The buspirone challenge test clearly distinguishes ME/CFS patients from healthy controls: why is it not being developed and deployed?

[Hoopoe]

It's interesting that the receptors buspirone acts on are also related to migraines. Which happens to be another illness where people are forced to lie in darkened rooms.

 

[Kitty]

The contrast with depression is particularly striking.

Yep. And that PET scan study on 5-HT binding potential—comparing ME/CFS with healthy controls rather than depression—did find a marked reduction in the hippocampus. Another very small group though, and I've only seen extracts from the paper.

 

[Jonathan Edwards]

Maybe we have thought enough about the hippocampus.

It is most often talked of in relation to memory.

However, it is clearly involved in interpreting sensory data, as in computing what 'place' you are in from input from vision.

It is quite close to hypothalamus in centimetres but people may tend to think of it as the 'far end' of the temporal lobe and thus rather distant functionally. I suspect one should not get too bothered either way.

Some of the risk genes were expressed in hippocampus i think.

 

[Hoopoe]

There are studies that claim abnormally high prolactin release in response to buspirone also occurs in some types of migraine, and in panic disorder and generalized anxiety disorder.

 

[Jonathan Edwards]

There are studies that claim abnormally high prolactin release in response to buspirone also occurs in some types of migraine, and in panic disorder and generalized anxiety disorder.

I don't think it matters if the response is not specific to ME/CFS. A high ESR is not specific to rheumatoid arthritis but it tells us something important over and above clinical assessment.

 

[jnmaciuch]

The last study posted above, Cleare et al, 1995, got the same result with a different serotonin agonist, d-fenfluramine, so maybe that makes it less likely to be about drug metabolism?

No, not necessarily. Less than a dozen CYP enzymes are responsible for metabolizing something like 90% of all small drug molecules, and things like cytokines each affect multiple CYP enzymes.

 

[jnmaciuch]

What would that difference in drug metabolism suggest?

It would encourage us to look at signaling that affects the liver. One thing drug companies have gotten very good about is keeping very detailed logs of specific factors that affect specific liver enzymes. So if we can figure out the specific enzymes affected, you might be able to deduce the upstream factor that’s most consistent with that pattern.

 

[V.R.T.]

It would encourage us to look at signaling that affects the liver. One thing drug companies have gotten very good about is keeping very detailed logs of specific factors that affect specific liver enzymes. So if we can figure out the specific enzymes affected, you might be able to deduce the upstream factor that’s most consistent with that pattern.

Didn't liver come up in a study by Ponting's team?

 

[bobbler]

There are studies that claim abnormally high prolactin release in response to buspirone also occurs in some types of migraine, and in panic disorder and generalized anxiety disorder.

Am I reading it right that some of these things tried were 5-ht basically?

If so I’m also thinking that the relationship between serotonin and feeling happy/excited etc is bidirectional too

Which could explain a bind where the better you feel /if you feel too good one day it triggers something else that makes you ill. Even without the ‘because of the exertion to do with excitement’ or ‘probably did more due to feeling so upbeat’ etc.

 

[Jonathan Edwards]

I think jnmaciuch's point about metabolism is very pertinent. My gut feeling is that it probably isn't the answer because 1. The profile of prolactin for ME/CFS does not look like just an amplified response due to poor clearance of drug to me. The shape is different at an early stage - even before the plasma peak and certainly before half-life. The caveat is that the profiles are a bit different for each study and it would be good to have better data. 2. The cytokines I know of that alter liver metabolism tend to tickle up C-reactive protein, which isn't tickled up in ME/CFS.

We need to think of someone who could do a study.

 

[forestglip]

I can try to send an email later after an appointment, if someone else hasn't already.

I sent emails to 11 of the authors of the linked papers - the ones I could find an email address for. I asked if there is anything they can recollect about this line of research, such as why it was not pursued further.

 

[ScoutB]

Thanks so much for doing that @forestglip.

 

[EndME]

I sent emails to 11 of the authors of the linked papers - the ones I could find an email address for. I asked if there is anything they can recollect about this line of research, such as why it was not pursued further.

Well done!

 

[ChronicallyOverIt]

@forestglip thinking of metabolism and liver and your genetic analysis wizardry in the DecodeME data is there any overlap with Gilbert’s syndrome genes?

 

[forestglip]

@forestglip thinking of metabolism and liver and your genetic analysis wizardry in the DecodeME data is there any overlap with Gilbert’s syndrome genes?

I hadn't heard of Gilbert's syndrome, but Wikipedia says it's caused by a single gene. It doesn't look like anything is significant in the immediate vicinity of that gene, UGT1A1, in DecodeME.

 

[jnmaciuch]

My gut feeling is that it probably isn't the answer because 1. The profile of prolactin for ME/CFS does not look like just an amplified response due to poor clearance of drug to me. The shape is different at an early stage - even before the plasma peak and certainly before half-life. The caveat is that the profiles are a bit different for each study and it would be good to have better data.

You think so? [Edit: Tmax seems to be pretty rapid (1 hr), pharmacological CYP3A4 inhibitors increased Cmax 5 and 16 fold (2 different drugs) and did not change half life]. That seems consistent with the graphs to me but I'll defer to you

[Edit: my guess is it has less to do with clearance and more to do with cycling between various active and inactive forms before being excreted]

Clinical Pharmacokinetics and Pharmacodynamics of Buspirone, an Anxiolytic Drug - Clinical Pharmacokinetics

Buspirone is an anxiolytic drug given at a dosage of 15 mg/day. The mechanism of action of the drug is not well characterised, but it may exert its effect by acting on the dopaminergic system in the central nervous system or by binding to serotonin (5-hydroxytryptamine) receptors. Following a...

link.springer.com

The cytokines I know of that alter liver metabolism tend to tickle up C-reactive protein, which isn't tickled up in ME/CFS.

Some of them would but definitely not all. IFN probably wouldn't. Some of CCLs would not

 

[Jesse]

We need to think of someone who could do a study.

Maybe not the fastest option but in The Netherlands there is still an ongoing research programme. The recent round of grants for drug repurposing trials got zero applications (because they excluded all drugs still under a patent..). I have no idea when there will be a new round of grants and what theme. Nor do I know if there are suitable research groups. But the money / infra should be there.. there's still like €15-20 million that has to be spent through 2031 as far as I know.

Last I heard Germany also has made quite a lot of money available for future research. It would be REALLY nice if we could get researchers from those two countries on this forum to increase the chances they will work on research that's actually novel and of interest..

Not sure where to go from here but maybe something to think about.

 

[Kitty]

We need to think of someone who could do a study.

I don't know about personnel, but the low cost of the drug and the fact that it can be taken at home might make put a trial at the sort of the scale the MEA could fund?