In the new year alone, ketamine has already made headlines in dozens of articles highlighting its increased off-label use. There has been a significant increase in exposure and interest for this old drug that seemingly has new tricks up its sleeve.
Ketamine received FDA approval in the early 1970s, only for use in induction and maintenance of anesthesia. Unlike other anesthetics, ketamine essentially “disconnects” the brain from the body’s sensations. Its hallucinogenic effects stem from the expanded awareness that results when the brain loses its ability to process incoming information from the body.1-3
Although ketamine, a schedule III controlled substance, has many off-label uses, the FDA currently does not offer any guidance for its use via alternative routes of administration and indications. In general, once a medication is FDA approved, healthcare providers may prescribe the drug off label for unapproved uses, often because of a patient’s condition and failing conventional therapy, or because no current medication is approved for his or her rare medical condition.1
Ketamine’s effectiveness led to the FDA approval in 2019 of Spravato, the S-enantiomer of ketamine, for treatment of treatment-resistant depression (TRD) and major depressive disorder (MDD), via an inhaled device. However, the recognition of its potential adverse effects has led to significant restriction for use via the FDA Risk Evaluation and Mitigation Strategies (REMS) program. 4
While off-label IV ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risks associated with the drug when considering its use as a therapeutic option.
Concerns with Ketamine Therapy
Although the exact mechanism of action is unknown, ketamine’s antidepressant activity has made it appealing to many patients seeking relief. Currently, there are no long-term studies about the effects of ketamine as opposed to many other conventional antidepressants. Also, ketamine is not 100 percent effective, like many other antidepressant treatments in existence. It is imperative to screen patients seeking ketamine thoroughly and monitor patients throughout ketamine therapy. Ketamine’s psychoactive properties can cause fatigue, restlessness, anxiety, dizziness, and hallucinations — all which makes its off-label use tricky to manage clinically. Ketamine can increase heart rate and blood pressure. There are also some concerns over risks to the liver, bladder, and kidneys.
Another concerning issue is the increasing ability of ketamine to serve as a gateway drug to other psychedelics. A growing practice, known as "microdosing," involves taking minute quantities of drugs such as LSD, psilocybin, or mescaline every few days. The trend of patients who are undergoing both ketamine treatments and microdosing with other psychedelics is worrisome.5 A prior claims data search found a case where a patient turned to LSD believing ketamine was no longer effective. Once the clinician discovered the concurrent LSD use, the ketamine was discontinued despite the patient’s multiple pleas. The patient subsequently stopped seeing the clinician.
Considering Offering Ketamine Therapy?
The global behavioral health market is forecasted to reach around $240 billion by 2026, currently sitting at about half that amount.6 This should come as no surprise as depression is the leading cause of disability worldwide, and its incidence has only increased as the pandemic continues.⁷
With single ketamine treatments costing anywhere from four hundred to several thousand dollars, providing ketamine therapy can be lucrative. Although many patients are reporting relief with treatment, some physicians worry that unscrupulous practices by ketamine providers may be taking advantage of a susceptible population with the appeal of a quick fix and hefty price tag.
The FDA’s approval of Spravato may have kickstarted psychedelic-assisted therapy options as several clinical trials have been fast-tracked by the FDA since then. Perhaps the lack of regulatory oversight on ketamine clinics may change as more psychedelics gain FDA approval. Because there is no regulation for the control and oversight of off-label ketamine, it’s a free-for-all on how the business is operated – including whether patient safety protocols are implemented. In contrast, Spravato has strict administration requirements and restrictions that ketamine clinics may be circumventing.
After all things considered, clinicians who are looking into providing ketamine therapy should have the following safety considerations in mind:
- Careful selection of patients for treatment via thorough medical and psychiatric evaluation, including history of drug dependence and potential for abuse.
- Providers should follow a guideline or protocol, ensuring all safety parameters are followed. Home treatment would not facilitate accurate safe monitoring. Unlike naloxone with opioids, there are no medications available to reverse the effects of ketamine that could rescue a patient, if needed.
- Patient monitoring should be done in collaboration between administrating provider and the mental health provider. Most patients seeking ketamine therapy are challenging patients, who are resistant to standard treatments, and often require continuous treatment.
- Caution should be taken when marketing the drug’s benefits on websites or other educational material where the clinical evidence is questionable.
- Although ketamine infusions can be administered by any licensed physician, those who are trained in its use have a high level of expertise and experience, which are indispensable qualities in assuring the safest and most successful outcome for their patients.
Monica Ludwick is a Senior Risk Management and Patient Safety Specialist for CAP. Questions or comments related to this article should be directed to MLudwick@CAPphysicians.com.
1Sanacora, G. et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017; 74(4):399-405.
2Witt, Emily. Ketamine therapy is going mainstream. Are we ready? NY Times, 29 December 2021. Accessed 1/7/22.
3Heitz, Jenny. Ketamine therapy will go mainstream in 2022 for better or worse. The Daily Beast, 29 December 2021. Accessed 1/11/22.
4Spravato [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.: February 2020.
5Hesse, Josiah. This isn’t the 60’s again: Psychedelics business takes off amid culture clash. The Guardian, 12 December 2021. Accessed 1/14/22.
6Behavioral Health Market (By Disorder: Alcohol Use Disorders, Schizophrenia, Bipolar Disorder, Depression, Anxiety, Post-Traumatic Stress Disorder, Substance Abuse Disorders, Eating Disorders, Others; By Service: Emergency Mental Health Services, Outpatient Counseling, Home-Based Treatment Services, Inpatient Hospital Treatment Services, Others) - Global Industry Analysis, Market Size, Opportunities and Forecast, 2019 – 2026. Behavioral Health Market Size Worth US$ 240 Billion by 2026 (acumenresearchandconsulting.com)
⁷Ettman et al. Persistent depressive symptoms during COVID-19: a national, population-representative, longitudinal study of U.S. adults. The Lancet Regional Health - Americas, Volume 5,2022, doi: 10.1016/j.lana.2021.100091.