The Diminished Availability of 2-AG in Aged Synaptic Terminals is Ameliorated by a Full-Spectrum Cannabis Extract with a High THC Content

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“We have previously demonstrated that the endocannabinoid system is dysregulated in the synaptic terminals of the cerebral cortex in aged rats. Specifically, the availability of the neuroprotective endocannabinoid 2-arachidonoylglycerol (2-AG) is reduced due to impairments in the enzymes involved in its metabolism, a deficit only partially compensated by the binding of cannabinoid receptor ligands.

Given that ∆9-tetrahydrocannabinol (THC) acts as a ligand for cannabinoid receptors (CBR), we designed the present study to investigate the effects of a full-spectrum cannabis extract with a high THC content, the THC-free fraction of this cannabis extract, and pure THC on the previously mentioned aging model. Thus, 2-AG metabolic enzymes were assayed incubating synaptosomes from aged and adult rat cerebral cortex, with ethanolic cannabis extract, the THC-free fraction of this cannabis extract or pure THC, and the corresponding radiolabeled substrates.

Our key findings indicate that the age-related decline in 2-AG bioavailability: (a) is exacerbated in the presence of either the THC-free fraction from the cannabis extract or pure THC, primarily due to a significant decrease in 2-AG synthesis; and (b) is partially mitigated by the inhibition of 2-AG hydrolysis when the extract contains THC.

These results provide compelling evidence for the regulation of 2-AG metabolism by a full-spectrum cannabis extract with high THC content, supporting the theory of the entourage effect among cannabis phytochemicals.

This highlights the potential of high THC content extracts as therapeutic agents for restoring the decreased 2-AG levels observed in the aging brain.”

https://pubmed.ncbi.nlm.nih.gov/41880097

https://link.springer.com/article/10.1007/s11064-026-04739-1

Cannabis oil modulates liver alterations and endocannabinoid system changes in a female rat model of diet-induced MASLD

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“Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to alterations in liver lipid metabolism, oxidative stress, fibrosis, and dysregulation of the endocannabinoid system (ECS). Although increasing evidence supports a role for cannabinoids in metabolic disorders, most preclinical studies have been conducted in male models, leaving female-specific responses largely unexplored.

Methods: This study evaluated the effects of oral administration of a full-spectrum cannabis oil (CBD:THC 2:1) on MASLD-related alterations and ECS regulation in female Wistar rats fed a sucrose-rich diet (SRD). Rats were assigned to reference diet (RD), SRD, or SRD plus cannabis oil (1 mg/kg/day) for 3 weeks.

Results: SRD-fed rats developed liver steatosis and increased NAFLD activity score (NAS), accompanied by enhanced de novo lipogenesis, reduced mitochondrial fatty acid oxidation, increased oxidative stress, early fibrotic changes, and ECS overactivation. Cannabis oil administration improved liver lipid metabolism, reduced NAS and fibrosis markers, attenuated lipid peroxidation and oxidative stress, increased NrF2 and decreased NF-κB p65 expression, and normalized hepatic CB1 expression and circulating endocannabinoid levels.

Discussion: These findings demonstrate that full-spectrum cannabis oil is associated with improved MASLD-related outcomes and modulation of ECS tone in a female-specific model of diet-induced metabolic liver disease.”

https://pubmed.ncbi.nlm.nih.gov/41883411

“For millions of years, medicinal plants have been employed in the treatment and handling of liver diseases”

 “Our results indicate that cannabis oil with this particular CBD:THC ratio may serve as a natural nutraceutical to help prevent metabolic disorders linked to hepatic steatosis, oxidative stress, liver fibrosis, and MASLD.”

https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2026.1770150/full

A sesquiterpene-rich essential oil from Cannabis sativa L. attenuates symptoms and neuroinflammation in experimental autoimmune encephalomyelitis model through a CB2-mediated signalling

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“Background: The efficacy of cannabinoid-based medication as analgesic and neuroprotective in multiple sclerosis (MS) has been described, but little is known on other cannabis active compounds, such as terpenes.

Purpose: To investigate the therapeutic potential and molecular mechanism of non-psychotropic Cannabis sativa L. essential oil (EO) in an animal model of MS.

Methods: Chemical composition of EO was analyzed using GC-MS and GC-FID. Mouse model of experimental autoimmune encephalomyelitis (EAE) was employed to evaluate EO efficacy on pain (hot and cold plate test, von Frey test), motor disability (clinical score, rotarod), emotional alterations (sucrose splash test, tail suspension test, open field, light-dark box test) (n = 11). Tissues and LPS-stimulated BV2 cells were analyzed by Western blot, immunofluorescence, Luxol Fast Blue (LFB), hematoxylin and eosin (H&E) staining, UHPLCHRMS analysis.

Results: β-caryophyllene, α-humulene, and caryophyllene oxide were the most abundant EO constituents. Intranasal administration of EO attenuated thermal and mechanical hypersensitivity, promoted motor function recovery, and induced antidepressant- and anxiolytic-like effects in EAE mice. EO increased LFB staining and MBP content while reducing H&E staining. In spinal cord and hippocampal tissues, EO reduced proinflammatory microglia (CD11b/IBA-1 ratio), restored the IL-17/IL-10 balance, and promoted a shift of microglia toward an anti-inflammatory phenotype by increasing CD206 and FoxP3 expression. Mechanistically, EO markedly upregulated CB2 receptor expression in both EAE mice and LPS-stimulated BV2 cells. The protective effect of EO was abolished by a CB2 antagonist (AM630) but not by CB1 blockade (AM251).

Conclusion: Intranasal EO alleviates EAE symptoms and comorbidities through a CB2-mediated attenuation of neuroinflammation and demyelination.”

https://pubmed.ncbi.nlm.nih.gov/41875735

“Studies on the use of medical cannabis in the treatment of MS suggest a reduction in pain and spasticity and most clinical trials have shown symptom improvement with cannabis-based drugs administration”

“Present findings provide the first evidence that a sesquiterpene-rich EO obtained from non-psychoactive C. sativa mitigates EAE neurological symptoms, alleviating pain hypersensitivity, motor disability and mood-related comorbidities through a CB2-mediated anti-neuroinflammatory mechanism.”

https://www.sciencedirect.com/science/article/pii/S0944711326003041?via%3Dihub

Bridging reward and resilience: the endocannabinoid system as a unifying mechanism in exercise-induced protection against major depressive disorder

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“Major depressive disorder (MDD) refers to a complex mental disorder defined by hindered reward system and hindered stress resilience. The limitations of traditional monoamine antidepressants have prompted the academic community to study new pathological processes and intervention strategies. Major depressive disorder arises from a complex interplay of psychological, social, and biological factors.

Among the latter, dysfunction of the endocannabinoid system (ECS) has emerged as a critical pathological mechanism contributing to the core symptoms.

This review demonstrates the key idea that exercise as a powerful non-pharmacological intervention can increase stress resilience and exert antidepressant effects by positively activating the ECS.

Exercise, especially moderate intensity aerobic exercise, can significantly increase the levels of major endogenous cannabinoids AEA and 2-AG, and exert effects at multiple levels by activating CB1 receptors: at the acute level, it can immediately promote mood, generate analgesic effects and improve the termination of the stress response; At the long-term level, it can drive synaptic plasticity, facilitate hippocampal neurogenesis, and regulate neuroimmunity, thereby obtaining lasting structural improvement of emotional and stress neural circuits.

These processes work together to reshape the brain’s reward function and establish internal resilience against stress. In comparison to drug therapy, ECS-regulated exercise interventions have the unique benefits of high safety, systemic advantages, and endogenous reward reinforcement.

Thus, individualized exercise therapy for ECS represents a promising mechanism-induced non-pharmacological intervention approach offering a new aspect and perspective for the prevention and rehabilitation of depression.”

https://pubmed.ncbi.nlm.nih.gov/41877874

https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2026.1766980/full

“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449

Cannabis Use by People with HIV is Associated with an Anti-Inflammatory Immunometabolic Phenotype in Monocyte-Derived Macrophages

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“Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown.

To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naïve/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma.

In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression.

These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition.

Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state.”

https://pubmed.ncbi.nlm.nih.gov/41867844

https://www.biorxiv.org/content/10.64898/2026.03.04.709579v1

Enhancing the endocannabinoid system to treat residual disease in relapse-free multiple sclerosis

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“The recent introduction of High-Efficacy Therapies (HETs) in clinical practice has drastically reduced the frequency of acute inflammatory episodes and relapses, in patients with Multiple Sclerosis (MS), gradually shifting the interest of clinicians toward preventing disease progression and treating symptoms associated with the residual disease. This article summarizes the output of a recent meeting (June 2025, in Rome) among an Italian group of neurologists, who discussed about published evidence supporting the involvement of the endocannabinoid system (ECS) in MS spasticity and its associated symptoms. Sharing their clinical experiences about the silent progression of the disease, in patients with Relapse-Free Multiple Sclerosis (RFMS), treated with HETs, authors propose a new algorithm to treat residual disease in RFMS, by enhancing ECS with both cannabinoid agents and lifestyle interventions (diet and physical activity).”

https://pubmed.ncbi.nlm.nih.gov/41859417

“authors developed a treatment algorithm, emphasizing the importance of timely intervention both with an increase in endogenous cannabinoids, through diet and physical activity, and with the use of an exogenous cannabinoid agent such as nabiximols.”

https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2026.1747131/full

“Nabiximols (brand name Sativex) is a pharmaceutical-grade, oromucosal spray containing a 1:1 ratio of cannabinoids THC and CBD derived from Cannabis sativa.”

Cannabinoids and cognition in Parkinson’s disease: Insights from animal models and emerging clinical evidence

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“Parkinson’s disease (PD) is a progressive, multisystem neurodegenerative disorder characterized not only by motor impairments but also by a broad spectrum of debilitating non-motor symptoms, including cognitive decline. The cognitive function depends on neuronal plasticity, which is tightly regulated by multiple signaling systems, among which the endocannabinoid system (ECS) plays a significant role.

Over the past three decades, substantial evidence has accumulated regarding how endogenous cannabinoids, plant-derived cannabinoids, and pharmacological modulators of ECS signaling influence synaptic plasticity, neuronal excitability, and neuroinflammation – processes that are critical in PD pathophysiology.

This narrative review synthesizes experimental and clinical evidence on the effects of cannabinoid compounds on cognition in preclinical PD models and patients. Available clinical data are limited, heterogeneous, and often underpowered, with cognition frequently assessed as a secondary outcome. Observed variability in cognitive effects likely reflects differences in cannabinoid formulation, dose and treatment duration, study design, patient characteristics, and the use of heterogeneous cognitive endpoints across studies.

Cannabinoid-based interventions hold promise for preserving neural circuits and modulating cognitive function in PD; however, well-designed, mechanism-informed trials with standardized, domain-specific cognitive endpoints are essential before clinical recommendations can be made.”

https://pubmed.ncbi.nlm.nih.gov/41864320

“Endocannabinoid system participates in cognitive modulation in Parkinson’s disease.”

https://www.ibroneuroscience.org/article/S0306-4522(26)00197-1/abstract

Cannabigerol Induces Endoplasmic Reticulum Stress-Mediated Apoptosis and Ferroptosis via the IRE1α-XBP1 Axis in Human Pancreatic Cancer Cells

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“Cannabigerol (CBG), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention owing to its antibiotic, anti-inflammatory, and anticancer properties. However, its therapeutic potential in pancreatic cancer remains unknown.

In this study, we demonstrated for the first time that CBG exerts a potent antiproliferative effect on human pancreatic cancer cells by inducing cell cycle arrest in the G1 phase and promoting programmed cell death.

Transcriptomic profiling revealed that CBG significantly modulates the gene networks involved in apoptosis and ferroptosis. Consistent with these findings, CBG treatment upregulated apoptosis-associated proteins, such as cleaved caspase-3, caspase-9, and PARP1, and increased the proportion of apoptotic cells. CBG triggered robust activation of the unfolded protein response (UPR), with a marked increase in the transcriptional levels of endoplasmic reticulum (ER) stress-related genes.

Mechanistically, CBG activated the IRE1α-XBP1 axis, a key branch of the UPR, as evidenced by enhanced XBP1 mRNA splicing. Inhibition of IRE1α by the small-molecule inhibitor 4μ8C substantially mitigated CBG-induced cytotoxicity, emphasizing the central role of ER stress pathways in the mechanism of CBG’s action. Moreover, CBG modulated the expression of ferroptosis-related genes and proteins, such as DDIT3, NFE2L2, and HMOX1, and their respective protein products, CHOP, NRF2, and HO-1.

These findings reveal a novel mechanism by which CBG concurrently induces apoptosis and ferroptosis via ER stress-driven activation of the IRE1α pathway, supporting its potential as a therapeutic agent targeting ER stress-related vulnerabilities in pancreatic cancer.”

https://pubmed.ncbi.nlm.nih.gov/41871732

“In conclusion, this study provides compelling evidence that CBG induces ER stress-mediated apoptosis and ferroptosis in pancreatic cancer cells via IRE1α–CHOP axis activation. These findings enhance our understanding of the anticancer mechanisms of CBG treatment and suggest its potential as a multitargeted therapeutic agent.”

https://www.sciencedirect.com/science/article/pii/S089158492600242X?via%3Dihub

Mechanistic insights into cannabidiol-mediated TrkB activation via FRS2 interaction in attenuating Alzheimer’s disease pathology and cognitive impairment

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“Alzheimer’s disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited.

Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity.

At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD.

Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models.

Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD.”

https://pubmed.ncbi.nlm.nih.gov/41857397

https://www.nature.com/articles/s41380-026-03525-3

Insights Into Cannabis and Cannabinoids: Chemical Properties, Legal Perspectives, and Therapeutic Applications

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“Cannabis sativa L. has been used for thousands of years in various cultural, medical, and industrial settings. This review brings together evidence from historical records, plant chemical studies, clinical trials, and laws to explain the chemical properties, healing potential, and regulatory environment of cannabis and its components.

We look at over 500 identified compounds, including cannabinoids (CBs), terpenes, flavonoids, and alkaloids, along with their effects on health. The therapeutic areas covered include chronic pain, epilepsy, cancer, mental health issues, and inflammation. We also address side effects, interactions with other drugs, and approved CB-based medications.

Despite the various healing effects, gaps still exist in our understanding of the best dosing, long-term safety, and standardized product formulations. This review highlights current research directions and emphasizes the need for thorough randomized controlled trials to support the evidence-based use of cannabis in modern medicine.”

https://pubmed.ncbi.nlm.nih.gov/41822997

https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202503030