If I take dextromethorphan (NyQuil) then four or so hours later I’m back to feeling like I did before I took it.
Just to be clear, I’m asking about taking ketamine under the supervision of a doctor. Not recreationally.
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Ketamine is a very interesting drug. There are a number of different effects induced by ketamine that may (or may not) be related.
First, you have the sedative effects that are mediated through NMDA.Then you have the so called “dissociative” effects. Dissociation is usually mediated through the serotonin system (think LSD, ecstasy, ayahuasca, etc), but ketamine doesn’t interact with the serotonin system. This effect is likely related to the sedative mechanism but is achieved at lower doses.
You also have analgesic (painkilling) effects, which could be mediated through the NMDA receptor, mu opioid receptor, the sigma receptor, or all/any/none of the above.
Then you have the rapid acting and long term antidepressant effects. This is the one we know least about because we generally have a poor understanding of how antidepressants work beyond their pharmacological binding profile. It’s weird too because we typically think of serotonin, norepinephrine, and occasionally dopamine as the mediators of depression and subsequent treatment. There are antidepressants that work through NMDA (i.e. gabapentin), but we don’t typically think of NMDA as being the main player in depression.
So what makes the effects of ketamine different than dextromethorphan? Well, the first one is potency. Ketamine is about 10,000 times more potent at NMDA than DXM is. But beyond that, ketamine is a “dirty” drug. That doesn’t necessarily mean that it’s bad, it just means that it binds at many receptors and isn’t super specific to just one. It interacts with at least 20 different receptors, and it’s metabolites could also interact with other receptors as well. (Of note, this is true for DXM as well, but for different receptors and at different potencies.) Because of this, it’s really difficult to pin down exactly what’s going on with ketamine. There is a lot of research looking into ketamine right now, including whether the analgesic and dissociative properties are related (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572586/), whether the dissociative and antidepressant effects are related (https://www.nature.com/articles/s41467-020-20190-4), and so on.
So, in brief, we don’t really know what makes ketamine different than other NMDA antagonists with respect to depression, but we’re trying to find out.
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