Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone

Molecular Psychiatry (2023)Cite this article

Subjects

Abstract

(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal1 receptor (Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use. One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Methadone and its enantiomers are MOR agonists.
Fig. 2: Analgesic, cataleptic and differential abuse liability profile of (R,S)-MTD, (R)-MTD, and (S)-MTD.
Fig. 3: VTA-dependent neurochemical and behavioral effects of (R)-MTD and (S)-MTD.
Fig. 4: MOR-Gal1R heteromer-dependent loss of efficacy of (S)-MTD.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Dole VP, Nyswander M. A medical treatment for diacetylmorphine (heroin) addiction. A clinical trial with methadone hydrochloride. JAMA. 1965;193:646–50.

    Article  PubMed  CAS  Google Scholar 

  2. Salsitz E, Wiegand T. Pharmacotherapy of opioid addiction: “putting a real face on a false demon". J Med Toxicol. 2016;12:58–63.

    Article  PubMed  CAS  Google Scholar 

  3. Chem KK. Pharmacology of methadone and related compounds. Ann N Y Acad Sci. 1948;51:83–97.

    Article  PubMed  CAS  Google Scholar 

  4. Casati A, Piontek D, Pfeiffer-Gerschel T. Patterns of non-compliant buprenorphine, levomethadone, and methadone use among opioid dependent persons in treatment. Subst Abuse Treat Prev Policy. 2014;9:19.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. Fogaça MV, Fukumoto K, Franklin T, Liu RJ, Duman CH, Vitolo OV, et al. N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects. Neuropsychopharmacology. 2019;44:2230–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hanania T, Manfredi P, Inturrisi C, Vitolo OV. The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats. Exp Clin Psychopharmacol. 2020;28:196–201.

    Article  PubMed  CAS  Google Scholar 

  8. De Martin S, Gabbia D, Folli F, Bifari F, Fiorina P, Ferri N, et al. REL-1017 (esmethadone) increases circulating BDNF levels in healthy subjects of a phase 1 clinical study. Front Pharmacol. 2021;12:671859.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, et al. Characterization of the safety and pharmacokinetic profile of D-methadone, a novel N-Methyl-D-aspartate receptor antagonist in healthy, opioid-naive subjects: results of two phase 1 studies. J Clin Psychopharmacol. 2019;39:226–37.

    Article  PubMed  CAS  Google Scholar 

  10. 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  PubMed  CAS  Google Scholar 

  11. 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  PubMed  PubMed Central  Google Scholar 

  12. Bonaventura J, Lam S, Carlton M, Boehm MA, Gomez JL, Solis O, et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry. 2021;26:6704–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Klein ME, Chandra J, Sheriff S, Malinow R. Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents. Proc Natl Acad Sci USA. 2020;117:2656–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Levinstein MR, Carlton ML, Di Ianni T, Ventriglia EN, Rizzo A, Gomez JL, et al. Mu opioid receptor activation mediates (S)-ketamine reinforcement in rats: implications for abuse liability. Biol Psychiatry. 2023;93:1118–26.

    Article  PubMed  CAS  Google Scholar 

  15. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56:PL45–50.

    Article  PubMed  CAS  Google Scholar 

  16. Cai NS, Quiroz C, Bonaventura J, Bonifazi A, Cole TO, Purks J, et al. Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids. J Clin Invest. 2019;129:2730–44.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Spiga R, Grabowski J, Silverman PB, Meisch RA. Human methadone self-administration: effects of dose and ratio requirement. Behav Pharmacol. 1996;7:130–7.

    Article  PubMed  CAS  Google Scholar 

  18. Martin TJ, Kim SA, Buechler NL, Porreca F, Eisenach JC. Opioid self-administration in the nerve-injured rat: relevance of antiallodynic effects to drug consumption and effects of intrathecal analgesics. Anesthesiology. 2007;106:312–22.

    Article  PubMed  CAS  Google Scholar 

  19. Steinpreis RE, Rutell AL, Parrett FA. Methadone produces conditioned place preference in the rat. Pharmacol Biochem Behav. 1996;54:339–41.

    Article  PubMed  CAS  Google Scholar 

  20. O’Connor EC, Chapman K, Butler P, Mead AN. The predictive validity of the rat self-administration model for abuse liability. Neurosci Biobehav Rev. 2011;35:912–38.

    Article  PubMed  Google Scholar 

  21. Kalvass JC, Maurer TS, Pollack GM. Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo p-glycoprotein efflux ratios. Drug Metab Dispos. 2007;35:660–6.

    Article  PubMed  CAS  Google Scholar 

  22. Holm KM, Linnet K. Determination of the unbound fraction of R- and S-methadone in human brain. Int J Legal Med. 2016;130:1519–26.

    Article  PubMed  Google Scholar 

  23. Smith DA, Di L, Kerns EH. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery. Nat Rev Drug Discov. 2010;9:929–39.

    Article  PubMed  CAS  Google Scholar 

  24. Allouche S, Noble F, Marie N. Opioid receptor desensitization: mechanisms and its link to tolerance. Front Pharmacol. 2014;5:280.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Finn AK, Whistler JL. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron. 2001;32:829–39.

    Article  PubMed  CAS  Google Scholar 

  26. Brase DA, Loh HH, Way EL. Comparison of the effects of morphine on locomotor activity, analgesia and primary and protracted physical dependence in six mouse strains. J Pharmacol Exp Therapeutics. 1977;201:368–74.

    CAS  Google Scholar 

  27. Kuschinsky K, Hornykiewicz O. Effects of morphine on striatal dopamine metabolism: possible mechanism of its opposite effect on locomotor activity in rats and mice. Eur J Pharmacol. 1974;26:41–50.

    Article  PubMed  CAS  Google Scholar 

  28. Middaugh LD, Kapetanovic IM, Sweeney DJ, Ingram DK. Methadone in brain and its effects on locomotor activity of young and aged mice. Neurobiol Aging. 1983;4:321–6.

    Article  PubMed  CAS  Google Scholar 

  29. Tzschentke TM, Schmidt WJ. Morphine-induced catalepsy is augmented by NMDA receptor antagonists, but is partially attenuated by an AMPA receptor antagonist. Eur J Pharmacol. 1996;295:137–46.

    Article  PubMed  CAS  Google Scholar 

  30. Costall B, Naylor RJ. On catalepsy and catatonia and the predictability of the catalepsy test for neuroleptic activity. Psychopharmacologia. 1974;34:233–41.

    Article  PubMed  CAS  Google Scholar 

  31. Zarrindast MR, Zarghi A. Morphine stimulates locomotor activity by an indirect dopaminergic mechanism: possible D-1 and D-2 receptor involvement. Gen Pharmacol. 1992;23:1221–5.

    Article  PubMed  CAS  Google Scholar 

  32. Chefer VI, Kieffer BL, Shippenberg TS. Basal and morphine-evoked dopaminergic neurotransmission in the nucleus accumbens of MOR- and DOR-knockout mice. Eur J Neurosci. 2003;18:1915–22.

    Article  PubMed  Google Scholar 

  33. Hnasko TS, Sotak BN, Palmiter RD. Morphine reward in dopamine-deficient mice. Nature. 2005;438:854–7.

    Article  PubMed  CAS  Google Scholar 

  34. Matsui A, Jarvie BC, Robinson BG, Hentges ST, Williams JT. Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal. Neuron. 2014;82:1346–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Santos EJ, Banks ML, Negus SS. Role of efficacy as a determinant of locomotor activation by mu opioid receptor ligands in female and male mice. J Pharmacol Exp Ther. 2022;382:44–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Vezina P, Kalivas PW, Stewart J. Sensitization occurs to the locomotor effects of morphine and the specific mu opioid receptor agonist, DAGO, administered repeatedly to the ventral tegmental area but not to the nucleus accumbens. Brain Res. 1987;417:51–58.

    Article  PubMed  CAS  Google Scholar 

  37. De Oliveira PA, Moreno E, Casajuana-Martin N, Casado-Anguera V, Cai NS, Camacho-Hernandez GA, et al. Preferential Gs protein coupling of the galanin Gal1 receptor in the μ-opioid-Gal1 receptor heterotetramer. Pharmacol Res. 2022;182:106322.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhuang Y, Wang Y, He B, He X, Zhou XE.Guo S,et al. Molecular recognition of morphine and fentanyl by the human mu-opioid receptor. Cell. 2022;185:4361–75.e4319.

  39. Huang W, Manglik A, Venkatakrishnan AJ, Laeremans T, Feinberg EN, Sanborn AL, et al. Structural insights into μ-opioid receptor activation. Nature. 2015;524:315–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Henningfield J, Gauvin D, Bifari F, Fant R, Shram M, Buchhalter A, et al. REL-1017 (esmethadone; D-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats. Sci Rep. 2022;12:11389.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Holtman JR Jr., Wala EP. Characterization of the antinociceptive and pronociceptive effects of methadone in rats. Anesthesiology. 2007;106:563–71.

    Article  PubMed  CAS  Google Scholar 

  42. Moroni F, Cheney DL, Peralta E, Costa E. Opiate receptor agonists as modulators of gamma-aminobutyric acid turnover in the nucleus caudatus, globus pallidus and substantia nigra of the rat. J Pharmacol Exp Therapeutics. 1978;207:870–7.

    CAS  Google Scholar 

  43. Turski L, Havemann U, Kuschinsky K. The role of the substantia nigra in motility of the rat. Muscular rigidity, body asymmetry and catalepsy after injection of morphine into the nigra. Neuropharmacology. 1983;22:1039–48.

    Article  PubMed  CAS  Google Scholar 

  44. Zangen A, Ikemoto S, Zadina JE, Wise RA. Rewarding and psychomotor stimulant effects of endomorphin-1: anteroposterior differences within the ventral tegmental area and lack of effect in nucleus accumbens. J Neurosci. 2002;22:7225–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. VanderWende C, Spoerlein MT. Morphine-induced catalepsy in mice. Modification by drugs acting on neurotransmitter systems. Neuropharmacology. 1979;18:633–7.

    Article  PubMed  CAS  Google Scholar 

  46. Badiani A, Belin D, Epstein D, Calu D, Shaham Y. Opiate versus psychostimulant addiction: the differences do matter. Nat Rev Neurosci. 2011;12:685–700.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Blum K, Thanos PK, Oscar-Berman M, Febo M, Baron D, Badgaiyan RD, et al. Dopamine in the brain: hypothesizing surfeit or deficit links to reward and addiction. J Reward Defic Syndr. 2015;1:95–104.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Nutt DJ, Lingford-Hughes A, Erritzoe D, Stokes PR. The dopamine theory of addiction: 40 years of highs and lows. Nat Rev Neurosci. 2015;16:305–12.

    Article  PubMed  CAS  Google Scholar 

  49. Corre J, van Zessen R, Loureiro M, Patriarchi T, Tian L, Pascoli V, et al. Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement. Elife. 2018;7:e39945.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Grilo LS, Carrupt PA, Abriel H. Stereoselective inhibition of the hERG1 potassium channel. Front Pharmacol. 2010;1:137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Eap CB, Crettol S, Rougier JS, Schlapfer J, Sintra Grilo L, Deglon JJ, et al. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther. 2007;81:719–28.

    Article  PubMed  CAS  Google Scholar 

  52. Andrassy G, Szabo A. Methadone-induced QTc prolongation: is it due to stereoselective block of hERG or to inappropriate QT interval correction? Clin Pharmacol Ther. 2008;83:671. author reply 672

    Article  PubMed  CAS  Google Scholar 

  53. Maxwell JC, McCance-Katz EF. Indicators of buprenorphine and methadone use and abuse: what do we know? Am J Addictions. 2010;19:73–88.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Shelley Jackson, PhD and Lindsay Kryszak from the Translational Analytical Core at NIDA. We also than Rik Kline, PhD from the Chemistry and Pharmaceutics Branch and the NIDA Drug Supply Program and David White, PhD from the Medications Discovery and Toxicology Branch at NIDA.

Funding

This work was supported by the intramural funds of the National Institute on Drug Abuse (ZIA DA000493, ZIA DA000069, ZIA DA000522); grant PID2020-113938RB-I00 (NL, VC-A, EM, VC), PID2022-140912OB-I00 (LP), and Juan de la Cierva fellowship FJC2019-041020-I (VC-A) from the Spanish MCIN/AEI/10.13039/501100011033; “Generalitat de Catalunya”, Spain, grant 2021-SGR-00230 (NL, EM, VC). D Weinshenker was supported by extramural funding from NIDA (DA049257).

Author information

Author notes

  1. These authors contributed equally: Marjorie R. Levinstein, Paulo A. De Oliveira, Nil Casajuana-Martin.

Authors and Affiliations

  1. Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA

    Marjorie R. Levinstein, Reece C. Budinich, Emilya N. Ventriglia & Michael Michaelides

  2. Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA

    Paulo A. De Oliveira, Cesar Quiroz, William Rea & Sergi Ferré

  3. Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193, Barcelona, Spain

    Nil Casajuana-Martin & Leonardo Pardo

  4. Johns Hopkins Drug Discovery, Neurology and Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Rana Rais

  5. Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institut de Biomedicina de la Universitat de Barcelona, 08028, Barcelona, Spain

    Natàlia Llopart, Verònica Casadó-Anguera, Estefanía Moreno & Vicent Casadó

  6. Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA

    Donna Walther, Grant C. Glatfelter & Michael H. Baumann

  7. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA

    David Weinshenker

  8. Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health Intramural Research Program, Bethesda, MD, 20892, USA

    Carlos A. Zarate Jr.

  9. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Michael Michaelides

Authors
  1. Marjorie R. Levinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paulo A. De Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nil Casajuana-Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cesar Quiroz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reece C. Budinich
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rana Rais
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. William Rea
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Emilya N. Ventriglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Natàlia Llopart
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Verònica Casadó-Anguera
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Estefanía Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Donna Walther
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Grant C. Glatfelter
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Weinshenker
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Carlos A. Zarate Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Vicent Casadó
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michael H. Baumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Leonardo Pardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Sergi Ferré
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Michael Michaelides
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Designed and performed experiments, analyzed data, and wrote the manuscript: MRL, PADO, MHB, Designed experiments, analyzed data, and wrote the manuscript: SF, MM, Designed and performed experiments, analyzed data: CQ, RR, VCA, Performed experiments and analyzed data: WR, NL, D Walther, Performed computational models, analyzed data and wrote the manuscript: NC, LP, Designed experiments and analyzed data: EM, VC, Performed experiments: ENV, RCB, GCG, Contributed resources and reagents and contributed to writeup of the paper: D Weinshenker, CAZ, All coauthors reviewed the manuscript and provided comments.

Corresponding authors

Correspondence to Sergi Ferré or Michael Michaelides.

Ethics declarations

Competing interests

MM has received research funding from AstraZeneca, Redpin Therapeutics, and Attune Neurosciences. CAZ is a full-time U.S government employee. He is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ is listed as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. CAZ is listed as 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 post-traumatic stress disorders. CAZ has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Levinstein, M.R., De Oliveira, P.A., Casajuana-Martin, N. et al. Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02353-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41380-023-02353-z

Search

Advanced search

Quick links