The main psychoactive component in Cannabis sativa, Δ⁹-tetrahydrocannabinol (THC), produces useful pharmacological effects such as analgesia by activation of the cannabinoid CB1 receptor (CB₁R), a GCPR located mainly in the CNS. There is strong evidence that CB₁R can form heterodimer complexes with the serotonin 5HT2A receptor (5HT_2AR) that lead to new functional outcomes. We have shown that THC co-activation of the CB₁R-5HT_2AR heteromer underpins the adverse cognitive effects that constitute the main drawback to the potential use of THC as an analgesic.¹ In this context, we have devised a novel therapeutic approach aimed at splitting the CB₁R-5HT_2AR heterodimer, allowing selective THC activation of CB₁R, hence dissociating therapeutic from unwanted side effects. Peptides reproducing the CB₁R transmembrane (TM) helices 5 and 6 involved in CB₁R-5HT_2AR dimerization, when fused to a cell-penetrating peptide, can reach and disrupt heterodimer complex formation.¹ Such peptides, named TM5 and TM6, were however unfit for therapeutic use due to their peptide-intrinsic inadequate pharmacokinetics.² We now report how, starting from those non-druggable CB₁R-5HT_2AR heterodimer-splitting peptides, we have developed DRT-017 (EU Patent WO/2021/064165, PCT/EP2020/077642), a small (16-residue) fully druggable, protease-resistant, orally available, non-immunogenic peptide that crosses the blood-brain barrier and blocks heterodimer formation both in vitro and in vivo.³ As expected, heterodimer disruption prevents the undesirable effects of cannabinoids (e.g., memory deficit) but preserves THC-linked analgesia under both acute and chronic conditions in mice.³ Hence DRT-017 is a first-in-class peptide lead capable of successfully preventing cognitive side effects in medical Cannabis users while maintaining pain relief.