What is the difference between IV ketamine, Spravato, and oral ketamine?

All three act primarily on the brain's NMDA glutamate system to support rapid neuroplasticity. IV ketamine is given as a precisely-dosed in-clinic infusion. Spravato (esketamine) is an FDA-approved nasal spray administered in a REMS-certified clinic. Oral/sublingual ketamine is taken at home after in-person evaluation and supervised induction. They differ in bioavailability, onset, monitoring, FDA status, insurance coverage, and cost.

Which ketamine treatment is most effective?

Randomized trials show meaningful response in roughly 50–70% of patients with treatment-resistant depression across IV ketamine and Spravato, with onset often within hours to days. Oral ketamine has a smaller evidence base but shows benefit when used inside a monitored program. The best route depends on your history, safety profile, and access — decided with your physician.

Is Spravato covered by insurance?

Spravato is FDA-approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation, and is commonly covered by commercial insurance and Medicare with prior authorization. IV and oral ketamine are off-label and typically cash-pay.

Ketamine IV vs Spravato vs At-Home Ketamine

Treatments

Three paths, one goal

IV ketamine, Spravato® (esketamine), and at-home oral ketamine all act on the same NMDA-glutamate pathway — but they differ in how they're given, how fast they work, what they cost, and who they fit. Here's an honest comparison so you can walk into your consultation already informed.

Off-label · Cash

IV Ketamine

Precisely-dosed in-clinic infusion with continuous monitoring. Fast onset, fine-grained titration.

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FDA-approved

Spravato®

Esketamine nasal spray, FDA-approved for treatment-resistant depression. Given in clinic under REMS, often insurance-covered.

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Off-label · Cash

At-Home Ketamine

Sublingual maintenance at home after in-person evaluation and supervised induction. Lower cost, lower commute.

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Side-by-side

How they actually compare

Mechanism, protocol, evidence, and fit. Numbers reflect published trial ranges; your physician will discuss what applies to you.

	IV Ketamine	Spravato®	At-Home Oral
Mechanism	NMDA antagonist → glutamate surge → rapid synaptic plasticity (BDNF / mTOR).	S-enantiomer of ketamine, same NMDA pathway, delivered intranasally.	Same NMDA pathway; lower, slower-rising plasma levels via sublingual absorption.
Route	Intravenous infusion	Intranasal spray (self-administered, observed)	Sublingual lozenge / rapid-dissolve tablet
Setting	In clinic, private suite	In clinic, REMS-certified	At home, after in-person eval + supervised induction
FDA status	Off-label for depression	FDA-approved (TRD & MDD w/ acute SI)	Off-label, compounded
Typical induction	6 infusions over 2–3 weeks	2×/week × 4 weeks → 1×/week × 4 weeks	2×/week × 4 weeks (peer-monitored)
Maintenance	Booster every 2–6 weeks based on response	Every 1–2 weeks indefinitely per response	Weekly or biweekly at home with check-ins
Session length	~40 min infusion + 30 min recovery	~5 min dose + 2 hr observation (REMS)	~60–90 min with monitor at home
Typical onset	Hours to 1–2 days	Within 24 hours, builds over weeks	Days to 2 weeks
Reported response rate*	~50–70% in TRD trials	~50–70% in pivotal TRD trials	Smaller evidence base; meaningful response in monitored programs
Insurance	Cash-pay	Commonly covered (prior auth)	Cash-pay
Cost band	$$ — per infusion	$ — copay (when covered)	$ — monthly subscription
Best fit for	Severe / urgent symptoms, prior partial response, wants precise titration	TRD with insurance, wants FDA-approved route, comfortable in clinic	Stable patients seeking maintenance with less commute, after induction
Not ideal if	Needle aversion, uncontrolled cardiovascular disease	Cannot commit to 2-hour monitored visits, nasal pathology	Unstable home environment, active substance use, untreated severe disease

Mechanism

IV NMDA antagonist → glutamate surge → rapid synaptic plasticity (BDNF / mTOR).

Spravato S-enantiomer of ketamine, same NMDA pathway, delivered intranasally.

Oral Same NMDA pathway; lower, slower-rising plasma levels via sublingual absorption.

Route

IV Intravenous infusion

Spravato Intranasal spray (self-administered, observed)

Oral Sublingual lozenge / rapid-dissolve tablet

Setting

IV In clinic, private suite

Spravato In clinic, REMS-certified

Oral At home, after in-person eval + supervised induction

FDA status

IV Off-label for depression

Spravato FDA-approved (TRD & MDD w/ acute SI)

Oral Off-label, compounded

Typical induction

IV 6 infusions over 2–3 weeks

Spravato 2×/week × 4 weeks → 1×/week × 4 weeks

Oral 2×/week × 4 weeks (peer-monitored)

Maintenance

IV Booster every 2–6 weeks based on response

Spravato Every 1–2 weeks indefinitely per response

Oral Weekly or biweekly at home with check-ins

Session length

IV ~40 min infusion + 30 min recovery

Spravato ~5 min dose + 2 hr observation (REMS)

Oral ~60–90 min with monitor at home

Typical onset

IV Hours to 1–2 days

Spravato Within 24 hours, builds over weeks

Oral Days to 2 weeks

Reported response rate*

IV ~50–70% in TRD trials

Spravato ~50–70% in pivotal TRD trials

Oral Smaller evidence base; meaningful response in monitored programs

Insurance

IV Cash-pay

Spravato Commonly covered (prior auth)

Oral Cash-pay

Cost band

IV $$ — per infusion

Spravato $ — copay (when covered)

Oral $ — monthly subscription

Best fit for

IV Severe / urgent symptoms, prior partial response, wants precise titration

Spravato TRD with insurance, wants FDA-approved route, comfortable in clinic

Oral Stable patients seeking maintenance with less commute, after induction

Not ideal if

IV Needle aversion, uncontrolled cardiovascular disease

Spravato Cannot commit to 2-hour monitored visits, nasal pathology

Oral Unstable home environment, active substance use, untreated severe disease

*Response rates reflect peer-reviewed trials in treatment-resistant depression and vary by population, dose, and concurrent therapy. Educational only — not a guarantee of outcome.

Educational, not medical advice. Eligibility, dose, and program are decided with your Trellis physician at your in-person evaluation. Final program recommendation considers your full medical and psychiatric history.

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