What “Long COVID” Actually Means

Long COVID is the umbrella term for symptoms that persist or appear weeks to months after an initial SARS-CoV-2 infection. The Centers for Disease Control and Prevention defines it as a multisystem condition that can include depression, anxiety, cognitive symptoms—commonly called “brain fog”—and fatigue lasting more than four weeks after the acute infection clears. The CDC’s Long COVID Clinical Overview (2024) explicitly recognizes the neuropsychiatric component of the syndrome.

The NIH RECOVER Initiative, which is the largest coordinated research effort to characterize long COVID, has reported in its 2023 protocol publications that mental health symptoms including major depression and anxiety are common in long-COVID patients and warrant standard psychiatric evaluation and treatment. RECOVER frames these symptoms as real, measurable, and treatable—not psychosomatic, not imagined, and not something patients should be expected to push through.

Important framing: long COVID is heterogeneous. Two patients with the same diagnosis can present with very different problems. One may be dealing primarily with profound fatigue and post-exertional malaise. Another may be dealing primarily with new-onset depression and panic. A third may have autonomic dysregulation showing up as POTS-like symptoms. The label is the same. The clinical pictures are not.

The Neuropsychiatric Symptom Picture

Within long COVID, the symptoms most likely to overlap with conditions ketamine has been studied for are major depression, generalized anxiety, panic, and treatment-resistant variants of both. Patients describe a mood that flattens out and stays flat. Sleep that no longer restores. Anxiety that arrived after the infection and never quite left. The cognitive symptoms—slow word-finding, lost trains of thought, the sense of working through fog—sit alongside the mood symptoms and often worsen them.

The relationship between mood and cognition is bidirectional. Untreated depression and anxiety blunt concentration and memory on their own, even in patients without any post-viral component. So when a long-COVID patient with depression reports brain fog, some portion of the cognitive complaint may reflect the depression rather than direct neurological effects of the virus. Treating the mood does not always lift the fog. Sometimes it does. We are honest that we cannot predict which.

For patients in this neuropsychiatric subgroup, the question becomes whether the existing evidence for ketamine in depression and anxiety can reasonably extend to a long-COVID context. The answer is partial and qualified.

Why Direct Ketamine Evidence Is Limited

Let us state this plainly. As of this writing, there is no large, randomized, controlled trial of IV ketamine specifically for long COVID. There are case reports. There are small case series. There are open-label observations. None of those rise to the level of evidence needed to claim that ketamine treats long COVID as a distinct entity. We will not claim it.

Ketamine is FDA-approved as an anesthetic. Its use for any psychiatric or pain condition—including the depression, anxiety, and chronic-pain components of long COVID—is off-label. Spravato (esketamine), the nasal-spray formulation, is FDA-approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation, but not for long COVID specifically. The off-label distinction matters because it shapes how we talk about evidence, expectations, and informed consent.

What we do have is decades of evidence in adjacent conditions. The reasonable scientific position is that if a long-COVID patient meets criteria for treatment-resistant major depression, the evidence supporting ketamine for treatment-resistant depression applies to them in the same way it would apply to any patient with that diagnosis. The same logic extends to severe anxiety. What it does not do is generalize to fatigue, post-exertional malaise, autonomic symptoms, or cognitive impairment as primary targets.

What the Underlying Depression and Anxiety Evidence Shows

Three named studies anchor the conversation about ketamine for the mood and anxiety components of long COVID.

A landmark 2013 randomized controlled trial by Murrough and colleagues, published in the American Journal of Psychiatry, compared IV ketamine to midazolam in patients with treatment-resistant depression. The ketamine group showed a 64% response rate at 24 hours, compared to 28% in the midazolam control group. The trial was important because midazolam produces sedation and dissociation similar to ketamine, ruling out simple expectancy effects. The mechanism appears to be NMDA receptor antagonism leading to a glutamate surge and rapid synaptic plasticity, which is the foundation of how ketamine works in mood disorders.

For anxiety, a 2017 study by Glue and colleagues, published in the Journal of Psychopharmacology, examined IV ketamine in patients with treatment-refractory anxiety disorders. The study reported rapid and large reductions in anxiety symptoms after ketamine dosing, with effects measurable within hours and sustained over the following days. The authors noted that the response was distinct from a generalized antidepressant effect—anxiety symptoms responded directly. This is part of why we treat ketamine for anxiety as a clinically meaningful indication when standard treatments have not worked.

The third anchor is the body of regulatory evidence: the FDA approved Spravato in 2019 for treatment-resistant depression and in 2020 for major depressive disorder with acute suicidal ideation, signaling that the agency considered the glutamate-modulating mechanism robust enough to support a labeled indication. None of these references settle the long-COVID question. They establish that ketamine is a reasonable option for the depression-and-anxiety subset of the long-COVID picture when those symptoms are severe and have not responded to standard care.

Cautions: Autonomic Dysfunction and POTS

One thing that is more common in long COVID than in the general depression population is autonomic dysregulation. A meaningful subset of long-COVID patients develop postural orthostatic tachycardia syndrome (POTS) or POTS-like patterns, with heart rate spikes on standing, dizziness, and blood-pressure swings. This is clinically relevant for ketamine because ketamine itself raises heart rate and blood pressure during the infusion, typically in a transient and predictable way, but more dramatically in patients whose autonomic system is already dysregulated.

For these patients, screening matters more than usual. We ask about cardiology workup, recent tilt-table testing if available, current medications including beta-blockers and other heart-rate agents, and whether the patient has had episodes of syncope. We may use a slower infusion, a lower starting dose, or stage treatment differently than we would for a patient without autonomic involvement. We may also decline to treat patients whose cardiovascular status makes ketamine an unreasonable risk. Saying no is part of how a careful clinic operates.

Ketamine is FDA-approved as an anesthetic; its use for the depression and anxiety symptoms common in long COVID is off-label. We say that explicitly during consultation, and we put it in writing.

How We Screen Long-COVID Patients in Nashville

The consultation for a long-COVID patient is longer than our typical intake. We want to understand the full symptom picture, not just the mood component. We ask when the acute infection occurred, what the recovery trajectory has looked like, what symptoms emerged or persisted, and what other clinicians are already involved—PCP, cardiology, neurology, infectious disease, psychiatry. Long COVID is not a one-clinician problem. We coordinate when we can.

We then look specifically at whether there is a treatable depression or anxiety picture inside the broader presentation. PHQ-9 and GAD-7 scores help anchor the conversation. We review medication history, prior treatment trials, and the current regimen, including stimulants sometimes prescribed for fatigue or cognitive symptoms. Stimulants and ketamine are not contraindicated together, but the combination warrants attention. So do certain antihypertensives.

If we proceed, sessions are conducted in a private treatment room with continuous pulse oximetry, blood pressure, and heart-rate monitoring. Marla Peterson, CRNA, oversees every infusion and provides anesthesia-level monitoring. She is on-site throughout the visit. Sleep, which is often disrupted in long COVID, is something we track between sessions; ketamine’s effect on sleep architecture can sometimes help and sometimes hinder, and we adjust accordingly.

For patients with chronic-pain features layered into their long-COVID picture, we may discuss how ketamine is used for chronic pain as a separate consideration. The protocols and dosing differ from mood-focused treatment, and we are careful not to conflate them.

Honest Expectations

We want to set expectations clearly because long COVID has produced its share of overpromising, and we will not add to that.

The honest framing is this: if long COVID has produced or worsened severe depression or anxiety that is not responding to standard care, ketamine is one of a small number of options with meaningful supporting evidence in those conditions. That is the case for considering it. It is not a case for expecting it to repair the post-viral syndrome itself. Evidence for that does not yet exist, and we will not pretend it does.