In recent years, a growing (if preliminary) body of research has suggested that ketamine — a drug legitimately used as a sedative and anesthetic and not-so-legitimately used as a party drug, alternatively called Special K — could be an effective therapy for depression. But a small new study led by Stanford University urges caution on ketamine depression treatments.

The reason has to do with the biology of how ketamine acts as an effective anti-depressant, according to research published in the American Journal of Psychiatry. In essence, researchers concluded that in order for ketamine treatment to actually work in depression patients, it has to activate the body’s opioid system.

Or, to put it in a more, well, nerdy way: “The findings suggest that ketamine’s acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.”

It’s important to note that the study had an extremely small sample size and corroborating research will have to be done. But the scientists said that the results “provide strong justification for further caution against widespread and repeated use of ketamine” over the risk of inadvertently fostering an opioid dependence.

The trouble is, the effectiveness of anti-depressants is fairly variable depending on the medicine in question, as a landmark study published in The Lancet in April shows. That’s led to a flurry of research in alternative biological pathways that might be used to treat depression, which afflicts some 16.1 million American adults.

Ketamine isn’t the only controlled substance that’s being tested for conditions like PTSD, depression, and anxiety. Recreational drugs like MDMA, psilocybin, and LSD have been experimented with for those disorders. In fact, the Food and Drug Administration (FDA) has actually given researchers the go-ahead to test MDMA’s potential to treat PTSD in late-stage clinical trials.

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