Ketamine Is an Opioid, New Molecular Evidence Shows

Ketamine is an unusual, chimera-like drug.

It has a remarkably wide range of effects, serving as an anaesthetic, painkiller, dissociative drug, hallucinogen, and unusually rapid-acting antidepressant.

Ketamine's dual action in the brain

This distinctive mix of properties has traditionally been linked to its effect on the N-methyl-D-aspartate (NMDA) receptor, one of the brain's principal receptors for the excitatory neurotransmitter glutamate.

Yet researchers have long thought the explanation was more complicated.

A team led by pharmacologist Tao Che at Washington University School of Medicine has now identified "unambiguous structural evidence" that some of ketamine's effects may also arise from its direct interaction with opioid receptors in the brain.

The finding, published in Nature Structural & Molecular Biology, helps clarify both what ketamine does and the mechanisms through which it works.

More importantly, perhaps, it addresses important gaps in knowledge that could improve the clinical use of ketamine.

"Ultimately, the unique therapeutic profile of ketamine cannot be reduced to a single molecular interaction," neuroscientists Jordi Bonaventura of the University of Barcelona in Spain and Michael Michaelides of the US National Institute on Drug Abuse write in a related commentary.

"Instead, the convergence of structural evidence confirming the direct engagement of ketamine with opioid receptors, together with its classical role as an NMDAR antagonist, establish a compelling case for a bifunctional mechanism of action."

From PCP to ketamine

Ketamine's history starts in the 1950s with phencyclidine, or PCP, a synthetic dissociative drug. Developed as an anaesthetic, PCP caused serious unwanted effects, including delirium and hallucinations, psychotic behaviour, and seizures.

Seeking a safer alternative, scientists altered PCP to create ketamine during the 1960s. It has since proved valuable as both an anaesthetic and an antidepressant. As with its parent compound, ketamine has generally been regarded primarily as an NMDA receptor antagonist.

Even so, evidence from decades ago suggested that ketamine involved more than a simple NMDA effect.

A 1978 paper reported that PCP and similar drugs could bind to opioid receptors. Then, a 1984 paper showed that naloxone, which blocks opioid receptors, reduced ketamine's effectiveness as a general anaesthetic.

Other experiments, however, delivered conflicting results. And although technological advances allowed scientists to image molecules, the crucial evidence remained missing: proof that ketamine physically occupied the main binding pocket of human opioid receptors.

That was the question Che and colleagues set out to answer, and their findings leave little doubt that ketamine directly engages with opioid receptors.

The researchers first tested ketamine against the three main opioid receptor types - mu, kappa and delta - using human opioid receptors expressed in laboratory-grown cells. The drug was able to bind to and activate all three, although its actions were more pronounced at the mu and kappa receptors.

Comparison of an unoccupied kappa opioid receptor with the same binding pocket occupied by PCP and ketamine. (Jiang et al., Nat. Struct. Mol. Biol. 2026)

They also determined that ketamine is a partial agonist. In other words, rather than merely binding to an opioid receptor, it activates it, though less strongly than the full opioid agonists used as comparisons by the researchers.

The team then used cryo-electron microscopy to observe precisely where ketamine attached.

There it was: positioned within the primary binding pocket of both the mu and kappa opioid receptors, the same broad pocket targeted by conventional opioids.

This was the missing evidence - direct structural proof that ketamine was not simply affecting the opioid system indirectly, but was physically engaging opioid receptors.

Opioid receptors and ketamine's pain-relieving effects

Binding physically to a receptor does not automatically mean that a compound will have a measurable or significant effect in a living animal. To address that question, the researchers turned to the familiar mouse model.

In animal experiments, ketamine's analgesic effects (light purple) were blocked by aticaprant (dark purple) and naloxone (dark blue). (Jiang et al., Nat. Struct. Mol. Biol. 2026)

The team administered mice a subanaesthetic dose of ketamine and measured how long it took them to pull their tails from warm water. As anticipated, ketamine delayed the mice's tail withdrawal.

But when the mice were first given medicines that block opioid receptors, this effect vanished.

When ketamine was paired with naloxone, which broadly blocks opioid receptors, or aticaprant, which specifically blocks kappa opioid receptors, the mice reacted to the warm water as if they had received no ketamine at all.

This does not overturn everything known about ketamine. The drug continues to bind more strongly to NMDA receptors, and that interaction remains significant for many of its effects.

However, the research indicates that ketamine's unusual characteristics may result from its capacity to act on both systems simultaneously.

The clearest evidence to date concerns pain relief. The mouse experiments indicate that opioid receptors contribute to ketamine's analgesic effects, although exactly how the various receptor systems interact is still uncertain. This could be an avenue for future research.

It is less certain whether opioid activity also helps account for ketamine's antidepressant effects. Earlier studies have indicated that opioid receptors are involved, but the new research did not investigate whether ketamine's direct interaction with these receptors underlies its antidepressant properties.

The finding could also matter for one of ketamine's less welcome traits: its potential for misuse and addiction.

The mu opioid receptor is of particular interest in this respect. Previous animal research has linked this receptor to ketamine's reinforcing effects - the characteristics that encourage repeated use. Discovering that ketamine can directly bind to and activate this receptor offers a possible molecular connection.

Related: Repeated Ketamine Use Fundamentally Changes The Brain's Dopamine System in Mice

That does not mean ketamine dependence is merely another type of opioid dependence. Ketamine is now known to act on several brain systems, and the precise contributions of each to its therapeutic effects, reinforcement and potential for misuse have yet to be established.

The encouraging prospect is that disentangling these effects could enable scientists to develop an improved form of ketamine.

"An important question is whether ketamine's therapeutic benefits can be pharmacologically dissociated from its abuse potential by appropriately balanced activation of NMDAR and opioid receptors," the researchers write in their paper.

"The structural insights gained here could guide the optimization of ketamine with reduced side effects."

The findings were published in Nature Structural & Molecular Biology.

This article was fact-checked and edited by Clare Watson. Although we take pride in our process, we are only human. If you notice an error, please let us know.