Author Archives: David Worrell

Perceived impact of medicinal cannabis on pelvic pain and endometriosis related symptoms in Aotearoa New Zealand: an observational cohort study

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“Endometriosis, characterised by the growth of endometrial-like tissue outside the uterus, often causes severe pelvic pain, dysmenorrhea, and fatigue. Current medical treatments frequently provide incomplete symptom control and/or significant side effects. Many individuals with endometriosis report symptom improvements with cannabis use, but high-quality evidence remains limited.

Methods

A prospective, mixed-methods cohort study was conducted. Participants aged 18–50 years with surgically or clinically diagnosed endometriosis self-engaged with a specialist consultant and were prescribed medicinal cannabis (cannabidiol [CBD] oil alone or in combination with dried cannabis flower). Weekly pain scores, and health-related quality of life (measured by the Endometriosis Health Profile-30 [EHP-30]) were assessed via surveys and standardised questionnaires over three months. Completion interviews were conducted to explore participants’ experiences with medicinal cannabis in greater depth.

Results

Participants reported limited adverse events during the study period. Pelvic pain scores decreased over 12 weeks: ‘overall’ pain reduced from 5.46 ± 1.55 (95% CI 0.57) to 3.77 ± 2.25 (95% CI 0.83), and ‘worst’ pain decreased from 7.62 ± 1.51 (95% CI 0.56) to 5.38 ± 2.69 (95% CI 1.00). The mean total EHP-30 score significantly decreased from 68.77 ± 15.17 (95% CI 5.61) to 37.40 ± 16.66 (95% CI 6.17). Qualitative analysis identified four major themes: motivations for seeking medicinal cannabis, experiences of use, barriers to use, and stigma.

Conclusions

Medicinal cannabis use was associated with reduction in pain measures and improvements in quality of life among some individuals with endometriosis during this study. Qualitative findings highlighted both perceived benefits and ongoing challenges related to access, dosage and social stigma. These results support the need for larger controlled studies to further evaluate the safety, efficacy, and long-term outcomes of medicinal cannabis as an adjunctive therapy for endometriosis-related pain.”

https://pubmed.ncbi.nlm.nih.gov/41566248

https://link.springer.com/article/10.1186/s12906-025-05189-y

The psychoactive cannabinoid THC inhibits peripheral nociceptors by targeting NaV1.7 and NaV1.8 nociceptive sodium channels

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“Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, is widely recognized for its central effects mediated by cannabinoid receptors. Here, we uncover a distinct peripheral mechanism by which THC inhibits the excitability of nociceptive neurons.

We show that THC directly targets the nociceptive voltage-gated sodium channels NaV1.7 and NaV1.8 through the conserved local anesthetic binding site. This interaction reduces sodium currents and suppresses action potential generation in peripheral sensory neurons.

Our findings demonstrate that, beyond its central psychoactivity, THC exerts direct peripheral nociceptor inhibition via modulation of NaV1.7 and NaV1.8, offering new insight into cannabinoid-based analgesia independent of cannabinoid receptor signaling.”

https://pubmed.ncbi.nlm.nih.gov/41565997

“Cannabis has been used for centuries for its analgesic properties, and its clinical relevance in pain management continues to grow.”

 “These findings reveal a previously unrecognized mechanism for THC-mediated peripheral analgesia and establish a non-canonical molecular pathway through which the psychoactive cannabinoid can inhibit nociceptor excitability and thereby pain.”

https://www.nature.com/articles/s41386-026-02355-9

Cannabidiol-Ion Channel Interactions Represent a Promising Preventive and Therapeutic Strategy in Hepatocellular Carcinoma

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“Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed.

The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response.

Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models.

The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC.

In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems.”

https://pubmed.ncbi.nlm.nih.gov/41562849

“The endocannabinoid system (ECS) plays a crucial role in the development and functioning of several biological systems. Classically, the endocannabinoid system comprises receptors, endogenous ligands, and enzymes that synthesize, transport, and degrade such ligands. ECS regulates many biological processes, both in normal conditions like brain function, neurotransmitter release, sleep regulation, appetite, movement, and coordination, as well as pathological states such as neurodegenerative disorders, headaches, chronic pain, anxiety, depression, and cancer, among others.

Accordingly, pharmacological modulation of the endocannabinoid system may be a potential target for preventing disease progression or enhancing symptom relief in multiple conditions, including cancer “

“Dysregulation of voltage-gated sodium channels causes the development of several diseases. CBD is a non-selective Nav1.1–1.7 sodium channel inhibitor and is effective in the treatment of epilepsy.”

“Exploiting the cannabidiol-ion channel-transporters association represents an extraordinary opportunity for liver cancer prevention and therapy, which may help to reduce the high mortality from this malignancy and to involve sociocultural, public health, regulatory, and economic systems.”

“Taken together, preclinical, epidemiological, and clinical data converge to support CBD as a promising candidate for the prevention and management of liver diseases and HCC, with potential implications for sociocultural, public health, and economic systems.”

https://www.mdpi.com/1873-149X/33/1/8

Exploring the neuroprotective effects and underlying mechanisms of medical cannabinoids in ischemic stroke: a systematic meta-analysis with bibliometric mapping of cerebral ischemia research

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“Background: Ischemic stroke is an acute neurological disorder with limited treatment options. Medical cannabinoids (MCs), primary bioactive compounds extracted from cannabis plants, have shown therapeutic prospects for ischemic stroke. This study integrates bibliometrics and meta-analysis to comprehensively summarize the research landscape of MCs in cerebral ischemia and thoroughly investigate their role and potential mechanisms in ischemic stroke.

Methods: Bibliometric analysis was performed based on literature retrieved from Web of Science Core Collection (WoSCC), PubMed, and Scopus. For meta-analysis, a comprehensive search was conducted across four databases (WoSCC, PubMed, Embase, and Cochrane Library) and grey literature repositories. Studies were screened according to predefined criteria. Pooled standardized mean differences with 95% confidence interval were calculated, followed by subgroup analysis.

Results: A total of 241 publications were identified for bibliometric analysis. From 2000 to June 2025, the annual publication output on MCs in cerebral ischemia displayed a fluctuating yet overall upward trend. Keyword co-occurrence analysis revealed three major research topics: neuroprotective mechanisms of MCs, pathological models of cerebral ischemia, and bioactive components of MCs. Meta-analysis of 26 studies demonstrated that MCs provided significant neuroprotection in animal models of ischemic stroke, including cerebral infarct volume, neurological function score (NFS), cerebral blood flow (CBF), blood-brain barrier (BBB) permeability, brain water content, apoptosis (TUNEL-positive cells), oxidative stress markers, inflammation (TNF-α, IL-1β), and excitotoxicity (Glu/NAA, Lac/NAA ratio). Subgroup analysis revealed that intraperitoneal administration and a full-course of cannabidiol (CBD) treatment were associated with reduced heterogeneity and enhanced therapeutic benefit. Isoflurane was identified as a potentially suitable anesthetic.

Conclusion: MCs exert multi-target neuroprotection in ischemic stroke by improving CBF, reducing brain edema and BBB permeability, and inhibiting oxidative stress, neuroinflammation, apoptosis, and excitotoxicity. Future research should focus on high-quality clinical trials to validate these findings and translate MCs into clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/41551042

“THC produces anti-inflammatory effects, reduces neuronal damage, and promotes hippocampal neurogenesis.”

“CBD acts as a negative allosteric modulator of cannabinoid receptors (CBR) and exerts brain-protective effects through multi-target regulatory properties “

 “Moreover, the results of meta-analysis consolidate preclinical evidence, demonstrating that MCs confer neuroprotection by mitigating multiple pathological processes, including cerebral tissue perfusion, BBB permeability and cerebral edema, oxidative stress, excitotoxicity, inflammatory responses, and apoptosis.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1731738/full

The Evidence for Medical Cannabis in Chronic Musculoskeletal Pain Management

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“Chronic musculoskeletal pain (CMP) is a pervasive condition that can impair daily functioning and quality of life. Traditional pharmaceutical therapies, including non-steroidal anti-inflammatory drugs, gabapentinoids, and opioids, often yield suboptimal results and carry notable risks, such as adverse side effects and dependence.

Increasing interest has turned toward medical cannabis, particularly combined formulations of cannabidiol (CBD) and tetrahydrocannabinol (THC), as a potential alternative or complement to current pain management strategies.

Evidence suggests that cannabinoids interact with the endocannabinoid system to modulate nociception and inflammation, offering meaningful pain relief and possibly reducing opioid requirements.

However, heterogeneity in study designs, product formulations, and regulatory frameworks presents challenges in drawing definitive conclusions. Additionally, while most adverse effects, such as fatigue, dizziness, and mild cognitive changes, are generally reported as tolerable, concerns remain about long-term safety and standardization of dosing.

Taken together, the existing literature points to a promising role for medical cannabis in CMP management, underscoring the need for further high-quality research to establish best practices, clarify patient selection, and guide clinicians in safe and effective cannabinoid therapy.”

“This scoping review highlights the potential role of medical cannabis in managing musculoskeletal pain. Evidence suggests it may reduce pain, enhance well-being, and improve quality of life, particularly as an alternative or adjunct to opioids. Adverse effects are typically mild, supporting its use as a safer long-term option. However, data on long-term efficacy, especially for CBD, remain limited.

Given the risks of opioid dependence, cannabis offers a promising therapeutic alternative.”

https://surgicoll.scholasticahq.com/article/138573-the-evidence-for-medical-cannabis-in-chronic-musculoskeletal-pain-management

Overlapping pathways of migraine and the endocannabinoid system: Potential therapeutic targets

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“Migraine is a disabling neurovascular disorder with limited therapeutic options, especially for patients unresponsive to current treatments targeting calcitonin gene-related peptide (CGRP) signaling.

The endocannabinoid system (ECS) has emerged as a promising alternative for migraine modulation, offering analgesic, anti-inflammatory, and neuroimmune-regulatory effects through its main ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degrading enzymes.

This review provides an updated map of endocannabinoid components in central and peripheral migraine-relevant regions, highlighting their spatial distribution and functional regulation in animal models.

We summarize the available preclinical evidence supporting the anti-nociceptive effects of endocannabinoid-degrading enzyme inhibitors and cannabinoid receptor agonists/antagonists, with particular emphasis on the therapeutic potential of multi-target compounds. Moreover, we explore non-canonical ECS pathways, including TRPV1, D2 dopamine receptors, serotonergic and ion channel interactions, and their roles in modulating CGRP release and trigeminovascular signaling to treat migraine pathophysiology.

Finally, we propose two sleep-related directions for treatments involving ECS modulation of circadian rhythms and glymphatic clearance. Although human translational data are limited, the ECS offers a multifaceted framework for developing next-generation therapeutics targeting migraine pathophysiology.”

https://pubmed.ncbi.nlm.nih.gov/41549028

“As alternative treatments, instead of using highly addictive painkillers, such as opioids, there is a great need for alternative, effective and safe medications. Despite potential negative psychoactive side effects and potential medication-overuse headache risk, medical marijuana has been shown to decrease the frequency of migraine headaches, suggesting a perspective for cannabinoids in treating migraine. The use of cannabis to relieve pain dates to ancient civilizations.

Cannabis has been used for millennia in ayurvedic medicine for the management of pain, nausea, and anxiety, as well as to promote appetite and sleep.

The cannabis plant has complex natural compounds, including, in addition to the generally safe cannabidiol (CBD), the psychotropic delta9-tetrahydrocannabinol (THC), and dozens of poorly characterized components. Recent studies have pointed to the therapeutic potential of a combination of CBD and THC in preclinical migraine models and in a clinical trial. These CBD and THC findings point to the importance of targeting the body’s endocannabinoid system (ECS). Thus, the stage is set for testing the enhancement of ECS signaling pathways that might provide analgesia with minimal adverse effects.”

“Current evidence shows that the ECS is embedded in multiple migraine-relevant pathways areas across the CNS and PNS. Preclinical studies demonstrate that enhancing endocannabinoid tone via inhibition of endocannabinoid-degrading hydrolases reduces migraine-like pain and neuroinflammation. Beyond these analgesic strategies, targeting cannabinoid receptors, modulating their activity, and influencing their modulation of circadian regulation and glymphatic clearance further highlight the therapeutic potential of engaging the ECS.”

https://www.neurotherapeuticsjournal.org/article/S1878-7479(26)00003-6/fulltext

Therapeutic potential of acidic cannabinoids: an update

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“Cannabis sativa yields a wide range of bioactive compounds, including terpenes, flavonoids, and cannabinoids.

Tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and cannabichromenic acid (CBCA) are the acidic biosynthetic precursors of the neutral cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which have been the subject of much research.

This review examines the biosynthesis, decarboxylation, molecular pharmacology, and therapeutic significance of acidic cannabinoids, intending to address a significant knowledge gap. Peer-reviewed literature from major scientific databases was used in a systematic narrative review with an emphasis on investigations of acidic cannabinoid chemistry, pharmacology, pharmacokinetics, and disease-specific applications.

According to the reviewed data, acidic cannabinoids exhibit unique biological activities that distinguish them from their neutral counterparts. These include neuroprotective, anti-inflammatory, anticonvulsant, and anti-proliferative actions, which are mediated by molecular targets such as serotonin 5-HT1A receptors, cyclooxygenase-2 (COX-2), transient receptor potential (TRP) channels, and peroxisome proliferator-activated receptor-γ (PPARγ).

Acidic cannabinoids are more appealing for therapeutic usage in children and the elderly, considering that they are not intoxicating like THC; however, this distinction applies primarily to non‑heated consumption. Chemical instability, low bioavailability, and a dearth of controlled human trials impede clinical translation despite their potential.

According to the findings, acidic cannabinoids are an underutilized yet potentially valuable class of precision medicines.

In this study, we outline existing understanding on acidic cannabinoids, discuss their production and transformation, and identify research needs that could influence cannabis science research.”

https://pubmed.ncbi.nlm.nih.gov/41545891

https://link.springer.com/article/10.1186/s42238-026-00387-y

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

https://pmc.ncbi.nlm.nih.gov/articles/PMC7409346


The differential effects of CBD and CBDA on viability and mRNA expression in colorectal cancer cells

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“Background: Cannabinoids have attracted significant attention for their potential therapeutic application in cancer research. However, recent studies have reported antitumor activity of cannabidiolic acid (CBDA)-the acidic precursor of CBD-in breast cancer cells, involving modulation of cyclooxygenase signaling. To our knowledge, no investigations have examined the effects of CBDA on RNA expression and signaling pathways in colorectal cancer (CRC) cells. Therefore, we aimed to investigate the effects of CBD, CBDA, and a CBDA-rich Cannabis sativa (C.s). extract on the growth and gene expression in CRC cell lines.

Methods: We assessed cell viability and clonogenic growth of the CRC cell lines HCT116 and DLD1 following treatment with pure CBD, pure CBDA, a CBDA-rich C.s. extract (CBDA/CBD ratio 20:1), and a corresponding mixture of pure CBDA/CBD. RNA sequencing was performed to analyze differentially expressed genes (DEGs) and the cell signaling pathways affected by these treatments.

Results: Of all tested compounds, CBD exhibited the strongest cytotoxic effect in both cell lines, whereas CBDA demonstrated minimal toxicity, particularly in HCT116 cells. Furthermore, we observed a greater inhibitory effect of the CBDA-rich C.s. extract on HCT116 cell growth compared to the CBDA/CBD mixture. RNA sequencing analysis revealed that CBD had the most pronounced impact on gene expression, while CBDA had the least. Notably, treatment with the C.s. extract resulted in a higher number of DEGs than the CBDA/CBD mixture in HCT116. Gene expression analysis indicated an upregulation of the Wnt and Hippo signaling pathways following CBD treatment. Additionally, CBDA, CBD/CBDA (1:20), and the C.s. extract primarily induced metabolic processes in DLD1 cells, suggesting a distinct metabolic response.

Conclusion: Our findings showed that CBD exerts stronger effects on cell survival and gene expression in CRC cells than CBDA, which showed only limited activity. Moreover, the CBDA-rich C.s. extract exhibited greater efficacy than the CBDA/CBD mixture. More research is needed to further elucidate the impact of cannabinoids on CRC cell biology and signaling pathways.”

https://pubmed.ncbi.nlm.nih.gov/41546069

https://link.springer.com/article/10.1186/s42238-026-00391-2

The Exploration of Cannabis Beverage Substitution for Alcohol: A Novel Harm Reduction Strategy

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“Alcohol consumption is associated with nearly 200 health conditions. As cannabis-infused beverages emerge in the legal market, their potential as a substitute for alcohol is of growing interest.

This study investigates whether cannabis beverages may reduce alcohol use.

A total of 438 anonymous adults who used cannabis in the past year completed a survey including cannabis use and alcohol consumption items from the Behavioral Risk Factor Surveillance System (BRFSS). Chi-square and t-tests compared alcohol use between cannabis beverage users and non-users, and before vs. after cannabis beverage initiation.About one-third (33.6%) of respondents used cannabis beverages, typically consuming one per session.

Users were more likely to report substituting cannabis for alcohol (58.6%) than non-users (47.2%). They also reported fewer weekly alcoholic drinks after starting cannabis beverages (M = 3.35) compared to before (M = 7.02), and binge drank less frequently (80.7% reported less than monthly or never, vs. 47.2% before). Those who cited reducing other substance use were more likely to use cannabis beverages (45.8%).

Findings suggest cannabis beverages may support alcohol substitution and reduce alcohol-related harms, offering a promising alternative for individuals seeking to lower alcohol intake.”

https://pubmed.ncbi.nlm.nih.gov/41533430

https://www.tandfonline.com/doi/full/10.1080/02791072.2026.2614506

Cannabidiol Inhibits Melanoma Progression by Regulating PPARγ-TET1 Complex-dependent LRASM1 Demethylation

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“Melanoma represents one of the most aggressive forms of skin cancers, with advanced metastatic stages largely managed through chemotherapy. However, current therapeutic strategies remain limited by drug resistance and systemic toxicity. Cannabidiol (CBD), the primary nonpsychoactive constituent of Cannabis sativa, has recently attracted attention for its anticancer properties across multiple tumor types.

OBJECTIVES

This study aimed to explore the antitumor efficacy of CBD in melanoma and elucidate its underlying molecular mechanisms, with the goal of identifying novel therapeutic strategies to overcome resistance and reduce adverse effects associated with conventional treatments.

METHODS

The antiproliferative and pro-apoptotic effects of CBD were assessed in vitro using MTS, EdU, Transwell invasion, and flow cytometry. In vivo efficacy was evaluated using a murine lung metastasis model. Potential CBD targets in melanoma were identified through network pharmacology and molecular docking, with a focus on peroxisome proliferator-activated receptor γ (PPARγ) and validation by western blotting and immunofluorescence. Integrated transcriptomic and genome-wide methylation analyses were performed to investigate epigenetic modifications induced by CBD. Co-immunoprecipitation and chromatin immunoprecipitation assays were employed to detect the interaction between PPARγ and ten-eleven translocation 1 (TET1), including their binding to promoter regions of downstream factors. Methylation-regulated target genes were further validated using qPCR and MeDIP PCR.

RESULTS

CBD significantly induced apoptosis and inhibited cell proliferation and invasion of melanoma cells in vitro, while reducing pulmonary metastasis in vivo. Pharmacological and molecular docking analyses, supported by protein-level validation, identified PPARγ as a critical mediator of CBD activity. Transcriptomic and methylation analyses revealed that CBD modulated global DNA methylation patterns, partly through the formation of a PPARγ-TET1 complex. This complex regulated the demethylation of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), a newly identified anticancer gene whose upregulation markedly enhanced melanoma cell apoptosis and suppressed proliferation.

CONCLUSIONS

CBD exhibited strong antitumor activity in melanoma by modulating the PPARγ–TET1 complex to induce demethylation of LRSAM1, thereby suppressing tumor progression. These findings identify CBD as a promising candidate for melanoma therapy.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711326000127

“In summary, this study investigated molecular targets and mechanisms by which CBD suppresses melanoma progression, emphasizing its role in PPARγ activation and epigenetic regulation. These findings establish a mechanistic basis and provide candidate targets for future clinical application of CBD in melanoma treatment.”

“This study provides the first evidence that CBD inhibits melanoma progression by modulating gene methylation. The identification of LRSAM1 as a PPARγ-TET1-regulated tumor suppressor expands current understanding of epigenetic regulation in melanoma and highlights LRSAM1 as a viable therapeutic target.”

https://www.scilit.com/publications/50c9c0a6d08f7880cebb9c69a2c3fca7