Disrupting a cannabinoid-related receptor heterodimer as a newly identified therapeutic approach for cannabis use disorder treatment

Cannabis Use Disorder (CUD) is a growing public health concern affecting over 20 million individuals worldwide, with no approved pharmacological treatments currently available and few compounds under development.

In this context, we have identified and characterised the formation of a functional heterodimer between the cannabinoid type 1 receptor (CB1R) and the serotonin type 2A receptor (5HT2AR), i.e., CB1R–5HT2AR, expressed in brain regions implicated in addiction and memory processes, contributing to both reinforcing and cognitive effects of cannabinoids. This receptor complex displays signalling properties that differ from those of the cannabinoid type 1 receptor alone [1]. We therefore hypothesised that selective disruption of this receptor complex would reduce cannabinoid-seeking behaviour and prevent cannabinoid-induced cognitive impairment, thereby representing a novel dual therapeutic strategy for CUD treatment.

Based on this rationale, we developed DRT-101, an optimised orally active peptide composed of D-amino acid residues and derived from previously non-druggable prototypes. DRT-101 (PCT/EP2020/077642; PCT/EP2025/065235) was designed to exhibit key drug-like properties, including proteolytic stability, absence of detectable humoral immune responses and blood–brain barrier permeability. In vitro, DRT-101 disrupted CB1R–5HT2AR heterodimer formation in a bimolecular fluorescence complementation assay, confirming its ability to interfere with receptor complex formation [2].

The aim of this study was to evaluate the pharmacological efficacy of DRT-101 in preclinical models relevant to CUD. Addiction-like behaviours were assessed in an operant self-administration paradigm using the cannabinoid receptor agonist WIN55,212-2 under fixed ratio and progressive ratio schedules. Mice were evaluated for persistence of response, motivation, impulsivity, and compulsivity under punishment resistance conditions. Cognitive performance was assessed using the Novel Object Recognition Test (NORT).

In the WIN55,212-2 operant self-administration model [3], oral DRT-101 significantly attenuated cannabinoid-seeking behaviour and reduced addiction-like phenotypes. Treatment decreased motivation for cannabinoid reinforcement under a progressive ratio schedule, reduced impulsivity during time-out periods, and decreased the proportion of animals classified as addiction-like according to behavioural domains recapitulating DSM-5 diagnostic criteria for CUD: persistence of response, motivation for the drug, and compulsive behaviour despite negative consequences (unpublished data).

In the NORT, DRT-101 prevented cannabinoid-induced recognition memory deficits following both acute and chronic exposure to Δ9-tetrahydrocannabinol (THC). In acute THC-treated mice, single oral DRT-101 significantly reversed THC-induced amnesic effects without altering THC-associated analgesic responses, as assessed in the hot plate test [2]. In chronic THC-treated mice, repetated oral DRT-101 preserved recognition memory and did not alter THC-associated analgesic responses, as assessed by plantar and von Frey paradigms in the partial sciatic nerve ligation model of chronic neuropathic pain, indicating preservation of CB1 receptor signalling (unpublished data).

DRT-101 demonstrated robust preclinical efficacy across two complementary models addressing key domains relevant to CUD: cannabinoid-seeking behaviour and cannabinoid-induced cognitive impairment. By selectively disrupting CB1R–5HT2AR heterodimer signalling, these findings support this receptor complex as a novel therapeutic target in addiction neuropsychopharmacology. DRT-101 is currently undergoing formulation development and toxicology-enabling preclinical development to support future clinical translation as a potential pharmacological treatment for CUD.

References

1. Viñals, X., Moreno, E., Lanfumey, L., Cordomí, A., Pastor, A., de La Torre, R., Gasperini, P., Navarro, G., Howell, L.A., Pardo, L., Lluís, C., Canela, E.I., McCormick, P.J., Maldonado, R., Robledo, P., 2015. Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors. PLoS Biol. 13, e1002194.
2. Gallo, M., Moreno, E., Defaus, S., Ortega-Alvaro, A., Gonzalez, A., Robledo, P., Cavaco, M., Neves, V., Castanho, M.A.R.B., Casadó, V., Pardo, L., Maldonado, R., Andreu, D., 2021. Orally active peptide vector allows using cannabis to fight pain while avoiding side effects. J. Med. Chem. 64, 6938-6950.
3. Cajiao-Manrique, M.M., Maldonado, R., Martín-García, E., 2023. A male mouse model of WIN 55,212–2 self-administration to study cannabinoid addiction. Front. Pharmacol. 14, 1143365.