One of my patients asked me what the long term effects of ketamine are. She was particularly interested in long-term adverse effects. The last time I did a review of the literature I noted that there seem to be very little information available. This is not surprising with the psychiatric literature since ketamine and its use for chronic depression are experimental and date back only a few years. However ketamine has been used for chronic pain for much longer and so I imagined there would be some literature on this and agreed to do a search.
In fact, there is very little in the literature about long-term effects, whether benefits or adverse effects, of repeat ketamine infusions at the doses used for treating chronic depression.
Even the pain literature provides us with little data. A recent comprehensive review of the use of ketamine for chronic pain in cancer patients concludes:
“Current evidence is insufficient to assess the benefits and harms of ketamine … for the relief of refractory cancer pain. The evidence was of very low quality…”
Most of the articles that I did find were speculative and linked to a handful of articles about the adverse effects of the much higher doses of ketamine taken by those with substance use problems.
That literature suggests the potential for significant adverse effects on brain function, particularly memory, and possibly even mood. However, the handful of studies looking at therapeutic use of ketamine seem to show quite different brain effects compared with the acute effects of taking higher doses.
The article by Zhu is representative, after reviewing significant animal and human data suggesting that, mostly at higher doses, repeat ketamine infusions and is associated with significant changes in brain structure and function, the authors conclude, on the basis of very limited data, that lower dose ketamine, which has a different pharmacologic effect, is probably safe.
In addition to potential brain adverse effects, it has been noted that ketamine can, at least in abusers, be associated with bladder problems (cystitis).
Further, because ketamine is off patent, there is no mechanism available to reliably track reports of adverse effects, such as exists with other new medications.
All of this points to the likelihood that it will be quite a while before we know with clarity what the long term effects of ketamine are. This needs to be considered and balanced against the clear long-term adverse effects of chronic depression.
References
Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2017 Jun 28;6:CD003351. doi:
10.1002/14651858.CD003351.pub3. Review. PubMed PMID: 28657160.
Li CR, Zhang S, Hung CC, Chen CM, Duann JR, Lin CP, Lee TS. Depression in chronic ketamine users: Sex differences and neural bases. Psychiatry Res. 2017 Sep 5;269:1-8. doi: 10.1016/j.pscychresns.2017.09.001. [Epub ahead of print] PubMed PMID: 28892733.
Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB; American Psychiatric Association (APA) Council of Research Task Force on Novel Biomarkers and Treatments. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017 Apr 1;74(4):399-405. doi: 10.1001/jamapsychiatry.2017.0080. Review. PubMed PMID: 28249076.
Zhang MW, Harris KM, Ho RC. Is off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications. BMC Med Ethics. 2016 Jan 14;17:4. doi: 10.1186/s12910-016-0087-3.
PubMed PMID: 26768892; PubMed Central PMCID: PMC4714497.
Zhu W, Ding Z, Zhang Y, Shi J, Hashimoto K, Lu L. Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant. Neurosci Bull. 2016 Dec;32(6):557-564. Epub 2016 Nov 22. Review. PubMed PMID: 27878517; PubMed Central PMCID: PMC5567488.