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Longitudinal peripheral DNA methylation remodeling following ketamine-assisted psychotherapy in major depressive disorder

Arghavan Nepton, Sonya C. Faber, Zachary A. Kaminsky, Mario Nucci, Hesam Farahani, Monnica T. Williams, Sergio Pérez Rosal

Epigenetics October 15, 2026 DOI: 10.1080/15592294.2026.2731659 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Longitudinal observational study (within-subject, pre-post DNA methylation analysis) Peer reviewed
Sample size 10
Population Adults with major depressive disorder
Interventions Ketamine ketamine-assisted psychotherapy
Duration Three sessions of intranasal racemic ketamine; two pre-treatment assessments (T1, T2) and one post-treatment assessment (T3)
Measures Beck Depression Inventory–II, Illumina MethylationEPIC v2.0 BeadChip
Topics Depression Esketamine Ketamine Psychedelic-assisted therapy
Key findings Depressive symptoms improved markedly, with mean Beck Depression Inventory–II scores declining from the severe to the mild range. Of 802,595 CpG loci, 962 were retained after filtering (517 gene-annotated), and exploratory enrichment of a 603-locus set identified NOTCH1-related Reactome terms driven by NOTCH1, DLL1, and ADAM17. The authors state the findings do not establish brain-specific pathway activation or causality.

Abstract

Ketamine produces rapid antidepressant effects, but the molecular processes associated with their persistence remain poorly defined in humans. We examined longitudinal DNA methylation changes in 10 adults with major depressive disorder undergoing ketamine-assisted psychotherapy using two pre-treatment assessments (T1, T2) and one post-treatment assessment (T3). Participants received three sessions of intranasal racemic ketamine within a structured psychotherapy protocol. Buccal DNA methylation was measured using the Illumina MethylationEPIC v2.0 BeadChip. Depressive symptoms improved markedly following treatment, with mean Beck Depression Inventory–II scores declining from the severe to the mild range (p < .001). Of 802,595 CpG loci evaluated, 20,770 met the nominal T3-versus-T2 screening criterion. Sequential filtering for methylation-change magnitude and movement relative to pre-treatment fluctuation identified 962 retained CpG loci, including 517 retained gene-annotated loci. A supplementary linear mixed-effects analysis modeled repeated measurements within participants across the 603 preselected gene-annotated magnitude-filtered loci; because these loci were selected using the same contrast and cohort, this analysis was not treated as independent confirmation. Exploratory enrichment analysis of this 603-locus set identified NOTCH1-related Reactome terms driven by NOTCH1, DLL1, and ADAM17. Within the retained signature, multiple core and adjacent Notch-related components formed a coherent signaling module spanning ligand, receptor processing, transcriptional regulation, and pathway cross-talk. These findings identify a structured peripheral methylation signature associated with ketamine-assisted psychotherapy. They do not establish brain-specific pathway activation or causality, but provide a longitudinal basis for investigating regulatory adaptations accompanying clinical improvement.

In the evidence

This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.

  • State of the evidence: Ketamine and psychedelic-assisted therapy Supports

    Depressive symptoms declined markedly (BDI-II from severe to mild range) after three intranasal ketamine sessions with psychotherapy, alongside exploratory DNA methylation changes the authors say do not establish causality.

    Synthesized

  • State of the evidence: Ketamine for depression Supports

    Depressive symptoms declined markedly after ketamine-assisted psychotherapy, alongside exploratory DNA methylation changes; authors state findings do not establish causality.

    Synthesized

Comparable studies

Other non-randomized and open-label trials on ketamine and psychedelic-assisted therapy, most cited first.

Study Year Design Participants
Ketamine Psychedelic Therapy (KPT): A Review of the Results of Ten Years of Research Alcoholic patients 1997 Controlled clinical trial n = 211
Ketamine-assisted psychotherapy provides lasting and effective results in the treatment of depression, anxiety and post traumatic stress disorder at 3 and 6 months: Findings from a large single-arm retrospective effectiveness trial Adults with a history of depression, anxiety, or PTSD who had not responded to prior... 2023 Retrospective single-arm effectiveness trial n = 1,806
Protocol of an open-label safety and feasibility pilot study of ketamine-assisted psychotherapy for methamphetamine use disorder (the KAPPA trial). Adults meeting DSM-5-TR criteria for methamphetamine use disorder seeking to reduce or... 2025 Open-label, single-arm clinical trial n = 20
Exploratory non-randomized clinical trial of subcutaneous esketamine in treatment-resistant depression: Effects of ketamine-assisted psychotherapy Patients with treatment-resistant depression 2026 Nonrandomized, open-label clinical trial n = 46
Navigating ‘k-land’: a qualitative exploration of participants’ experiences of ketamine-assisted psychotherapy for methamphetamine use disorder Participants with methamphetamine use disorder who completed core components of... 2026 Qualitative study embedded within an open-label pilot trial n = 14

Citations in the library

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Depression Esketamine Ketamine Psychedelic-assisted therapy

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Ketamine and psychedelic-assisted therapy Ketamine for depression