Key Clinical Trials on Ketamine Tablet

The clinical trial landscape for ketamine tablet is smaller and less mature than for IV ketamine or Spravato, but has grown substantially since 2010. Understanding the key trials, their limitations, and what they collectively tell us helps patients and clinicians interpret evidence-based claims about ketamine tablet's efficacy.

Context: The Treatment-Resistant Depression Landscape

To appreciate ketamine tablet's clinical significance, consider the STAR*D trial (Sequenced Treatment Alternatives to Relieve Depression). This landmark NIMH-funded study followed over 4,000 depressed patients through sequential treatment steps. Key findings:

• Only about one-third of patients achieved remission with their first antidepressant (citalopram)
• Each subsequent treatment step had lower remission rates
• After 4 treatment steps, only 67% of patients had achieved remission at any point — and many relapsed
• Approximately 15–20% of patients were "true" treatment-resistant, failing multiple adequate trials

This establishes the size of the unmet need that ketamine tablet is attempting to address. For a clinical overview of how ketamine is used for this population, see our article on ketamine tablet for treatment-resistant depression.

Foundational IV Ketamine Trials (Context for Oral Research)

Berman et al. (2000) — The Landmark Publication

This 2000 paper in Biological Psychiatry was the first randomized controlled trial demonstrating ketamine's rapid antidepressant effects. Seven depressed patients received IV ketamine (0.5 mg/kg) or placebo in crossover design. Ketamine produced significant antidepressant effects within 72 hours — a finding that launched two decades of research.

Zarate et al. (2006) — NIMH Confirmation

NIMH researchers (Carlos Zarate and colleagues) replicated and expanded the Berman findings in 18 patients with TRD. Single IV ketamine infusions produced remission in 71% of patients within 1 day, with effects lasting approximately 1 week. This high-profile NIMH paper substantially increased research and clinical interest.

These IV trials provided the mechanistic and clinical foundation upon which ketamine tablet research was built — establishing that ketamine's antidepressant mechanism was real and clinically significant, before the oral route was studied.

Key Ketamine Tablet Clinical Trials

Lara et al. (2013) — Early Evidence for Oral Route

Design: Open-label prospective study, 26 patients with TRD

Intervention: Oral racemic ketamine 0.5 mg/kg once daily for 21 days

Results:

• 77% achieved antidepressant response
• 31% achieved remission
• Effects appeared within the first week
• No serious adverse events

Significance: This was one of the first systematic publications specifically examining ketamine tablet for psychiatric use. For broader comparison of oral and IV approaches, see our article on oral vs. IV comparative research. While open-label and small, it provided early proof-of-concept for the oral route.

Limitations: No placebo control; small sample; short duration; patients not blinded

Jafarinia et al. (2016) — Controlled Iranian Trial

Design: Randomized controlled trial, 46 patients with TRD

Intervention: Ketamine tablet vs. oral diclofenac (active comparator, an NSAID with anti-inflammatory properties), both as add-ons to existing antidepressant treatment

Results: Ketamine tablet showed significantly greater MADRS score reduction than diclofenac at weeks 6 and 12. Response rates significantly favored ketamine.

Significance: This was a randomized, controlled comparison — a significant methodological improvement over open-label studies. The use of an active comparator (rather than placebo) controlled for non-specific effects.

Limitations: Active comparator was not an inert placebo; single-center; conducted in Iran (generalizability questions); relatively small sample

Domany et al. (2019) — Sublingual Ketamine Study

Design: Prospective open-label study, 31 patients with TRD

Intervention: Sublingual/buccal ketamine 1 mg/kg (in lozenge/solution form)

Results:

• Response rate of 74% at Day 7
• MADRS scores reduced significantly from baseline
• Effects began within 1–2 days
• Some patients maintained response at Day 30 without re-dosing

Significance: Documented rapid onset with sublingual route; higher bioavailability than swallowed tablets

Limitations: Open-label; small sample; heterogeneous TRD population; variable follow-up

Swainson et al. (2020) — First Canadian Pilot RCT

Design: Randomized double-blind pilot study, 27 patients with TRD

Intervention: Ketamine tablet (0.5 to 3.0 mg/kg, flexible dosing) vs. oral midazolam (active placebo) over 4 weeks

Results: Ketamine showed significantly greater antidepressant response than midazolam. Response rates were meaningfully higher in the ketamine arm, though the study was underpowered as a pilot.

Significance: First double-blind RCT comparing ketamine tablet to an active placebo in TRD. The use of an active placebo (midazolam produces mild sedation) was a methodological strength.

Limitations: Small pilot sample (underpowered); flexible dose protocol complicates interpretation; single center

Glue et al. (2017–2020) — Pain and Depression Studies

New Zealand-based researcher Paul Glue and colleagues conducted multiple dose-finding and clinical studies of ketamine tablet:

Glue et al. (2017): Phase 2 dose-finding study of ketamine tablet for TRD. Identified dose range of 0.5–3.0 mg/kg as potentially therapeutic with acceptable tolerability.

Glue et al. (2020): Open-label extension study of ketamine tablet for depression, documenting tolerability and sustained response over 6 months in responders.

These studies have been important in establishing dosing parameters for larger trials.

Iglewicz et al. (2015) — Palliative Care RCT

Design: Randomized placebo-controlled trial in palliative care patients with depression, 40 participants

Intervention: Ketamine tablet 0.5 mg/kg once daily vs. placebo for 4 weeks

Results: Ketamine tablet produced significant reductions in depression scores within 3 days — well before the typical antidepressant onset of conventional drugs. Response rates significantly favored ketamine.

Significance: One of the few RCTs of ketamine tablet vs. true placebo; conducted in a clinically distinct and important population (palliative care); demonstrated rapid onset

Limitations: Specific to palliative care population; short duration; small sample

Phase 3 Trials and Current Research (2020–Present)

Several Phase 2 and Phase 3 trials of ketamine tablet are underway or recently completed as of 2024:

Clexio Biosciences (CLE011 — Ketamine Tablet ER): Phase 2 trials of an extended-release ketamine tablet formulation for TRD. This pharmaceutical development program could lead to the first FDA approval of an ketamine tablet product for depression.

Various academic trials: Multiple academic centers in the US, Canada, Australia, and Europe are conducting or planning randomized trials of ketamine tablet for TRD, with larger sample sizes and more rigorous designs than the early studies.

What the Evidence Collectively Shows

Drawing conclusions from the available ketamine tablet clinical trial data:

Efficacy is supported: Multiple studies across different designs and populations demonstrate antidepressant effects of ketamine tablet in TRD patients. Response rates of 50–77% are consistently reported, though controlled trials show lower rates due to placebo response.

The evidence base is limited by study quality: The absence of large, double-blind, placebo-controlled RCTs with diverse populations is the primary limitation. The existing studies are largely open-label, small, single-center, or use active comparators rather than true placebos.

Rapid onset is consistently documented: Every study that assessed early time points found antidepressant effects within 24–72 hours — faster than any conventional antidepressant.

Tolerability is generally good at therapeutic doses: Side effects are documented but serious adverse events are rare in clinical trial populations.

More rigorous evidence is coming: The current pharmaceutical development programs and ongoing academic trials will substantially strengthen or refine these conclusions within the next several years.

References

• StatPearls: Ketamine — Comprehensive clinical reference on ketamine pharmacology, mechanisms of action, and therapeutic applications
• PubChem: Ketamine Compound Summary — NCBI chemical database entry with ketamine molecular data, pharmacokinetics, and bioactivity profiles
• MedlinePlus: Ketamine — National Library of Medicine consumer drug information on ketamine including uses, proper administration, and precautions
• NIMH: Depression — National Institute of Mental Health overview of depressive disorders, treatment-resistant forms, and emerging therapies
• WHO: Depression Fact Sheet — World Health Organization global data on depression prevalence, burden, and treatment approaches