new study suggests that a metabolite of ketamine — not the drug itself — fights depression. Inside the body, ketamine gets converted into a slew of related molecules. One of these breakdown molecules, a chemical called (2R,6R)-hydroxynorketamine, is behind the benefits, neuropharmacologist Todd Gould of the University of Maryland School of Medicine in Baltimore and colleagues found.
On its own,
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, a single dose of (2R,
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,6R)-HNK reduced signs of depression in mice,
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, restoring their drive to search for a hidden platform in water, to try to escape a shock and to choose sweet water over plain. A type of ketamine that couldn’t be broken down easily into HNKs didn’t ease signs of depression in mice. Finding that a breakdown product, and not ketamine itself,
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, was behind the results was a big surprise, Gould says.
That surprise could turn out to be valuable. Ketamine comes with serious side effects for people — hallucinations, floating sensations and clumsiness, for example. And at high enough doses,
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, the drug is an anesthetic. But (2R,6R)-HNK may avoid these problems, experiments on mice movement indicate. “It’s actually pretty amazing how high a dose we went up to and didn’t see any ill effects,
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,” Gould says. And since ketamine has already been used to treat depression, he says,
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, the breakdown product has been inside people with no apparent ill effects.
Gould says that the behavioral improvements and lack of side effects make him optimistic that (2R,
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,6R)-HNK can be developed into a safe and effective antidepressant. He and his colleagues plan to test the ketamine

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