Exploring the Efficacy of Oral Ketamine for Treatment-Resistant Depression (TRD)
What the research shows about oral ketamine for treatment-resistant depression — response rates, clinical evidence, and how it compares to other routes.
The Evidence for Oral Ketamine
Treatment-resistant depression (TRD) — defined as major depressive disorder that hasn't responded to at least two adequate antidepressant trials — affects a significant portion of the estimated 280 million people worldwide living with depression. Approximately 30–40% of patients fall into this category.
Oral ketamine has emerged as a promising option for this population, with growing clinical evidence supporting its efficacy.
What the Research Shows
Randomized controlled trials demonstrate that oral ketamine produces significantly greater reductions in depression scores compared to placebo. A landmark 2022 study published in the British Journal of Psychiatry found oral ketamine to be non-inferior to extended-release venlafaxine (a commonly prescribed SNRI) — with a faster onset of action.
Response rates for oral ketamine in treatment-resistant depression consistently range from 50–70% across clinical trials. This is remarkable given that these patients, by definition, have already failed multiple conventional treatments.
How Oral Compares to Other Routes
| Route | Bioavailability | Cost per Session | Setting | FDA Status |
|---|---|---|---|---|
| IV | ~100% | $400–800 | Clinic | Off-label |
| Intranasal (Spravato) | 45–50% | $10–50 (insured) | Clinic | FDA-approved |
| Oral/Sublingual | 25–35% | Significantly less | Home | Off-label |
While oral ketamine has lower bioavailability than IV, this is compensated by higher dosing. The therapeutic outcomes are comparable, and the practical advantages — home administration, lower cost, greater convenience — are significant.
For a detailed comparison of all routes, see all the ways ketamine can be given and IV vs. sublingual ketamine.
How Treatment Is Structured
Oral ketamine therapy typically follows three phases:
- Induction (weeks 1–4): 1–2 sessions per week to establish therapeutic response
- Stabilization (weeks 5–12): Gradually reduced frequency based on symptom improvement
- Maintenance (ongoing): Periodic sessions as needed to sustain benefits
Each session is conducted under medical supervision via telehealth, with a peer supervisor physically present.
The Mechanism
Oral ketamine works through the same fundamental mechanism as all ketamine formulations — NMDA receptor antagonism leading to increased glutamate, BDNF release, and enhanced neuroplasticity. The route of delivery changes the pharmacokinetics, not the pharmacology.
This is why patients who can't access or afford IV treatment can still experience comparable therapeutic benefits with properly dosed oral or sublingual formulations.
Important Context
Compounded oral ketamine for depression is not FDA-approved. However, it has accumulated substantial clinical evidence and has been used safely in medical settings for decades. Off-label prescribing is a standard, legal medical practice when supported by evidence.
For patients with treatment-resistant depression who haven't found relief with conventional antidepressants, oral ketamine represents an accessible, evidence-supported treatment option.
Stay Informed
Get the latest research and insights on ketamine therapy delivered to your inbox.
Disclaimer: Compounded ketamine for anxiety, depression, PTSD, and chronic pain is not FDA approved. The information provided is for educational purposes only and should not be considered medical advice. Individual results may vary. Always consult with a qualified healthcare provider before starting any treatment.
