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.
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.
Ketamine is interesting because nobody can just reduce its mode of action to “opiates feel good”. Although it was long known to have some weak opiate effects, it doesn’t feel good; all the dissociation and hallucinations and stuff make sure of that. Whatever is going on is probably something more complicated.
The psychiatric establishment’s response, as published in the prestigious American Journal of Psychiatry, is basically “well, f@#k”. Here we were, excited about NMDA (or AMPA) giving us a whole new insight into the mechanisms of depression and the opportunity for a whole new class of treatment – and instead it looks like maybe it’s just pointing to The Forbidden Drugs That Nobody Is Supposed To Prescribe. The article concludes that ketamine should not be abandoned, but ketamine clinics under anaesthesiologists should be discouraged in favor of care monitored by psychiatrists. I will try not to be so cynical as to view this as the establishment seizing the opportunity for a power grab.
What happens now? A lot of this depends on addiction. One way we could go would be to say that although ketamine might have some opiate effects, it’s not addictive to the same degree as morphine, and it doesn’t seem to turn users into drug fiends, so we should stop worrying and press forward. We could even focus research on finding other opiates in a sweet spot where they’re still strong enough to fight depression but not strong enough to get people addicted. Maybe very-low-dose-buprenorphine is already in this sweet spot, I don’t know.
But all of this is going to be shaped by history. Remember that heroin was originally invented (and pushed) as a less-addictive, safer opiate that would solve the opiate crisis. Medicine has a really bad habit of seizing on hopes that we have found a less addictive version of an addictive thing, and only admitting error once half the country is addicted to it. And there are all sorts of weird edge cases – does ketamine cross-sensitize people to other opiates? Does it increase some sort of domain-general addiction-having-center in the brain? I know substance abuse doctors who believe all of this stuff.
Also, should we start thinking opiates have some sort of deep connection to depression? “Depression is related to the stuff that has the strongest effect on human happiness of any molecule class known” seems…actually pretty plausible now that I think about it. I don’t know how much work has been done on this before. I hope to see more.
Source: Ketamine: An Update