Cannabinoid receptor deficiencies drive immune response dynamics in Salmonella infection

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“This study investigated the roles of cannabinoid receptors 1 and 2 (CB1R and CB2R) in regulating host responses to Salmonella Typhimurium in C57BL/6 mice.

The absence of both receptors significantly impaired host resilience, as evidenced by increased weight loss, deteriorated body condition, and reduced survival following infection.

Notably, CB1R deficiency resulted in more pronounced weight loss and heightened susceptibility to bacterial proliferation, as demonstrated by increased Salmonella dissemination to organs. In addition, both CB1R and CB2R knockout mice exhibited alterations in immune cell recruitment and cytokine production. CB1R-KO mice displayed increased T cell and macrophage populations, whereas CB2R-KO mice showed a reduction in NK cells, indicating receptor-specific effects on immune cell mobilization.

Cytokine profiling of macrophages post-infection revealed that CB1R-KO mice had reduced IL-10 levels, along with increased IL-6 and TGF-β, suggesting a dysregulated polarization state that combines pro-inflammatory and regulatory elements. In contrast, CB2R-KO mice exhibited a profile consistent with a more straightforward pro-inflammatory shift.

Furthermore, microbiota analysis demonstrated that CB2R-KO mice experienced significant gut dysbiosis, including reduced levels of beneficial Lactobacillus and Bifidobacterium species and an increase in pro-inflammatory Alistipes species post-infection. Functional microbiome analysis further indicated declines in key metabolic pathways, such as the Bifidobacterium shunt, L-glutamine biosynthesis, and L-lysine biosynthesis, suggesting microbiota-driven immune dysregulation.

Together, these findings highlight the distinct, non-redundant roles of CB1R and CB2R in modulating innate immunity, host defense, and microbiota composition during bacterial infections.

Significance statement: Understanding the role of cannabinoid receptors in immune regulation is important for identifying new therapeutic targets for bacterial infections. Our study demonstrates that CB1R and CB2R play distinct, non-redundant roles in host defense against Salmonella Typhimurium. The absence of these receptors impairs host resilience, increases bacterial dissemination, and alters immune cell recruitment and cytokine production. Notably, CB1R deficiency leads to enhanced weight loss, increased bacterial spread, and a dysregulated macrophage cytokine profile-characterized by reduced IL-10 and elevated IL-6 and TGF-β-while CB2R deficiency is associated with reduced NK cell numbers and a more pronounced pro-inflammatory cytokine profile. These findings reveal a receptor-specific balance in immune responses, suggesting that cannabinoid signaling modulates infection outcomes.

Targeting CB1R and CB2R pathways may offer novel strategies to enhance host immunity and improve treatments for bacterial infections in the future.”

https://pubmed.ncbi.nlm.nih.gov/40161677/

https://www.biorxiv.org/content/10.1101/2025.03.10.642352v1

Cannabinoids in Chronic Pain Management: A Review of the History, Efficacy, Applications, and Risks

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“Background/Objectives: Chronic pain remains a pervasive and challenging public health issue, often resistant to conventional treatments such as opioids, which carry substantial risks of dependency and adverse effects. Cannabinoids, bioactive compounds derived from the Cannabis sativa plant and their synthetic analogs, have emerged as a potential alternative for pain management, leveraging their interaction with the endocannabinoid system to modulate pain and inflammation. 

Methods: The current, evolving literature regarding the history, efficacy, applications, and safety of cannabinoids in the treatment of chronic pain was reviewed and summarized to provide the most current review of cannabinoids. 

Results: Evidence suggests that cannabinoids provide moderate efficacy in managing neuropathic pain, fibromyalgia, cancer-related pain, and multiple sclerosis-related spasticity. Patient-reported outcomes further indicate widespread perceptions of cannabinoids as a safer alternative to opioids, with potential opioid-sparing effects. However, the quality of existing evidence is limited by small sample sizes and methodological inconsistencies. Regulatory barriers, including the classification of cannabis as a Schedule I substance in the United States, continue to hinder robust research and clinical integration. Moreover, the risks associated with cannabinoids, such as psychiatric effects, addiction potential, and drug interactions, necessitate cautious application. 

Conclusions: Cannabinoids represent a promising, albeit complex, alternative for chronic pain management, particularly given the limitations and risks of traditional therapies such as opioids. However, significant deficiencies remain in the research. While smaller trials and systematic reviews indicate therapeutic potential, the quality of evidence is often low due to limited sample sizes, short study durations, and methodological inconsistencies. Large-scale, randomized controlled trials with long-term follow-up are urgently needed to confirm efficacy and safety across diverse patient populations and pain etiologies.”

https://pubmed.ncbi.nlm.nih.gov/40149508/

“The future for cannabis research is bright, and as regulatory frameworks adapt to balance access and oversight, cannabinoids may transition from an experimental adjunct to a well-established option in chronic pain care, provided scientific rigor and evidence-based policymaking remain at the forefront.”

https://www.mdpi.com/2227-9059/13/3/530

Parthanatos and apoptosis: unraveling their roles in cancer cell death and therapy resistance

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“Cell death is a fundamental process that needs to be maintained to balance cellular functions and prevent disease. There are several cell death pathways; however, apoptosis and parthanatos are the most prominent and have important roles in cancer biology. As an extremely well-regulated process, apoptosis removes damaged or abnormal cells via caspase activation and mitochondrial involvement.

Unlike in the healthy cells, the loss of ability to induce apoptosis in cancer permits tumor cells to survive and multiply out of control and contribute to tumor progression and therapy resistance. On the contrary, parthanatos is a caspase-independent metabolic collapse driven by poly (ADP-ribose) polymerase 1 (PARP1) overactivation, translocation of apoptosis-inducing factor (AIF), and complete DNA damage. Several cancer models are involved with parthanatos. Deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells by excessive ROS generation, PARP1 upregulation, and AIF nuclear translocation.

Like in acute myeloid leukemia (AML), the cannabinoid derivative WIN-55 triggers parthanatos, and the effects can be reversed by PARP inhibitors such as olaparib.

Developing cancer treatment strategies involving advanced cancer treatment strategies relies on the interplay between apoptosis and parthanatos. However, such apoptosis-based cancer therapies tend to develop resistance, so there is an urgent need to look into alternative pathways like parthanatos, which may not always trigger apoptosis.

In overcoming apoptosis resistance, there is evidence that combining apoptosis-inducing agents, such as BH3 mimetics, with PARP inhibitors synergistically enhances cell death.

Oxidative stress modulators have been found to promote the execution of parthanatic and apoptotic pathways and allow treatment. In this review, apoptosis and parthanatos are thoroughly compared at the molecular level, and their roles in cancer pathogenesis as related to cancer therapeutic potential are discussed.

We incorporate recent findings to demonstrate that not only can parthanatos be used to manage therapy resistance and enhance cancer treatment via the combination of parthanatos and apoptosis but also that immunity and bone deposition can feasibly be employed against long-circulating cancer stem cells to treat diverse forms of metastatic cancers.”

https://pubmed.ncbi.nlm.nih.gov/40166425/

“Cannabinoids induce cell death in leukaemic cells through Parthanatos and PARP-related metabolic disruptions.”

https://pubmed.ncbi.nlm.nih.gov/38461169/

Early oral administration of THC:CBD formulations prevent pain-related behaviors without exacerbating paclitaxel-induced changes in weight, locomotion, and anxiety in a rat model of chemotherapy-induced neuropathy

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“Rationale: Paclitaxel-induced neuropathy stands out as the primary, dose-limiting side effect of this extensively used chemotherapy agent. Prolonged hypersensitivity and pain represent the most severe clinical manifestations. Effective preventive and therapeutic strategies are currently lacking.

Objectives: Our study aimed to assess the impact of early oral administration of pharmaceutical-grade formulations containing the phytocannabinoids THC and CBD in a rat model of paclitaxel-induced neuropathy.

Methods: The experimental design involved the co-administration of paclitaxel and cannabinoid formulations with different THC to CBD ratios (THC:CBD 1:1 and THC:CBD 1:20) to adult male rats. Mechanical and thermal sensitivity, locomotor activity, vertical exploratory behaviors, anxiety-related parameters, weight gain, food and water consumption, and liver functionality were assessed.

Results: Daily administration of THC:CBD 1:1 successfully prevented paclitaxel-induced cold allodynia, while THC:CBD 1:20 effectively prevented both thermal and mechanical hypersensitivities. Additionally, THC:CBD 1:1 formulation restored rearing behavior, significantly reduced by paclitaxel. Conversely, neither cannabinoid formulation was able to counteract paclitaxel-induced hypo-locomotion, reduced vertical exploratory activity, increased anxiety-like behaviors, attenuated weight gain, or decreased food and water intakes. However, the formulations employed did not induce further alterations or toxicity in animals receiving paclitaxel, and no signs of liver damage were detected.

Conclusions: Our results suggest a differential therapeutic effect of two THC:CBD formulations on pain-related behaviors and spontaneous activities, particularly in the context of peripheral neuropathy. These formulations represent a promising therapeutic strategy not only to managing pain but also for enhancing daily activities and improving the quality of life for cancer patients.”

https://pubmed.ncbi.nlm.nih.gov/40163146/

Cannabidiol/tetrahydrocannabinol-enrich extract decreases neuroinfalmmation and improves locomotor outcome following spinal cord injury

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“Neuroinflammation is one of the main players in lesion expansion and locomotor deficits after spinal cord injury (SCI), thus treatments to control the inflammatory process emerge as novel therapeutic strategies. In this context, the anti-inflammatory effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), the main phytocannabinoids of Cannabis sativa, are increasingly recognized.

The aim of this work was to investigate the effects of a standardized Cannabis sativa extract (CSE), which is mainly composed by THC/CBD in equimolar concentration, on neuroinflammation, secondary damage and locomotor outcome after SCI in rats.

After acute SCI, CSE therapy increased the number of non-inflammatory (arginase-1 positive) microglial cells in the epicenter of the lesion and decreased the number of pro-inflammatory ones (arginase-1 negative) in the epicenter and in the rostral and caudal regions of the lesion. CSE also reduced the number of reactive astrocytes in the grey matter of the rostral and caudal regions.

These results are consistent with the downregulation of mRNAs of inflammatory mediators (IL-1β, TNFα, IL-6, C3) and the upregulation of anti-inflammatory markers (ARG-1, MRC). In the chronic phase, CSE treatment prevented cyst expansion and also increased the volume of spared grey and white matter. Regarding locomotor outcome, CSE-treated rats showed better locomotor scores (open field test), higher latency to fall (Rotarod test) and lower number of hindlimb foot misplacements (horizontal ladder walking test) than untreated injured rats.

These results suggest that this standardized CSE offers a promising perspective for reducing acute neuroinflammation and promoting functional recovery after SCI.”

https://pubmed.ncbi.nlm.nih.gov/40157632/

https://www.ibroneuroscience.org/article/S0306-4522(25)00258-1/abstract

Evaluating Vaporized Cannabinoid Therapy in Multiple Sclerosis: Findings from a Prospective Single-Center Clinical Study

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“Introduction: Multiple Sclerosis (MS) is associated with a wide range of debilitating symptoms, and conventional therapies often fail to adequately address the disease’s multifaceted challenges. Cannabidiol (CBD) 13.0% + Delta9-tetrahydrocannabinol (THC) 9.0% (CBD13/THC9), a vaporized cannabis-based medicinal product, presents a novel therapeutic option for managing MS symptoms. 

Methods: This single-center longitudinal study followed 69 MS patients over a six-month period. Participants were assessed at treatment initiation and at three- and six-month intervals. Key measures included muscle spasticity, urine bladder dysfunction, and the evaluation of disability progression rate. The evaluation included the Modified Ashworth Scale (MAS), the Post Void Residual (PVR) volume, and the Expanded Disability Status Scale (EDSS). 

Results: Significant improvement was observed across all outcome assessments. The EDSS score was decreased over time (p = 0.009), indicating a slight reduction in disability progression rate, while MAS scores showed substantial improvement in muscle spasticity (p < 0.001). Urine bladder function improved significantly, with PVR volume showing notable improvement between baseline and the six-month assessment (p < 0.001). Correlation analyses revealed that a gradual increase in vaporized CBD13/THC9 dose was correlated with slightly lower EDSS scores, while the adverse effects were negatively associated with the frequency of cannabinoid use. Finally, patients who were smokers used CBD13/THC9 more frequently. 

Conclusions: The vaporized CBD13/THC9 formulation demonstrated notable efficacy in slightly improving disability progression rate via reduction in muscle spasticity and urine bladder dysfunction in MS patients. This highlights its addon therapeutic value during rehabilitation in MS patients with debilitating disability symptoms.”

https://pubmed.ncbi.nlm.nih.gov/40142928/

https://www.mdpi.com/2077-0383/14/6/2121

Transcriptomic Alterations Induced by Tetrahydrocannabinol in SIV/HIV Infection: A Systematic Review

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“Given the high prevalence of cannabis use among people with HIV (PWH) and its potential to modulate immune responses and reduce inflammation, this systematic review examines preclinical evidence on how tetrahydrocannabinol (THC), a key compound in cannabis, affects gene and micro-RNA expression in simian immunodeficiency virus (SIV)-infected macaques and HIV-infected human cells.

Through a comprehensive search, 19 studies were identified, primarily involving SIV-infected macaques, with a pooled sample size of 176, though methodological quality varied across the studies. Pathway analysis of differentially expressed genes (DEGs) and miRNAs associated with THC revealed enrichment in pathways related to inflammation, epithelial cell proliferation, and adhesion. Notably, some DEGs were targets of the differentially expressed miRNAs, suggesting that epigenetic regulation may contribute to THC’s effects on gene function.

These findings indicate that THC may help mitigate chronic immune activation in HIV infection by altering gene and miRNA expression, suggesting its potential immunomodulatory role. However, the evidence is constrained by small sample sizes and inconsistencies across studies. Further research employing advanced methodologies and larger cohorts is essential to confirm THC’s potential as a complementary therapy for PWH and fully elucidate the underlying mechanisms, which could inform targeted interventions to harness its immunomodulatory effects.”

https://pubmed.ncbi.nlm.nih.gov/40141240/

https://www.mdpi.com/1422-0067/26/6/2598

The use of cannabinoid therapy in treatment-refractory isolated REM sleep behavior disorder: a case report

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“Current treatments for rapid eye movement (REM) sleep behavior disorder (RBD) are not always effective and can lead to dose-limited adverse events, and new treatments are needed for this condition.

We present a case of a patient with treatment-refractory isolated RBD who had a dramatic and sustained improvement in dream enactment behaviors using oral tinctures containing cannabidiol and tetrahydrocannabinol without adverse events over 5 years of follow-up.”

https://pubmed.ncbi.nlm.nih.gov/40130438/

https://jcsm.aasm.org/doi/10.5664/jcsm.11704

UK Medical Cannabis Registry: An Analysis of Outcomes of Medical Cannabis Therapy for Hypermobility-Associated Chronic Pain

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“Objective: The study aims to evaluate the clinical outcomes in patients with hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) with chronic pain following treatment with cannabis-based medicinal products (CBMPs).

Methods: This was a case series conducted with the UK Medical Cannabis Registry. The primary outcomes were changes in the following validated patient-reported outcome measures at 1, 3, 6, 12, and 18 months compared with baseline: Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2), pain visual analog scale score (Pain-VAS), Brief Pain Inventory (BPI), five-level EQ-5D (EQ-5D-5L), Single-Item Sleep Quality Scale (SQS), General Anxiety Disorder Seven-Item Scale (GAD-7), and Patient Global Impression of Change. The incidence of adverse events was analyzed as secondary outcomes. Statistical significance was defined as P <0.050.

Results: A total of 161 patients met inclusion criteria. Improvements were observed in BPI severity and interference subscales, SF-MPQ-2, and Pain-VAS (P < 0.001). Changes were also seen in the EQ-5D-5L index value, SQS, and GAD-7 (P < 0.001). A total of 50 patients (31.06%) reported one or more adverse event with a total incidence of 601 (373.29%). The most frequent rating for adverse events was moderate (n = 258; 160.25%), with headache being the most common (n = 44; 27.33%).

Conclusion: An association was identified between patients with HSD/hEDS with chronic pain and improvements in pain-specific and general health-related quality of life following the commencement of CBMPs. CBMPs were also well tolerated at 18 months. These findings must be interpreted within the context of the limitations of study design but add further weight to calls for randomized controlled trials.”

https://pubmed.ncbi.nlm.nih.gov/40079426/

“Cannabis-based medicinal products (CBMPs) have emerged as a potential alternative for chronic pain management, acting on the endocannabinoid system (ECS), which plays a pivotal role in pain regulation.”

“This study reports an association between CBMP treatment and reported improvements in pain and HRQoL among patients with HSD/hEDS.”

https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr2.70024

A Pilot Randomized Placebo-Controlled Crossover Trial of Medicinal Cannabis in Adolescents with Tourette Syndrome

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“Introduction: Medicinal cannabis (MC) has potential therapeutic effects in Tourette Syndrome (TS), however there has been limited research in adolescent patients. This pilot study aimed to investigate the feasibility of conducting a randomized placebo-controlled crossover trial of MC in adolescents with TS. 

Method: This was a phase I/II double-blind, cross-over pilot study comparing MC with matched placebo in adolescents aged 12-18 years with TS. The active medication was Δ9-tetrahydrocannabinol (THC) 10 mg/mL and CBD 15 mg/mL in peppermint-flavored medium-chain triglyceride oil. The dose titration schedule was stratified into two participant weight bands: below 50 kg (max THC 10 mg/day) or ≥50 kg (max THC 20 mg/day). Each treatment phase lasted 10 weeks, with a 4-week washout period. 

Results: Ten adolescents were randomized (mean age 14.8 years, 50% male) and seven completed the full study protocol. Two adolescents discontinued due to adverse events (one on MC, one placebo) and one was lost to follow-up. The most common adverse event was dizziness (67%). There were no serious adverse events. Among actively enrolled participants, protocol adherence was excellent: study visits 100%, blood test completions 100%, and online questionnaire completion 97.6%. Medication adherence was acceptable in 63.6%. Parents reported a high degree of study design acceptability. On the Clinical Global Impression-Improvement scale, three participants were rated as much improved on MC compared with one on placebo at 10 weeks. 

Discussion: The findings suggest that the study protocol is feasible and acceptable to patients with TS and their families. A fully powered study is needed to evaluate the efficacy of MC in adolescent TS.”

https://pubmed.ncbi.nlm.nih.gov/40082070/

https://www.liebertpub.com/doi/10.1089/can.2024.0188