Sublingual Ketamine Protocols
Sublingual ketamine at 10 mg (from a 100 mg/ml solution held for 5 minutes then swallowed) administered every 2-3 days or weekly has demonstrated rapid antidepressant effects with excellent tolerability in refractory depression, though this route lacks formal guideline endorsement and remains off-label. 1
Clinical Context and Evidence Base
The available evidence for sublingual ketamine is limited to psychiatric applications, specifically treatment-resistant depression and anxiety. No established guidelines exist for sublingual ketamine administration—all current guideline-based protocols focus exclusively on intravenous, intramuscular, or intranasal routes for acute pain management, procedural sedation, or anesthesia. 2
Dosing Protocols for Sublingual Administration
Depression and Anxiety Treatment
- Initial dose: 10 mg sublingual (from 100 mg/ml solution, held sublingually for 5 minutes then swallowed), repeated every 2-3 days or weekly based on response 1
- Alternative dosing range: 0.25-7 mg/kg has been reported in various oral/sublingual protocols, though specific sublingual data remains limited 3, 4
- Rapid dissolve tablet formulation at unspecified doses has shown 47.6% response rates after three doses for both depression (PHQ-9) and anxiety (GAD-7), with higher response rates after six doses 5
Pharmacokinetic Considerations
- Sublingual bioavailability is approximately 30%, substantially higher than oral administration (20-25%) due to reduced first-pass metabolism 6, 1
- Onset of action is rapid with sublingual administration, producing quick therapeutic effects comparable to other routes 1
- Metabolism occurs primarily via CYP3A and CYP2B6 to norketamine, with sublingual route producing less norketamine conversion than oral administration 6, 1
Safety Profile and Monitoring
Expected Side Effects
- Mild, transient light-headedness is the most common side effect with very low dose sublingual ketamine 1
- Psychotomimetic effects (euphoria, dissociation, hallucinations) are notably absent at the 10 mg sublingual dose, contrasting with higher IV doses 1
- No respiratory depression or cardiovascular instability reported with sublingual dosing in psychiatric applications 5, 1
Contraindications (Based on IV/IM Guidelines)
While sublingual-specific contraindications are not established, extrapolating from parenteral ketamine guidelines: avoid in uncontrolled cardiovascular disease, pregnancy, active psychosis, severe liver dysfunction, elevated intracranial pressure, and elevated ocular pressure 2
Clinical Outcomes
Efficacy Data
- 77% response rate in refractory unipolar and bipolar depression with very low dose sublingual ketamine (10 mg) 1
- Rapid onset of therapeutic effects including improved mood stability, cognition, and sleep quality 1
- Sustained remission observed in some patients even after discontinuation 1
- 47.6% significant reduction in both depression and anxiety scores after three sublingual rapid dissolve tablet doses 5
Treatment Duration
- Repeated administration every 2-3 days or weekly appears effective for maintaining therapeutic response 1
- Extended treatment courses can be continued as clinically indicated, with some patients achieving sustained remission allowing discontinuation 1
Critical Limitations and Caveats
The sublingual route lacks formal guideline support and remains entirely off-label—all published guidelines address only IV, IM, or intranasal ketamine for acute pain, procedural sedation, or anesthesia settings. 2
The evidence base consists solely of small retrospective studies and case series (n=26 and retrospective chart review) without randomized controlled trials specifically for sublingual administration. 5, 1
Abuse potential must be considered when prescribing ketamine for at-home, self-administered use, particularly given the lack of supervised administration. 3
No pediatric data exists for sublingual ketamine—all pediatric ketamine guidelines address only IV or IM routes for procedural sedation. 2, 7, 8