Author Archives: David Worrell

Therapeutic Drug Monitoring of Cannabinoids: Therapeutic Reference Ranges for Delta-9-tetrahydrocannabinol in Medical Cannabis, Nabiximols, Dronabinol and Nabilone

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“Medical cannabis, nabiximols, dronabinol and nabilone are used for various medical conditions.

Despite their pronounced pharmacokinetic variability and complex concentration-effect relationships, therapeutic drug monitoring recommendations are lacking. We aimed to identify therapeutic reference ranges based on blood concentration-clinical effect relationships. Studies reporting blood concentrations and clinical effects/adverse effects or assessing cannabinoid receptors 1 and 2 occupancy were selected through a systematic literature search in the MEDLINE database via PubMed. Twenty-three articles were selected for vaporized/smoked medical cannabis, three for nabiximols, nine for dronabinol and one for nabilone. No article was identified for delta-9-tetrahydrocannabinol-dominant cannabis extracts.

For vaporized/smoked medical cannabis, an orienting therapeutic reference range of 15-30 ng/mL delta-9-tetrahydrocannabinol was identified for pain reduction in diabetic peripheral neuropathy, while concentrations of <20 ng/mL delta-9-tetrahydrocannabinol were significantly correlated with intraocular pressure reduction and 7.5-10 ng/mL with improvement of tic symptoms. Half-maximum effective concentrations of 7-29 ng/mL delta-9-tetrahydrocannabinol were reported for “high” effects.

For nabiximols, a preliminary therapeutic reference range of 1-10 ng/mL delta-9-tetrahydrocannabinol was determined for treating neuropathic pain and spasticity in adults with multiple sclerosis. For chemotherapy-induced nausea and vomiting, a preliminary therapeutic reference range of 1-5 ng/mL for nabilone and 5-15 ng/mL delta-9-tetrahydrocannabinol for dronabinol was assessed.

In conclusion, relatively low concentrations may be sufficient to achieve therapeutic effects across all substances studied, with medical cannabis demonstrating these effects at lower concentrations than typically observed in recreational use. Nevertheless, adverse effects at therapeutic reference ranges cannot be excluded.”

https://pubmed.ncbi.nlm.nih.gov/42269696

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2853-4984

Endocannabinoid system and skeletal muscle health: insights from cannabidiol

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“The endocannabinoid (EC) system is a complex network comprising endogenous ligands, enzymes responsible for their synthesis and degradation, and various receptors (including CB1 and CB2).

Present in many peripheral tissues, including skeletal muscle, EC system is now recognized to influence key physiological processes such as insulin sensitivity, mitochondrial metabolism, protein homeostasis and muscle development. Alterations in this system are associated with a variety of pathologies, including obesity, type 2 diabetes, sarcopenia, cachexia and muscle dystrophies.

In this context, cannabidiol (CBD), a phytocannabinoid devoid of psychoactive properties, is attracting growing interest as a potential therapeutic agent.

This article provides an analysis of the mechanisms by which the EC system, and more specifically the CB1 receptor, influences skeletal muscle development and function, while exploring emerging data on the potential benefits of CBD in various pathological conditions affecting skeletal muscle.”

https://pubmed.ncbi.nlm.nih.gov/42264146

“The endocannabinoid system (ECS) is composed of endogenous ligands (AEA, 2-AG), enzymes for their synthesis or degradation, and receptors (e.g., CB1, CB2). It also includes exogenous molecules like cannabidiol (CBD) produced from Cannabis sativa. Widely expressed in peripheral tissues such, the ECS plays a central role in the regulation of key skeletal muscle physiological processes, including insulin sensitivity, mitochondrial metabolism, protein homeostasis and skeletal muscle development.

Dysregulation of this system is associated with the development of metabolic and muscular disorders, such as obesity, type 2 diabetes, sarcopenia, cachexia and muscular dystrophies.

In this context, CBD, a non-psychoactive phytocannabinoid, has emerged as a potential therapeutic agent capable of modulating ECS activity, thereby contributing to the restoration of skeletal muscle function and homeostasis.”

https://www.sciencedirect.com/science/article/pii/S2212877826000803?via%3Dihub

Targeting Phantom Limb Pain with Cannabinoids in a Rat Model

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“Introduction: Phantom limb pain (PLP) is a debilitating neuropathic condition arising after limb loss or nerve injury, with limited effective treatments. Cannabinoids, including cannabidiol (CBD), β-caryophyllene (BCP), and Δ9-tetrahydrocannabinol (THC), possess analgesic and anti-inflammatory properties. This study evaluated their combined efficacy as preventive or delayed interventions in a rodent model of PLP.

Methods: To model PLP, a chronic constriction injury was used to mimic pre-amputation pain, followed by formalin-induced localized inflammation and complete sciatic nerve transection to simulate extremity amputation. Cannabinoid treatments (CBD/BCP/THC, CBD/BCP, or THC) or vehicle control were administered either preemptively on the day of axotomy (prevention paradigm) or after the emergence of pain behaviors (reversal paradigm). Progression of pain behaviors were assessed over a 72-day period, and modulation of spinal cytokine levels, glial reactivity, and GABAergic signaling was evaluated.

Results: Preemptive THC or CBD/BCP reduced PLP onset and severity, while the full combination was less effective. In contrast, with delayed treatment, CBD/BCP and the CBD/BCP/THC combination were most effective in mitigating PLP. Pain reduction was correlated with restoration of spinal GABAergic inhibition. All cannabinoid treatments decreased microglial and astrocyte reactivity and shifted cytokines toward an anti-inflammatory state.

Conclusion: Cannabinoid-based interventions demonstrate significant therapeutic promise for PLP, showing efficacy as both early and delayed treatments. Findings suggest that THC may exert greater therapeutic effects when administered pre-emptively, while CBD and BCP may offer greater therapeutic advantages in established pain states. These findings highlight the therapeutic potential of tailored cannabinoid interventions for neuropathic pain and underscore the importance of optimizing dosing strategies for maximal analgesic effect.”

https://pubmed.ncbi.nlm.nih.gov/42267080

“Cannabis contains a complex mixture of cannabinoids, terpenes, and flavonoids that have demonstrated therapeutic potential in a variety of pathologies and conditions. Their anti-inflammatory, analgesic, and antioxidant activities are believed to play a central role in mediating pain relief.”

“Our findings support the therapeutic potential of cannabinoid-based treatments in both preventing and reversing PLP, with efficacy varying by cannabinoid pairing and timing of treatment.

Together, these results underscore the therapeutic promise of cannabinoid-based treatments while highlighting the need to carefully consider how specific compounds and dosing strategies interact in different stages of pain.”

https://karger.com/mca/article/9/1/92/946968/Targeting-Phantom-Limb-Pain-with-Cannabinoids-in-a

Cannabidiol Protects Against 1-Methyl-4-Phenylpyridinium and Manganese-Induced Neurotoxicity via Nod-Like Receptor Protein 3 Inflammasome Suppression

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“Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurodegeneration, alpha-synuclein (α-Syn) accumulation, and neuroinflammation. The NOD-Like Receptor (NLR) family pyrin domain containing 3 NLRP3 inflammasome has recently been identified as a central mediator of PD-associated inflammatory responses.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits anti-inflammatory and neuroprotective properties; however, its effects on NLRP3 inflammasome in PD remain insufficiently understood.

This study investigated the neuroprotective effects of CBD-rich oil against 1-methyl-4-phenylpyridinium (MPP+) and manganese-induced neurotoxicity in SH-SY5Y cells.

Cells were exposed to these substances with or without CBD co-treatment, and cell viability, α-Syn, dopamine, inflammatory markers [C reactive protein (CRP) and interleukin 18 (IL-18)], and NLRP3 expressions were evaluated.

MPP+ and manganese exposures significantly decreased cell viability and dopamine levels while increasing α-Syn accumulation and inflammatory markers. Manganese induced an approximately twofold upregulation in NLRP3 mRNA and 1.5-fold increase in protein expression.

CBD co-treatment preserved dopamine levels, attenuated α-Syn accumulation, reduced IL-18 and CRP concentrations, and attenuated NLRP3 expression.

These findings demonstrate that CBD-rich oil exerts neuroprotective effects in a PD cellular model by attenuating α-Syn accumulation, preserving dopamine homeostasis, which is associated with reduced NLRP3 expression and potential modulation of inflammasome-related signaling, supporting further investigation of CBD as a potential therapeutic strategy for PD.”

https://pubmed.ncbi.nlm.nih.gov/42262723

“There is growing interest in phytocannabinoids as potential interventions for neurodegenerative disorders. Cannabidiol (CBD), a non-intoxicating constituent of Cannabis sativa, exhibits neuromodulatory and neuroprotective properties, including anti-inflammatory and antioxidant effects mediated through multiple molecular targets relevant to basal ganglia function and PD symptomatology.”

“Accordingly, the present study investigated the neuroprotective potential of CBD-rich oil in an in vitro PD model using SH-SY5Y cells exposed to MPP+ and/or manganese.”

“In conclusion, CBD-rich oil mitigated multiple PD-relevant pathological features in a neurotoxicant-based cellular model. CBD reduced α-synuclein accumulation, preserved dopamine content, attenuated inflammatory markers, and was associated with reduced NLRP3 expression at both mRNA and protein levels. These findings support CBD as a potential neuroprotective agent and suggest that NLRP3 modulation may be a contributing mechanism.”

https://onlinelibrary.wiley.com/doi/10.1002/jbt.70957

Potential antitumor effect of cannabidiol (CBD) in canine oncology: a systematic review

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“Introduction: Preparations of Cannabis sativa have been used for medicinal purposes for many centuries Currently, it is known that the phytocannabinoids present in the Cannabis sativa plant can modulate the endocannabinoid system, producing a variety of effects. Among the most abundant phytocannabinoids are delta-9-tetrahydrocannabinol (19-THC) and cannabidiol (CBD). CBD lacks psychotropic properties and has been shown to inhibit cell proliferation and migration, while inducing apoptosis in various human tumor cells. Studies evaluating CBD in dogs are more recent than those in humans, and to date, fewer publications are available. However, CBD has been shown to be safe and well-tolerated in dogs, supporting its potential clinical use. Since approximately 2015, some studies have been conducted evaluating CBD in different types of canine cancer; however, no comprehensive review of these findings has been performed.

Methods: we conducted a systematic review Following the PRISMA 2020 guidelines.to compile the existing evidence on the anticancer effects of CBD in dogs.

Results: We found that the studies conducted so far are pre-clinical, mostly based on cellular models, and that available data are primarily in lymphoma, mammary cancer, glioma, prostate cancer, osteosarcoma, and urothelial carcinoma. These studies consistently show that CBD exerts antiproliferative and proapoptotic effects, in some cases by modulating intracellular signaling pathways, including ERK, JNK, and caspases. Additionally, some studies have evaluated the combination of CBD with other drugs, reporting both synergistic and antagonistic effects.

Overall, these findings highlight the potential of CBD as an anticancer agent across different cancer types.

Discussion: Further studies are required to better elucidate the mechanisms underlying the effects of CBD and to standardize concentrations and formulations, enabling reliable, comparable results and the development of clinical studies evaluating the role of CBD in canine oncology.”

https://pubmed.ncbi.nlm.nih.gov/42254894

“The findings from pre-clinical studies in dogs are consistent with those observed in humans, where CBD triggers antiproliferative and pro-apoptotic effects on several cancer cell types, which support clinical trials to elucidate the pharmacodynamics, pharmacokinetics, and potential antitumor efficacy of CBD in dogs with cancer.”

https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2026.1800410/full

High-dose cannabidiol for chronic neuropathic pain associated with spinal cord injury: a randomised clinical trial

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“Background: Chronic neuropathic pain is common after spinal cord injury (SCI), yet current treatments have limited efficacy and significant side effects. Cannabidiol (CBD), a non-intoxicating component of cannabis, has demonstrated efficacy in preclinical neuropathic pain models. Here, we investigated the effect of high-dose (up to 800 mg/day) CBD on chronic neuropathic pain in SCI.

Methods: This randomised, double-blinded, placebo-controlled, crossover clinical trial was conducted at Neuroscience Research Australia. Adults with SCI and neuropathic pain (≥three months duration) were recruited. Participants were randomised to one of two treatment orders by an unblinded investigator who had no participant contact. Participants and all other investigators were blinded. Participants consumed oral CBD and placebo over two six-week treatment periods separated by a four-week washout. Treatment was titrated up to 800 mg/day of CBD over two-weeks. The primary outcome was change in self-reported pain intensity on a zero (no pain) to ten (worst pain imaginable) Visual Analogue Scale. Statistical comparisons included CBD versus placebo treatment, and pre-treatment (inactive phase) versus on-treatment (active phase). Outcomes were analysed by modified intention-to-treat. The study is registered with anzctr.org.au, ACTRN12622000634774 (not recruiting).

Findings: Forty participants were randomised (August 1, 2022 to December 16, 2024) and 38 included in the primary analysis (n = 6 female). A significant treatment by phase interaction effect (p < 0.001) was observed on self-reported pain. Pairwise comparison showed lower pain intensity during the active phase with CBD (mean ± SEM: 3.82 ± 0.23) compared to placebo (mean difference = -0.54, SEM = 0.15, p < 0.001), with a 95% confidence interval for the difference of -0.88 to -0.21. Treatments did not differ during the inactive phase (mean difference <0.01, SEM = 0.17, p = 1.00, 95% CI = -0.38 to 0.38). Adverse events, nearly all minor, were reported by 68.4% of participants during CBD (n = 67 events), and by 52.6% during placebo (n = 51 events) treatment.

Interpretation: In this placebo-controlled trial, CBD significantly reduced the self-reported intensity of neuropathic pain and was generally well-tolerated. While modest in magnitude, the observed effect supports further research into high-dose CBD for chronic neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/42256679

“This trial provides evidence that high-dose CBD is safe and effective in treating chronic neuropathic pain following SCI. Additionally, the study provides initial evidence of a subgroup effect, whereby CBD is more effective in some individuals than others: this also warrants further exploration.”

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(26)00234-8/fulltext

Long-term follow-up of children with autism spectrum disorder and severe treatment-resistant behavioral symptoms treated with purified cannabidiol

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“Background: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition often associated with severe behavioral disturbances and limited pharmacological treatment options. Cannabidiol (CBD) has emerged as a potential therapeutic option; however, evidence on its long-term effectiveness and safety in children with ASD is scarce.

Objective: To evaluate the long-term effectiveness and safety of purified CBD as addon therapy in children with severe ASD and treatment-resistant behavioral symptoms.

Material and methods: We conducted a prospective observational before-and-after study in children and adolescents (3-18 years) with ASD severity levels 2 or 3 and intellectual disability treated with add-on CBD. The primary outcome was change in caregiver-identified symptoms, while secondary outcomes included standardized behavioral scales (Repetitive Behavior Scale-Revised [RBS-R], Vineland Adaptive Behavior Scales-II maladaptive behavior domain, Aberrant Behavior Checklist [ABC], Pediatric Sleep Clinical Global Impressions-Severity, Autism Family Experience Questionnaire, and Parental Stress Scale). Safety and tolerability were assessed through caregiver-reported adverse events.

Results: Twenty children were enrolled, of whom 13 completed the long-term follow-up (mean 27.6 ± 1.3 months). Of the caregiver-identified symptoms, improvements observed during the initial short-term study were maintained or further improved during follow-up. Standardized scales showed modest but sustained improvements, particularly in irritability, social withdrawal, and hyperactivity. Mild, transient adverse events, mainly irritability or decreased appetite, did not recur during long-term followup, and concomitant medications were reduced in 40% of patients.

Conclusion: Long-term treatment with purified CBD in children with severe ASD was well tolerated and associated with sustained improvement in caregiver-reported outcomes and standardized scales.”

https://pubmed.ncbi.nlm.nih.gov/42248366

“Cannabidiol (CBD), a non-psychoactive cannabinoid, has gained increasing interest as a potential therapeutic option for both core symptoms of ASD and associated comorbidities, based on its anxiolytic, anti-inflammatory, and neuromodulatory properties, together with a generally favorable safety profile.”

“In this long-term follow-up of children with severe ASD treated with purified CBD, no significant differences were observed between the three-month and the 26-month evaluations, suggesting that the initial improvements were maintained over time. Among patients who completed the extended follow-up, purified CBD was well tolerated and associated with sustained improvement in several symptoms, particularly those identified by families as most disruptive in daily life.”

https://www.sciencedirect.com/science/article/abs/pii/S0091305726000754?via%3Dihub

Combined peripheral cannabinoid CB1 and CB2 receptor activation abolishes cystitis-induced bladder hyperalgesia

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“Cannabinoid agonists may ameliorate bladder pain associated with interstitial cystitis/bladder pain syndrome.

Visceromotor responses (VMRs) to bladder distension were recorded in urethane-anesthetised control and protamine/zymosan-treated guinea pigs. The peripherally restricted preferential CB1 receptor agonist PrNMI and the selective CB2 receptor agonist 4Q3C each reduced cystitis-induced enhancement of VMRs at high intravesical pressures.

Co-activation of CB1 and CB2 receptors abolished cystitis-induced bladder hyperalgesia.

These findings indicate that simultaneous targeting of peripheral CB1 and CB2 receptors may provide clinically meaningful benefits for the treatment of bladder pain associated with cystitis.”

https://pubmed.ncbi.nlm.nih.gov/42247877

“Combined activation of peripheral CB1 and CB2 receptors using peripherally restricted agonists effectively reverses bladder hyperalgesia in a preclinical model of IC/BPS.

These findings provide strong support for the development of peripherally acting combination therapies targeting both cannabinoid receptors as a strategy to treat bladder pain and associated symptoms in IC/BPS, while minimising central cannabinoid-related side effects.”

https://www.autonomicneuroscience.com/article/S1566-0702(26)00066-4/fulltext

Industrial Cannabis, Cannabic Residue or Industrial Cannabis Waste? Perspectives on the Utilization, Reutilization, and Recycling of Cannabis

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“Introduction: Cannabis sativa L. is an annual herbaceous plant with a long history of multipurpose use, including food, textile, and medicinal applications. The progressive legalization in several countries has significantly increased its large-scale cultivation, consequently generating a substantial amount of biomass waste. This scenario calls for innovative and sustainable strategies to valorize Cannabis residues, aiming at promoting the circular economy and technological innovation.

Materials and methods: An integrative review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Systematic searches were performed in SCOPUS, PubMed, and SciELO, complemented by specialized platforms such as CANNUSE and CONSENSUS. Peer-reviewed empirical studies were included if they addressed the utilization, reutilization, or recycling of C. sativa by-products or residues for the development of industrial products, processes, or inputs. The analysis considered thematic and commercial domains, geographic origin, and biomass type.

Results: A total of 262 studies were included, with 144 retrieved from indexed databases and 118 from alternative methods. The most commonly explored residues were stems (48.2%), seeds (21.0%), and postextraction residuum (9.7%). The majority of applications were related to technology and innovation (37.5%) and industrial sectors (36.9%). A total of 328 technologies were identified, highlighting applications such as textile fibers, bioplastics, biofuels, functional foods, adsorbents, and natural cosmetics. Italy, China, and the United States led in scientific production. Leaves (7.0%) and roots (0.9%) were significantly underexplored despite their bioactive potential.

Discussion: The findings demonstrate a growing global interest in the valorization of C. sativa residues, with promising applications in bioeconomy, regenerative agriculture, phytoremediation, and energy transition. The integration of traditional knowledge and green technologies is a key strategy to enhance sustainability and socioterritorial inclusion. Nonetheless, regulatory gaps and a lack of robust clinical and toxicological studies limit the use of by-products in food and feed chains.

Conclusion: The residual biomass of C. sativa holds high technological, environmental, and economic value. Strategic valorization demands regulatory advancement, the development of green technologies, and the strengthening of multidisciplinary research. Industrial Cannabis emerges as a driver of ecological, social, and economic transformation toward sustainable circular production systems.”

https://pubmed.ncbi.nlm.nih.gov/41652844

https://journals.sagepub.com/doi/10.1177/25785125261421439

Harnessing Cannabis sativa as a dual-use platform for biohydrogen production and pharmaceutical synthesis: a hypothesis and theory

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“Cannabis sativa, long established as a cornerstone of the pharmaceutical and industrial fiber markets, represents a radical and underexplored platform for renewable energy innovation.

In this Hypothesis and Theory framework, we introduce a novel, patented (Provisional Patent No. 63916615) dual-use bio-refinery paradigm. This model harnesses engineered cannabis photosynthesis to drive green hydrogen production without compromising its established value as a high-yield medicinal crop.

By strategically redirecting photosynthetic electron flow toward oxygen-protected hydrogenase activity, it is possible to generate molecular hydrogen at commercially relevant scales while maintaining plant viability.

Unique to this model is the ability to leverage over $10 billion in existing controlled-environment agriculture (CEA) infrastructure, bypassing the capital-intensive barriers that have hindered traditional algal biohydrogen systems. We outline a tripartite circular economy strategy that integrates hydrogen capture during the vegetative phase with the subsequent harvest of therapeutic cannabinoids and industrial biomass.

This convergence of synthetic biology, clean energy, and biomedicine positions cannabis as a uniquely versatile multipurpose crop capable of fueling both the pharmaceutical industry and the global transition to a sustainable hydrogen economy.”

https://pubmed.ncbi.nlm.nih.gov/42245109

“The global transition toward a net-zero carbon economy necessitates the development of scalable, carbon-negative energy sources. While hydrogen (H2) is a premier clean energy carrier, biological production methods have traditionally struggled with economic viability due to low feedstock density and high infrastructure costs. We propose that Cannabis sativa, a crop already optimized for high-density biomass and metabolic output, serves as the ideal biological “factory” to overcome these hurdles.”

“Cannabis sativa stands at the intersection of the most disruptive shifts in modern industry: the legalization of medicinal biotechnologies and the urgent need for carbon-negative energy transition.

By adopting this patented dual-use framework, we can transform one of the world’s most valuable crops into an engine for a sustainable, hydrogen-powered future.”

“Collaborative frameworks between synthetic biologists, agricultural engineers, and regulatory bodies will be essential to advance this platform toward commercial viability.”

https://www.frontiersin.org/journals/plant-science/articles/10.3389/fpls.2026.1833491/full