Optimization and Evaluation of Cannabis-Based Magistral Formulations: A Path to Personalized Therapy

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“Introduction: The official implementation of pharmaceutical-grade cannabis raw materials for medicinal use has permitted doctors to prescribe and pharmacists to prepare cannabis-based formulations. The objective of the pharmaceutical development and manufacturing process optimization work was to propose a suppository formulation containing doses of 25 mg and 50 mg of tetra-hydrocannabinol (∆-9-THC) as an alternative to existing inhalable or orally administered formulations. The formulation could be used for rectal or vaginal administration, thereby providing dosage control in the treatment of endometriosis and other conditions involving pain. In this study, two substrates from suppositories with standardized Cannabis extractum normatum (CEX) were used: cocoa butter and Witepsol® H15.

Materials and methods: The long-term stability of CEX was investigated over a period of up to 24 months. The concentrations of ∆-9-THC, cannabidiol (CBD), and cannabinol (CBN) were determined using an HPLC method. Furthermore, the water content of the extract, the ethanol residue, and the microbiological purity were determined. The pharmaceutical properties of CEX-incorporated suppositories, namely content uniformity, hardness, softening time, total deformation time, disintegration time, and the release profile of ∆-9-THC, CBD, and CBN, were evaluated in order to develop optimal preparation procedures for pharmacists.

Results and discussion: Following a 24-month stability study on CEX, no significant alterations in component content were observed beyond the specified requirements. The disintegration time, total deformation time, and hardness of the suppositories based on Witepsol® H15 with CEX were found to be longer and higher, respectively, than those of suppositories formulated with cocoa butter. In vitro studies demonstrated that suppositories prepared with Witepsol® H15 exhibited superior release of ∆-9-THC compared to those prepared with cocoa butter.

Conclusions: We suggest that pharmacists making prescription drugs in a pharmacy setting in the form of medical marijuana suppositories will receive a better release profile of the drug by choosing Witepsol® H15 as a substrate.”

https://pubmed.ncbi.nlm.nih.gov/39861136/

https://www.mdpi.com/1424-8247/18/1/73

Anti-Inflammatory Effects of Cannabigerol In Vitro and In Vivo Are Mediated Through the JAK/STAT/NFκB Signaling Pathway

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“Cannabinoid compounds have potential as treatments for a variety of conditions, with cannabigerol (CBG) being known for its anti-inflammatory properties.

In this study, we investigated the effects of CBG in a cellular model of 1-chloro-2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD).

In the cellular model, we confirmed the cytotoxicity of CBG and downregulated the expression of inflammatory markers CCL26IL1BIL6, and TNF (p < 0.001). In the mouse model, clinical, histological, and immunological changes were analyzed.

The results showed that CBG improved dermatitis severity score, epidermal thickness, and mast cell count and reduced inflammatory cytokines (TslpIl1bIl4Il6Il13Il17Il18Il22, and Il33) by qRT-PCR (p < 0.001). Western blot results showed modulated changes in JAK1, JAK2, TYK2, STAT1, STAT2, STAT3, p-STAT3, STAT6, and p-STAT6 (p < 0.05). Subsequently, p-IκBα, NF-κB, and p-NF-κB signaling factors were also reduced (p < 0.05), with corresponding changes in skin barrier factors.

The results of this study indicate that CBG effectively alleviates AD-like symptoms and suggest the potential of CBG as a therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/39851511/

https://www.mdpi.com/2073-4409/14/2/83

Unveiling Cannabinoids and Terpenes Diversity in Cannabis sativa L. from Northern India for Future Breeding Strategies

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“Cannabis sativa L. is an important medicinal plant with high commercial value.

In recent years, the research interest in cannabidiol (CBD) and terpene-rich cannabis has been rapidly expanding due to their high therapeutic potential.

The present study aims to explore the phytocannabinoids and terpenes diversity in Cannabis sativa collected from different parts of northern India.

Our findings revealed that the cannabinoids and terpenes synthesize together in capitate stalked and capitate sessile glandular trichomes, whereas bulbous glands synthesize only terpenes. The North Indian C. sativa is mainly dominated by tetrahydrocannabinol (THC). The CBD-rich plant diversity is nominal (1.11%) in studied north Indian C. sativa. The essential oil profiling reveals (E)-caryophyllene (10.30-36.80%) as the major constituent, followed by α-humulene (0.50-15.29%) and α-bisabolol (0.00-16.40%) in the North Indian population.

The cannabinoids and terpenes content showed significant diversity among and within the five studied populations. The correlation analysis between cannabinoids and terpenes indicates that α-pinene, β-pinene, and limonene positively correlated with CBD content. Similarly, α- and β-selinene correlate positively with tetrahydrocannabinolic acid (THCA) content. This study could help to identify the key cultivars from India and establish a consistent chemotype for future breeding programs.”

https://pubmed.ncbi.nlm.nih.gov/39853702/

https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202402278

Oral cannabidiol did not impair learning and memory in healthy adults

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“Background: The effect of oral Cannabidiol (CBD) on interference during learning and memory (L&M) in healthy human volunteers has not been studied.

Method: A two-arm crossover, randomized, double-blind, placebo-controlled trial was conducted at Colorado State University Pueblo (CSU Pueblo) to evaluate the effects of 246 mg oral CBD on L&M in healthy adults. Among 57 healthy volunteers enrolled, 35 were included in the analyses. For assessment of L&M, Montreal Cognitive Assessment (MOCA) was used to evaluate verbal baseline cognitive function; RAVLT-R tests (List A and List B recalls, Proactive and Retroactive Interference ratios, and Forgetting Speed ratio) were used to evaluate verbal declarative memory; and total prose recall was used to evaluate verbal logical memory. Linear Mixed Models with Bonferroni Corrections were used to compare L&M results between primary outcomes (CBD vs. placebo) and secondary demographic outcomes, with a two-tailed statistical significance of P < 0.05.

Results: CBD administration did not affect any of the dependent variables measured compared to the placebo group. There were no effects of THC, history of CBD use, or sex on CBD’s modulation of L&M. However, a highly significant interaction effect between treatment groups (CBD vs. placebo) and age of subjects was observed for the PI ratio (P = 0.008; n = 35).

Conclusions: The results of this study suggest that administration of oral CBD alone does not significantly impair L&M in healthy adults. However, age might influence CBD related modulation of proactive interference during human L&M. Future research involving a larger group of older adults is needed to confirm this potential effect.”

https://pubmed.ncbi.nlm.nih.gov/39849639/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00262-2

Mechanisms and strategic prospects of cannabinoids use: Potential applications in antimicrobial food packaging-A review

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“This review focuses on antimicrobial packaging for food safety, critically examining the activity and efficacy of cannabinoids against commonly found microorganisms and exploring their antimicrobial mechanisms.

Specifically, the review considers cannabinoids derived from industrial hemp plants, which are characterized by low levels of psychoactive components. It also outlines viable strategies to control the sustained release of cannabinoids from the packaging, enabling extended storage and enhanced safety of food products.

Research demonstrates that cannabinoids are effective against both foodborne bacteria and fungi, with their antimicrobial action primarily attributed to microbial membrane instability.

Cannabinoids can be utilized to prepare effective antimicrobial films and edible coatings; however, the number of studies in this area remains limited.

The potential of cannabinoids to contribute to intelligent packaging systems is also discussed, with an emphasis on the regulatory aspects and challenges associated with incorporating cannabinoids into food packaging. Finally, the review identifies future research directions to address current limitations and advance hemp-based antimicrobial food packaging solutions.”

https://pubmed.ncbi.nlm.nih.gov/39840610/

https://ift.onlinelibrary.wiley.com/doi/10.1111/1541-4337.70113

Therapeutic potential of cannabidiol polypharmacology in neuropsychiatric disorders

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“Cannabidiol (CBD), the primary non-intoxicating compound in cannabis, is currently approved for treating rare, treatment-resistant seizures.

Recent preclinical research suggests that CBD’s multifaceted mechanisms of action in the brain, which involve multiple molecular targets, underlie its neuroprotective, anti-inflammatory, anxiolytic, and antipsychotic effects. Clinical trials are also exploring CBD’s therapeutic potential beyond its current uses.

This review focuses on CBD’s polypharmacological profile and discusses the latest preclinical and clinical findings regarding its efficacy in neuropsychiatric disorders.

Existing evidence suggests that CBD’s ability to modulate multiple signaling pathways may benefit neuropsychiatric disorders, and we propose further research areas to clarify its mechanisms, address data gaps, and refine its therapeutic indications.”

https://pubmed.ncbi.nlm.nih.gov/39837749/

https://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(24)00271-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0165614724002712%3Fshowall%3Dtrue

Exploring the antifungal potential of Cannabis sativa-derived stilbenoids and cannabinoids against novel targets through in silico protein interaction profiling

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“Cannabinoid and stilbenoid compounds derived from Cannabis sativa were screened against eight specific fungal protein targets to identify potential antifungal agents.

The proteins investigated included Glycosylphosphatidylinositol (GPI), Enolase, Mannitol-2-dehydrogenase, GMP synthase, Dihydroorotate dehydrogenase (DHODH), Heat shock protein 90 homolog (Hsp90), Chitin Synthase 2 (CaChs2), and Mannitol-1-phosphate 5-dehydrogenase (M1P5DH), all of which play crucial roles in fungal survival and pathogenicity.

This research evaluates the binding affinities and interaction profiles of selected cannabinoids and stilbenoids with these eight proteins using molecular docking and molecular dynamics simulations. The ligands with the highest binding affinities were identified, and their pharmacokinetic profiles were analyzed using ADMET analysis. The results indicate that GMP synthase exhibited the highest binding affinity with Cannabistilbene I (-9.1 kcal/mol), suggesting hydrophobic solid interactions and multiple hydrogen bonds. Similarly, Chitin Synthase 2 demonstrated significant binding with Cannabistilbene I (-9.1 kcal/mol). In contrast, ligands such as Cannabinolic acid and 8-hydroxycannabinolic acid exhibited moderate binding affinities, underscoring the variability in interaction strengths among different proteins.

Despite promising in silico results, experimental validation is necessary to confirm therapeutic potential. This research lays a crucial foundation for future studies, emphasizing the importance of evaluating binding affinities, pharmacokinetic properties, and multi-target interactions to identify promising antifungal agents.”

https://pubmed.ncbi.nlm.nih.gov/39834844/

“This study provides a comprehensive assessment of how selected cannabinoid and stilbenoid compounds interact with eight different fungal proteins, highlighting the promising potential of these compounds as antifungal agents. In conclusion, this study highlights the therapeutic potential of cannabinoids and stilbenoids and provides a solid foundation for the development of new antifungal therapies.”

https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2024.1515424/full

Investigation of Cannabidiol’s Protective Effects on Cadmium-Induced Toxicity in Mice

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“Current chelation treatments used for cadmium poisoning may cause some serious side effects. Thus, safer novel treatments could be promising for clinical use.

This study evaluated the effects of cannabidiol on Cd toxicity.

Four groups of 10 mice were formed: Groups I and III were cadmium-free, while groups II and IV received 50 mg/L cadmium in drinking water. Groups III and IV received daily cannabidiol (25 mg/kg) via intragastric gavage. After 30 days, the animals were killed, and blood and tissue samples were collected. Oxidative stress and inflammation markers, including glutathione, catalase, myeloperoxidase, TNF-α, IL-1β and IL-6, were analysed using ELISA. Additionally, histological evaluations of the liver, kidney and testis were performed. Cadmium exposure reduced glutathione and catalase levels in the blood, liver, kidney and testis, while increasing myeloperoxidase.

Cannabidiol mitigated these effects on oxidative stress markers. Cannabidiol also reduced the increase in proinflammatory cytokines. Histopathological analysis revealed reduced liver and kidney damage in cannabidiol-treated groups compared to cadmium-only groups. In addition, histopathological evaluation showed CBD had no protective effect on the testicular tissue against Cd toxicity.

Our results indicate that cannabidiol protects against some toxic effects of cadmium. If confirmed by future studies, cannabidiol may be proposed as a novel treatment for cadmium toxicity.”

https://pubmed.ncbi.nlm.nih.gov/39832793/

“Cadmium (Cd) is a heavy metal that can have toxic effects on multiple organs. Chelation treatments that are used for treating Cd toxicity can have serious side effects, which limit their use. This study aimed to investigate cannabidiol (CBD), a non-psychoactive compound derived from hemp, for its potential to reduce Cd toxicity.

Our experiments on mice showed CBD had significant protective effects against Cd-induced tissue damage in the liver and the kidneys by reducing oxidative stress and inflammation. These findings suggest that CBD can be explored as a safer treatment option for Cd toxicity in a clinical setting.”

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.14131

Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery

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“G protein-coupled receptors (GPCRs) adopt conformational states that activate or inhibit distinct signaling pathways, including those mediated by G proteins or β-arrestins. Biased signaling through GPCRs may offer a promising strategy to enhance therapeutic efficacy while reducing adverse effects.

Cannabinoid receptor 1 (CB1), a key GPCR in the endocannabinoid system, presents therapeutic potential for conditions such as pain, anxiety, cognitive impairment, psychiatric disorders, and metabolic diseases.

This review examines the structural conformations of CB1 coupling to different signaling pathways and explores the mechanisms underlying biased signaling, which are critical for the design of functionally selective ligands. We discuss the structure-function relationships of endogenous cannabinoids (eCBs), phytocannabinoids, and synthetic cannabinoid ligands with biased properties. Challenges such as the complexity of ligand bias screening, the limited availability of distinctly biased ligands, and the variability in receptor signaling profiles in vivo have hindered clinical progress.

Although the therapeutic potential of biased ligands in various clinical conditions remains in its infancy, retrospective identification of such molecules provides a strong foundation for further development. Recent advances in CB1 crystallography, particularly insights into its conformations with G proteins and β-arrestins, now offer a framework for structure-based drug design. While there is still a long way to go before biased CB1 ligands can be widely used in clinical practice, ongoing multidisciplinary research shows promise for achieving functional selectivity in targeting specific pathways.

These progresses could lead to the development of safer and more effective cannabinoid-based therapies in the future.”

https://pubmed.ncbi.nlm.nih.gov/39828030/

https://www.sciencedirect.com/science/article/abs/pii/S0163725825000075?via%3Dihub

∆9-Tetrahydrocannabinol Increases Growth Factor Release by Cultured Adipose Stem Cells and Adipose Tissue in vivo

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“Background: Because of its biocompatibility and its soft and dynamic nature, the grafting of adipose tissue is regarded an ideal technique for soft-tissue repair. The adipose stem cells (ASCs) contribute significantly to the regenerative potential of adipose tissue, because they can differentiate into adipocytes and release growth factors for tissue repair and neovascularization to facilitate tissue survival. The present study tested the effect of administering a chronic low dose of ∆9-tetrahydrocannabinol (THC) on these regenerative properties, in vitro and in vivo.

Methods: Human ASCs were exposed to increasing concentrations of THC. Resazurin conversion was applied to investigate the effect on metabolic activity, cell number was assessed by crystal violet staining, tri-linear differentiation was evaluated by specific colorimetric approaches, and the release of growth factors was analyzed by ELISA. Two groups of mice were treated daily either with a low dose of THC (3 mg/kg) or a vehicle solution. After 3 weeks, adipose tissue was obtained from excised fat deposits, homogenized and tested for growth factor contents.

Results: THC decreased ASC proliferation but increased metabolic activity as well as adipogenic and chondrogenic differentiation. A low concentration of THC (1 µM) enhanced the growth factor release by ASCs. The concentration of these cytokines was also increased in adipose tissue of mice treated with THC.

Conlusion: Our results indicate that chronic activation of the endocannabinoid system promoted differentiation and growth factor release of ASCs, which could be of specific value for enhancing the regenerative potential of adipose tissue.”

https://pubmed.ncbi.nlm.nih.gov/39825991/

“Our findings may offer a new approach for improved application of adipose tissue in regenerative medicine.”

https://link.springer.com/article/10.1007/s13770-024-00692-8