Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability
Open accessAbstract
Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States' FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine's abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.
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Reported μ and κ opioid receptor affinities for (S)- and (R)-ketamine fell in similar ranges.
“Likewise, similar range of affinity values at μ and κ opioid receptors were recently reported for (S)-ketamine (μ: Ki = 7 μM and κ: Ki = 19 μM) and (R)-ketamine (μ: Ki = 14 μM and κ: Ki = 40 μM) (Bonaventura et al.,”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
The Results section on in vitro target engagement reports micromolar affinities for both enantiomers at μ and κ opioid receptors, supporting the claim that they fall in similar ranges. However, the citing sentence swaps two values: the paper gives (R)-ketamine μ Ki = 19 ± 5 μM and (S)-ketamine κ Ki = 14 ± 7 μM, not 14 and 19 μM respectively. (LLM, conf=0.92)
Experimental — accuracy not yet measuredThe Joseph et al. conclusions depend on computational predictions, and their reported affinities and G protein recruitment values conflict with earlier work.
“However, this study’s main findings rely on computational analysis and the predicted affinity and G protein recruitment values it reports are not consistent with several prior publications (Bonaventura et al., 2021; Hirota et al., 1999; Nemeth et al., 2010).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
The Results section reports measured ketamine binding affinities and opioid-receptor signaling, including G-protein-sensitive [35S]GTPγS recruitment. Bonaventura et al. do not discuss Joseph et al.’s predictions or computational methods, so this source alone cannot establish that Joseph et al.’s values conflict with these measurements or that their conclusions depend on computational analysis. No page numbers were provided in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredLever responding for (S)-ketamine extinguished quickly, with under 10 responses in three hours on the first extinction day.
“conditioned lever responding for (S)-ketamine is rapidly extinguished with fewer than 10 responses over three hours on the first extinction training day”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
The Results (page not supplied) say that rats trained to respond for (S)-ketamine showed rapid extinction of drug seeking. The Methods (page not supplied) specify three-hour extinction sessions. Neither passage establishes fewer than 10 responses on the first extinction day. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBoth (S)- and (R)-ketamine act as agonists at μ and κ opioid receptors, and this activity might be required for their antidepressant effects.
“On the other hand, (S) and (R)-ketamine have agonist properties at μ and κ opioid receptors, an interaction which may be necessary for their antidepressant effects (Bonaventura et al., 2021).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
The Results section on in vitro target engagement reports that both enantiomers activate μ and κ opioid receptors, though (R)-ketamine is a weaker partial agonist. The Discussion links opioid receptors to ketamine’s antidepressant effects but notes conflicting human evidence and does not establish that this activity is necessary for the antidepressant effects of both enantiomers. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPreclinical evidence suggests ketamine therapy may be associated with risks such as increasing drug-dependence-related behaviors like self-administration, conditioned place preference, hyperlocomotion, and prepulse inhibition deficits.
“preclinical evidence suggests that ketamine therapy may be associated with certain risks, such as increasing drug-dependence-related behaviors like self-administration, conditioned place preference, hyperlocomotion, and prepulse inhibition deficits [155-157]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [155]
The Abstract and Discussion report that (S)-ketamine, but not (R)-ketamine, produced self-administration, conditioned place preference, and increased locomotor activity in preclinical models. The cited paper does not report prepulse inhibition deficits, and its findings do not apply equally to both enantiomers. No page numbers were supplied for these passages. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Preclinically, (R)-ketamine does not induce conditioned place preference, deficits in prepulse inhibition, or hyperlocomotion.
“Preclinically, (R)-ketamine does not induce conditioned place preference, deficits in prepulse inhibition, or hyperlocomotion [155-157]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [155]
The Results section reports no conditioned place preference with (R)-ketamine in male mice. It does not report a prepulse-inhibition test. Contrary to the hyperlocomotion claim, the Results state that 20 mg/kg (R)-ketamine increased locomotor activity; the finding absent for (R)-ketamine was locomotor sensitization over days (page not specified in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn mice, (S)-ketamine produced conditioned place preference, and in rats it supported operant lever pressing for infusion; (R)-ketamine largely did not.
“(S)-ketamine induces conditioned place preference in mice and conditioned operant lever responding for an infusion in rats whereas (R)-ketamine largely does not”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
At μ receptors, (S)-ketamine behaved as a partial agonist of G protein signaling; at κ receptors, it behaved as a full agonist.
“this study showed that (S)-ketamine acted as a partial G protein signaling agonist at μ opioid receptors (EC50 = 9 μM, Emax = 48%) and as a full agonist at κ opioid receptors (EC50 = 16 μM, Emax = 84 %)”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
Neither ketamine enantiomer activated β-arrestin.
“Interestingly, neither enantiomer activated ß-arrestin.”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
At both μ and κ opioid receptors, (R)-ketamine behaved as a weak partial agonist.
“whereas (R)-ketamine acted as a weak partial agonist at both μ opioid receptors (EC50 = 34 μM, Emax = 39 %) and κ opioid receptors (EC50 > 100 μM, Emax < 50%).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
Both (R)- and (S)-ketamine show agonist activity at μ and κ opioid receptors, and (S)-ketamine has greater affinity.
“Intriguingly, (R) and (S)-ketamine appear to have agonist properties at μ and κ opioid receptors, with (S)-ketamine having a higher affinity”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Bonaventura et al., 2021
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- Authors
- Bonaventura, J., Lam, S., Carlton, M., Boehm, M. A., Gomez, J. L., Solís, O., Sánchez-Soto, M., Morris, P. J., Fredriksson, I., Thomas, C. J., Sibley, D. R., Shaham, Y., Zarate, C. A., & Michaelides, M.
- Affiliations
- National Institutes of Health (US)
- National Institute on Drug Abuse (US)
- National Center for Advancing Translational Sciences (US)
- National Institute of Neurological Disorders and Stroke (US)
- National Institute of Mental Health (US)
- Corresponding author
- Bonaventura, Jordi
- Michaelides, Michael
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2021-04-15
- Volume
- 26
- Issue
- 11
- Pages
- 6704-6722
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC8517038
- OpenAlex
- W3156594315
- Cited by
- 271
- References
- 86
- Citations by year
- 2026: 35 · 2025: 46 · 2024: 64 · 2023: 56 · 2022: 53 · 2021: 17
- FWCI
- 27.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (DA000069)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- ketamine, enantiomers, esketamine, (R)-ketamine, abuse liability, self-administration, conditioned place preference, locomotor activity, locomotor sensitization, medial prefrontal cortex, dopamine, opioid receptors, mu-opioid receptor, kappa opioid receptor, antidepressant efficacy, treatment-resistant depression
- MeSH terms
- Animals, Antidepressive Agents, Depression, Ketamine, Stereoisomerism, Mice, Rats, Depressive Disorder, Treatment-Resistant
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