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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

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

The Use of Cannabis sativa L. for Pest Control: From the Ethnobotanical Knowledge to a Systematic Review of Experimental Studies

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“Background: Despite the benefits that synthetic pesticides have provided in terms of pest and disease control, they cause serious long-term consequences for both the environment and living organisms. Interest in eco-friendly products has subsequently increased in recent years. 

Methods: This article briefly analyzes the available ethnobotanical evidence regarding the use of Cannabis sativa as a pesticide and offers a systematic review of experimental studies. 

Results: Our findings indicate that both ethnobotanical and experimental procedures support the use of C. sativa as a pesticide, as remarkable toxicity has been observed against pest organisms. The results included in the systematic review of experimental studies (n=30) show a high degree of heterogeneity, but certain conclusions can be extracted to guide further research. For instance, promising pesticide properties were reported for most of the groups of species tested, especially Arachnida and Insecta; the efficacy of C. sativa as a pesticide can be derived from a wide variety of compounds that it contains and possible synergistic effects; it is crucial to standardize the phytochemical profile of C. sativa plants used as well as to obtain easily reproducible results; appropriate extraction methods should be explored; and upper inflorescences of the plant may be preferred for the production of the essential oil, but further studies should explore better other parts of the plant. 

Conclusion: In the coming years, as new findings are produced, the promising potential of C. sativa as a pesticide will be elucidated, and reviews such as the present one constitute useful basic tools to make these processes easier.”

https://pubmed.ncbi.nlm.nih.gov/34612729

https://journals.sagepub.com/doi/10.1089/can.2021.0095

The potential of Allium sativum and Cannabis sativa extracts for anti-tick activities against Rhipicephalus (Boophilus) microplus

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“The efficacy of Allium sativum and Cannabis sativa against Rhipicephalus microplus ticks was evaluated using the adult immersion and the larval packet test. In addition, an in silico approach was utilized by performing a docking study in order to identify the active ingredients from both plants.

Results showed a comparatively high lethal effect of A. sativum and C. sativa on egg laying (index of egg laying = 0.26 and 0.24, respectively), egg hatching (33.5 and 37.1, respectively), and total larval mortality (100%, both), at 40 mg/mL.

When applied to cattle which had been inoculated with larvae ticks, it was observed that a 45% solution of both herbal extracts significantly reduced the number of ticks by 96 h post treatment.

We analyzed in silico 27 known active molecules from both plants and identified in the PubChem database to explore the hypothesis that the effect found on ticks was based on inhibition of acetylcholinesterase (AChE).

Vitamin E and cannabidiol are the most potent AChE inhibitors with docking scores of -15.85 and -14.38, respectively.

Based on these findings, we conclude that A. sativum and C. sativa may potentially be used for the control of R. microplus, and should be further investigated as a potential supplement to or replacement of synthetic acaricides.”

https://pubmed.ncbi.nlm.nih.gov/32886258

https://link.springer.com/article/10.1007/s10493-020-00540-z

Cannabidiol-thiosemicarbazone exhibits dual tyrosinase inhibition and antioxidant activity in human skin-derived cells

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“The search for modulators of melanogenesis with improved biological compatibility remains an active area of investigation, as existing tyrosinase (TYR) inhibitors are often limited by low potency, instability, or cytotoxicity.

Here, we investigated CBD-TSC1, a cannabidiol-based thiosemicarbazone derivative, as a TYR-targeting scaffold.

Structural characterization confirmed a single, stable E-isomer, and pKa profiling together with kinetic analyses indicated reversible mixed-type inhibition of human TYR, involving interactions with both free enzyme and enzyme-substrate complexes. CBD-TSC1 exhibited higher inhibitory activity than CBD and kojic acid under the tested conditions while maintaining low cytotoxicity in G361 melanoma and HaCaT keratinocyte cell lines. In addition, CBD-TSC1 reduced intracellular oxidative stress at low micromolar concentrations. In zebrafish larvae, treatment with CBD-TSC1 resulted in a dose-dependent reduction in melanin content, comparable to that of kojic acid under identical experimental conditions, supporting an association between thiosemicarbazone modification and the observed biological activity.

Overall, CBD-TSC1 demonstrated consistent activity across biochemical, cellular, and zebrafish-based assays under the tested conditions. Although the mechanistic relationship between TYR inhibition, redox modulation, and melanogenesis regulation remains to be fully clarified, the present findings support further investigation of cannabidiol-based thiosemicarbazone derivatives as modulators of TYR-related pathways.”

https://pubmed.ncbi.nlm.nih.gov/42235859

“CBD-TSC1 is a novel cannabidiol-thiosemicarbazone hybrid with dual anti-melanogenic activity.”

“Thiosemicarbazone modification is essential for superior enzymatic and redox performance.”

https://www.sciencedirect.com/science/article/abs/pii/S0960894X26001745?via%3Dihub

Structural characterization and in vitro evaluation of the hypolipidemic activity of the HSP-Ia, a bioactive polysaccharide derived from hemp (Cannabis sativa L.) seeds

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“A novel polysaccharide, HSP-Ia, with a molecular weight of 973.6 kDa, was isolated from hemp (Cannabis sativa L.) seed residues using sequential aqueous extraction, ethanol-induced precipitation, and chromatographic fractionation.

Its structural attributes were determined through methylation profiling and nuclear magnetic resonance spectroscopy. The physicochemical characteristics were examined using X-ray diffraction, atomic force microscopy, scanning electron microscopy, and circular dichroism spectroscopy. The hypolipidemic potential of HSP-Ia was assessed using oxidized low-density lipoprotein-induced RAW264.7 macrophages.

HSP-Ia was predominantly comprised of glucose, with minor proportions of arabinose and galactose. It had a backbone of →6)-α-D-Glcp-(1 → residues with side chains attached at the O-2 and O-3 positions. HSP-Ia possessed an amorphous, nonuniform, and discontinuous morphology, with height distributions ranging from 0.7 to 10.5 nm. It exhibited a zeta potential of -7.4 mV and retained a triple-helix conformation in aqueous media. Notably, HSP-Ia facilitated lipid efflux in foam cells in a dose-dependent manner, associated with the upregulation of Liver X receptor α/ATP-binding cassette transporter signaling pathway.

Overall, these findings enhance the current knowledge of the structural features of hemp seed-derived polysaccharides and underscore the potential application of HSP-Ia as a lipid-modulating agent in the development of functional food products and pharmaceutical formulations.”

https://pubmed.ncbi.nlm.nih.gov/42230038

“Hemp seed, the mature dried seed of Cannabis sativa L., is a prominent traditional medicinal and dietary crop in China, recognized as one of the “Dragon Nine Flavours” and often termed “longevity hemp”. According to traditional Chinese medicine theory, hemp seed is associated with the meridians of the spleen, stomach, and large intestine and is used to lubricate the intestines, alleviate constipation, tonify deficiency, and enhance circulation. Hemp seed is rich in proteins, lipids, vitamins, and carbohydrates and has extensive applications in the food and livestock feed sectors. Contemporary studies support these traditional uses, demonstrating that regular consumption of hemp seed can improve gastrointestinal function and reduce the risk of chronic diseases.”

“This study successfully isolated and characterized a novel polysaccharide, designated HSP-Ia, from hemp (C. sativa L.) seed residues.”

https://www.sciencedirect.com/science/article/abs/pii/S0144861726005564?via%3Dihub

Structural Characterization and Antioxidant Activity of a Crude Polysaccharide from Cannabis sativa Leaves

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“As a traditional Chinese herbal medicine, Cannabis sativa holds broad prospects for application in the development of functional foods, pharmaceutical formulations, dietary supplements, and cosmetic products. However, the bioactivity of polysaccharides in C. sativa has been largely overlooked.

In this study, crude C. sativa leaf polysaccharide (CSLP) was extracted using the hot-water extraction and ethanol-precipitation method.

CSLP contains 64.15 ± 1.96% carbohydrates and 2.13 ± 0.47% protein, with a yield of 6.71 ± 0.84% (w/w). Preliminary structural characterization showed that CSLP was mainly composed of arabinose, galactose, and glucose, with a molecular weight of 28.867 kDa.

CSLP not only demonstrated potential in vitro antioxidant activity against ABTS, DPPH, superoxide anion, and hydroxyl radicals, but also repaired H2O2-induced oxidative damage in RAW 264.7 macrophages by increasing the cellular levels of SOD, CAT, and GSH-Px, and reducing MDA levels. Mechanistically, CSLP possibly modulated the Nrf2/Keap1 signaling pathway in H2O2-stimulated RAW 264.7 cells via upregulating the gene expressions of Nrf2, NQO1, and HO-1, while downregulating Keap1 expression.

These results suggest that CSLP could potentially be used as an antioxidant ingredient in the food, pharmaceutical, and cosmetic industries.”

https://pubmed.ncbi.nlm.nih.gov/42195853

“Hemp (Cannabis sativa L.), a member of the Cannabaceae family, is a plant with both medicinal and edible properties.”

“C. sativa and its extracts exhibit various bioactivities, showing broad application prospects in functional foods, pharmaceutical formulations, dietary supplements, and cosmetics.”

“These findings provide a theoretical foundation for the development of C. sativa leaf polysaccharides as natural antioxidants in the functional food and pharmaceutical sectors.”

https://www.mdpi.com/2304-8158/15/10/1649