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

Preclinical assessment of pharmacokinetics and anticonvulsant activity of CBDTech, a novel orally administered cannabidiol (CBD) formulation for seizure and epilepsy

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“Oral cannabidiol (CBD) product use is increasing despite suboptimal pharmacokinetics (PK) of currently available formulations. This study aimed to investigate the PK of CBD formulated using the drug delivery technology DehydraTECH™, which is hypothesized to increase absorption by bypassing first-pass liver metabolism due to enhanced lipophilic composition.

Anticonvulsant activity of the leading formulation was investigated in the maximal electroshock seizure (MES) model. For the PK studies, Sprague Dawley rats were orally administered 25 mg/kg CBD in MCT oil or test formulations incorporating DehydraTECH™ (n = 10 per group). Plasma, brain tissue and urine and feces samples were collected to determine comparative absorption, distribution, and excretion by liquid chromatography with tandem mass spectrometry (LC-MS/MS). For the efficacy studies, a series of experiments was conducted using the lead formulation (CBDtech) from the PK trial. Effective dose (ED) of CBDtech in comparison to Epidiolex® (50-100 mg/kg), time of peak efficacy (TPE), and median ED (ED50) were assessed in the acute MES model. Clinical observations, presence/absence of hind limb extension (HLE), and maximum seizure severity (MSS) were recorded. No abnormal clinical signs were observed following dosing in any study. Area under the curve from dosing to the last measurable concentration (AUClast) was 391 to 2708% improved following treatment with DehydraTECH™ formulations as compared with the MCT control (all p < 0.01). CBD was detected in brain, urine, and feces samples following all DehydraTECH™ treatments.

Treatment with the ED of CBDtech (75 mg/kg) resulted in full protection (absence of HLE) in 66.6% of test subjects following MES test compared to 50% in the Epidiolex® group. The one-hour timepoint was determined to be the TPE for CBDtech; HLE was absent in 75% of animals and partial in 12.5% of animals. In comparison, in the Epidiolex® group HLE was absent in 50% of animals and partial in 12.5% of animals. The calculated ED50 was 75 mg/kg.

Formulation of CBD with DehydraTECH™ resulted in improved bioavailability and efficacy in an acute seizure model. These findings contribute to a deeper understanding of CBD PK and will aid in the design of more effective CBD-based therapeutic interventions.”

https://pubmed.ncbi.nlm.nih.gov/41029806/

“In summary, these data demonstrate the improved bioavailability and anticonvulsant activity of CBD using advanced formulations employing DehydraTECH™. These findings support the further investigation of novel CBD formulations, to improve the efficacy of lipophilic drug candidates, including CBD.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00322-7

VER-01 Shows Enhanced Gastrointestinal Tolerability, Superior Pain Relief, and Improved Sleep Quality Compared to Opioids in Treating Chronic Low Back Pain: A Randomized Phase 3 Clinical Trial

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“Introduction: Chronic low back pain (CLBP) affects over half a billion people worldwide. Current pharmacologic treatments, comprising mainly non-steroidal anti-inflammatory drugs and opioids, offer limited efficacy and pose significant risks, warranting the development of tolerable, safe and effective alternatives.

Methods: This randomized controlled trial on adults with CLBP was designed to confirm the superior efficacy and gastrointestinal tolerability of VER-01, a novel, standardized full-spectrum extract from Cannabis sativa DKJ127 L., over opioids. Subjects were randomized (1:1) to receive VER-01 or a range of commercially available opioids. After a 3-week titration, subjects underwent 24 weeks of treatment, followed by 2 weeks of wash-out. The primary endpoint was the relative risk of constipation occurrence after 27 weeks treatment. Secondary endpoints included changes in pain and sleep scores, determined using an 11-point numeric rating scale (NRS), with key secondary endpoints defined for week 27.

Results: A total of 384 individuals were randomized to receive VER-01 (n = 192) or opioids (n = 192). Subjects receiving VER-01 were fourfold less likely to develop constipation than those receiving opioids (relative risk [RR] VER-01/opioids 0.25; 95% confidence interval [CI] 0.09-0.69; p = 0.007) and threefold less likely to use laxatives (RR 0.34; 95% CI 0.18-0.65; p < 0.001). Longitudinal analysis revealed that VER-01 was superior to opioids in terms of pain reduction over 6 months of treatment, although differences in secondary endpoints limited to week 27 alone were not significant. Throughout the 6 months of treatment, mean pain reduction was 2.50 NRS points with VER-01 versus 2.16 with opioids (mean difference [MD] 0.34; 95% CI 0.00-0.67; p = 0.048), and sleep improved by 2.52 points with VER-01 versus 2.07 with opioids (MD 0.45; 95% CI 0.11-0.79; p = 0.009). These benefits were particularly pronounced in participants with severe pain, with greater pain reduction (MD 0.58; 95% CI 0.01-1.15) and sleep improvement (MD 0.66, 95% CI 0.05-1.27) compared to opioids.

Conclusions: VER-01 demonstrated superiority over opioids in treating CLBP, both in terms of efficacy and gastrointestinal tolerability.”

https://pubmed.ncbi.nlm.nih.gov/41028525/

“In summary, this study provides robust evidence that VER-01 offers better tolerability, as well as superior pain relief and sleep quality compared to opioids in patients with CLBP. These findings highlight its potential as a promising new pharmacological option within a multimodal treatment approach that could fundamentally shift the paradigm in the treatment of chronic pain.”

https://link.springer.com/article/10.1007/s40122-025-00773-z

Cannabidiol engages the peripheral endogenous opioid system to produce analgesia in neuropathic mice

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“Cannabidiol (CBD) has been getting attention from the scientific community regarding its potential for the treatment of different conditions, such as epilepsy, anxiety, and pain.

This potential can be useful in clinical practice as an alternative or as an adjuvant alongside conventional therapeutic approaches; however, its mechanisms of action should be best described for its more effective application. Thus, our study aimed to evaluate whether the peripheral opioid system is involved in the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain.

Male Swiss mice were subjected to the sciatic constriction injury, and their nociceptive threshold was evaluated using the mechanical paw pressure test.

Cannabidiol 20 mg/Kg produced an antinociceptive effect. Bestatin (400 µg/paw), a selective aminopeptidase-N inhibitor, potentiates the intermediate analgesic response of CBD at the dose of 2 mg/Kg. Naloxone (50 µg/paw), a non-selective opioid receptor antagonist, reversed the CBD-mediated analgesia. CTOP (5, 10, and 20 µg/paw) and naltrindole (30, 60, and 120 µg/paw), μ and Δ opioid receptor antagonists, but not norBNI (200 µg/paw), a κ opioid receptor antagonist, partially reversed the CBD analgesia.

Thus, our study shows that cannabidiol may induce activation of opioid receptors in the periphery as a part of its analgesic mechanism in neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/41022278/

“CDB induces the activation of µ and δ opioid receptors as a part of its analgesia mechanism, leading us to suggest a possible interaction between opioid and cannabinoid systems as a complementary mechanism for generating peripheral analgesia in neuropathic mice treated with cannabidiol.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394025002824?via%3Dihub

The effects of cannabidiol on nitric oxide synthases: a narrative review on therapeutic implications for inflammation and oxidative stress in health and disease

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“Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, shows promise as a therapeutic agent for conditions associated with inflammation and oxidative stress, often involving nitric oxide (NO) signaling dysregulation.

This review summarizes preclinical and clinical data on CBD’s impact on nitric oxide synthase (NOS) isoforms and NO levels in cardiovascular, neurological, metabolic, and immune systems.

Studies suggest that CBD can reduce inflammation-induced inducible NOS (iNOS) expression while maintaining or enhancing endothelial NOS (eNOS)-mediated NO production, leading to decreased oxidative stress, improved endothelial function, and reduced neuroinflammation.

The effects of CBD vary based on dose, formulation, timing, and disease state, with potential interactions with metabolites and other drugs affecting safety. Further research is needed to determine optimal dosing, formulation, pharmacokinetics, metabolite profiles, and long-term safety for specific conditions.”

https://pubmed.ncbi.nlm.nih.gov/41024292/

“In summary, the ongoing exploration of CBD’s interaction with NOS and its broader implications for human health underscores the need for rigorous scientific inquiry. As we continue to unravel its potential, the integration of cannabinoid-based therapies into mainstream medical practice could revolutionize approaches to treating chronic diseases characterized by inflammation and oxidative stress.”

“These findings suggest that CBD may serve as a promising cannabinoid-based therapeutic agent in treating chronic diseases associated with inflammation and oxidative stress. Overall, the review underscores the need for further research to explore the clinical applications of CBD and its mechanisms in various health scenarios, paving the way for evidence-based treatments that harness the therapeutic potential of cannabinoids.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00332-5

Full-spectrum extract from Cannabis sativa DKJ127 for chronic low back pain: a phase 3 randomized placebo-controlled trial

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“Chronic low back pain (CLBP) affects over half a billion people worldwide. Current pharmacologic treatments offer limited efficacy and carry substantial risks, warranting the development of safe and effective alternatives.

This multicenter, randomized, placebo-controlled phase 3 trial evaluated the efficacy and safety of VER-01 in CLBP. It enrolled 820 adults with CLBP (VER-01, n = 394; placebo, n = 426) and included a double-blind 12-week treatment phase (phase A), a 6-month open-label extension (phase B), followed by either a 6-month continuation (phase C) or randomized withdrawal (phase D). The primary endpoint of phase A was a change in mean numeric rating scale (NRS) pain intensity, with a change in total neuropathic pain symptom inventory (NPSI) score as a key secondary endpoint in participants with a neuropathic pain component (PainDETECT > 18). The primary endpoint for phase D was time to treatment failure.

The study met its primary endpoint in phase A, with a mean pain reduction of -1.9 NRS points in the VER-01 group (mean difference (MD) versus placebo = -0.6, 95% confidence interval (CI) = -0.9 to -0.3; P < 0.001). Pain further decreased to -2.9 NRS points in phase B, with effects sustained through phase C.

The study also met its key secondary endpoint of phase A, with a mean NPSI decrease of -14.4 (standard error, 3.3) points from baseline in the VER-01 arm (MD versus placebo = -7.3, 95% CI = -13.2 to -1.3; P = 0.017). Although phase D did not meet its primary endpoint (hazard ratio = 0.75, 95% CI = 0.44-1.27; P = 0.288), pain increased significantly more with placebo upon withdrawal (MD = 0.5, 95% CI = 0.0-1.0; P = 0.034). In phase A, the incidence of adverse events-mostly mild to moderate and transient-was higher with VER-01 than with placebo (83.3% versus 67.3%; P < 0.001). VER-01 was well-tolerated, with no signs of dependence or withdrawal.

VER-01 shows potential as a new, safe and effective treatment for CLBP.”

https://pubmed.ncbi.nlm.nih.gov/41023483/

“In conclusion, this phase 3 study provides robust evidence supporting the efficacy and safety of VER-01 in the treatment of CLBP.”

https://www.nature.com/articles/s41591-025-03977-0

Cannabidiol attenuates diet-induced metabolic endotoxemia, neuroinflammation, and anxiety-like behaviors in male aged rats

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“Obesity and aging synergistically reinforce neuroinflammation and disruption of homeostatic mechanisms, triggering pathological behaviors such as increased anxiety.

Cannabidiol (CBD) has been reported to exert anxiolytic, anti-inflammatory, and neuroprotective effects, supporting the hypothesis that it may attenuate the detrimental consequences of obesity, even in aged animals.

To test this hypothesis, 18-month-old male Wistar rats were divided into four experimental groups: control + vehicle (CT + vehicle), CT + CBD, cafeteria diet + vehicle (CAF + vehicle) and CAF + CBD. The animals were fed their diets for 8 weeks. Oral treatment with CBD (15 mg/kg/day) or vehicle began in the 9th week and continued until the end of the experiment, concurrently with the ongoing diet.

We found that the CAF increased anxiety-like behaviors in the open field and elevated plus maze tests, while CBD mitigated these behaviors in the open field. Obesogenic diet also increased circulating levels of lipopolysaccharide, which were reduced by CBD. In the prefrontal cortex, CAF increased levels of interleukin-6 (IL-6), which were decreased by CBD. Additionally, CBD reduced the expression of tumor necrosis factor-α (TNF-α) and toll-like receptor 4 (TLR4). CAF feeding also caused a reduction in the main endocannabinoids, 2-Arachidonoylglycerol (2-AG) and anandamide (AEA). In the prefrontal cortex, CAF increased transcripts of cannabinoid receptor 1 (CB1) and reduced those of cannabinoid receptor 2 (CB2) and serotonin receptor 5-Hydroxytryptamine receptor 1A (5-HT1A). Moreover, levels of triggering receptor expressed on myeloid cells 2 (TREM2) were reduced by the diet.

These findings support the notion that obesity, through its metabolic and inflammatory consequences, exacerbates neuroinflammation and contributes to the dysregulation of the endocannabinoid system in aged animals. Notably, CBD demonstrated the ability to attenuate inflammatory markers and improve anxiety-like behavior, suggesting its potential as a therapeutic strategy to counteract obesity-induced neurobiological alterations in aging.”

https://pubmed.ncbi.nlm.nih.gov/41022293/

“CBD reversed systemic and central inflammatory effects of obesity.”

https://linkinghub.elsevier.com/retrieve/pii/S0889159125003630

Cannabis sativa Root Extract Exerts Anti-Nociceptive and Anti-Inflammatory Effects via Endocannabinoid Pathway Modulation In Vivo and In Vitro

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“Cannabis sativa root has traditionally been used to relieve pain and inflammation, but its pharmacological properties remain underexplored due to low levels of psychoactive cannabinoids.

This study aimed to investigate the anti-inflammatory and antinociceptive effects of the ethyl acetate fraction of Cannabis sativa root (CSREA) using in vivo rodent pain models. Mice were subjected to formalin and acetic acid-induced nociceptive tests, while rats were evaluated using a carrageenan-induced paw edema model.

CSREA significantly reduced pain-related behaviors in both early (0-10 min) and late phases (15-30 min) of the formalin test and decreased writhing responses in the acetic acid model. Notably, CSREA also improved survival rates following acetic acid injection. Inflammatory markers, including IL-6 and IL-1β, were significantly lowered in serum.

Furthermore, CSREA suppressed paw edema and redness in the carrageenan-induced rat model, demonstrating dose-dependent anti-inflammatory efficacy comparable to diclofenac. CSREA also downregulated pain-related gene expression (SCN9A, ASIC1A, TACR1) and regulated key enzymes involved in endocannabinoid metabolism (FAAH, MAGL, DAGL), suggesting its role in the molecular modulation of pain pathways.

These effects are likely mediated via modulation of the endocannabinoid system, particularly by rebalancing the CB1R/CB2R ratio. The findings suggest that CSREA holds promise as a natural therapeutic agent for managing pain and inflammation and warrants further investigation into its molecular mechanisms and long-term effects.”

https://pubmed.ncbi.nlm.nih.gov/41009431/

“This study provides evidence for the in vivo analgesic and anti-inflammatory effects and underlying mechanism of CSREA in vitro. Our results from the formalin and writhing tests demonstrate that CSREA significantly reduced nociceptive pain-related behaviors and inflammatory cytokine levels indicating strong anti-nociceptive properties in a dose-dependent manner. In addition, CSREA markedly reduced paw edema in the carrageenan-induced rat model, suggesting its potential as a natural product with anti-inflammatory activity. These effects are likely mediated through modulation of the endocannabinoid system, particularly by altering cannabinoid levels as demonstrated in the in vitro model.”

https://www.mdpi.com/1422-0067/26/18/8863

Putative Effects of Lead on the Endocannabinoid System: A Literature Review and Summary

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“Lead is a naturally occurring metal found in numerous compounds used in everyday life. Toxicity from lead is a well-known public health problem. Its effects are implicated in multiple tissues, encompassing the gastrointestinal, renal, cardiovascular, and neurological systems.

Endocannabinoid receptors are involved in each of these systems, but the effects of lead on the receptors themselves are not well elucidated. In the neurological system, lead has varying interactions with neurotransmitters and downstream regulators implicated in neuronal transmissions influenced by endocannabinoid receptor function.

Lead’s effect is likely indirect on endocannabinoid receptor function; however, its influence on neuronal function is likely inhibitory to the receptor’s functioning. Lead has also been implicated in oxidative stress states, which would influence endocannabinoid receptors’ function.

The literature clearly supports lead having a negative impact on the overall function of endocannabinoid receptors, setting the stage for pathological states related to diminished neurosynaptic function and, in embryology, altered neuronal development, especially of the neural tube.”

https://pubmed.ncbi.nlm.nih.gov/41009561/

https://www.mdpi.com/1422-0067/26/18/8994

Investigating the Antimicrobial Efficacy of Cannabinoids and Their Derivatives Against Neisseria Gonorrhoeae by Computational Analysis

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“Neisseria gonorrhoeae is a Gram-negative diplococcus that causes gonorrhea through sexual contact. This ancient STD remains a major public health concern due to reproductive health impacts, antimicrobial resistance (AMR), and lack of a vaccine.

Cannabis sativa contains antibacterial cannabinoids, though its role in combating antibiotic resistance is underexplored. The 2Fe-2S iron-sulfur cluster protein is a potential antibiotic target, as these clusters are vital for bacterial proteins involved in electron transport, enzyme activity, and gene regulation. Disrupting them may impair bacterial survival and function.

In this investigation, the 2Fe-2S iron sulfur cluster binding domain-containing protein (NGFG_RS03485), identified as a potential therapeutic target from the core proteome of 12 Neisseria gonorrhoeae strains, was selected for this study. Potential antimicrobial agents were explored through molecular docking studies involving 16 cannabinoid analogs-9 obtained from literature sources and 7 identified via fingerprint similarity searches.

The study revealed that four cannabinoids form favorable bonds with active regions against our targeted protein; with a high binding affinity formed from the molecular docking; 1,3-Benzenediol, 2-[3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-, (1R-trans). Dronabinol, Cannabinolic acid A (CBNA), Cannabigerolic acid (CBGA), and Ferruginene C are derivatives identified. Drug-likeness assessments were conducted to evaluate the pharmacokinetic and toxicity properties of the cannabinoids and compared against the antibiotics.”

https://www.mdpi.com/2079-7737/14/9/1272

“Neisseria gonorrhoeae, the bacterium responsible for gonorrhoea, has developed increasing resistance to multiple antibiotics, making new treatment strategies urgently needed. This study explores the potential of cannabinoids and their derivatives as antimicrobial agents targeting N. gonorrhoeae.

Using computational methods, including molecular docking and fingerprint-based compound searches, the study identified five promising cannabinoid compounds with strong binding affinities to the 2Fe-2S iron–sulfur cluster binding domain-containing protein, a critical bacterial enzyme involved in electron transport and cellular function. These include 1,3-Benzenediol (a cannabidiol derivative), Ferruginene C, Dronabinol, Cannabinolic acid A (CBNA), and Cannabigerolic acid (CBGA). Their interactions were visualized using PyMOL and PLIP, revealing significant hydrogen bonding and hydrophobic interactions at active binding sites. Additionally, drug-likeness and pharmacokinetic assessments were performed, showing favorable absorption and low toxicity for several compounds compared to standard antibiotics.

Importantly, these cannabinoids showed potential to disrupt bacterial metabolic processes without inducing typical resistance pathways. The findings support further exploration of Phyto cannabinoids as natural alternatives for treating multidrug-resistant N. gonorrhoeae, with the 2Fe-2S cluster protein as a novel target. Further in vivo validation is recommended to confirm their therapeutic efficacy and safety.”

https://pubmed.ncbi.nlm.nih.gov/41007416/