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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Posted on by

“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

Inhibitory effects of Δ8-tetrahydrocannabinol on nicotine metabolism and implications as a smoking cessation agent

Posted on by

“Tobacco use remains the leading cause of preventable death worldwide. The major metabolic pathway for nicotine, the addictive component in tobacco, is via cytochrome P450 (CYP) 2A6-mediated metabolism to cotinine.

Cannabidiol has been shown to reduce cigarette consumption in vivo and inhibit CYP2A6-mediated nicotine metabolism in vitro. In the present study, Δ-8-tetrahydrocannabinol (Δ8-THC), an isomer of Δ-9-tetrahydrocannabinol, was examined as a potential inhibitor of CYP2A6-mediated nicotine metabolism.

While Δ-9-tetrahydrocannabinol showed no significant inhibition of nicotine metabolism to cotinine, Δ8-THC demonstrated unbound IC50 values of 0.57 ± 0.04 μM in microsomes from recombinant wild-type CYP2A6 overexpressing human embryonic kidney 293 cells and 0.70 ± 0.16 μM in human liver microsomes (HLMs). A similar unbound IC50 value was observed for recombinant CYP2A6∗5 microsomes (0.52 ± 0.17 μM) and was modestly elevated in recombinant CYP2A6∗2 microsomes (1.00 ± 0.12 μM). IC50 shift experiments were consistent across pooled HLM (5.3-fold) and microsomes from liver specimens exhibiting the CYP2A6 (∗2/∗2) and (∗9/∗9) genotypes (6.1- and 4.0-fold, respectively) but were reduced in CYP2A6 (∗35/∗35) microsomes (1.0-fold). Irreversible inhibition kinetics in pooled HLMs by Δ8-THC yielded a kinact value of 0.022 ± 0.001 min-1 and an unbound KI value of 0.232 ± 0.062 μM. Static modeling predicted that oral dosing with 10 mg Δ8-THC increased the nicotine plasma area under the curve by 189%, with further increases observed at 20 mg and 40 mg; interactions were also observed with inhalation doses ≥70 mg.

These findings suggest that, based on CYP2A6 genotype, Δ8-THC could be a candidate for smoking cessation therapy.

SIGNIFICANCE STATEMENT: This study is the first, to the best of our knowledge, to identify Δ-8-tetrahydrocannabinol as a potent and irreversible inhibitor of nicotine metabolism to cotinine. The extent of inhibition is modulated by genetic variation in cytochrome P450 2A6. These findings suggest that further investigations focusing on Δ-8-tetrahydrocannabinol and its potential as a candidate for smoking cessation therapy are warranted.”

https://pubmed.ncbi.nlm.nih.gov/41830876

“In conclusion, the present study is, to our knowledge, the first to demonstrate the irreversible inhibition of nicotine metabolism by Δ8-THC in vitro, highlighting its potential as a smoking cessation agent.”

https://dmd.aspetjournals.org/article/S0090-9556(26)00004-8/fulltext

Cannabidiol in Epilepsy: Restoring Locomotion and Seizure Control

Posted on by

“Epilepsy remains a global challenge, with about one-third of affected patients being resistant to treatment. Seizures and motor abnormalities characterized by movement difficulties are common in epilepsy, highlighting the need for treatments that can both improve motor outcomes and control seizures.

The therapeutic potential of Cannabidiol (CBD) in this regard necessitates a review that explores its effects and underlying mechanisms of action. This study reviewed studies from major scientific databases on the use of CBD in animal and human models of epilepsy. We also integrated tools of network pharmacology and molecular modeling to investigate how CBD may interact with various biological targets. The cannabinoid broadly demonstrates minimal or no changes in motor outcomes, reinforcing its low toxicity and tolerability.

Evidence suggests that CBD has potential for seizure control by prolonging the time to seizure onset and decreasing seizure severity. The antiepileptic effects of CBD involve the modulation of multiple targets or genes. This multitarget interaction network may underlie its neuroprotective effects by regulating endocannabinoid signaling, neurotransmission, inflammation, and metabolic pathways. Chemical bonding between CBD and key protein residues reinforces evidence supporting its interaction with these targets.

Despite the limited clinical data and algorithmic constraints of network pharmacology, the present findings reveal the potential of CBD to improve epileptic outcomes. The multitarget mechanisms of this phytocannabinoid offer valuable insights that may guide and advance epilepsy research.”

https://pubmed.ncbi.nlm.nih.gov/41833036

https://www.eurekaselect.com/article/153518

Role of Oncoviruses in Cancer Progression and Emerging Phytochemical-Based Therapies from Medicinal Plants

Posted on by

“Oncoviruses continues to be an unattended cause of the global cancer load as they cause about 12-15 % of human malignancies in the world. The oncogenic infections that become persistent, such as Human Papillomavirus (HPV), Epstein-Barr Virus (EBV), Hepatitis B and C viruses (HBV, HCV), Human T cell Leukemia Virus-1 (HTLV-1), and Kaposi Sarcoma-associated Herpesvirus (KSHV), are associated with malignant transformation by continuous destabilization of host cell cycle regulation, immune surveillance, and metabolic homeostasis. These viruses abuse critical oncogenic signaling networks like PI3K/AKT/mTOR, NF -KB, JAK/STAT, MAPK, Wnt/β-catenin, and p53-dependent networks, hence, facilitating unchecked proliferation, chronic inflammation, genomic instability, and tumor progression.

Although there have been improvements in the traditional forms of treatment, such as chemotherapy, radiotherapy, antiviral agents, immunotherapy, and gene-based treatments, yet clinical outcomes are still hampered by drug resistance, viral latency, systemic toxicity, and inaccessibility, and other severe side effects especially in low- and middle-income nations. Hence, there is a dire need to introduce new medicinal plant-based therapeutic approaches against oncovirus.

This review analyses the molecular pathways of viral oncogenesis critically and discusses the clinical translation and a promising future potential of phytochemicals derived from medicinal plants like Phyllanthus emblica, Datura stramonium, Cannabis sativa, Andrographis paniculata, Aegle marmelos, Calotropis procera, and Prosopis cineraria proven to have bioactive compounds functioning as antivirals, immune-modulator, pro-apoptotic, and cell cycle regulatory effects in the preclinical models along with multi-targets.”

https://pubmed.ncbi.nlm.nih.gov/41824191

https://link.springer.com/article/10.1007/s12033-026-01561-6

Hyaluronic Acid-Functionalized Liposomes for Co-delivery of 5-Fluorouracil and Cannabidiol Against Colorectal Cancer

Posted on by

“Purpose: Colorectal cancer (CRC) is a formidable global health challenge, ranking as the third most prevalent cancer. Conventional treatments like surgery, radiation, and chemotherapy are limited by adverse effects, driving the search for more effective alternatives.

Methods: This study investigates the synergistic potential of co-delivering 5-fluorouracil (5-FU) and cannabidiol (CBD) using hyaluronic acid (HA)-decorated liposomes. While 5-FU is a cornerstone of CRC treatment, CBD offers promise as an anti-tumor agent. The HA-decorated liposomes enable potential targeted drug delivery to CD44 receptors, which are overexpressed in CRC, while minimizing systemic toxicity by reducing the concentrations of anticancer drugs required.

Results: The liposomal formulation displays optimal physicochemical properties (a sub100nm size and an appropriate negative zeta potential) and acceptable encapsulation and loading efficiencies, ensuring effective drug release. In vitro studies demonstrate that the targeted liposomes have superior anticancer effects, inducing apoptosis (up to 59.1%), cell cycle arrest in the Sub-G1 and G0-G1 phases, reduction of cell viability to 6.98% in human colorectal adenocarcinoma (HT-29) cells, induction of oxidative stress, and inhibition of colony formation. Additionally, HepG2 (non-CD44-expressing) cells were used as a control to evaluate CD44-targeting efficiency. Gene expression analysis by real-time PCR indicates modulation of key genes associated with cell cycle progression and apoptosis.

Conclusion: This multifaceted approach presents a promising strategy for CRC therapy, but requires additional optimization and rigorous in vivo investigations to facilitate successful clinical translation. In particular, optimization of drug-release kinetics and thorough in vivo validation are essential to advance this platform toward clinical application.”

https://pubmed.ncbi.nlm.nih.gov/41835056

https://apb.tbzmed.ac.ir/Article/apb-43401