N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects
Open accessAbstract
Currently available antidepressants have a delayed onset and limited efficacy, highlighting the need for new, rapid and more efficacious agents. Ketamine, an NMDA receptor antagonist, has emerged as a new rapid-acting antidepressant, effective even in treatment resistant patients. However, ketamine induces undesired psychotomimetic and dissociative side effects that limit its clinical use. The d-stereoisomer of methadone (dextromethadone; REL-1017) is a noncompetitive NMDA receptor antagonist with an apparently favorable safety and tolerability profile. The current study examined the rapid and sustained antidepressant actions of d-methadone in several behavioral paradigms, as well as on mTORC1 signaling and synaptic changes in the medial prefrontal cortex (mPFC). A single dose of d-methadone promoted rapid and sustained antidepressant responses in the novelty-suppressed feeding test (NSFT), a measure of anxiety, and in the female urine sniffing test (FUST), a measure of motivation and reward. D-methadone also produced a rapid reversal of the sucrose preference deficit, a measure of anhedonia, in rats exposed to chronic unpredictable stress. D-methadone increased phospho-p70S6 kinase, a downstream target of mTORC1 in the mPFC, and intra-mPFC infusion of the selective mTORC1 inhibitor rapamycin blocked the antidepressant actions of d-methadone in the FUST and NSFT. D-methadone administration also increased levels of the synaptic proteins, PSD95, GluA1, and Synapsin 1 and enhanced synaptic function in the mPFC. Studies in primary cortical cultures show that d-methadone also increases BDNF release, as well as phospho-p70S6 kinase. These findings indicate that d-methadone induces rapid antidepressant actions through mTORC1-mediated synaptic plasticity in the mPFC similar to ketamine.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Esmethadone can alleviate neural dysfunction linked to symptoms of depression by boosting synapse and spine density and restoring spinogenesis, in addition to correcting depressive-like behaviors in animal models of depression.
“Esmethadone can also alleviate neural dysfunction linked to symptoms of depression by boosting the synapse and spine density and restoring spinogenesis, in addition to correcting depressive-like behaviors in animal models of depression. 378 , 477”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [477]
The Discussion reports that d-methadone reversed behavioral deficits in a rat model of depression, and the Abstract reports increased synaptic proteins and enhanced synaptic function. But the spine measurements section says it increased spine head diameter without changing dendritic spine density. The paper does not establish increased synapse density or restored spinogenesis. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe d-stereoisomer of methadone acts as an NMDA receptor antagonist, binding at the same synaptic site as ketamine and dizocilpine (MK-801).
“The d-stereoisomer likewise acts as an NMDA receptor antagonist, binding at the same synaptic site as ketamine and dizocilpine (MK-801) [131,132].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [131]
Human and animal trials have not linked d-methadone to any reinforcement, respiratory depression, or other adverse effects seen with opioids or ketamine.
“Human and animal trials have not linked d-methadone to any reinforcement, respiratory depression, or other adverse effects seen with opioids or ketamine [131].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [131]
Other exploratory antidepressant compounds that exemplify NMDAR antagonism without ketamine's associated psychotomimetic and dissociative properties include memantine, lanicemine, and CERC 301.
“Other exploratory AD compounds that exemplify NMDAR antagonism without ketamine’s associated psychotomimetic and dissociative properties include memantine [131], lanicemine [142], and CERC 301 [143].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [131]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.11.1905 · Cited by 5,643 · cited 1× · see citing works
“Moreover, these drugs require several weeks to produce an antidepressant response, a significant limitation for patients experiencing personal suffering and at risk of suicide [3].”
BackgroundA randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · see citing works
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P.-F., Kavalali, E. T., & Monteggia, L. M. (2011) · Nature · doi:10.1038/nature10130 · Cited by 1,926 · see citing works
Recurrence after recovery from major depressive disorder during 15 years of observational follow-up
Mueller, T. I., Leon, A. C., Keller, M. B., Solomon, D. A., Endicott, J., Coryell, W., Warshaw, M., & Maser, J. D. (1999) · American Journal of Psychiatry · doi:10.1176/ajp.156.7.1000 · Cited by 897 · see citing works
Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation
Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. N., Witztum, J., Shaver, D. C., Rosenthal, D. L., Alway, E. J., et al. (2019) · Science · doi:10.1126/science.aat8078 · Cited by 643 · see citing works
Bipolar and major depressive disorder: Neuroimaging the developmental-degenerative divide
Savitz, J., & Drevets, W. C. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2009.01.004 · Cited by 494 · see citing works
MacQueen, G. M., Yucel, K., Taylor, V. H., Macdonald, K., & Joffe, R. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.06.027 · Cited by 274 · see citing works
Lepack, A. E., Bang, E., Lee, B., Dwyer, J. M., & Duman, R. S. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.09.011 · Cited by 174 · see citing works
Self-citationLiu, R.-J., Duman, C., Kato, T., Hare, B., Lopresto, D., Bang, E., Burgdorf, J., Moskal, J., Taylor, J., Aghajanian, G., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.202 · Cited by 105 · see citing works
Self-citationBDNF Release and Signaling Are Required for the Antidepressant Actions of GLYX-13
Kato, T., Fogaça, M. V., Deyama, S., Li, X.-Y., Fukumoto, K., & Duman, R. S. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.220 · Cited by 88 · see citing works
Self-citationKetamine regulates the presynaptic release machinery in the hippocampus
Müller, H. K., Wegener, G., Liebenberg, N., Zarate, C. A., Popoli, M., & Elfving, B. (2013) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2013.03.008 · Cited by 61 · see citing works
Differential regulation of GluA1 expression by ketamine and memantine
Zhang, K., Yamaki, V. N., Wei, Z., Zheng, Y., & Cai, X. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.09.002 · Cited by 51 · see citing works
Hanania, T., Manfredi, P., Inturrisi, C., & Vitolo, O. V. (2020) · Experimental and Clinical Psychopharmacology · doi:10.1037/pha0000310 · Cited by 27 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 30
- Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-27.
- Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-4.
- Maeng S, Zarate CA Jr., Du J, Schloesser RJ, McCammon J, Chen G, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha- amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349-52.
- Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238-49.
- Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Sci- ence. 2010;329:959-64.
- Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neu- rotrophic factor Val66Met allele impairs basal and ketamine-stimulated synap- togenesis in prefrontal cortex. Biol Psychiatry. 2012;71:996-1005.
- Harward SC, Hedrick NG, Hall CE, Parra-Bueno P, Milner TA, Pan E, et al. Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature. 2016;538:99-103.
- Liu RJ, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of sub- threshold doses of ketamine. Neuropsychopharmacology. 2013;38:2268-77.
- Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with keta- mine use in depression: a systematic review. Lancet Psychiatry. 2018;5:65-78.
- Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, et al. Char- acterization 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.
- Callahan RJ, Au JD, Paul M, Liu C, Yost CS. Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: stereospecific and subunit effects. Anesth Analg. 2004;98:653-9.
- 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 fore- brain and spinal cord. Neurosci Lett. 1997;223:5-8.
- Matsui A, Williams JT. Activation of micro-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L-and D-methadone in rat locus coeruleus. Br J Pharm. 2010;161:1403-13.
- Chizh BA, Schlutz H, Scheede M, Englberger W. The N-methyl-D-aspartate antagonistic and opioid components of d-methadone antinociception in the rat spinal cord. Neurosci Lett. 2000;296:117-20.
- Franklin TC, Wohleb ES, Zhang Y, Fogaca M, Hare B, Duman RS. Persistent increase in microglial RAGE contributes to chronic stress-induced priming of depressive-like behavior. Biol Psychiatry. 2018;83:50-60.
- Malkesman O, Scattoni ML, Paredes D, Tragon T, Pearson B, Shaltiel G, et al. The female urine sniffing test: a novel approach for assessing reward-seeking beha- vior in rodents. Biol Psychiatry. 2010;67:864-71.
- Rodriguez A, Ehlenberger DB, Dickstein DL, Hof PR, Wearne SL. Automated three- dimensional detection and shape classification of dendritic spines from fluores- cence microscopy images. PLoS ONE. 2008;3:e1997.
- Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:140-4.
- Willner P. The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiol Stress. 2017;6:78-93.
- Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacol (Berl). 1987;93:358-64.
- Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the anti- depressant effects of mGluR(2)/(3) blockade. Int J Neuropsychopharmacol. 2012;15:429-34.
- Carreno FR, Donegan JJ, Boley AM, Shah A, DeGuzman M, Frazer A, et al. Acti- vation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol Psy- chiatry. 2016;21:1298-308.
- Liu CY, Jiang XX, Zhu YH, Wei DN. Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine produces antidepressant effects in rats: role of brain-derived neurotrophic factor. Neuroscience. 2012;223:219-24.
- Liu RJ, Ota KT, Dutheil S, Duman RS, Aghajanian GK. Ketamine strengthens CRF- activated amygdala inputs to basal dendrites in mPFC layer V pyramidal cells in the prelimbic but not infralimbic subregion, a key suppressor of stress responses. Neuropsychopharmacology. 2015;40:2066-75.
- Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced anti- depressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2014;29:419-23.
- Fukumoto K, Fogaca MV, Liu RJ, Duman C, Kato T, Li XY, et al. Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proc Natl Acad Sci USA. 2019;116:297-302.
- Ghosal S, Bang E, Yue W, Hare BD, Lepack AE, Girgenti MJ, et al. Activity- dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biol Psychiatry. 2018;83:29-37.
- Fogaça MV, Campos AC, Coelho LD, Duman RS, Guimaraes FS. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endo- cannabinoid system: role of neurogenesis and dendritic remodeling. Neuro- pharmacology. 2018;135:22-33.
- Cook SC, Wellman CL. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol. 2004;60:236-48.
- Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL. Brain penetration of methadone (R)-and (S)-enantiomers is greatly increased by P- glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice. Psychopharmacol (Berl). 2004;173:132-8.
Cited by
Sorted by citations
Major depressive disorder: hypothesis, mechanism, prevention and treatment
Cui, L., Li, S., Wang, S., Wu, X., Liu, Y., Yu, W., Wang, Y., Tang, Y., Xia, M., & Li, B. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01738-y · Cited by 1,061 · see citing works
Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels
Hansen, K. B., Wollmuth, L. P., Bowie, D., Furukawa, H., Menniti, F. S., Sobolevsky, A. I., Swanson, G. T., Swanger, S. A., Greger, I. H., Nakagawa, T., et al. (2021) · Pharmacological Reviews · doi:10.1124/pharmrev.120.000131 · Cited by 686 · see citing works
Duman, R. S., Deyama, S., & Fogaça, M. V. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14630 · Cited by 321 · see citing works
Self-citationNovel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status
Henter, I. D., Park, L. T., & Zarate, C. A. (2021) · CNS Drugs · doi:10.1007/s40263-021-00816-x · Cited by 142 · see citing works
Fogaça, M. V., Wu, M., Li, C., Li, X.-Y., Picciotto, M. R., & Duman, R. S. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00916-y · Cited by 129 · see citing works
Self-citationFava, M., Stahl, S., Pani, L., De Martin, S., Pappagallo, M., Guidetti, C., Alimonti, A., Bettini, E., Mangano, R. M., Wessel, T., et al. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2021.21020197 · Cited by 83 · see citing works
Self-citationNeurobiology of the rapid-acting antidepressant effects of ketamine: impact and opportunities
Shinohara, R., Aghajanian, G. K., & Abdallah, C. G. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.006 · Cited by 54 · see citing works
Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression
Vecera, C. M., C. Courtes, A., Jones, G., Soares, J. C., & Machado-Vieira, R. (2023) · Pharmaceuticals · doi:10.3390/ph16111572 · Cited by 48 · see citing works
“The d-stereoisomer likewise acts as an NMDA receptor antagonist, binding at the same synaptic site as ketamine and dizocilpine (MK-801) [131,132].”
BackgroundClinical specificity profile for novel rapid acting antidepressant drugs
Scala, M., Fanelli, G., De Ronchi, D., Serretti, A., & Fabbri, C. (2023) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000488 · Cited by 41 · see citing works
Bettini, E., Stahl, S. M., De Martin, S., Mattarei, A., Sgrignani, J., Carignani, C., Nola, S., Locatelli, P., Pappagallo, M., Inturrisi, C. E., et al. (2022) · Pharmaceuticals · doi:10.3390/ph15080997 · Cited by 31 · see citing works
De Martin, S., Gabbia, D., Folli, F., Bifari, F., Fiorina, P., Ferri, N., Stahl, S., Inturrisi, C. E., Pappagallo, M., Traversa, S., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.671859 · Cited by 28 · see citing works
All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants
Freudenberg, F., Reif-Leonhard, C., Dawson, G. R., McKernan, R. M., & Reif, A. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107918 · Cited by 23 · see citing works
- Authors
- Fogaça, M. V., Fukumoto, K., Franklin, T., Liu, R.-J., Duman, C. H., Vitolo, O. V., & Duman, R. S.
- Affiliations
- Yale University (US)
- Relmada Therapeutics, Inc. (United States) (US)
- Corresponding author
- Duman, Ronald S.
- Venue
- Neuropsychopharmacology
- Published
- 2019-08-27
- Volume
- 44
- Issue
- 13
- Pages
- 2230-2238
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC6898593
- OpenAlex
- W2970683278
- Cited by
- 82
- References
- 13
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 12 · 2023: 16 · 2022: 18 · 2021: 13 · 2020: 8 · 2019: 1
- FWCI
- 6.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Relmada Therapeutics Inc
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- dextromethorphan, NMDA receptor antagonists, rapid-acting antidepressants, mTORC1 signaling, p70 S6 kinase, medial prefrontal cortex, synaptic plasticity, anhedonia, chronic unpredictable mild stress, BDNF release, ketamine, rapamycin, PSD-95, GluR1, synapsin-1
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Antidepressive Agents, Ketamine, Male, Methadone, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Prefrontal Cortex, Excitatory Postsynaptic Potentials, Dendritic Spines
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
