CNR1 and Cognitive impairment: We have shown that peptides reproducing CB1R transmembrane(TM) helices 5 and 6, fused to a cell-penetrating sequence (CPP),can alter the structure of the CB1R–5HT2AR heteromer and avert THC cognitive impairment while preserving analgesia.Here, we report the optimization of these prototypes into drug-likeleads by (i) shortening the TM5, TM6, and CPP sequences, without losingthe ability to disturb the CB1R–5HT2AR heteromer, and (ii) extensive sequence remodeling to achieve proteaseresistance and blood–brain barrier penetration.