Ketamine’s Cognitive Side Effects: Fact or Myth?

Subanesthetic ketamine is a rapid remedy for suicidal ideation and severe depression. But some health providers may still refuse to give it a chance due to lingering concerns about its neurocognitive side effects.

Then again, it’s easy for busybodies in the medical field to fall prey to sensational headlines. Unless we take a few minutes to skim the evidence, we might miss out on a lifesaving, quality-of-life-preserving drug.


Does ketamine cause problems with memory and thinking? The answer is complicated but is nothing that cannot be further explained by evidence-based medicine.


What Do We Know about Ketamine’s Cognitive Side Effects?


Decades of research show that intravenous ketamine treatment induces a rapid antidepressant response. But we also know that the drug can be abused and erode cognitive functioning in heavy users.


The pros and cons of ketamine use are currently hot internet topics. Unless we distill what turns up on a Google search, we may not fully appreciate the meaning of the message.


What has science found out about ketamine’s neurocognitive effects?


Discovery #1: Ketamine Infusion Results in Transient Cognitive Impairment Followed by Longer-Lasting Improvement


After ketamine therapy, misfiring neurons experience a short, hard reset then go back to normal. We see something similar in patients undergoing electroconvulsive therapy. The difference, though, is that ketamine works much faster (Basso et al., 2020).

Transient cognitive dysfunction occurs because ketamine’s mechanisms of action disrupt multiple signaling systems at once, not just the NMDA receptor (Acevedo-Diaz et al., 2020). They include:

  • Nicotinic receptors

  • GABAergic neurons in the hippocampus and prefrontal cortex

  • AMPA and dopaminergic receptors in the hippocampus

  • Frontal, cingulate, and temporal synapses

The most affected areas of cognitive performance are attention, executive function, and verbal memory. The symptoms resolve within two hours, with patients totally recuperating the next day (Davis et al., 2021). Once recovered, patients experience significant improvements in depression severity, visual memory, and working memory (Shiroma et al., 2014).

The antidepressant effect of a single IV treatment lasts for up to a week (Abdallah et al., 2016). But six repeated ketamine infusions can bring about longer-lasting remission (Shiroma et al., 2014). The magnitude of response negatively correlates with baseline functioning, i.e. individuals with poorer functionality scores before therapy show greater improvement after (Murrough et al., 2015).


Discovery #2: Ketamine’s Side Effects Are Dose-Dependent


When you search ketamine’s neurocognitive effects online, you get seemingly conflicting results. For example:

  • The NMDA receptor blocker enhances cognitive functioning when used during cardiac surgery (Mazzeffi et al., 2015; Hudetz et al., 2009).

  • Low-dose ketamine does not improve pain scores, mood, cognitive function and memory after major gynecological surgery (Aubrun et al., 2008).

  • Emergence delirium makes the dissociative drug “a tiger to be tamed” (Domino, 2010).

And so on.


It’s easy to get confused if you just focus on the titles. Sometimes, even abstracts don’t help us much. But as in all other aspects of medicine, the devil is in the details.


In 2004, Morgan and colleagues reported that ketamine’s neuropsychiatric effects are dose-dependent. The higher the dose, the more likely a patient will develop adverse reactions (Morgan et al., 2004).


Diving deep into the above studies’ methodologies will make you realize that their conclusions are not contradictory at all. Rather, they all agree with the findings of Morgan’s group.

  • The ketamine dose used on the cardiac patients above was 0.5 mg/kg given as an IV bolus (Hudetz et al., 2009).

  • The gynecological patients received a single intraoperative bolus of 0.15 mg/kg ketamine along with premedications. For postoperative breakthrough pain, they got 0.5 mg ketamine via PCA for every milligram of morphine.

Below 0.15 mg/kg, the drug’s neuropsychological effects are known to be negligible. Giving it through PCA and not as a continuous infusion also reduces its efficacy (Aubrun et al., 2008).

  • Surgical patients receiving dissociative doses of ketamine, i. e. 1-2 mg/kg, are more likely to develop more severe emergence reactions (Domino, 2010).

Meanwhile, the typical initial dose used on individuals with major depression is 0.5 mg/kg infused over 40-45 minutes, and it is generally tolerated well (Zarate et al., 2006; Andrade, 2017). So it seems that taming the ketamine tiger requires only dose and delivery rate adjustments.


Discovery #3: Ketamine Therapy Does Not Cause Long-Term Cognitive Deficits in Patients with Treatment-Resistant Depression


Should TRD patients worry about losing their wit when they go on regular ketamine treatment sessions?

Souza-Marques and colleagues answer, “No,” settling the debate once and for all.

The group performed a systematic literature review that included 14 studies with a pooled sample of 1,019 patients.

  • In six of the studies, participants had repeated ketamine infusions for two to three weeks.

  • Seven used a single intravenous infusion on each patient.

  • One involved 44 weeks of intranasal esketamine use.

While the nasal spray trial participants did not develop significant cognitive changes, five of the infusion studies reported improvements in performing mental tasks.


Only one article documented post-treatment memory and processing speed problems. However, these symptoms resolved a week after the last infusion. Moreover, the patients’ mental function improved afterward.


As in other studies, participants with the worst pretreatment functionality showed the greatest post-infusion cognitive and mood improvements (Souza-Marques et al., 2021).


Discovery #4: Cognitive Impairment Is Associated with Years of Heavy Ketamine Abuse


So if experts are saying that subanesthetic ketamine does not impair cognitive function, where do the demonizing stories about the drug’s effect on cognition come from?

We already talked about surgical patients experiencing dissociative anesthesia and strong emergence phenomena after high-dose ketamine administration. Our mentors make sure that we never forget that.


Then there are also the heavy recreational users, more commonly seen in Asian countries than in the U.S.


In one study, participants with years of ketamine abuse would consume about 4 grams daily and more than 10 grams weekly on average. These are much higher than the usual clinical doses, and the duration of continuous exposure is much longer. Additionally, most patients with a history of heavy ketamine consumption take it concomitantly with other drugs of abuse (Morgan et al., 2014).


Ketamine abuse is associated with spatial memory deficits and schizotypal and dissociative symptoms. On functional MRI, you may see abnormalities in the following areas (Morgan et al., 2014):

  • Hippocampus

  • Parahippocampal gyrus

  • Caudate nucleus

  • Medial temporal cortex

But at subanesthetic doses, ketamine can protect against postoperative cognitive dysfunction (Hovaguimian et al., 2018). It can also significantly improve the neurocognitive symptoms of major depressive disorder (Murrough et al., 2015).


Now that this information is sorted out, you’re better equipped to address concerns about ketamine’s potential neuropsychiatric side effects.


And the Verdict Is…


Ketamine therapy is lifesaving for a wide range of conditions. Its reputation as a club drug has raised red flags, but studies show that its effects on cognitive function are dose-dependent.


A single high dose or chronic abuse can dim mental performance. However, multiple lines of evidence show that subanesthetic ketamine treatment is neuroprotective and may improve TRD’s psychomotor deficits.


So, is ketamine-induced cognitive impairment a fact or myth? The simple answer is, “Show me the dose.”

References


Abdallah, C. G., Adams, T. G., Kelmendi, B., Esterlis, I., Sanacora, G. & Krystal, J. H. (2016). Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants. Depression and Anxiety, 33(8), 689-697. https://dx.doi.org/10.1002%2Fda.22501


Acevedo-Diaz, E. E., Cavanaugh, G. W., Greenstein, D., Kraus, C., Kadriu, B., Zarate, C. A. J. & Park. L. T. (2020). Comprehensive Assessment of Side Effects Associated with a Single Dose of Ketamine in Treatment-Resistant Depression. Journal of Affective Disorders, 263, 568-575. https://doi.org/10.1016/j.jad.2019.11.028


Andrade, C. (2017). Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long and at What Frequency? The Journal of Clinical Psychiatry, 78(7), e852-e857. https://doi.org/10.4088/jcp.17f11738


Aubrun, F., Gaillat, C., Rosenthal, D., Dupuis, M., Mottet, P., Marchetti, F., Coriat, P. & Riou, B. (2008). Effect of Low-Dose Ketamine Regimen on Pain, Mood, Cognitive Function and Memory After Major Gynaecological Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial. European Journal of Anaesthesiology, 25, 97-105. https://doi.org/10.1017/s0265021507002566


Basso, L., Bonke, L., Aust, S., Gartner, M., Heuser-Collier, I., Otte, C., Wingenfield, K., Bajbouj, M. & Grimm, S. (2020). Antidepressant and Neurocognitive Effects of Serial Ketamine Administration versus ECT in Depressed Patients. Journal of Psychiatric Research, 123, 1-8. https://doi.org/10.1016/j.jpsychires.2020.01.002


Davis, M. T., DellaGiogia, N., Maruff, P., Pietrzak, R. H. & Esterlis, I. (2021). Acute Cognitive Effects of Single-Dose Intravenous Ketamine in Major Depressive and Posttraumatic Stress Disorder. Translational Psychiatry, 11(1), 1-10. https://doi.org/10.1038/s41398-021-01327-5


Domino, E. F. (2010). Taming the Ketamine Tiger. Anesthesiology, 113(3), 678-686. https://doi.org/10.1097/aln.0b013e3181ed09a2


Hovaguimian, F., Tschopp, C., Beck-Schimmer, B. & Puhan, M. (2018). Intraoperative Ketamine Administration to Prevent Delirium or Postoperative Cognitive Dysfunction: A Systematic Review and Meta-Analysis. Acta Anaesthesiologica Scandinavica, 62(9), 1182-1193. https://doi.org/10.1111/aas.13168


Hudetz, J. A., Iqbal, Z., Gandhi, S. D., Patterson, K. M., Byrne, A. J., Hudetz, A. G., Pagel, P. S. & Warltier, D. C. (2009). Ketamine Attenuates Post-Operative Cognitive Dysfunction After Cardiac Surgery. Acta Anaesthesiologica Scandinavica, 53(7), 864-872. https://doi.org/10.1111/j.1399-6576.2009.01978.x


Mazzeffi, M., Johnson, K. & Paciullo, C. (2015). Ketamine in Adult Cardiac Surgery Intensive Care Unit: An Evidence-Based Clinical Review. Annals of Cardiac Anesthesia, 18(2), 202-209. https://doi.org/10.4103/0971-9784.154478


Morgan, C. J. A., Dodds, C. M., Furby, H., Pepper, F., Fam, J., Freeman, T. P., Hughes, E., Doeller, C., King, J., Howes, O. & Stone, J. M. (2014). Long-Term Heavy Ketamine Use Is Associated with Spatial Memory Impairment and Altered Hippocampal Activation. Frontiers in Psychiatry, 5, 1-11. https://dx.doi.org/10.3389%2Ffpsyt.2014.00149


Morgan, C. J. A., Mofeez, A., Brandner, B., Bromley, L. & Curran, H. V. (2004). Acute Effects of Ketamine on Memory Systems and Psychotic Symptoms in Healthy Volunteers. Neuropsychopharmacology, 29(1), 208-218. https://doi.org/10.1038/sj.npp.1300342


Murrough, J. W., Burdick, K. E., Levitch, C. F., Perez, A. M., Brallier, J. W., Chang, L. C., Foulkes, A., Charney, D. S., Mathew, S. J. & Iosifescu, D. V. (2015). Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial. Neuropsychopharmacology, 40(5), 1084-1090. https://doi.org/10.1038/npp.2014.298


Shiroma, P. R., Albott, C. S., Johns, B., Thuras, P., Wels, J. & Lim, K. O. (2014). Neurocognitive Performance and Serial Intravenous Subanesthetic Ketamine in Treatment-Resistant Depression. International Journal of Neuropsychopharmacology, 17(11), 1805-1813. https://doi.org/10.1017/s1461145714001011


Souza-Marques, B., Santos-Lima, C., Araujo-de-Freitas, L., Vieira, F., Jesus-Nunes, A. P., Quarantini, L. C. & Sampaio, A. (2021). Neurocognitive Effects of Ketamine and Esketamine for Treatment-Resistant Major Depressive Disorder: A Systematic Review. Harvard Review of Psychiatry, 29(5), 340-350. https://doi.org/10.1097/hrp.0000000000000312


Zarate, C. A. J., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S. & Manji, H. K. (2006). A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression. Archives of General Psychiatry, 63(8), 856-864. https://doi.org/10.1001/archpsyc.63.8.856