Ketamine Therapy For Depression
A Patient-Researcher’s Guide To What Actually Matters

Ketamine therapy is different from antidepressants—and works faster—because it repairs the brain’s structure instead of altering brain chemistry. SSRIs work by increasing serotonin levels, which may slowly improve mood over time, but ketamine immediately crosses the blood-brain barrier, triggers a glutamate surge, and begins restoring damaged neural circuits. That physical repair process begins within hours, not weeks.

Antidepressants can take 4 to 8 weeks because they rely on indirect, downstream changes that slowly influence brain connectivity, if at all. Ketamine skips that delay by directly activating BDNF, reorganizing brain networks, and promoting the growth of new connections between cells.

Patients often feel sharper, calmer, and more emotionally regulated after their first or second session—not because of chemical mood shifts, but because their brain is functioning differently. This treatment does not reset brain chemistry; it rebuilds the brain’s communication systems. The difference isn’t subtle. The speed comes from structural change, not chemical modulation.

The overwhelming majority of patients describe ketamine treatment as calm and contained regardless of how intense the session gets. That’s because ketamine creates a dissociative state where you feel physically and psychologically safe, even while accessing fear, grief, or trauma. The drug suppresses the default mode network and blocks NMDA receptors, which interrupts ordinary thought patterns and opens the door to subconscious material.

Some people do have vivid psychedelic visions, but many do not. What’s consistent is the strange emotional distance ketamine creates: you might relive painful memories or see disturbing imagery, but from behind a kind of glass. You can feel fear without panic, sadness without collapse. This buffer is what makes the experience manageable—not the absence of emotion, but the detachment from it.

The treatment setting is also quiet, structured, and closely supervised. Most patients feel groggy, introspective, or emotionally raw afterward—but not unsafe, not out of control. The power of the experience comes from what surfaces, not from how wild it gets.

Spravato is FDA-approved only for patients with treatment-resistant depression who’ve failed at least two prior antidepressants, and it must be administered in a REMS-certified clinic under strict supervision. IV ketamine is off-label but backed by decades of research, isn’t limited to REMS facilities, and is available to patients with a broader range of diagnoses—including major depression, bipolar depression, persistent depressive disorder, and seasonal affective disorder—regardless of how many medications they’ve tried.

IV ketamine is racemic ketamine—both R- and S-ketamine—administered by infusion. Spravato is esketamine, the S-isomer only, delivered through a nasal spray. IV dosing is based on body weight and can be precisely adjusted between sessions to optimize response and minimize side effects. Spravato comes in two fixed doses—56 mg and 84 mg—regardless of weight or sensitivity.

IV delivers 100% of the medication into your bloodstream. Spravato averages 48% bioavailability, with variability caused by nasal congestion or spray technique.

There are no head-to-head trials, but systematic reviews and meta-analyses comparing each treatment to placebo found that IV ketamine is up to five times more effective than Spravato at reducing depressive symptoms and 2.5 times more likely to bring patients into remission.

Ketamine is typically delivered through IV infusion, intramuscular (IM) injection, esketamine nasal spray (Spravato), or oral/sublingual forms. Each method has major trade-offs in effectiveness, cost, and accessibility.

IV infusion is the most effective and fastest-acting, with nearly 100% bioavailability and real-time dose control. But it’s always self-pay and often runs $400–$800 per session. IM injection is more affordable than IV and works faster than the nasal spray, but it offers less dosing flexibility. Spravato is FDA-approved and partially covered by insurance, but out-of-pocket costs can still exceed $8,000 without the manufacturer’s subsidy. It’s slower to work, less effective than IV, and requires treatment at a REMS-certified clinic.

Oral and sublingual forms are the least effective and slowest acting. They’re also less researched and carry more risk due to inconsistent absorption.

Choosing a method isn’t just about preference. It often comes down to real-world barriers: cost, insurance coverage, clinic access, and how quickly you need relief.

Ketamine therapy is not covered by insurance—except for Spravato, the esketamine nasal spray. IV infusions and injections are considered “off-label,” so they are excluded from coverage by commercial insurance, Medicare, and Medicaid. Spravato, by contrast, is FDA-approved and at least partially covered by most commercial insurers. Medicare covers it under Part B, and Medicaid covers it in many states, though eligibility varies significantly.

Despite this coverage, ketamine remains a very expensive treatment across the board—with or without insurance—unless you qualify for the substantial manufacturer subsidy, which requires commercial insurance that already covers Spravato. Without insurance, the 14-session Spravato protocol costs about $24,000. With coverage, your out-of-pocket cost typically ranges from $7,691 to $9,451 depending on your deductible, copays, and coinsurance.

IV ketamine and injection therapy cost less—around $6,000 and $3,380 respectively for a full protocol—but must be paid entirely out of pocket.