Spravato vs Ketamine (IV)
How intranasal esketamine and IV racemic ketamine compare for treatment-resistant depression.
How they're similar
Spravato and IV ketamine share a lot.
- Same broad mechanism. Both act on the NMDA glutamate receptor, along with effects on AMPA receptors and downstream on the mTOR pathway. This is different from how SSRIs, SNRIs, or bupropion work.
- Both work quickly for depression. Where SSRIs typically take four to six weeks to show a full effect, ketamine and esketamine often produce measurable improvement in mood within 24 to 72 hours, sometimes within hours. That's part of why they're studied for acute suicidal ideation, where waiting weeks isn't safe.
- Both are given only in supervised medical settings. Neither is a take-home medication.
- Both cause dissociation and sedation during and shortly after dosing. Dissociation means a temporary altered sense of self, body, or surroundings. It can feel strange, sometimes uncomfortable, sometimes neutral. It generally clears within an hour or two.
- Both raise blood pressure and heart rate transiently, so monitoring during and after treatment is standard.
- Both carry Schedule III status in the United States, reflecting abuse potential.
- Both need a full plan around them. That means continuing psychiatric care, still taking an oral antidepressant for Spravato, addressing therapy and lifestyle factors, and not treating the infusion or nasal dose as the whole treatment.
The clinical impression is that these two are more similar than different in what they do to the brain and mood. The differences are mostly in how they're delivered, regulated, and paid for.
How they differ
The differences are practical rather than pharmacologic.
| Spravato (esketamine) | IV ketamine | |
|---|---|---|
| FDA approval | TRD (2019), MDD with acute suicidal ideation (2020) | Anesthesia only; depression use is off-label |
| Route | Intranasal spray | IV infusion |
| Setting | REMS-certified clinic | Ketamine clinic, some medical practices |
| Dosing | 56 or 84 mg per session | Typically 0.5 mg/kg over 40 minutes |
| Schedule of visits | Twice weekly x 4 weeks, then weekly x 4 weeks, then every 1 to 2 weeks | Twice weekly x 2 to 3 weeks, then taper based on response |
| Monitoring | 2-hour post-dose observation required | Usually 1 to 2 hours observation |
| Insurance | Often covered under medical benefit, prior auth required | Rarely covered, mostly cash-pay |
| Cost | Expensive, but insurance helps for many | $400 to $800 per infusion, cash |
| Concurrent antidepressant | Required (oral SSRI or SNRI) | Not required, though usually continued |
Spravato is the only FDA-approved ketamine-family drug for depression. That approval came in August 2019 for treatment-resistant depression, then extended in 2020 to major depressive disorder with acute suicidal ideation. Because it's approved, insurance often covers it under the medical benefit, though prior authorization is standard and can take time to arrange.
IV ketamine has been used in medicine since the 1960s, mostly for anesthesia and pain. Its use for depression is off-label, meaning it's used for a purpose the FDA hasn't formally approved. That doesn't mean it's experimental or unsupported. There's substantial published research showing IV ketamine improves depression rapidly, especially in treatment-resistant cases. But because it's off-label, insurance rarely covers it, and it's usually paid out of pocket.
The delivery route matters. Spravato is a nasal spray given in a clinic. Absorption through the nasal mucosa is somewhat variable, and some of the dose is swallowed and absorbed through the gut. IV ketamine is delivered over about 40 minutes as a controlled infusion, giving more predictable blood levels. Some clinicians and patients feel the IV route is more consistent.
Spravato requires a Risk Evaluation and Mitigation Strategy (REMS) program. That means clinics have to be certified, patients are registered, and specific monitoring rules are followed. After a dose, patients stay for at least two hours of observation, and they can't drive that same day. They need someone to drive them home, and full clearance to drive returns the day after a full night's sleep. IV ketamine clinics have similar practical rules, though the structure isn't federally mandated the same way. Most reputable clinics observe for one to two hours and require a driver.
Dosing schedules differ. Spravato has a defined regimen: 56 mg or 84 mg twice a week for four weeks, then weekly for four more weeks, then every one or two weeks for maintenance, alongside a continued oral antidepressant. IV ketamine doesn't have a standardized regimen because it's off-label. A common protocol is 0.5 mg/kg over 40 minutes, twice a week for two to three weeks, then a taper based on response. Some clinics do six infusions upfront, some more, some fewer, and maintenance schedules vary widely.
Side effect tendencies
The side effect profiles overlap heavily.
Dissociation is the most notable acute effect for both. It usually starts within 20 to 40 minutes of dosing and eases by an hour or two after. It can feel like floating, feeling disconnected from the body, seeing colors differently, or a sense of unreality. Most people find it tolerable, some find it uncomfortable, and a few find it deeply unpleasant. Some people find it interesting or even meaningful. It's important to be prepared for it before the first dose.
Sedation is common. Most people feel drowsy or heavy during and shortly after the session. Some sleep. Full alertness usually returns within a few hours, but driving isn't allowed until the next day.
Blood pressure elevation is common and typically peaks about 40 minutes after dosing. It's usually mild and settles on its own. People with uncontrolled hypertension, a history of aneurysm or arteriovenous malformation, recent heart attack, or unstable heart disease usually aren't candidates. Screening blood pressure before each session and monitoring during is standard.
Nausea, dizziness, headache, and a feeling of being "off" are all common in the hours after treatment. Anxiety, both during dosing and briefly after, happens for some.
Longer-term concerns are shared. Bladder problems (ketamine cystitis) have been reported with heavy or recreational use of ketamine. At medical doses given weekly or less, this is rare, but any new urinary symptoms should be reported. Cognitive effects with repeated use over months to years aren't fully mapped, though studies so far don't show major concerning trends at therapeutic dosing.
Abuse potential is real. Ketamine has recreational use potential, and Schedule III reflects that. Screening for substance use history is part of standard evaluation before starting either treatment. Ongoing use should be reviewed regularly.
What tips the choice
The practical factors usually decide.
Insurance coverage often points toward Spravato. Because it's FDA-approved, most insurance plans have a pathway, even if it takes prior authorization. That can make a course of Spravato financially possible when IV ketamine would cost thousands out of pocket.
Cash cost points toward IV ketamine only if insurance won't cover Spravato and IV ketamine is cheaper on a per-session basis where a person lives. For most people with insurance, Spravato is the better financial deal.
Access to a certified clinic matters. Spravato clinics are more common in urban areas and near academic centers. IV ketamine clinics exist in many places, but quality varies. Both need to be a real medical setting with monitoring, not a wellness spa.
Comfort with the route matters. Some people find nasal sprays awkward and prefer an IV. Some hate needles. That's a real factor.
Prior response matters. If someone had a good response to IV ketamine and now needs maintenance that insurance can help pay for, transitioning to Spravato is common. Response to one usually predicts response to the other.
Suicide risk. Spravato has an FDA-approved indication for MDD with acute suicidal ideation, which gives it a specific role when someone is acutely at risk. IV ketamine is used for the same purpose in practice, but Spravato has the formal label.
Neither is a first attempt at antidepressant treatment. Both are considered after several standard antidepressants haven't worked or after ECT has been considered.
Common questions
Are Spravato and IV ketamine the same drug? Not quite. IV ketamine is racemic, meaning it contains both the S and R mirror-image forms of the molecule. Spravato is only the S form (esketamine). The S form is more potent at the NMDA receptor per milligram. In practice, both improve depression through similar pathways, and clinical response is broadly comparable. The regulatory status, delivery route, and cost are what mostly separate them.
How fast do they work? Both can improve depression within hours to a few days. That's dramatically faster than SSRIs, which usually take four to six weeks. In studies, mood improvements are often measurable at 24 hours after the first dose. Full response usually needs the initial series of treatments rather than a single dose. The rapid effect is one of the main reasons these treatments are used for people with acute suicidal thinking.
Do I keep taking my regular antidepressant? For Spravato, yes. The FDA approval is for use with a concurrent oral antidepressant (an SSRI or SNRI). Stopping the oral drug during Spravato treatment isn't part of the approved protocol. For IV ketamine, there's no requirement, but most people continue their existing medication unless there's a specific reason to change. The plan is set with a prescriber.
Is dissociation dangerous? The temporary dissociation during a session isn't physically dangerous, and it clears by itself as the drug wears off. It can be uncomfortable emotionally, and it's why monitoring in a supervised setting is required. Being prepared for what it might feel like before the first dose helps a lot of people. Some clinics offer support during dosing that helps make the experience more tolerable or even useful.
Can I drive after a session? No, not the same day. After either Spravato or IV ketamine, you need a driver to take you home. Full clearance to drive comes back the next day after a full night of sleep. This is a firm safety rule, not a suggestion.
Sources
This guide draws on current prescribing information and public health references. It is reviewed for clinical accuracy and updated as guidance changes. This is not medical advice.
- U.S. Food and Drug Administration. Esketamine (Spravato) prescribing information and REMS program.
- American Psychiatric Association. Consensus statement on the use of ketamine in the treatment of mood disorders.
- MedlinePlus, U.S. National Library of Medicine.
- National Institute of Mental Health. Treatment-resistant depression resources.
Managing a medication needs a prescriber
Any psychiatric medication has to be started and adjusted by a clinician who can follow you over time. If you don't have a prescriber, our guides section explains the options, including in-person care and telepsychiatry, and how to choose between them.