- What Is Ketamine?
- Take our Depression Test
- Find a therapist to overcome depression
Key points
- 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, a pain reliever, a dissociative drug, a hallucinogen, a club drug, and an 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. (I’ve written previously about ketamine’s benefits, risks, and controversies.)
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
Human PET imaging with an opioid ligand may be next to see if ketamine displaces it. This competitive displacement experiment is the best way to determine whether in vitro and in vivo, or rat and human, findings agree
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, anesthetic, and probably some therapeutic effects. In native rat brain tissue, the new study found (S)-ketamine had about 21 times greater affinity for NMDA receptors than mu-opioid receptors
- What Is Ketamine?
- Take our Depression Test
- Find a therapist to overcome depression
Putting this together, ketamine is most accurately described as a bifunctional—or polypharmacological—drug acting on glutamate and opioid systems, among others
The new debate is how much of ketamine’s acute antidepressant or anti-suicidal effects are due to direct opioid binding. We don’t yet know how much ketamine occupies opioid receptors in the human brain at commonly used antidepressant doses. Opioid effects may be more apparent at higher ketamine doses, with polysubstance use, or during anesthesia or intoxication
The most accurate conclusion is not that everything previously believed about ketamine is wrong. It’s that an NMDA-only explanation is inadequate
Schatzberg’s Warning Looks Prescient
In 2018, Nolan Williams, Schatzberg, and Stanford colleagues reported that pretreatment with naltrexone markedly reduced ketamine’s antidepressant effect in patients with treatment-resistant depression, while leaving dissociation intact. Later studies did not all agree, and differences in study design kept the debate alive
Ketamine Essential Reads
The Ketamine Paradox
Ketamine as Therapeutic Dynamite
Evidence continued to accumulate. A 2025 randomized crossover study of 26 adults with major depression partially replicated the earlier finding. Naltrexone reduced ketamine’s day-one improvement on the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) and its acute effect on glutamatergic activity in the anterior cingulate cortex. Naltrexone doesn’t reverse or cancel ketamine’s antidepressant response, and differences on self-reported depression measures were not statistically significant.
A 2026 Cellstudy found ketamine’s antidepressant-like behavioral effects in mice required mu-opioid receptors on a specific group of somatostatin-positive inhibitory neurons in the medial prefrontal cortex. The new structural study supplied a missing piece: Ketamine can directly occupy opioid receptors. What remains unresolved is how much this interaction contributes to each of ketamine’s clinical effects
What This May Explain About Addiction
The mu-opioid receptor contributes importantly to reward and reinforcement. Prior animal research has found that its activation also contributes to the reinforcing effects of (S)-ketamine. In rats, naltrexone reduced ketamine self-administration, and a reinforcing dose occupied brain mu-opioid receptors. Direct visualization of ketamine binding provides a plausible molecular link to its abuse potential
That does not mean ketamine use disorder is simply opioid use disorder under another name. Ketamine acts on several brain systems and does not share the typical respiratory-depression profile of full mu-opioid agonists. Nor should naloxone be assumed to reverse ketamine overdose or intoxication. A mouse pain experiment does not establish Narcan as a ketamine antidote
However, the former reassuring claim that ketamine is non-addictive because it is not an opioid should now be retired. Ketamine is a controlled drug with reinforcing effects, and opioid-receptor activation is probably one contributor
Spravato Is Neither a Club Drug Nor At-Home Ketamine
FDA-approved intranasal esketamine, sold as Spravato, is effective for properly selected patients with severe depression. It is given at a standardized dose in a certified health care setting, with blood pressure assessment and at least two hours of monitoring. Patients do nottake it home. The patient must have a prearranged ride home and is strictly forbidden to drive or operate machinery until the day after a restful night of sleep. Its label warns about sedation, dissociation, respiratory depression, abuse, and misuse.
Pharmacist-compounded ketamine nasal sprays, lozenges, or oral liquids do not undergo FDA evaluation for safety, effectiveness, or manufacturing quality. The FDA does not review compounded products for safety, effectiveness, quality, or dosing. Still, risky Illicit online sales and home and club use occur. This type of use also obviously lacks Spravato’s FDA patient safety protections
Safety controls over adulteration, the dose, purity, route, frequency, and drug combinations may be absent. Alcohol, opioids, benzodiazepines, and other sedatives add to the danger. Unlike the controlled, tapering schedules of FDA-approved, REMS-guided Spravato treatment, unsupervised access carries a high risk of dependence and compulsive use. A history of substance use disorder should not automatically exclude a patient from treatment but does call for care
The same molecule can therefore be a treatment in one setting and a drug of abuse in another. Dose, route, frequency, patient selection, monitoring, and the surrounding treatment plan make much of the difference
The Bright and Dark Sides Are Connected
The bright and dark sides don’t come from separate drugs inside the sameamate and opioid systems
Ketamine’s opioid activity may contribute to analgesia, reinforcement, misuse liability, and possibly some rapid antidepressant and anti-suicidal effects. NMDA-receptor blockade and downstream glutamatergic plasticity remain important. Exactly how these mechanisms interact within patients remains unresolved
For me, the important question is no longer whether ketamine is a glutamate drug or an opioid drug. It is both—and probably more. The challenge now is to determine which of its actions produce rapid therapeutic relief and which contribute to repeated use, addiction, and toxicity
Ketamine deserves neither demonization nor casual reassurance. Spravato, administered with FDA-required safeguards, is an important and potentially life-saving treatment for treatment-resistant depression. Unsupervised or self-administered ketamine is not simply Spravato without the paperwork. It amounts to conducting unmonitored, high-stakes neuropharmacology on your own brain with a drug known to cause addiction and serious medical complications—and now shown to have enough opioid activity to warrant additional caution.
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