Author Archives: David Worrell

Cannabinoid Therapies in Less-Common Disorders: Clinical Evidence and Formulation Strategies

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“Background/Objectives: Cannabinoids are increasingly recognised for their therapeutic potential beyond well-established indications such as chronic pain, multiple sclerosis, and specific epileptic syndromes. Recent advances have highlighted their possible role in less-common or orphan diseases, opening new avenues for pharmaceutical research and clinical application. 

Methods: This review provides a critical synthesis of the most recent evidence (2020-2025), available in PubMed and Scopus, regarding the use of cannabinoids in conditions including refractory epilepsies beyond Dravet and Lennox-Gastaut syndromes, movement disorders such as dystonia and Tourette syndrome, rare dermatological diseases like epidermolysis bullosa, and emerging data in Crohn’s disease. 

Results: Negative outcomes, such as those reported in Fragile X syndrome trials, are also discussed as instructive examples of methodological and pharmacological challenges. Particular attention is given to the optimisation of pharmaceutical formulations and advanced separation technologies, including oromucosal sprays, transdermal gels, and novel nanocarrier systems, which aim to overcome issues of bioavailability and variability in patient response. Finally, safety concerns, regulatory aspects, and the need for robust clinical trials are addressed. 

Conclusions: Overall, cannabinoids represent a promising yet underexplored therapeutic option in rare and complex disorders, warranting further investigation supported by innovative pharmaceutical approaches.”

https://pubmed.ncbi.nlm.nih.gov/41745121

 “Thus, cannabinoids may play an important role in the development of innovative therapies, particularly in the treatment of less-common diseases that often lack effective therapeutic options.”

https://www.mdpi.com/2079-9721/14/2/83


Endocannabinoid Modulation in Headache: Mechanisms, Models, and Translational Therapies

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“Headache disorders, including migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache and medication overuse headache, represent a major global health burden and remain difficult to treat despite therapeutic advances.

The endocannabinoid system (ECS) has emerged as a key regulator of neural, vascular, and immune processes central to headache pathophysiology.

Through coordinated actions of CB1 and CB2 receptors, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes, the ECS modulates trigeminovascular activity, descending pain control, cortical excitability, and neuroimmune sensitization.

Preclinical studies demonstrate that ECS activation suppresses trigeminal firing, reduces calcitonin gene-related peptide (CGRP) release, attenuates neurogenic inflammation, stabilizes cortical susceptibility to spreading depression, and limits glial activation following traumatic brain injury. Conversely, ECS dysregulation contributes to central sensitization and impaired descending inhibition underlying medication overuse headache and other headache disorders.

Pharmacological strategies targeting endocannabinoid degradation, such as inhibition of FAAH, MAGL, and COX-2, enhance endogenous cannabinoid tone and consistently reduce headache-like behaviors across diverse models. Importantly, sex differences shape ECS function, with females exhibiting distinct hormonal regulation, receptor expression, and glial activation that influence responsiveness to ECS-targeted interventions.

Collectively, mechanistic and translational evidence highlights the ECS as a promising therapeutic target across primary and secondary headache disorders. Future clinical studies should incorporate sex-informed designs, integrate biomarkers of trigeminovascular and neuroimmune activity, and evaluate peripherally restricted ECS modulators and cannabinoid-based formulations as candidates for individualized headache therapy.”

https://pubmed.ncbi.nlm.nih.gov/41744774

  • “The endocannabinoid system (ECS) is a central regulator of neural, vascular, and immune mechanisms driving headache disorders.
  • ECS dysfunction contributes to central sensitization and reduced descending inhibition, particularly in chronic headaches.
  • Targeting endocannabinoid hydrolysis and oxygenation shows consistent preclinical efficacy and represents a promising therapeutic strategy.”

https://www.mdpi.com/2073-4409/15/4/331

Potential therapeutic role of Cannabidiol and vitamin D in Hepatocellular carcinoma: evidence from in vitro studies

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“Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. Natural compounds with anticancer properties have gained increasing attention.

Cannabidiol (CBD) and Vitamin D have individually been reported to exert anti-proliferative and pro-apoptotic effects in various cancer models.

Methods and results

The effects of Vitamin D and CBD, alone and in combination, were investigated in two human HCC cell lines, Hep3B and Huh7. Cell viability was assessed using MTS assays, and drug interactions were evaluated by the Chou–Talalay method. Apoptosis, cell cycle progression, and molecular changes related to apoptosis, autophagy, cell proliferation, and DNA damage response were analyzed by flow cytometry and real-time PCR. Combined treatment with Vitamin D and CBD resulted in a synergistic reduction in cell viability in both cell lines, with lower IC₅₀ values compared to single treatments. The combination enhanced apoptotic signaling and inhibited cell proliferation in a cell line–dependent manner. In Hep3B cells, combined treatment induced G1 phase arrest, modulation of autophagy-related genes, and alterations in DNA damage response pathways, whereas Huh7 cells exhibited distinct transcriptional responses.

Conclusions

These findings demonstrate that the combination of Vitamin D and CBD exerts enhanced anticancer effects in HCC cells in vitro. This study provides mechanistic insight supporting further investigation of Vitamin D and CBD as a potential combinatorial therapeutic approach for HCC.”

https://link.springer.com/article/10.1007/s11033-026-11555-x

Cannabidiol-rich extract suppresses the activation of proinflammatory genes IL-1β and IL-6 in equine mesenchymal stem cells stimulated with lipopolysaccharide

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“Peripheral nerve injuries (PNI) often lead to long-term functional impairment. Mesenchymal stem cells (MSCs) and cannabidiol (CBD) have shown anti-inflammatory and neuroprotective effects in vitro, which may be relevant for PNI research.

The aim of this study was to evaluate CBD-rich cannabis extract’s potential to induce anti-inflammatory and neurotrophic gene expression in equine adipose tissue-derived MSCs (EqAT-MSCs) in an inflammatory in vitro environment.

The morphology and metabolic activity of EqAT-MSCs (n = 4) were assessed after CBD-rich extract priming at concentrations of 3, 5, 7, and 9 µM for 24 and 48 h. Cytokine and neurotrophic gene expression was evaluated under these conditions: DMEM (unprimed), DMEM + LPS (lipopolysaccharide) (10 ng/ml), and LPS (10 ng/ml) + DMEM + CBD at 3, 5, and 7 µM for 24 and 48 h. No morphological changes were observed in primed EqAT-MSCs versus unprimed cells. EqAT-MSCs showed a reduction in metabolic activity at 9 µM after 24 h. CBD priming following LPS stimulation led to statistically significant changes in EqAT-MSC gene expression. BDNF expression increased after 48 h (3 and 5 µM), while NGF expression decreased at both 24 and 48 h (3, 5, and 7 µM). IL-1β expression decreased after 24 h (3 and 7 µM), and IL-6 levels decreased at both 24 (5 and 7 µM) and 48 h (3, 5, and 7 µM). No significant changes were observed in GDNF, TNF-ɑ, IFN-ɣ, or IL-10.

These results indicate that CBD-rich extract selectively modulates inflammatory and neurotrophic gene expression in EqAT-MSCs while maintaining metabolic integrity.”

https://link.springer.com/article/10.1007/s11259-026-11105-7

Aerobic training and cannabidiol activate the PI3K/AKT/PDX1 axis to ameliorate beta-cell dysfunction in a rat model of diet-induced obesity

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“Background: This study investigated the therapeutic potential of cannabidiol (CBD) and aerobic training (AT), both alone and in combination, to ameliorate beta-cell dysfunction in a rat model of diet-induced obesity, with a specific focus on the phosphatidylinositol 3-kinase (PI3K)/ protein Kinase B (AKT)/pancreatic and duodenal homeobox 1 (PDX1) pathway.

Methods: Thirty-two male Wistar rats were fed a high-fat diet (HFD) for 8 weeks to induce obesity. They were then randomly assigned to four groups (n = 8/group): HFD (sedentary), HFD + CBD (10 mg/kg, 5x/week), HFD + AT (30-minute treadmill running,50-80% maximal speed, 5x/week, 8 week), and HFD + CBD+AT (combined treatment) for a further 8 weeks. Following the intervention, beta-cell function was assessed via the HOMA-Beta index, and pancreatic gene expression of PI3K, AKT, and PDX1 was analyzed using RT-PCR.

Results: Both the HFD + CBD and HFD + CBD+AT groups showed a significant improvement in beta-cell function, as indicated by a higher HOMA-Beta index compared to the HFD group (p = 0.002 and p = 0.001, respectively). AT alone (HFD + AT) did not significantly alter HOMA-Beta. In contrast, all intervention groups (HFD + CBD, HFD + AT, and HFD + CBD+AT) demonstrated a significant upregulation in the gene expression of PI3K, AKT, and PDX1 compared to the HFD group (p < 0.001 for all). Notably, the combined treatment of CBD and AT (HFD + CBD+AT) produced a synergistic effect, resulting in a greater increase in the expression of all three genes compared to either intervention alone. No significant correlation was found between HOMA-Beta and the gene expression levels within any group (p > 0.05).

Conclusions: CBD and AT independently activate the pancreatic PI3K/AKT/PDX1 pathway, with their combination showing synergy. CBD, but not AT alone, improved functional beta-cell mass. This pathway activation represents a key mechanism for protecting beta-cells in obesity.”

https://pubmed.ncbi.nlm.nih.gov/41721911

https://link.springer.com/article/10.1007/s11033-026-11573-9

Cannabidiol mitigates secondary genital injury after thoracic trauma by regulating systemic inflammation and hormone receptor signaling

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“Blunt thoracic trauma-induced pulmonary contusion is a major cause of acute lung injury and triggers a systemic inflammatory response characterized by cytokine release, oxidative stress, and apoptosis. These systemic effects may disrupt vascular homeostasis and contribute to secondary injury in distant organs, particularly within the female reproductive system, which is dependent on vascular and hormonal balance.

This study evaluated the effects of cannabidiol (CBD), a non-psychotropic phytocannabinoid with anti-inflammatory, antioxidant, and anti-apoptotic properties, on secondary reproductive organ injury following blunt thoracic trauma.

Forty adult female Wistar albino rats were assigned to Sham, Trauma, Trauma + CBD, and CBD groups. Pulmonary contusion was induced using a standardized weight-drop model (200 g from 1 m), and CBD (5 mg/kg, i.p.) was administered 30 min before trauma. Forty-eight hours later, lung, ovary, uterus, and fallopian tube tissues were collected for histopathological and immunohistochemical analyses. Trauma induced pulmonary injury accompanied by degenerative changes in reproductive tissues, including reduced estrogen receptor (ER) expression and increased hypoxia-inducible factor-1α (HIF-1α) and oxytocin receptor (OTR) expressions.

CBD treatment attenuated pulmonary and reproductive tissue injury, preserved ER immunoreactivity, and reduced HIF-1α and OTR expression.

These findings indicate that CBD mitigates secondary reproductive organ injury after thoracic trauma by modulating systemic inflammatory responses and regulating receptor expression, suggesting its potential role as a cytoprotective agent in trauma-related multi-organ injury.”

https://pubmed.ncbi.nlm.nih.gov/41723193

https://www.nature.com/articles/s41598-026-39310-z

Medical Cannabis for the Treatment of Peripheral Neuropathy due to Diabetes: A Systematic Review

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“Introduction: This systematic review evaluated randomized controlled trials (RCTs) conducted specifically in participants with diabetes and painful peripheral neuropathy to assess the effectiveness and safety of medical cannabis, isolated cannabinoids, or nationally approved cannabis-based medicines as adjuvant treatment, compared with placebo or baseline.

Materials and methods: Controlled clinical studies and RCTs in adults with diabetic peripheral neuropathy were eligible. Animal and in vitro studies were excluded. We searched PubMed, Google Scholar, Cochrane Library, and Scopus and screened 15,377 records; 35 full-text articles were assessed for eligibility, and 4 RCTs were included in the qualitative synthesis.

Results: Three of four studies reported statistically significant reductions in neuropathic pain with cannabinoid-based interventions compared with placebo, whereas one trial did not demonstrate superiority. In two trials using vaporized or sublingual Δ9-tetrahydrocannabinol (THC), doses in the range of approximately 16-18 mg were associated with clinically meaningful pain relief in participants. Adverse effects, including dizziness and cognitive symptoms, were common but generally mild-to-moderate, and discontinuations due to adverse effects varied across studies.

Discussion/conclusion: Evidence from four small, heterogeneous RCTs suggests that cannabinoid-based therapies may reduce pain in some patients with diabetic peripheral neuropathy; however, the limited number of studies, variability in formulations and comparators, and risk of bias preclude firm conclusions regarding efficacy. Observed THC doses around 16-18 mg/day delivered via vaporized or sublingual routes should be viewed as preliminary, hypothesis-generating ranges rather than definitive recommendations. Larger, contemporary RCTs with rigorous risk-of-bias control, standardized outcomes, and detailed safety reporting are needed.”

https://pubmed.ncbi.nlm.nih.gov/41714301

“three of four identified studies demonstrated statistically significant reductions in pain compared with placebo or baseline, suggesting that cannabinoid-based interventions may offer analgesic benefit for some patients with diabetic peripheral neuropathy.”

https://journals.sagepub.com/doi/10.1177/25785125261425444

The Paradoxical Effect of Cannabis Use on Cognition in Chronic Psychotic Disorders

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“Background/objectives: Cannabis use has a particularly high prevalence in individuals with psychotic disorders. Although cannabis use is generally associated with cognitive impairments in the general population, its impact on cognition in psychosis remains controversial. This study aimed to investigate the association between cannabis use and cognitive performance in a cohort of individuals affected by psychotic disorders.

Methods: A total of 105 inpatients with psychotic disorders (mean age: 40.3 years; 34 females) were recruited from the University Hospital Center “Mother Teresa” in Tirana. Data collection included socio-demographic and clinical variables. Cognitive functioning was evaluated using the Montreal Cognitive Assessment (MoCA), while psychopathology was assessed with the Brief Negative Symptom Scale (BNSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Psychotic Symptom Rating Scales (PSYRATS), and the Scale for the Assessment of Thought, Language, and Communication (TLC).

Results: Cannabis users (CU) were more frequently male, younger, and exhibited an earlier onset of psychosis compared to non-users (No-CU). Importantly, CU demonstrated higher MoCA scores, with the most favorable outcomes observed among daily users.

Conclusions: Contrary to the prevailing assumption that cannabis use exacerbates cognitive decline, our findings indicate an unexpected association between cannabis use and preserved cognitive functioning in psychosis. These results underscore the need to consider dosage, frequency, and cannabinoid composition (THC/CBD ratio) when interpreting cannabis-related cognitive outcomes in psychotic disorders.”

https://pubmed.ncbi.nlm.nih.gov/41718389

“the present study highlights that, in certain cases, patients with psychosis who use cannabis may demonstrate relatively preserved or even superior cognitive performance compared with non-using patients. These results raise important clinical and research questions.”

https://www.mdpi.com/1873-149X/33/1/11

The dual roles of natural cannabidiol in combating oxidative stress and inflammation: A potential intestinal guardian

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“Cannabidiol (CBD), a non-psychoactive and non-addictive phytocannabinoid derived from Cannabis sativa L., has attracted increasing attention for its therapeutic potential in intestinal diseases.

Accumulating evidence indicates that CBD exerts prominent antioxidant and anti-inflammatory effects within the gastrointestinal tract. Oxidative stress and redox imbalance are key drivers of epithelial barrier dysfunction, chronic inflammation, and disease progression in disorders such as inflammatory bowel disease (IBD) and colorectal cancer (CRC).

This review focuses on the redox-related mechanisms underlying CBD’s intestinal protective actions, highlighting its ability to regulate reactive oxygen species (ROS) production, activate the Nrf2-Keap1 antioxidant pathway, and modulate redox-sensitive inflammatory signaling, including NF-κB and the NLRP3 inflammasome.

In parallel, CBD engages the endocannabinoid system (ECS) and related receptors to preserve epithelial barrier integrity, regulate gut microbiota composition, and modulate intestinal oxidative stress and inflammation. We further discuss emerging evidence linking CBD’s regulation in the gut to systemic effects along the gut-organ axis, including the gut-brain and gut-liver axes.

Overall, this review synthesizes current evidence on how CBD integrates redox modulation, inflammation control, and intestinal barrier protection, providing a mechanistic framework for its potential application in intestinal disease and health.”

https://pubmed.ncbi.nlm.nih.gov/41713221

“CBD, as a non-psychoactive phyto-CB, has demonstrated substantial therapeutic potential for gastrointestinal health. By modulating the ECS, CBD enhances intestinal barrier integrity, regulates GM composition, and mitigates oxidative stress and inflammation. These effects contribute to its promising role in treating oxidative stress-related gastrointestinal conditions and maintaining intestinal homeostasis.”

https://www.sciencedirect.com/science/article/pii/S2213231726000492?via%3Dihub

Cannabis sativa L. roots extract modulates gastrointestinal motility and ameliorates ethanol-induced gastric ulcers in animal models

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“Introduction: Cannabis sativa L. roots are traditionally used to manage gastrointestinal (GI) disorders; however, experimental pharmacological evidence supporting these uses remains limited. This study investigated the chemical profile, safety, and GI-related pharmacological effects of an ethanolic extract of C. sativa roots (CEECs).

Methods: Chemical characterization was performed by spectrophotometric determination of total triterpenes and HPLC profiling. Safety and pharmacological effects were assessed through acute oral toxicity testing, antibacterial assays, and in vivo murine models of gastric emptying, diarrhea, and ethanol-induced gastric ulcer.

Results: CEECs showed a total triterpene content of 67.64 ± 5.39 μg LE·mg-1, and HPLC analysis detected p-coumaric acid and N-trans-feruloyltyramine. In vivo, CEECs significantly delayed gastric emptying at 50 mg·kg-1 (P = 0.0033) and reduced fecal output in the castor oil-induced diarrhea model at 50 (P < 0.001) and 100 mg·kg-1 (P = 0.0233), with no effect in the magnesium sulfate-induced model. CEECs also significantly reduced ethanol-induced gastric mucosal injury at 50 mg·kg-1 (P = 0.0484) and 100 mg·kg-1 (P = 0.0164). No signs of acute toxicity were observed at 2000 mg·kg-1. Antibacterial activity against Staphylococcus aureus strains was weak under the tested conditions.

Discussion: These findings provide experimental support for the traditional use of C. sativa roots in GI disorders and indicate their potential as a non-psychoactive source of bioactive constituents.”

https://pubmed.ncbi.nlm.nih.gov/41693782

“Overall, this study provides experimental support for the traditional use of cannabis roots in the management of diarrhea and gastric discomfort.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1743428/full