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Ketamine for Depression: What I Want My Patients to Know

Side effects, expectations, and planning for treatment.

This is part 3 in a multi-part series on ketamine. Click here for part 1 and part 2.

As rates of depression and anxiety have increased dramatically, people have sought therapies outside the standard regimen of oral antidepressants and talk therapy. Beginning in the mid-2010s, more and more doctors started offering ketamine as a treatment for depression. In 2019, the Food and Drug Administration (FDA) approved esketamine as a treatment for forms of depression that haven’t improved with standard antidepressants (like citalopram/Celexa or bupropion/Wellbutrin). Given over ten years of experience with ketamine as a researcher and physician at the Yale School of Medicine, in this article I try to answer some basic questions prospective patients often have about ketamine/esketamine. Please note that the information below assumes that ketamine is given at a dose of approximately 0.5mg/kg over 40 minutes. Doses significantly higher than this might have very different side effects and would not be permitted in clinical studies by the Food and Drug Administration.

Before Treatment

Before a patient begins treatment with ketamine/esketamine, he or she should have an evaluation by a competent physician or nurse practitioner to assess whether treatment is the right fit. Usually, this takes about an hour. If this does not happen, this is a sign that the clinic is probably not delivering an adequate quality of care. (See Dr. Brian Johns’ great prior Psychology Today post that points out other ways to recognize good quality care among providers who offer ketamine.)

Before treatment, you should not eat for at least 2 hours prior to your scheduled appointment time (your clinic may advise you to have a longer period of fasting, depending on different factors). You will also not be able to drive later that day after treatment, so you’ll have to make arrangements for transportation home from the clinic. Your clinic may also advise you to adjust other medications you are taking for depression or anxiety on the days of treatment.

What Should I Expect for My First Treatment?

The experiences of ketamine (most commonly delivered intravenously) and esketamine (delivered as a nasal spray) are quite similar. Many patients are understandably nervous for their first treatment. Patients can expect to feel quite unusual for about an hour while they are receiving treatment. Doctors often refer to this as a "dissociative" experience. Some patients have described that they feel like they are having an out-of-body experience during this time. Others describe that time itself seems to move differently, perhaps more quickly or more slowly. Still others say that their perception of reality is altered: people look unusually tall or the sound of their voice is different.

The published data and my clinical experience suggest that at the proper dose, the vast majority of patients are able to get through this experience without problems. Some people like this "dissociative" experience, other people dislike it but find it bearable, and for others it’s not pleasant or unpleasant. The important thing to remember, especially for those who do not like this feeling, is that it reliably goes away after about an hour. Nonetheless, it’s not uncommon for patients to feel a little unsteady the remainder of the day (which is the reason you can’t drive on treatment days). Until you know how you will react to ketamine, it’s best to avoid big plans later in the day.

It's also important for patients to understand that this "dissociative" experience is almost always most intense for the first treatment. Your brain and your mind seem to adjust quickly to the "dissociative" experience and, thus, the second and subsequent treatments are not as intense. Some patients worry that this is a problem and that the drug is not "working" as much as it did during the first treatment. This belief stems from older reports suggesting that there was a relationship between the intensity of the "dissociative" experience and the antidepressant effects the patient experienced. Subsequent studies which are of higher quality have shown that there isn’t any relationship between these things. In other words, if the primary goal is for a patient to overcome his or her depression, then it doesn’t much matter whether a patient feels an intense "dissociative" experience or not.

What About Other Side Effects?

It’s not uncommon for patients to experience a headache later in the day after treatment. Generally, this is a mild headache and can be alleviated with an over-the-counter remedy, such as acetaminophen (Tylenol) or ibuprofen (Advil). In my experience, it’s extremely rare for a patient to want to stop treatment because the headaches are too much to bear. Another common side effect around the time of the treatment is nausea. This can almost always be treated adequately with an anti-nausea medicine your doctor can give you, such as ondansetron (Zofran). In rare cases, the nausea can be severe enough that patients vomit. This is why patients are asked to abstain from food for 2 hours prior to treatment. If a patient comes to treatment with a very full stomach, it’s more likely that he or she will vomit. Finally, some patients can experience a fleeting but very unpleasant taste in the mouth (more commonly with the esketamine nasal spray), which is called dysgeusia. This can easily be remedied with a lollipop.

What If I Have an Unpleasant Experience?

On rare occasions, a patient has an intensely unpleasant or anxious experience with ketamine. This experience may resemble a panic or anxiety attack. Sometimes patients later describe the sensation as if they were dying or already dead. Among those who use ketamine recreationally, this seems to be similar to what is sometimes called a "K-hole." We don’t have precise estimates as to how often this happens in medical settings, but I would peg the frequency at about once every three hundred treatments based on my clinical experience. These experiences can be quite frightening for patients. Fortunately, as long as the treatment is being done properly (at a clinic as opposed to at home), these instances are not dangerous and can be easily and safely managed.

When this happens, the doctor or nurse might provide a “rescue” medication to help quell intense anxiety. If the patient is receiving ketamine intravenously, merely stopping the infusion will usually provide significant relief in a matter of minutes. While this experience is fortunately rare, patients should understand this is a risk.

There’s not much evidence as to what might trigger one of these intensely unpleasant experiences or which patients are at greater risk. However, in my clinical experience, if a patient begins treatment when he or she is in an unpleasant emotional state (i.e., weeping or sobbing), this seems to heighten the risk. Because of this, it’s reasonable for a patient to temporarily delay treatment until emotional composure can be regained. Fortunately, it seems that just because a patient experiences an intense reaction to ketamine/esketamine does not necessarily mean this will happen again. I’ve seen patients that had an intense negative reaction to the 2nd treatment and then went on to have 50 subsequent treatments (over several years) with no problem.


Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression. Chen G, Chen L, Zhang Y, Li X, Lane R, Lim P, Daly EJ, Furey ML, Fedgchin M, Popova V, Singh JB, Drevets WC. Int J Neuropsychopharmacol. 2022 Apr 19;25(4):269-279.

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