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Scientists have now directly visualized ketamine inside human mu- and kappa-opioid receptors.

Proving opioid-receptor engagement with ketamine, some but not all effects of ketamine are opioid-driven.

These findings strengthen the case for FDA-approved, REMS-compliant, carefully dosed and monitored esketamine.

Ketamine has always been a strange chimera of a wonder drug. It’s an anesthetic, pain reliever, dissociative drug, hallucinogen, club drug, and unusually rapid antidepressant.

It may relieve suffering when other treatments fail. Ketamine may also reinforce repeated use, leading to and causing addiction, cognitive impairment, bladder injury, and death. In this blog, I’ve discussed ketamine’s benefits, risks, and controversies. And there's a discussion of ketamine-assisted psychotherapy here.

For years, ketamine’s many effects were explained primarily by one mechanism: blockade of the brain’s N-methyl-D-aspartate (NMDA) glutamate receptor. But my friend and colleague Stanford Professor Alan Schatzberg and his colleagues argued that this explanation was incomplete and not well supported by human data. They proposed ketamine’s rapid antidepressant effects might depend, at least partly, on the opioid system.

This suggestion sparked considerable debate; to say it was controversial would be an understatement. Ketamine’s chemistry and clinical effects don’t look much like morphine, heroin, or fentanyl. It generally preserves breathing better, raises rather than lowers blood pressure, and produces dissociation rather than typical opioid intoxication. Many researchers considered the opioid findings weak, indirect, or unimportant.

Now new molecular research from Washington University changes that debate. Researchers can prove ketamine sits in the opioid receptor.

The Molecular Smoking Gun

In their new study, Qianru Jiang, Tao Che, and colleagues used cryo-electron microscopy to study ketamine’s interactions with human opioid receptors. They found (S)-ketamine lodged in the primary binding pocket of both the mu- and kappa-opioid receptors used by conventional opioids.

In this research modeling, ketamine behaves as a relatively weak partial agonist at all three major opioid receptors—mu, kappa, and delta. Ketamine has greater affinity and potency at mu and kappa receptors than delta receptors. Ketamine does not simply have an indirect effect on the brain’s own opioids or alter opioid signaling downstream. It binds to and activates opioid receptors.

The researchers then asked whether this mattered in a living animal. A subanesthetic dose of ketamine reduced pain responses in mice. Naloxone, which broadly blocks opioid receptors, eliminated this analgesic effect.

Is Ketamine an Opioid?

In an important molecular sense, yes: Ketamine is a direct, partial opioid-receptor agonist. But calling it “just another opioid” is misleading.

Ketamine binds more strongly to NMDA receptors, and NMDA blockade remains central to its dissociative, cognitive,........

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