In 2016, I wrote Ketamine Research In A New Light, which discussed the emerging consensus that, contra existing theory, ketamine's rapid-acting antidepressant effects had nothing to do with NMDA at all. I discussed some experiments which suggested they might actually be due to a related receptor, AMPA.

The latest development is Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism, which finds that the opioid-blocker naltrexone prevents ketamine's antidepressant effects. Naltrexone does not prevent dissociation or any of the other weird hallucinatory effects of ketamine, which are probably genuinely NMDA-related. This suggests it's just a coincidence that NMDA antagonism and some secondary antidepressant effect exist in the same drug. If you can prevent an effect from working by blocking the opiate system, a natural assumption is that the effect works on the opiate system, and the authors suggest this is probably true.

(unexpected national news tie-in: Kavanaugh accuser Christine Blasey Ford is one of the authors of this paper)

In retrospect, there were warnings. The other study to have found an exciting rapid-acting antidepressant effect for an ordinary drug was Ultra-Low-Dose Buprenorphine As A Time-Limited Treatment For Severe Suicidal Ideation. It finds that buprenorphine (the active ingredient in suboxone), an opiate painkiller also used in treating addictions to other opiates, can quickly relieve the distress of acutely suicidal patients.

This didn't make as big a splash as the ketamine results, for two reasons. First, everyone knows opiates feel good, and so maybe this got interpreted as just a natural extension of that truth (the Scientific American article on the discovery focused on an analogy where "mental pain" was the same as "physical pain" and so could be treated with painkillers). Second, we're currently fighting a War On Opiates, and discovering new reasons to prescribe them seems kind of like giving aid and comfort to the enemy.