Ketamine is gaining ground as a promising option for treatment-resistant depression, but not everyone’s buying in. Before the turn of the year, the editorial staff at Psychiatry Advisor predicted that debate on the matter would intensify in 2019. We take a look at the clinical evidence, concerns about safety and efficacy, and a recent major development.

Through the Years

Ketamine was first synthesized in 1962 and approved for use in anesthesia by the US Food and Drug Administration (FDA) in 1970. Starting in the 1960s, the drug was used to treat soldiers in Vietnam. In the 1970s, it was introduced in veterinary medicine. In the 2000s, researchers began to examine its efficacy in treating major depressive disorder (MDD).1

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Yet, ketamine also has a lengthy history of illicit use. In the early 1970s, recreational substance users began taking high doses of the drug for its euphoric effects. By the mid 1980s, ketamine had become a drug of choice among club-goers in the United States and Europe.2 At least 58 countries have reported it on the illicit drugs market.1

Clinical Evidence

There is some evidence that ketamine – taken in doses much lower than those used for anesthesia and recreational use – may be a viable treatment option for patients with MDD that has been unresponsive to standard treatments.

  • A randomized controlled trial in the American Journal of Psychiatry found that ketamine demonstrated rapid antidepressant effects.3
  • A review of 7 randomized controlled trials in Mental Health Clinician revealed that ketamine provided a statistically significant improvement over placebo in treating MDD.4
  • A double-blind placebo-controlled study in the British Journal of Psychiatry found that repeated oral ketamine produced rapid improvement in symptoms of treatment-resistant depression.5

Clinical Approval

In March, the FDA approved esketamine in conjunction with an oral antidepressant for treatment-resistant MDD. Esketamine is the chemical cousin of ketamine and the first ketamine-derived medicine approved for this indication. Due to concerns about the potential for misuse and abuse, the FDA is closely monitoring and restricting availability of the nasal spray formulation. The medication is not available at local pharmacies for take-home use. Instead, it must be administered in a certified medical office where the patient can be monitored.6

Ketamine is not approved for depression, but that hasn’t stopped an estimated 300 clinics from providing the drug off-label to patients with treatment-resistant MDD.7

Criticisms and Concerns

Despite widespread off-label use, skepticism remains that the popular party drug should be considered a viable treatment option for MDD.

A 2018 review in Neurobiology of Stress concluded that “both preclinical and clinical studies indicate that repeated treatment with low-dose ketamine infusions can have addictive properties and induce cognitive deficits.”8 The drug’s side-effect profile – hallucinations, out-of-body experiences, and fluctuations in blood pressure – are also cause for concern.9

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Some clinicians, such as Lee Hoffer, PhD, argue that concerns about addiction are overblown. “Some reports about esketamine have sensationalized this issue by referring to ketamine as a highly addictive street drug. In my research, this is not true. Taking this drug can be very unpleasant. Out-of-body experiences, time-perception distortions, tunnel vision, and dissociation are common. These effects limit the popularity of ketamine and make it difficult to use habitually.”10

In addition, questions linger about the clinics providing off-label ketamine. Some mental health specialists caution that although new potential treatments are always welcome, “some clinics are going too far in their promises and not caring appropriately for patients.”11

Many sites do not have a psychiatrist or other mental health professional on staff to provide care for patients. Some sites overhype the efficacy of ketamine and offer the drug for uses that aren’t supported by clinical evidence. Cost is also a factor: infusions range from $350 to nearly $1000, and many patients receive at least 6 rounds of treatment.12

Where do you stand? Should ketamine be approved for use in treatment-resistant depression? Participate in our poll.


  1. Fact file on ketamine. World Health Organization. March 2016. Accessed July 12, 2019.
  2. Moore D. How ketamine opens a new era for depression treatment. Washington Post. June 14, 2019. Accessed July 12, 2019.
  3. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142.
  4. Grady SE, Marsh TA, Tenhouse A, Klein K. Ketamine for the treatment of major depressive disorder and bipolar depression: a review of the literature. Ment Health Clin. 2017;7(1):16-23.
  5. Domany Y, Bleich-Cohen M, Tarrasch R, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. Br J Psychiatry. 2019;214(1):20-26.
  6. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic [press release]. US Food and Drug Administration; March 6, 2019.
  7. Reardon S. Party-drug-turned-antidepressant approaches approval. Scientific American. December 18, 2018. Accessed July 12, 2019.
  8. Strong CE, Kabbaj M. On the safety of repeated ketamine infusions for the treatment of depression: effects of sex and developmental periods. Neurobiol Stress. 2018;9:166-175.
  9. Cox D. Ketamine: can it really be an antidepressant? The Guardian. March 23, 2019. Accessed July 12, 2019.
  10. Hoffer L. The FDA approved a ketamine-like nasal spray for hard-to-treat depression. Vice. March 6, 2019. Accessed July 12, 2019.
  11. Thielking M. Ketamine gives hope to patients with severe depression. But some clinics stray form the science and hype its benefits. STAT News. September 24, 2018. Accessed July 12, 2019.
  12. Thielking M. Is the ketamine boom getting out of hand? Scientific American. September 26, 2018. Accessed July 12, 2019.