Effects of legal access versus illegal market cannabis on use and mental health: A randomized controlled trial

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“Aims: We measured the effects of public health-oriented cannabis access compared with the illegal market on cannabis use and related mental health outcomes in adult cannabis users.

Design: This was a two-arm, parallel group, open-label, randomized controlled trial. Follow-up outcome measurement took place after 6 months.

Setting: The study was conducted in Basel-Stadt, Switzerland.

Participants: A total of 378 adult (aged ≥18 years) cannabis users were enrolled and randomized between August 2022 and March 2023, although only 374 users who completed baseline measures could be included.

Intervention and comparator: Participants were randomly assigned to the intervention group with public health-oriented recreational cannabis access in pharmacies (regulated cannabis products, safer use information, voluntary counseling, no advertisement; 189/188) or the illegal market control group (continued illicit cannabis sourcing; 189/186).

Measurements: The primary outcome was self-reported severity of cannabis misuse after 6 months, as measured by the Cannabis Use Disorders Identification Test – Revised (range 0-32). Secondary outcomes involved depressive, anxiety, and psychotic symptoms, cannabis consumption amount, alcohol, and drug use.

Findings: Ten participants were not followed (2.7%). Primary analysis included those with complete data (182 vs. 182). There was some evidence of a difference in cannabis misuse between the legal cannabis intervention group (mean [M] = 10.1) and the illegal market control group (M = 10.9; β = -0.69, 95% confidence interval [CI] = -1.4 to 0.0, P = 0.052). These results were supported by an intention-to-treat multiple imputation analysis (n = 374). Additional sub-group analysis by whether the participant used other drugs or not suggested that any reduction in cannabis misuse was confined to those in the legal cannabis intervention group who used other drugs (PInteraction < 0.001). We found no statistically significant changes in any of the secondary outcomes.

Conclusions: Public health-oriented recreational cannabis access may decrease cannabis use and cannabis-related harms, especially among those using other drugs.”

https://pubmed.ncbi.nlm.nih.gov/40289676/

“Our results indicate that public health-oriented RCL could be an effective policy model to make cannabis safer without increasing cannabis use and cannabis-related harms.”

https://onlinelibrary.wiley.com/doi/10.1111/add.70080

“Cannabis study finds legalization reduces problematic consumption, especially among those using other drugs”

https://medicalxpress.com/news/2025-05-cannabis-legalization-problematic-consumption-drugs.html

“Researchers uncover causal evidence that cannabis legalization reduces problematic consumption”

Researchers uncover causal evidence that cannabis legalization reduces problematic consumption

“Legal Cannabis Linked to Less Problematic Use, Better Mental Health”

Legal Cannabis Linked to Less Problematic Use, Better Mental Health

Cannabinol improves exemestane efficacy in estrogen receptor-positive breast cancer models: a comparative study with cannabidiol

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“Cannabinoids have been used as anti-emetic agents in cancer. However, multiple studies suggest that cannabinoids present important anti-tumor actions as well.

Estrogen receptor-positive (ER+) breast cancer is the most diagnosed breast cancer subtype, and despite the success of endocrine therapy, endocrine resistance development is a major challenge, demanding the discovery or implementation of alternative therapeutic approaches.

In line with this, and following our previous work, the benefits of combining the aromatase inhibitors (AIs) used in the clinic, anastrozole (Ana), letrozole (Let), and exemestane (Exe), with cannabinol (CBN) were evaluated. Experiments were performed in MCF-7aro cells and spheroids to assess activity against specific molecular targets and underlying mechanisms of action.

Among the three AIs studied, only the combination of CBN with Exe induced a significant beneficial impact on viability and growth of ER+ breast cancer cells and spheroids.

Our results demonstrated that this combination was more effective than Exe in preventing the expression of aromatase and in modulating ERα and androgen receptor (AR) activity.

In fact, the results revealed that CBN can prevent de novo synthesis of aromatase, surpass Exe’s weak estrogen-like effect, and avoid the unfavorable overexpression of AR. By comparing these two therapeutic strategies, as well as the previously studied combination of Exe plus cannabidiol (CBD), differential transcriptome profiles were detected, which may help to better understand the mechanism of action of cannabinoids and disclose their full potential in breast cancer treatment.

In conclusion, this study strengthens the hypothesis that cannabinoids are important anti-cancer agents with attractive co-adjuvant properties.”

https://pubmed.ncbi.nlm.nih.gov/40345424/

https://www.sciencedirect.com/science/article/pii/S0014299925004662?via%3Dihub

Oral cannabinoid formulation elevates sensory nerve conduction velocity and mitigates oxidative stress to alleviate neuropathic pain in rats

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“Background and aim: Use of potent painkillers like opiates are limited by their abuse potential and adverse physiological effects necessitating new therapeutics for pain management. This study assessed the efficacy of oral cannabinoid formulations (F1-F4) in alleviating chronic neuropathic pain (CP) and investigated their mechanisms through thermal algesia, inflammatory and oxidative stress biomarkers, and sensory nerve conduction velocity (SNCV).

Experimental procedures: A 21-day rat model of chronic constriction injury (CCI) of the sciatic nerve was used to evaluate the effects of oral cannabinoid formulations (F1: 500 mg, F2: 1000 mg, F3: 2000 mg, F4: 3000 mg) in MCT oil, with pregabalin as the reference. Male Wistar rats (35) were divided equally into seven groups, with all except the Sham group undergoing sciatic nerve ligation and receiving different formulations.On day 22, behavioral (hot plate, tail flick) and electrophysiological (sensory nerve conduction velocity, SNCV) assessments were performed. SNCV was also measured in the presence of CB1 and CB2 receptor antagonists. Additionally, blood-based markers of inflammation (TNF-α) and oxidative stress (MDA, GSH and CAT) were analysed.

Results and conclusions: The vehicle group exhibited significant hyperalgesia (p <0.005), reduced sensory nerve conduction velocity (SNCV) (p <0.005) and elevated MDA and TNF-α levels, along with decreased GSH and CAT levels in both serum and sciatic nerve tissue.Among the formulations, F2 significantly improved pain latency and SNCV (p <0.005) compared to the vehicle group and outperformed F1, F3, F4 and pregabalin (p <0.05). Its effects were mediated through CB1 and CB2 receptor agonism while simultaneously reducing oxidative stress and inflammation, highlighting its potential as a promising candidate for neuropathic pain management.”

https://pubmed.ncbi.nlm.nih.gov/40336142/

https://www.tandfonline.com/doi/full/10.1080/01616412.2025.2500112

A novel antioxidant and anti-inflammatory carboxymethylcellulose/chitosan hydrogel loaded with cannabidiol promotes the healing of radiation-combined wound skin injury in the 60Co γ-irradiated mice

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“Background: Combined radiation and wound skin injury (RW) are frequently observed in patients undergoing tumor surgery plus radiotherapy, and but specific treatment is lacking. Chitosan (CS) and carboxymethyl cellulose (CMC) are commonly used to prepare hydrogel with good biocompatibility and low toxicity.

Cannabidiol (CBD) has presented anti-inflammatory, antioxidant, and neuroprotective properties.

Methods: CMC, CS, and CBD were used and designed for three types of hydrogels (CMC/CS2/CBD, CMC/CS3/CBD, CMC/CS4/CBD) with different ratios of CMC and CS based on previous report and our preliminary experiments. The CMC/CS/CBD hydrogel was synthesized using electrostatic interaction without chemical crosslinking, characterized via fourier transform infrared (FT-IR), and tested for mechanical properties, swelling behavior, biocompatibility, antioxidant activity, cytotoxicity, and hemocompatibility. 60Co γ irradiation (5 Gy, 0.62 Gy/min) combined with 1 cm circular trauma was applied to establish RW mice model. Topical applications of CMC/CS3, CMC/CS2/CBD, CMC/CS3/CBD were used to treat RW injury once a day for 10 consecutive days. The mice were euthanized 7, 14, 21 days after radiation, and samples were collected.

Results: FT-IR confirmed the successful formation of a polyelectrolyte network. The CMC/CS3/CBD hydrogel exhibited optimal mechanical strength, rapid gelation, high swelling capacity, and excellent biocompatibility. Both CMC/CS2/CBD and CMC/CS3/CBD hydrogels effectively improved RW injury 7, 14, 21 days after radiation. Reduced inflammation and increased collagen production were observed the two groups. The significant increased expression of interleukin (IL)-1β, IL-22, IL-17A, IL-6, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, CC motif chemokine ligand (CCL)2, CCL3, CCL4, CCL5, CCL11 in the RW group was greatly inhibited after treatment with CMC/CS3/CBD hydrogel. Transcriptome analysis revealed the hydrogel’s impact on lipid metabolism and epithelial differentiation pathways.

Conclusions: By integrating CBD into a CMC/CS-based hydrogel without using toxic crosslinkers, this study provides a novel, biomaterial-based, biocompatible approach for RW injury. These findings pave the way for future clinical application of CMC/CS3/CBD hydrogel in RW injury.”

https://pubmed.ncbi.nlm.nih.gov/40318533/

“We developed an injectable CMC/CS/CBD hydrogel for the treatment of RW injuries. The hydrogel was fabricated via electrostatic self-assembly, eliminating the need for toxic chemical crosslinkers, exhibiting excellent biocompatibility and low cytotoxicity. Our work firstly integrated CBD into a hydrogel matrix specifically for RW treatment, and confirmed its ability to suppress inflammation and regulate macrophage polarization.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711325004283?via%3Dihub

Efficacy of a Neuroimmune Therapy Including Pineal Methoxyindoles, Angiotensin 1-7, and Endocannabinoids in Cancer, Autoimmune, and Neurodegenerative Diseases

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“Purpose: Recent advancements in psycho-neuro-endocrine-immunology indicate that numerous noncommunicable diseases (NCDs) originate from disruptions in the cytokine immune network, resulting in chronic inflammatory responses. This persistent low-degree inflammation is attributed to deficiencies in crucial endogenous anti-inflammatory neuroendocrine systems, including the pineal gland, the endocannabinoid system, and the angiotensin-converting enzyme 2 / angiotensin 1-7 axis.

The administration of pineal methoxyindoles (melatonin, 5-methoxytryptamine), cannabinoids, and angiotensin 1-7 may entail potential therapeutic benefits for NCDs, particularly for patients who do not respond to conventional treatments.

Patients and methods: This study evaluates the safety and efficacy of a neuroimmune regimen comprising melatonin (100 mg/day at night), 5-methoxytryptamine (30 mg in the early afternoon), angiotensin 1-7 (0.5 mg twice daily), and cannabidiol (20 mg twice daily) in 306 patients with NCDs, including advanced cancer, autoimmune diseases, neurodegenerative disorders, depression, and cardiovascular disease.

Results: The neuroimmune regimen successfully halted cancer progression in 68% of cancer patients, who also reported improvements in mood, sleep, and relief from anxiety, pain, and fatigue. In patients with autoimmune diseases, the treatment effectively controlled the disease process, remarkable in cases of multiple sclerosis. Additionally, positive outcomes were observed in patients with Parkinson’s disease, Alzheimer’s disease, and depression.

Conclusion: Randomized controlled trials are required to assess this therapeutic approach for NCDs that includes endogenous neuroendocrine molecules regulating immune responses in an anti-inflammatory manner.”

https://pubmed.ncbi.nlm.nih.gov/40330271/

“This study highlights the potential of leveraging endogenous molecules to treat NCDs by modulating cell proliferation, inflammation, immune responses, metabolism, and neurological functions. The findings suggest that a neuroimmune regimen incorporating melatonin, angiotensin 1–7, and other bioactive compounds could offer a low-cost, minimally toxic therapeutic approach.”

https://www.dovepress.com/efficacy-of-a-neuroimmune-therapy-including-pineal-methoxyindoles-angi-peer-reviewed-fulltext-article-CIA

Effects of heat reflux extraction on the content, antioxidant, and immune activity of polyphenols and flavonoids from hempseed threshing residues

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“Objective: Hempseed threshing residues are rich in phytochemicals such as polyphenols and flavonoids. Phenolic and flavonoid compounds have been associated with antioxidant, antibacterial and anticancer activities. The re-use of the hempseed threshing residues as value-added materials is, not only cost-saving, but also environmentally beneficial. It is therefore important to develop an effective method for extraction of phenolic compounds and flavonoids from hempseed threshing residues.

Methods: In this investigation, the extraction of phenolic constituents and flavonoids from hempseed threshing residues using heat reflux extraction (HRE) were optimized through response surface methodology (RSM). Four HRE parameters to enhance the yield of crude extracts (CE), total phenolic content (TPC), and total flavonoids content (TFC) were evaluated. Additionally, the study evaluated the chemical compounds, antioxidant characteristics of the extracts, and the immune activity of the extracts was assessed by quantifying the levels of inflammatory cytokines, specifically IL-6, IL-10, and TNF-α.

Results: The best extraction parameters were determined as: for the extraction time of 69.71 min, a liquid-solid proportion of 5.12:1, a particle size of 1150 µm, and an ethanol concentration of 69.60%. Under these optimized conditions, the yields for CE, TPC, and TFC were 4.74%, 27.54%, and 16.02% respectively. The data conformed well to multiple regression models, showing that these extraction parameters markedly influence the yields of CE, TPC, and TFC. Most of the compounds found may belong to the class of polyphenol and flavonoids. Cellular assays indicated that extracts from hempseed threshing residue notably reduced pro-inflammatory factors (TNF-α, IL-6) and increased anti-inflammatory factors (IL-10) in RAW 264.7 cells.

Conclusion: This research lays a theoretical foundation for extracting polyphenols and flavonoids from hempseed threshing residue and for the comprehensive assessment of antioxidant and immune-enhancing products. However, the antioxidant and immune activity of hempseed threshing residues extracts under physiological conditions in vivo, and the relevant mechanism should be further studied.”

https://pubmed.ncbi.nlm.nih.gov/40333885/

“These findings highlight the potential of utilizing hempseed threshing residues in food or health product industries as natural alternatives to synthetic antioxidants.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0322134

Cannabinoids: Therapeutic Perspectives for Management of Orofacial Pain, Oral Inflammation and Bone Healing-A Systematic Review

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“Cannabinoids, particularly cannabidiol (CBD) and tetrahydrocannabinol (THC), have been increasingly studied for their therapeutic applications in various medical fields. This systematic review aims to explore their role in oral surgery, focusing on pain management, inflammation control, and bone regeneration.

A systematic review was conducted using the PRISMA framework to identify relevant studies from the PubMed, Scopus, and Web of Science databases published up to November 2024. The review included clinical and preclinical studies investigating the effects of cannabinoids on orofacial pain, oral inflammation, and bone healing. Data on study design, cannabinoid types, and relevant outcomes were extracted and analyzed. CBD was the most commonly studied compound, with other studies evaluating CB1/CB2 receptor agonists, THC, and cannabis smoke.

Clinical trials showed mixed results: some studies found CBD effective in reducing dental or myofascial pain, while others found limited or non-superior outcomes compared to standard treatments (e.g., NSAIDs, corticosteroids). Among the four RCTs, three had a low risk of bias, and one moderate; all nine animal studies had a high risk of bias.

In conclusion, preclinical and clinical studies suggest that cannabinoids represent a promising non-opioid alternative for pain management and for oral inflammation.

Although some evidence suggests potential benefits of cannabinoids, particularly CBD, in oral health contexts, findings are derived from heterogeneous studies-many with high risk of bias. More high-quality, standardized clinical trials are necessary before recommending cannabinoids for routine dental practice.”

https://pubmed.ncbi.nlm.nih.gov/40332414/

“Within the limitations of this review, cannabinoids—especially cannabidiol (CBD)—demonstrated potential in managing orofacial pain, reducing inflammation, and promoting bone healing.”

https://www.mdpi.com/1422-0067/26/8/3766

Cannabinoids: Adaptogens or Not?

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“Since ancient times, humanity has been exploring natural substances with the aim of increasing stress resistance, enhancing biochemical homeostasis, and treating different diseases. In this way, the objective of the present review is to compare the biological effects of cannabinoids (CNBs) with adaptogens, this exploration allows us to consider the controversy if they can be classified together considering the effects on the body.

First, the work revises different features of adaptogens such as their chemical structure, ligand-receptors properties, and homeostasis-stress capabilities. Also, this review includes an overview of preclinical and clinical studies of the effect of adaptogens considering a broad spectrum of adverse biological, chemical, and physical factors.

Then, the work does a review of the CNBs effects on the body including the principal uses for the treatment of several diseases as neurodegenerative disorders, arthritis, cancer, cardiovascular affections, diabetes, anxiety, chronic pain, among others. In addition, the different characteristics of the specific endocannabinoid system are described explaining the wide CNBs body effects.

Finally, this review presents a comparative analysis between CNBs and adaptogens properties, expecting to contribute to understanding if CNBs can be classified as adaptogens.”

https://pubmed.ncbi.nlm.nih.gov/40332769/

https://www.liebertpub.com/doi/10.1089/can.2024.0108

“Adaptogens are herbs and plant-based substances believed to help the body manage stress and restore balance after stressful situations”

“Adaptogens are active ingredients in certain plants and mushrooms that may impact how your body deals with stress, anxiety and fatigue.”

Impact of cannabis consumption on perioperative outcomes in patients undergoing hepatobiliary and pancreatic surgery: a nationwide analysis

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“Background: There is paucity of high-quality data on the effect of cannabis consumption on perioperative outcomes after hepatobiliary and pancreatic (HPB) surgery.

Methods: Data from the Nationwide Inpatient Sample (2016-2020) were used. In-hospital complications, length-of-stay and hospitalisation charges were compared among patients undergoing HPB surgery.

Results: We identified 191,315 patients, of which 1705 (0.89 %) were cannabis consumers. Cannabis consumers were more likely to be male (67.5 % vs 50.2 %), younger, and Black (22.6 % vs 11.0); p < 0.001 for all. Multivariate analysis demonstrated a significantly lower risk of pneumonia (OR 0.54, 95 % CI 0.29-0.99) among cannabis consumers. There was no significant difference in risk of in-hospital mortality (OR 0.64, 95 % CI 0.31-1.30), acute kidney injury, hemodialysis, blood transfusion, vasopressor use, invasive and non-invasive mechanical ventilation, venous thromboembolism, portal vein thrombosis, intraabdominal abscess, peritonitis, surgical site infection, post-procedure haemorrhage/hematoma, wound dehiscence, liver failure, or sudden cardiac arrest. There was no significant difference in length-of-stay (mean 10.99 vs 9.69 days; p = 0.348) or hospitalisation costs ($49,444 vs $43,661; p = 0.109).

Conclusion: There is no significant difference in major perioperative complications after HPB surgery among patients with cannabis use disorder. Further, there is no significant difference in health services utilisation among consumers versus non-consumers.”

https://pubmed.ncbi.nlm.nih.gov/40324909/

https://www.hpbonline.org/article/S1365-182X(25)00550-7/abstract

Cannabigerol and Cannabinoid Receptors in Major Depressive Disorder: Network Pharmacology, Molecular Docking, and In-vivo Analysis

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“Introduction: Cannabigerol (CBG), being one of the non-psychotropic phyto-cannabinoid, has been labelled and recognized to be antioxidant and neuroprotective; it may conceivably hold depression-relieving activity. Consequently, the objective of the present research procedure was to explore the depression-alleviating competence of cannabigerol in both stressed and unstressed mice using computational/in-silico modelling, followed by in-vivo analysis.

Method: Target genes for Major Depressive Disorder (MDD) were identified using GeneCards and Swiss Target Prediction, with common targets screened via Venny software. STRING database anal-ysis established protein-protein interactions (PPI), identifying CNR2 (CB2 receptor) as a key target. Molecular docking of CBG with CB2 (PDB ID: 8GUR) showed strong binding, prompting in vivo evaluation. ADME profiling via Schrödinger Maestro v10.5 confirmed CBG’s high oral absorption and favorable pharmacokinetics. Male Swiss albino mice underwent chronic unpredictable mild stress (CUMS) for three successive weeks, with CBG (10, 20, 40 mg/kg) and imipramine (15 mg/kg) administered and various behavioral and biochemical parameters being analyzed.

Results: Cannabigerol demonstrated maximum oral absorption in ADME predictions using Schrö-dinger’s Maestro (v10.5). Wayne diagram illustrated MDD-related targets, with CB2 (CNR2) rank-ings in top targets, based on SwissADME and Venny software analysis. Docking analysis revealed a high binding affinity (-10.53) for CB2, outperforming cannabidiol (-9.56) and comparable to Δ9-THC (-10.11). During in vivo evaluation, CBG (40 mg/kg) and Imipramine 15mg/kg significantly reduced CUMS-induced exalted plasma corticosterone, nitrite quantities, and monoamine oxidase-A action in the brain of stressed mice. Additionally, both treatments substantially reversed the unpre-dictable chronic stress-induced decline in catalase action, demonstrating CBG’s possible potential in alleviating depression-like symptoms in mice.

Conclusion: Cannabigerol has shown significant depressive alleviating potential in mice exposed to chronic and unpredictable stress regimes, possibly via interaction with cannabinoid receptors as in-dicated by in-silico modelling, which has been validated by our findings of the in-vivo protocol.”

https://pubmed.ncbi.nlm.nih.gov/40326034/

https://www.eurekaselect.com/article/148152