05. The Safety and Tolerability of Ketamine: Concerns and Questions

I’d like to talk a little bit about the risk profile of ketamine. Now, the exciting potential therapeutic effect of ketamine must be weighed carefully against the potential adverse consequences that can indeed come from long-term exposure. These potential adverse clinical effects can include abuse liability, cognitive changes as well as interstitial cystitis.

Ketamine abuse is a widely recognized problem throughout the world and is especially prevalent in Southeast Asia. In the United States, the prevalence of abuse is not precisely known. This comes from a lack of data on ketamine abuse in the United States. However, this is a real problem and the degree to which the therapeutic use of ketamine in clinical settings lead to iatrogenic substance use disorders is not known and has not been studied.

At least one case report published in the American Journal of Psychiatry has documented how the clinical use of ketamine may have led to iatrogenic ketamine abuse in a patient. Much remains unknown about ketamine abuse including risk factors that may predispose patients to abuse. In particular, it’s unknown whether careful screening of risk factors for general abuse might reduce or minimize the risk of leading to dependence or abuse.

Another important question is whether repeated use of ketamine can induce long-lasting cognitive or perceptual changes or psychotic symptoms. A number of studies conducted by Celia Morgan and colleagues in the United Kingdom have found changes in cognitive abilities and schizophrenia-like symptoms among frequent ketamine recreational users. Compared to other groups such as ex-ketamine users and non-ketamine polydrug users, frequent ketamine users have shown impairments in spatial working memory as well as pattern recognition task. Notably, frequent ketamine users also scored higher on measures of dissociative and delusional symptoms compared to other groups including ex-ketamine users and non-ketamine polydrug users.

The key points to this section are that despite the exciting finding of high rates of response and remission following a single dose of ketamine, there are limited reports of the long-term safety and efficacy of ketamine. Most studies of repeated dosing of ketamine have examined four or six total doses over approximately two to three weeks. While the reported studies of low-dose sub-anesthetic ketamine for use in depression have not generated significant safety concerns, the field awaits further evidence of the long-term safety of ketamine. Concerns still exist for adverse clinical outcomes that may stem from indefinite exposure to ketamine. These include cognitive impairment, bladder toxicity, increased propensity for delusions and abuse liability.

References:

1. Li, J. H., Vicknasingam, B., Cheung, Y. W., Zhou, W., Nurhidayat, A. W., Des Jarlais, D. C., & Schottenfeld, R. (2011). To use or not to use: an update on licit and illicit ketamine use. Substance abuse and rehabilitation , 2, 11.
2. Sassano‐Higgins, S., Baron, D., Juarez, G., Esmaili, N., & Gold, M. (2016). A review of ketamine abuse and diversion . Depression and anxiety, 33(8), 718-727.
3. Bokor, G., & Anderson, P. D. (2014). Ketamine: an update on its abuse . Journal of pharmacy practice, 27(6), 582-586.
4. Schak, K. M., Vande Voort, J. L., Johnson, E. K., Kung, S., Leung, J. G., Rasmussen, K. G., … & Frye, M. A. (2016). Potential risks of poorly monitored ketamine use in depression treatment . American Journal of Psychiatry, 173(3), 215-218.
5. Morgan, C. J., Muetzelfeldt, L., & Curran, H. V. (2009). Ketamine use, cognition and psychological wellbeing: a comparison of frequent, infrequent and ex‐users with polydrug and non‐using controls . Addiction, 104(1), 77-87.
6. Morgan, C. J., Muetzelfeldt, L., & Curran, H. V. (2010). Consequences of chronic ketamine self‐administration upon neurocognitive function and psychological wellbeing: a 1‐year longitudinal study . Addiction, 105(1), 121-133.
7. Wilkinson, S. T., Wright, D., Fasula, M. K., Fenton, L., Griepp, M., Ostroff, R. B., & Sanacora, G. (2017). Cognitive behavior therapy may sustain antidepressant effects of intravenous ketamine in treatment-resistant depression . Psychotherapy and psychosomatics, 86(3), 162-167.