Evaluation of long-term safety profile of an EU-GMP certified Cannabis sativa L. strain in a naturally aging preclinical model

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“Aging is characterized in part by chronic, low-grade inflammation, a major driver of cognitive decline, metabolic imbalance and organ dysfunction. Despite its central role in age-related morbidity, pharmacological strategies with well-defined long-term safety profiles remain limited.

Phytocannabinoids have been proposed as modulators of neuroinflammatory and metabolic pathways, but their chronic safety during natural aging is poorly characterized.

Our team has previously reported the acute and 28-day repeated-dose toxicity profile of an EU-GMP certified Cannabis sativa L. strain (Cannabixir® Medium Flos). Here, we extend this work by assessing its long-term safety in a naturally aging preclinical model. Mature to older mice received chronic, intermittent administration of Cannabixir® Medium Flos (2.5, 5, and 10 mg/kg), defined as daily weekday dosing for 3 or 6 months. Clinical and histopathological evaluations were conducted with a focus on systemic and central nervous system safety.

Chronic administration was well tolerated across all doses and durations.

Body weight remained stable despite increased food intake. Respiratory quotient values were preserved and close to 1 across all groups. Histological analyses confirmed preserved neuronal and glial architecture with no evidence of central nervous system injury or other organ-level toxicity. Long-term, intermittent Cannabixir® Medium Flos administration was well tolerated in naturally aged mice, with no adverse effects on systemic physiology or central nervous system integrity.

Together with prior acute and sub-chronic toxicity data, these findings provide robust evidence supporting the long-term safety of EU-GMP certified Cannabis sativa L. strain in the context of aging.”

https://pubmed.ncbi.nlm.nih.gov/41357885

“Importantly, the endocannabinoid system itself undergoes profound remodeling with aging, including reduced endocannabinoid tone, altered receptor expression and impaired signaling efficiency, changes that correlate with increased vulnerability to inflammation, metabolic imbalance, and neurodegeneration. These age-related alterations highlight the importance of evaluating the long-term safety of cannabinoid-based interventions in naturally aging bodies.”

“These findings suggest the potential for phytocannabinoid-mediated neuroprotection via modulation of the endocannabinoid system, although the precise molecular pathways remain to be elucidated.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1716366/full

Multifaced roles of cannabinoid therapy in cancer: balancing analgesia, antitumor potential, and systemic toxicity

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“Introduction: Cannabinoids hold promise in oncology for symptom relief and antitumor effects, though concerns about safety and efficacy persist. This study assessed the impact of JWH-182 and phytocannabinoids NC1 – Cannabixir® Medium dried flowers and NC2 – Cannabixir® THC full extract, in a murine breast cancer model with paclitaxel-induced peripheral neuropathy (CIPN).

Methods: Female BALB/c mice with breast tumors received paclitaxel alone or combined with cannabinoids, and outcomes included pain sensitivity, tumor progression (imaging and histopathology), cachexia (body weight, food intake, imaging), as well as hematological and organ toxicity profiles.

Results: All cannabinoids alleviated neuropathic pain, with NC1 most effective for central and thermal protection (72% and 100%, p < 0.0001), NC2 showing strong central and mechanical benefit (>60% and >33%), and JWH-182 intermediate (∼50%). Tumor growth was not significantly altered, but metastasis incidence was 41.7% for NC1, 58.3% for NC2, compared with 70% for PTX, suggesting antitumoral activity. Effects on cachexia were modest, JWH-182 tended to improve food intake, whereas NC1 and NC2 reduced it, yet body weight remained stable and significant muscle loss was observed only with NC2 (p < 0.05). Hematology showed immunomodulatory effects, with cannabinoids reversing lymphopenia (p = 0.0005), raising monocytes and neutrophils, and partly restoring platelets. Toxicity was highest with NC2 (renal and hepatic injury), moderate with NC1, and lowest for kidney with JWH-182 but with greater hepatic inflammation.

Conclusion: Cannabinoids show potential in oncology by relieving CIPN and influencing tumor dynamics, with mostly neutral effects on cachexia. GMP-certified formulations enhance translational value, though safety concerns warrant further study.”

https://pubmed.ncbi.nlm.nih.gov/41357884

“Cannabinoids have emerged as promising agents in oncology for both symptom relief and potential antitumor effects. By acting on cannabinoid receptors 1 and 2 (CB1R, CB2R), Tetrahydrocannabinol (THC) and Cannabidiol (CBD) help regulate pain, appetite, and inflammation, making them effective in managing CIPN, cancer pain, and cachexia.

Preclinical studies also suggest that cannabinoids can inhibit tumor growth, metastasis, angiogenesis, and reverse chemoresistance, with potential to enhance chemotherapy efficacy and reduce its toxicity.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1691893/full

Full-spectrum cannabis extracts for women with chronic pain syndromes: a real-life retrospective report of multi-symptomatic benefits after treatment with individually tailored dosage schemes

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“Chronic pain syndromes (CPS) are debilitating conditions for which cannabis extracts and cannabinoids have shown promise as effective treatments. However, accessibility to these treatments is limited due to the absence of suitable formulations and standardized dosage guidelines. This is particularly critical for women, who present sex-specific differences in pain burden, pain perception, and pain-related cannabinoid pharmacology.

We conducted a retrospective open-label cross-sectional study on 29 female CPS patients who received full-spectrum cannabis extracts (FCEs) with standardized compositions produced by two patient-led civil societies. An individually tailored dosage protocol was used, with dosage schemes adjusted based on individualized clinical assessments of initial conditions and treatment responses. Patients received either CBD-dominant extracts, THC-dominant extracts, or a combination of both. To evaluate the results, we conducted a comprehensive online patient-reported outcome survey covering core CPS symptoms, comorbidities, personal burden, and quality of life-including open-ended questions to capture the practical and subjective impacts of CPS and FCEs treatment on patients’ lives.

Despite most patients already using medications for pain and mood disorders, all reported some level of pain relief, and most reported improvements in cognitive function, motor abilities, professional activities, irritability, anxiety, melancholy, fatigue, and sleep quality. Qualitative content analysis of open-ended responses revealed that FCEs had relevant positive effects on practical and subjective domains, as well as personal relationships. No patients had to discontinue extract use due to adverse effects, and most reduced or ceased their use of analgesic and psychiatric medications. The optimal dosage regime, including CBD-to-THC proportions, was established through a response-based protocol, varied considerably, and showed no clear link to specific pain types.

These real-life results strongly suggest that a broad scope of benefits can be achieved by using flexible dosing schemes of cannabis extracts in managing diverse CPS conditions in female patients. Therefore, this study highlights the significance of tailoring treatment plans to individual CPS cases. Moreover, it demonstrates the feasibility of utilizing quality-controlled cannabis extracts produced by civil societies as either adjuncts or primary pharmacotherapeutic options in CPS management.”

https://pubmed.ncbi.nlm.nih.gov/41357862

“Studies with isolated cannabinoids revealed relief of chronic pain, inflammation, depression, and other CPS-associated comorbidities in animal models.

Isolated cannabidiol (CBD) has shown analgesic and anti-inflammatory effects in humans, while tetrahydrocannabinol (THC) seems to produce pain relief by modulating neuronal activity in pain-associated areas of the central nervous system, such as the periaqueductal area, and the descending supraspinal inhibitory pathways, often involved in cases of CPS. Accordingly, THC isolated oil promoted significant relief of chronic neuropathic pain in comparison to placebo.”

“Our study provides compelling real-world evidence of the broad, integrative benefits of full-spectrum cannabis extracts (FCEs) for women with chronic pain syndromes (CPS).”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1538518/full


UK Medical Cannabis Registry: An Updated Analysis of Cannabis-Based Medicinal Products for Multiple Sclerosis

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“Introduction: Multiple sclerosis (MS) is a neurodegenerative disease presenting with a wide range of motor, sensory, and psychiatric symptoms. Although nabiximols is licensed for MS-induced spasticity, cannabis-based medicinal products (CBMPs) have also displayed promising therapeutic potential for managing pain, sleep, and anxiety. Therefore, further evaluation of CBMP treatment for MS is warranted. This study aimed to assess the efficacy and tolerability of CBMP treatment in patients with MS by investigating changes in MS-specific and general health-related patient-reported outcome measures and adverse events.

Methods: This was a prospective case series including patients with MS enrolled on the UK Medical Cannabis Registry. Changes in MS Quality of Life-54 (MSQOL-54), Generalised Anxiety Disorder-7 (GAD-7), Single-Item Sleep Quality Scale (SQS), and EQ-5D-5L scores were assessed from baseline up to 24 months. The prevalence and severity of all adverse events were also assessed.

Results: This study included 203 patients, of whom 47.29% (n = 96) were female and 80.79% (n = 164) had prior cannabis exposure. Improvements in the MSQOL-54 subscales: change in health, energy, health distress, pain, physical function, and physical role limitations, along with improvements in SQS and EQ-5D-5L scores, were seen at all follow-up times compared to baseline (p < 0.050). A total of 278 adverse events were reported by 26 patients (12.81%). Most adverse events were mild (n = 91, 32.73%) or moderate (n = 138, 49.64%) in severity, with fatigue (n = 27, 13.30%) and spasticity (n = 17, 8.37%) being the most common.

Conclusion: CBMP treatment over 24 months was associated with improvements in health-related quality of life and was well tolerated in patients with MS. Future randomised controlled trials with more representative study populations are needed to establish causal relationships.”

https://pubmed.ncbi.nlm.nih.gov/41357430

“There is increasing evidence for the involvement of the endocannabinoid system (ECS) in modulating inflammatory and neurodegenerative processes.”

“Through interactions with the ECS, THC and CBD have displayed analgesic, muscle relaxant, neuroprotective, and anti-inflammatory properties in preclinical and clinical studies.”

“Therefore, cannabis-based medicinal products (CBMPs) containing these phytocannabinoids show promise for managing MS symptoms.”

“In conclusion, this observational study found CBMP treatment was associated with improvements in many HRQoL measures, including pain and sleep in patients with MS. Also, CBMP use over 2 years was generally well tolerated.”

https://karger.com/mca/article/8/1/201/938322/UK-Medical-Cannabis-Registry-An-Updated-Analysis

Aromatisation-based extract engineering of Cannabis sativa L. Unveils rare cannabinoids with anticancer potential

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“Cancer remains a major global health challenge, necessitating new, effective therapies. Phytocannabinoids from Cannabis sativa L. show significant anticancer potential, yet their natural scarcity limits research and development.

This study presents an innovative extract engineering approach to generate rare varin-type cannabinoids from abundant precursors. Through this strategy, nine cannabinoid analogues were synthesised, including four rare varin-type compounds, and screened against five human cancer cell lines.

Among them, cannabinovarin (CBNV) and Δ6a,10a-THCV exhibited potent cytotoxicity against breast (MCF-7) and colon (HCT-116) cancer cells, with IC50 values of 15-30 µM. Mechanistic investigations revealed apoptosis induction via mitochondrial membrane disruption and reactive oxygen species generation.

These findings establish extract engineering as a rapid and efficient route to access rare cannabinoids, highlighting CBNV and Δ6a,10a-THCV as promising anticancer leads for further mechanistic and in vivo evaluation.”

https://pubmed.ncbi.nlm.nih.gov/41355760

https://www.tandfonline.com/doi/full/10.1080/14786419.2025.2595528

Anti-Cancer Potential of Cannabinoids, Terpenes, and Flavonoids Present in Cannabis

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“In recent years, and even more since its legalization in several jurisdictions, cannabis and the endocannabinoid system have received an increasing amount of interest related to their potential exploitation in clinical settings.

Cannabinoids have been suggested and shown to be effective in the treatment of various conditions.

In cancer, the endocannabinoid system is altered in numerous types of tumours and can relate to cancer prognosis and disease outcome. Additionally, cannabinoids display anticancer effects in several models by suppressing the proliferation, migration and/or invasion of cancer cells, as well as tumour angiogenesis.

Along with cannabinoids, cannabis contains several other compounds that have also been shown to exert anti-tumorigenic actions.”

https://pubmed.ncbi.nlm.nih.gov/32708138

“Dysregulation of the endocannabinoid system has been implicated in several diseases, including cancer.”

“Based on the preliminary evidence in various models, it appears that cannabinoids target key signaling pathways involved in all the hallmarks of cancer. Additionally to the cannabinoids, a large number of terpenes and flavonoids, some of them also present in cannabis, exhibit cytotoxicity against a variety of cancers.”

“Considering all the available literature at this time, much stronger experimental evidence (obtained in vitro, in vivo and even in a few clinical trials) support that THC and cannabidiol (CBD) have better anticancer activity than for the other cannabinoids.”

https://www.mdpi.com/2072-6694/12/7/1985

Evaluation of two different Cannabis sativa L. extracts as antioxidant and neuroprotective agents

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“Cannabis sativa L. is a plant that contains numerous chemically active compounds including cannabinoids such as trans-Δ-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), and flavone derivatives, such as luteolin-7-O-glucuronide and apigenin glucuronide.”

“These extracts could be a source of compounds with potential benefit on human health, especially related to neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/36176449

“In conclusion, this study provided new insights into the biological activities of two different extracts of C. sativa. It was revealed that these extracts constitute a valuable and interesting natural source of bioactive molecules with great antioxidant properties, potentially capable of preventing neurodegenerative diseases.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.1009868/full

 

A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer’s Disease

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“Importance: Agitation in Alzheimer’s disease (AD) is a great source of distress for patients and caregivers and a major public health burden. Current treatments are only modestly effective and many have safety issues including mortality risk. Novel therapeutic options are needed.

There is preliminary evidence for the safety and efficacy of dronabinol (tetrahydrocannabinol, THC) for agitation in AD.

Objective: Assess the safety and efficacy of dronabinol (THC) to decrease agitation in AD.

Design: THC-AD was a 3-week randomized parallel double-blind placebo-controlled clinical trial, conducted between 2017 and 2024.

Setting: 5 inpatient and outpatient academic clinical research centers in the Eastern U.S.

Participants: Volunteer sample of 75 participants meeting inclusion criteria for agitation of AD (International Psychogeriatric Association Provision Criteria) with Neuropsychiatric Inventory Clinician Version Agitation or Aggression (NPI-C A/A) domains total score of 4 or greater. Major exclusion criteria included seizure disorder, delirium, and non-AD dementia.

Interventions: 3 weeks dronabinol vs. placebo titrated up to target dose of 10 mg daily in divided twice-daily.

Main outcomes and measures: Prespecified co-primary agitation outcomes were the Pittsburgh Agitation Scale (PAS) and NPI-C A/A total score.

Results: The majority of participants were female and were taking concomitant psychotropic medications (antidepressants and antipsychotics) at baseline. Study participants were moderately agitated at baseline, were diverse in ethnic background (9% Black, 11% Hispanic/Latina/Latino), and had severe cognitive impairment evidenced by MMSE or SIB-8. 84% completed the 3-week trial.

Dronabinol decreased agitation on both primary outcomes greater than placebo to a clinically relevant extent. The fitted between-arm difference in PAS decline/week was -0.74 (SE 0.3, p = 0.015, effect size = 0.53) and for NPI-C A/A the decline was not significant at -1.26 (SE 0.67, p = 0.094, effect size = 0.36). No secondary outcomes differed between treatment arms including sleep, activities of daily living, Cohen-Mansfield Agitation Inventory (CMAI), cognition, intoxication, or use of ‘as-needed’ lorazepam or trazodone. Dronabinol treatment was not associated with greater intoxication nor with other adverse events (AEs) except for somnolence.

Conclusions and relevance: Adjunctive dronabinol treatment was safe and effective for treating agitation in AD.”

https://pubmed.ncbi.nlm.nih.gov/41350162

“Highlights

•What is the primary question addressed by this study?

Is dronabinol (synthetic THC) a safe and effective treatment for reducing agitation in individuals with Alzheimer’s disease?

•What is the main finding of this study?

In a 3-week randomized, placebo-controlled trial of 75 participants with moderate to severe Alzheimer’s disease, dronabinol significantly reduced agitation as measured by the Pittsburgh Agitation Scale (effect size = 0.53) and showed a trend toward improvement on the NPI-C Agitation/Aggression domain. The medication was well tolerated, with somnolence as the only notable side effect and no increased risk of delirium, falls, or intoxication.

•What is the meaning of the finding?

These results suggest that dronabinol may be a relatively safe and effective pharmacologic option for managing agitation in Alzheimer’s disease.”

https://www.ajgponline.org/article/S1064-7481(25)00506-8/abstract

Characterization and antifungal properties against Botrytis cinerea of bacteria isolated from hemp seed oil

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“Botrytis cinerea is a pathogen infecting Cannabis sativa L. plants, causing economic losses, and can develop resistance to chemical fungicides, the use of which is restricted in cannabis production. Thus, developing biocontrol methods is imperative.

Seven bacterial strains were isolated from hemp seed oil, characterized, and examined for the potential to control a B. cinerea isolate from cannabis.

Three isolates, Bacillus mojavensis HOB3, Paenibacillus sp. HOB6 and Bacillus subtilis HOB7 exhibited significant inhibition of B. cinerea. These isolates were further evaluated for their biosurfactant activity using two liquid media, Lysogeny Broth (LB) and hydrocarbon-amended Bushnell and Haas (BH). The oil-spreading and drop-collapse assays revealed growth-medium-dependent variation in surface activity associated with biosurfactant presence. The BH cell-free extract (BH-CFE) of B. subtilis HOB7 showed the highest estimated biosurfactant presence and antifungal activity against B. cinerea, but both activities were absent when using the LB cell-free extract (LB-CFE) of B. subtilis HOB7.

Thus, a potential relationship between antifungal activity and biosurfactant production was suggested. Genome mining of the strains identified gene clusters encoding compounds with antifungal activity, including the biosurfactants polymyxin B, fusaricidin B, fengycin, and surfactin.

To our knowledge, this is the first report of the isolation of hemp seed oil bacteria with potential biocontrol properties against fungal phytopathogens.”

https://pubmed.ncbi.nlm.nih.gov/41349011

https://cdnsciencepub.com/doi/10.1139/cjm-2025-0241

“Polymyxin B, fusaricidin B, fengycin, and surfactin are all natural lipopeptides (or cyclic non-ribosomal peptides) produced by bacteria of the Paenibacillus and Bacillus genera. They act as biosurfactants and have various antimicrobial properties, particularly as antibiotics and fungicides.” 

UK Medical Cannabis Registry: a case series analysing clinical outcomes of medicinal cannabis therapy for fibromyalgia

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“Introduction: Fibromyalgia is a common condition characterised by widespread chronic pain, associated with comorbid mental health disorders and reduced quality of life. Preclinical data suggest cannabis-based medicinal products (CBMPs) may have potential benefits in fibromyalgia, but there is a paucity of high-quality clinical evidence. This study aims to assess the change in patient-reported outcome measures (PROMs) and incidence of adverse events (AEs) in patients treated with CBMPs for fibromyalgia.

Methods: This case series analysed data from the UK Medical Cannabis Registry (UKMCR). The primary outcome was change in PROMs [Fibromyalgia Symptom Severity, Fibromyalgia Widespread Pain Index, EQ-5D-5L, Generalised Anxiety Disorder-7, and Single-Item Sleep Quality Scale] from baseline to follow-up at 1, 3, 6, 12, and 18 months. Statistical significance was defined as p < 0.050.

Results: Four hundred ninety-seven patients were included. The mean age was 44.66 ± 12.02 years, 341 patients (68.61%) were female, and the majority of patients were unemployed (n = 268, 53.92%). There was an improvement in all PROMs (p < 0.010) from baseline to all follow-up periods. Higher CBD doses (> 25.00 mg/day) and previous cannabis use were associated with increased odds of improvement on fibromyalgia-specific scales (p < 0.050). 227 patients (45.67%) reported 2100 AEs (422.54%). Most AEs were mild-to-moderate (n = 1792, 85.33%). The most common AE was fatigue (n = 153, 30.78%).

Conclusions: There was an association between treatment with CBMPs and improvements in pain, anxiety, sleep, and general quality of life. The high incidence of AEs in relation to other patient cohorts from the UKMCR may relate to the central sensitisation mechanism of fibromyalgia. Key Points • This study found that CBMPs were associated with short to medium-term improvements in pain, anxiety, sleep, and general quality-of-life in patients with fibromyalgia. • More randomised controlled trials are warranted to consolidate the literature, but this large analysis provides real-world data to inform their rollout.”

https://pubmed.ncbi.nlm.nih.gov/41343025