A psychiatrist reflects on two decades of treating depression with ketamine

Twenty years ago, if you’d told most psychiatrists that an old operating-room anesthetic would become one of the most talked-about tools in depression care, you’d have gotten a polite smilethe kind that says, “Sure, and my pager is going to start sending compliments.” Yet here we are: ketamine (and its FDA-approved cousin, esketamine) reshaped the conversation about what depression treatment can look like when it needs to move faster.

This isn’t a love letter to a “miracle drug,” and it’s definitely not a DIY guide. It’s a practical, evidence-based reflectionequal parts hope and humilityabout what ketamine has taught clinicians over two decades: about brains, about suffering, about expectations, and about the fine art of doing something powerful as safely as possible.

Note up front: the only ketamine-derived depression treatment approved by the FDA is intranasal esketamine (Spravato) for specific adult indications under strict safety controls. Ketamine itself is FDA-approved as an anesthetic, not as a psychiatric treatment, even though it’s sometimes used “off-label” in carefully monitored medical settings.

How we got here: from anesthesia to antidepressant (with a lot of science in between)

Ketamine has been used in medicine for decades as an anesthetic. What changed the psychiatric world wasn’t a marketing campaignit was an observation: at certain doses and in controlled settings, ketamine could relieve depressive symptoms with unusual speed in some patients. Early clinical research at the turn of the century helped legitimize the idea that depression could sometimes improve within days, not weeks.

Those first studies didn’t “solve” depression. They did something arguably more important: they cracked open a door. For decades, most antidepressants targeted serotonin and norepinephrine. Ketamine pushed the field to take glutamate and synaptic plasticity seriously, sparking an explosion of research into rapid-acting antidepressants.

Then came a major milestone: in 2019, the FDA approved intranasal esketamine (Spravato) for treatment-resistant depression in adults, used under medical supervision with a risk management program (REMS). In January 2025, the FDA expanded approval so Spravato could be used as a standalone treatment for adults with treatment-resistant depression (not only alongside an oral antidepressant).

Ketamine vs. esketamine: same family, different rulebooks

Clinically, people often say “ketamine” when they mean a whole universe of treatments. But the details matter. Ketamine (typically given by IV in many medical settings) is not FDA-approved for depression, even though it is used off-label by some clinicians for patients with hard-to-treat illness. Esketamine is a specific formulation that went through FDA review for depression indications and must be administered in certified settings with monitoring.

The FDA has also warned patients and clinicians about risks associated with compounded ketamine products marketed for psychiatric conditionsespecially products intended for home use, where on-site monitoring isn’t available. Translation: if you’re reading about “ketamine at home” online, understand that regulators are worried for very real reasons.

What a supervised treatment day feels like (without the hype)

If you imagine ketamine treatment as a dramatic movie montagemoody lighting, a single tear, credits rollyou’re not alone. In reality, well-run programs look more like careful aviation: checklists, screening, monitoring, and a strong preference for boring outcomes (in medicine, “boring” is excellent).

Before treatment: screening and setting expectations

A responsible clinic doesn’t start with ketamine. It starts with questions: What’s been tried? What’s the diagnosis? Any history that changes risk (for example, uncontrolled blood pressure, certain substance use risks, or conditions where dissociation would be destabilizing)? For esketamine, FDA labeling emphasizes supervised administration and monitoring for sedation and dissociation.

The most important “pre-treatment medication,” in my view, is expectation management. Ketamine isn’t a personality transplant. It’s not a guarantee. And it’s not a substitute for a long-term plan. It can create a windowsometimes a surprisingly fast onewhere depression loosens its grip enough for other supports to work better.

During treatment: monitoring, not mysticism

In supervised care, the environment is intentionally calm and staff keep a close eye on vital signs and overall safety. Side effects can include feeling disconnected from yourself or reality, sedation, dizziness, nausea, and temporary blood pressure increaseseffects that clinics are specifically set up to monitor.

Some people describe the experience as dreamlike; others feel mainly sleepy or “odd.” A small number find it unpleasant. The key clinical point: the altered sensations are expected, time-limited, and managedthis is one reason reputable programs emphasize in-clinic care. Johns Hopkins public health experts have been blunt about the dangers of self-medicating with ketamine.

After treatment: the “don’t just go back to life like nothing happened” phase

Depression care isn’t only about what happens in the chair; it’s what happens after. Clinics typically advise patients not to drive immediately afterward and to plan for a low-demand day. More importantly, good programs build follow-up into the process: symptom tracking, coordination with a primary clinician, and a plan for what comes next. (If the treatment is a match, the goal is improvementnot a perpetual loop of appointments.)

Who ketamine-based treatments are for (and who they’re usually not)

The most common clinical target is treatment-resistant depressiongenerally meaning a person hasn’t improved adequately after trying multiple standard antidepressant treatments at appropriate doses and durations. Esketamine’s FDA indication focuses on adults with treatment-resistant depression, with specific requirements and monitoring.

This matters because ketamine is not typically positioned as a first-step option. It enters the conversation when depression has been stubborn, severe, or dangerously disablingwhen the cost of waiting weeks for a conventional medication to work is simply too high.

That said, ketamine doesn’t replace other effective treatments. For some people, therapies like antidepressant combinations, psychotherapy, transcranial magnetic stimulation (TMS), or electroconvulsive therapy (ECT) may be appropriate. Research groups have continued comparing approaches, including studies suggesting IV ketamine may be comparable to ECT in certain treatment-resistant cases (with important nuances about patient selection).

What makes ketamine different: the rapid-acting antidepressant idea

Traditional antidepressants often require weeks to reach full effect. Ketamine challenged that timeline. Early controlled research showed that some patients experienced meaningful symptom improvement within days after ketamine compared with placebo.

Mechanistically, ketamine is often described as an NMDA receptor antagonist that shifts glutamate signaling, setting off downstream effects related to synaptic plasticity. Think of it less like “adding happiness” and more like “reopening flexibility” in circuits that have gotten stuck. Reviews describe cascades involving glutamate surges and synaptogenesis, especially in stress-affected brain regions.

Researchers are still debating detailsscience is a living thing, not a finalized group project. But the big takeaway holds: ketamine helped validate the concept that fast biological shifts can translate into fast mood shifts for some people.

The hard part: when fast relief meets long-term reality

If ketamine has a headline, it’s speed. If it has a footnote, it’s durability. Many studies and clinical experiences suggest that relief can be substantial yet time-limited, especially after a single administration. That’s why programs often consider a structured course plus a maintenance strategyalways individualized, always balanced against risk.

Side effects and safety: why clinics don’t “wing it”

Side effects can include dissociation, sedation, and temporary increases in blood pressure. Esketamine labeling includes warnings and emphasizes monitoring after administration, and medical centers describe similar short-lived effects in clinical practice.

Over the years, clinicians have also paid attention to broader concerns: cognitive effects, urinary symptoms with repeated exposure, and potential for misuseespecially outside supervised settings. FDA warnings about compounded ketamine underscore these risks and the importance of provider oversight.

What the consensus-minded clinicians keep saying

One of the most influential tone-setters in the field has been the “enthusiastic but cautious” camp: yes, ketamine can help some people; no, we shouldn’t pretend the evidence answers every long-term question. A major consensus statement emphasized both the promise and the limitations, urging careful consideration of risks and the gaps in knowledge.

That balanced approach has aged well. Over two decades, the most reliable clinical posture hasn’t been hype or hostility. It’s been vigilance.

Ketamine-assisted psychotherapy: promising, but not a magic shortcut

Some clinics pair ketamine sessions with psychotherapyoften called ketamine-assisted psychotherapy (KAP). The theory is intuitive: if ketamine temporarily increases cognitive and emotional flexibility, therapy might use that window to build new patterns.

The evidence base here is evolving and heterogeneous. The responsible stance is curiosity plus standards: patients should know what’s evidence-backed, what’s still emerging, and what’s simply branded well. If a program can’t explain its safety protocols and clinical rationale in plain English, that’s your cue to keep shopping.

Access, cost, and equity: the part nobody wants to put on a billboard

Even when a treatment works, the real world can be rude about it. Esketamine requires in-clinic administration and monitoring, which can mean time off work, transportation planning, and childcare logistics. Off-label ketamine infusions may not be covered by insurance and can be financially out of reach for many.

Independent evaluations have analyzed costs and resource use associated with delivering esketamine and ketamine in clinic settingshighlighting how “promising” doesn’t automatically translate to “accessible.” If the next era of depression care is going to be more humane, it has to be more reachablenot just more innovative.

Twenty years of lessons: what ketamine taught me about depression care

If I could go back and talk to my younger selfthe one who still believed that “a new treatment” meant “problem solved”I’d offer a few practical truths:

1) The right goal isn’t “a ketamine response.” It’s a life that restarts.

A score on a symptom checklist matters, but it’s not the whole story. The better question is: did the person start showering again, answering texts, eating breakfast, showing up for therapy, returning to work, feeling less trapped? Ketamine can be a bridgesometimes a sturdy oneto those changes, but the bridge has to land somewhere.

2) Fast relief can be emotionally complicated

When someone has been depressed for years, improvement can feel unfamiliareven scary. There can be grief (“So many years lost”), anger (“Why did it take so long?”), or anxiety (“What if it fades?”). This is where follow-up, therapy, and steady clinician support become as important as the medication itself.

3) “Set and setting” isn’t just a cultural phraseit’s clinical common sense

A calm environment, clear explanations, and staff who treat patients like humans (not like “cases”) can reduce distress during transient perceptual effects. That’s not mysticism. That’s good medicine.

4) Safety is not negotiable, and boredom is underrated

The best ketamine day is uneventful: stable vitals, manageable side effects, clear discharge plan. The FDA’s emphasis on supervision and monitoring for esketamine exists for a reason. If a clinic’s vibe is “we’re rebels,” ask yourself whether you want your healthcare to be a music festival.

5) Ketamine’s story is also a warning about shortcuts

Ketamine’s rise has attracted everything from rigorous research to questionable business models. The FDA has explicitly warned about compounded ketamine products marketed for psychiatric use, especially for home administration. In depression care, convenience and safety often fight. Your job is to pick safety.

Extra reflections (about ): the moments that changed my practice

Over two decades, ketamine didn’t just change what I prescribe; it changed what I listen for. And because real patient stories deserve privacy, the “patients” below are compositestrue-to-life patterns stitched together from many experiences, not any one person.

The first lesson was humility. Early on, I met a middle-aged teacher who had tried what felt like everything: several antidepressants, thoughtful psychotherapy, lifestyle changes, the whole “have you tried yoga?” bingo card. When ketamine helped, the improvement was noticeable enough that family members commented without prompting. But what surprised us wasn’t the liftit was what came after. She didn’t instantly become a new person. She became a person with options. Once the fog thinned, she could finally do the unglamorous work that depression had made nearly impossible: keeping therapy appointments, restarting routines, rebuilding sleep, repairing relationships. Ketamine didn’t do those things for her. It made them doable. That’s the difference between a headline and a treatment plan.

The second lesson was patience with non-responders. Another composite patient, a young adult with long-standing depression and intense anxiety, didn’t improve the way we hoped. The disappointment felt sharp, because ketamine’s reputation had inflated expectations. That experience forced a better clinical habit: before starting, we now talk explicitly about the full range of outcomesincluding “no meaningful change.” We also plan the next steps in advance, so a non-response doesn’t become a free fall into hopelessness. In practice, this means having a clear map: medication adjustments, therapy intensification, other neuromodulation options, and supports that don’t depend on one tool working. Hope is important. So is redundancy.

The third lesson was how much environment matters. Some people feel calm during transient perceptual changes; others feel frightened. I learned to stop treating the experience as a side note and start treating it as a clinical variable. A quieter room, fewer interruptions, a staff member who narrates what’s happening in plain language, and a short grounding conversation afterward can be the difference between “manageable” and “never again.” It’s not about making ketamine feel specialit’s about making patients feel safe. Medical centers describing esketamine care often emphasize that side effects peak and then fade under supervision, which matches what good clinics see in practice.

The fourth lesson was that “rapid” doesn’t mean “simple.” Some patients felt better quickly and then panicked: “What if it wears off?” That fear can become its own symptom. We began to treat that anxiety as part of the care planbuilding coping strategies, scheduling follow-ups, and pairing symptom tracking with real-life goals (getting back to work, reengaging with family, cooking again, exercising gently). I learned to celebrate functional wins as loudly as mood scores.

The fifth lesson was the importance of boundaries. Over time, the broader culture started talking about ketamine as if it were a trendy life upgrade. That is not what severe depression feels like, and it is not what responsible treatment is. When the FDA warned about compounded ketamine productsespecially those positioned for home useit echoed what clinicians were already seeing: the more you loosen guardrails, the more you invite preventable harm. Two decades in, my stance is simple: if a treatment is powerful enough to help quickly, it’s powerful enough to demand respect.

Conclusion: a realistic kind of hope

Ketamine changed depression care by changing our expectationsabout speed, about biology, and about what’s possible when standard treatments fall short. But its real contribution isn’t that it “solves” depression. It’s that it can, for some people, open a window. What we do with that windowsafe monitoring, honest conversations, therapy integration, long-term planningdetermines whether the gains become a turning point or just a temporary break in the weather.

If you’re considering ketamine-based treatment, treat it like you’d treat any serious medical decision: choose reputable, supervised care; ask about monitoring and follow-up; and avoid any approach that encourages unsupervised use. (And if you’re in the U.S. and you or someone you know is in immediate danger or needs urgent help, you can call or text 988 for the Suicide & Crisis Lifeline.)