Citation: Christensen, C.; Rose, M.; Cornett, C.; Allesø, M. Decoding the Postulated Entourage Effect of Medicinal Cannabis: What It Is and What It Isn’t. Biomedicines 2023, 11, 2323. https://doi.org/10.3390/ biomedicines11082323 Academic Editor: Wesley M. Raup-Konsavage Received: 15 June 2023 Revised: 11 August 2023 Accepted: 16 August 2023 Published: 21 August 2023 Copyright: © 2023 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/). biomedicines Review Decoding the Postulated Entourage Effect of Medicinal Cannabis: What It Is and What It Isn’t Catalina Christensen 1, * , Martin Rose 1 , Claus Cornett 2 and Morten Allesø 1 1 Tetra Pharm Technologies ApS, Rugmarken 10, DK-3650 Ølstykke, Denmark; martin@tetrapharm.eu (M.R.); morten@tetrapharm.eu (M.A.) 2 Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; claus.cornett@sund.ku.dk * Correspondence: catalina@tetrapharm.eu; Tel.: +45-41-26-44-90 Abstract: The ‘entourage effect’ term was originally coined in a pre-clinical study observing en- dogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement). Keywords: entourage effect; synergy; bioenhancer; antagonism; drug–drug interaction; polypharmacology; polypharmacy; medicinal cannabis; cannabinoids; active pharmaceutical ingredient 1. Introduction—The Emergence of the ‘Entourage Effect’ Term Ever since the discovery of the endocannabinoid system (ECS) in 1988, the scientific community has had a strong interest in exploring the therapeutic potential of Cannabis sativa L. (hereafter referred to as “Cannabis”). The ECS is almost ubiquitously distributed throughout the body and as such is implicated in maintaining homeostasis across multi- ple physiological functions. It is often observed as being either up- or downregulated in different disease states. Targeting this system with ECS modulatory compounds, e.g., exoge- nous Cannabis-derived cannabinoids (e.g., Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD)) can aid in rebalancing the system to homeostasis, resulting in therapeutic effects. It is generally recognized that the system is composed of cannabinoid receptors (e.g., cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)); endocannabinoid signal- ing molecules (e.g., anandamide (AEA) and 2-arachidonoylglycerol (2-AG)); and enzymes responsible for the metabolism and availability of endocannabinoids. These ECS compo- nents are regulated in response to disturbances in the homeostasis of various body systems at any given time [1]. To the best of our knowledge, the ‘entourage effect’ term was used for the first time in a pre-clinical study performed by Ben-Shabat et al. in 1998 [2]. They found that endogenous metabolites (i.e., fatty acid glycerol esters), which are otherwise individually pharmacologi- cally inactive, potentiated the activity of the endocannabinoid 2-AG when tested collectively Biomedicines 2023, 11, 2323. https://doi.org/10.3390/biomedicines11082323 https://www.mdpi.com/journal/biomedicines