Ketamine IV therapy has been hailed for its rapid antidepressant effects in patients diagnosed with treatment-resistant depression (TRD).¹  As the use of ketamine continues to expand into the mainstream of psychiatric treatment, understanding the comparative efficacy of different administration routes—intravenous (IV), versus nasal, versus oral—becomes crucial for optimizing patient outcomes.

Ketamine primarily acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, a type of receptor for the neurotransmitter glutamate. By blocking NMDA receptors, ketamine increases the availability of glutamate. These receptors are critical in synaptic plasticity, enabling the brain to reorganize itself, forming new neural connections as well as modifying existing ones. NMDA receptor antagonists have various therapeutic applications, including the treatment of mood disorders and certain pain syndromes.

IV Ketamine Therapy
Intravenous ketamine administration allows for precise dosing while ensuring 100% bioavailability, maximizing efficacy. Ketamine IV therapy has the benefit of rapid onset of action, offering faster and more potent relief from depressive symptoms. For this reason, ketamine IV therapy should be considered as a treatment option for patients with treatment-resistant depression, acute cases of suicidal ideation, as well as certain pain syndromes. Clinical trials have consistently demonstrated the efficacy of ketamine IV therapy in alleviating depressive symptoms near real-time, often providing relief where traditional antidepressants have failed.

Nasal Ketamine Therapy
Intranasal administration of ketamine has a slower onset compared to IV, typically taking several hours to days to exhibit antidepressant effects. The nasal route is less precise in terms of dosing, given that it’s dependent on the patient’s technique, clear nasal passages, and the condition of the nasal mucosa. Nasal ketamine has a bioavailability of approximately 45%, lower than IV but still sufficient for therapeutic effects.

Oral Ketamine Therapy
Several pharmacokinetic factors influence oral ketamine’s efficacy compared to IV administration. Due to the need for gastrointestinal absorption and first-pass metabolism, oral ketamine has a slower onset of action. Studies show a lower bioavailability—around 20 – 30%. This lower bioavailability can lead to less predictable and often weaker effects. It can also make it challenging to maintain the desired therapeutic effect. Due to its variable absorption and metabolism, oral ketamine may lead to a higher incidence of side effects like nausea, dissociation, or cognitive impairment. Additionally, because it is typically self-administered outside of a medical setting, there is less control over managing potential adverse effects.

Ketamine IV therapy is often considered superior to nasal and oral ketamine due to its precision in dosing, rapid onset of action, higher bioavailability, ability to be customized and controlled, and constant monitoring by physicians and nurses trained in ketamine administration. These factors make ketamine IV therapy particularly effective for treating patients with severe depression.