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Sublingual Versus Oral Administration of Ketamine

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Sublingual Ketamine | Ketamine trochee held under the tongue until fully dissolved

Oral Ketamine | Ketamine tablet that is immediately swallowed

Ketamine is a medication that can be administered in a variety of ways, including sublingually (under the tongue) and orally (by mouth and then swallowed). While both methods can provide therapeutic benefits, they have distinct differences in terms of onset of action, bioavailability, and potential side effects.

Sublingual Ketamine | Ketamine trochee held under the tongue until fully dissolved

Onset of Action: Sublingual ketamine has a faster onset of action compared to oral administration. This is because it is more directly moved into the bloodstream through buccal absorption via the rich vascular network under the tongue, bypassing the digestive system.
Bioavailability: Sublingual ketamine has a higher bioavailability 28.6%(1) compared to oral ketamine, meaning that a greater proportion of the drug reaches the bloodstream and exerts its effects.
Side Effects: Sublingual ketamine may have a higher incidence of side effects, such as increased salivation, numbness in the mouth, disagreeable taste of the medication and mild nausea, compared to oral administration.

Oral Ketamine | Ketamine tablet that is immediately swallowed

Onset of Action: Oral ketamine has a slower onset of action compared to sublingual administration. This is because it needs to be absorbed from the gastrointestinal tract, which takes longer than direct absorption through the sublingual mucosa.
Bioavailability: Oral ketamine has a lower bioavailability 22.8%(1) than sublingual ketamine, meaning that a smaller proportion of the drug reaches the bloodstream. This seems mainly due to the first-pass metabolism in the liver, more research is needed to understand exactly how and where in vivo metabolism is occurring and where the drug is metabolized before reaching the bloodstream.
Side Effects: Oral ketamine may have a lower incidence of side effects compared to sublingual administration, as it is less likely to cause local irritation in the mouth and less likely to have a disagreeable taste

Graph outlining the differences in bioavailability of Sublingual versus Oral Ketamine

Explanation of terms

Cmax (μg/L) is a measurement of the highest concentration of a ketamine in the blood.

The + or - 6.6% and 12.8% are measurements of 1 standard deviation from the average.

Additional Considerations

Patient Preference: The choice between sublingual and oral ketamine may depend on the patient's preference and tolerance for side effects. One of the side effects that comes up often is the taste. Some patients describe the taste as so unbearable that they are unwilling to hold it in their mouth for increased bioavailability and instead opt to quickly swallow the medication.
Therapy preference: Some ketamine assisted psychotherapists might prefer one method over another depending on the therapeutic goals. Oftentimes a slower onset allows for more patient mental cohesion and quicker onsets can be more disorienting and less helpful for certain goals.
Medical Condition: The specific medical condition being treated may also influence the choice of administration route.
Dosage: The dosage of ketamine may need to be adjusted depending on the administration route to achieve the desired therapeutic effect.
It is important to consult with a healthcare professional to determine the most appropriate administration route and dosage of ketamine for your individual needs.

Clinical observations

Between oral and sublingual ketamine, sublingual ketamine is almost always initially prescribed to patients at our clinic. This aligns with our clinic goals of lowest, most effective dose. The side effect profile of sublingual is rarely so problematic for our patients that it requires a prescription change to oral.