Cannabidiol Alleviates Aβ1–42-Induced Cognitive Deficits and Neuronal Injury Associated with Modulation of the AEA–FAAH–CB1R Axis and BDNF/TrkB Signaling

Yan Kong, Juan Peng, Jian Sun, Yinglan Nie

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuronal injury. Cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa L., has neuroprotective potential, but its underlying mechanisms remain unclear. Purpose: This study investigated the effects of CBD on Aβ1–42-induced cognitive impairment and hippocampal…

Vascular Contractile and Structural Properties in Diet-Induced Atherosclerosis-Prone CB1-LDL Receptor Double Knockout Animal Model

Kinga Shenker-Horváth, Zsolt Vass, Bálint Bányai, Stella Kiss, Kinga Bernadett Kovács, Judit Kiss +9 more

Exploring cannabinoid receptor CB1 autophagy and the obesity phenotype of p62-deficient mice.

Christina Keller, Sebastian Rading, Bahar Candur, Laura Bindila, Gabriele Loers, Meliha Karsak

The endocannabinoid system (ECS) and the autophagy receptor p62 are both implicated in metabolic regulation and obesity, yet the mechanisms linking these pathways remain unclear. Here, we investigated whether p62 modulates CB1 receptor (CB1R) turnover or function and whether CB1R contributes to the metabolic phenotype of p62 knockout (KO) mice. In primary cortical neurons from wild-type mice, inhibition of autopha…

Exercise-induced anandamide–CB1R signaling and prefrontal–amygdala stress circuits in adolescent depression: a critical hypothesis-driven narrative review

Yongxin Luan, Shupei Wang, Yutang Gao, Qiang Kong, Zhenhua Ma, Chuankai Luan

Adolescent depression emerges during a developmental period characterized by ongoing maturation of corticolimbic and stress-regulatory systems. This narrative review critically evaluates a hypothesis that acute exercise-related endocannabinoid mobilization, particularly changes in circulating anandamide (AEA), may be linked to CB1 receptor (CB1R)-dependent processes relevant to prefrontal–amygdala function and str…

Cannabinoid receptor expression profiling in lymphocyte subsets reveals clinically relevant immune patterns in SLE.

Angie M. Rosero, Lady J. Rios-Serna, Carlos A. Cañas

Introduction This study aimed to determine the expression of cannabinoid receptors in lymphocytes from patients with systemic lupus erythematosus (SLE) compared with healthy controls, and to evaluate whether receptor expression is associated with disease activity. Methods Using peripheral blood mononuclear cells from 35 SLE patients and 35 healthy controls, we employed multiparametric flow cytometry to characteriz…

5-HT2A receptor activation induces CB1-dependent presynaptic inhibitory long-term depression in the nucleus accumbens core

Camila Estay-Olmos, Koyam Morales-Weil, Juan Ahumada, Ramón Sotomayor-Zárate, Marco Fuenzalida

The serotonin 2A receptor (5-HT2A) is a Gq/11-coupled receptor implicated in reward processing, neuropsychiatric disorders, and the actions of serotonergic psychedelics. Although 5-HT2A activation has been shown to engage endocannabinoid (eCB) signaling in several brain regions, its role in inhibitory synaptic plasticity within the nucleus accumbens (NAc) remains poorly understood. Here, we investigated whether 5-…

Overview of Novel Mechanisms in Obesity Pharmacotherapy and Implications for Cardiovascular Disease: A Narrative Review.

Michael Bonafede, Aditi Rao, Beverly G. Tchang

Purpose of review While nutrient-stimulated hormone (NuSH) therapies (e.g., glucagon-like pepide-1 receptor agonists and dual/triple agonists) have transformed the landscape of obesity pharmacotherapy, the next generation of medications may target body composition optimization or other cardiovascular benefits. This review examines novel obesity mechanisms outside of the NuSH class. Recent findings Unique mechanism…

Central Blockade of Cannabinoid CB1 and CB2 Receptors Increases Force Generation in Reserpine-Treated Mice, but Only CB1 Blockade Extends the Duration of Effort

Beatriz Carminati dos Santos, Izabely Guedes da Rosa, Laíze de Freitas Mazzardo, Naiara de Souza Santos, Izabel Feltrin Fabro, Tatyana Nery +2 more

Motor impairment in parkinsonism extends beyond the classical triad to weakness and a reduced capacity to sustain motor output, whose neuromodulatory control is poorly resolved. The endocannabinoid system is a candidate regulator, but CB1 and CB2 receptors have not been separated within one preparation. Reserpine-treated adult female Swiss mice received vehicle, the CB1 antagonist AM251, or the CB2 antagonist AM63…

Evaluation of Anti-Inflammatory Effects of Cannabis sativa Extracts via Possible Modulation of mRNA Levels of Inflammatory Cytokines and Cannabinoid Receptors.

Joanna Bartkowiak-Wieczorek, Radosław Kujawski, Michał Szulc, Kamila Czora-Poczwardowska, Joanna Szymczak, Julia Gierszewska +4 more

Background: Low-THC Cannabis sativa L. extracts are commonly believed to offer potential alternatives to non-steroidal anti-inflammatory drugs (NSAIDs) for inflammatory pain management. This study evaluated the anti-inflammatory effects of two C. sativa extracts (Tygra, Dora) and pure cannabidiol (CBD) compared with acetylsalicylic acid (ASA) in a carrageenan-induced rat paw inflammation model. Materials and Metho…

Circuit-Selective FAAH Inhibition Suppresses Experimental Absence Seizures.

Tatiana P Morais, Cristiano Bombardi, Vincenzo Crunelli, Giuseppe Di Giovanni

Background Childhood absence epilepsy (CAE) arises from dysfunctional corticothalamic networks generating spike wave discharges (SWDs) and behavioral arrest. Despite available treatments, a significant proportion of patients remain pharmacoresistant and develop neuropsychiatric comorbidities. The endocannabinoid system (ECS), through activity-dependent signaling, is a key regulator of synaptic and network stabilit…

The Endocannabinoid System in the Development and Treatment of Obesity: Searching for New Ideas.

Anna Serefko, Joanna Lachowicz-Radulska, Monika Elżbieta Jach, Katarzyna Świąder, Aleksandra Szopa, Jorge Manzanares +1 more

Obesity is a complex, multifactorial disease and a growing global health challenge associated with type 2 diabetes, cardiovascular disorders, cancer, and reduced quality of life. The existing pharmacological therapies are characterized by their limited number and efficacy, and safety concerns further restrict their utilization. This review synthesizes extensive knowledge regarding the role of the endocannabinoid s…

Naringin Alleviates Autistic-Like Behaviors in BTBR Mice Through Cannabinoid Receptor Type 1-Mediated Restoration of Hippocampal Neurogenesis.

Yulong Liu, Meiling Xia, Xinggao Zhang, Jing Luo, Tianyao Liu, Hong Gong +7 more

Background Naringin, a flavanone glycoside (naringenin 7-O-neohesperidose), exhibits a broad range of pharmacological activities, including neuroprotection. However, its effects on autistic-like behavior have not been extensively studied. Methods In this investigation, we utilized the autistic BTBR T + tf/J (BTBR) mice to conduct behavioral tests assessing autistic-like phenotypes. We evaluated hippocampal neuroge…

Cannabinoid Receptors Reduced Early Brain Damage by Regulating NOX-2 and the NLRP3 Inflammasome in an Animal Model of Intracerebral Hemorrhage.

Ari Misael Martínez‐Torres, Crisalde Ramírez‐Celis, Julio Morán

Background Intracerebral hemorrhage (ICH) is a leading cause of death and disability worldwide. Following the initial mechanical injury caused by hematoma expansion, a secondary injury occurs, characterized by the production of reactive oxygen species (ROS) generated by NOX-2 and neuroinflammation, which is exacerbated by the upregulation of the NLRP3 inflammasome. These conditions collectively aggravate brain dam…

The Endocannabinoid System in Human Disease: Molecular Signaling, Receptor Pharmacology, and Therapeutic Innovation.

Matei Șerban, Corneliu Toader, Răzvan-Adrian Covache-Busuioc, Deanne H Hryciw, Natalia Battista

The endocannabinoid system (ECS) is a primary regulatory system in human physiology that serves to help maintain homeostasis throughout the nervous system, immune system, and gastrointestinal system. This review has the goal of evaluating the unique opportunity for the ECS to provide a regulatory axis within the microbiota-gut-brain axis, particularly with regard to neurodevelopment, immune tolerance, and gut heal…

Integrating endocannabinoid signaling, CCK interneurons, and hippocampal circuit dynamics in behaving animals.

Shreya Malhotra, Florian Donneger, Jordan S Farrell, Barna Dudok, Attila Losonczy, Ivan Soltesz

The brain's endocannabinoid signaling system modulates a diverse range of physiological phenomena and is also involved in various psychiatric and neurological disorders. The basic components of the molecular machinery underlying endocannabinoid-mediated synaptic signaling have been known for decades. However, limitations associated with the short-lived nature of endocannabinoid lipid signals had made it challengin…

Efficacy and safety of cannabidiol in a single-center pediatric drug-resistant epilepsy cohort: a retrospective study.

Ambra Butera, Giulia Spoto, Graziana Ceraolo, Maria Grella, Ivana Giunta, Maria Ludovica Albertini +5 more

Background Pharmacoresistance to conventional antiseizure medications has been described in approximately 30% of the pediatric epileptic patients, making pharmacological management particularly challenging for physicians. Currently, cannabidiol (CBD) is approved as an adjunctive therapy in combination with clobazam for Dravet Syndrome (DS), Lennox-Gastaut Syndrome (LGS), and as adjunctive treatment for Tuberous Sc…

Omega-3 Fatty Acids Mitigate Long-Lasting Disruption of the Endocannabinoid System in the Adult Mouse Hippocampus Following Adolescent Binge Drinking.

Maitane Serrano, Miquel Saumell-Esnaola, Garazi Ocerin, Gontzal García del Caño, Edgar Soria-Gómez, Amaia Mimenza +10 more

Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3. The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear wh…

In vitro activation of the CB1 receptor by the semi-synthetic cannabinoids hexahydrocannabinol (HHC), hexahydrocannabinol acetate (HHC-O) and hexahydrocannabiphorol (HHC-P).

Mattias Persson, Robert Kronstrand, Michael Evans‐Brown, Henrik Green

Semi-synthetic cannabinoids (SSCs) including hexahydrocannabinol (HHC) are emerging on the drug market and sold openly as purportedly legal replacements for cannabis and Δ9-THC. By the beginning of 2024, 24 European countries had identified HHC, often sold openly in edibles (foods/candy), vapes and low-THC cannabis flowers and resins. The SSC market is developing rapidly, with HHC acetate (HHC-O), hexahydrocannabi…

Type-1 Cannabinoid Receptor Promiscuous Coupling: Computational Insights into Receptor-G Protein Interaction Dynamics.

Alessandro Berghella, Tomasz Maciej Stepniewski, Annalaura Sabatucci, Marta Lopez-Balastegui, Krzysztof Nowicki, Beatrice Dufrusine +3 more

Cannabinoid receptor (CB1), a G protein coupled receptor (GPCR), is a known pharmacological target in several diseases and modulates key physiological processes through Gi protein-mediated signaling. However, recent evidence suggests that CB1 can also activate other G proteins, including the stimulatory Gs protein, a phenomenon with unclear structural determinants. Here, we use a computational approach to elucidat…

The CB1 receptor: linking impulsivity and substance use disorder.

Octavio Amancio-Belmont, Lorena Alline Becerril-Melendez, Mónica Méndez-Díaz

The cannabinoid receptor type 1 (CB1R) is the most widely expressed G protein-coupled receptor in the brain, with high concentrations in the basal ganglia, hippocampus, and cerebellum. Predominantly localized in presynaptic terminals, CB1R modulates synaptic transmission through retrograde endocannabinoid signaling. Its expression follows an ontogenetic trajectory, with region- and age-specific patterns that are p…