URB597 / Merck (MSD) - LARVOL DELTA

Sex-specific metabolic reprogramming of arachidonic acid pathways to reverse stress-induced depression in female mice (Neuroscience 2025) - "This effect was abolished by AM251, a CB1 receptor antagonist, suggesting that URB597's actions are mediated by CB1 receptor activation due to increased anandamide (AEA) levels. These findings indicate that metabolic differences may underlie sex-specific depression and that metabolic reprogramming, specifically targeting the FAAH pathway, could offer a novel, female-specific therapeutic strategy for depressive disorders."

Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry

Sex differences in elevating endocannabinoid signaling in hippocampal-dependent fear conditioning in adolescent rats (Neuroscience 2025) - "Next, we assessed the effects of enhancing tonic levels of Anandamide (AEA) through inhibition of FAAH (URB597, 0.5 µl, 1 µg/µl)...Continuing studies are focused on the interaction of estrogen and eCBs. These findings have implications in the use of medical cannabinoid treatment of disorders such as PTSD, as well as recreational cannabis use in adolescent/young adult females."

Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Post-traumatic Stress Disorder • Psychiatry

Effects of endocannabinoid system activation in neuroinflammatory induced depressive and anxiety behaviors through lipopolysaccharide injection and its role on the insular cortex (Neuroscience 2025) - "These findings suggest that increasing AEA via URB597 inhibition may reverse neuroinflammation CB1R downregulation in the AIC, a brain region responsible for emotional processing. Our data support the therapeutic potential of ECS modulation in mood disorders and highlight the AIC as a promising but underexplored target for cannabinoid-based interventions."

CNS Disorders • Depression • Mood Disorders • Psychiatry

Sex differences in endocannabinoid-modulation of hippocampal CA1 synaptic plasticity during adolescence (Neuroscience 2025) - "Furthermore, enhancing AEA levels via FAAH inhibition (URB597, 1 µM) blocked LTP induction (~102% over baseline values), indicating an occlusion effect of tonic AEA levels...Furthermore, the decrease in male LTP threshold via an increase in 2-AG tone suggests a lower excitatory drive in male CA1. Our preliminary data support the hypothesis that sex differences in tonic eCB activity are observed in eCB-mediated synaptic plasticity."

CNS Disorders

The effects of URB507 on social, anxiety-like and motor behaviors in the BTBR mouse model of ASD (Neuroscience 2025) - "URB597, a fatty acid amide hydrolase (FAAH) inhibitor, prevents the breakdown of anandamide...Previous data from our lab indicated that increasing anandamide improved repetitive behaviors in female BTBR mice. These data suggest that anandamide plays a bigger role in repetitive behaviors than social and anxiety-like behaviors."

Preclinical • CNS Disorders • Mood Disorders • Psychiatry

Inhibition of fatty acid amide hydrolase leads to uterine vascular defects and decreased fertility in pregnant rats. (PubMed, Reproduction) - "Wistar rats received an intrauterine injection of URB-597 (a highly selective FAAH inhibitor) on day 5 of gestation and were euthanized on day 8 of pregnancy. The pre-incubation with meloxicam blocked AEA stimulation. Our results highlight the importance of AEA tone for proper vascular adaptations of the uterus during early gestation and the relevance of COX-2 in this action."

Journal • Preclinical

Sex-specific effects of endocannabinoid system modulation on cognition and stress hormone release in a rat model of cognitive impairment (ECNP 2025) - "The primary aim of this study was to evaluate the effect of acute inhibition of the enzyme FAAH using URB597 (0,3mg/kg, intraperitoneally (i.p.) on cognitive performance and neuroendocrine response in adult Wistar rats...These findings indicate that modulation of the HPA axis may partly underlie the pro-cognitive effects of FAAH inhibition. In conclusion, our results support the therapeutic potential of FAAH inhibitors in the treatment of cognitive deficits and stress-related psychiatric disorders and emphasise the importance of sex-specific approaches in drug development."

Preclinical • ADHD (Impulsive Aggression) • Alzheimer's Disease • Attention Deficit Hyperactivity Disorder • Bipolar Disorder • CNS Disorders • Cognitive Disorders • Depression • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia

Differential Effects of Adolescent Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibition on Adolescent and Adult Behaviors in Male Rats. (PubMed, Res Sq) - "Methods : Male Sprague-Dawley rats received daily injections with the monoacylglycerol lipase inhibitor JZL184 (JZL; 10 mg/kg, ip), the fatty acid amide hydrolase inhibitor URB597 (URB; 0.4 mg/kg, ip) or vehicle (saline) for ten days during early adolescence (PND31-40) and were tested for play behaviors and behavior on the elevated plus maze in adolescence and social preference, open field behavior and cocaine self-administration and seeking in adulthood...Neither drug altered anxiety-associated behaviors during adolescence or adulthood. Conclusions : These findings are consistent with a critical role of endocannabinoid signaling during adolescence in shaping long-term behavioral outcomes, including vulnerability to addiction and social functioning in adulthood."

Journal • Preclinical • CNS Disorders • Mental Retardation • Mood Disorders • Psychiatry

Intra-dlPAG administration of a FAAH inhibitor attenuates mechanical hypersensitivity in a rat model of chemotherapy-induced peripheral neuropathy (NeuPSIG 2025) - "Direct administration of a FAAH inhibitor into the dlPAG reduces mechanical hypersensitivity induced by PTX suggesting that FAAH substrates within the descending modulatory pain system regulate PTX-induced nociceptive behaviour."

Preclinical • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain

Lactiplantibacillus Plantarum strengthens the intestinal barrier: involvement of the endocannabinoidome. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "URB597 and JZL184, two selective inhibitors of NAE and 2-MAG catabolism, reduced the trans-epithelial permeability of organoids, as observed with L. plantarum strains. Interestingly, both inhibitors also reversed inflammation-induced trans-epithelial permeability in organoids. Elevated endogenous levels of NAEs or 2-MAGs promote improvement in small intestine trans-epithelial permeability, and L. plantarum strains may exploit this mechanism to exert this same beneficial effect."

Journal • Inflammation • CDH1 • DEFA1 • MUC2 • OCLN • REG3A • TJP1

URB597 downregulates DJ-1 expression in the mouse striatum and induces neurodegeneration. (PubMed, Exp Cell Res) - "Gene expression and pathway enrichment analyses revealed that URB597 targets DJ-1 in the mouse striatum and regulates the expression of genes involved in protein acetylation. Collectively, these findings underscore the critical role of DJ-1 in protecting dopaminergic neurons from oxidative damage and uncover its potential implications in regulating protein acetylation."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

Aging-Associated Amyloid-β Plaques and Neuroinflammation in Bottlenose Dolphins (Tursiops truncatus) and Novel Cognitive Health-Supporting Roles of Pentadecanoic Acid (C15:0). (PubMed, Int J Mol Sci) - "C15:0 was a dose-dependent inhibitor of two targets, fatty acid amide hydrolase (FAAH) (IC50 2.5 µM, 89% maximum inhibition at 50 µM relative to URB597) and monoamine oxidase B (MAO-B) (IC50 19.4 µM, 70% maximum inhibition at 50 µM relative to R(-)-Deprenyl). These activities have demonstrated efficacy against Aβ formation and neuroinflammation, including protection of cognitive function in the hippocampus. These findings suggest that, in addition to protecting against AD co-morbidities, C15:0 may play a distinct role in supporting cognitive health, especially at higher concentrations."

Journal • Alzheimer's Disease • CNS Disorders • Diabetes • Hematological Disorders • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • CD68

The endocannabinoid system offers a target for Alzheimer's disease treatment through inhibition of fatty acid amide hydrolase (FAAH). (PubMed, FEBS J) - "FAAH inhibition induced a decrease in the accumulation, synthesis, and release of β-Amyloid, along with diminished expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), and this change may be associated with epigenetic changes induced by the drug. In summary, prolonged treatment with URB597 impinges on different aspects of AD pathophysiology, suggesting its therapeutic relevance in treating AD."

Journal • Alzheimer's Disease • Amyloidosis • CNS Disorders • Inflammation

URB597 Modulates Neuroplasticity, Neuroinflammatory, and Nrf2/HO-1 Signaling Pathways in the Hippocampus and Prefrontal Cortex of Male and Female Rats in a Stress-Induced Model of Depression. (PubMed, Physiol Behav) - "URB597 also exerts neuroprotective effects through region-specific antioxidant properties. These results have implications for sex-specific treatment strategies in stress-related neuropsychiatric disorders."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Inflammation • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

EICAS: Evaluation Study of New Compounds with Potential Use in Schizophrenia (clinicaltrials.gov) - P1 | N=0 | Withdrawn | Sponsor: Central Institute of Mental Health, Mannheim | N=86 ➔ 0 | Trial completion date: Dec 2022 ➔ Jan 2025 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Jun 2022 ➔ Jan 2025

Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • CNS Disorders • Psychiatry • Schizophrenia

Role of endocannabinoid neurotransmission in the insular cortex on cardiovascular, autonomic and behavioral responses evoked by acute restraint stress in rats. (PubMed, Neuropharmacology) - "For this, bilateral guide cannulas directed to the IC were implanted in male Wistar rats for intrabrain microinjection of the selective CB1 receptor antagonist AM251, the selective TRPV1 receptor antagonist capsazepine, the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the monoacylglycerol lipase (MAGL) inhibitor JZL184...The other pharmacological treatments did not modify the cardiovascular, autonomic and behavioral responses evoked by restraint. Taken together, these findings suggest that endocannabinoid neurotransmission in the IC, potentially acting through the endocannabinoid 2-arachidonoylglycerol, plays an inhibitory role in both tachycardia and anxiogenic-like effect evoked by stressful events."

Journal • Preclinical • Cardiovascular

The Effects of Indirect and Direct Modulation of Endocannabinoid System Function on Anxiety-Related Behavior in Mice Assessed in the Elevated Plus Maze Test. (PubMed, Molecules) - "In our experiments, we confirmed the clearly significant involvement of the ECS in anxiety-related responses. In particular, the pharmacological indirect manipulation of ECS functions is able to elicit promising anxiolytic effects. Therefore, the ECS could be a potential target for novel anxiolytic drugs; however, further studies are needed."

Journal • Preclinical • Mood Disorders • Psychiatry

FAAH Inhibition Reverses Depressive-like Behavior and Sex-Specific Neuroinflammatory Alterations Induced by Early Life Stress. (PubMed, Cells) - "Some of these effects began in late adolescence, including mPFC-nfκb1 expression in both sexes, mPFC-il6 and mPFC-il1β in females, CA1-il1β and CA1-tnfα in males, and CA1-il1β in females. These findings highlight URB597 as a therapeutic approach for reversing ELS-induced depressive-like behavior by associating with changes in the gene expression of neuroinflammatory cytokines, with notable sex differences."

Journal • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mood Disorders • Oncology • Psychiatry • IL1B • IL6 • TNFA

FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models. (PubMed, Int J Mol Sci) - "URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • ATG7 • BECN1 • SQSTM1

Effects of increased endocannabinoid levels during adolescence on anxiety-related and cocaine-seeking behaviors in adulthood (Neuroscience 2024) - "Adolescent male Sprague Dawley rats were given daily intraperitoneal injections of either JZL184 (JZL;10 mg/kg), URB597 (URB; 0.4 mg/kg), or vehicle from PND 31-40...During reinstatement testing, JZL-treated animals had reduced drug-seeking behavior following a priming injection of cocaine (10.0 mg/kg, i.p.). In conclusion, the data we gathered indicate that while effects on anxiety-related behaviors do not persist into adulthood, there is an increase in drug seeking in adults when eCB levels are increased during adolescence."

Clinical • CNS Disorders • Mood Disorders • Psychiatry

Insights into Paclitaxel-Induced Neuropathic Pain: The Endocannabinoid System as a Therapeutic Target (Neuroscience 2024) - "Additionally, anxiety-related tests (Elevated Plus Maze and Open Field) were performed on day 16.On day 21, animals received acute i.p. injections of either vehicle, URB597 (FAAH inhibitor, 1mg/kg), SB366791 (TRPV1 antagonist, 1mg/kg) or AA-5-HT (FAAH inhibitor and TRPV1 antagonist, 5mg/kg)...However, only AA-5-HT attenuated the cold hypersensitivity induced by PTX treatment in both sexes. In PTX-treated rats, the FAAH inhibitor increased levels of PEA in the Spinal Cord, Periaqueductal Grey (PAG), Rostral Ventromedial Medulla, and Prefrontal Cortex (PFC), and increased levels of OEA in the PAG and PFC.These results suggest that the endocannabinoid system may be a viable therapeutic target for PTX-induced neuropathic pain."

CNS Disorders • Mood Disorders • Neuralgia • Pain • Psychiatry • TRPV1

Endocannabinoid System Activation Effects in Neuroinflammatory Induced Depressive and Anxiety behaviors and its role on the rat insular cortex. (Neuroscience 2024) - "However, the rats that received URB597+VEH exhibited higher anxiety-like behavior and lower swimming behavior, suggesting a positive effect of this FAAH inhibitor only when the animal is in need of decreasing inflammation. These findings indicate that FAAH inhibitors may have therapeutic potential for the treatment of depression and anxiety when the rodent expresses specific inflammatory markers and may contribute to our understanding of the neural circuits involved in these behaviors."

Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry

Examining the role of the endocannabinoid system in reward and aversion in social contexts (Neuroscience 2024) - "To this end male and female mice were trained on this procedure and then underwent 9 test sessions on which they received various doses of the endocannabinoid antagonist AM251, the agonist JZL187, the agonist URB597, each agonist in conjunction with AM251, or vehicle...Further, endocannabinoid manipulations significantly altered several behavioral outcomes in males and females, such as approach towards the conspecific during shock delivery or cues that predict shock. These data suggest a role for endocannabinoid signaling in socially-determined behaviors during reward and aversion."

CNS Disorders

The effect of URB597 on repetitive/restricted behaviors in the BTBR mouse model of Autism Spectrum Disorder (Neuroscience 2024) - "URB597 did not affect reversal learning in the BTBR mice in the water T-maze, suggesting that URB597 does not work on higher-order RRBs at the doses tested. These results suggest that the effects of URB597 may be specific to the sex of the mouse and the type of RRBs (i.e., lower-order or higher-order repetitive behaviors) tested."

Preclinical • CNS Disorders • Psychiatry

Unraveling neuroprotective pathways: targeting enzymes that inactivate endocannabinoids for ALS therapeutic management (Neuroscience 2024) - "We have employed three experimental strategies using these TDP43A315T mice: (i) to induce genetic ablation of FAAH enzyme in these mice by their crossing with FAAH-deficient mice; (ii) to inhibit FAAH enzyme with the selective FAAH inhibitor URB597 (0.2 mg/kg) given i.p. from presymptomatic (PND65) to symptomatic stages (PND95); and (iii) to inhibit MAGL enzyme using the irreversible inhibitor RO727 (3 mg/kg) or the reversible inhibitor RO723 (10 mg/kg)...In summary, our results strongly suggest the neuroprotective potential of modulating endocannabinoid inactivation in ALS using genetic or pharmacological tools. This inactivation increased neuronal survival and attenuated glial reactivity, providing a promising avenue for further development toward the clinical scenario with pharmacological agents inhibiting FAAH and/or MAGL enzymes."

Amyotrophic Lateral Sclerosis • CNS Disorders • CLSPN,