Ketamine Therapy: A Complete Guide to Forms, Administration, and What to Expect | JourneyŌM

What Is Ketamine, and Why Is It Being Used for Depression?

Ketamine has been an FDA-approved anesthetic since 1970, used for decades in operating rooms, emergency departments, and battlefield medicine. Its role in mental health is much newer. In the late 1990s and early 2000s, researchers noticed something unexpected: at doses far below anesthetic levels, ketamine appeared to lift severe depression within hours rather than weeks. That observation is the origin of everything now marketed as ketamine therapy.

There is an important legal distinction worth understanding before you evaluate any provider. Esketamine, sold as Spravato, is a purified form of the molecule that carries formal FDA approval for treatment-resistant depression. Racemic ketamine, the standard anesthetic formulation used in infusion clinics, has no FDA approval for any psychiatric condition and is prescribed off-label. Off-label prescribing is legal, common across medicine, and not inherently a red flag, but it does mean the quality of oversight varies enormously from one clinic to the next.

Ketamine also occupies a practical position that no other compound in this space currently holds. Because it is a Schedule III controlled substance rather than Schedule I, licensed clinicians can prescribe it in every state. For most people in the United States, it remains the only rapid-acting option a physician can legally offer today.

How Does Ketamine Work Differently From Psilocybin or MDMA?

Classic psychedelics like psilocybin act primarily on serotonin receptors. Ketamine works on a different system entirely. It blocks the NMDA receptor, part of the brain’s glutamate signaling network, and that blockade triggers a rebound surge of glutamate activity in the hours that follow.

What that means in practical terms is that the brain enters a brief period of heightened plasticity, a window in which it forms new connections more readily than usual. Researchers believe this window, rather than the dissociative experience itself, is what carries the antidepressant effect. The experience during the session lasts under an hour. The neurological opening it creates appears to last considerably longer, which is why what you do in the days afterward matters so much.

This mechanism also explains a difference people often find surprising. A single psilocybin session can produce effects that persist for months, while ketamine’s benefits typically fade within days to weeks unless the treatment is repeated. For a closer look at how the two compare across the research, see our comparison of psilocybin and ketamine therapy.

What Are the Main Routes of Ketamine Administration?

The single most useful concept for comparing routes is bioavailability, which simply means the percentage of a dose that actually reaches your bloodstream. A 100mg sublingual tablet and a 100mg intravenous dose are not remotely the same treatment, because the digestive tract and liver destroy most of what you swallow before it ever circulates.

Intravenous Infusion

The most studied route and the standard in dedicated clinics. A typical protocol delivers roughly 0.5mg per kilogram of body weight over about forty minutes, with an initial series of six sessions spread across two to three weeks. Bioavailability is complete, dosing is precise, and the infusion can be slowed or stopped mid-session if you become uncomfortable or your vital signs shift. That degree of control is the main argument in its favor.

Intramuscular Injection

An injection into muscle delivers roughly 93 percent of the dose, making it nearly as efficient as an infusion and considerably simpler to administer. The trade-off is that once the injection is given, it cannot be adjusted or halted. Some clinics prefer it for cost and simplicity; others avoid it for exactly that reason.

Esketamine Nasal Spray (Spravato)

The only formulation in this category with FDA approval for depression. It was approved in March 2019 alongside an oral antidepressant, and in January 2025 the FDA approved it as a standalone treatment for adults who have not responded to at least two antidepressants. Bioavailability sits around 45 to 50 percent. Because it falls under a federal risk management program, it can only be administered at a certified facility, where you remain under observation for at least two hours and cannot drive for the rest of the day.

Sublingual Troches and Rapid-Dissolve Tablets

Held under the tongue or between cheek and gum, these deliver roughly 25 to 35 percent of the dose through the oral mucosa. This is the dominant format in at-home telehealth programs. It is convenient and considerably less expensive, but absorption varies with saliva, technique, and how long you hold the medication in place, so two identical doses can produce noticeably different experiences.

Oral Capsules and Compounded Nasal Sprays

Swallowed ketamine has the poorest and least predictable absorption of any route, with published estimates ranging from about 17 to 25 percent. Compounded nasal sprays sit somewhere in the middle, though they are prepared by individual pharmacies rather than manufactured to a single standard, so potency is not guaranteed to be consistent between refills.

What Does a Ketamine Session Actually Feel Like?

Most people describe the experience as dissociative rather than visionary. The boundary between self and surroundings softens. Time stretches. Bodily sensation becomes distant or floaty, and thoughts often feel observed rather than owned. It is not sleep, and it is not the vivid narrative imagery associated with psilocybin or ayahuasca.

In a well-run clinic you will typically wear an eye mask, listen to a curated playlist, and remain in a reclined position with a clinician nearby monitoring blood pressure and heart rate. The peak lasts roughly forty minutes to an hour, with another hour or so of gradual return. Mild nausea, blurred vision, and a temporary rise in blood pressure are common and expected.

The hours afterward tend to matter more than most people anticipate. Many describe a period of unusual mental openness in the following days, when patterns of thought feel less fixed than usual. Without something structured to do with that openness, the window tends to close without much lasting change. Our overview of how to prepare for ketamine treatment covers what to put in place beforehand.

What Does the Evidence Actually Show?

The foundational trial came from the National Institute of Mental Health in 2006, where Zarate and colleagues gave a single subanesthetic infusion to eighteen patients with treatment-resistant depression. Symptom improvement appeared within twenty-four hours. The sample was tiny, but the speed of the response was unlike anything in psychiatry at the time.

The most substantial evidence arrived in 2023. The ELEKT-D trial, conducted across five US academic medical centers with 403 participants, compared intravenous ketamine directly against electroconvulsive therapy for non-psychotic treatment-resistant depression. Ketamine produced a response in 55 percent of patients compared with 41 percent for ECT, meeting the standard for non-inferiority. That is a meaningful result, given that ECT has long been considered the most effective option available for severe depression.

For esketamine specifically, the phase 4 monotherapy trial supporting the 2025 approval found that 22.5 percent of participants reached remission at four weeks, against 7.6 percent on placebo. Real benefit, and also a reminder that most participants did not reach remission.

Two caveats deserve emphasis. Durability is the persistent weakness: relapse is common once treatment stops, which is why maintenance sessions are usually part of the plan rather than an upsell. And the evidence base for anxiety, PTSD, and addiction is considerably thinner than for depression, consisting largely of small trials and clinical observation rather than large controlled studies.

What Are the Risks, and Who Should Be Cautious?

Acutely, ketamine raises blood pressure and heart rate, which is why cardiovascular screening is not optional. People with uncontrolled hypertension, a history of aneurysm, significant cardiac disease, or active psychosis are generally poor candidates. A fuller picture is covered in our discussion of who should pause before pursuing this kind of treatment.

Bladder toxicity is the risk most often glossed over in marketing material. Ketamine-induced cystitis is well documented in frequent, high-dose non-medical use, where roughly a quarter of regular users report lower urinary tract symptoms. A 2025 systematic review of therapeutic populations found urinary symptoms in 0 to 24.5 percent of patients, mostly mild, and across fourteen randomized trials the rates did not differ meaningfully from placebo. Early symptoms usually resolve when treatment stops, which is precisely why any provider should be asking about them at every visit.

Misuse potential is real. Ketamine is scheduled as a controlled substance for good reason, and the risk concentrates in unsupervised repeated use. In October 2023 the FDA issued a public warning about compounded ketamine products prescribed for at-home use, citing the absence of monitoring for sedation, dissociation, and changes in vital signs. That warning is not an argument against ketamine, but it is a strong argument against loosely supervised models. The circumstances surrounding Matthew Perry’s death illustrate what happens when clinical boundaries dissolve.

How Should You Evaluate a Provider?

Ask who is physically present during your session and what their credentials are. Ask how the medical screening is conducted, and treat a five-minute video call as insufficient. Ask what happens between sessions, because a clinic that administers medicine without any integration support is selling half a treatment. Ask what the maintenance plan looks like and how it ends, and ask whether they screen for urinary symptoms as a matter of routine.

A provider who answers these questions readily is demonstrating something more useful than any marketing claim. Our overview of what a proper screening assessment covers gives you a benchmark to measure against.