For people with depression, especially treatment-resistant depression, this is the practical branch point: what is legal, what insurance may cover, what evidence supports, and what to ask before the first appointment.
| Option | Best fit | Insurance | First move |
|---|---|---|---|
| Spravato (esketamine) | Treatment-resistant depression when coverage and regulatory guardrails matter. | Most likely of the options here; prior authorization is common. | Ask your psychiatrist or insurer for REMS-certified sites and TRD criteria. |
| IV/IM ketamine clinic | Patients who can self-pay and want the most studied ketamine administration model. | Rare for depression; sometimes partial superbill reimbursement. | Vet medical leadership, dose protocol, monitoring, and maintenance plan. |
| At-home oral ketamine | Lower-cost access where telehealth is allowed and risk profile is low. | Usually no; HSA/FSA may apply. | Confirm real psychiatric evaluation, state licensure, and session support. |
| Psilocybin trial or regulated service | People seeking a classic psychedelic model and able to travel or enroll in research. | No coverage for state service programs; trials may cover study costs. | Search clinical trials, then compare Oregon/Colorado licensed services. |
Both are evidence-based in-clinic options for treatment-resistant depression, but they differ sharply on insurance coverage, administration, and regulatory standing. If cost or coverage is your main constraint, this comparison is the decision point.
| Dimension | Spravato (esketamine nasal spray) | IV ketamine infusion |
|---|---|---|
| FDA status | Approved for treatment-resistant depression (2019) and MDD with suicidal ideation (2020); standalone TRD approval (Jan 2025). | Not FDA-approved for depression; used off-label under a doctor's prescription. Ketamine itself is Schedule III and legal to prescribe. |
| Insurance coverage | Frequently covered by commercial insurance and Medicare after failing two or more antidepressants; prior authorization is common but usually obtainable. | Rarely covered for psychiatric indications; most patients pay out of pocket. Some plans reimburse via superbill, especially for chronic pain. |
| Typical out-of-pocket cost | $590–$885 per drug vial + clinic observation fee; often near $0 with coverage. Patient Assistance Program available for uninsured. | $400–$800 per infusion; typical induction series is 6 infusions over 2–3 weeks, totaling $2,400–$4,800. |
| How it's given | Patient self-administers nasal spray in a certified provider office and is observed for 2 hours before leaving. No IV line required. | Clinician administers 0.5 mg/kg over ~40 minutes by IV drip. Anesthesia-trained monitoring on-site. Patient needs a driver home. |
| Speed of effect | Onset hours to days; most pivotal trials measured effects at 4 and 28 days. | Onset typically within hours; effect often noticeable by the second or third infusion of the series. |
| Evidence base | Multiple FDA-registration-level RCTs (TRANSFORM, SUSTAIN series); remission data vs. placebo. Real-world outcomes registry growing. | Decades of academic trials; foundational Berman 2000 paper; strong short-term effect size. Long-term durability data thinner than Spravato. |
| Who it fits | Most patients with insurance pursuing TRD treatment; those who want the most regulatory oversight; those who prefer no IV. | Self-pay patients who want the most-studied delivery model; those whose doctors aren't REMS-certified; sometimes preferred for rapid crisis response. |
Start with Spravato. It is the only ketamine-family depression treatment here with FDA approval and broad payer pathways.
Compare in-clinic IV/IM ketamine against at-home oral programs by supervision, not just price.
Psilocybin is promising for depression, but access is very different from ketamine.
Do the clinician conversation before booking anything.
Ketamine-family treatment is usually fast-acting but not one-and-done. Some people notice mood shifts within hours or days; durability often depends on repeated dosing, psychotherapy, medication management, and a maintenance plan. Psilocybin trials sometimes report longer follow-up effects after one or two dosing sessions, but access is narrower and the blinding problem makes headline effect sizes hard to interpret.
For most US patients, the practical first branch is ketamine-family care: Spravato if insurance coverage matters, or clinic-based IV/IM ketamine if paying out of pocket is possible. Psilocybin is not FDA-approved and is legally accessible mainly through clinical trials or regulated Oregon and Colorado service programs.
No. Spravato is esketamine nasal spray, FDA-approved for treatment-resistant depression and administered only in certified offices under a REMS program. IV ketamine usually means racemic ketamine infusion used off-label for depression; it is commonly self-pay and not governed by the Spravato REMS.
Do not stop or taper psychiatric medication without the prescriber who manages it. Ketamine is often used while patients remain on antidepressants. Psilocybin effects can be reduced by SSRIs/SNRIs, but any taper decision requires medical supervision.
Ask who performs the medical evaluation, whether they screen cardiovascular and psychosis/mania risk, what route and dose protocol they use, how blood pressure and distress are handled during sessions, whether integration support is included, and what maintenance or exit plan they recommend after the initial series.
Spravato (esketamine) is made by <a href="https://www.janssen.com/" target="_blank" rel="noopener noreferrer">Janssen Pharmaceuticals</a>, the pharmaceutical subsidiary of Johnson & Johnson. It was FDA-approved in 2019 for treatment-resistant depression and is only available through the Spravato REMS (Risk Evaluation and Mitigation Strategy) program, which requires administration in a certified office with 2 hours of post-dose monitoring.
Related, not identical. Ketamine used in clinics is usually the racemic (both-mirror-image) form. Esketamine is just one of those two mirror-image molecules, isolated and formulated as a nasal spray. Only the Janssen-branded esketamine nasal spray is FDA-approved and REMS-regulated; IV, IM, sublingual, and compounded ketamine are chemically related but are prescribed off-label, not as Spravato.
Spravato is intranasal only, self-administered under observation. IV infusion is 100% bioavailable and the most-studied off-label route; IM is similar but injected rather than dripped. Sublingual troches/lozenges are roughly 25–30% bioavailable, so the dose is higher to compensate, and they're usually self-administered at home through a telehealth program rather than in a clinic. Our <a href="/guides/ketamine">ketamine guide</a> has the full route-by-route breakdown. One distinction worth naming: "street" or recreational ketamine is neither dosed, tested for purity, nor legal to obtain that way — it is not a cheaper version of a clinical or Spravato protocol, just an unregulated and legally risky one.
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Insurance decisions, new providers, and pricing shifts for ketamine and psilocybin depression treatments.
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