modulating the endocannabinoid system in alcohol use disorder: A translational systematic review and meta-analysis of preclinical and human studies. (PubMed, Mol Psychiatry) - "In contrast, human studies showed inconsistent and generally null effects, with limited studies examining newer ECS modulators beyond rimonabant or CBD. While preclinical evidence supports ECS modulation, particularly CB-1R antagonism and CBD, as promising strategies for reducing alcohol use behaviors, clinical translation has been limited by safety concerns, methodological inconsistencies, and under-investigation of novel compounds. Mechanistically informed trials of novel compounds, including next-generation CB-1R antagonists and CBD, are needed to bridge this translational gap and yield new treatments for AUD."

Journal • Preclinical • Retrospective data • Review • Addiction (Opioid and Alcohol)

Involvement of CB1 cannabinoid receptors in methamphetamine-related decision-making and social behavior deficits. (PubMed, BMC Neurosci) - No abstract available

Journal • Mood Disorders • Psychiatry

Differential Disruption of Gonadal Development by DEHP and Paracetamol in Male and Female Wistar Rats. (PubMed, Reprod Toxicol) - "In a parallel in vitro approach, fetal rat testes from unexposed animals were incubated for three hours with paracetamol or its metabolite AM404, with or without the CB1 antagonist rimonabant...These findings suggest greater ovarian sensitivity to paracetamol compared to the testis.Unlike paracetamol, DEHP altered the expression of key ECS genes, suggesting a possible interplay between phthalates and the ECS. This raises the possibility that ECS components may be involved in the mechanisms of phthalate toxicity and could represent potential biomarkers, warranting further investigation."

Journal • Preclinical

Discrete Choice Experiment (DCE) as a Tool to Elicit Patient Preferences in a Complex Benefit-Risk Evaluation: A Case Study. (PubMed, Clin Drug Investig) - "This case study reaffirmed the utility of DCE as a valuable tool for BR evaluations, which aligned with what patients deemed important. The case study demonstrated essential attributes for anti-obesity medications. The methodological rigor and flexibility of DCE provided a robust framework for understanding, quantifying and analyzing preferences. The integration of elicited patient preferences, utility functions, and relevant clinical data offered quantitative insights into the structured BR assessment for regulatory decision-making and beyond."

Benefit-risk assessment • Journal • Cardiovascular • CNS Disorders • Depression • Gastrointestinal Disorder • Genetic Disorders • Mood Disorders • Obesity • Psychiatry

2-Linoleoylglycerol decreased seizure through the regulation of 5-hydroxytryptamine 1A receptor and G protein-coupled receptor 55 interaction in mice. (PubMed, Neuroreport) - "These results suggest that 2-LG exerts an antiseizure effect through interactions between the 5-HT1A receptor and GPR55."

Journal • Preclinical • CNS Disorders • Epilepsy • GPR55