Ketamine is definitely an interesting compound, but not always in a good way. It’s been around for decades, and its main medical use is as an adjunct to anaesthesia. But it’s also long been a recreational drug/drug of abuse (the line between those categories is famously thin, even for a single individual). It has strong and fast-acting CNS effects, including sedation, hallucinations, euphoria, and its exact opposite. A pretty fair number of recreational users over the years have gotten a lot less (or maybe a lot more) recreation than they signed up for; people get killed while on the stuff every year, often via inadvertent suicide while deranged. But for some years, the compound has been reported as a very unusual antidepressant, a property that’s brought a lot of attention, since the field is notoriously difficult to show efficacy in. The duration of the effect can be up to several days after a single dose, and the fact that there’s an effect at all is very much worth noting.

The problem is, even after all these years, no one’s completely sure how ketamine works, in any of its capacities. It definitely hits the NMDA receptor, but that’s only of limited use, since we don’t really understand the NMDA receptor well enough, either. Still, that almost certainly accounts for the anaesthetic action, but the compound also has effects on opioid receptors, dopamine reuptake, dopamine receptors, muscarinic receptors, sodium and calcium channels “and much, much more!” as the ads would say were it to be advertised on cheap cable stations. No wonder it’s hard to figure out what’s going on: this is one of those compounds – and there are many – that approaches the complicated multikeyboard instrument of the brain by giving it a Jerry Lee Lewis style bashing with both hands and a foot.

A new paper, though, may shed some light. A large team from the NIH and the University of Maryland has been working on evidence that the antidepressant action might be due to some sort of ketamine metabolite rather than the parent compound. This seems to be the case: the main human metabolite ((2S,6S;2R,6R)-hydroxynorketamine, or HNK, which results from loss of an N-methyl group and hydroxylation next to the ketone) has no anaesthetic activity at all, and no NMDA activity at all, but turns out to be quite active in a number of animal models that are broadly predictive of antidepressant activity. In a rather elegant experiment, the authors deuterated ketamine at the methylene next to its carbonyl group, and showed that this compound (as expected) displayed the same NMDA activity as the parent compound – but that it was far slower at producing the metabolite, and had no activity in the antidepressant screens.

What HNK does seem to hit is the AMPA receptor system, which had been already been suspected as a player in the ketamine story. But that evidence was being interpreted as “something that NMDA antagonists do that has an effect on the AMPA system”, which latest work clarifies quite a bit: NMDA seems to be out of the picture entirely now. HNK does not seem to cause disorientation in the animals or locomotor problems, and may well be free of the alarming ketamine effects (the headfirst-through-a-glass-door stuff) that have limited its use as an antidepressant. Interestingly, the compound’s effects are seen well after its concentrations in the brain go down below detection. This isn’t unheard of for CNS agents; things can disrupt signaling in ways that aren’t obvious. But all this makes a human trial of HNK seem like a very interesting project, and validates the interest in AMPA (here’s a recent report) as an antidepressant mechanism.