The Rapidly Shifting Ketamine Landscape in the US

In recent years, ketamine has been hailed as a miracle treatment for depression and related disorders. The US Food and Drug Administration (FDA) approved the S-enantiomer of ketamine, esketamine, as the first antidepressant in a new class for treatment-resistant depression in 2019.¹ Emerging evidence suggests that the landscape of ketamine both as a medical therapeutic and as a recreational substance is shifting. Herein, we highlight several key points that health care practitioners, policy makers, and patients and families should be aware of given this changing landscape.

Tight Control for Esketamine But Not Ketamine

Ketamine was approved in 1970 as an anesthetic. Early research in the 1990s and 2000s demonstrated that subanesthetic doses of ketamine could lead to rapid and powerful antidepressant effects. Without any regulatory approval regarding treatment of psychiatric disorders, in the 2010s, a growing number of health care practitioners began offering subanesthetic doses of ketamine to patients with depression and other disorders, judging that existing evidence justified therapeutic use in some individuals.² Preliminary reports suggest that this practice of off-label ketamine use as a therapeutic in psychiatry has continued to grow in prevalence, largely without regulation.³

The protocol with the most evidence comprises 0.5 mg/kg of ketamine delivered intravenously over 40 minutes, which achieves plasma concentration levels of 70 to 200 ng/mL.⁴ This is much lower than the plasma ketamine levels observed in patients awakening from ketamin eanesthesia (500–1000 ng/mL) as well as the peak plasma levels used while patients are anesthetized (2000–3000 ng/mL).⁴ Patients often experience perceptual disturbances and dissociative adverse effects during the infusion that subside approximately 30 to 60 minutes following the end of the infusion, which necessitates a period of posttreatment monitoring. While this is the most commonly used protocol, there is considerable variability among health care practitioners in the community with respect to the way ketamine is administered. A consensus statement from key stakeholders strongly advised that ketamine treatment be conducted in a medical facility (as opposed to in a home setting) to limit drug diversion and so that health care professionals can immediately respond to acute medical and behavioral changes.⁴

Following completion of registration trials, the FDA formally approved esketamine as a therapy for treatment-resistant depression in March 2019. Esketamine was approved with a strict treatment protocol enforced by a mandatory drug safety program (the Risk Evaluation and Mitigation Strategy). In contrast, physicians continue to have flexibility in how off-label ketamine is prescribed, for which no drug safety program exists. It should be noted that compared with the large, rigorous phase 3 trials of esketamine, the clinical trials of ketamine are smaller, of comparatively short duration (typically 1 or 2 doses), and not sufficiently powered to inform clinical guidelines.^5,6

The lack of regulatory oversight of ketamine was particularly relevant during the relaxed restrictions that accompanied the COVID-19 pandemic, which allowed physicians to prescribe controlled substances without an in-person examination. Some clinics began prescribing ketamine lozenges for oral administration so that patients could take the medicine at home. (Notably, at-home administration of the FDA-approved esketamine is explicitly forbidden.) One prominent case documented a health care practitioner who obtained medical licenses in most US states and was prescribing ketamine for at-home administration to thousands of patients; this clinic was shut down by the Drug Enforcement Administration,⁷ marking the first time a federal agency has regulated ketamine clinics.

Potential Consequences of Increasingly Widespread Off-Label Prescribing

While some leaders in the field predicted that the FDA approval of esketamine (which is more likely to be reimbursed by insurance companies compared with ketamine) would minimize the therapeutic use of off-label ketamine (which is largely paid for in cash), it appears that clinics that offer off-label ketamine treatment will continue to exist for the foreseeable future.³ Notably, attempts to elicit a national coverage determination from Medicare for ketamine for depression have been unsuccessful. There remains uncertainty in the field as to whether ketamine (most commonly administered intravenously in clinical settings) represents a significantly different (or superior) therapeutic compared with esketamine. Nonetheless, there are significant disadvantages to such common off-label use in this context, including the unregulated nature of ketamine clinics, potential overuse or repeated exposure to very high doses (which can cause long-term adverse sequelae), and the potential for diversion.

As ketamine has become more popular as a therapy and with the approval of esketamine, there has been increased attention to the drug’s potential benefits in the media and popular press. While the prevalence of recreational ketamine use remains low compared with other common drugs (eg, cannabis, cocaine), there is emerging evidence that ketamine is becoming more widely used as a recreational substance. This increase may be associated with increased media attention to the drug and advertising from medical clinics. While a small amount of ketamine or esketamine may be diverted from medical settings, most of the increase in recreational use seems to be supplied by an increasing amount of illicit ketamine trafficking. This is reflected in the fact that the amount and total weight of illicit ketamine seized in the US on an annual basis increased substantially through 2022.⁸

Increases in Recreational Use, Poisonings, and Law Enforcement Seizures

As the prevalence of recreational ketamine use has increased, there has been a concurrent increase in law enforcement seizures (confiscations) of ketamine as well as poisonings. The number of ketamine seizures in the US increased by 349% from 2017 through 2022, while the number of ketamine poisonings reported to a national poison control center increased 81% between early 2019 and late 2021.⁹ Although ketamine is generally considered a safe anesthetic agent due to its ability to maintain blood pressure, misuse can clearly lead to serious adverse outcomes. This is demonstrated by recent news events of young and otherwise healthy individuals who died from a combination of alcohol and ketamine.

Several aspects of ketamine and esketamine are concerning with respect to the potential for misuse. First, ketamine is relatively cheap and easy to manufacture in laboratory settings. This has led to a situation in which it is generally significantly cheaper to obtain ketamine illicitly than it is to obtain ketamine or esketamine in a therapeutic setting. This contrasts with many other drugs that have potential to lead to substance use disorder but also have medical benefit (ie, opioids, benzodiazepines, and amphetamine) and for which street prices are more expensive than when they are prescribed. Second, the majority (>98%) of seized ketamine between 2017 and 2022 was in powder form.⁸ This is concerning because it suggests that illicit versions of the drug may not be pharmaceutical grade and may possibly be adulterated with substances such as fentanyl.

Further Research and Surveillance Are Urgently Needed

Research and surveillance efforts are needed, as the ketamine landscape appears to be shifting at a rapid pace. Specifically, surveillance needs to monitor the prevalence of both medical and nonmedical use, off-label prescribing, and related adverse effects including poisonings and use disorder. A clinical registry for off-label therapeutic ketamine use would be immensely helpful to further understand the salient issues. More focus is also needed on ketamine diversion and trafficking, focusing not only on psychiatric clinics but also on veterinary clinics. Furthermore, it is important to determine potential drivers of medical and nonmedical use, with a particular focus on how media coverage and advertising may be affecting such shifts in use. A recent notice of special interest in related research grant applications (NOT-DA-24–10) published by the National Institute on Drug Abuse is encouraging, but we believe widespread surveillance efforts are also needed to fully understand the current ketamine landscape and to quickly detect changes in order to rapidly alert scientists and public health practitioners.