URB597 / Merck (MSD) - LARVOL DELTA

URB597 attenuates experimental sepsis-associated acute kidney injury with reduced renal inflammation, apoptosis, and TLR4/NF-κB activation. (PubMed, Mol Biol Rep) - "URB597 attenuated renal injury, inflammatory responses, and apoptosis-related alterations in experimental sepsis-associated AKI. These effects were accompanied by reduced renal TLR4/NF-κB pathway activation."

Journal • Acute Kidney Injury • Infectious Disease • Inflammation • Nephrology • Oncology • Renal Disease • Septic Shock • CASP3 • CASP8 • IL1B • IL6 • LCN2 • TLR4 • TNFA

Amygdala endocannabinoid and astrocyte signaling contributes to mGlu5 modulation of neuropathic pain (Neuroscience 2026) - "A fatty acid amide hydrolase (FAAH) inhibitor (URB597) alone did not significantly alter pain-related behaviors, but co-administration of URB597 with alloswitch-1 decreased or prevented the anti-nociceptive effects of alloswitch-1 on evoked behaviors...These findings suggest that mGlu5 inhibition in the CeA decreases neuropathic pain-related behavior and that this effect is modulated by AEA signaling and potentially by astrocyte-dependent mechanisms. Together, these data support a functional interaction among mGlu5, endocannabinoid signaling, and glial mechanisms in the amygdala and identify CeA mGlu5-dependent signaling as a potential regulator of pain-related amygdala output in neuropathic pain."

CNS Disorders • Neuralgia • Pain

FAAH Inhibition with URB-597 Attenuates Neuroinflammation-Induced Deficits in Working and Recognition Memory in Male Rats (Neuroscience 2026) - "Appreciation to Dr. Carmen Maldonado-Vlaar’s mentorship throughout the development of this project, and the Julio García Díaz Biological Research Center for providing equipment and technical support."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Effects of anandamide (AEA) on GABAergic synaptic transmission in rat ventrolateral periaqueductal gray (VlPAG) in persistent inflammation (Neuroscience 2026) - "It is noted that the maximal effect of URB597 inhibited GABAergic IPSCs less than the maximal effect of 2-AG (~50%). Taken together, those results suggest a differential sensitivity of 2-AG and AEA on presynaptic CB1Rs in the vlPAG under inflammatory pain conditions."

Preclinical • CNS Disorders

Diminazene Aceturate-Induced Relaxation in Isolated Rat Thoracic Aorta: Contribution of Cannabinoid and Vanilloid Signaling. (PubMed, Eur J Pharmacol) - "Following phenylephrine-induced precontraction, cumulative concentrations of DIZE were applied in the absence or presence of the CB1 receptor antagonist AM251, the CB2 receptor antagonist AM630, the TRPV1 antagonist capsazepine, the FAAH inhibitor URB597, or anandamide...Although DIZE did not significantly change tissue ACE2 or Ang-(1-7) levels, the findings indicate an interaction with the ECS at multiple levels. These results suggest that DIZE may represent a promising therapeutic candidate in cardiovascular conditions associated with endothelial dysfunction."

Journal • Preclinical • Cardiovascular

Photoreceptor preservation by FAAH inhibition in a murine model of retinitis pigmentosa. (PubMed, Mol Neurobiol) - "Treatment with URB597 led to a 30% reduction in reactive oxygen species content at P19. Together, these data indicate a neuroprotective role of the endocannabinoid system in the context of photoreceptor degeneration in retinitis pigmentosa."

Journal • Preclinical • CNS Disorders • Genetic Disorders • Inherited Retinal Dystrophy • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • GFAP

Short Communication: The Peripheral Cannabinoid CB1 Receptor Antagonist AM6545 Modifies Cardiovascular Effects of Endocannabinoids in DOCA-Salt Rats. (PubMed, Int J Mol Sci) - "For this purpose, we applied methanandamide (MethAEA), a stable analogue of anandamide, and URB597, an inhibitor of its degradation, in urethane-anesthetized animals. In conclusion, AM6545 modifies the cardiovascular effects of endocannabinoids in hypertension in a model-dependent manner. The cardiovascular effects of CB1R antagonists should be carefully evaluated when assessing their potential therapeutic significance, as they may unmask an increase in BP."

Journal • Preclinical • Anesthesia • Cardiovascular • Hypertension • Hypotension

Chronic intranasal URB597 treatment reverts short-term memory deficits in a rat model of metabolic syndrome. (PubMed, Life Sci) - "These findings highlight memory deficits associated with MetS and point to N-acylethanolamine signaling as a potential modulatory pathway, with URB597 serving as a pharmacological tool to investigate its therapeutic relevance."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Metabolic Disorders

Role of Concentration in Opposing Effects of Anandamide on Nociceptive Synapses versus Non-Nociceptive Synapses. (PubMed, eNeuro) - "However, the results differed when using URB597, a drug that raises AEA by inhibiting fatty acid amine hydrolase (FAAH), the enzyme that metabolizes AEA...Both types of synapses were equally sensitive to exogenously applied AEA, but when endogenous AEA levels were increased using inhibitors of AEA metabolism, nociceptive synapses were much more sensitive compared to non-nociceptive synapses. These findings may inform why past cannabinoid-based therapies have failed as analgesics and how to develop effective analgesic therapies in the future."

Journal • CNS Disorders • Depression • Pain • Psychiatry • UBR5

Differential effects of adolescent fatty acid amide hydrolase and monoacylglycerol lipase inhibition on adolescent and adult behaviors in male rats. (PubMed, Psychopharmacology (Berl)) - "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

L-Malic acid from Cissus gongylodes induces cannabinoid-mediated antinociception in mice. (PubMed, J Ethnopharmacol) - "It provides scientific validation for the traditional use of C. gongylodes and identifies L-malic acid as a constituent with notable antinociceptive properties, suggesting its potential as a lead compound for the development of novel therapeutics that act via the endocannabinoid system."

Journal • Preclinical • Diabetes • Gastrointestinal Disorder • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Nephrology • Orthopedics • Pain • Renal Calculi • Rheumatology

Inhibition of Fatty Acid Amide Hydrolase Alters Cortical CREB Signaling and Social Behavior in a Rat Model of Schizophrenia. (PubMed, Eur J Neurosci) - "Although URB597 did not significantly reverse the pCREB reduction in PCP-treated rats, pCREB levels in the AI positively correlated with time spent in social interaction (r = 0.43, p < 0.05). These findings identify the AI as a key neural substrate underlying social withdrawal in this model and suggest that targeting the endocannabinoid system within this region may represent a promising therapeutic strategy for alleviating the negative symptoms of schizophrenia."

Journal • Preclinical • CNS Disorders • Psychiatry • Schizophrenia

Alteration of brain endocannabinoids on restraint stress-induced anxiety-like behaviors in mice. (PubMed, Physiol Behav) - "This anxiogenic behavior was ameliorated by the administration of JZL184 (a monoacylglycerol lipase inhibitor) or URB597...Furthermore, restraint stress induces anxiogenic behavior, which is ameliorated by inhibitors of eCB-degrading enzymes. These findings indicate that the reduction in eCB levels in the PFC and HC may be due to the development of stress-induced anxiety."

Journal • Preclinical • Mood Disorders • Psychiatry

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