Ketamine is an unusual and multifaceted drug.
It serves multiple purposes: acting as an anesthetic, pain reliever, dissociative drug, hallucinogen, and a particularly rapid-acting antidepressant.
This unique combination of effects has traditionally been linked to its interaction with the N-methyl-D-aspartate (NMDA) receptor, a primary receptor in the brain for the excitatory neurotransmitter glutamate.
However, scientists have long speculated that there might be more to this story.
Recently, a team of researchers led by pharmacologist Tao Che from Washington University School of Medicine has discovered “clear structural evidence” indicating that some of ketamine’s effects could also stem from its direct interaction with the brain’s opioid receptors.
This breakthrough, published in Nature Structural & Molecular Biology, sheds light on ketamine’s mechanisms and actions. More importantly, it addresses critical knowledge gaps that could enhance its application in medical settings.
“Ultimately, the unique therapeutic profile of ketamine cannot be reduced to a single molecular interaction,” write neuroscientists Jordi Bonaventura from the University of Barcelona, Spain, and Michael Michaelides from 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.”
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The origins of ketamine trace back to the 1950s with a synthetic dissociative drug called phencyclidine (PCP). PCP was initially developed as an anesthetic but was found to have severe side effects, such as delirium, hallucinations, psychotic behavior, and seizures.
In the 1960s, researchers modified PCP to create ketamine, which has since been widely used as both an anesthetic and an antidepressant. Like PCP, ketamine was mainly considered an NMDA receptor antagonist.
Hints of ketamine’s broader capabilities emerged decades ago.
A 1978 study revealed that PCP and related drugs could bind to opioid receptors, while a 1984 study found that naloxone, which blocks opioid receptors, reduced ketamine’s effectiveness as a general anesthetic.
However, other experiments produced inconsistent results, and despite advancements in molecular imaging, definitive evidence of ketamine occupying the primary binding pocket of human opioid receptors remained elusive.
Che and his team aimed to uncover this evidence, and their findings strongly indicate that ketamine directly interacts with opioid receptors.
Initially, the researchers tested ketamine against three major opioid receptor classes: mu, kappa, and delta, using human opioid receptors expressed in lab-grown cells. They discovered that ketamine could bind to and activate all three, with stronger effects at the mu and kappa receptors.
They also found ketamine acts as a partial agonist. Instead of merely binding to an opioid receptor, it activates the receptor but less strongly than full opioid agonists used for comparison.
Using cryo-electron microscopy, the team observed the exact location where ketamine binds.
Indeed, ketamine was found nestled inside the primary binding pocket of both the mu and kappa opioid receptors, the same pocket targeted by conventional opioids.
This discovery provides direct structural evidence that ketamine engages with opioid receptors, not just indirectly influencing the opioid system.
However, binding to a receptor doesn’t always translate to significant effects in living organisms. Thus, the researchers turned to mouse models for further investigation.
Mice were administered a subanesthetic dose of ketamine, and the time taken for them to withdraw their tails from warm water was measured. Ketamine caused the mice to withdraw more slowly.
However, when the mice were pre-treated with drugs blocking opioid receptors, this effect vanished.
When ketamine was combined with naloxone, which blocks opioid receptors broadly, or aticaprant, which specifically blocks kappa opioid receptors, the mice reacted to the warm water as if they had not received ketamine at all.
This doesn’t mean that previous understandings of ketamine are incorrect. The drug still binds more robustly to NMDA receptors, and this interaction is crucial for many of its effects.
Nonetheless, the study suggests ketamine’s unique properties might arise from its concurrent action on both systems.
The most substantial evidence so far supports its pain-relief capabilities. The mouse experiments suggest opioid receptors contribute to ketamine’s analgesic effects, though how different receptor systems interact remains unclear, indicating a possible direction for future research.
Whether this opioid activity also clarifies ketamine’s antidepressant properties is less certain. Previous studies indicated opioid receptor involvement, but the new study did not assess whether ketamine’s direct interaction with these receptors accounts for its antidepressant effects.
This discovery might also have implications for ketamine’s potential for misuse and addiction.
Particularly, the mu opioid receptor is noteworthy. Previous animal research has linked this receptor to ketamine’s reinforcing effects, which encourage repeated drug use. The discovery that ketamine can bind to and activate this receptor offers a possible molecular connection.
Related: Repeated Ketamine Use Fundamentally Changes The Brain’s Dopamine System in Mice
However, ketamine dependence is not merely another form of opioid dependence. We now understand that ketamine affects multiple brain systems, and how each system contributes to its therapeutic effects, reinforcement, and misuse potential remains to be explored.
The positive aspect is that understanding these effects may help scientists develop an improved version 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.
