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

[Hutan]

Maureen Hanson is on the WE&ME 2026 panel, so there would be a bit of a conflict of interest, but she might have the contacts to help a team member pull something together? @MelbME Chris Armstrong has an interest in hormones, and access to a good number of characterised ME/CFS patients. As @V.R.T. notes up thread, Fluge and Mella are another possible team.

Maybe there is a non-ME/CFS team, maybe in an endocrinology research team, in an area with a good number of patients, or where there is a strong ME/CFS charity to help with recruitment and ME/CFS knowledge.

 

[Jonathan Edwards]

I think this idea needs a bit more preparation before putting in for a grant. The reality is that grants are usually applied for to cover work you have already done or know exactly how you are going to do. For a clinical study like this there needs to be considerable groundwork in terms of setting up a cohort that could be studied. There needs to be a scientifically-minded clinician at the steering wheel. I have not managed to find one yet. There might be some in Germany I guess.

 

[SugarSquared]

I can share that some of us have reached out to multiple people, but there have been nothing much in responses yet unfortunately.

 

[mariovitali]

@forestglip Thank you for your work and document. After analysing the PDF you wrote in an ME/CFS-aware AI environment, AI has suggested using the same ME/CFS subjects and controls in a randomized crossover study, so each person undergoes several separate challenge days using placebo, buspirone, buspirone+5-HT1A blockade, Domperidone, TRH, Cabergoline or another D2 agonist.

All the above is way above my current understanding. AI also mentions several aspects "not yet looked at". As I cannot post AI content in the forum, please let me know if I could share this information in another way.

 

[forestglip]

AI also mentions several aspects "not yet looked at". As I cannot post AI content in the forum, please let me know if I could share this information in another way.

I'd say just put it in your own words as far as you can understand it, or link any sources it provides.

AI has suggested using the same ME/CFS subjects and controls in a randomized crossover study, so each person undergoes several separate challenge days using placebo, buspirone, buspirone+5-HT1A blockade, Domperidone, TRH, Cabergoline or another D2 agonist.

Yes, it'd certainly be more comprehensive. But also probably a very grueling experience for patients, and an expensive trial for researchers, with the risk that maybe this group of patients doesn't have an increased response to anything. So maybe it'd be good to first identify a group of patients that reliably have an increased response to buspirone, to ensure money isn't wasted. Then probe the specific mechanism in those patients.

 

[ChronicallyOverIt]

Wasn’t there a grant from a group for an “evolving” or new researcher? I think ideally you could have someone take that grant and roll this forward as a developed plan.

 

[forestglip]

Yes, it'd certainly be more comprehensive. But also probably a very grueling experience for patients, and an expensive trial for researchers, with the risk that maybe this group of patients doesn't have an increased response to anything. So maybe it'd be good to first identify a group of patients that reliably have an increased response to buspirone, to ensure money isn't wasted. Then probe the specific mechanism in those patients.

I mean maybe for the mechanistic probing part, you might only need one, two, or three patients? For the same reason they only use just a small handful of mice for mechanistic studies.

The researchers would start with a decent sized cohort of ME/CFS and healthy, just to replicate the main difference of prolactin response to buspirone. Then they'd select 1-3 patients from the ME/CFS group who have prolactin responses so high that there's no question something is different in these patients.

Then do many tests on these few patients. Does buspirone reliably increase prolactin very high every time? What about all sorts of other probes?

 

[ME/CFS Science Blog]

Impressive work @forestglip, thanks for digging into this!

Small suggestion for your summary: it would be useful to have a table of the ME/CFS studies with the number of participants they used (male/female), the type stimulant and dosage used and possibly info about the effect size.

 

[forestglip]

Small suggestion for your summary: it would be useful to have a table of the ME/CFS studies with the number of participants they used (male/female), the type stimulant and dosage used and possibly info about the effect size.

Thanks, good idea. I'll try to get it into a future version.

 

[Hutan]

I think this idea needs a bit more preparation before putting in for a grant. The reality is that grants are usually applied for to cover work you have already done or know exactly how you are going to do. For a clinical study like this there needs to be considerable groundwork in terms of setting up a cohort that could be studied. There needs to be a scientifically-minded clinician at the steering wheel. I have not managed to find one yet. There might be some in Germany I guess.

You may well be right, and I guess there probably isn't time now, but just to note that the proposal due on 25 August is only a short proposal. The full proposal is due on 10 November. So, I imagine that if a team can make a strong case that they have a track record for pulling something like this together and that the concept is strong, they might be invited to submit the full proposal. And they'd have a couple of months to put that together.

I guess there will be other funding opportunities.

 

[jnmaciuch]

but just to note that the proposal due on 25 August is only a short proposal.

Unfortunately even the short proposal requires quite a bit of work, especially since they're requiring institutional sign off and review boards can have wildly different strictness for what needs to be in place by then. As Jonathan said such a short deadline tends to only be feasible for groups that already have a whole study underway and are just looking for funding for specific parts (especially for the full application, since even 2-3 months might not be enough time to get ethics board approval pushed through for a study being planned from scratch)

 

[forestglip]

This is just a very minor update to the PDF about prolactin response. One of the reference numbers in the text was wrong, so I really wanted to correct that. And I made some other minor style and typo fixes.

 

[ME/CFS Science Blog]

Small suggestion for your summary: it would be useful to have a table of the ME/CFS studies with the number of participants they used (male/female), the type stimulant and dosage used and possibly info about the effect size.

Am re-reading the studies anyway, so here's an example of the table I had in mind:

Study	Patients - controls	Stimulant	Effect on prolactin	Notes
Bakheit 1992 (Behan group)	15 post-viral fatigue syndrome patients 40% female 13 healthy controls 13 depressed controls	60 mg buspirone	Similar baseline but prolactin levels rose 4.9 (males) – 8.2 (females) fold in patients, compared to 1.7 and 3.5 fold in depressed controls and 2.4 and 3.8 fold in healthy controls	Peak was after 1 hour of 3 hours tested Females tested during luteal phase “The buspirone caused excessive fatigue, lightheadedness, and nausea in patients but not in controls”
Clear 1995 (Wessely group)	10 CFS patients Holmes and Oxford criteria 40% female 20 healthy controls 10 depressed controls	30 mg d-fenfluramine	1.5 fold increase in patients compared to less than 1.16 increase in controls	Peak after 3-4 hours, 5 hours tested. Females tested during follicular phase Cortisol showed no significant group changes
Bearn 1995 (Wessely group)	9 CFS patients Oxford criteria 44% female 10 controls	30 mg d-fenfluramine	No significant group difference in the prolactin response	Cortisol showed no group difference; ACTH response was greater in patients
Bearn 1995 (Wessely group)	9 CFS patients Oxford criteria 44% female 8 controls	Insulin tolerance test	Lower response in patients: Almost 7 fold increase in controls, only 4 fold increase in patients	Growth hormone also showed slightly lower response in patients, cortisol or ACTH showed no group difference
Yatham 1995	11 CFS patients Fukuda criteria 72% female 11 healthy controls	60 mg dl-fenfluramine	No group difference	5 hours tested, cortisol also showed no difference
John Richardson 1995	25 CFS/ME patients ca. 83% female Fukuda and Oxford criteria 25 controls (family members)	50 mg buspirone	Similar baseline but prolactin levels rose almost 7 fold in patients, compared to 2 fold in controls	Single author, a GP not an academic “Nausea in patients as a response to buspirone was very marked in comparison to controls, and in most cases predicted the outcome of the test.”
Sharpe 1996 (Cowen group)	11 CFS patients Oxford criteria 0% female 11 controls (hospital and university staff)	0.5 mg/kg 45mg max buspirone	Prolactin levels increased ca. 2.6 fold in patients compared to ca 1.7 fold in controls	Peak at 1.5 hour, 4 hours tested Growth hormone showed no significant changes Patients also had more nausea in response to buspirone but this did not correlate with prolactine response Plasma levels of buspirone and its major metabolite I-(2-pyrimidinyl)piperazine (I-PP) were not significantly different between groups. They found “excessive variance in buspirone-induced prolactin release in both female CFS subjects and controls.”
Behan 1996	10 CFS patients with chronic exposure to organophosphate (OP) insecticides. 0% female 30 controls from previous study (50% female)	60 mg buspirone	Ca. 5 fold increase in patients compared to ca 2 fold increase in controls.	Single authors study and Behan was later found to have made errors, e.g. stating the controls were 10 males. Controls were matched for sex Patients had lower growth hormone response to pyridostigmine and dexamethasone
Majeed 1996 (Thesis)	30 CFS patients Fukuda criteria 50% female 30 healthy controls	60 mg buspirone	Similar baseline but ca. 2.7 fold increase in patients compared to ca. 1.8 fold increase in controls.	Tested for 4 hours “none of our subjects reported any feelings of nausea.” Growth hormone release after bromocriptine showed no difference (page 145 of thesis). Results never published
Sharpe 1997 (Cowen group)	10 CFS patients Oxford + neurasthenia criteria 0% female 10 controls	30 mg d-fenfluramine	Ca. 1.6 fold increase in patients compared to stable levels in controls	Levels first dropped after 1 hour then rose with the biggest difference appeared after 4 hours
Richardson & Da Costa 1998	39 CFS patients Fukuda and oxford criteria 56% female	50 mg Buspirone	Prolactin rose ca. 4.5 fold in males and ca. 7.8 fold in females.	No control group. One female patient received only 20 mg because she had epilepsy and showed less prolactin increase
Ottenweller 2001 (Natelson group)	20 CFS patients Holmes and Fukuda criteria 100% female 14 controls	Maximal exercise test on treadmill	Lower response in patients: ca. 2 fold increase in controls versus only ca. 1.2 fold in patients	Adrenocorticotropin, epinephrine, thyrotropin responses were lower, growth hormone higher and norepinephrine the same as controls
Racciatti 2001	14 CFS patients 5 after toxic exposure, 4 after EBV, and 5 with comorbid depression 71% female No controls	Buspirone	“…an abnormal increase of prolactine levels followed the buspirone challenge test”	No figures or data reported Dosage unclear No control group.
Sharma 2001	1 female CFS patient	30 mg Buspirone	10 fold increase in prolactin during illness but stable response after successful graded exercise program	No control group
Vasallo 2001 (Cowen group)	20 CFS patients (4 male, 16 female) 21 controls	m-chlorophenylpiperazine (mCPP)	No group difference: prolactin doubled in both patient and controls,	Patients also received a placebo which didn’t raise prolactin
Weaver 2010 (Natelson group)	22 CFS only 68% female 11 CFS + fibromyalgia 72% female 16 controls 62% female	120 mg of l-tryptophan per kg	“Women with CFS alone, but not CFS + FM, showed upregulated plasma PRL responses compared with Controls” Ca. 2 fold increase in female CFS only versus 2 fold in female controls. No difference in males.

 

[ME/CFS Science Blog]

Limitations
After reading the studies, one big limitation is that they were all quite small: almost all studies have less than 30 ME/CFS patients.
The prolactine results also show a lot of variability in the results and there are multiple factors that might influence it (sex, menstruation phase, medication, co-morbid depression, stress, time of day, etc).

Only the buspirone studies show a consistent effect but the one by Majeed 1996 was only published in a thesis, the one by Racciatti 2001 had no controls, the one by Sharma 2001 was a case study, the Behan 1996 study had errors and no matched control group, and Richardson was a GP not an academic, who published in a lower journal, mostly on his own. So that only leaves the Bakheit 1992 and Sharpe 1996 studies as the more reliable ones.

Strengths
Strengths are that the effect is quite large, was found by multiple authors but wasn't anticipated by the researchers in advance (it didn't match any pre-conceived theories). Ill controls with depression didn't show the same response and other hormones like growth hormone, cortisol, ACTH didn't show the same pattern.

 

[Jonathan Edwards]

After reading the studies, one big limitation is that they were all quite small: almost all studies have less than 30 ME/CFS patients.

Reasonable point but I come back to the fact that in the days when people were finding what turned out to be important biological differences between a disease group and normals, 30 was plenty. The recent obsession with large cohorts largely reflects the fact that people are looking for slight statistical shifts that at best will be indirect clue and at worst systemic bias (worse with large numbers). Genetics is, of course, different, in that you have serious multiple analysis problems but even slight statistical relations have to be causal.

Richardson was a GP not an academic, who published in a lower journal, mostly on his own.

My guess is that a GP who actually does stuff on his own and publishes is at least as likely to be as reliable as an academic!

 

[ME/CFS Science Blog]

Some thoughts about the cause and mechanism
The normal prolactin response after mCPP (and some dl-fenfluramine studies), and attenuated response after exercise and the insulin stress test suggests that there isn't some mechanism at play that simply shows increased prolactin responses in ME/CFS patients, regardless of the trigger.

I also read somewhere that nausea itself can increase prolactin (probably because it indicates a stressful situation) and Bakheit 1992, Richardson 1995 and Sharpe 1996 found much more nausea in patients than controls. But the latter found that nausea and prolactin response didn't correlate. The Vasallo 2001 study also found that giving patients a placebo didn't increase their prolactin, and we saw the same with the exercise and insulin test. So stress, nausea or being tested alone doesn't seem like a good explanation.

EDIT: The Sharpe 1996 study measured plasma levels of buspirone and its major metabolite I-(2-pyrimidinyl)piperazine (I-PP) and these were not significantly different between groups. So that probably results out different metabolism of the drug as the cause.

It looks like testing the serotonin system was the main rationale for doing these tests, but the evidence is pretty strong that its much less relevant on the prolactin response than dopamine. That would explain why drugs that directly on the latter like buspirone had clearer results than those that mostly target serotonin mechanism more upstream such as fenfluramine.

So the dopamine explanation also seems like the most plausible one to me. But we don't see clear dopamine abnormalities in CSF or dopamine-related symptoms such as the hallucinations of schizophrenia or the movement-problems of Parkinson. We also don't see dopamine receptors or other genes coming up in DecodeME. So if there's a dopamine abnormality in ME/CFS it seems like a subtle/specific one that is downstream of something else and doesn't have broad effects across the brain. That doesn't fit will with simply more dopamine input overall. So perhaps its a change in a specific dopamine receptor function but I still wonder why it doesn't cause problems in other functions where we know dopamine is involved.

So maybe there's another factor that is increased in ME/CFS which makes the dopamine brake more potent at the pituitary cells that make prolactin?

 

[forestglip]

Am re-reading the studies anyway, so here's an example of the table I had in mind:

Nice!

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

Growth hormone also showed slightly lower response in patients, cortisol or growth hormone showed no group difference

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.

 

[Jonathan Edwards]

So if there's a dopamine abnormality in ME/CFS it seems like a subtle/specific one that is downstream of something else and doesn't have broad effects across the brain. That doesn't fit will with simply more dopamine input overall. So perhaps its a change in a specific dopamine receptor function but I still wonder why it doesn't cause problems in other functions where we know dopamine is involved.

That sounds cogent. I would not have expected thee to be a general abnormality of dopamine production or recognition. It would be very hard to explain how that would occur as an acquired but long term response to a trigger or chance shift.

My guess is that, as in autoimmunity, the corrupted information repository involves something much more specific, like an Ig gene rearrangement (one in a trillion), but one that happens to make itself known through dopamine signalling.

 

[nataliezzz]

My guess is that a GP who actually does stuff on his own and publishes is at least as likely to be as reliable as an academic!

Umm... GPs, just not pulmonologists/sleep medicine doctors, I guess...

No but I checked up on Dr Gold and PubMed.
It seems that Gold has been batting on about this for twenty years but not published anything of interest.

 

[Jonathan Edwards]

Umm... GPs, just not pulmonologists/sleep medicine doctors, I guess...

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