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Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications
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Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: 20 May 2026 | Viewed by 11670

Special Issue Editor

Dr. Grace Blest Hopley

E-Mail Website
Guest Editor
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE5 8AF, UK
Interests: cannabis use; cannabinoid

Special Issue Information

Dear Colleagues,

This Special Issue delves into the molecular mechanisms underlying cannabinoids' therapeutic effects, focusing on detailed mechanistic studies, proof-of-concept research, and comprehensive reviews of their clinical applications. Cannabinoids, particularly through their influence on the endocannabinoid system and other physiological pathways, have shown significant promise in treating diseases and enhancing overall human health.

Their effects on systemic modulation and symptom management have been documented in a growing body of research. Emerging evidence highlights the potential of cannabinoids for addressing a range of health conditions, with trials currently investigating their efficacy in treating epilepsy, psychosis, chronic pain, cancer-related symptoms, and neurodegenerative disorders, to name a few. This Special Issue welcomes submissions that provide rigorous experimental insights and theoretical frameworks, aiming to foster a deeper understanding of cannabinoids' potential in advancing healthcare.

Dr. Grace Blest Hopley
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • cannabinoids
  • endocannabinoid system
  • δ9-tetrahydrocannabinol (THC)
  • cannabidiol (CBD)
  • inflammation
  • chronic pain
  • neurodegenerative disorders
  • epilepsy
  • psychosis
  • cancer-related symptoms

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Published Papers (5 papers)

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Research

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15 pages, 2652 KB  
Article
Cannabidiol as a Prophylactic Agent Against Glioblastoma Growth: A Preclinical Investigation
by Lei P. Wang, Bidhan Bhandari, Sahar Emami Naeini, Breanna Hill, Hannah M. Rogers, Jules Gouron, Nayeli Perez-Morales, Aruba Khan, William Meeks, Ahmed El-Marakby, Nancy Young, Fernando L. Vale, Salman Ali, Gerald Wallace, Jack C. Yu, Ali S. Arbab, Évila Lopes Salles and Babak Baban
Int. J. Mol. Sci. 2026, 27(2), 757; https://doi.org/10.3390/ijms27020757 - 12 Jan 2026
Viewed by 352
Abstract
Glioblastoma (GBM) remains one of the most lethal brain tumors, with current therapies offering limited benefits and high relapse rates. This study presents the first preclinical evidence that pretreatment with inhaled cannabidiol (CBD) before tumor establishment can markedly inhibit GBM progression. We hypothesized [...] Read more.
Glioblastoma (GBM) remains one of the most lethal brain tumors, with current therapies offering limited benefits and high relapse rates. This study presents the first preclinical evidence that pretreatment with inhaled cannabidiol (CBD) before tumor establishment can markedly inhibit GBM progression. We hypothesized that early CBD exposure could prime the immune and molecular landscape to resist tumor growth. C57BL/6 mice were pretreated with inhaled CBD for 3 or 14 days, or with placebo, prior to intracranial implantation of glioblastoma cells. Tumor growth, immune checkpoint expressions (IDO, PD-L1), and key biomarkers (MGMT, Ki67) were analyzed to evaluate tumor dynamics and immune modulation. Fourteen-day CBD pretreatment significantly reduced tumor burden compared with both placebo and 3-day CBD groups, accompanied by decreased IDO, PD-L1, MGMT, and Ki67 expression, which are signatures of a less aggressive tumor phenotype. These findings suggest that prolonged CBD exposure can precondition the tumor microenvironment toward an anti-tumor state, improving disease control and potentially lowering relapse risk. This study introduces a novel concept of CBD pretreatment as an immune-modulatory strategy with high translational potential for glioblastoma management. Full article
(This article belongs to the Special Issue Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications)
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16 pages, 2576 KB  
Article
Skin-Whitening Effects of Cannabinol (CBN) Through Melanin Inhibition in B16F10 Melanoma Cells
by Joon-Hee Han, Jong-Hui Kim, Min Hong, Byeong-Ryeol Ryu, Jung Dae Lim, Keun-Cheol Kim and Tae-Hyung Kwon
Int. J. Mol. Sci. 2025, 26(21), 10752; https://doi.org/10.3390/ijms262110752 - 5 Nov 2025
Viewed by 1433
Abstract
Melanogenesis, the key biological process underlying skin hyperpigmentation, is tightly regulated by complex molecular signaling pathways. Consequently, targeting molecular regulators of this pathway is a crucial strategy for developing effective skin-whitening agents. Cannabinol (CBN), a minor cannabinoid, has been largely unexplored owing to [...] Read more.
Melanogenesis, the key biological process underlying skin hyperpigmentation, is tightly regulated by complex molecular signaling pathways. Consequently, targeting molecular regulators of this pathway is a crucial strategy for developing effective skin-whitening agents. Cannabinol (CBN), a minor cannabinoid, has been largely unexplored owing to its role in modulating skin pigmentation. This study aimed to elucidate the molecular mechanisms of CBN’s depigmenting effects using an α-MSH-induced B16F10 melanoma cell model. High-purity CBN was obtained via conversion of cannabidiol (CBD) and confirmed by HPLC. CBN significantly inhibited melanin synthesis and tyrosinase activity in a concentration-dependent manner, without any cytotoxicity. Furthermore, we investigated CBN’s impact on the melanogenesis signaling cascade. Our analysis revealed that CBN significantly downregulated the mRNA and protein levels of key melanogenic master regulators, including MITF, TYR, TYRP1, and TYRP2. Importantly, we also observed that CBN treatment selectively suppressed the protein phosphorylation of upstream signaling molecules such as p38 and JNK MAP kinases and NF-κB, while ERK phosphorylation remained unaffected. This finding indicates that its mechanism of action involves the selective modulation of pro-melanogenic signaling components. Collectively, these findings demonstrate that CBN effectively modulates the melanogenesis signaling pathway by targeting both upstream kinases and downstream melanogenic genes. These findings suggest that CBN holds great promise as a bioactive agent for skin-whitening applications and warrants further research to confirm its clinical efficacy and safety. Full article
(This article belongs to the Special Issue Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications)
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22 pages, 3063 KB  
Article
Benzo[d]imidazole–Naphthalen-Arylmethanone Regioisomers as CB1 Ligands: Evaluation of Agonism via an Indirect Cytotoxicity-Based Approach
by Analia Young Hwa Cho, Renato Burgos Ravanal, Valeria Zuñiga Salazar, Marco Mellado, Marcos Lorca, David Pessoa-Mahana, Jaime Mella, Germán Günther Sapunar and Javier Romero-Parra
Int. J. Mol. Sci. 2025, 26(20), 9986; https://doi.org/10.3390/ijms26209986 - 14 Oct 2025
Viewed by 638
Abstract
CB1 agonist compounds may be potential drug candidates for the treatment of gliomas, as they have been shown to inhibit tumor cell proliferation, induce apoptosis, and reduce angiogenesis in various preclinical models. Their ability to modulate the endocannabinoid system suggests a promising [...] Read more.
CB1 agonist compounds may be potential drug candidates for the treatment of gliomas, as they have been shown to inhibit tumor cell proliferation, induce apoptosis, and reduce angiogenesis in various preclinical models. Their ability to modulate the endocannabinoid system suggests a promising therapeutic approach for targeting glioma growth and progression. Herein, we report the design, synthesis, biological studies, and bioinformatics assays of novel benzo[d]imidazole–naphthalen-arylmethanone regioisomers with affinity for the CB1 receptor, as well as propose an indirect methodology to evaluate their presumed CB1 agonist activity. Compounds that showed a propensity for binding to the CB1 receptor were regioisomers 4d, 5b, 5e, 5f, and 5f′. Likewise, derivatives that displaced more than 50% of the radioligand [3H]CP-55940 at the CB1 receptor were subjected to in vitro viability experiments. Compounds 4d, 5b, 5e, and 5f′ showed toxicity against U87MG cells (malignant glioma) in a considerable percentage. Notably, compound 5f′ showed CB1 affinity, with a Ki of 2.12 µM, and was selectively toxic to U87MG cells, which highly express the CB1 receptor, while exhibiting no toxicity toward the healthy HEK293 cell line, which expresses both cannabinoid receptors at negligible levels. Docking studies at the CB1 orthosteric site indicate that 5f′ forms π-π interactions, a T-shaped interaction, and hydrogen bonding through the oxygen atom of the furan ring. Biologically, our experimental indirect model-based on a simple viability assay is supported by well-established evidence that activation of CB1 and CB2 receptors by agonists induces cell death and inhibits tumor cell growth. Structurally, we conclude that the presence of a furan ring at the 2-position of the benzo[d]imidazole core is beneficial for the development of new ligands with potential CB1 agonist activity. Full article
(This article belongs to the Special Issue Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications)
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Review

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37 pages, 1280 KB  
Review
The Endocannabinoid System in Human Disease: Molecular Signaling, Receptor Pharmacology, and Therapeutic Innovation
by Matei Șerban, Corneliu Toader and Răzvan-Adrian Covache-Busuioc
Int. J. Mol. Sci. 2025, 26(22), 11132; https://doi.org/10.3390/ijms262211132 - 18 Nov 2025
Cited by 2 | Viewed by 2965
Abstract
The endocannabinoid system (ECS) is a primary regulatory system in human physiology that serves to help maintain homeostasis throughout the nervous system, immune system, and gastrointestinal system. This review has the goal of evaluating the unique opportunity for the ECS to provide a [...] Read more.
The endocannabinoid system (ECS) is a primary regulatory system in human physiology that serves to help maintain homeostasis throughout the nervous system, immune system, and gastrointestinal system. This review has the goal of evaluating the unique opportunity for the ECS to provide a regulatory axis within the microbiota–gut–brain axis, particularly with regard to neurodevelopment, immune tolerance, and gut health. Cannabinoid receptors CB1 and CB2 and endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG have the ability to provide a variety of signaling pathways that can regulate cognitive resilience, emotional tuning, and immune regulation. Because the ECS has the ability to regulate multiple neurochemicals, alter immune cell functions, and maintain gut barriers, the ECS exists at the crossroads of many physiological systems, which also have a predictive role in neurodegenerative disease, chronic inflammation, and mental illness. Our goal is to present the latest and best recent advances in the ECS literature and establish evidence that there exists some modest potential for the therapeutic modulation of the ECS to improve pathological manifestations of cross-system dysregulation. In addition to cellular signaling pathways, the ECS affects other homeostatic processes, such as synaptic plasticity and the level of neuroprotection in the CNS, immune-related homeostasis, and coordinating the composition of gut microbiota. We argue that the ECS represents a suitable new therapeutic target that could modulate dysregulation across these systems more inclusively. This paper aims to emphasize the proposed potential of the ECS’s position in this axis and propose advanced cannabinoid-based interventions as a novel mechanism for developing personalized medicine and health systems through multi-system integration. Full article
(This article belongs to the Special Issue Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications)
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33 pages, 1463 KB  
Review
Molecular Mechanisms of the Endocannabinoid System with a Focus on Reproductive Physiology and the Cannabinoid Impact on Fertility
by Patrycja Kalak, Piotr Kupczyk, Antoni Szumny, Tomasz Gębarowski, Marcin Jasiak, Artur Niedźwiedź, Wojciech Niżański and Michał Dzięcioł
Int. J. Mol. Sci. 2025, 26(15), 7095; https://doi.org/10.3390/ijms26157095 - 23 Jul 2025
Cited by 1 | Viewed by 5777
Abstract
The endocannabinoid system (ECS) is a complex neuromodulatory network involved in maintaining physiological balance through interactions with various neurotransmitter and hormonal pathways. Its key components—cannabinoid receptors (CBRs)—are activated by endogenous ligands and exogenous cannabinoids such as those found in the Cannabis sativa plant. [...] Read more.
The endocannabinoid system (ECS) is a complex neuromodulatory network involved in maintaining physiological balance through interactions with various neurotransmitter and hormonal pathways. Its key components—cannabinoid receptors (CBRs)—are activated by endogenous ligands and exogenous cannabinoids such as those found in the Cannabis sativa plant. Although cannabinoids like cannabidiol (CBD) have garnered interest for their potential therapeutic effects, evidence regarding their safety, particularly for reproductive health, remains limited. This review summarizes the structure and molecular mechanisms of the ECS, its role in reproductive physiology—including its interactions with the hypothalamic–pituitary–gonadal axis (HPG axis), gametogenesis, implantation, and lactation—and the possible consequences of cannabinoid exposure for fertility. In addition, we focus on the involvement of the ECS and cannabinoids in breast cancer, highlighting emerging evidence on their dual role in tumor progression and therapy. These insights emphasize the need for further research to better define the therapeutic potential and risks associated with cannabinoid use in reproductive health and breast cancer. Full article
(This article belongs to the Special Issue Exploring Cannabinoids: Molecular Mechanisms and Potential Therapeutic Applications)
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