The Ketamine Challenge: When Practice Leaps Ahead of Science

When is a promising new drug a medically valid treatment for a diagnosed disorder? And when is a promising but unproven treatment liable to be used prematurely?

The growing popularity of ketamine as a treatment for mental disorders poses an interesting challenge for clinicians, patients, and policymakers. The drug, an anesthetic that has traditionally been prescribed for pediatric patients undergoing minor surgical procedures and for burn victims, has been used over the last few years to treat severe, difficult-to-treat cases of mental disorders such as depression and obsessive-compulsive disorder (OCD). And its use is on the rise. At the same time, because of its mind-bending and euphoriant effects, ketamine has also found favor as a recreational or “club drug” that some refer to as “Special K.”

Ketamine is related to the drug phencyclidine, more commonly known as PCP. Both medications act by blocking the excitatory effects of the neurotransmitter glutamate, which is integral to information processing and memory formation in the brain. PCP was a popular recreational hallucinogen in the late 1970s and 1980s before the medical community recognized its toxicity and understood the severe, and sometimes psychotic, reactions it caused.

I vividly remember my own experience as a psychiatric resident seeing desperate, maniacal patients intoxicated with PCP brought into the emergency room by police or ambulance. Many were wildly agitated and completely detached from reality. Even the most potent medications seemed to have no effect on them. Most were recreational users who, through their abuse of PCP, had developed psychotic behaviors.

Research has shown that PCP and ketamine do have genuine therapeutic uses but a narrow therapeutic index. This means that the difference in the dosage of the drug at which it will produce therapeutic (beneficial medical) effects and that at which it will cause adverse or toxic effects is very small. So if too much is taken, the drug can cause adverse, and potentially disastrous, consequences. There is a fine line between a medicinal substance producing salutary effects and toxic effects.

When research with ketamine first showed dramatic therapeutic potential in alleviating the symptoms of depression that had resisted all approved forms of treatment (psychotherapy, antidepressant medications, even electroshock therapy), desperate patients began to seek and demand the treatment, and clinicians were eager to use it. But the question is, how can this new therapeutic option be best applied to serve patients in a beneficial way as we continue to learn about its potential and its consequences?

Ketamine is usually given by injection in single doses. Yet the conditions for which it is used (depression, OCD, etc.) require ongoing and often lifelong therapy. The dosing intervals for ketamine, to maintain improvement in patients, are not yet understood. Although the results of research with ketamine appear promising, we must determine what the consequences are of repeated administrations and long-term use. We need to know how much and how often.

The pressure to use promising new treatments for clinical purposes before they have been fully tested is not unique to psychiatry or ketamine. And it’s not hard to understand this pressure or the urgency. People are suffering from disabling and often life-threatening conditions, and they want—and deserve—appropriate treatment. We experienced the same phenomenon with treatments for HIV/AIDS in the late 1980s, treatments for cancer over the last half-century, and recent responses to the devastating Ebola outbreak in Africa.

I believe that we must translate new research findings as rapidly as we can into treatments to improve patients’ lives, but we must be cautious about moving too quickly to apply therapies we don’t completely understand in clinical practice. We must resist the temptation and pressure and be deliberate and careful. In mental illness, as in every form of human disease, we must stay true to our oldest and most essential principle: primum non nocere. First, do no harm. ■