Nature structural & molecular biologyJun 22, 2026

How PCP and ketamine activate opioid receptors at the molecular level

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 23, 2026

Abstract

Ketamine exhibits notable binding dynamics at opioid receptors, which may contribute to its unique pharmacological effects.

Ketamine and phencyclidine (PCP) can directly bind and activate human opioid receptors.
Structural evidence reveals key motifs that influence how ketamine and PCP are recognized by these receptors.
The structure of the ligand-free state of the human κ opioid receptor provides insights into its configuration before drug binding.
Ketamine shows distinct binding characteristics compared to PCP, potentially affecting its therapeutic use.
Understanding interactions with opioid receptors may enhance insights into ketamine's clinical applications.

Simplified

Ketamine offers rapid relief for treatment-resistant depression and severe pain in the clinic, providing immediate benefits that traditional medications often fail to deliver. While its antagonistic action at the N-methyl-D-aspartate receptor (NMDAR) is a key mechanism, ketamine's dual nature as both a promising treatment and a drug with abuse potential suggests its therapeutic effects extend beyond NMDAR inhibition. Here we provide structural evidence of human opioid receptors bound to ketamine and its parent analog phencyclidine (PCP), supporting that both ligands can directly bind and activate opioid receptors. The structures, together with site-directed mutagenesis and structure-activity relationship studies, identify key motifs involved in ketamine and PCP recognition and efficacy modulation. Furthermore, we determine the structure of the ligand-free state of human κ opioid receptor, revealing molecular details before ligand engagement. Compared to PCP, ketamine displays more notable binding dynamics in the orthosteric site that may contribute to its unique pharmacology at opioid receptors. Our findings highlight the importance of including opioid receptors to fully understand ketamine's versatility in clinical settings.