Opioid Antagonists for Hedonic Liberation—Not All Is Over

Recent Phase 3 clinical trials of selective kappa-opioid peptide (KOP) receptor antagonists – aticaprant (Johnson & Johnson, VENTURA trial, 2025) and navacaprant (Neumora, KOASTAL-1 trial, 2025) – failed to demonstrate sufficient clinical efficacy in treatment-resistant depression (TRD). We propose two hypotheses that could explain these setbacks: (1) neutral antagonists may be poorly effective in patients with TRD due to constitutive KOP receptor hyperactivation and (2) the KOP receptor paralog – nociceptin opioid peptide (NOP) receptor – can effectively compensate for KOP receptor blockade decreasing the magnitude of clinical efficacy. We hypothesize that functional redundancy provided by NOP receptor signaling requires dual KOP/NOP blockade to achieve clinically meaningful improvement in reward function. Recent insights gained from paralogous compensation in drug-resistant tumors underscore the need for dual-target approaches. We propose that future studies, if successful, may yield a novel pharmacological class targeting opioid-mediated hedonic suppression, advocating for the development of opioid inverse agonists (such as norBNI), pan-antagonists (such as AT-076), and combinations of selective blockers.