Oral and Sublingual Ketamine

Background and Rationale:

1.1 Introduction Major Depressive Disorder (MDD) represents one of the most prevalent and debilitating psychiatric disorders, with the WHO stating that it is the most disabling illness worldwide, affecting over 300 million people. Current pharmacotherapies, although effective for some, often fail to provide rapid and lasting relief for many patients, with remission rates of 67% and treatment-resistant depression occurring in approximately 30% of those diagnosed with MDD.

Ketamine has been shown to improve symptoms of treatment-resistant major depressive disorder. The increasing acceptance and use of ketamine, specifically intravenous ketamine (IVK) and intranasal esketamine (INE), have shown promise in bridging this therapeutic gap, particularly given its rapid onset of action.

However, these routes of administration are not without their challenges.

• These challenges include the high cost of IVK and INE preparations compared to oral ketamine. The cost of a single session with IVK can be $400 to $800 CAD due to fees for hospital room and staff. The cost of a single dose of INE is $600 to $1000, not including any hospital costs. On the other hand, the cost of a single dose of compounded oral ketamine (75 mg) is only $5 to $15 CAD.
• The second issue is accessibility. Patients have to be admitted to hospital for IVK administration. Hence, this is done in specialised urban centres, a disadvantage for rural residents.
• The third is administration logistics, like arranging the time of clinical staff to do the IVK and INE treatment.
• Lastly, INE and IVK carry a higher burden of common adverse effects of ketamine, with more dissociation and hypertension occurring compared to oral dosing.

1.2 Current Landscape of Ketamine Administration: While IVK offers rapid antidepressant effects, its administration demands specialised facilities, anaesthesiologists, and nursing staff, leading to heightened costs. INE, though more accessible, still incurs significant costs per dose in the US, raising questions regarding its cost-effectiveness. These challenges highlight an urgent need for more affordable and easily administrable ketamine alternatives.

1.3 The Case for Oral and Sublingual Ketamine: Oral and sublingual (SL) routes of ketamine present, as such, alternative and affordable methods of treatment but have been relatively under-explored in the academic and medical communities. Patients in Ontario have access to oral ketamine therapy; however, this is mostly through private clinics, and it is not covered by OHIP. Preliminary research indicates oral ketamine's efficacy in treating MDD or suicidality; however, the quality of previous studies varies.

Oral ketamine studies Appendix A provides a summary of the studies available on oral ketamine in MDD, which detail the significant variation in doses and frequency of administration. For example, the dose of oral ketamine in these studies varies between 0.5 and 7 mg/kg. The frequency of medication administration is from once or twice a week to once a month. A few review papers that summarise these findings on oral ketamine in MDD have also been published, which also indicate the variability in dose and frequency of oral ketamine.

Sub-lingual ketamine studies When we reviewed SL ketamine for depression (in April 2025), there were very few studies that investigated sublingual ketamine. The earliest study of SL ketamine was in refractory unipolar and bipolar depression. This study investigated very low-dose sublingual ketamine in refractory unipolar and bipolar depression. They observed a rapid onset of action with good tolerability. After that, there was a gap in terms of studies and publications on sublingual ketamine in depression. The most recent studies on SL ketamine in MDD were published by Hull et al. 2022 and Liester et al. 2024. They also observed effective reduction in symptoms of depression and anxiety with sublingual ketamine. Hence, there are very few studies on SL ketamine in MDD.

Lack of use of pharmacokinetic profiles in previous studies

1.4 Absence of consistency in dosing Oral and SL Ketamine for MDD: A major gap in the current literature in this area is the significant variability in dosage, administration frequency, and rationale behind dosing decisions. The dose of oral ketamine varied between 0.5 and 7 mg/kg. The frequency of administration varies from daily to weekly. While it's understood that oral ketamine undergoes significant metabolism (approximately 80%), resulting in variable bioavailability ranging from 10% to 20%, there exists no standardised dosing protocol. This inconsistency in dosing, coupled with the lack of clear rationale for dose determination in clinical trials, underscores the pressing need for a standardised protocol.

1.5 Need for this study - can pharmacokinetics help improve Oral and SL Ketamine dose determination in MDD? The pharmacokinetics (PK) of oral and sublingual (SL) ketamine are relatively well characterised in the context of anaesthesia; however, their PK profiles in the treatment of major depressive disorder (MDD) remain insufficiently studied. This is a critical gap: ketamine's antidepressant effects may depend not only on the parent drug but also on metabolites, particularly norketamine and hydroxynorketamine, which have demonstrated antidepressant properties in preclinical models. Without PK data linking plasma concentrations to clinical response, rational dose selection is impossible.

Sublingual administration theoretically offers pharmacokinetic advantages: by bypassing hepatic first-pass metabolism, it may achieve higher and more consistent plasma concentrations at equivalent doses. However, whether these theoretical benefits translate into improved clinical outcomes in MDD is unknown-no study has directly compared oral versus sublingual ketamine PK profiles within the same patients

Comparison of oral and sublingual ketamine ORAL Bioavailability - 10-20% First-pass metabolism - High Peak plasma concentration - Low Antidepressant onset - 2-4 hours Tolerability - Mild SUBLINGUAL Bioavailability - 20-30% First-pass metabolism - Comparatively less Peak plasma concentration - Moderate Antidepressant onset - 1-3 hours Tolerability - Mild to moderate

Why Current Dosing Is Problematic

Published studies of oral and sublingual ketamine for depression report doses ranging from 0.5 to 7 mg/kg, selected empirically rather than based on target plasma concentrations. This approach has three consequences:

• Unexplained response variability - Patients who fail to respond may have inadequate drug exposure rather than true treatment resistance. Without PK data, these scenarios cannot be distinguished.
• Lack of clarity on dose-response relationship - The optimal plasma concentration for antidepressant effect is unknown. Higher doses increase adverse effects; lower doses may be subtherapeutic. PK data are required to identify the therapeutic window.
• No basis for route selection - Clinicians cannot determine whether oral or sublingual administration is preferable for a given patient because comparative PK data do not exist in MDD.

How This Study Will Address the Gap This pilot study will characterise the pharmacokinetic profiles of oral and sublingual ketamine (75 mg) in patients with MDD using a crossover design in which each participant serves as their own control. Plasma concentrations of ketamine and norketamine will be measured at multiple timepoints to determine Cmax, Tmax, and AUC for each route.

The resulting data will:

• Establish whether sublingual administration achieves higher bioavailability than oral administration in MDD patients
• Quantify within-subject and between-subject variability in PK parameters
• Provide preliminary data on the relationship between plasma concentrations and clinical response
• Inform evidence-based dose selection for future efficacy trials

This study represents a necessary first step towards standardised, pharmacologically rational dosing of oral and sublingual ketamine for depression.

Research Question(s) and Objectives/Hypotheses:

2.1 Research Questions: How do the pharmacokinetic (PK) profiles of oral and sublingual ketamine differ in individuals diagnosed with major depressive disorder? Do PK parameters of oral and SL ketamine correlate to changes in depressive symptoms? 2.2 Primary Objective: To delineate and compare the pharmacokinetic profiles of oral and sublingual administration of ketamine, including serum ketamine and norketamine levels, in a cohort of individuals diagnosed with major depressive disorder.

2.3 Primary Hypothesis: There will be distinct differences in the pharmacokinetic parameters, specifically AUC(0-8), Cmax, and Tmax, between oral and sublingual administration of ketamine in individuals diagnosed with major depressive disorder.

2.4 Exploratory Objective/Hypothesis: To explore potential correlations between specific PK parameters, including serum ketamine and norketamine levels, of oral and sublingual ketamine and therapeutic response and improvement in depressive symptoms. We will use depressive symptom ratings with the Hamilton Depression Rating Scale (HAMD) and the Montgomery-Aspberg Depression Rating Scale (MADRS). Preliminary evidence might suggest that specific PK parameters could be associated with clinical improvements based on a trending reduction on both HAMD & MADRS.

Inclusion criteria

• Participants must meet all the following criteria to be eligible for the study. Appendix B is a checklist that will be used by Dr. Hammound for screening, based on the following inclusion and exclusion criteria.

• Age: Between 18 and 65 years (inclusive) at the time of screening.
• Weight: Equal to or greater than 50 kg (110 lbs).
• Diagnosis: A current diagnosis of Major Depressive Disorder (MDD), moderate to severe in intensity, as defined by the DSM-5 criteria.
• Current Episode: Experiencing a moderate to severe Major Depressive Episode (MDE) at screening.
• Ongoing Treatment: Actively receiving pharmacological treatment for MDD at the time of enrollment.
• Treatment Resistance: Documented history of inadequate response to at least two antidepressant medications, each from a different pharmacological class, administered at an adequate dose and duration.
• Capacity and Consent: Able and willing to provide written informed consent after understanding the nature, risks, and potential benefits of the study.
• Clinical Oversight: Currently under the regular care of a psychiatrist or general practitioner (GP).
• Support System: Has a responsible adult (e.g., family member or caregiver) who can accompany them from study visits or ensure safe transportation after ketamine has been used.
• Able to speak, read and understand English

Exclusion criteria

• Participants will be excluded if any of the following criteria apply:

• Suicidality: Active suicidal ideation with plan or intent, or suicidal behavior, within the past 3 months.
• Concomitant Medications: Use of medications that may pose a risk of respiratory depression or serious adverse events when combined with ketamine (e.g., benzodiazepines, opioids, barbiturates).
• Medical Comorbidities: Presence or history of significant or unstable medical conditions that could interfere with study participation or pose a safety risk, including but not limited to cerebrovascular accident, cardiac decompensation, large vessel aneurysms, glaucoma etc.. Participants with clinically significant laboratory abnormalities, as determined by the investigator, will also be excluded.
• Hypersensitvity to ketamine
• Uncontrolled hypertension (blood pressure ≥140/90 mmHg at screening, which may be repeated after 30 minutes rest)
• Psychiatric Comorbidities: Diagnosis of bipolar disorder, psychotic disorders, or history of psychotic symptoms.
• Substance Use: Clinically significant alcohol or substance use disorder within the last 6 months, as defined by DSM-5 criteria.
• Cognitive Impairment: Any condition resulting in impaired capacity to understand or consent to participation or to comply with study procedures.
• Pregnancy and Lactation: Pregnant or breastfeeding individuals.
• Concurrent Research Participation: Participation in another interventional clinical trial or use of an investigational drug within the 30 days prior to screening.
• Current or recent (within 90 days) treatment with ketamine (oral, IV or intranasal).
• ECG demonstrates abnormalities like Qtc interval>470 ms or any arrhythmia reported as clinically significant or abnormal by the interpreting physician. Exclusionary findings would include uncontrolled atrial fibrillation, ventricular arrhythmias, heart block, or other abnormalities that could pose a safety risk with ketamine administration