Ketamine is an anesthetic drug that, at lower doses, rapidly reduces symptoms of severe depression and chronic pain. Originally developed for surgical anesthesia in the 1960s, it has become one of the fastest-acting treatments available for depression that hasn’t responded to standard medications. In clinical studies, about 54% of patients with treatment-resistant depression showed a meaningful response after a series of low-dose infusions, with effects beginning within hours rather than the weeks typical of conventional antidepressants.
How Ketamine Works in the Brain
Most antidepressants target serotonin or similar chemical messengers and take weeks to produce noticeable changes. Ketamine works through a completely different pathway. It blocks a specific type of receptor involved in glutamate signaling, the brain’s primary excitatory communication system. This blockade sets off a chain reaction: it triggers the production of a protein called BDNF (brain-derived neurotrophic factor), which acts like fertilizer for neurons. BDNF promotes the growth of new connections between brain cells, a process known as synaptic plasticity.
This is why ketamine’s effects can feel so dramatic compared to traditional medications. Rather than slowly adjusting chemical levels over weeks, it essentially jump-starts the brain’s ability to form and strengthen neural pathways. Researchers at Vanderbilt University described this as a “desuppression” of protein building in neurons, meaning ketamine removes a brake that was preventing the brain from repairing and rewiring itself.
Ketamine for Depression
Ketamine’s most studied psychiatric use is for treatment-resistant depression, meaning depression that hasn’t improved after trying two or more standard antidepressants. In a real-world study of 537 patients who received a series of four to eight infusions over one to four weeks, 53.6% experienced at least a 50% reduction in depression scores, and 28.9% reached full remission.
The speed is what sets ketamine apart. Many patients notice a shift in mood within hours of their first session, and the initial treatment phase typically involves multiple sessions clustered together over a few weeks. The challenge is that the benefits fade relatively quickly. In most patients who respond well to a single dose, the antidepressant effect disappears within about two weeks. Even with repeated dosing, the median time to relapse after stopping treatment is only two to three weeks. This means many people need ongoing maintenance sessions, though there are no firm clinical guidelines yet on exactly how often those should happen.
Ketamine for Chronic Pain
Beyond depression, ketamine is used to treat chronic pain conditions that haven’t responded to other approaches. Complex regional pain syndrome (CRPS) and fibromyalgia are among the most commonly treated conditions. Pain protocols often involve a series of short infusions, sometimes five sessions over five consecutive days. The doses used for pain management are generally low, similar to those used for depression, and are far below anesthetic levels.
The mechanism for pain relief overlaps with the one for depression. By blocking glutamate receptors, ketamine can interrupt pain signaling pathways that have become overactive. For people with chronic pain conditions where the nervous system has essentially learned to amplify pain signals, this reset can provide meaningful relief.
What a Ketamine Session Feels Like
Ketamine is classified as a dissociative anesthetic, and even at the low doses used therapeutically, it produces noticeable psychological effects. During a session, people commonly report altered perceptions of time and space, a feeling of floating or detachment from their body, and changes in how they process sensory information. Some people experience visual distortions or what researchers describe as “mystical-type” experiences. These effects are dose-dependent: higher doses produce more intense dissociation.
Many patients describe the experience as difficult to put into words. Researchers have noted that this quality of “ineffability,” the sense that the experience simply can’t be captured in language, is a hallmark of the dissociative state. The acute psychological effects typically begin within minutes of administration and resolve relatively quickly, which is why clinical settings require monitoring for at least two hours after a dose. Most people feel mostly normal within a few hours, though some report lingering grogginess or mild nausea for the rest of the day.
IV Ketamine vs. Nasal Spray
There are two main ways ketamine is delivered in clinical settings, and they differ in important ways. Intravenous (IV) ketamine uses the original form of the drug, given through a vein over about 40 minutes. The FDA-approved nasal spray, sold under the brand name Spravato, uses esketamine, a slightly different version of the molecule.
Spravato is FDA-approved specifically for treatment-resistant depression and for adults with major depression who have acute suicidal thoughts, always alongside an oral antidepressant. IV ketamine, on the other hand, is FDA-approved only as an anesthetic. When clinics offer IV ketamine for depression or pain, they’re using it off-label, meaning for a purpose the FDA hasn’t formally evaluated for that form of the drug.
A meta-analysis comparing the two routes found that IV ketamine produced a substantially larger effect on depression symptoms than intranasal esketamine. IV ketamine showed benefit across a range of doses, from low (0.2 mg/kg) to standard (0.5 mg/kg), without higher doses necessarily working better. For the nasal spray, the 84 mg dose was more effective than lower doses, and the lowest dose tested (28 mg) showed no significant benefit over placebo. Despite these differences in study data, the nasal spray has the regulatory advantage of formal FDA approval, which means it comes with standardized safety monitoring protocols.
Side Effects and Safety Concerns
The most common side effects during a ketamine session are temporary increases in blood pressure and heart rate, dissociation, nausea, and dizziness. Blood pressure typically peaks about 40 minutes into an infusion, with systolic pressure rising an average of 16 points and diastolic rising about 11 points. In a study of 138 patients across more than 2,300 infusions, about 12.5% of patients experienced at least one episode of significantly elevated blood pressure requiring intervention. Older patients and those with a history of high blood pressure are at greater risk. These spikes tend to happen more during the first few sessions.
The cardiovascular effects are one reason clinical ketamine is administered in supervised settings with monitoring equipment. For the nasal spray specifically, the FDA requires a certified healthcare setting and a minimum two-hour observation period after each dose.
Bladder and Urinary Risks
One of the more concerning long-term risks is bladder damage, sometimes called ketamine-associated uropathy. Symptoms include frequent urination, urgency, painful urination, blood in the urine, and pelvic pain. In severe cases, it can lead to kidney damage. This complication has primarily been documented in people using ketamine recreationally at very high doses, typically over 1 gram per day for months. The minimum reported dose associated with bladder problems in one study was 1 gram daily for three months, which is dramatically higher than therapeutic doses (usually 0.2 to 0.5 mg/kg per session, working out to roughly 15 to 40 mg for an average adult). Still, the long-term effects of repeated low-dose therapeutic use over months or years are not yet fully understood.
Who Should Avoid Ketamine
People with uncontrolled high blood pressure face the highest cardiovascular risk during infusions. A history of psychotic disorders is generally considered a disqualifying condition, since ketamine can temporarily alter perception and cognition in ways that could worsen psychotic symptoms. Active substance use disorders also raise concerns, given that ketamine is a Schedule III controlled substance with potential for misuse.
The FDA has specifically warned about compounded ketamine products, which are custom-mixed formulations sometimes prescribed by telehealth companies or compounding pharmacies for at-home use. These products are not FDA-approved for any indication, have not been evaluated for safety or effectiveness, and are not subject to the same monitoring requirements as the approved nasal spray. The agency has flagged these as carrying additional risk because patients may use them without appropriate medical supervision.