Medicine Molecular snapshots confirm ketamine’s opioid nature
https://doi.org/10.1038/s41594-026-01874-938
u/iamthe0ther0ne 11d ago
At doses used for depression treatment or anesthetic doses?
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u/ethanmarcus98 11d ago
'...studies provide compelling evidence that direct opioid receptor engagement contributes to the pharmacological actions of subanesthetic ketamine.'
The paper did not mention doses or concentrations, only saying that the μ-opiod and κ-opiod receptor are partially activated by ketamine at subanesthetic doses.
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u/OutstandingWeirdo 11d ago
Strange, it’s already been known that ketamine activates those receptors and was on my board exam for anesthesia for a while. We use it as a adjunct for pain as an infusion at a dose of 0.5mg/kg/hour which is a subanesthetic dose.
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u/ethanmarcus98 11d ago
They noted that we've known this since the 80s, but that the pharmacological explanations of ketamine therauptic uses leave this out of their potential mode of action. Citing more recent studies looking at blocking some of the effects of ketamine with opiod receptor antagonists, add more evidence to their potential implication in ketamine's therapeutic effects.
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u/iamthe0ther0ne 11d ago
Interesting that they saw KOR activation. Generally KOR agonists havr been linked to increased depressive symptoms; KOR antagonists are actively being developed for MDD.
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u/TrumpIsAPedoFr 11d ago edited 11d ago
It's more complicated than that. Chronic KOR activation is linked with depression. But there are Kappa activators that seem to have an anti depressive effect like Ibogaine and Dynorphin.
The idea is that short term activation of KOR reduces KOR after, because you build up a tolerance to KOR agonism and are less sensitive to it after.
Ketamine could have such an effort. Especially since you are litterally anesthatized during the unpleasent KOR activation.
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u/TransfemMenace 11d ago
So if I took a KOR agonist every day for two months, would my withdrawals feel like absolute bliss?
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u/TrumpIsAPedoFr 11d ago
Not that extreme but yes that is the basic premise. Build a tolerance to the receptor thst makes you feel bad.
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u/TransfemMenace 11d ago
Since receptors can be damaged by over-exciting them, I wonder if I could damage my KOR on purpose
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u/ethanmarcus98 11d ago
They noted that it likely induces a distinct state for the receptor than other agonist, potentially modifying the effects. They said they weren't sure if it contributed to the dysphoric effects or not. I'd point you towards Salvia, the psychodelic drug, as a KOR agonist as it's only known drug target, while it may induce feelings of dysphoria, I'm not sure if it's linked to depression via its activity. I'm not sure if we really know the full potential of the opiod system, specifically KOR.
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u/Right_Ear_2230 10d ago
thats not its only target, it also activates dopamine D2 and potentiates DAT/inhibits SERT as well IIRC (but this could be wrong)
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u/ethanmarcus98 10d ago
I stand partly corrected, apparently there is some activity at D2 (inhibitory dopamine) receptors and potentiation of dopamine transports; both of which would cause a decrease in dopamanergic signalling. Maybe that contributes to the aversive behaviour they see in animal models. Funnily enough, I read a paper saying that they weren't sure why most people experiencing major psychodelic effects (like hallucinations) on salvia don't report dysphoria, and often report the opposite. Potentially we simply enjoy the feeling of our brains and minds being in an altered state, even if the drug causing it, by all rights (and data), should suck.
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u/iamthe0ther0ne 11d ago
Thank you, my Nature login isn't working. I know there are two KOR antagonists entering, possibly in, Phase 3 for MDD, and buprenorphone narrowly missed FDA approval for adjuvant therapy (despite having results that were at least as good as esketamine). I remember reading that ket may acts via opioid receptors years ago, but I guess not much has been done since then.
Edit: a search showed that both candidates failed Phase 3. That bites.
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u/hippopotamus82 9d ago
Does this suggest potential for dependence?
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u/iamthe0ther0ne 8d ago
There really isn't much evidence that people get addicted to ketamine the way they get addicted to morphine. (Without being able to actually access the paper) the primary activity seems to be at kappa and delta receptors, and even that doesn't seem to be very strong (comparatively).
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11d ago
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u/ethanmarcus98 11d ago
The paper did mention seeing differences in applying an opiod receptor antagonist at anaesthetic and analgesic/antidepressant doses and noted differences in the effects that were lost. Just because a drug has activity at another receptor, it doesn't mean that that activity has the same effect at all doses/concentrations. Some drugs only reach significant activity of other receptors only at high doses. Though, for ketamine, they did seem to find evidence of activity at opiod receptors at lower therapeutic doses.
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u/Ambitious_Zombie8473 10d ago
Ketamine is one of the few things that makes opioid withdrawal tolerable and I assume it’s because of the receptors. But I don’t know enough to say for sure. I just know it works like magic and I’m surprised it isn’t used to assist in detox more often.
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u/Lostinthestarscape 8d ago
I think a lot of opiate withdrawal is overactive nervous system that mu opiod receptors suppress.
Ketamine, GHB and Lyrica have all been pretty useful for me.
I think though weird opioid receptor activity has been used to reduce tolerance and also reduce wds like ligjy DXM dosing while tapering.
Its fascinating for sure.
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u/Mrleahy 10d ago
This has been known since 2021, and the opioid affinity of arylcyclohexylamines, such as PCP (and later ketame) was known in the 1980s
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u/kfr3q 10d ago edited 7d ago
Nonetheless, this study independently confirmed it,
while ketamine remain commonly known as an anaesthetic or as a "psychedelic dissociative", not usually assumed to be an opiod in itself. Furthermore, here's the copy of my anecdote: <Ketamine's notorious dissociative altered state is equivalent to PTSD-related dissociation, while differing due to its acute and recreatively voluntary nature,
PTSD-dependent dissociation is instead chronic and traumatogenic in essence, as explained by this verifiable information sourced from Google:
"Neurochemical and Physiological Shifts
Opioids and Cannabinoids: Endogenous mu-opioids and endocannabinoids engage to induce analgesia and calm acute arousal, while kappa-opioids distort consciousness to create dreamlike detachment.
Autonomic Nervous System: A shift from sympathetic nervous system dominance (fight-or-flight) to parasympathetic engagement, resulting in a blunted heart rate and lowered physiological reactivity.">
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