Brazilian study proposes new interpretation of the "entourage effect" of medicinal Cannabis

A study published in the Brazilian Journal of Surgery and Clinical Research by researchers from the Federal University of Piauí (UFPI) presents an innovative reinterpretation of the so-called "entourage effect" of Cannabis, proposing a symbolic nomenclature that facilitates the understanding of how different compounds of the plant interact with the human Endocannabinoid System.

The four roles of cannabinoids

The research, led by professors Paulo Jordão de Oliveira Cerqueira Fortes and Lair Geraldo Theodoro Ribeiro, analyzed 68 scientific publications and proposes a functional structure that translates the dynamics of the Endocannabinoid System into four complementary roles, attributing "personalities" to the main phytocannabinoids of Cannabis.

THC (tetrahydrocannabinol) is defined as the "Promiscuous", for its ability to activate multiple receptors simultaneously, mimicking the natural endocannabinoids Anandamide and 2-arachidonoylglycerol. CBD (Cannabidiol) assumes the role of "Homeostatic Brake", modulating the intensity and duration of signals. CBG (Cannabigerol) acts as the "Primary Mediator", responsible for peripheral integration and immunoregulation. Finally, CBN (Cannabinol) is identified as the "Peacemaker", a restorative agent of homeostasis and physiological rest.

More than the sum of its parts

The study demonstrates that the entourage effect is not just the sum of the compounds, but constitutes a synergistic network of biochemical cooperation that mirrors the endogenous mechanisms of self-regulation of the human body.

The researchers argue that natural endocannabinoids — Anandamide and 2-arachidonoylglycerol — have a short duration of action due to rapid enzymatic degradation. In contrast, plant cannabinoids, not undergoing immediate enzymatic metabolism, exhibit greater systemic persistence, prolonging the functional activity of the Endocannabinoid System.

Demystifying THC in medical practice

In an interview, Professor Paulo Jordão explains that THC is often treated as a villain in clinical practice, but theoretically it is a promiscuous element, precisely because it activates various receptors and participates in multiple biochemical circuits. "The symbolic proposal presented in the study helps the physician understand that part of this 'bad reputation' arises not from the substance itself, but from the lack of knowledge on how to apply its brake," he states.

According to the researcher, prescription accuracy tends to improve when the functional role of each cannabinoid is understood. "For example, CBN, commonly used in sleep disorders, also acts as an anxiolytic, demonstrating that each molecule has more than one therapeutic function," explains Fortes.

The symbolic nomenclature serves as a pedagogical tool to translate biochemical complexity into functional clinical reasoning, making the prescription process more conscious and integrated.

Beyond fixed formulas

Regarding dosages and therapeutic combinations, the professor highlights that THC is a biphasic phytocannabinoid — it can exert different effects depending on the context and intensity of stimulation. "In different doses or conditions, it acts either as a therapeutic agent or as a destabilizing element," he clarifies.

AGROCANN, a research center at UFPI coordinated by Fortes, has been collaborating on formulations and trials conducted in postgraduate programs in Pharmacy, analyzing combinations of THC, CBD, CBG, and CBN. However, the researcher emphasizes that these interactions are not limited to "recipes" or fixed formulas.

"The goal is not to find an ideal ratio, but to understand the systemic logic that governs the joint behavior of these compounds," he points out. In various case follow-ups — including difficult-to-control epilepsy — it is observed that the functional interdependence between the four symbolic roles favors therapeutic balance, although in different doses and formulations throughout the day.

Theory as the first step

Regarding Brazilian regulatory challenges, Fortes is straightforward: "There is currently no way to expect effective collaboration from the public authorities". The researcher notes that Brazil has numerous state and municipal laws aimed at integrating Cannabis into the Unified Health System (SUS), but many are not enforced, revealing a gap between discourse and practice.

"The article advances by presenting an original theoretical view, something that can still be done freely in the country, even in the face of regulatory limitations. Producing theory is an essential step before empirically testing it — and the university is the legitimate space for that," he argues.

The viable path, according to the professor, is to strengthen private and academic initiatives, investing in the production of theoretical knowledge. The next steps of AGROCANN focus on producing scientific and pedagogical materials for physicians, considered the pillars of responsible prescription and commercialization of Cannabis-based medicines.

"Formal clinical trials are not essential to validate the theory — it already relies on foundations present in the international scientific literature. Here we present a translation of these concepts into language accessible to the Brazilian medical public," explains Fortes.

Cannabis as a biomimetic model

The combination of phytocannabinoids reproduces the natural sequence of activation, modulation, and resolution of the Endocannabinoid System, showing that Cannabis functions as a biomimetic model of homeostasis, in which the plant and the body work together to restore balance.

The center maintains research lines in the cultivation and formulation of medicinal derivatives, seeking to build a solid scientific basis in the Portuguese language. "The goal is also to inform legislators and public managers, as the creation of effective policies requires prior knowledge of the endocannabiome — a biome composed of lipid sensors, enzymes, and bioactive mediators present in cells," concludes the researcher.

The study represents a significant contribution to advancing knowledge about medicinal Cannabis in Brazil, offering a conceptual basis for the development of future research and educational materials in the field of biomedical and pharmaceutical sciences, translating what the authors call the "pharmacology of harmony".