What we mean by “treatment-resistant” anxiety
Anxiety is one of the most common reasons people walk into a primary care office, and it is also one of the conditions where the standard playbook works reasonably well—for most people. SSRIs, SNRIs, cognitive behavioral therapy, and short-term benzodiazepine support help a large majority of patients reduce symptoms enough to function. The trouble is the people for whom that playbook does not work.
There is no single regulatory definition of treatment-resistant anxiety the way there is for treatment-resistant depression, but most clinicians draw the line at roughly the same place. Two adequate trials of an SSRI or SNRI at therapeutic dose for eight to twelve weeks each, with or without benzodiazepine augmentation, plus an evidence-based therapy like CBT. If you have done that and you are still anxious every day, you fit the population this article is about.
It is a larger group than people often realize. Across generalized anxiety disorder and social anxiety disorder, about 30% of patients fail to achieve adequate response to first- and second-line treatment. Many cycle through three, four, or five medication trials over a decade before someone finally uses the phrase “treatment-resistant” out loud. By that point the cost is not just symptomatic. It is jobs, relationships, and a slow narrowing of life around the things that don't trigger the panic.
The clinically interesting question is whether a different mechanism, acting on a different neurotransmitter system, can produce response in the people for whom serotonin-targeted medications have not. That is where ketamine comes in.
The Glue 2017 RCT: why it mattered
For most of the 2010s, the ketamine literature was almost entirely about depression. Ketamine for anxiety was extrapolation. It was reasonable extrapolation—the comorbidity between anxiety and depression is enormous—but it was not the same thing as a clean trial in non-depressed anxiety patients.
That changed in 2017. A randomized, double-blind, placebo-controlled trial published in the Journal of Psychopharmacology by Glue and colleagues enrolled twelve patients with treatment-refractory generalized anxiety disorder or social anxiety disorder. Importantly, none of these patients had current major depressive disorder. The team gave each patient single subcutaneous doses of ketamine at 0.25, 0.5, and 1 mg/kg, plus midazolam as an active placebo, in randomized order separated by at least a week.
The results were strong enough that they reframed the conversation. Ten of twelve patients responded at the 0.5 and 1 mg/kg doses, with significant reductions on the Fear Questionnaire and Hamilton Anxiety Rating Scale. Anxiolytic effects persisted up to seven days after a single dose. Researchers also identified a clear dose-response curve, both for efficacy and for dissociative side effects. Higher doses produced more relief and more transient dissociation; the 0.5 mg/kg dose looked like the sweet spot.
Glue 2017 was small. Twelve patients is not a definitive trial. But it was the first randomized evidence that ketamine produces an anxiolytic signal independent of its antidepressant effect. That distinction matters because for years skeptics argued ketamine only seems to help anxiety because it lifts the depression underneath. Glue isolated the anxiety signal in patients who did not have current depression to lift.
Ketamine is FDA-approved as an anesthetic; its use for anxiety is off-label. Glue's findings sit firmly in research territory rather than regulatory approval, and any clinical use today is built on that off-label foundation.
Maintenance and dose-response: what came after Glue 2017
The natural follow-up question after Glue 2017 was whether the response could be sustained without escalating doses or losing effect over time. Glue and colleagues addressed it directly in a 2018 follow-up in the same journal, where they tracked patients on maintenance ketamine for treatment-refractory GAD and SAD. The signal held. Patients sustained response with weekly to fortnightly dosing over months, without dose escalation, and without clear evidence of tolerance.
The picture got broader in Hartland and colleagues' 2023 systematic review and meta-analysis, also in the Journal of Psychopharmacology. This was a transdiagnostic look at ketamine's anxiolytic effects across GAD, social anxiety disorder, PTSD, and depression-related anxiety. The reviewers concluded that the anxiolytic effect of ketamine was consistent across diagnostic categories, with effect sizes that warranted further study. It was not a definitive endorsement of ketamine for anxiety as a first- or second-line treatment. It was a credible body of evidence saying the signal seen in Glue 2017 was not a fluke.
What we still do not have is a large multi-site phase 3 trial dedicated to anxiety, comparable to what exists for ketamine in depression. That trial would settle a lot of open questions about optimal dose, optimal frequency, and which subtypes of anxiety respond best. Until then, clinical practice draws on the smaller trials, the maintenance data, and the much larger depression literature, with appropriate hedging.
How this differs from ketamine for depression
People who have read about ketamine for treatment-resistant depression sometimes assume the anxiety story is identical. It is not, in three meaningful ways.
First, the dose-response curve looks different. The depression literature has converged around 0.5 mg/kg over 40 minutes as the standard antidepressant dose. The anxiety literature, especially Glue 2017, suggests that 0.5 to 1 mg/kg is the productive range, and that anxiolytic effects may be more dose-sensitive than depressive ones. We pay close attention to where someone lands on that curve.
Second, the time course is different. Antidepressant effects from ketamine typically peak around 24 hours after infusion and fade over one to two weeks. The anxiolytic effects in Glue 2017 persisted up to seven days from a single dose, which is a slightly different rhythm. In our experience, patients with primary anxiety often describe the change as quieter and steadier than the dramatic mood lift sometimes seen in depression responders.
Third, Spravato is not on the table. Spravato (esketamine) is FDA-approved for treatment-resistant depression and for major depressive disorder with acute suicidal ideation. It is not approved for anxiety. The Glue research used parenteral ketamine, and clinical practice for anxiety relies on IV racemic ketamine because it gives precise dose control across the range the studies actually used. Use of ketamine for anxiety is off-label.
Benzo overlap — the conversation no one wants to have
Most of the patients who walk into our clinic with treatment-resistant anxiety are taking, or have recently taken, a benzodiazepine. Often for years. This is the conversation no one wants to have, and it has to happen anyway.
There is a signal in the literature—clearer in depression than in anxiety, but worth taking seriously—that chronic benzodiazepine use may blunt ketamine's effect. The mechanism is plausible: benzodiazepines enhance GABA-A inhibition, which is the brake on the same glutamate system ketamine works through. Pressing the brake harder while trying to release glutamate-driven plasticity is, at minimum, working against yourself.
What we do not do is ask people to stop their benzodiazepine cold. That is dangerous. Abrupt benzodiazepine discontinuation can produce seizures and severe rebound anxiety. Any taper has to be slow, planned, and run by your prescribing provider. What we do is have an honest conversation about timing—whether holding the benzodiazepine the morning of an infusion makes sense, whether a longer-term taper coordinated with your psychiatrist might be appropriate, and what the realistic interaction looks like for you. Our article on ketamine medication interactions covers this in more detail.
Who's a candidate, who isn't
Treatment-resistant anxiety is not a clean category, and ketamine is not the right tool for everyone in it. Based on the published evidence and our own clinical experience, the strongest candidates tend to share a few features.
- Documented failure of two or more SSRI or SNRI trials at therapeutic dose for an adequate duration. If first-line treatment was never really tried, that is the place to start, not here.
- Engagement with therapy. CBT for anxiety has strong evidence, and ketamine works best when the post-infusion neuroplastic window is being used for something. People who have done the therapy work and still feel stuck are exactly the people the research best describes.
- Functional impairment that is not improving. The honest version of this is: are you missing work, withdrawing from people you love, sleeping poorly, and unable to picture relief from where you sit today? If yes, the calculus shifts.
- No active uncontrolled hypertension, severe cardiovascular disease, or active substance use disorder that would make ketamine medically inappropriate. We screen carefully.
Sleep is worth flagging separately. A lot of treatment-resistant anxiety presents with chronic insomnia that drives the anxiety as much as the anxiety drives the insomnia. Our piece on ketamine and sleep covers what the early data suggests there. If your anxiety is general, the broader ketamine for anxiety overview is the right starting point. This article is for the harder cases.
What a treatment-resistant anxiety consult at MCK looks like
The first step is a real conversation, not a sales pitch. We want to know what you have tried, at what doses, for how long, and what happened. We want to know what your prescribing psychiatrist or PCP thinks. We want to understand the shape of your anxiety—generalized worry, social, panic, or some mix—because the published evidence is stronger in some of those than others. How it works walks through our process at a higher level.
If we agree ketamine is reasonable to try, the typical induction is four to six IV infusions over two to three weeks, with the dose individualized based on weight, history, and response. Marla Peterson, CRNA, oversees every infusion. She is on-site throughout your session and provides anesthesia-level monitoring—continuous pulse oximetry, blood pressure, and heart rate—the same standard you would expect in a pre-op holding area, only quieter and considerably more comfortable.
Sessions run roughly 40 minutes of infusion time, plus monitoring before and after. You will need a driver. Most patients return to normal activity the next day. After induction we re-evaluate honestly: meaningful response, partial response, or no response. If you are responding, we discuss a maintenance cadence informed by Glue 2018 and your own clinical course. If you are not responding, we tell you that and stop.
Honest expectations and cost
We try to be straight about what ketamine can and cannot do for treatment-resistant anxiety in 2026.
- Not everyone responds. Even in Glue 2017, two of twelve patients did not respond at the higher doses. Real-world response rates are likely in a similar range, with a meaningful minority who do not benefit.
- The evidence base is smaller than for depression. Research suggests ketamine helps treatment-resistant anxiety; it does not yet support strong claims of efficacy at the level we have for treatment-resistant depression. We hedge accordingly.
- It works alongside, not instead of, your other care. We do not ask anyone to come off SSRIs, therapy, or anxiety-specific psychotherapy. The goal is to add a different mechanism to a stack that has not been enough on its own.
- Insurance generally does not cover off-label ketamine. Sessions at Music City Ketamine are $475 each, and we are transparent about that from the first conversation. We do not surprise people with pricing.
- We will refer out when ketamine isn't right. If your situation looks like it needs a different tool—TMS, more intensive therapy, a psychiatric medication change—we say so. The product is the clinical standard, not pushing infusions.
If you have spent years working through the standard playbook and you are still anxious every morning when you wake up, the question is not whether ketamine is a guarantee. It is not. The question is whether a different mechanism, with credible randomized evidence in exactly the population you fit, is worth a careful conversation. For a lot of people, it is.