Esketamine vs. Ketamine: Why the Rules Still Differ

A Psychiatrist Flags an Uneven Set of Rules

Lisa Harding, MD, a psychiatrist who has prescribed esketamine nasal spray for seven years, used an October 2026 interview with Psychiatric Times to ask a pointed question: why does the FDA-approved nasal spray version of ketamine face strict monitoring requirements while the off-label, generic form used in most ketamine clinics does not? The interview, published October 3, 2026, does not announce a policy change. It is one clinician's reflection on a regulatory split that has shaped the ketamine treatment field since infusion clinics and telehealth ketamine programs expanded rapidly after 2020.

Esketamine, sold under the brand name Spravato, is the S-enantiomer of the ketamine molecule. The FDA approved it in 2019 specifically for treatment-resistant depression, and it is dispensed under a Risk Evaluation and Mitigation Strategy (REMS), a federal safety program that requires patients to take the drug at a certified clinic and stay for monitored observation afterward because of sedation and dissociation risks. Racemic ketamine, the mixed-molecule form of the same drug, has long been approved only as a surgical anesthetic. When clinics prescribe it for depression, anxiety, or PTSD, that use is off-label, meaning it falls outside the FDA-approved indication. Off-label prescribing is legal and common across medicine, but it means dosing, patient screening, and monitoring protocols for racemic ketamine are set by each individual clinic rather than mandated by a federal program like the esketamine REMS.

According to the Psychiatric Times interview description, Harding's reflection centers on this contrast: a nasal spray with years of structured, in-clinic oversight sits next to a chemically related compound administered with far less uniform federal structure, often through IV infusion, intramuscular injection, or take-home lozenges and troches.

Why This Gap Has Persisted Since 2019

The REMS program attached to esketamine exists because the FDA tied its approval to a specific, narrow clinical pathway: in-clinic administration, a required observation period, and enrollment in a monitoring system. Racemic ketamine never went through that same FDA review for psychiatric use, so no parallel federal requirement was created for it. That is a structural accident of how each drug entered the market, not a finding that one version is medically superior to the other. A substantial body of published research on racemic ketamine for depression predates and parallels the esketamine trials, and many psychiatrists consider both forms clinically reasonable tools when used by trained providers.

What Harding's comments highlight, consistent with the interview's framing, is that the absence of a federal monitoring mandate for off-label ketamine creates inconsistency across the industry. Two clinics offering the same molecule can have very different intake screening, different rules about who qualifies for take-home dosing, and different plans for what happens if a patient has a difficult psychological reaction. That inconsistency is the operational risk worth paying attention to, separate from any question about whether ketamine itself is effective.

What This Means If You're Evaluating a Ketamine Provider in 2026

For readers weighing online or in-person ketamine treatment, the practical lesson from this discussion is to ask providers to fill the gap that federal regulation does not. Before starting treatment, ask any clinic, telehealth platform, or in-person provider the following: What is the required pre-treatment medical and psychiatric screening, and does it include a review of cardiovascular history and current medications? Who administers or supervises each dose, and is there a required observation period afterward comparable in spirit to the esketamine REMS model? If take-home dosing is offered, what specific criteria determine eligibility, and what is the follow-up schedule with a licensed clinician? How does the provider document outcomes and manage dose adjustments over time?

These questions matter more for off-label racemic ketamine programs precisely because no single federal checklist governs them. A credible provider should be able to answer each one specifically, not generically. A provider who cannot describe a clear monitoring and follow-up protocol is asking the patient to absorb the oversight gap that Harding's interview describes, rather than closing it.

What to Watch Next

This interview does not signal an imminent regulatory change. The FDA has not announced new rules for off-label racemic ketamine as of this writing, and the esketamine REMS remains in effect for Spravato. Readers should treat this as an expert perspective worth factoring into provider selection, not as a new legal standard. State medical boards, which license the physicians and nurse practitioners who prescribe ketamine off-label, remain the primary source of enforceable standards in the absence of a federal monitoring program, so checking a provider's licensing status and any board actions is a reasonable complement to the questions above.

Source: Psychiatric Times, "Esketamine, Off-Label Ketamine, and the Regulatory Gap: A Conversation With Lisa Harding, MD" (October 3, 2026).