Major depressive disorders and drug abuse are both massive public health concerns, affecting people from every socioeconomic class, race, and gender. The two share similarities besides their ubiquity — people suffering from depression and those illicitly using drugs sometimes have trouble seeking out help, and both situations are highly misunderstood by the public. A team led by Dr. Todd Gould of the University of Maryland School of Medicine, however, has decided to bring the two worlds together, testing the metabolites of an often abused drug, ketamine, for antidepressant effects.

Under the United States Controlled Substance Act, ketamine is a Schedule III substance. This means that the government accepts the drug’s medical potential, but its abuse could lead to “moderate or low physical dependence or high psychological dependence.” Unlike many other controlled substances, ketamine is not medically useful only for anesthetic effects, but for the very psychological effects that got it scheduled. Though the substance has a reputation as a party drug due to its hallucinogenic and dissociative effects, ketamine is also gaining traction as a treatment for depression.

Ketamine is unique among antidepressants, since traditional ones — including selective serotonin reuptake inhibitors (SSRIs) like Prozac — take weeks or months to begin working.

“Ketamine is different,” Gould told Medical Daily. “Effects are seen within hours, and ketamine works for patients who typically have failed to respond to SSRIs.”

The only problem is this instantaneous relief comes with some sticky side effects. Ketamine has the potential to cause feelings of detachment from the environment, others, and oneself. Its hallucinogenic effects can cause anxiety as well. These side effects limit the possibility of widespread clinical use.

Gould and his team, however, suspected that they could harness the antidepressant effects of ketamine while avoiding its undesirable side effects. Gould said ketamine was first shown to have antidepressant effects about 15 years ago, when it was assumed these effects targeted the same receptor as ketamine’s anesthetic effects: the NMDA glutamate receptor. However, further studies with other NMDA receptor antagonists failed to show antidepressant effects.

“This prompted us to look elsewhere,” Gould said.

He, along with his colleagues, decided to test a specific ketamine metabolite called (2R, 6R)-HNK for antidepressant effects after observing that it was the major metabolite found in the plasma and brain of mice given ketamine. The team saw that a single dose of the metabolite had antidepressant effects similar to those induced by regular ketamine. The effects showed up rapidly and lasted three days.

The best part was that the metabolite alone did not cause the side effects normally associated with ketamine, and it had less potential for abuse — when given the option, mice self-administered ketamine but not (2R, 6R)-HNK. This revealed that ketamine’s antidepressant properties lay within this metabolite, rather than the drug itself.

Gould said there are several possible directions for further research. One is studying other metabolites of ketamine to investigate if they play a part in the substance’s antidepressant action. Another, to chemically alter the (2R, 6R)-HNK metabolite to test if alterations could improve its effectiveness. Finally, Gould told Medical Daily, the team is developing a plan to get the metabolite to humans.

Source: Zanos P, Moaddel R, Morris P, Georgiou P, Fischell J, Gould T, et al. NMDR Inhibition-independent Antidepressant Actions of Ketamine Metabolites. Nature. 2016.