Ketamine Therapy (IV & Intranasal) — Psychedelics & Neuroplasticity
FDA-approved NMDA antagonist with the fastest-acting antidepressant effect of any drug class — proven for treatment-resistant depression, suicidality, and chronic pain.
Overview
Ketamine is a dissociative anesthetic that at sub-anesthetic doses produces rapid antidepressant, anxiolytic, and anti-suicidal effects. It is the only legally accessible psychedelic compound in widespread clinical use in the USA. The NMDA receptor antagonism of ketamine disinhibits AMPA receptor signaling, triggering a cascade leading to mTORC1 activation and BDNF-TrkB signaling — rapidly synthesizing new synaptic proteins and reversing stress-induced synaptic deficits within hours. A single IV infusion of 0.5 mg/kg over 40 minutes produces antidepressant effects in ~70% of treatment-resistant patients within 4-24 hours — effects that persist 1-2 weeks. Six infusions over 2-3 weeks extend response duration. Esketamine (Spravato) nasal spray received FDA approval in 2019 for treatment-resistant depression (TRD) and 2020 for major depressive disorder with acute suicidal ideation — the only psychedelic-adjacent compound with FDA approval. Ketamine clinics (over 2,000 in USA) now offer infusion therapy for TRD, PTSD, OCD, and chronic pain.
Indications
- Treatment-resistant depression (2+ failed adequate antidepressant trials)
- Acute suicidal ideation (most rapid intervention available)
- Post-traumatic stress disorder (adjunct)
- Bipolar depression (with mood stabilizer)
- Chronic pain syndromes (CRPS, fibromyalgia)
- OCD (anecdotal and emerging evidence)
Mechanism of Action
Ketamine blocks NMDA receptors on GABAergic interneurons, disinhibiting glutamate release onto pyramidal neurons and triggering a downstream cascade of antidepressant signaling
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Ketamine IV (induction) | 0.5 mg/kg over 40 minutes | 6 infusions over 2-3 weeks | Most studied protocol; some use 0.5-1.0 mg/kg; produced by compounding pharmacy; $400-800/infusion cash-pay |
| Esketamine (Spravato) nasal spray | 56mg or 84mg | 2x/week x 4 weeks, then weekly x 4 weeks, then biweekly | FDA-approved; insurance coverage for TRD and MDD with suicidal ideation; must remain in clinic 2 hours post-dose |
| Ketamine maintenance | 0.5 mg/kg IV or 56-84mg nasal | Monthly or as needed to prevent relapse | Frequency highly variable; some patients maintain with biweekly booster; pair with psychotherapy for best long-term outcomes |
Evidence Grade
GRADE A
Safety & Contraindications
- Dissociative and psychotomimetic effects during infusion — supervision mandatory
- Bladder toxicity (ketamine cystitis) with frequent/high-dose recreational use; rare at therapeutic dosing schedules
- Addiction potential in predisposed individuals — do not use in active substance use disorder without specialist oversight
- Hemodynamic effects: transient hypertension and tachycardia — avoid in uncontrolled hypertension or heart disease
- Esketamine (Spravato) requires 2-hour post-dose monitoring in REMS-certified facility (mandatory REMS program)
- Drug interactions: CNS depressants, stimulants