Ketamine has been around since 1962, sitting quietly in operating rooms and battlefield medic kits, doing its job as an anesthetic. The depression piece is newer, and the public conversation around it is louder than the evidence usually deserves. Somewhere between the breathless headlines and the people who treat any psychiatric drug as suspicious, there’s an actual treatment with actual indications and actual limits.
This post is the overview. There are separate, more specific pieces on ketamine-assisted therapy, high-dose in-clinic work, and the low-dose at-home protocols. Start here if you don’t yet know what shape of treatment you’re looking at. The decision tree matters as much as the molecule.
One thing to say up front. Ketamine sits past the first line. If you haven’t tried therapy, real lifestyle changes, and a couple of first-line antidepressants, those are where you start. Ketamine is for people who’ve already done the standard stuff and are still suffering. Treatment-resistant depression. PTSD that hasn’t budged after years of work. Suicidal ideation that won’t quit between episodes. That’s the population the data is on.
How the molecule actually works
Ketamine is an NMDA receptor antagonist. In plain language, it temporarily blocks one of the glutamate receptors your brain uses to do most of its routine signaling. That sounds like the kind of thing that should make people feel worse, and at anesthetic doses it does take you somewhere most people can’t come back from on their own (that’s why anesthesiologists use it). At psychiatric doses, which are a fraction of surgical doses, something different happens. The NMDA blockade triggers a downstream cascade involving AMPA receptors and BDNF, and the net effect is a rapid increase in synaptic plasticity. Your brain becomes briefly more able to form new connections than it normally is.
What that looks like in clinic. People who’ve been stuck in the same depressive groove for five, ten, twenty years sometimes describe getting unstuck within hours. Not the SSRI version of feeling better, where you wait six weeks to notice the volume dropping. More like the rut they were walking in suddenly has walls that aren’t as tall as they were yesterday. The window doesn’t stay open forever. Most of the research suggests the plasticity effect lasts somewhere from a few days to a couple of weeks per session, which is why ketamine is dosed in courses, not single hits, and why what you do in that window matters more than the drug itself.
The dissociation patients experience during sessions appears to be part of how it works, not a side effect to engineer around. Studies that have tried to separate the antidepressant effect from the dissociative experience have not had a clean time of it. You feel weird, and the weird isn’t incidental.
From battlefield anesthetic to depression treatment
Ketamine was synthesized in 1962 and FDA-approved as an anesthetic in 1970. It got heavy use in Vietnam because it doesn’t suppress breathing the way most anesthetics do, which made it usable in field conditions without a ventilator. It’s still on the WHO’s essential medicines list. That’s the boring fifty-year history almost nobody talks about.
The depression piece came later. A team at Yale ran a small trial in 2000 giving subanesthetic IV ketamine to people with depression and watched their scores drop within hours. The result was so unusual that for about a decade most of the field assumed something was wrong with the study. Replications kept coming back the same. By the mid-2010s ketamine clinics were opening across the country using off-label IV racemic ketamine, and in 2019 the FDA approved esketamine (Spravato), an intranasal version, specifically for treatment-resistant depression. In 2020 they expanded the approval to include depression with active suicidal ideation. First new mechanism for treating depression to get a label in roughly thirty years.
The drug opens a window. You still have to walk through it.
Spravato, IV, and the rest of the menu
The regulatory landscape confuses almost everyone, including some referring physicians. Here’s the short version. Spravato (esketamine) is FDA-approved, intranasal, must be administered in a certified clinic with a two-hour monitoring period, and is covered by a growing list of insurance plans for treatment-resistant depression. IV racemic ketamine, which is what most ketamine clinics actually use, is off-label. The molecule is the same one anesthesiologists have used for decades, but the FDA hasn’t approved it for psychiatric use, which means insurance usually doesn’t cover it. Off-label is a normal part of psychiatric prescribing. It does mean you’ll often pay out of pocket.
Beyond Spravato and IV, there’s intramuscular ketamine (similar profile to IV, easier logistics, slightly less precise dosing), sublingual lozenges or troches for at-home protocols at much lower doses, and oral capsules in some boutique programs. Four delivery models, give or take, and they don’t do the same thing. High-dose in-clinic sessions are built around producing a meaningful dissociative experience under monitoring, often paired with therapy. Low-dose at-home protocols are closer to a maintenance approach, sub-psychedelic, used between in-clinic sessions or on their own for people who can’t get to a clinic regularly.
IV or IM, higher doses
0.5 mg/kg infusion over 40 minutes is the canonical research dose. Six sessions over two to three weeks. Real dissociation, full monitoring, usually paired with therapy.
Spravato (esketamine)
FDA-approved for treatment-resistant depression. Twice weekly for the first month, tapering after. Two-hour clinic monitoring. Increasingly covered by insurance.
Sublingual lozenges
Lower doses (often 100 to 400mg dissolved under the tongue), sub-psychedelic to mildly dissociative. Maintenance, not breakthrough. Tighter prescriber oversight because of abuse potential.
Who’s a candidate and who isn’t
The clearest indication is treatment-resistant depression, which is the technical name for depression that hasn’t responded to at least two adequate trials of standard antidepressants. If you’ve done a real eight to twelve weeks each on a couple of SSRIs and you’re still stuck, you meet the criteria most clinics use. The second clear indication is suicidality, particularly the kind that lingers between episodes of depression. The rapid onset matters there. You can’t ask somebody to wait six weeks for an SSRI to maybe work when they’re not sure they have six weeks. PTSD has solid emerging data. Severe anxiety, especially the kind tangled up with depression, has weaker but real data.
Who shouldn’t get ketamine. Anybody with a history of psychosis or a strong family history of schizophrenia (NMDA antagonism can trigger or worsen psychotic symptoms in vulnerable people). Anybody with uncontrolled hypertension or significant cardiac disease, because sessions transiently bump blood pressure and heart rate. Anybody with active alcohol or stimulant use disorders. Active ketamine misuse, obviously. Pregnancy. Some liver and bladder conditions, since chronic high-dose ketamine use has well-documented bladder toxicity (this is a recreational-use problem, not a clinic-dose problem, but it’s worth screening).
The gray zones. Bipolar depression is treatable with ketamine but needs careful monitoring for mood elevation. Older patients with cardiovascular risk factors can often be treated with tighter pre-session screening. People in active trauma therapy sometimes do better waiting until they’ve built scaffolding with a therapist before adding ketamine in.
The piece nobody puts on the brochure
Ketamine doesn’t replace your personality. It doesn’t fix your marriage. It doesn’t give you a way out of doing the work. People who use it as a chemical bypass for actually changing their life don’t get the same results as people who use it as a tool alongside doing the work. I had a woman in clinic last spring who’d been on four antidepressants over eight years, did a six-session IV course at 0.5 mg/kg, came back two weeks later saying it was the first time in a decade she’d felt like there was anywhere to go. She also restarted therapy that week and took a new job that summer. The drug didn’t do those things. It made them possible to consider.
The other thing nobody puts on the brochure is what it costs. Coverage for Spravato is improving and patchy. IV is almost always out of pocket, often in the 400 to 800 dollar range per session, and a standard course is six sessions plus maintenance. At-home lozenge protocols are usually the cheapest entry point and aren’t right for everyone. If a clinic quotes you a number and won’t talk about whether the cheapest option is actually the right one for what you’re dealing with, that’s a clinic to leave.
If you’ve tried the standard stuff and you’re still stuck, ketamine is worth a real conversation. That doesn’t mean it’s the right tool. It means it’s a real option, and the four delivery models are not interchangeable. Read the specific pieces on whichever one your situation points toward, and bring the questions you’d normally be embarrassed to ask.