As interest in ketamine as a treatment for depression increases, so do concerns about side effects. A recent analysis takes a closer look and concludes that, at least in the short term, ketamine appears safe.

In March 2019, the Food and Drug Administration (FDA) approved esketamine—a ketamine-based nasal spray—for the treatment of depression.

Studies have shown that small doses of ketamine can quickly relieve symptoms of depression. Even individuals who have not responded to other antidepressants report a beneficial effect within hours.

Ketamine's ability to work for these difficult-to-treat people might be because of its novel mode of action. The drug blocks glutamatergic N-methyl-D-aspartate (NMDA) receptors; other antidepressants interact with serotonin, norepinephrine, or adrenaline.

Because there have been very few advances in depression treatment in recent years, ketamine has caused excitement and renewed hope.

Alongside this fervor, scientists have voiced concerns regarding ketamine's side effects; these can include feelings of dissociation, increased blood pressure, respiratory depression, vomiting, and cystitis.

Also, because some people use ketamine recreationally, some experts are worried about the drug's potential for abuse.

Looking for side effects

Currently, there is little detailed information about ketamine's side effects. Although some papers have collated the side effects of ketamine, often, these did not include a placebo. Also, few scientists have studied longer term effects.

With this in mind, researchers from the National Institutes of Health (NIH) designed an analysis to investigate the side effects of esketamine in more detail; they recently published their findings in the Journal of Affective Disorders. The authors write:

"The primary aim of this study was to comprehensively report [side effects] associated with ketamine by reviewing 120 symptoms associated with a single intravenous infusion of subanesthetic-dose ketamine."

To investigate, they accessed data from studies that the NIH carried out over the past 13 years; this data included 163 individuals with major depressive disorder or bipolar disorder and 25 healthy controls.

The researchers chose NIH studies because of their rigorous monitoring of side effects at specified time points, including standardized rating scales and clinician interviews.

'Strange or loopy'

Overall, of the 120 symptoms, the researchers could significantly associate 33 with ketamine treatment.

Eight of these symptoms occurred in more than half of participants; these were feeling strange, weird, or bizarre; feeling spacey; feeling woozy or loopy; dissociation; floating; visual distortions; difficulty speaking; and numbness.

However, none of these effects lasted for more than 4 hours. At a 3-month follow-up session, the researchers did not identify any serious adverse events, such as cravings, memory problems, or cognitive deficits.

The authors also note that there was no evidence of "any increased propensity for recreational ketamine use or abuse."

"The most common short-term side effect was feeling strange or loopy. Most side effects peaked within an hour of ketamine administration and were gone within 2 hours. We did not see any serious, drug-related adverse events or increased ketamine cravings with a single administration."

—Author Dr. Elia Acevedo-Diaz

Limitations and conflicts of interest

The study does have significant limitations, though. For instance, the scientists did not investigate side effects associated with longer periods of use and multiple infusions. Also, they only tested the injected drug, so they cannot know whether nasal application might change the way that side effects appear.

The authors also note that, although they followed participants for 3 months, they did not "formally measure cravings or other indicators of abuse or dependence" during the participants' initial stay in their unit.

Nevertheless, this study is another step along the path to a full understanding of the impact of ketamine treatment.

It is also worth noting that one of the authors, Dr. Carlos A. Zarate, is listed as the co-inventor of a number of ketamine-based therapies for conditions such as depression, anxiety, suicidal ideation, post-traumatic stress disorders, and neuropathic pain.

Because ketamine works to relieve depression so swiftly when other drugs have failed, interest in ketamine is likely to continue. However, there are still many questions outstanding, particularly in regards to extended use.