Ketamine, developed in the 1960s, was initially recognized as an anesthetic and approved by the FDA for this purpose in 1970. Researchers have since uncovered its potential for treating certain mental health conditions. Sublingual ketamine is a method of administration where the medication, often a lozenge or tablet, is placed and dissolved under the tongue. It is absorbed directly into the bloodstream through blood vessels in the oral mucosa, bypassing the digestive system.
Medical Applications for Sublingual Ketamine
Sublingual ketamine is used for Treatment-Resistant Depression (TRD) and Major Depressive Disorder (MDD). It offers a rapid onset of action compared to conventional antidepressants, with symptom improvement often reported within hours or days. It also finds off-label use for conditions like anxiety disorders, Post-Traumatic Stress Disorder (PTSD), bipolar depression, and Obsessive-Compulsive Disorder (OCD). Studies indicate it can significantly reduce scores on depression and anxiety assessment scales.
Mechanism of Action in the Brain
Ketamine’s therapeutic effects stem from its interaction with specific brain receptors. It acts as an antagonist of N-Methyl-D-Aspartate (NMDA) receptors, part of the glutamate system, a major excitatory neurotransmitter system in the brain. By blocking these receptors, ketamine leads to a surge in glutamate release, which then activates AMPA receptors.
This activation triggers a cascade of intracellular events, involving the Brain-Derived Neurotrophic Factor (BDNF) and mechanistic Target of Rapamycin (mTOR) pathways. These pathways promote neuroplasticity, the brain’s ability to reorganize and form new neural connections. This process helps establish healthier communication pathways by facilitating the growth of new synapses and dendritic spines.
The Treatment Process and Patient Experience
A typical sublingual ketamine treatment involves placing a prescribed lozenge or troche under the tongue. Patients hold the medication there, allowing it to dissolve and absorb through the mucous membranes. Avoiding swallowing saliva during this period maximizes sublingual absorption. Effects typically begin within 15 to 30 minutes and can last for up to two hours, though residual effects may persist longer if swallowed.
During the experience, patients may enter a dissociative state, often described as a temporary detachment from their body, thoughts, or surroundings. This can manifest as feelings of lightness, floating, or altered perceptions of time and space. Some individuals report vivid imagery or a dream-like state, while others experience a profound sense of calmness or introspection. While intense, the dissociative experience is temporary and occurs under medical guidance, with providers ensuring patient safety and support. Dosage can be adjusted in subsequent sessions based on the patient’s response and desired therapeutic outcome.
Side Effects and Safety Considerations
When administered under medical supervision, sublingual ketamine has a manageable side effect profile. Common short-term effects during or shortly after treatment include nausea, dizziness, mild confusion, headache, and blurred vision. Patients may also experience a temporary increase in blood pressure and heart rate, increased salivation, or a disagreeable taste. These effects are transient and resolve within a few hours.
Concerns about long-term risks, such as bladder issues like ketamine cystitis, are primarily associated with chronic, high-dose, non-medical ketamine use. In therapeutic settings, this complication is rare. Medical providers carefully screen patients for contraindications before starting treatment. Individuals with active psychosis or schizophrenia, uncontrolled hypertension, serious cardiovascular conditions, active substance abuse disorders, or severe liver disease are not considered suitable candidates. Regular monitoring of blood pressure, heart rate, and, in some cases, liver, kidney, and bladder function is part of the safety protocol.
Comparison with Other Ketamine Formulations
Sublingual ketamine is one of several administration methods, each with distinct characteristics concerning bioavailability, convenience, and required supervision. Bioavailability refers to the proportion of the drug that enters the circulation and can have an active effect. Sublingual ketamine has a bioavailability ranging from 24% to 30%, as some may be swallowed and metabolized by the liver. This method offers the convenience of at-home use, often with remote medical guidance, and can be a more affordable option for maintenance treatments.
Intravenous (IV) ketamine infusions deliver the drug directly into the bloodstream, resulting in nearly 100% bioavailability. This route allows for precise dosage control and rapid onset of effects within minutes. IV administration requires a clinical setting with continuous medical monitoring due to the intensity of the experience and the need for immediate adjustments if side effects occur. Intranasal esketamine, marketed as Spravato, is an FDA-approved formulation that delivers an S-enantiomer of ketamine via a nasal spray, with a bioavailability of approximately 45-50%. While a non-invasive alternative to IV, it requires administration in a certified healthcare setting, with patients monitored for at least two hours post-administration. The choice of formulation often depends on individual patient needs, clinical presentation, and accessibility.