Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Time will tell. Reply to “Comments to pharmacological and behavioral divergence of ketamine enantiomers by Jordi Bonaventura et al.” by Chen et al.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout


  1. Chen G, Mannens G, De Boeck M, Daly EJ, Canuso CM, Teuns G, et al. Comments to pharmacological and behavioral divergence of ketamine enantiomers by Jordi Bonaventura et al. Mol Psychiatry. 2022. In press.

  2. Bonaventura J, Lam S, Carlton M, Boehm MA, Gomez JL, Solís O, et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry. 2021.

  3. Hess EM, Riggs LM, Michaelides M, Gould TD. Mechanisms of ketamine and its metabolites as antidepressants. Biochem Pharmacol. 2022;197:114892.

    Article  CAS  Google Scholar 

  4. Pacheco DDF, Romero TRL, Duarte IDG. Central antinociception induced by ketamine is mediated by endogenous opioids and μ- and δ-opioid receptors. Brain Res. 2014;1562:69–75.

    Article  CAS  Google Scholar 

  5. Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175:1205–15.

    Article  Google Scholar 

  6. Fava M, Stahl S, Pani L, De Martin S, Pappagallo M, Guidetti C, et al. REL-1017 (Esmethadone) as Adjunctive treatment in patients with major depressive disorder: a phase 2a randomized double-blind trial. Am J Psychiatry. 2022;179:122–31.

  7. Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995;274:1263–70.

  8. Matsui A, Williams JT. Activation of µ-opioid receptors and block of KIR3 potassium channels and NMDA receptor conductance by l- and d-methadone in rat locus coeruleus. Br J Pharmacol. 2010;161:1403–13.

    Article  CAS  Google Scholar 

  9. Gorman AL, Elliott KJ, Inturrisi CE. The d- and l- isomers of methadone bind to the non-competitive site on the N-methyl-d-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997;223:5–8.

    Article  CAS  Google Scholar 

  10. Kenakin T, Christopoulos A. Analytical pharmacology: the impact of numbers on pharmacology. Trends Pharmacol Sci. 2011;32:189–96.

    Article  CAS  Google Scholar 

  11. Zhang JC, Li SX, Hashimoto K. R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav. 2014;116:137–41.

    Article  CAS  Google Scholar 

  12. Zanos P, Highland JN, Liu X, Troppoli TA, Georgiou P, Lovett J, et al. (R)-Ketamine exerts antidepressant actions partly via conversion to (2R,6R)-hydroxynorketamine, while causing adverse effects at sub-anaesthetic doses. Br J Pharmacol. 2019;176:2573–92.

    Article  CAS  Google Scholar 

  13. Shaffer CL, Osgood SM, Smith DL, Liu J, Trapa PE. Enhancing ketamine translational pharmacology via receptor occupancy normalization. Neuropharmacology. 2014;86:174–80.

    Article  CAS  Google Scholar 

  14. De Luca MT, Badiani A. Ketamine self-administration in the rat: evidence for a critical role of setting. Psychopharmacology. 2011;214:549–56.

    Article  Google Scholar 

  15. Geisslinger G, Hering W, Thomann P, Knoll R, Kamp HD, Brune K. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br J Anaesth. 1993;70:666–71.

    Article  CAS  Google Scholar 

  16. Portmann S, Kwan HY, Theurillat R, Schmitz A, Mevissen M, Thormann W. Enantioselective capillary electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize ketamine and norketamine in vitro. J Chromatogr A. 2010;1217:7942–8.

    Article  CAS  Google Scholar 

  17. Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther. 1992;260:1209–13.

  18. Vollenweider FX, Leenders KL, Øye I, Hell D, Angst J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol. 1997;7:25–38.

    Article  CAS  Google Scholar 

  19. Heifets BD, Bentzley BS, Williams N, Schatzberg AF. Unraveling the opioid actions of S-ketamine and R-ketamine: comment on Bonaventura et al. Mol Psychiatry. 2021;26:6104–6.

    Article  Google Scholar 

  20. Leal GC, Bandeira ID, Correia-Melo FS, Telles M, Mello RP, Vieira F, et al. Intravenous arketamine for treatment-resistant depression: open-label pilot study. Eur Arch Psychiatry Clin Neurosci. 2021;271:577–82.

    Article  Google Scholar 

  21. Takahashi N, Yamada A, Shiraishi A, Shimizu H, Goto R, Tominaga Y. Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study. BMC Psychiatry. 2021;21:1–13.

    Article  Google Scholar 

  22. Sapkota A, Khurshid H, Qureshi IA, Jahan N, Went TR, Sultan W, et al. Efficacy and safety of intranasal esketamine in treatment-resistant depression in adults: a systematic review. Cureus. 2021;13:e17352.

  23. Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. Letters to the editor. Am J Psychiatry. 2017;174:695–6.

  24. Passie T, Adams HA, Logemann F, Brandt SD, Wiese B, Karst M. Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers. Eur Neuropsychopharmacol. 2021;44:92–104.

    Article  CAS  Google Scholar 

  25. Hashimoto K. Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochem Pharmacol. 2020;177:113935.

  26. Brady JV. Animal models for assessing drugs of abuse. Neurosci Biobehav Rev. 1991;15:35–43.

    Article  CAS  Google Scholar 

  27. Schatzberg AF. A word to the wise about ketamine. Am J Psychiatry. 2014;171:262–4.

    Article  Google Scholar 

  28. Schatzberg AF. A word to the wise about intranasal esketamine. Am J Psychiatry. 2019;176:422–4.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations



JB, YS, CJZ, and MM wrote the paper with input from all coauthors. All authors critically reviewed the content and approved the final version before submission. This work was supported by the NIDA Intramural Research Program (ZIA000069), and by Grants RYC-2019-027371-I (JB) and PID2020-117989RA-I00 (JB) funded by MCIN/AEI /10.13039/501100011033 and by “ESF Investing in your future”. .

Corresponding authors

Correspondence to Jordi Bonaventura or Michael Michaelides.

Ethics declarations

Competing interests

CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ is listed as co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereo-isomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. PJM and CJT are coinventors on patents regarding the use and methods of production for (2R,6R)-hydroxynorketamine. They have assigned their patent rights to the US government but will share a percentage of any royalties that may be received by the government. MM has received research funding from AstraZeneca, Redpin Therapeutics, and Attune Neurosciences. All other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bonaventura, J., Lam, S., Carlton, M. et al. Time will tell. Reply to “Comments to pharmacological and behavioral divergence of ketamine enantiomers by Jordi Bonaventura et al.” by Chen et al.. Mol Psychiatry 27, 1863–1865 (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links