Therapeutic Potential of Cannabinoid Receptors Type 1 and 2—Novel Insights for Enhancing the Chance of Clinical Success, 2nd Edition

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 30 June 2026 | Viewed by 1058

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Medicinal Chemistry, F. Hoffmann-La Roche AG, Basel, Switzerland
Interests: medicinal chemistry; chemical biology; endocannabinoid system; inflammation; neurodegenerative diseases
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Dear Colleagues,

The endocannabinoid system (ECS) is an important lipid signaling system ubiquitous to all vertebrates that is involved in mediating the key processes of central and peripheral diseases, including chronic pain, multiple sclerosis, Alzheimer’s disease, obesity, diabetes, and kidney diseases, all of which cause a significant health and socioeconomic burden. The ECS’s key elements include lipid signaling molecules, termed ‘endocannabinoids’, their respective receptors, biosynthetic and hydrolytic enzymes, and transporters. In particular, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) hold great therapeutic potential. While Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most prominent plant-derived cannabinoids, numerous other phytocannabinoids and synthetic ligands targeting CB1R and CB2R have been identified and generated within recent decades. Although some of these ligands have been evaluated in humans, their clinical success is still limited. Recent developments, including the generation of CB1R and CB2R’s 3D structures, the identification of allosteric binding pockets, the synthesis of organ-system-selective ligands, and a better understanding of biased signaling and mechanisms of action, could facilitate the design of next-generation drugs, thus unlocking the receptors’ full therapeutic potential. In this Special Issue of Pharmaceuticals, authors are invited to submit original and review articles covering preclinical and clinical findings that enhance the chance of CB1R and CB2R therapies achieving clinical success. The proposed topics include novel ligands; chemical probes; and in vitro and in vivo mechanistic, translational, and biomarker studies. We look forward to your valuable contributions.

Dr. Uwe M. Grether
Guest Editor

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Keywords

  • endocannabinoid system (ECS)
  • cannabinoid receptor type 1 (CB1R)
  • cannabinoid receptor type 2 (CB2R)
  • cannabinoids
  • ligand

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Published Papers (2 papers)

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Review

33 pages, 1907 KB  
Review
Topical β-Caryophyllene for Dermatologic Disorders: Mechanisms, Human Evidence, and Clinical Translation
by Amina M. Bagher
Pharmaceuticals 2025, 18(11), 1605; https://doi.org/10.3390/ph18111605 - 23 Oct 2025
Viewed by 201
Abstract
Background: Chronic inflammatory skin disorders, including atopic dermatitis, psoriasis, acne, and chronic wounds, affect nearly two billion people worldwide, impose substantial morbidity and economic burden, and remain only partially controlled by existing therapies. The cutaneous endocannabinoid system (ECS), comprising cannabinoid receptors, endocannabinoids, and [...] Read more.
Background: Chronic inflammatory skin disorders, including atopic dermatitis, psoriasis, acne, and chronic wounds, affect nearly two billion people worldwide, impose substantial morbidity and economic burden, and remain only partially controlled by existing therapies. The cutaneous endocannabinoid system (ECS), comprising cannabinoid receptors, endocannabinoids, and their metabolic enzymes, regulates inflammation, pruritus, barrier integrity, and tissue repair; cannabinoid receptor type 2 (CB2) has emerged as a particularly relevant target. β-Caryophyllene (BCP), a dietary sesquiterpene and highly selective CB2 agonist with favorable safety and pharmacokinetic attributes, has attracted attention as a promising topical candidate. Methods: We systematically searched PubMed, Embase, and Web of Science (inception–30 July 2025) for studies on “β-caryophyllene” and dermatological outcomes, prioritizing purified BCP and analytically characterized BCP-rich fractions. Quantitative parameters, including tested concentration ranges (0.5 µM–10%) and principal mechanistic outcomes, were extracted to provide a translational context. Results: BCP penetrates the stratum corneum, suppresses NF-κB/MAPK and IL-4/TSLP pathways, enhances Nrf2-driven antioxidant defenses, and accelerates re-epithelialization and collagen remodeling. Across in vitro, in vivo, and formulation studies, BCP produced consistent anti-inflammatory and barrier-restorative effects within this concentration range. CB2 antagonism attenuated these responses, confirming receptor specificity. BCP’s volatility and autoxidation to β-caryophyllene oxide (BCPO) necessitate stability-by-design strategies using antioxidants, low-oxygen processing, and protective packaging. Human evidence, limited to BCP-rich botanicals such as Copaifera oleoresins, suggests benefits for scars, wounds, and acne but lacks compound-specific validation. Conclusions: BCP exhibits coherent CB2-mediated anti-inflammatory, antipruritic, antioxidant, and reparative actions with a favorable safety profile. Dose-defined, oxidation-controlled clinical trials of purified BCP are warranted to establish its potential as a steroid-sparing topical therapy. Full article
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19 pages, 799 KB  
Review
Nanotechnology for the Efficacious Delivery of Medicinal Cannabis and Pharmaceutical Medicines
by Luis Vitetta, Jeremy David Henson, Evan Hayes, David Rutolo and Sean Hall
Pharmaceuticals 2025, 18(9), 1385; https://doi.org/10.3390/ph18091385 - 16 Sep 2025
Viewed by 637
Abstract
The application of nanoparticles as nanomedicines, particularly for the targeted and efficacious delivery of drugs is an expanding platform in the field of cannabinoid and pharmaceutical drug delivery. By refocusing the route of drug administration beyond the oral gut pathway, this technology provides [...] Read more.
The application of nanoparticles as nanomedicines, particularly for the targeted and efficacious delivery of drugs is an expanding platform in the field of cannabinoid and pharmaceutical drug delivery. By refocusing the route of drug administration beyond the oral gut pathway, this technology provides significant advancements that are especially relevant for cancer treatments. Orally administered drugs face significant challenges as they traverse the gastrointestinal tract (GIT) and are subject to first-pass GIT metabolism. Physiological conditions encountered in the GIT such as food effects, hormones, gastric pH, emptying time, and intestinal transit time vary widely across individuals. Fluid composition and enzymatic activity in the small intestine and large bowel also influence drug dissolution and absorption. These factors in conjunction with the intestinal cohort of bacteria can metabolize drugs before absorption, contributing to poor and variable drug bioavailability, which can be exacerbated by gut dysbiosis. Drug delivery that bypasses the oral-GIT route and hence first-pass metabolism offers a plausible solution for enhanced safety and drug efficacy. Full article
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