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Proof of concept for high-dose Cannabidiol pretreatment to antagonize opioid induced persistent apnea in mice

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“Background: Opioid related fatalities remain a public health crisis in the US. Currently, the only way to restore breathing following an opioid induced persistent apnea is with the administration of the opioid antagonist naloxone, but it also reverses analgesia, euphoria, and induces precipitated withdrawal in opioid dependent individuals.

Methods: Using whole-body plethysmography, we assessed changes in breathing frequency in awake behaving mice resulting from a single fentanyl dose (50 mg/kg i.p.) that followed i.p. pretreatment with saline, vehicle, naloxone (100 mg/kg), cannabidiol (CBD) (250 mg/kg), or CBD + naloxone. Then we assessed the delay to opioid-induced persistent apnea (OIPA) and the median lethal dose (LD50) of fentanyl during a continuous i.c.v. infusion of fentanyl (100 ng/min), in urethane anesthetized mice, following pretreatment with saline, vehicle, naloxone (100 mg/kg), CBD (250 mg/kg), or CBD + naloxone i.p.

Results: Here we show acute pretreatment with CBD is as effective as naloxone at preventing opioid-induced respiratory depression from fentanyl in awake mice, and increasing LD50 of fentanyl in urethane anesthetized mice. When pre-administered together, CBD + naloxone, increased LD50 of fentanyl even more than CBD or naloxone alone in urethane anesthetized mice.

Conclusion: CBD may be an effective preventative therapy for OIPA by increasing the time before apnea onset and potentially enhancing the efficacy of naloxone as an additional strategy to save lives.”

https://pubmed.ncbi.nlm.nih.gov/41132595/

“This proof of concept using CBD as a prophylactic therapeutic for prevention of fatal OIPA in mice has considerable potential for public health benefit.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1654787/full

Targeting the antioxidant, antimicrobial and anti-inflammatory activity of non-psychotropic Cannabis sativa L.: a comparison with chemotype V

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“Non-psychotropic Cannabis sativa L. chemotypes have gained increasing interest due to their diverse profiles of bioactive compounds. While cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), are known for their biological effects, the role of other cannabinoids such cannabichromene (CBC) remains underexplored as for chemotype V, which lacks in cannabinoids but is characterized by other minor phytochemicals.

This study aimed to evaluate the individual and combined contributions of cannabinoids and non-cannabinoid phenolics to the antioxidant, antimicrobial, and anti-inflammatory properties of extracts derived from four C. sativa chemotypes, including a cannabinoid-free variant as a comparison.

Ethanolic extracts were obtained from four hemp chemotypes: CBD-rich (CS1), CBG-rich (CS2), CBC-rich (CS3), and cannabinoid-free (CS4). Phytochemical profiling was conducted using UHPLC-HRMS. Antioxidant properties were assessed via DPPH, ABTS, and FRAP assays. Antimicrobial activity was tested against Gram-positive and Gram-negative bacteria through MIC, MBC, and time-kill assays. Anti-inflammatory activity was evaluated in LPS-stimulated RAW 264.7 macrophages via gene expression analysis of pro- and anti-inflammatory mediators (IL1b, IL6, Cox2, IL10, IL1Ra).

Phytochemical analysis confirmed the chemotype-specific profiles, with CS3 showing the highest levels of canniprene and the early discovered 5-methoxy-dihydrodenbinobin. Antioxidant assays revealed that cannabinoids were the main contributors to radical scavenging capacity, though CS3 exhibited additional ferric ion reducing power likely due to non-cannabinoid phenolics. Antibacterial activity was confined to Gram-positive bacteria, where CS1 showed the highest efficacy, and CS4 showed no activity, highlighting the critical role of cannabinoids. All extracts reduced LPS-induced Il1b, Il6, and Cox2 gene expression, but only cannabinoid-rich extracts upregulated the anti-inflammatory cytokines IL10 and IL1Ra, indicating a cannabinoid-dependent effect.

Both cannabinoids and non-cannabinoid phenolics contribute to the biological activity of Cannabis sativa extracts, with cannabinoids playing a central role in antimicrobial responses and stronger anti-inflammatory effect as a pure cannabinoid or as an extract. From this point of view, the cannabinoid-free chemotype V could be a valuable functional control for isolating the effects of cannabinoids, reinforcing the need for integrative analyses in evaluating the therapeutic potential of cannabis-derived formulations.”

“In this study, we provided a phytochemical characterization and biological activity of non-psychoactive Cannabis sativa L. extracts from III, IV, V and the emerging CBC chemotype. The phytochemical profile confirmed the distinct percentage of cannabinoid and non-cannabinoid composition of each chemotype, with the CS3 sample exhibiting the highest levels of canniprene and 5-methoxy-dihydrodenbinobin. Antioxidant assays demonstrated that cannabinoids significantly contribute to the radical scavenging capacity of the extracts, with an additional support from non-cannabinoid phenolics as testified by the CS4. Antimicrobial assays showed that only the cannabinoid-containing extracts exhibited potent bactericidal activity against Gram-positive pathogens, including drug-resistant MRSA, while the cannabinoid-free extract lacked such activity. Furthermore, all extracts, including the cannabinoid-free one, were able to suppress LPS-induced pro-inflammatory gene expression in macrophages. However, only the cannabinoid-rich extracts promoted the anti-inflammatory cytokines IL-10 and IL-1Ra, underscoring a cannabinoid-dependent immunomodulatory effect.

Taken together, these results highlight the importance of cannabinoid in the biological properties of Cannabis sativa with a contribution apported by non-cannabinoid phenolic compounds. Moreover, the anti-inflammatory, antimicrobial, and antioxidant effects observed with both pure cannabinoids and cannabinoid-containing extracts support their potential use in topical formulation for the treatment of chronic inflammatory skin disorders, such as atopic dermatitis and psoriasis. These conditions are often exacerbated by skin dysbiosis and colonization by Gram-positive bacteria like Staphylococcus aureus, which contribute to skin barrier dysfunction and amplify immune dysregulation (Zhang et al. 2025). Therefore, while the cannabinoid-free chemotype V serves as a valuable control for dissecting the specific contributions of individual cannabinoids within CS extracts, our findings pave the way for future investigations into the therapeutic potential of selected cannabis-derived products—particularly in the context of antimicrobial resistance and inflammatory diseases associated with dysbiosis.”

https://pubmed.ncbi.nlm.nih.gov/41121423/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00336-1

The endocannabinoid system as a therapeutic target in intestinal fibrosis

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“Intestinal fibrosis is a common and serious complication of inflammatory bowel diseases, often leading to strictures that require endoscopic or surgical intervention.

Despite advances in anti-inflammatory therapies, effective antifibrotic treatments is currently not available. Therefore, new treatment methods for intestinal fibrosis are sought with the endocannabinoid system (ECS) as a potential therapeutic target.

Cannabinoid receptors 1 and 2 (CB1/2) are classic receptors of the ES involved in the modulation of intestinal inflammation and permeability of the mucosal barrier. Experimental evidence from liver and lung models suggests that CB1 receptor activation promotes fibrosis through enhancement of the TGF-β/Smad pathway, interaction with the renin-angiotensin system, and upregulation of profibrotic markers, such as collagen and α-SMA.

In contrast, CB2 receptor signaling appears to exert protective effects by limiting inflammation, fibroblast activation, and extracellular matrix deposition. Recent findings also suggest cross-talk between cannabinoid signaling and platelet-derived growth factor pathways, which are key drivers of myofibroblast proliferation and fibrogenesis. Although these mechanisms are well-established in hepatic, pulmonary and skin fibrosis, data from small and large intestine is scarce. However, direct evidence in intestinal fibrosis is scarce, representing a major knowledge gap.

Elucidating ECS mechanisms in the alimentary tract could enable targeted antifibrotic strategies, complement current therapies, and reduce progression to fibrostenotic disease.”

https://pubmed.ncbi.nlm.nih.gov/41111512/

“The ECS is widespread in the human body, which proves its many functions in the body. Due to its presence in the digestive system and immune cells, it can influence the modulation of inflammation and the process of fibrosis in IBD. Numerous studies, both in animal models, cell cultures and in human tissue, show that the activation or inhibition of individual elements of the ECS can affect the process of intestinal fibrosis. Hence, the ECS may be a potential target aiming at the fibrosis reduction.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1669951/full

Cannabis-Derived Compounds Against Plasmodium sp.: A Systematic Review of Preclinical Studies

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“Objective: This study aims to evaluate preclinical studies on the effects and toxicity of cannabis-derived compounds against Plasmodium sp.

Methods: A literature search was conducted in Web of Science, PubMed, Scopus and LILACS databases until December 2024. Studies that assessed the activity or toxicity of cannabis against Plasmodium sp. in in vitro or in vivo studies were included. Two reviewers independently performed the study selection, data extraction and methodological assessment.

Results: Eight studies published between 2001 and 2022 were included, with the majority conducted in North America (n = 5). Most in vitro studies focused on assessing antimalarial activity through half-maximal inhibitory concentration (IC50), which ranged from 0.16 to 4.1 μg/mL, indicating mild to high activity.

For the in vivo studies, all reported positive effects, including moderate antimalarial activity and disease tolerance. The toxicity profile of these compounds has not been extensively studied, and most studies present an unknown or unclear risk of bias due to insufficient methodological information.

Conclusions: Future studies should provide more comprehensive details on study design and further validate these findings, especially concerning toxicity.”

https://pubmed.ncbi.nlm.nih.gov/41093288/

https://onlinelibrary.wiley.com/doi/10.1111/tmi.70044

Antinociceptive, anti-inflammatory, and anti-dysmenorrheal activities of aerial parts of Cannabis sativa L. from the sub-middle region of the Vale do São Francisco

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“Introduction: Cannabis sativa L. has been used for thousands of years to treat intestinal and uterine diseases and as an anti-inflammatory, analgesic, and antiepileptic, among others. This study aimed to conduct preclinical studies based on the ethnopharmacological properties of C. sativa.

Methods: For this purpose, the police and health authorities provided the raw plant material, and a crude ethanolic extract of the aerial parts of C. sativa (APCs) was produced, which was subsequently chemically analyzed using combined chromatographic and spectrometric methods. Subsequently, APCs were administered to Swiss mice and Wistar rats for evaluation using the open field test, acetic acid-induced abdominal contraction model, hot plate test, formalin test, carrageenan-induced paw edema, Saccharomyces cerevisiae-induced fever, and primary dysmenorrhea models.

Results: Chemical analysis suggests the presence of classic cannabinoids, such as cannabidiol, tetrahydrocannabinol, and cannabigerol, as well as flavonoids and alkaloids. The doses used in the open field test were 1, 3, 10, 30, and 100 mg/kg (gavage, po), with the last two doses responsible for reducing mobility and inducing hypothermia in the animals. In subsequent pharmacological protocols, the doses used were 1, 3, and 10 mg/kg (gavage, po). In the abdominal contraction model, the number of writhing events was reduced by APCs at a dose of 10 mg/kg [median 0.5 (Q25 = 0; Q75 = 5.75, p < 0.05)]. In the hot plate test, the doses of 1, 3, and 10 mg/kg increased the latency time to 17.67 ± 1.33, 18.50 ± 1.31, and 17.33 ± 1.69 s (p < 0.05), respectively. In the formalin test, the effect was restricted to the first phase, with values of 42.33 ± 7.588, 45.50 ± 6.657, and 39.50 ± 7.869 s (p < 0.05) in paw-licking time. In paw edema, the doses of 1 and 3 mg/kg were more constant, restricting the volume to 0.168 ± 0.004 and 0.150 ± 0.004 mL (p < 0.05), respectively. In dysmenorrhea, the doses of 3 and 10 mg/kg reduced abdominal contractions [0 (Q25 = 0; Q75 = 3.0) and 1.0 (Q25 = 0; Q75 = 3.0)].

Conclusion: APCs at the tested doses did not promote an antipyretic effect. These data indicate that APCs have antinociceptive, anti-inflammatory, and anti-dysmenorrheal effects in animal models.”

https://pubmed.ncbi.nlm.nih.gov/41089847/

“Cannabis sativa L. is a plant from the family Cannabaceae and one of the oldest to be domesticated in the world, with its use dating back to approximately 12,000 years in the Central Asian region.”

“C. sativa has a variety of indications in traditional medicine, in the most diverse forms of use (tea, smoke, vapor, etc.), and is used as a wound healing agent, analgesic, anticonvulsant, hypnotic, tranquilizer, anesthetic, anti-inflammatory, antibiotic, antiparasitic, antispasmodic, digestive, appetite stimulant, diuretic, aphrodisiac, antitussive, and expectorant.”

“Our results suggest that APCs contain classic cannabinoids, flavonoids, and alkaloids, and that classic cannabinoids, THC, and CBD are present. The administration of APCs promoted behavioral changes in the animals consistent with the pharmacological effects of these substances, such as reduced ambulation and hypothermic effect at doses of 30 and 100 mg/kg. In pharmacological studies, antinociceptive, anti-inflammatory, and anti-dysmenorrheal effects were observed in different experimental models and in the 1–10 mg/kg dose range; however, the APCs failed to show an antipyretic effect at these doses.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1677987/full

In silico insights on the binding site and function of cannabinoids and cannabinoid acids on human 5-HT1A receptor

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“Previous studies reported that the acid congener of the cannabinoids, cannabidiolic acid, was approximately 1000 times more effective than the neutral congener, cannabidiol, in alleviating emesis.

The biological actions of cannabinoids were proposed to be mediated by the enhancement of somatodendritic 5-HT1A receptors. However, to date, the potential mechanism that may be involved in the enhancement of the 5-HT1A activity by the acid congener is still lacking. To address this gap, molecular docking and molecular dynamics simulations were performed on different pairs of neutral and acidic cannabinoids in a human 5-HT1A receptor model.

Analyses showed that simulated cannabinoid acids (cannabidiolic acid and tetrahydrocannabivarinic acid) and tetrahydrocannabivarin were preferentially bound at the allosteric site of 5-HT1A and were able to maintain the receptor in its active state when a full agonist, R(+)-8-OH-DPAT, was bound at the orthosteric site. Importantly, these results also suggest that the strong activity of cannabidiolic acid is not due to its strong affinity for the 5-HT1A receptor but its positive allosteric modulation of the agonist activity on 5-HT1A, presumably by blocking the exit of the orthosteric ligand, hence promoting continuous activation of the receptor. This study also demonstrates that cannabidiol and both neutral and acidic cannabigerol prefer binding at the orthosteric site and are potential partial agonists of 5-HT1A.

In conclusion, these findings propose that every cannabinoid, regardless of whether neutral or acidic, is unique on its own in terms of its binding and function.”

https://pubmed.ncbi.nlm.nih.gov/41056675/

“Importantly, these findings indicate that every individual cannabinoids, regardless of neutral or acid congeners, is unique on its own and deserves its investigation, on its binding, function and therapeutic potential.”

https://www.sciencedirect.com/science/article/pii/S1093326325002463?via%3Dihub

The Associative Impact of Recreational Cannabis Use on Sinonasal Diseases

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“Objectives: With growing cannabis use in the US, it is crucial to understand the impact of recreational use on sinonasal diseases like chronic rhinosinusitis (CRS), allergic rhinitis (AR), and chronic rhinitis (CR).

Methods: This cross-sectional study leveraged the NIH AllOfUs database to query patient surveys assessing cannabis usage frequency (lifetime never, monthly, weekly, or daily within the past 3 months) and consumption route (smoking or non-smoking). Cannabis users were matched to never users for demographics, healthcare visit frequency, and insurance. A stringent logistic regression model calculated odds ratios (OR) of developing AR, CRS, or CR after survey completion. Cox regression hazard ratios (HR) compared consumption routes.

Results: Twenty-five thousand one hundred sixty-four cannabis users were matched with 113,418 never users. Users demonstrated significantly lower odds of AR, CRS, and CR than never users. For CRS, the ORs compared to never users are as follows: daily users 0.64 (95% CI 0.53-0.78), weekly users 0.61 (95% CI 0.48-0.77), and monthly users 0.80. For AR, the ORs were 0.64 (95% CI 0.58-0.71) for daily users, 0.62 (95% CI 0.54-0.71) for weekly users, and 0.69 (95% CI 0.58-0.80) for monthly users. For CR, the ORs were 0.61 (95% CI 0.47-0.79) for daily users, 0.64 (95% CI 0.47-0.87) for weekly users, and 0.41 (95% CI 0.26-0.65) for monthly users. There was no significant difference between smokers and non-smokers (HR 0.64, 95% CI 0.27-1.5).

Conclusion: There is an inverse, associative relationship between cannabis use and sinonasal disease. This relationship is insufficiently understood, and there remain significant concerns about the impact of cannabis use, especially smoking, on airway pathologies.”

https://pubmed.ncbi.nlm.nih.gov/41064579/

“This is the largest study to specifically comment on the association between cannabis use and three of the most common sinonasal diseases—AR, CRS, and CR. We found lower odds of AR, CRS, and CR in patients who use cannabis compared to those who do not, which is strengthened by the size of our cohorts and by incorporating demographic and comorbidity information in our analysis. Route of consumption did not change CRS incidence. “

https://onlinelibrary.wiley.com/doi/10.1002/lio2.70261

Ex vivo study of the vasorelaxant activity induced by cannabigerol in human pulmonary artery- the role of endothelium, sex and selected clinical factors

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“Cannabigerol (CBG) is a non-psychoactive phytocannabinoid with an antioxidant and anti-inflammatory properties.

Because CBG has a promising pharmacological profile involving activation of α2adrenergic and peroxisome proliferator-activated γ (PPARγ) receptors it may have relevance in the pharmacotherapy of cardiovascular diseases.

Cannabigerol was also effective in lowering blood pressure in normotensive mice. In addition, it has been shown that cannabinoids can exhibit vasorelaxant effects in various vascular beds, and another plant cannabinoid-cannabidiol-has been shown to be effective in attenuating the development of pulmonary arterial hypertension.

In view of these reports, the aims of our study were to investigate whether CBG, exhibits a vasorelaxant effect on human pulmonary arteries (hPAs), to determine the mechanisms of CBG’s potentiating effects and to assess the influence the selected clinical factors and patients’ comorbidities on the vascular response induced by CBG.

Our study reports that CBG relaxes hPAs, and post-hoc analysis has shown that this response can be modified by hypertension and hypercholesterolaemia. We showed that the vasorelaxant effect of CBG depends on the vascular endothelium and the following mechanisms are involved: 1) cyclooxygenase-dependent pathway, 2) nitric oxide-dependent pathway, 3) voltage- and calcium-dependent K+ channels and 4) probably cannabinoid type 1 and 2, PPARγ, G-protein-coupled 55 and transient receptor potential vanilloid 1 receptors.

At all, CBG appears to be a possible vasorelaxant agent, but its therapeutic efficacy may vary based on the patient’s condition and comorbidities. CBG’s mild vasorelaxant property may provide an added benefit in addition to its anti-inflammatory and antioxidant properties in hemp preparations.”

https://pubmed.ncbi.nlm.nih.gov/41046075/

“In conclusion, this study reports for the first time that CBG causes a vasorelaxant effect in hPAs. This effect is primarily mediated by vascular endothelium-dependent mechanisms. CBG-induced vasorelaxation was mediated by the 1) COX-1/COX-2-dependent pathway, 2) NO-dependent pathway, 3) voltage- and calcium-dependent K+ channels and 4) probably by the CB1, CB2, PPARγ, GPR55 and TRPV1 receptors.

This study provides evidence that CBG may be a potentially important agent with vasorelaxant effect, but its therapeutic efficacy may be modified by the patient’s condition and comorbidities. In addition to the well-documented anti-inflammatory and antioxidant properties, the mild vasorelaxant effect of CBG may be an additional advantage in the context of the use of hemp preparations.”

https://www.sciencedirect.com/science/article/pii/S0006295225006483?via%3Dihub

No differences in neural responses or performance during cannabis cue-specific inhibitory control tasks between recreational cannabis users and non-users: Insights from fNIRS

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“Background: Impaired inhibitory control has been observed in regular cannabis users. Theories suggest that regular cannabis use is maintained by reward-driven behaviour, which may be underpinned by adaptations in neural reward and inhibitory control systems, thus increasing vulnerability to dependency.

Aims: This study investigated neural correlates of cannabis cue-specific inhibitory control in regular cannabis users and non-users using functional near-infrared spectroscopy (fNIRS).

Methods: Thirty regular cannabis users and thirty non-user controls completed two inhibitory control tasks (Go/No/Go and Stop-Signal Task), and a measure of attentional bias (Cannabis Stroop task). fNIRS recorded prefrontal and orbitofrontal haemodynamic responses (oxygenated haemoglobin and deoxygenated haemoglobin). Group comparisons and exploratory regressions examined cannabis use characteristics as predictors of behavioural and neural outcomes.

Results: No significant group differences were found in behavioural performance or haemodynamic activity across tasks. Exploratory regressions showed no significant associations between cannabis use characteristics and behavioural or neural outcomes after adjusting for covariates.

Conclusions: No evidence of impaired inhibitory control, attentional bias, or differences in prefrontal function were found in non-dependent cannabis users. Future studies should investigate whether such deficits emerge with heavier or dependent use.”

https://pubmed.ncbi.nlm.nih.gov/41037310/

“In summary, this study found no significant differences in behavioural performance or neural activation between regular cannabis users and non-user controls during cue-specific inhibitory control tasks.”

https://journals.sagepub.com/doi/10.1177/02698811251358814

New insights into the crosstalk between endocannabinoids and sphingosine-1-phosphate

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“This review aims at highlighting the interplay between the endocannabinoids (eCBs) anandamide and 2-arachidonoylglycerol, and sphingosine-1-phosphate (S1P) signaling. The eCBs and S1P are bioactive compounds that exemplify a paradigm of crosstalk among lipid signals, with profound implications for physiological processes and disease pathogenesis.

Cross-communication between eCBs and S1P occurs through multiple mechanisms: (i) receptor heterodimerization and co-regulation, (ii) mutual metabolic modulation, and (iii) integrated regulation of downstream effectors. The latter emerged as a key mechanism underlying the bidirectional interactions between eCBs and S1P, with functional overlaps that regulate several processes including inflammation, vascular function, and neuronal activity.

In addition, cannabis-derived compounds (such as cannabidiol) can influence eCBs and S1P signaling, calling for further research into their therapeutic exploitation.

Overall, the dynamic interplay between endogenous eCBs and S1P – as well as with exogenous cannabidiol – described here offers a compelling example of the complexity of interactions among bioactive lipids. A deeper mechanistic understanding of these relationships could pave the way to novel strategies in drug design and development, emphasizing the importance of integrated approaches in the study of bioactive lipid biochemistry.”

https://pubmed.ncbi.nlm.nih.gov/41033556/

“In conclusion, it seems apparent that eCB and S1P signaling pathways operate through interconnected networks of remarkable complexity. As yet, the biochemical crosstalk between these bioactive lipids remains incompletely understood, potentially limiting the therapeutic exploitation of these signals. Future strategies targeting the spatiotemporal dynamics of lipid transport – from intracellular trafficking to extracellular distribution – combined with selective receptor engagement, may unlock novel therapeutic opportunities that current approaches have not fully realized.”

https://www.jbc.org/article/S0021-9258(25)02633-X/fulltext