Esketamine's REMS vs. Ketamine's Loophole: A Regulatory Paradox

Lisa Harding, MD, a psychiatrist at Yale University who also maintains a private practice, has spent the past seven years watching esketamine move from FDA approval into clinical reality. She was chief of interventional psychiatry at Yale when the nasal spray formulation—esketamine, the S-enantiomer of ketamine—received approval in 2019 for treatment-resistant depression, followed by a second indication in 2020 for depressive symptoms in patients with acute suicidal ideation. The drug works as an NMDA receptor antagonist, building on research Yale scientists had begun in the 1990s documenting ketamine's rapid antidepressant effects. But seven years of clinical experience has revealed something Harding finds troubling: the regulatory framework governing esketamine bears almost no resemblance to the one—or rather, the absence of one—governing ketamine prescribed off-label.

The suicidal ideation indication, Harding believes, remains the most underutilized approval esketamine has received. Unlike the treatment-resistant depression indication, which requires documentation of prior antidepressant failures, the acute suicidality approval does not demand that prerequisite. Yet clinicians have been slow to adopt it. Economics matter, Harding acknowledges, but so does comfort level. The drug requires blood pressure monitoring at the beginning, middle, and end of each session. Treatment centers must be certified under a Risk Evaluation and Mitigation Strategy, or REMS, and staff must be trained to manage both physiologic events and dysphoric reactions. These logistical demands, combined with the gap between trial populations and the more complex patients seen in everyday practice, have created friction. Harding has helped launch esketamine in Australia, Saudi Arabia, Brazil, Mexico, and Colombia—and she estimates that roughly 90 percent of her work over seven years has gone simply to helping clinicians feel comfortable administering the drug.

It is worth pausing on what the suicidal ideation indication actually means. In the two registration trials, hospitalized patients began at 84 milligrams, with one permitted dose reduction to 56 milligrams if adverse effects emerged. Depressive symptoms declined rapidly enough to give clinicians a window in which to plan next steps for patient safety. But Harding is precise about the language: "No medicine to date has been given an FDA approval to target suicidal ideation," she said. "It targets those depressive symptoms, so that clinicians can make other interventions to keep the patient safe." The drug is a tool for reducing the acute psychiatric distress that can accompany suicidal thinking, not a direct treatment of suicidality itself.

The regulatory paradox becomes stark when one considers racemic ketamine—the full molecule, not just the S-enantiomer. Racemic ketamine can be prescribed off-label, given orally, sublingually, intramuscularly, or intravenously, and in some cases mailed directly to patients' homes. It faces none of the REMS requirements that govern esketamine. The reason, Harding explained, is historical: racemic ketamine was approved decades ago as an anesthetic for use in hospitals. It never needed a Risk Evaluation and Mitigation Strategy because it was never meant to leave the hospital setting. Regulators do not govern off-label prescribing itself, only the labeled indication. But the gaps that have opened up are substantial. Compounding pharmacy rules remain loose. Prescription drug monitoring programs do not reliably communicate across state lines. During the pandemic, the Ryan Haight Act's requirement for in-person evaluation was relaxed, allowing prescribers to evaluate patients and mail ketamine across state lines. Harding called this "a legal loophole that has been exploited."

The human cost has surfaced in news reports in which families have linked suicides to oral ketamine mailed to their homes. The FDA, recognizing the problem, convened a two-day public meeting in 2024 through the Reagan-Udall Foundation to examine ketamine use more broadly. Harding has administered esketamine more than 10,000 times over seven years, and she credits her outcomes not to the drug itself but to rigorous patient selection. Every patient must first be medically cleared—contraindications include aneurysmal vascular disease and other serious conditions. They must then meet psychiatric criteria. According to her business manager, approximately 30 of every 1,000 screened patients proceed to treatment. That is a three percent acceptance rate. "The crux of this is screening the appropriate patient for the treatment," Harding said. "The right patient has to be treated, and to reduce the amount of treatment emergent adverse events, it is patient preparation." The implication is clear: outcomes depend far less on which formulation of ketamine a clinician chooses than on whether the clinician has done the work to identify who should receive it in the first place.