Ketamine's effect on depression may hinge on hope
Beyond the importance of controlling the placebo effect, I am worried that a lot of the drug-depression research is overlooking an important possibility:  that the thing about ketamine/psilocybin/etc that is helping with depression is not some latent property of the molecule, but rather the actual transcendent experience of the trip.  In other words, the trip is the point, not the mechanistic neuro-tinkering [0].Importantly, this tracks with what we know about the protective effects of things like religiosity against depression.  As such, the qualitative experience of the drug might not be something we can (or should) do away with.  I would even go as far as suggesting that an absence of transcendence in one's life is precisely what causes a large segment of people to become depressed in the first place, and that perhaps drugs are helpful only insofar as they produce a transcendent experience.This isn't to say we can't take a scientific approach to treating depression, but that has to be balanced with something profoundly metaphysical:  the actual qualia of life experience.  Wellness isn't the absence of disease; it's the presence of thriving, and that includes within it a component of things like hope, inspiration, and elevation above the ordinary.  We used to have various ceremonies designed to turn us towards the numinous, but we've pretty systematically dismantled those in favor of a grounded hyper-rationality [1].  As a scientist, I can't really object to rationality on its own, but it may be worth considering non-rational, transcendent experience as a fundamental psychological need.[0] If you're a materialist, you might object that neurological machinery is not differentiable from qualia.  Fair enough!  I even agree!  My point is simply that medicine needs to consider qualia as a major parameter in the treatment of depression.  Fixing depression is not like fixing a car.[1] I suspect most people here are familiar with Nietzsche's "God is dead quote".  Many people in my entourage are floored to discover that he correctly predicted the dramatic increase in anxiety, depression, neuroticism and nihilism that is present in modern life.