Ketamine therapy works by blocking a specific type of receptor in the brain, triggering a cascade of changes that rapidly strengthen neural connections in areas linked to mood. Unlike traditional antidepressants that take weeks to build up, ketamine can produce noticeable relief within hours of a single infusion. It’s currently used primarily for treatment-resistant depression, and a nasal spray version called Spravato (esketamine) is FDA-approved for that purpose.
What Ketamine Does in the Brain
Ketamine’s primary target is the NMDA receptor, a gateway on brain cells that normally responds to glutamate, the brain’s main excitatory chemical messenger. What makes ketamine unusual is which cells it affects most. It preferentially blocks NMDA receptors on inhibitory neurons, the cells whose job is to keep other neurons quiet. When these “braking” neurons go offline, the result is a surge of activity in excitatory neurons, particularly in the prefrontal cortex, the region most involved in mood regulation, decision-making, and emotional processing.
This burst of excitatory signaling sets off a chain reaction. The increased neural activity stimulates the release of a growth factor called BDNF, a protein that acts like fertilizer for brain cells. BDNF drives the formation of new synapses, the connection points between neurons. In people with chronic depression, many of these synaptic connections in the prefrontal cortex have weakened or disappeared. Ketamine essentially helps rebuild them. Research has shown that this process depends on BDNF being produced and released at the dendrites (the branching ends of neurons where connections form). People who carry certain genetic variations that impair BDNF function show a markedly reduced response to ketamine, reinforcing that this growth factor is central to how the drug works.
This mechanism is fundamentally different from conventional antidepressants like SSRIs, which increase serotonin levels and require weeks of daily use before synaptic remodeling gradually takes hold. Ketamine jumpstarts that remodeling process directly, which explains its speed.
How Quickly It Works and How Long It Lasts
The antidepressant effects of ketamine become evident within a few hours to one day of a single infusion. In a randomized controlled trial published in the American Journal of Psychiatry, 27% of participants met antidepressant response criteria just 24 hours after one infusion, and 5% achieved full remission. Those are meaningful numbers for people who, by definition, had not responded to other treatments.
The catch is duration. After a single dose, the benefits generally disappear within one week. This is why ketamine therapy typically involves a series of infusions rather than a one-time treatment. When participants in the same trial received repeated infusions (three times weekly for two weeks), 59% met response criteria and 23% achieved remission. The repeated dosing appears to give the brain enough time to consolidate the new synaptic connections that ketamine initiates.
What a Treatment Course Looks Like
For IV ketamine, the standard protocol involves a dose of 0.5 mg/kg delivered through an intravenous drip over 40 minutes. Sessions are spaced at least two days apart and given no more than twice weekly, typically for about four weeks during the initial phase. Some clinics use doses up to 1 mg/kg depending on the patient’s response.
The nasal spray version, Spravato, follows a different schedule and is administered in a certified healthcare setting. It’s FDA-approved for two specific uses: treatment-resistant depression in adults (either alone or alongside an oral antidepressant) and depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behavior. The FDA has noted that Spravato has not been shown to actually prevent suicide, despite its use in people experiencing suicidal thoughts.
After the initial induction phase with either form, many patients transition to maintenance “booster” sessions. The frequency varies based on individual response, but the goal is to sustain the neural changes before they fade.
What the Session Feels Like
Ketamine produces dissociative effects, meaning you may feel detached from your body, experience altered perceptions of time, or have dreamlike visual experiences during the infusion. For some people this is mildly unsettling; for others it feels calm or even meaningful. These effects are temporary and typically resolve within an hour or two after the infusion ends.
The psychological state you bring into a session and the physical environment both influence the experience. Feeling safe, emotionally prepared, and supported by the clinical team makes it more likely you’ll engage with the experience productively. Most clinics set up treatment rooms with dim lighting, comfortable recliners, and sometimes music. A therapist or clinician stays present throughout, monitoring both your physical safety and providing emotional support if the dissociative experience becomes uncomfortable.
Common Side Effects
Beyond dissociation, the most frequently reported side effects are nausea, headache, and anxiety. The one that clinicians watch most closely is a temporary spike in blood pressure. Ketamine stimulates the cardiovascular system, increasing heart rate, blood pressure, and cardiac output.
Blood pressure typically peaks about 40 minutes after the infusion starts, with an average increase of about 16 points systolic and 11 points diastolic. In roughly 10% to 50% of patients (depending on the study), blood pressure rises noticeably during the session. One study of 84 patients found that 20% to 30% experienced blood pressure exceeding 180/100 mmHg or a heart rate above 110 beats per minute, and about 12% required medication to bring it down. These spikes occurred more often during the first three infusions. All of these cardiovascular effects are transient, resolving after the session ends, but they’re the reason ketamine is administered in a monitored clinical setting rather than at home.
Who It’s Designed For
Ketamine therapy is used primarily for people with treatment-resistant depression, generally defined as depression that hasn’t improved after trying two or more standard antidepressants. It’s not a first-line treatment. The speed of its effects makes it particularly relevant for people in acute depressive crises, including those experiencing suicidal ideation, where waiting weeks for a traditional antidepressant to take effect is not a viable option.
IV ketamine for depression remains an off-label use of a drug that has long been FDA-approved as an anesthetic. Spravato is the only ketamine-based product specifically approved for depression. This distinction matters practically: Spravato is more likely to be covered by insurance, while IV ketamine infusions at private clinics often cost several hundred dollars per session out of pocket.
People with uncontrolled high blood pressure, certain heart conditions, or a history of psychosis are generally not good candidates, given ketamine’s cardiovascular and dissociative effects. The treatment also appears less effective in people with certain genetic profiles that impair BDNF production, though genetic testing for this is not yet part of standard screening.