The Bright and Dark Sides of Ketamine

Actor Matthew Perry was addicted to intravenous ketamine when he overdosed and died in 2023, reminding us that ketamine is dangerous and too accessible. However, the drug Spravato, a form of ketamine and the first novel FDA-approved antidepressant in 50-plus years, can be lifesaving when used appropriately, under supervision, in those with severe and nonresponsive depression.

But what to make of unsupervised, home-injected ketamine, as in Matthew Perry’s case, made available as a result of telemedicine exceptions created during the pandemic?

Looking Back in Time

Ketamine was synthesized in 1962 (a mixture of two mirror-image molecules, R- and S-ketamine) and developed as an alternative to phencyclidine (PCP). Ketamine has anesthetic, hallucinatory, and dissociative effects similar to PCP but without respiratory depression and with a shorter duration of action. In 1964, Drs. Edward and Toni Domino tested ketamine in humans, coining the term “dissociative anesthesia” to describe its unique effects.

In early rat testing, ketamine did not appear addicting. Still, nonhuman primate testing has shown it is addicting, depending on dose, route of administration, frequency, and current and past drug use. Reports of abuse and the dissociative and hallucinogenic effects of ketamine emerged in the 1980s. Known as “Special K,” ketamine was abused for psychedelic out-of-body experiences.

In 1999, the Drug Enforcement Administration (DEA) classified ketamine as a Schedule III controlled substance. This meant it was similar to codeine and buprenorphine—having accepted medical benefits but abuse potential.

John Krystal, MD

Source: Yale University School of Medicine

Psychiatric Uses for Ketamine

In 2000, Yale’s Dr. John Krystal and colleagues demonstrated that low-dose, intravenous racemic ketamine produced rapid, significant antidepressant effects in patients with treatment-resistant depression. This discovery sparked additional psychiatric research on ketamine.

The late George Aghajanian, M.D., collaborated with neuroscientist Ronald Duman on a Yale study showing how ketamine worked—by inducing synaptic neuroplasticity. They showed that stress-related reductions in dendritic spines in rodents could be reversed for 24 hours from a single dose of ketamine, creating rapid antidepressant effects. Pharmaceutical companies worked with Krystal and colleagues to develop esketamine, an intranasal version of ketamine with fast-acting, potent antidepressant effects.

The drug was approved by the FDA as Spravato in 2019, first for treatment-resistant depression and, later, for major depressive disorder with acute suicidal ideation. In 2023, the National Academy of Medicine awarded Dennis Charney, John Krystal, and Husseini Manji the Sarnat International Prize in Mental Health for their discovery leading to esketamine.

A Special Controlled Program

The FDA approved Spravato contingent on patients enrolling in a risk evaluation and mitigation strategies (REMS) program before receiving the drug at a center approved to administer it. Patients are monitored for sedation, blood pressure, and possible dissociation during treatment and observation. They are also counseled on the risks of engaging too soon in activities requiring full alertness; for example, they are advised to avoid driving until the day after treatment.

Spravato rules mandate that the drug cannot be taken at home. Patients are observed at least two hours after receiving the agent and typically receive psychotherapy and other treatments for depression.

“Ketamine has garnered so much attention because small doses produce rapid relief—in as little as four hours—in some patients who suffer from treatment-resistant depression," observes Stanford psychiatrist Alan Schatzberg, M.D. "In contrast, it usually takes weeks for patients to see any benefits with selective serotonin re-uptake inhibitors (SSRIs), the most common form of antidepressants.”

Alan Schatzberg, MD

Source: Stanford University

Issues with Off-Label Ketamine

During the COVID-19 pandemic, the DEA loosened its restrictions, allowing for prescribing of Schedule III substances like ketamine via telemedicine—but not including Spravato. While patients being treated with the opioid antagonist Suboxone (buprenorphine and naloxone) cheered the new telemedicine rules, extended through 2024, the rules also currently enable an at-home ketamine phenomenon.

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An ever-increasing number of online “ketamine clinics” have emerged, prescribing off-label generic ketamine for multiple disorders, such as major depressive disorder (MDD), bipolar disorder, anxiety, and post-traumatic stress disorder (PTSD). Disturbingly, the online "facilities" need not follow FDA guidelines for Spravato. Consequently, patients may be prescribed ketamine off-label, by injection, at home.

The number of patients with a ketamine prescription rose more than fivefold between 2017 and 2022. Some providers assess patients via telepsychiatry for the first visit and then mail or give patients ketamine to take home and self-administer.

How Ketamine to Be Used in Psychiatry

"When administered correctly and under supervision of a professional, ketamine can be a life-changing, even a lifesaving treatment for individuals suffering with major depression, Gerard Sanacora, M.D., Ph.D,. Director of the Yale Depression Research Program and Co-Director of Yale’s interventional psychiatry program, told me, "But following regulatory changes put in place during the COVID-19 pandemic that made telemedicine more accessible, the drug’s off-label, unsupervised use has skyrocketed, despite limited data supporting the safety and efficacy of that practice.”

Gerard Sanacora, MD, PhD

Source: Yale University School of Medicine

Sanacora continued, “There are real risks associated with any version of ketamine. It is an anesthetic. If you get enough of it, you become completely sedated; that’s always a risk associated with it. But it has other physiologic effects on heart rate and blood pressure that can be pronounced.”

There are also psychological risks. “Large amounts of data suggest that your ability to make rational, correct decisions is completely disrupted when you take ketamine, as long as it’s in your system," Sanacora says.. "People can hear things, see things, feel things differently. The physiological and psychological reasons are the main reason the FDA declared Spravato safe only in a health care facility under supervision.”

Stanford psychiatrist Schatzberg adds, "Risks of long-term ketamine use are unknown, but abuse and addiction are increasingly reported around the world." Black-market ketamine is made in clandestine laboratories in Mexico, China, Southeast Asia, and India. These unsafe and often contaminated drugs can contain MDMA or ketamine-like analogs that are created and distributed illegally.

In Australia, 300,000 people said they used ketamine in the previous 12 months, compared to 70,000 in 2016. Ketamine is now a controlled substance in Australia, meaning it has a high potential for abuse. In Canada, ketamine is a Schedule I Controlled Drug.

Note that ketamine is remarkable because of its unique mechanism, rapidity of action, antisuicidal effects, and ability to treat depressed patients for whom every other treatment has failed. But it is also reasonable to curb our enthusiasm for all forms of ketamine except Spravato until studies show that ketamine is better than Spravato, as well as safe and efficacious.

How many patients with a past history of a substance use disorder (SUD), or someone currently being treated for an SUD, may develop a ketamine addiction like Matthew Perry? Also, why use an intravenous or injected ketamine instead of intranasal Spravato, with its precautions?

Another issue: why do we need ketamine infusion clinics offering off-label ketamine by self-administration to patients when Spravato is safe and effective and the FDA’s strict usage protocols protect patients?

Summary

Spravato offers hope to patients with treatment-resistant depression. It is so unique it may generate other treatments as good or better, such as new molecular variants without psychedelic effects.

Data suggest it is misinformed to think that ketamine alone will make depression go away forever—one and done. That's not how it works. Ketamine is part of a treatment plan, not the whole of a treatment plan. A psychiatrist should prescribe and give it only following REMS protocol in the office.