The Ketamine Paradox

In the morning, a psychiatrist administers ketamine to help a suicidal patient rediscover hope. That evening, an emergency physician treats someone whose recreational ketamine use contributed to an accident, overdose, or dangerous drug combination. The same drug. Two very different stories. A treatment moves from the laboratory to carefully selected patients, and then, use expands. Then consequences emerge—not apparent or measurable—at the beginning.

The National Drug Early Warning System rang an alarm bell on July 17, 2026. NDEWS identified 71,924 nonfatal EMS encounters involving suspected ketamine overdoses nationwide between January 2023 and June 2026.

These data are alarming, but surveillance cannot establish illicit versus prescribed. Nevertheless, this is a public health signal that addiction medicine cannot ignore.

Ketamine's Two Stories

Source: Mark Gold, MD, with permission

A New Way of Thinking About Depression

For 50+ years, ketamine has been an anesthetic in surgery, trauma care, and battlefield medicine. What changed was the question scientists asked. That question belonged to a Yale bench-to-bedside tradition I knew well. I worked with George Aghajanian, where LSD was studied not as a curiosity but as an instrument to gain insight into serotonin and the brain. George helped demonstrate that noradrenergic neurons become hyperactive during opioid withdrawal and that clonidine could suppress them. I helped carry those insights from rats into nonhuman primates and later human patients, establishing clonidine as the first non-opioid treatment for opioid withdrawal.

Ketamine grew from the Yale Psychiatry research culture that asked what an unusual drug might teach us about the brain. Decades later, Aghajanian’s research helped connect serotonin, glutamate, cortical plasticity, and rapid-acting antidepressant effects.

In 2000, John Krystal and his Yale colleagues reported that a subanesthetic ketamine dose could rapidly reduce major depression. Patients with treatment-resistant depression, hopelessness, or suicidal thinking sometimes improved within hours rather than weeks. Ketamine can save lives.

Ketamine also changed how we think about depression. Although it blocks NMDA receptors, no single receptor explains everything. It affects glutamate signaling, reward responsiveness, and cortical plasticity, perhaps loosening rigid brain activity and creating an opportunity for new learning.

A July 2026 Molecular Psychiatry study expands the story beyond glutamate. Investigators compared ketamine, its metabolite hydroxynorketamine, LSD, and psilocybin. Despite acting initially through different receptors, these rapid-acting antidepressants apparently converged on downstream neuroimmune pathways, particularly IL-7 and IL-15 signaling. Some biological signatures also distinguished ketamine responders from nonresponders.

These preliminary findings show why ketamine and psychedelics should be studied neither as miracle drugs nor solely as intoxicants. They may teach us how depression becomes entrenched—and reversed. That is also where ketamine treatment and ketamine addiction begin to intersect.

The Marketplace in Between

Racemic ketamine is approved by the U.S. Food and Drug Administration (FDA) as an anesthetic; psychiatric use is off-label. Esketamine (Spravato) nasal spray is approved for specific depressive disorders and administered under an FDA-regulated monitoring program. We once had two easily recognized categories: ketamine administered medically and ketamine obtained on the street. Now there is a third category between them. The home delivery market.

A 2026 study identified 233 clinics advertising ketamine treatment in metropolitan New York. More than one-third advertised at-home treatment, but only 51.5 percent listed a physician on the team.

At-home treatment is not automatically illegal or unsafe. Some programs provide appropriate evaluation, prescribing, monitoring, and follow-up; others provide far less. Uniform standards for patient selection, dosing, and duration are lacking.

In June 2026, the FDA warned 14 internet marketers who were selling unapproved or misbranded ketamine products. A package and mailing label are not substitutes for patient selection, standardized dosing, monitoring, and follow-up.

When Treatment Becomes Escape

In clubs and festivals, ketamine is used to produce dissociation, altered perception, and temporary escape. In an earlier Psychology Today post, I called this “Generation K.” Among New York City nightclub attendees, past-year use nearly doubled between 2017 and 2024, from 7.4 to 14.3 percent.

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Nightclub populations do not represent all Americans, but often reveal emerging trends early. Every addictive drug becomes associated with something the person wants or needs. For some people, ketamine becomes associated with escape. Emotional distress → Ketamine → Rapid escape

The brain learns what it repeats. Tolerance increases. Doses escalate. More time is spent obtaining, using, and recovering from ketamine—attempts to cut down fail. Eventually, ketamine has become the brain’s learned solution to distress.

A Decade of New Medical Evidence

In 2016, my colleagues and I reviewed early evidence about ketamine misuse and diversion. We raised questions about addiction, cognition, and harm to the bladder and other organs. A decade later, we have more answers and medical complications.

Heavy ketamine use is also associated with cognitive impairment, persistent dissociative symptoms, severe abdominal pain known as “K-cramps,” and liver or biliary disease. One of the most devastating complications is ketamine-associated cystitis. It may begin with urinary frequency, urgency, pain, or bleeding, but repeated use can progressively shrink and scar the bladder.

Severe disease may lead to urinary obstruction, kidney damage, reconstructive surgery, or even bladder removal. Stopping ketamine early may permit substantial recovery. Once structural damage is advanced, however, some injury may be permanent.

Combining ketamine with other drugs adds another layer of danger.

A standard five-panel urine drug screen does not test for ketamine. If ketamine use is suspected, a urine test for ketamine and norketamine must be ordered. Blood testing may be useful in acute ketamine intoxication but has a shorter detection window.

There is no ketamine overdose antidote. Narcan is given when opioid contamination or co-use is possible.

Medical Ketamine Is Different

Carefully supervised ketamine treatment should never be confused with chronic, high-dose recreational use. Medical treatment includes patient selection, known composition and dosing, monitoring, follow-up, and a therapeutic goal. Nonmedical use may involve uncertain purity, escalating doses, dangerous combinations, craving, and dependence on dissociation to manage life.

We’ve learned this lesson before. Promising psychedelic research became entangled with recreational self-administration, weak science, counterculture advocacy, and Timothy Leary overwhelming scientific investigation, delaying research for decades.

The difference is not simply the setting or where ketamine is taken. It is why, how much, how often, under what safeguards, and what happens afterward. In medical treatment, the dose is determined and monitored by a clinician. With self-administration, the person may begin increasing the dose or frequency in pursuit of dissociation, relief, or an effect that no longer comes as easily. That loss of control is an early warning, the clearest sign that treatment may be turning into a ketamine use disorder.

The Better Question

During 50 years in addiction medicine, I have repeatedly watched valuable medications acquire a second identity. Morphine relieves pain. Benzodiazepines stop seizures. Stimulants improve attention. Each can also become a drug of misuse.

With ketamine, the question is not whether it’s good or bad. The better questions are: Who is the right patient? Under what supervision? For how long? With what safeguards? And toward what therapeutic goal?

Ketamine may prove to be one of psychiatry’s most important advances in decades. It is also becoming one of addiction medicine’s newest challenges. Our responsibility is to preserve its capacity to relieve depression, hopelessness, and suicidal suffering while preventing another generation from learning that dissociation is the only escape from emotional pain.

The brain learns what it repeats. Treatment must give it something better to learn.

If you or someone you love is contemplating suicide, seek help immediately. For help 24/7, dial 988 for the 988 Suicide & Crisis Lifeline, or reach out to the Crisis Text Line by texting TALK to 741741. To find a therapist near you, visit the Psychology Today Therapy Directory.