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

[nataliezzz]

Absolutely right . 'Sleep medicine doctors' have something they want to market.

Care to elaborate?

ETA: No, he didn't care to elaborate, because it obviously makes no sense. A sleep medicine doctor writing a one-time prescription for CPAP (with perhaps a follow-up visit or two) has less to "market" than a GP who writes a prescription for a medication that you have to keep coming back for over and over to get refills.

 

[ME/CFS Science Blog]

For Cleare et al., 2025, they excluded 5 healthy and 5 depressed, so it was 10 ME/CFS, 10 depressed, and 20 healthy.

I think the second "growth hormone" should be ACTH.

For Richardson 1995, I think they excluded 5 patients. No indication of which sex the excluded patients were.

The two Sharpe papers and the Vasallo paper share Cowen as a senior author, so maybe it'd be good to have (Cowen group) for those.

Thanks, updated. There may be other errors because I didn't double-check.

The 'effect size' are based on simply eyeballing the graphs and dividing the peak by the baseline value regardless at which hour the peak was. If the plan is to publish in a journal, one could perhaps use software to retrieve exact data from the figures, although I don't think it matters much.

 

[forestglip]

If the plan is to publish in a journal

I'm crashed from writing the little review and have very little ability to think or focus at present. I'm not sure I'm going to be able to polish it or deal with any of the other parts of publication, as I think it'd take even more of a toll. I mainly just wanted to write it to give people something to share with researchers who might have an interest in this topic if they knew the basic details. But if someone else wanted, I'm happy to support them adapting my writing into something more professional.

 

[V.R.T.]

m crashed from writing the little review and have very little ability to think or focus at present.

Sorry to hear this. your efforts on this topic on really appreciated. I hope you can get some rest and get out of your crash.

 

[ME/CFS Science Blog]

I'm crashed from writing the little review and have very little ability to think or focus at present.

Your little review was probably the most interesting paper I read on ME/CFS in 2026! Hope you can rest well and recover.

 

[ME/CFS Science Blog]

There are a couple of studies that tried to block the serotonin route of buspirone and measure what effect it had on its prolactin effect. This 2001 study found that approximately 50% of its effect on prolactin disappeared when participants are first given the 5-HT1A antagonist pindolol.

So they think the effect of buspirone is about 50% serotonine pathway and 50% direct dopamine pathway.

Bridge et al. 2001. Quantifying the 5-HT1A agonist action of buspirone in man.

Bridge et al. 2001. Quantifying the 5-HT1A agonist action of buspirone in man.​

Rationale: Buspirone is used as a neuroendocrine challenge in which the increase of circulating prolactin is taken as a measure of the sensitivity of central serotonergic (5-HT(1A)) pathways. Interpretation of the test is complicated, however, by the fact that buspirone possesses D(2) antagonist and 5-HT(1A) agonist activity, both of which will result in the release of prolactin. To understand the significance of prolactin secretion in response to buspirone, it is important to measure the differential actions of the two controlling pathways.

Objective: To characterise the dual action of buspirone in stimulating the secretion of prolactin by blocking the 5-HT(1A) action with the 5-HT1A antagonist action of pindolol.

Methods: Healthy male subjects (n=35) received buspirone (0.5 mg x kg bw(-1) orally) with and without pre-treatment with the 5-HT(1A) receptor antagonist pindolol (40 mg over 2 days, 0.5 mg x kg bw(-1) on test day). Nine subjects underwent two additional trials in which they received a placebo with and without pre-treatment with pindolol.

Results: Pindolol alone caused a small but significant reduction (18%) in the tonic release of prolactin. Buspirone alone produced a robust prolactin response which was reduced to approximately half by pindolol pre-treatment. Pindolol pre-treatment also, on average, delayed the onset and peak of the prolactin response. There was wide variation among individuals both in the absolute response to buspirone and in the proportion that could be attributed to the non-serotonergic agonist action of buspirone (22-82% IQ range).

Conclusions: Our results indicate that while serotonergic pathways play a minor role in the tonic release of prolactin, the response to a buspirone challenge alone cannot be used as a simple index of central serotonergic activity. However, if two challenges are carried out, one with buspirone and the other with buspirone plus pindolol, quantitative measures can be made of the sensitivity of both the 5-HT(1A) and the putative D(2) pathways controlling prolactin release.

Source: Quantifying the 5-HT1A agonist action of buspirone in man - PubMed

 

[forestglip]

There are a couple of studies that tried to block the serotonin route of buspirone and measure what effect it had on its prolactin effect. This 2001 study found that approximately 50% of its effect on prolactin disappeared when participants are first given the 5-HT1A antagonist pindolol.

So they think the effect of buspirone is about 50% serotonine pathway and 50% direct dopamine pathway.

Bridge et al. 2001. Quantifying the 5-HT1A agonist action of buspirone in man.

Source: Quantifying the 5-HT1A agonist action of buspirone in man - PubMed

Also see this study where blocking the dopamine receptors prevented buspirone from increasing prolactin:

Prolactin response to buspirone challenge in the presence of dopaminergic blockade (Maskall et al., 1995)

I think these studies are consistent with some of the effect of buspirone on prolactin being through serotonin receptors and some being through dopamine receptors, but where even the serotonin pathways mostly affect prolactin through modulating dopamine release.

I think I did see a study providing some evidence that at least part of the serotonin effect on prolactin [edit: not specifically about buspirone, but in general] is through other pathways than through affecting dopamine, but I can't find it at the moment and will post if I do.

Edit: This might be what I was thinking of, where they saw that giving a serotonin drug increased prolactin more than the effect of fully blocking dopamine, suggesting that serotonin drugs may do more than only block dopamine.

Evidence that serotonin neurons stimulate secretion of prolactin releasing factor (Clemens et al., 1978)

 

[DHagen]

I'm crashed from writing the little review and have very little ability to think or focus at present. I'm not sure I'm going to be able to polish it or deal with any of the other parts of publication, as I think it'd take even more of a toll. I mainly just wanted to write it to give people something to share with researchers who might have an interest in this topic if they knew the basic details. But if someone else wanted, I'm happy to support them adapting my writing into something more professional.

I am very sorry that this has taken so much out of you. This thread in general and the excellent work that you have done in connecting it all has been amazing - really, some of the most interesting and exciting work on ME/CFS I've encountered since the affliction forced an interest in the subject. Thank you for all of this.

Wishing you much deserved rest and recovery.

 

[DHagen]

Your little review was probably the most interesting paper I read on ME/CFS in 2026! Hope you can rest well and recover.

Seconded!

 

[hotblack]

Thirded? There’s a handful of really impactful and thought provoking papers or pieces each year and this is absolutely one of them this year.

@forestglip deserves to be proud and deserves all the praise here. And a thank you to everyone else prodding away on this topic too, great work.

I’d love to see someone take it on and publish it or even better use it as the basis for their own new research in the area.

 

[Chandelier]

I'm crashed from writing the little review and have very little ability to think or focus at present.

Ah, sorry to hear that!
Thank you so much for your hope-inspiring work and wishing you a quick recovery!

 

[Nightsong]

haven't been well enough to keep up with anything on s4me for quite a while but just randomly occurred to me today that there is a discussion on prolactin, buspirone etc in both the British Medical Bulletin book on PVFS and a couple of detailed discussions on it in the CIBA conference book.

might also be something on it in "chronic fatigue and its syndromes" although not entirely sure - it was published in the relevant timeframe by people who would have been aware of it.

don't have the energy to dig out my box of books at the moment or track them down online but a free copy of CIBA 173 used to be on archive.org and was also available via the publisher; for the British Medical Bulletin PVFS book the chapter pdfs were on the publisher's website I think; not sure about CF&iS. may be free copies on archive.org/libgen/anna's archive

apologies if this has been mentioned, can't read back through the thread atm. if there is still interest in this topic those 3 books are definitely worth checking. the CIBA conference had some of the authors of buspirone/d-fenfluramine papers in attendance iirc

 

[ME/CFS Science Blog]

So could it be that the blunted responses represent the body's inability to send a strong enough signal to increase prolactin in the event of natural stimuli such as exercise and hypoglycemia? Maybe to compensate, the pituitary gland tries to greatly increase how strongly it responds to such stimuli, but the method it uses to upregulate this response still can not fully compensate for the blunted stimulation. However, drugs that directly target the upregulated pathways clearly highlight the upregulation.

Yeah maybe the dopamine system in ME/CFS is less responsive so that those natural stimuli that reduce it centrally have less impact and thus we see a blunted prolactin response.

But when you don't impact the dopamine system itself but simply block the dopamine that's already there, we see an exaggerated response because the lactotrophs had compensated by being more responsive to changes.

 

[ME/CFS Science Blog]

I have the CIBA symposium book from 1993 but it doesn't have much discussion on the buspirone tests. Doesn't work to upload the doc but here are some screenshot of the places where buspirone or prolactin is mentioned, the discussion moves to other topic afterwards.

First section:



Then a bit further up:



And this was mentioned during Wessely's talk

 

[Axel]

Yeah maybe the dopamine system in ME/CFS is less responsive

I wonder whether patients reporting improvements with LDA might show a normalisation of their prolactin response.

 

[neophyte32]

I wonder whether patients reporting improvements with LDA might show a normalisation of their prolactin response.

But why LDA poop out after several month for the majority of patients ?

 

[Jaybee00]

But why LDA poop out after several month for the majority of patients ?

Probably receptor desensitization

Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release - PMC

Neurons of the ventral tegmental area (VTA) are the source of dopaminergic (DAergic) input to important brain regions related to addiction. Prolonged exposure of these VTA neurons to moderate concentrations of dopamine (DA) causes a time-dependent ...

pmc.ncbi.nlm.nih.gov

Imaging Agonist-Induced D2/D3 Receptor Desensitization and Internalization In Vivo with PET/fMRI - Neuropsychopharmacology

This study investigated the dynamics of dopamine receptor desensitization and internalization, thereby proposing a new technique for non-invasive, in vivo measurements of receptor adaptations. The D2/D3 agonist quinpirole, which induces receptor internalization in vitro, was administered at...

www.nature.com

 

[forestglip]

might also be something on it in "chronic fatigue and its syndromes" although not entirely sure

"Chronic fatigue and its syndromes" is indeed on archive.org. A 1998 book by Wessely, Hotopf, and Sharpe. Prolactin response is mainly discussed on pages 261-262: https://archive.org/details/chronicfatigueit0000wess/page/261/mode/1up

It's mostly a short review of what the prolactin response studies found, but there is also some speculation including how it could tie in to CRH, ACTH, and cortisol findings.

there is a discussion on prolactin, buspirone etc in both the British Medical Bulletin book on PVFS

I'm not sure if this is specifically what you're referencing, but Bakheit and Behan, two of the authors of the initial 1992 study of prolactin response in PVFS, wrote an article in the British Medical Bulletin in 1991: Clinical spectrum of postviral fatigue syndrome

They just quickly mention the prolactin response finding and include some plots from their study that was not yet published, on pages 804-805.

 

[V.R.T.]

Probably receptor desensitization

Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release - PMC

Neurons of the ventral tegmental area (VTA) are the source of dopaminergic (DAergic) input to important brain regions related to addiction. Prolonged exposure of these VTA neurons to moderate concentrations of dopamine (DA) causes a time-dependent ...

pmc.ncbi.nlm.nih.gov

Imaging Agonist-Induced D2/D3 Receptor Desensitization and Internalization In Vivo with PET/fMRI - Neuropsychopharmacology

This study investigated the dynamics of dopamine receptor desensitization and internalization, thereby proposing a new technique for non-invasive, in vivo measurements of receptor adaptations. The D2/D3 agonist quinpirole, which induces receptor internalization in vitro, was administered at...

www.nature.com

Perhaps if we find a suitable clinican for this prolactin business they might be able to do a proper LDA trial too and put the LDA question to bed once and for all.

 

[marshtacky]

I wonder whether patients reporting improvements with LDA might show a normalisation of their prolactin response.

Hmm, perhaps ditto for those reporting response to benzos?

I’m crashing, so just grabbing the first result—

https://www.sciencedirect.com/science/article/pii/0014299986901184

Biphasic effect of GABAA receptor agonists on prolactin secretion: Evidence for two types of GABAAreceptor complex on lactotrophes​

Richard Anderson, Rory Mitchell
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Abstract​

The effects of GABA receptor agonists on prolactin secretion in vitro was examined using a rapid superfusion system. GABA and muscimol caused a biphasic effect on prolactin secretion, both components of which were antagonised by bicuculline methiodide, while baclofen had no effect on basal or stimulated secretion, demonstrating the GABAA receptor specificity of both components. Homocarnosine caused only inhibition of secretion, and a range of partly rigid GABA analogues were relatively poor at causing stimulation of secretion. Both effects of muscimol were antagonised by low-chloride medium and the anion channel blocker DIDS, but strychnine and picrotoxinin were both potent and selective antagonists of the stimulatory effect. These results demonstrate a novel biphasic effect of GABAAagonists or prolactin secretion, the two components of which appear to be independent and mediated by different types or states of GABAA receptor/chloride channel complex.