When the Dissociation Isn’t Enough: A Reassessment of Ketamine in Depression Treatment

What the New Study Actually Found

A recent randomized, double-blind, active-placebo-controlled inpatient trial — the KARMA‑Dep 2 trial — compared serial intravenous infusions of racemic ketamine (0.5 mg/kg) to the sedative midazolam (0.045 mg/kg) in adults hospitalised with moderate to severe major depressive episodes. Participants continued usual inpatient psychiatric care; infusions were administered up to eight times, twice weekly, with follow-up extending to 24 weeks. While mood improved in both arms, there was no statistically significant difference between ketamine and midazolam on the primary outcome (MADRS score change at end-of-treatment) (Jelovac et al., 2025). Furthermore, no meaningful differences emerged across secondary outcomes: self-report symptoms, cognition, cost-effectiveness or quality of life (Jelovac et al., 2025).

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In short: adjunctive ketamine infusions did not outperform an active psychoactive comparator in this rigorous inpatient setting.

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Why This Doesn’t Mean “Ketamine Doesn’t Work”

It’s important to nuance this finding rather than swing to an “it failed completely” reading.

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1. Earlier signal of rapid benefit
Meta-analytic and review data show that a single sub-anesthetic IV ketamine infusion can lead to rapid improvements in depression symptoms (within hours) in treatment-resistant depression (TRD) populations, with response rates up to ~50-70%, though typically with effect durations limited to several days (aan het Rot et al., 2012; Coyle & Laws, 2015; Feder et al., 2014; see Murrough et al., 2013). For example, Zarate et al. (2006) reported ~71 % response 24 h after infusion compared to placebo saline (Zarate et al., 2006, cited in Coyle & Laws, 2015). Thus there is pharmacologic signal.

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2. Active control matters—and blinding is difficult
The KARMA-Dep 2 trial used midazolam, a psychoactive control, specifically to guard against unblinding due to ketamine’s obvious dissociative effects. Prior ketamine trials that used saline (inert placebo) may have over-estimated effect size due to expectancy and unmasking (Ketamine effect may hinge on hope, 2023). Thus, the negative result may reflect the challenge of robust trial design rather than absence of any ketamine effect.

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3. Context of delivery differs
The large benefit studies often feature outpatient TRD populations, or participants receiving ketamine as a catalyst in an expressly therapeutic container (therapist presence, set/setting, integration). By contrast, KARMA-Dep 2 was adjunctive to usual inpatient care. In what has been called the “Montreal Model” trial, combining ketamine with structured psychotherapy and a supportive environment produced substantial and more durable symptom reductions (≈30% drop) lasting 8 weeks or more (Montreal Model trial, 2025). This suggests that delivery context matters: the drug + relational/experiential scaffolding may yield more robust outcomes.

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4. Different goals: symptom suppression vs system re-organization
From a somatic trauma and psychedelic-informed perspective (which aligns with your work at OmTerra), the question isn’t just “does ketamine reduce depression scores?” but “does ketamine facilitate nervous system shift, dissociation containment, relational reattachment, memory reconsolidation and flexibility?” A mere score drop is useful, but your field is pointing toward deeper change (3D Healing™, Selective Inhibition, Somatic Intelligence). The trial above addresses the first but not the second dimension.

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Why This Matters for Trauma-Informed, Psychedelic-Aware Practice

From a ketamine practioner focus, several implications arise:

• Expectation management is crucial. Ketamine is not a guaranteed standalone cure for depression. When the dissociative “trip” is disengaged from relational containment and integration, benefit may be minimal or short-lived.
• Therapeutic container is part of the medicine. The “Montreal Model” data suggest that when ketamine is used like a psychedelic catalyst—embedded in a supportive environment with therapist/sitter, preparation + music + integration—the outcomes improve. In your language: the molecule opens the nervous system, but the subsequent scaffold (Selective Inhibition, boundary, re-attachment) mediates repair.
• Blinding and placebo effects are not just methodological annoyances—they reflect how nervous systems heal in relationship. The fact that midazolam performed similarly suggests that sedation + sense of care + altered state can each contribute to improvement. That doesn’t invalidate ketamine’s pharmacology, but it reminds us that embodied neurobiology + autonomic regulation + attachment are co-actors.
• Dosing & pacing must be attuned to dissociative nervous systems. Especially with dissociation and complex trauma, rapid destabilisation risks PISD (psychedelic iatrogenic structural dissociation). A careful titration, containment, integration and relationship-anchored approach (which you emphasise) remains necessary.
• Long-term strategy is emerging, not settled. For example, slow-release ketamine tablets (phase 2) showed that among responders, relapse risk was lower: 43% versus 71% in placebo over ~13 weeks (The Guardian, 2024). This hints at a maintenance paradigm—less “six heavy infusions then done” and more “micro-dosing + integration + nervous system sequencing”.

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Summary & Take-aways

• A rigorous new inpatient trial found that serial ketamine infusions did not outperform an active psychoactive placebo (Jelovac et al., 2025).
• This highlights that ketamine is not magic in isolation; context, expectations, relational containment, and integration matter.
• For trauma-informed and psychedelic-friendly care : the molecule is a door, but healing happens in the vestibule—in the nervous system, in relationship, in integration.
• Clinics and practitioners should incorporate dosing pace, set/setting, somatic tracking, parts work (e.g., Dissociative Child), and integration scaffolding—not simply offer infusions without depth.
• Future work needs to clarify: for whom, when, in what container, at what dose does ketamine become transformative rather than marginal?
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References

Coyle, C. E., & Laws, K. R. (2015) ‘The use of ketamine as an antidepressant: a systematic review and meta-analysis’, Human Psychopharmacology: Clinical & Experimental, 30(3), pp. 152-163.
Jelovac, A. et al. (2025) ‘Serial Ketamine Infusions as Adjunctive Therapy to In-patient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial’, JAMA Psychiatry [online ahead of print]. doi:10.1001/jamapsychiatry.2025.3019.
Murrough, J. W. et al. (2013) ‘Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial’, American Journal of Psychiatry, 170(10), pp. 1134-1142.
Shiroma, P. R. et al. (2020) ‘A randomized, double-blind, active placebo-controlled trial of repeated ketamine versus midazolam in treatment-resistant depression’, Translational Psychiatry, 10(1): 421.
Time Magazine (2018) ‘Ketamine May Ease Depression by Acting Like an Opioid, Study Suggests’. Time, 8 August 2018. Available at: https://time.com/5381387/ketamine-opioid/ (Accessed: 29 October 2025).
Yale Medicine (2023) ‘Ketamine for Depression: How It Works’. Yale Medicine, 4 April 2023. Available at: https://www.yalemedicine.org/news/ketamine-for-depression (Accessed: 29 October 2025).

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