This may be too dense for many people, mainly because of some notes I've interspersed to help me remember some things. So it's more to have the information available for research purposes.
I've been looking at the more recent studies on the hydroxynorketamine (HNK) metabolites of ketamine. The effect of ketamine itself is primarily as a NMDA receptor antagonist (an effect HNK does not have, at least not directly). This aspect might be helpful for some people but it's probably not the mechanism by which ketamine works to facilitate energy production in ME/CFS.
Instead, one or both of the two HNK enantiomers (2S,6S)- and (2R,6R)-HNK are likely responsible for this, along with the intermediate metabolite norketamine to a lesser extent. Ketamine is metabolized to these compounds within minutes in the body.
In this
2014 study, (2S,6S)-HNK and also norketamine significantly increased the activation of the Akt/mTOR (mTORC1) pathway. (2S,6S)-HNK was perhaps 200 times more potent at doing this than norketamine which in turn was about 100 times more potent than ketamine itself.
The authors found that this Akt/mTORC1 activation appeared to occur via inhibition of the α7-nicotinic acetylcholine receptor. (Note: The 2R,6R-HNK enantiomer is apparently less active for Akt/mTORC1 purposes in this study's assays than 2S,6S-HNK, but the authors didn't formally look at this so we don't know by how much. 2R,6R-HNK does have a potent and selective ability to inhibit α7-nAChR on the same order as 2S,6S-HNK, though, so it may not be too dissimilar in its ability to activate Akt/mTORC1.)
Next, in this
2016 study, the other enantiomer, (2R,6R)-HNK, was found to be the metabolite of ketamine most responsible for its antidepressant effect. (2S,6S)-HNK also had this capability but required a higher concentration (more than double, it appears).
According to the authors, (2R,6R)-HNK exerts its antidepressant effect by activation of the AMPA receptor.
(Note: In the 2016 study, the authors found that neither 2R,6R-HNK nor ketamine itself affected mTOR, but that appears to be because of the particular methodology used. Several other studies clearly show that ketamine activates mTOR. Being cynical here, the 2016 study seems to have been reported in such a way as to improve the prospects for obtaining a patent on the 2R,6R enantiomer.)
Anyway, when ketamine is used, HNK appears to be mostly responsible for activating the Akt/mTORC1 pathway and apparently does so by inhibition of α7-nAChR, and HNK is also responsible for ketamine's antidepressant effect which occurs via activation of the AMPA receptor. The 2S,6S enantiomer of HNK is apparently better at the former, while the 2R,6R enantiomer appears better at the latter.
However, to add a twist to this, it's been shown that activating the AMPA receptor increases brain-derived neurotrophic factor (BDNF), which then can also activate the Akt/mTORC1 pathway. (
Reference) So it's possible that ketamine (via HNK) may actually be activating that pathway through both the α7-nAChR and AMPA receptors.
Akt/mTORC1 is important because I believe the recent
Fluge & Mella study is indicating that this pathway is under-activated in ME/CFS, and that may be what's causing the impairment of the PDH complex that was found. Hence, this may be why ketamine can be helpful for some patients (for energy purposes), if only temporarily.
Interestingly, tianeptine (available as a supplement in the US) has a similar mechanism of action to ketamine in that it also simultaneously activates both the Akt/mTORC1 pathway and the AMPA receptor. (
Reference)
Unfortunately, tianeptine is not only weaker than ketamine, but also much shorter acting and even more prone to development of tolerance of its effect.
