  Citation: Mahmoudinoodezh, H.; Telukutla, S.R.; Bhangu, S.K.; Bachari, A.; Cavalieri, F.; Mantri, N. The Transdermal Delivery of Therapeutic Cannabinoids. Pharmaceutics 2022, 14, 438. https://doi.org/10.3390/ pharmaceutics14020438 Academic Editors: Salette Reis, Sofia Lima and Tânia Moniz Received: 17 December 2021 Accepted: 26 January 2022 Published: 18 February 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Review The Transdermal Delivery of Therapeutic Cannabinoids Haleh Mahmoudinoodezh 1 , Srinivasa Reddy Telukutla 1 , Sukhvir Kaur Bhangu 2 , Ava Bachari 1 , Francesca Cavalieri 3 and Nitin Mantri 1,4, * 1 The Pangenomics Lab, School of Science, RMIT University, Bundoora, VIC 3083, Australia; s3826111@student.rmit.edu.au (H.M.); srinivasareddy.telukutla@rmit.edu.au (S.R.T.); s3756626@student.rmit.edu.au (A.B.) 2 School of Science, RMIT University, Melbourne, VIC 3000, Australia; roop.bhangu@rmit.edu.au 3 Applied Chemistry and Environmental Science, RMIT University, Melbourne, VIC 3000, Australia; francesca.cavalieri@rmit.edu.au 4 The UWA Institute of Agriculture, The University of Western Australia, Perth, WA 6009, Australia * Correspondence: nitin.mantri@rmit.edu.au Abstract: Recently, several studies have indicated an increased interest in the scientific community re- garding the application of Cannabis sativa plants, and their extracts, for medicinal purposes. This plant of enormous medicinal potential has been legalised in an increasing number of countries globally. Due to the recent changes in therapeutic and recreational legislation, cannabis and cannabinoids are now frequently permitted for use in clinical settings. However, with their highly lipophilic features and very low aqueous solubility, cannabinoids are prone to degradation, specifically in solution, as they are light-, temperature-, and auto-oxidation-sensitive. Thus, plant-derived cannabinoids have been developed for oral, nasal-inhalation, intranasal, mucosal (sublingual and buccal), tran- scutaneous (transdermal), local (topical), and parenteral deliveries. Among these administrations routes, topical and transdermal products usually have a higher bioavailability rate with a prolonged steady-state plasma concentration. Additionally, these administrations have the potential to eliminate the psychotropic impacts of the drug by its diffusion into a nonreactive, dead stratum corneum. This modality avoids oral administration and, thus, the first-pass metabolism, leading to constant cannabinoid plasma levels. This review article investigates the practicality of delivering therapeutic cannabinoids via skin in accordance with existing literature. Keywords: transdermal; topical; therapeutic cannabinoids; THC; CBD; bioavailability 1. Introduction For many years, cannabis has been used both as a fibre source and as an edible seed [1,2]. Most notably, it produces a distinctive category of terpenophenolic compounds known as cannabinoids [2]. Cannabinoids are the principal bioactive components of this plant; however, other compounds of interest, such as terpenoids and flavonoids, have also been reported [3]. In recent years, the pharmacological characteristics of cannabinoids have been widely studied, and new applications of cannabis extracts have been proposed [4]. Due to the medicinal and recreational value of cannabinoids, cannabis agribioculture is a flourishing industry. Countries that lead investments in this marketplace include the USA, Canada, and Australia, with signifigant investments in both cultivation and manufacturing facilities [5]. Based on the production source, cannabinoids have been categorised into three groups: (i) phytocannabinoids; (ii) endogenous cannabinoids; and (iii) synthetic cannabinoids [6–9] (Table 1). This review mainly focuses on the plant-derived cannabinoids. Resources have reported nearly 565 cannabis constituents in C. sativa; 120 are phytocannabinoids, some of which have been extensively explored for their therapeutic potential. The predominant cannabinoids in plant material are delta-9-tetrahydro-cannabinol [10], cannabidiol (CBD), Pharmaceutics 2022, 14, 438. https://doi.org/10.3390/pharmaceutics14020438 https://www.mdpi.com/journal/pharmaceutics