Ketamine is a weird chimera of a drug.
It does so many different things. It acts as an anesthetic, painkiller, dissociative drug, hallucinogen, and unusually fast-acting antidepressant.
This strange combination of properties has traditionally been attributed to its interaction with the N-methyl-D-aspartate (NMDA) receptor – one of the brain's major receptors for the excitatory neurotransmitter glutamate.
But scientists have long suspected there was more to the story.
Now, a team led by pharmacologist Tao Che of Washington University School of Medicine has found "unambiguous structural evidence" that at least some of ketamine's effects may also involve its direct interaction with the brain's opioid receptors.
It's a discovery, published in Nature Structural & Molecular Biology, that helps explain what ketamine does and how it does it.
But perhaps more importantly, it fills crucial knowledge gaps that could improve how ketamine is used in clinical settings.
"Ultimately, the unique therapeutic profile of ketamine cannot be reduced to a single molecular interaction," write neuroscientists Jordi Bonaventura of the University of Barcelona in Spain and Michael Michaelides of the US National Institute on Drug Abuse 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."
The story of ketamine begins in the 1950s with a synthetic dissociative drug called phencyclidine, or PCP. PCP was developed as an anesthetic, but had pretty severe adverse side effects, such as delirium and hallucinations, psychotic behavior, and seizures.
In search of a safer version, scientists modified PCP to derive ketamine in the 1960s, and it has since proven very useful both as an anesthetic and as an antidepressant. Like its parent drug, it has generally been considered primarily an NMDA receptor antagonist.
Even decades ago, however, there were hints that there was more to ketamine than a straightforward NMDA action.
A 1978 paper found that PCP and related drugs could bind to opioid receptors, and a 1984 paper found that naloxone – which blocks opioid receptors – interfered with ketamine's efficacy as a general anesthetic.
But other experiments produced conflicting results, and despite technological advancements that enabled researchers to image molecules, the smoking gun – evidence of ketamine physically occupying the primary binding pocket of human opioid receptors – remained elusive.
This is what Che and his colleagues set out to find – and their results leave little room for doubt that ketamine directly engages opioid receptors.
First, the researchers tested ketamine against the three major classes of opioid receptor: mu, kappa, and delta, using human opioid receptors expressed in cells grown in the laboratory. They found that the drug could bind to and activate all three, although its effects were stronger at the mu and kappa receptors.
They also found that ketamine acted as what is known as a partial agonist. Rather than simply attaching to an opioid receptor, it activates the receptor, albeit less strongly than the full opioid agonists the researchers used for comparison.
Next, the team used cryo-electron microscopy to actually see where ketamine was binding.
And boom, there it was: nestled snugly inside the primary binding pocket of both the mu and kappa opioid receptors – the same general pocket targeted by conventional opioids.
This was it, the smoking gun, direct structural evidence that ketamine wasn't just influencing the opioid system indirectly – it was physically engaging opioid receptors.
But physically binding to a receptor does not necessarily mean a compound has a measurable or meaningful effect on a living animal. This is where the researchers pulled out the good old mouse model.
They gave mice a subanesthetic dose of ketamine, then timed how quickly the animals withdrew their tails from warm water. As expected, ketamine made the mice slower to withdraw their tails.
When the researchers first gave the mice drugs that block opioid receptors, however, that effect disappeared.
When ketamine was combined with naloxone, which broadly blocks opioid receptors, or aticaprant, which specifically blocks kappa opioid receptors, the mice responded to the warm water as though the ketamine had not been given at all.
This doesn't mean everything we thought we knew about ketamine was wrong. The drug still binds more strongly to NMDA receptors, and its interaction with them remains important for many of its effects.
However, the study suggests that ketamine's unusual properties may emerge from its ability to act upon both systems at the same time.
The strongest evidence so far is for its pain-relieving effects. The mouse experiments suggest that opioid receptors contribute to ketamine's analgesic effects, although precisely how the different receptor systems work together remains unclear. That may be a direction for future research.
Whether this opioid activity also helps explain ketamine's antidepressant effects is less clear. Previous studies found evidence that opioid receptors are involved, but the new study did not test whether ketamine's direct interaction with those receptors is responsible for its antidepressant properties.
The discovery may also have implications for one of ketamine's less desirable properties: its potential for misuse and addiction.
The mu opioid receptor is particularly interesting here. Previous animal research has implicated this receptor in the reinforcing effects of ketamine – the properties that encourage repeated drug use. The discovery that ketamine can directly bind to and activate the receptor provides a possible molecular link.
Related: Repeated Ketamine Use Fundamentally Changes The Brain's Dopamine System in Mice
That doesn't mean ketamine dependence is simply another form of opioid dependence, however. We now know that ketamine acts on multiple systems in the brain, and exactly how each contributes to its therapeutic effects, reinforcement, and potential for misuse remains to be determined.
The good news is that sorting out those effects could help scientists develop an even better 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 have been published in Nature Structural & Molecular Biology.
This article was fact-checked by Clare Watson and edited by Clare Watson. While we pride ourselves on our process, we are only human. If you spot a mistake, please let us know.