Substance Spotlight: dissociatives — ketamine clinics, Spravato, and the regulatory gray zone

This is Day 6 of the spotlight rotation. Of the ten substance classes Rize tracks, dissociatives are the one most likely to confuse people — including providers — because the same molecule, ketamine, plays three very different roles in the U.S. healthcare system.

What “dissociatives” means

The dissociative class includes ketamine, dextromethorphan (DXM), phencyclidine (PCP), nitrous oxide, and several emerging research and grey-market analogs. The shared mechanism is antagonism at the NMDA glutamate receptor, which produces the characteristic experience of perceived separation from the body, environment, and sometimes from one’s own emotional state. At lower doses, dissociatives produce mood elevation and analgesia. At higher doses they produce dissociative anesthesia — the original clinical use.

Patterns of harm differ widely across this class. Ketamine, used clinically, has a wide therapeutic index and a long safety record. Used outside clinical settings, particularly chronically and at high doses, it carries risks of bladder damage (ketamine cystitis), cognitive impairment, and dependence. DXM is implicated in adolescent overdoses linked to high-volume cough-syrup ingestion. PCP-related ER visits are uncommon now but have not gone to zero. Inhalant nitrous oxide use among young adults is well-documented and rising.

What is FDA-approved, and what is not

This is where the confusion gets practical. The only FDA-approved dissociative for psychiatric use is Spravato (esketamine) nasal spray, the S-enantiomer of ketamine. Spravato is approved for treatment-resistant depression, and as of January 2025 for monotherapy use — the first and only psychiatric medication of its class with that label. It is restricted to a Risk Evaluation and Mitigation Strategy (REMS) program: patients must receive each dose under direct medical observation, in a certified setting, with at least two hours of post-dose monitoring. Sedation occurs in 48–61% of patients; loss of consciousness in 0.3–0.4% of patients. The REMS exists because of those numbers.

Everything else operates outside that approval. Intravenous ketamine clinics use racemic ketamine — the same molecule, but as the original 50/50 mix of S- and R-enantiomers — for off-label psychiatric indications: depression, PTSD, anxiety, sometimes substance use disorder. Compounded ketamine — typically a sublingual or oral formulation — is mailed by telehealth-affiliated compounding pharmacies for at-home use. The FDA has issued repeated warnings about compounded ketamine and has flagged the safety profile as substantially different from the supervised Spravato model.

The result is a market in which someone seeking “ketamine therapy” can encounter products and protocols that range from rigorously supervised in-clinic infusion to mail-order tablets with minimal screening — all referred to in casual conversation as the same thing.

Where the field disagrees

Two debates are still live. The first is whether ketamine has a therapeutic role in substance use disorder treatment itself — particularly for alcohol use disorder, where small randomized trials have shown signals. The literature is genuinely promising and not yet definitive. The second is what to do about the at-home compounded model. Patient advocates argue that telehealth ketamine has expanded access to a treatment that demonstrably works for treatment-resistant depression and that the supervised in-clinic model is unaffordable for most people. Regulators, and many clinicians, argue that the dissociative experience and abuse potential warrant the supervision that Spravato’s REMS requires.

The DEA’s continued telemedicine flexibility through 2026 — covered in today’s other policy pulse — adds to the complexity here. Audio-video prescribing of Schedule III controlled substances is permitted, and ketamine is Schedule III. The framework is still unsettled.

What this means for navigation

For someone looking for ketamine treatment in 2026, the practical questions are: Is the provider affiliated with a Spravato-certified REMS site? Is the medication being administered in a supervised setting or shipped to your home? What is the screening, monitoring, and follow-up? What is the plan if you have a difficult experience? These are the questions a navigation tool should ask, on the user’s behalf, before pointing them at a provider.

Is the medication being administered in a supervised setting or shipped to your home?

For people whose dissociative use has become a problem — whether ketamine, DXM, or nitrous oxide — the treatment system is thinner than it should be. There is no FDA-approved medication for dissociative use disorder. Most evidence-based care is psychosocial: motivational interviewing, cognitive behavioral therapy, and contingency management adapted from the stimulant literature. Inpatient detox is rarely needed for ketamine but can be appropriate for very high-volume DXM use, where serotonergic effects complicate things.

Resources

If you are evaluating ketamine clinics or telehealth ketamine providers, the American Society of Ketamine Physicians, Psychotherapists & Practitioners maintains a credentialing directory. If you have concerns about your own dissociative use — including ketamine, DXM, or nitrous — SAMHSA’s National Helpline at 1-800-662-HELP is free, confidential, and 24/7. And if you are looking for treatment options in Arizona that take dissociative use seriously, start at rizerecovery.org — we index providers across the substance spectrum.

If you or someone you know is in immediate danger, call 911 or 988.