The Studies That Did Not Work

Coverage of ketamine research skews positive, partly because positive trials get press releases. But some of the most methodologically interesting work published between 2023 and 2026 produced null or negative results — and those findings are arguably more useful to patients making decisions than another favorable open-label series.

Three areas deserve particular scrutiny: chronic pain, oral ketamine formulations, and the role of expectancy in ketamine's measured benefits.

1. Chronic Pain: A Cochrane Review Says No

Ketamine has been used off-label for chronic pain conditions, including complex regional pain syndrome and fibromyalgia, for years. In August 2025, a Cochrane systematic review (Ferraro et al.) synthesized 67 randomized controlled trials of ketamine and other NMDA receptor antagonists for chronic pain.

The conclusion was blunt: there is no clear evidence of clinically meaningful benefit for chronic non-cancer pain. Certainty of evidence was rated low to very low, observed benefits were short-lived and inconsistent, and the review noted that potential harms may outweigh uncertain benefits. The authors found insufficient evidence to support routine use, including for CRPS.

This matters because the guidance most often cited by pain clinics — the 2018 consensus guidelines from ASRA, AAPM and ASA — is now several years old and reported only moderate evidence for CRPS at up to 12 weeks. It has not been updated to reflect the newer synthesis.

A related 2024 systematic review of ketamine for fibromyalgia (Advances in Rheumatology, 6 studies, 115 patients) similarly found only short-term reductions in pain scores with unclear long-term value.

2. Oral Ketamine: A Missed Primary Endpoint

At-home oral and sublingual ketamine has expanded rapidly through telehealth, largely without randomized evidence behind it. A 2025 randomized controlled trial (Silberbauer et al., Journal of Affective Disorders) tested oral ketamine 1 mg/kg against midazolam across six doses over two weeks in 45 patients with major depressive or bipolar disorder.

The trial missed its primary endpoint: there was no significant MADRS difference at one week. The same publication included a meta-analysis of 592 patients that did find efficacy overall, with a number needed to treat of 4.89 for response and 9.16 for remission — a useful reminder that pooled evidence and individual well-controlled trials can disagree.

Two pharmaceutical programs developing controlled-release oral ketamine formulations have reported mixed results, including one Phase 2 program that also failed to meet its primary endpoint despite favorable tolerability. Oral ketamine is not a settled treatment; it is an active area of drug development. See our guide to at-home oral and sublingual ketamine for the practical and regulatory considerations.

3. The Placebo Problem

Ketamine produces unmistakable dissociative effects. Participants in blinded trials can often tell whether they received the drug, which undermines blinding and can inflate measured benefit. Two studies attacked this problem directly.

Ketamine masked by surgical anesthesia

Lii and colleagues (Nature Mental Health, October 2023) designed an unusual trial: 40 patients with major depression scheduled for routine surgery received either ketamine 0.5 mg/kg or saline while under general anesthesia, so that no one could perceive the drug's psychoactive effects.

The result: no significant antidepressant advantage for ketamine (MADRS difference −5.82; 95% CI, −13.3 to 1.64; p = 0.13). Both groups improved substantially, and only 36.8% of participants correctly guessed their assignment — meaning the masking worked. The trial is small and the surgical context is a real confound, but it is the strongest existing evidence that expectancy contributes meaningfully to observed ketamine responses.

KARMA-Dep 2

Jelovac and colleagues (JAMA Psychiatry, October 2025) randomized 65 depressed inpatients to up to eight twice-weekly ketamine infusions or midazolam, added to standard inpatient care. The adjusted mean MADRS difference was −3.16 (95% CI, −8.54 to 2.22) — not statistically significant. There were also no differences in cognition, quality of life, or cost.

The trial was underpowered due to pandemic-era recruitment difficulties, was conducted at a single site, and experienced high rates of unblinding. But a well-run randomized trial that fails to separate from active control is data, not noise.

Reconciling This With the Positive Evidence

None of this negates the substantial positive literature. A 2024 meta-analysis of 12 randomized trials found a large placebo-controlled effect for IV ketamine in depression (Hedges g = 1.52), and the ELEKT-D trial showed ketamine performing at least as well as ECT. Both things can be true: ketamine has a real pharmacological antidepressant effect and the size of that effect in open-label or poorly blinded settings is likely overstated by expectancy.

The practical implications:

  • Be skeptical of clinics quoting response rates from uncontrolled case series or their own internal data
  • Treat indications outside depression and suicidal ideation as investigational, especially chronic pain
  • Understand that dissociation intensity is not a measure of therapeutic effect
  • Ask what happens if you do not respond — a good program has a plan for that scenario

For a grounded view of whether treatment makes sense for your situation, see our candidacy and screening guide, or compare clinics by state.

Sources

  • Ferraro MC, et al. Ketamine and other NMDA receptor antagonists for chronic pain. Cochrane Database of Systematic Reviews. 2025. PubMed 40819842
  • Lii TR, et al. Randomized trial of ketamine masked by surgical anesthesia in patients with depression. Nature Mental Health. 2023;1:876-886. Nature Mental Health
  • Jelovac A, et al. Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. JAMA Psychiatry. 2025;82(12):1216-1224. PubMed 41123905
  • Silberbauer LR, et al. Oral ketamine for the treatment of major depressive and bipolar disorder, a randomized controlled trial and meta-analysis. Journal of Affective Disorders. 2026. doi:10.1016/j.jad.2025.120466
  • Valente MEDL, et al. Ketamine for fibromyalgia: a systematic review. Advances in Rheumatology. 2024. PubMed 39075628