Can Ketamine Treatment for Depression Lead to Addiction?

In March 2019, the U.S. Food and Drug Administration (FDA) approved a medication called Spravato® to help people who have depression, but who have not been helped by other medications. This condition is known as treatment-resistant depression.

Spravato® contains esketamine, which is a variant of the drug ketamine. It is administered via a nasal spray. The medication has proved to be extremely beneficial for many people who had been suffering with treatment-resistant depression.

However, even with Spravato’s documented history of success and the FDA’s strict usage guidance in place, ketamine’s reputation as a dangerous drug has prompted researchers to investigate the safety of this approach.

Before we take a closer look at research into the safety and effectiveness of ketamine treatment, let’s first take a moment to discuss some basic facts about ketamine and esketamine.

What Is Ketamine?

Ketamine is a dissociative anesthetic. It is used by doctors and veterinarians to sedate patients (both humans and animals) prior to certain medical procedures. It is also sometimes used to treat people who have been experiencing severe pain due to burns, cancer, or chronic nerve conditions.

Ketamine was first synthesized in the early 1960s. After the drug earned FDA approval in 1970, the U.S. military began to use it to treat wounded service members in Vietnam. It has been included in the World Health Organization’s list of essential medicines since the 1980s. In the early 2000s, researchers discovered ketamine’s ability to alleviate symptoms of depression.

Unfortunately, ketamine’s dissociative properties have also made this drug attractive to people who are seeking a recreational high. People who abuse “Special K” may experience disorientation, hallucinations, impaired coordination, and changes in heart rate and breathing. Continued ketamine abuse can lead to tolerance, addiction, and withdrawal symptoms if a person tries to stop using the drug.

Esketamine, which is present in Spravato®, is an enantiomer of ketamine. This means that esketamine’s chemical structure is a mirror image of ketamine’s. Esketamine is also sometimes referred to as (S)-ketamine and (S+)-ketamine. Esketamine is a bit stronger than ketamine, so it can be used in smaller doses than ketamine.

When ketamine is used in depression treatment, it is typically administered by intravenous injection. Esketamine, as noted above, is delivered via a nasal spray

The Effectiveness of Ketamine Treatment

Researchers have been studying ketamine’s ability to help people who have been struggling with depression for more than two decades now. Many studies have reported that ketamine can be an effective element of care for depression, particularly when combined with therapy and a traditional antidepressant.  

The effectiveness of ketamine treatment for depression was addressed in a 2019 study in the Indian Journal of Psychiatry. This was a small study, involving 25 male subjects, all of whom had severe depression.

The study’s subjects received six subanesthetic doses of ketamine over a two-week period. The researchers assessed the effect of the ketamine doses multiple times throughout the study, with the final assessment occurring one month after the subjects received their final dose.

The research team’s findings included the following:

• The ketamine doses had “a robust and rapid effect on depression,” with improvements occurring immediately after the first dose and lasting through the end of the study.
• Subjects showed significant improvement in symptoms of depression and anxiety at the two-week point and again during the final assessment one month after they had stopped receiving ketamine.
• Some subjects experienced “transient adverse effects,” after receiving ketamine, but these effects typically subsided within an hour.

The authors of the 2019 study also referenced prior research into ketamine treatment for depression:

• In an open-label study involving patients who had major depressive disorder, the study’s subjects showed sustained improvements after receiving six ketamine doses in 12 days.
• In a randomized control trial that included 67 people with treatment-related depression, the subjects showed “significant improvements in depressive symptoms” after receiving ketamine infusions either two or three times per week for a period of 15 days.

These results were consistent with the findings of previous studies. For example, a 2018 study in the journal Neurobiology of Stress reported the following about the effectiveness of multiple-infusion ketamine treatment:

• People who received three ketamine infusions per week for two weeks scored better on both the Montgomery-Asberg Depression Rating Scale (MADRS) and the Visual Analog Scale (VAS).
• Patients who received multiple ketamine infusions had a higher rate of remission and a longer duration of symptom improvement than did individuals who only received one infusion.

Research into ketamine treatment has not been limited to its usefulness for people who have treatment-resistant major depressive disorder. A December 2019 article on the website of Columbia University’s Irving Medical Center discussed a study on the potential benefits of ketamine treatment for people who are addicted to alcohol.

Features of this study, which was conducted by researchers with Columbia University Vagelos College of Physicians and Surgeons and New York State Psychiatric Institute, included the following:

• The study involved 40 people who had been seeking treatment for alcohol addiction.
• The study’s subjects received a single dose of either ketamine or midazolam (a benzodiazepine that may be used to ease the symptoms of alcohol withdrawal).
• All of the study’s subjects also participated in motivational enhancement sessions.

The study yielded the following results:

• 82% of subjects who received ketamine remained abstinent from alcohol three weeks after receiving the medication.
• 65% of subjects in the midazolam group remained alcohol-free after three weeks.
• The members of the ketamine group remained abstinent from alcohol for a longer period of time than did the members of the midazolam group.
• When they did relapse, the members of the ketamine group were less likely to engage in heavy drinking than were the subjects who had received midazolam.
• After relapsing, the members of the ketamine group were more likely to return to abstinence than were the subjects in the midazolam group.

“[K]etamine appears to have increased resilience and reduced demoralization after a lapse,” the study’s lead author, Elias Dakwar, MD, said in the 2019 article. “Participants may have been better able to bounce back after slipping, and they may have been more motivated to resume the work of recovery.”

The Safety of Ketamine Treatment

Because ketamine is such a powerful drug, the FDA’s approval of Spravato included several restrictions on where and how the medication can be used:

• Spravato can only be administered in a doctor’s office or another authorized medical setting. Patients are not permitted to take Spravato home with them.
• Patients who receive Spravato must remain under the supervision of a qualified healthcare provider for at least two hours following the administration of the medication.
• The patient must sign a form acknowledging that they know they should not drive or use heavy machinery for the rest of the day after receiving Spravato.
• Spravato’s packaging must contain a boxed warning to inform patients that the medication cause sedation, impaired judgment, dissociation, and other effects.

The safety of ketamine treatment was also the focus of a July 2020 study in the journal Pharmaceuticals. This study involved a survey of healthcare providers who offered ketamine treatment for depression, along with a review of published papers. The study’s lead author, David Feifel, MD, PhD, reported the following findings:

• Of the 6,630 patients whose cases were discussed in the surveys, only 47 (or 0.7% of the population) had adverse effects that prompted the discontinuation of ketamine treatment.
• Of the 333 patients with treatment-related depression whose cases were mentioned in the published papers, only eight (or 2.4%) stopped receiving ketamine treatment due to adverse effects.

“Our finding of a low adverse event rate with repeated administrations of parenteral ketamine are consistent with the small but growing number of published reports describing multiple IV ketamine infusions to treat depression,” Dr. Feifel wrote.

Minimal Risk of Addiction from Ketamine Treatment

As described earlier, ketamine is a powerful and potentially dangerous drug. When someone abuses ketamine, they put themselves at risk for myriad negative outcomes, including addiction.

But there is a vast difference between abusing ketamine to achieve a recreational high and using the medication under the supervision of a qualified healthcare professional in the context of a reputable treatment program.

In the latter circumstance – receiving ketamine treatment from a trusted provider — the risk of becoming addicted to ketamine appears to be quite low.

The link between ketamine treatment and addiction was explored in the November 2018 study in the journal Neurobiology of Stress that we referenced earlier in this article.

The co-authors of this study, C.E. Strong and Mohamed Kabbaj of Florida State University, noted that repeated ketamine infusions can have addictive properties. However, they did not find evidence of a high risk of addiction among people who received ketamine treatment for treatment-resistant depression.

“In recent years, few case reports have documented the development of a full-blown ketamine addiction following clinical treatment of depression with repeated low-dose ketamine,” Strong and Kabbaj wrote.

Virtually every prescription medication is accompanied by some risk of addiction. But when people use the medications as directed, most have no problems with chemical dependency. This appears to be the case with ketamine and esketamine treatment. According to current research, the likelihood of addiction among adults who receive this treatment from trusted and reputable providers appears to be extremely low.