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Biomedicines
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Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies
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Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: 31 October 2026 | Viewed by 6831

Editors

Dr. Jan Rožanc

E-Mail Website
Guest Editor
Medical Faculty, University of Maribor, Taborska Ul. 8, 2000 Maribor, Slovenia
Interests: cannabinoids; pharmacology; cancer; targeted therapies; personalized medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Uroš Maver

E-Mail Website
Guest Editor
1. The Institute of Biomedical Sciences, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia
2. The Department of Pharmacology, Faculty of Medicine, University of Maribor, Taborska ulica 8, 2000 Maribor, Slovenia
Interests: polysaccharide-derived biomaterials; advanced drug delivery systems; organ-on-a-chip technologies; biocompatibility and cellular interactions; translational tissue engineering
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue, which will focus on the emerging therapeutic potential of cannabinoids in diverse disease contexts. With increasing scientific interest in cannabinoid-based treatments, it is essential to explore their underlying molecular mechanisms, receptor signaling pathways, and promise of personalized approaches in cannabinoid pharmacotherapy.

This Special Issue aims to advance our understanding of how cannabinoids influence disease-modifying processes through receptor-mediated and receptor-independent mechanisms. Additionally, it aligns with the journal’s scope by addressing pharmacological innovations, drug development, and translational strategies in personalized medicine.

We welcome original research articles and reviews addressing areas including (but not limited to) the following:

  • Cannabinoid receptor biology (CB1, CB2, TRP channels, PPARs, GPR55, GPR18, etc.);
  • The endocannabinoid system in health and disease;
  • The cannabinoid modulation of inflammation, immunity, pain, metabolism, and/or neurodegeneration;
  • Anticancer mechanisms and tumor-specific cannabinoid effects;
  • Pharmacokinetics, delivery systems, and formulation strategies for cannabinoids;
  • Pharmacogenomics and interindividual variability in cannabinoid response;
  • Combination therapies involving cannabinoids and standard treatments;
  • Clinical trials and real-world data on cannabinoid efficacy and safety;
  • Novel synthetic or plant-derived cannabinoids;
  • Systems biology, omics approaches, and AI-driven cannabinoid drug discovery.

We look forward to receiving your contributions.

Dr. Jan Rožanc
Dr. Uroš Maver
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cannabinoids
  • endocannabinoid system
  • cancer
  • pain
  • inflammation
  • personalized medicine
  • receptor signaling
  • therapeutic development
  • drug delivery
  • pharmacogenomics
  • systems pharmacology

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (6 papers)

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Research

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21 pages, 8356 KB  
Article
Cannabis Oil and Exploratory Gut–Immune Signatures During Breast Cancer Chemotherapy: A Randomized Pilot Trial
by May Soe Thu, Thunnicha Ondee, Barry J. Campbell, Joanne L. Fothergill, Mawin Vongsaisuwon, Chanida Vinayanuwattikun, Kamonwan Banchuen, Sunchai Payungporn, Phanupong Phutrakool, Preecha Nootim, Pajaree Chariyavilaskul, Kulthanit Wanaratna, Krit Pongpirul and Nattiya Hirankarn
Biomedicines 2026, 14(6), 1367; https://doi.org/10.3390/biomedicines14061367 - 17 Jun 2026
Viewed by 638
Abstract
Background: Approximately 42% of breast cancer patients report cannabis use for chemotherapy-related symptom relief, yet its impact on the gut–immune axis remains unexplored. This trial evaluated the feasibility of monitoring short-chain fatty acids (SCFAs) and systemic cytokines as exploratory biomarkers during cannabis oil [...] Read more.
Background: Approximately 42% of breast cancer patients report cannabis use for chemotherapy-related symptom relief, yet its impact on the gut–immune axis remains unexplored. This trial evaluated the feasibility of monitoring short-chain fatty acids (SCFAs) and systemic cytokines as exploratory biomarkers during cannabis oil intervention. Method: In a double-blind, placebo-controlled pilot trial, women with breast cancer (n = 10) receiving chemotherapy were randomized to cannabis oil (n = 6) or placebo (n = 4) for 12 weeks. Fecal SCFAs and plasma cytokines were analyzed in paired samples. Results: Dietary stability was systematically assessed using a food frequency questionnaire, with stability defined as <30% shift in functional protein and fiber indices. High dietary stability was confirmed, with all participants maintaining consistent intake of fermentation substrates. Numerical trends, none reaching statistical significance (all p > 0.05), were observed in both exploratory endpoints. Fecal short-chain fatty acid profiling revealed a descriptive numerical reduction in the proteolytic dysbiosis marker iso-butyric acid within the cannabis arm compared with a marginal increase in placebo. Directionally, the cannabis group demonstrated greater median reductions in inflammatory cytokines such as IL-6, IL-8, IL-1β, and TNF-⍺ whereas the placebo group exhibited persistent or heterogeneous profiles. Conclusions: These directional trends toward reduced proteolytic metabolites and attenuated systemic cytokines suggest possible associations between cannabis oil exposure and exploratory gut microbial and immune biomarkers. Given the small pilot sample size, these hypothesis-generating findings lack formal statistical power but warrant adequately powered confirmatory trials. Full article
(This article belongs to the Special Issue Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies)
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12 pages, 2076 KB  
Article
The Effects of CB2R Activation on Inflammatory Pathways in Dermatomyositis
by Rohan Dhiman, Ahmed Eldaboush, Navin Vijayarangan, Darae Kang, Nilesh Kodali, DeAnna Diaz, Caroline Stone, Rui Feng and Victoria P. Werth
Biomedicines 2026, 14(6), 1296; https://doi.org/10.3390/biomedicines14061296 - 7 Jun 2026
Viewed by 374
Abstract
Background/Objectives: Dermatomyositis is an autoimmune disease with heterogeneous symptoms and many potential drivers. Nonpsychoactive cannabinoids have shown promise in treating some subtypes of DM; however, the reasons behind this were unclear. In this project, we tested the effects of CB2R activation on PBMCs [...] Read more.
Background/Objectives: Dermatomyositis is an autoimmune disease with heterogeneous symptoms and many potential drivers. Nonpsychoactive cannabinoids have shown promise in treating some subtypes of DM; however, the reasons behind this were unclear. In this project, we tested the effects of CB2R activation on PBMCs from amyopathic and classic DM patients to determine its anti-inflammatory effects on pathways biologically relevant to DM. Methods: We determined the % CB2R positivity and intracellular cytokines in PBMCs from amyopathic DM and classic DM patients. CB2R positivity was determined by analyzing patient PBMCs via flow cytometry. PBMCs were stimulated by dsRNA for RIG1, dsDNA for cGAS, LPS for TLR4, and LPS/ATP for NLRP3, with and without CB2R pretreatment, and IFNβ, IFNγ, p65 NFkB, and pSTING levels were used as markers of pathway activation. The CB2R agonist JWH133 was used to pretreat PBMCs before stimulation. Results: Amyopathic DM PBMCS were found to be 101.3% more positive for CB2R compared to classic DM PBMCS (p < 0.05). In amyopathic DM PBMCs stimulated by LPS/ATP to target the NLRP3 inflammasome, CB2R activation resulted in a significant reduction in IFNβ MFI for MoDCs (p < 0.05) and Macs (p < 0.05), with a similar trend observed in cDCs relative to classic DM PBMCS. On the other hand, no difference in IFNβ response to CB2R activation was observed across all cell types investigated between classic and amyopathic DM PBMCs stimulated with LPS only to target TLR4. Conclusions: Amyopathic DM PBMCs were significantly more positive for CB2R and had better anti-inflammatory responses to CB2R activation for many inflammatory pathways implicated in DM. Full article
(This article belongs to the Special Issue Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies)
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13 pages, 1935 KB  
Article
Cytotoxicity of Cannabinoids in Combination with Traditional Lymphoma Chemotherapeutic Drugs Against Non-Hodgkin’s Lymphoma
by Saba Omer, Mahmoud Mansour, Satyanarayana R Pondugula, Muralikrishnan Dhanasekaran, Brad Matz, Omer Khan and Dawn Boothe
Biomedicines 2026, 14(1), 3; https://doi.org/10.3390/biomedicines14010003 - 19 Dec 2025
Cited by 2 | Viewed by 1446
Abstract
Background: Cannabinoids (CBs) are FDA-approved for mitigating chemotherapy-induced side effects such as pain, nausea, and loss of appetite. Beyond palliative care, CBs exhibit anti-tumor properties in various cancers, including non-Hodgkin’s lymphoma (NHL). Previously, we demonstrated the cytotoxic effect of endogenous and exogenous [...] Read more.
Background: Cannabinoids (CBs) are FDA-approved for mitigating chemotherapy-induced side effects such as pain, nausea, and loss of appetite. Beyond palliative care, CBs exhibit anti-tumor properties in various cancers, including non-Hodgkin’s lymphoma (NHL). Previously, we demonstrated the cytotoxic effect of endogenous and exogenous cannabinoids on human and canine B- and T-cell-type NHL cell lines. The purpose of this study was to establish the cytotoxic effect of cannabinoids in combination with the components of CHOP and lomustine. This traditional NHL chemotherapy regimen comprises cyclophosphamide, doxorubicin, vincristine, and prednisolone. Methods: In this study, we studied three cannabinoids, one from each of the three major categories of cannabinoids (endocannabinoid AEA, phytocannabinoid CBD, and synthetic cannabinoid WIN-55 212 22). Each cannabinoid was selected based on potency, as determined in our previous experiments. For the combination, we used five NHL chemotherapy drugs. We analyzed the cytotoxicity of each drug alone and in combinations using canine malignant B-type NHL cell line 1771 and a colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide) cell proliferation assay and combination index (CI) based on the Chou–Talalay method. Results: Our results demonstrate that the cytotoxic effects of all traditional NHL chemotherapy drugs are synergistically enhanced (interaction with CI < 1) by each of the three cannabinoids at sub-IC50 concentrations. Conclusions: This work provides a proof of concept for using cannabinoids and traditional NHL drugs in combination to reduce the dose, and thereby potentially reducing the toxicity, of chemotherapeutic drugs and increasing the survival benefit in lymphoma clinical translation studies, offering a significant advancement in cancer treatment. Full article
(This article belongs to the Special Issue Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies)
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Review

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27 pages, 7181 KB  
Review
The Endocannabinoid System in Neuropsychiatric Disorders: Mechanisms, Dysregulation and Therapeutic Potential
by Timur Mušić and Tamara Lah Turnšek
Biomedicines 2026, 14(5), 968; https://doi.org/10.3390/biomedicines14050968 - 23 Apr 2026
Cited by 1 | Viewed by 1294
Abstract
The endocannabinoid system (ECS) is a fundamental regulator of brain and body homeostasis, integrating neural, immune, and stress-related signaling pathways. Dysregulation of ECS components, including cannabinoid receptors (CB1 and CB2), endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes (FAAH [...] Read more.
The endocannabinoid system (ECS) is a fundamental regulator of brain and body homeostasis, integrating neural, immune, and stress-related signaling pathways. Dysregulation of ECS components, including cannabinoid receptors (CB1 and CB2), endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes (FAAH and MAGL), has been increasingly implicated in the pathophysiology of neuropsychiatric disorders, including mood, anxiety, psychotic, stress-related, and eating disorders. Altered endocannabinoid signaling contributes to maladaptive stress responses, emotional dysregulation, and impaired synaptic plasticity, highlighting the role of the ECS as a core integrative mechanism. Therapeutic strategies targeting ECS, particularly through FAAH inhibition and the use of plant-derived cannabinoids, such as cannabidiol (CBD), show promise in restoring endogenous homeostasis while minimizing the adverse cognitive and affective effects associated with direct CB1 activation. ECS function and treatment response are further influenced by genetic polymorphisms in CNR1, CNR2, FAAH, and MGLL, as well as epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation. Despite these advances, clinical translation remains limited by interindividual variability, the complexity of ECS interactions, and the relatively small size of existing clinical studies. Future research integrating longitudinal clinical trials with multi-omics approaches is essential to support the development of evidence-based, personalized interventions. Overall, understanding ECS mechanisms and dysregulation provides a valuable framework for the development of targeted therapies in neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies)
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38 pages, 2122 KB  
Review
Cannabinoid-Driven Rewiring of GPCR and Ion Channel Signaling in Lung Cancer
by Didik Setyo Heriyanto, Fahrul Nurkolis, Jinwon Choi, Sohyun Park, Min Choi, Raymond Rubianto Tjandrawinata, Amama Rani, Moon Nyeo Park, Min-Jin Kwak, Bum Sang Shim and Bonglee Kim
Biomedicines 2026, 14(4), 856; https://doi.org/10.3390/biomedicines14040856 - 9 Apr 2026
Cited by 1 | Viewed by 1437
Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion [...] Read more.
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer accounting for the majority of cases and exhibiting persistent challenges related to therapy resistance and metastatic progression. Increasing evidence indicates that dysregulated G protein-coupled receptor signaling and ion channel activity function cooperatively as master regulators of tumor cell proliferation, migration, survival, and therapeutic response. Cannabinoids, including phytocannabinoids such as delta-9-tetrahydrocannabinol and cannabidiol, as well as endogenous endocannabinoids, are uniquely positioned to modulate both G protein-coupled receptors and ion channels, thereby influencing key oncogenic signaling networks. This review synthesizes current knowledge on the role of major ion channel families, including transient receptor potential channels, potassium channels, and sodium channels, and principal G protein-coupled receptor pathways involved in lung cancer progression. We further discuss how cannabinoids reprogram these interconnected signaling systems through canonical cannabinoid receptors, non-classical targets such as G protein-coupled receptor 55 and adenosine receptors, and direct modulation of ion channel activity. Special attention is given to G protein-coupled receptor–ion channel coupling within membrane microdomains and to the capacity of cannabinoids to act as biased ligands, redirecting downstream pathways, such as the phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin and epidermal growth factor receptor signaling, toward apoptosis and reduced metastatic potential. Emerging strategies, including cannabinoid-based combination therapies, selective receptor biasing, and targeted delivery systems, are also highlighted. Altogether, cannabinoid-driven rewiring of G protein-coupled receptor and ion channel signaling represents a promising mechanistic framework for developing innovative therapeutic approaches against lung cancer. Full article
(This article belongs to the Special Issue Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies)
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17 pages, 1073 KB  
Review
Cannabinoids in Motor Control: From Receptor Distribution to Motor Disorders
by Dan Faganeli and Metoda Lipnik-Stangelj
Biomedicines 2026, 14(4), 844; https://doi.org/10.3390/biomedicines14040844 - 8 Apr 2026
Viewed by 829
Abstract
Cannabinoid receptors occupy strategic control nodes within motor circuitry, making them potential targets for modulating different motor manifestations. They are positioned both within basal ganglia circuits that regulate movement and within spinal circuits that control skeletal muscle tone. Consequently, cannabinoids have been studied [...] Read more.
Cannabinoid receptors occupy strategic control nodes within motor circuitry, making them potential targets for modulating different motor manifestations. They are positioned both within basal ganglia circuits that regulate movement and within spinal circuits that control skeletal muscle tone. Consequently, cannabinoids have been studied across diverse motor disorders, most notably in movement disorders and tone disorders, particularly those resulting in spasticity. Because motor control spans multiple anatomically and functionally distinct levels, relating cannabinoid signaling to effects on motor function is not straightforward. Limited understanding of cannabinoid receptor distribution has led to cannabinoids being tested even in disorders where receptor localization would predict little or no benefit. Mapping receptor distribution within individual motor circuits and integrating them with their pharmacological effects can help anticipate how cannabinoid signaling shapes motor output. Combined with characteristic motor manifestations, one can identify motor disorders in which cannabinoids may have therapeutic value. In this review, we integrate existing evidence to place cannabinoid receptors within key motor pathways, ranging from basal ganglia circuits controlling movement to peripheral mechanisms governing muscle tone. We consider both cannabinoid 1 receptor (CB1R) and cannabinoid 2 receptor (CB2R), with CB2R gaining attention only recently for its potential relevance within the central nervous system. Building on this framework, we infer how cannabinoids acting at these sites may modulate motor control, and consequently, influence motor manifestations across major motor disorders. Finally, we examine how these distribution-based expectations align with available clinical observations. Full article
(This article belongs to the Special Issue Cannabinoids in Therapeutics: Mechanisms, Signaling Pathways and Personalized Treatment Strategies)
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