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

[ScoutB]

There must be a way to also combine PET scans and the buspirone test to help figure out what's going on.

You may be interested in post #141

They gave people a radioligand that binds to dopamine receptors, as well as various doses of buspirone. Then they measured how buspirone competed with the radioligand for dopamine receptors.

 

[forestglip]

You may be interested in post #141

Oh yes, I read that one. Plasma prolactin correlated with how occupied the D2 receptors were in the brain (which I guess means either buspirone or one of its metabolites is binding to the D2 receptors).

I'm a bit unsure of that study in terms of providing evidence for dopamine's involvement in the prolactin response because it didn't look like they controlled for something like plasma levels of buspirone or its metabolite.

If an individual poorly metabolizes buspirone, leading to confounding from higher levels of the drug, the buspirone will more highly occupy D2 receptors and also lead to more of a prolactin response, even if the buspirone is causing the prolactin response through the serotonin system instead.

 

[ScoutB]

If an individual poorly metabolizes buspirone, leading to confounding from higher levels of the drug, the buspirone will more highly occupy D2 receptors and also lead to more of a prolactin response, even if the buspirone is causing the prolactin response through the serotonin system instead.

Yes I had the same thought. I also don't know enough biology to know if metabolism is the only confounding factor we might to need worry about.

 

[jnmaciuch]

I also don't know enough biology to know if metabolism is the only confounding factor we might to need worry about.

Probably not the only relevant factor, but it's the first and foremost thing you need to check before you can interpret any of the data in terms of neurotransmitter receptors and beyond.

Once you confirm the pharmacokinetics are comparable between groups, then it's the standard list of demographic confounders that might drive changes at the receptor-and-beyond: age, sex, BMI, activity level....

 

[forestglip]

Looking in more detail at the study that tested hormone responses to insulin and d-fenfluramine in ME/CFS:

Neuroendocrine Responses to d-Fenfluramine and Insulin-Induced Hypoglycemia in Chronic Fatigue Syndrome (1995, Society of Biological Psychiatry)
Jenny Bearn, Theresa Allain, Patsy Coskeran, Neil Munro, Joan Butler, Alan McGregor, Simon Wessely

Spoiler: Extended notes

My impression from the introduction is that they went into it expecting to find abnormal serotonin function.

Neuroendocrine strategies have also been applied to estimate central serotonin (5-HT) neurotransmission, as reflected by the size of the prolactin and cortisol responses to a range of serotoninergic agonists. This strategy has recently been applied in CFS, not only because of the high comorbidity with depression in which serotonergic mediated neuroendocrine responses are attenuated (Beam and Raven 1993), but also because of the role of 5-HT in the regulation of sleep, appetite, pain, and inflammation, all commonly disturbed in CFS (Leibowitz 1990; Jensen et al 1990).

Bakheit et al (1992) have demonstrated enhanced prolactin responses to buspirone, a 5-HT agonist selective for 5-HTIa receptors. In this study we have further explored serotonergic function using d-fenfluramine, which has a high degree of 5-HT specificity (Garatini et al 1987) and is clinically well-tolerated by patients.

The cohort was nondepressed ME/CFS patients based on 1991 Oxford criteria. No one had taken any medication for 12 weeks prior.

This says 9 patients in the first paragraph, but 11 patients are described in the second quote and in Table 1, so I think it should say 11:

Nine patients who had been referred to the psychiatric clinic at King's College Hospital specializing in chronic fatigue volunteered to participate in the study.

Seven patients underwent both an insulin tolerance test (ITT) and d-fenfluramine test, whereas two patients only had an ITT and two only had a d-fenfluramine test.

Ten normal controls were recruited from the staff and student body of King's College and Maudsley Hospitals. They were all in good health, without a history of serious illness (particularly epilepsy and cardiovascular disease), medication free (including the oral contraceptive), normal on physical examination and had normal hematological and biochemical screening profiles. Eight controls underwent both an ITT and d-fenfluramine test and the remaining two only had a d-fenfluramine test.

In the premenopausal females, all tests were performed on day 3-5 of their menstrual cycle.

Significant differences in both sex ratio and age for the insulin test. Very slightly higher BMI for patient group.

The ITT was conducted on nine patients (four women and five men) and eight controls (six women and two men). The mean age of the patient group was 36.6 ± 2.7 (SEM) years, which was significantly greater than the control group (25.9 ± 1.7 years) (p < 0.01).

There was no significant difference between the body mass index of the patient group (25.3 ± 1.01) and the controls (23.6 ± 1.37).

There was a significantly smaller prolactin response to the insulin test in ME/CFS:

The prolactin response to hypoglycemia was significantly attenuated in the CFS patients (F = 4.17; p = 0.04).

And close to significantly smaller growth hormone response:

Although there was a trend toward an attenuated growth hormone response in the patients, this just failed to achieve statistical significance (p > 0.05).

No difference in cortisol or adrenocorticotropic hormone (ACTH) response to insulin.

There was no difference in the cortisol (F = 2.28; p = 0.14) or ACTH (F= 0.03;p = 0.86) responses to hypoglycemia between the two groups.

For the d-fenfluramine test, there were again differences in sex ratio and age:

The d-fenfluramine test was conducted on nine patients (four women and five men) and 10 controls (six women and four men). The mean age of the patient group (37.3 ± 3.5 years) was significantly greater than that of the controls (26.8 ± 1.5 years) (p < 0.02). The body mass index of the patient group (24.40 ± 1.12) did not differ significantly from that of the control group (23.00 ± 1.15).

The ACTH response to d-fenfluramine was higher in patients, but the cortisol response was not different:

Although there was no significant difference in the cortisol response (F = 1.14; p = 0.29), the ACTH response was significantly greater in the patient group (F = 4.08; p = 0.04).

No significant difference in prolactin response to d-fenfluramine. If anything, it's a bit lower in patients:


Discussion
They say that while the growth hormone response to insulin wasn't quite significant here, they had unpublished data with an overlapping cohort where they saw a significant effect on this measure:

We have shown a clear trend toward an attenuated GH response, however, and in a parallel study conducted by our group using an overlapping series of patients and controls, we have shown significantly reduced GH responses to hypoglycemia (T. Allain et al., unpublished data) so that our sample size may have been too small to detect a difference.

With regard to the smaller prolactin response from insulin (I added the link the cited source in case anyone wants to look at it), they ultimately conclude that it doesn't support altered serotonin signaling because of the other normal parameters (ACTH and cortisol):

Prolactin secretion in response to hypoglycemia is mediated by 5-HT activation (Fish et al 1986) and it is possible that the attenuated prolactin response is related to subsensitivity of 5-HT hypothalamic neurons. The ACTH-cortisol response to ITF is also mediated through 5-HT activation (Cavagnini et al 1976), however, and our patients exhibit normal ACTH and cortisol responses. This finding fails to support a role for altered 5-HT neurotransmission in the attenuated prolactin response.

For the age differences, they say they don't think it affected the GH or prolactin responses:

Age does not affect the growth hormone response to insulin-induced hypoglycemia (Brunswick et al 1988) or cortisol responsiveness (Nelson and Tindall 1978), however. Furthermore, the large intersubject variability in the prolactin response extends across a wide age range (Amsterdam et al 1987).

They say the gender difference may have influenced the results:

In some studies women have lower growth hormone responses to ITT than men (Casper et al 1977; Osterman and Wide 1976). Other workers have failed to detect any difference between male and female neuroendocrine responsiveness to ITT and have combined data acquired from men and women in their analysis (Brunswick et al 1988).

For d-fenfluramine, they say that not matching age and sex might have been the reason there was not a difference for prolactin response:

Women tend to have enhanced prolactin responses, which also tends to decrease with age (McBride et al 1990), so the incomplete age and gender matching of patients and controls may have biased our findings.

What is d-fenfluramine? This is basically all that is said about it in this paper:

In this study we have further explored serotonergic function using d-fenfluramine, which has a high degree of 5-HT specificity (Garatini et al 1987)

I'm not going to read about it right now, but they cite: From fenfluramine racemate to d-fenfluramine. Specificity and potency of the effects on the serotoninergic system and food intake (1987, Ann N Y Acad Sci)

Final interpretation is hypothalamic dysfunction in ME/CFS:

In conclusion, we have demonstrated impaired prolactin responsiveness to metabolic stress in chronic fatigue syndrome, which cannot be explained by any concurrent depression. Neuroendocrine responses to d-fenfluramine provide evidence for impairment of adrenal cortical function. This study thus provides further evidence for hypothalamic dysfunction in chronic fatigue syndrome and further studies are merited to determine more precisely the basis of this dysfunction.

Taking into account the differences in sex ratio (44% vs 75% for first test and 44% vs 60% for second test), and the two significantly different hormone findings being just barely below .05, I don't think this study provides strong evidence on its own of any differences between patients and controls. For example, one study found a very significantly higher prolactin response (p<.001) to sulpiride (D2 antagonist) in females than males (Bell et al. 2012), so sex might affect the prolactin response to hypoglycemia too.

Age might be a confound too, but they say previous studies showed it does not play a large role in growth hormone at least.

Structured summary:

Cohort
Cases: Nondepressed ME/CFS (Oxford 1991 criteria)

Controls: Healthy

Insulin test: Nine patients (four women and five men, average age: 36.6) and eight controls (six women and two men, average age: 25.9)

d-fenfluramine test: Nine patients (four women and five men, average age: 37.3) and ten controls (six women and four men, average age: 26.8)

Two of the patients only did the insulin test and two patients only did d-fenfluramine test. Two controls only did d-fenfluramine test.

For premenopausal females, all tests were done on days 3-5 of menstrual cycle.

Findings
ME/CFS patients demonstrated a significantly smaller prolactin response following insulin-induced hypoglycemia test. Growth hormone response was nonsignificantly smaller. Adrenocorticotropic hormone (ACTH) and cortisol responses were not significantly different.

ME/CFS patients demonstrated a significantly larger ACTH response to d-fenfluramine. Cortisol and prolactin responses to d-fenfluramine were not significantly different from controls.

Author interpretation
The authors say the findings suggest impaired hypothalamic function in ME/CFS leading to abnormal corticotropin-releasing hormone synthesis or secretion.

Notes
Sex may confound hormone responses, thus the nonmatched sex ratio for cases and controls should be taken into account when interpreting the findings.

The p-values for the significant hormone group differences were all higher than 0.04, thus there is a possibility that some of the results may have been false positives.

 

[V.R.T.]

I cannot believe that none of this was followed up on! All this talk of how we need a biomarker etc and there's been one potentially right here for the taking all along...

I really hope a good research group jumps on this soon.

 

[Axel]

Same.
And I really don’t understand how there could have been such a fuss about the HPA axis, yet so few studies – with so few participants, unclear criteria, and substances being tested without us knowing exactly what they act on. (Sorry for the exaggeration – I’m feeling a bit down.)
Well done for putting all these studies into perspective.
I suspect that the differences regarding vasopressin, the issue of CRH and the prolactin response have something to say.

 

[forestglip]

My main hope, until some researchers take on this topic in new studies, is that there will be interesting clues in papers unrelated to ME/CFS.

There are a whole lot of papers about prolactin response in other conditions (many but not all of these found abnormal results). Many of these are just from a search of "buspirone prolactin", so this list is probably still missing prolactin challenge papers using other probes.

• Brewerton, Timothy D., et al. “Neuroendocrine Responses to M-Chlorophenylpiperazine and i-Tryptophan in Bulimia.” Archives of General Psychiatry, vol. 49, no. 11, Nov. 1992, pp. 852–61. Silverchair, https://doi.org/10.1001/archpsyc.1992.01820110016002
• Cassidy, E. M., et al. “Central 5-HT Receptor Hypersensitivity in Migraine without Aura.” Cephalalgia: An International Journal of Headache, vol. 23, no. 1, Feb. 2003, pp. 29–34. PubMed, https://doi.org/10.1046/j.1468-2982.2003.00441.x
• Cherek, D. R., et al. “Prolactin Response to Buspirone Was Reduced in Violent Compared to Nonviolent Parolees.” Psychopharmacology, vol. 142, no. 2, Feb. 1999, pp. 144–48. Springer Link, https://doi.org/10.1007/s002130050873
• Coccaro, E. F., et al. “Buspirone Challenge: Preliminary Evidence for a Role for Central 5-HT1a Receptor Function in Impulsive Aggressive Behavior in Humans.” Psychopharmacology Bulletin, vol. 26, no. 3, 1990, pp. 393–405
• Coccaro, E. F., and R. J. Kavoussi. “Neuropsychopharmacologic Challenge in Biological Psychiatry.” Clinical Chemistry, vol. 40, no. 2, Feb. 1994, pp. 319–27.
• Condren, Rita M., et al. “A Preliminary Study of Buspirone Stimulated Prolactin Release in Generalised Social Phobia: Evidence for Enhanced Serotonergic Responsivity?” European Neuropsychopharmacology, vol. 12, no. 4, Aug. 2002, pp. 349–54. ScienceDirect, https://doi.org/10.1016/S0924-977X(02)00043-3.
• Corrêa, Humberto, et al. “Prolactin Response to D-Fenfluramine and Suicidal Behavior in Depressed Patients.” Psychiatry Research, vol. 93, no. 3, Apr. 2000, pp. 189–99. ScienceDirect, https://doi.org/10.1016/S0165-1781(00)00114-1.
• Cubała, Wiesław Jerzy, and Jerzy Landowski. “Prolactin Response to Buspirone Is Not Impaired in Drug-Naïve First Episode Patients with Major Depressive Disorder.” Journal of Affective Disorders, vols. 152–154, Jan. 2014, pp. 468–73. ScienceDirect, https://doi.org/10.1016/j.jad.2013.08.005.
• Dinan, T. G., et al. “A Double-Blind Placebo-Controlled Study of Buspirone-Stimulated Prolactin Release in Non-Ulcer Dyspepsia—Are Central Serotoninergic Responses Enhanced?” Alimentary Pharmacology & Therapeutics, vol. 15, no. 10, 2001, pp. 1613–18. Wiley Online Library, https://doi.org/10.1046/j.1365-2036.2001.01090.x.
• Duval, Fabrice, et al. “Lack of Effect of HPA Axis Hyperactivity on Hormonal Responses to D-Fenfluramine in Major Depressed Patients: Implications for Pathogenesis of Suicidal Behaviour.” Psychoneuroendocrinology, vol. 26, no. 5, July 2001, pp. 521–37. ScienceDirect, https://doi.org/10.1016/S0306-4530(01)00011-7.
• Gómez-Gil, Esther, et al. “Hormonal Responses to the 5-HT1A Agonist Buspirone in Remitted Endogenous Depressive Patients after Long-Term Imipramine Treatment.” Psychoneuroendocrinology, vol. 35, no. 4, May 2010, pp. 481–89. ScienceDirect, https://doi.org/10.1016/j.psyneuen.2009.08.012.
• Malt, Eva Albertsen, et al. “Altered Dopamine D2 Receptor Function in Fibromyalgia Patients: A Neuroendocrine Study with Buspirone in Women with Fibromyalgia Compared to Female Population Based Controls.” Journal of Affective Disorders, vol. 75, no. 1, June 2003, pp. 77–82. ScienceDirect, https://doi.org/10.1016/S0165-0327(02)00025-3.
• Meltzer, Herbert Y., and Michael maes. “Effects of Buspirone on Plasma Prolactin and Cortisol Levels in Major Depressed and Normal Subjects.” Biological Psychiatry, vol. 35, no. 5, Mar. 1994, pp. 316–23. ScienceDirect, https://doi.org/10.1016/0006-3223(94)90035-3.
• Mobayed, Mamoun, and Timothy G. Dinan. “Buspirone/Prolactin Response in Post Head Injury Depression.” Journal of Affective Disorders, vol. 19, no. 4, Aug. 1990, pp. 237–41. ScienceDirect, https://doi.org/10.1016/0165-0327(90)90100-M.
• Moeller, Frederick G., et al. “A Preliminary Neuroendocrine Study with Buspirone in Major Depression.” Neuropsychopharmacology, vol. 10, no. 2, Apr. 1994, pp. 75–83. www.nature.com, https://doi.org/10.1038/npp.1994.9.
• Mohr, Pavel, et al. “Prolactin Response to D-Fenfluramine Challenge Test as a Predictor of Treatment Response to Haloperidol in Acute Schizophrenia.” Schizophrenia Research, vol. 30, no. 1, Feb. 1998, pp. 91–99. ScienceDirect, https://doi.org/10.1016/S0920-9964(97)00124-2.
• Murialdo, Giovanni, et al. “Changes in the Dopaminergic Control of Prolactin Secretion and in Ovarian Steroids in Migraine.” Cephalalgia, vol. 6, no. 1, Mar. 1986, pp. 43–49. SAGE Journals, https://doi.org/10.1046/j.1468-2982.1986.0601043.x.
• Navinés, Ricard, Rocío Martín-Santos, et al. “Effects of Citalopram Treatment on Hypothermic and Hormonal Responses to the 5-HT1A Receptor Agonist Buspirone in Patients with Major Depression and Therapeutic Response.” Psychoneuroendocrinology, vol. 32, no. 4, May 2007, pp. 411–16. ScienceDirect, https://doi.org/10.1016/j.psyneuen.2007.01.006.
• Navinés, Ricard, Esther Gómez-Gil, et al. “Hormonal Response to Buspirone Is Not Impaired in Major Depression.” Human Psychopharmacology: Clinical and Experimental, vol. 22, no. 6, 2007, pp. 389–95. Wiley Online Library, https://doi.org/10.1002/hup.862.
• Riedel, W., et al. “Secretory Pattern of GH, TSH, Thyroid Hormones, ACTH, Cortisol, FSH, and LH in Patients with Fibromyalgia Syndrome Following Systemic Injection of the Relevant Hypothalamic-Releasing Hormones.” Zeitschrift F�r Rheumatologie, vol. 57, no. 8, Dec. 1998, pp. S81–87. DOI.org (Crossref), https://doi.org/10.1007/s003930050242.
• Sevinçok, Levent, and Atila Erol. “The Prolactin Response to Buspirone in Poststroke Depression: A Preliminary Report.” Journal of Affective Disorders, vol. 59, no. 2, Aug. 2000, pp. 169–73. ScienceDirect, https://doi.org/10.1016/S0165-0327(99)00143-3.
• Sobczak, S., et al. “Serotonergic Dysregulation in Bipolar Disorders: A Literature Review of Serotonergic Challenge Studies.” Bipolar Disorders, vol. 4, no. 6, 2002, pp. 347–56. Wiley Online Library, https://doi.org/10.1034/j.1399-5618.2002.01217.x.
• “Tardive Dyskinesia Predicts Prolactin Response to Buspirone Challenge in People With Schizophrenia.” The Journal of Neuropsychiatry and Clinical Neurosciences. psychiatryonline.org, https://psychiatryonline.org/doi/10.1176/jnp.17.2.221 Accessed 15 May 2026.
• Thakore, J. H., et al. “D-Fenfluramine-Induced Prolactin Responses in Mania: Evidence for Serotonergic Subsensitivity.” The American Journal of Psychiatry, vol. 153, no. 11, Nov. 1996, pp. 1460–63. PubMed, https://doi.org/10.1176/ajp.153.11.1460.
• Waller, David A., et al. “Impulsivity and Neuroendocrine Response to Buspirone in Bulimia Nervosa.” Biological Psychiatry, vol. 39, no. 5, Mar. 1996, pp. 371–74. ScienceDirect, https://doi.org/10.1016/0006-3223(95)00524-2.
• Yatham, Lakshmi N. “Buspirone Induced Prolactin Release in Mania.” Biological Psychiatry, vol. 35, no. 8, Apr. 1994, pp. 553–56. ScienceDirect, https://doi.org/10.1016/0006-3223(94)90102-3.
• ———. “Prolactin and Cortisol Responses to Fenfluramine Challenge in Mania.” Biological Psychiatry, vol. 39, no. 4, Feb. 1996, pp. 285–88. ScienceDirect, https://doi.org/10.1016/0006-3223(95)00133-6.
• Alexander, Susanna, et al. “Evaluation of Central Serotonin Sensitivity in Breast Cancer Survivors with Cancer-Related Fatigue Syndrome.” Journal of Pain and Symptom Management, vol. 40, no. 6, Dec. 2010, pp. 892–98. PubMed, https://doi.org/10.1016/j.jpainsymman.2010.03.023.
• Cassidy, Eugene M., et al. “Differing Central Amine Receptor Sensitivity in Different Migraine Subtypes? A Neuroendocrine Study Using Buspirone.” Pain, vol. 101, no. 3, Feb. 2003, pp. 283–90. PubMed, https://doi.org/10.1016/S0304-3959(02)00335-4.
• Mattsson, H., et al. “Altered Neuroendocrine Response and Gastric Dysmotility in the Flinders Sensitive Line Rat.” Neurogastroenterology and Motility, vol. 17, no. 2, Apr. 2005, pp. 166–74. PubMed, https://doi.org/10.1111/j.1365-2982.2005.00665.x.
• McAllister-Williams, R. H., et al. “Somatodendritic 5-hydroxytryptamine1A (5-HT1A) Autoreceptor Function in Major Depression as Assessed Using the Shift in Electroencephalographic Frequency Spectrum with Buspirone.” Psychological Medicine, vol. 44, no. 4, Mar. 2014, pp. 767–77. PubMed, https://doi.org/10.1017/S0033291713001475.
• Abdel Gadir, A., et al. “The Aetiology of Galactorrhoea in Women with Regular Menstruation and Normal Prolactin Levels.” Human Reproduction [Oxford, England], vol. 7, no. 7, Aug. 1992, pp. 912–14. PubMed, https://doi.org/10.1093/oxfordjournals.humrep.a137768.
• Anderson, I. “Serotonin, Gastric Emptying, and Dyspepsia.” BMJ [Clinical research ed.], vol. 305, no. 6864, Nov. 1992, p. 1295. PubMed, https://doi.org/10.1136/bmj.305.6864.1295.
• Cassidy, Eugene M., et al. “Differing Central Amine Receptor Sensitivity in Different Migraine Subtypes? A Neuroendocrine Study Using Buspirone.” Pain, vol. 101, no. 3, Feb. 2003, pp. 283–90. PubMed, https://doi.org/10.1016/S0304-3959(02)00335-4.
• Chua, A., et al. “Central Serotonin Receptors and Delayed Gastric Emptying in Non-Ulcer Dyspepsia.” BMJ [Clinical research ed.], vol. 305, no. 6848, Aug. 1992, pp. 280–82. PubMed, https://doi.org/10.1136/bmj.305.6848.280.
• Dinan, T. G., S. Barry, et al. “A Pilot Study of a Neuroendocrine Test Battery in Posttraumatic Stress Disorder.” Biological Psychiatry, vol. 28, no. 8, Oct. 1990, pp. 665–72. PubMed, https://doi.org/10.1016/0006-3223(90)90453-9.
• Dinan, T. G., A. S. Chua, et al. “Serotonin and Physical Illness: Focus on Non-Ulcer Dyspepsia.” Journal of Psychopharmacology [Oxford, England], vol. 7, no. 1, Jan. 1993, pp. 126–30. PubMed, https://doi.org/10.1177/026988119300700104.
• Dinan, T. G., L. N. Yatham, et al. “Serotonin Supersensitivity: The Pathophysiologic Basis of Non-Ulcer Dyspepsia? A Preliminary Report of Buspirone/Prolactin Responses.” Scandinavian Journal of Gastroenterology, vol. 25, no. 5, May 1990, pp. 541–44. PubMed, https://doi.org/10.3109/00365529009095527.
• Kavoussi, R., et al. “The Neurobiology of Impulsive Aggression.” The Psychiatric Clinics of North America, vol. 20, no. 2, June 1997, pp. 395–403. PubMed, https://doi.org/10.1016/s0193-953x(05)70319-1.
• Lucey, J. V., et al. “Buspirone Induced Prolactin Responses in Obsessive-Compulsive Disorder (OCD): Is OCD a 5-HT2 Receptor Disorder?” International Clinical Psychopharmacology, vol. 7, no. 1, 1992, pp. 45–49. PubMed, https://doi.org/10.1097/00004850-199200710-00006.
• Mattsson, H., et al. “Altered Neuroendocrine Response and Gastric Dysmotility in the Flinders Sensitive Line Rat.” Neurogastroenterology and Motility, vol. 17, no. 2, Apr. 2005, pp. 166–74. PubMed, https://doi.org/10.1111/j.1365-2982.2005.00665.x.
• Meltzer, H. Y., and M. Maes. “Effects of Buspirone on Plasma Prolactin and Cortisol Levels in Major Depressed and Normal Subjects.” Biological Psychiatry, vol. 35, no. 5, Mar. 1994, pp. 316–23. PubMed, https://doi.org/10.1016/0006-3223(94)90035-3.
• Mobayed, M., and T. G. Dinan. “Buspirone/Prolactin Response in Post Head Injury Depression.” Journal of Affective Disorders, vol. 19, no. 4, Aug. 1990, pp. 237–41. PubMed, https://doi.org/10.1016/0165-0327(90)90100-m.
• Norman, T. R., et al. “Neuroendocrine Responses to Single Doses of Buspirone in Obsessive-Compulsive Disorder.” International Clinical Psychopharmacology, vol. 9, no. 2, 1994, pp. 89–94. PubMed, https://doi.org/10.1097/00004850-199400920-00004.
• Sevinçok, L., and A. Erol. “The Prolactin Response to Buspirone in Poststroke Depression: A Preliminary Report.” Journal of Affective Disorders, vol. 59, no. 2, Aug. 2000, pp. 169–73. PubMed, https://doi.org/10.1016/s0165-0327(99)00143-3.
• Waller, D. A., et al. “Impulsivity and Neuroendocrine Response to Buspirone in Bulimia Nervosa.” Biological Psychiatry, vol. 39, no. 5, Mar. 1996, pp. 371–74. PubMed, https://doi.org/10.1016/0006-3223(95)00524-2.
• Yatham, L. N. “Is 5HT1A Receptor Subsensitivity a Trait Marker for Late Luteal Phase Dysphoric Disorder? A Pilot Study.” Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie, vol. 38, no. 10, Dec. 1993, pp. 662–64. PubMed, https://doi.org/10.1177/070674379303801007.

Until there is good evidence to the contrary, my working hypothesis is that in all these conditions like ME/CFS, migraine, IBS, social anxiety, and dyspepsia, the abnormal prolactin response is the same phenomenon, and so the prolactin evidence can be considered together. We might accidentally discover some useful insights about all of the other conditions as well.

I wonder if the prolactin response research for migraine stopped as well. Only 10 studies cite the previously discussed 1986 migraine study, according to PubMed, so it's definitely not the most active field.

But here's a migraine prolactin challenge paper that could give another clue, in that it provides evidence against a role for the 5-HT1D receptor, according to the abstract:

Neuroendocrine effects of subcutaneous sumatriptan in patients with migraine (2001, J Endocrinol Invest)

We evaluated the sensitivity of 5-HT1D receptors in patients with migraine using sumatriptan as a pharmacological probe. The drug inhibits the release of ACTH, cortisol and prolactin and this effect may be used to explore the function of serotoninergic systems in vivo. We administered sumatriptan (6 mg sc) and placebo to 15 migraineurs, during the headache-free period, and to 10 healthy controls. Blood samples were collected -15, 0, 15, 30, 45, 60 and 90 min after injections. Sumatriptan induced a significant (p<0.01) decrease of ACTH, cortisol and prolactin concentrations both in patients with migraine and in controls. The neuroendocrine response was not significantly different in the two groups. Our results suggest that 5-HT1D receptor sensitivity is not altered in migraine. [emphasis added]

Edit: Google Scholar gives 55 citations for the 1986 migraine paper: https://scholar.google.com/scholar?cites=4237710747732516659&as_sdt=5,44&sciodt=0,44&hl=en

 

[forestglip]

I found very interesting data in a 1986 study on prolactin response in migraine: Changes in the dopaminergic control of prolactin secretion and in ovarian steroids in migraine (Cephalalgia)

According to the paper, there are even earlier papers about abnormal prolactin release in migraine from dopaminergic agents.

(The third quote repeats things from the first two quotes)

These observations confirm previous findings on sulpiride effects in migrainous subjects by Nappi et al. (5) and by Horowski (11).

A more prolonged PRL release but not higher peak levels have been observed after reserpine administration (9) and after benserazide (10). Bussone et al. (14) have reported an enhanced stimulatory effect on PRL by morphine. In their study, the trend was evident, but the data were expressed as the absolute values and did not reach statistical significance.

Reserpine induces a greater and more prolonged rise of PRL serum levels in this condition than in healthy subjects (9). Similar data have been obtained after the administration of sulpiride, a DA receptor blocker (5, 10, 11) and of benserazide, an aromatic amino acid decarboxylase inhibitor (5, 10).

Spoiler: References

5. Nappi G, Martignoni E, Bono G, Savoldi F, Murialdo G, Polleri A. THDA system function in migraine. In: Clifford Rose F, Zilkha KJ eds Progress in migraine research. London: Pitman 1981;1:110-23

9. Nappi G, Savoldi F, Bono G, Martignoni E. Reserpine: headache and prolactin release in migraine. Headache 1979;19:273-7

10. Polleri A, Nappi G, Masturzo P, Martignoni E, Murialdo G, Bono G, Testa E, Savoldi F. Neuroendocrine approach to headache. Adv Neurol 1982;33:173-82

11. Horowski R. Role of monoaminergic mechanisms in the mechanism of action of ergot derivatives used in migraine. In: Clifford Rose Fed Advances in migraine. New York: Raven Press 1982:187-98

14. Bussone G, Boiardi A, La Mantia L, Frediani F, Vescovi A, Parati EA. Long-acting ergot: clinical and neuroendocrinological aspects in migraine patients. Cephalalgia 1983;3(suppl 1):163-7

I tried starting by looking for the first one on the list, Nappi 1981, about sulpiride. It's a book and costs a couple hundred dollars to buy, so probably not worth it. (Please no one buy it. I'm not even sure that's the right book.) Google Scholar links to 20 papers that cite it, so piecing those together might give insights into what it showed.

For reference 9 about reserpine, it looks to me like the sentence about it might be wrong. Based on the abstract, there were basically no differences in prolactin release, except that male migraineurs had a less prolonged prolactin release, which is the opposite of what the paper above says:

The reserpine-induced PRL increase was similar for migraine and control groups during the first 5 hours, with no relationship to occurrence and severity of headache. Only the control males, however, had returned to basal PRL levels after 24 hours.

The full text seems to confirm that.

Though there's this other interesting part about a drug that blocked reserpine-induced migraine, and this being evidence of dopamine involvement:

Finally, the reserpine test was repeated in 10 responsive migrainous subjects after 1 month of pre-treatment with bromocriptine, (7.5 mg./day p .o. ). The basal PRL levels were reduced significantly by treatment with this DA agonist, but the ability of bromocriptine to block PRL increase, induced by reserpine, was striking. [...] the blocking action was really dramatic in male subjects. [...]

Besides this inhibition of PRL release, the dopaminergic treatment was also effective in completely preventing the headache attacks in 8 of 10 patients. Specifically, this occurred in all males, where the PRL increase by reserpine was almost completely abolished by bromocriptine.

The failure of drugs affecting 5HT mechanisms and the efficacy of bromocriptine emphasizes the role played by DA pathways in precipitating reserpine-induced attacks. The bromocriptine treatment has been reported as positive by Hockaday,30 in premenstrual or early menstrual migraine. Lechin31 recently reported the effectiveness of DA blockers in large groups of headache patients responsive and non-responsive to other drugs. If DA is involved in spontaneous attacks,8 it may be that receptor blockers or agonists may counteract mediator deficiencies.

It doesn't seem like bromocriptine is presently described as a migraine medication, though.

 

[SugarSquared]

I’m simultaneously afraid of an exaggerated prolactin response being a part of many diseases, but also excited about it. Any replicable biological finding in ME/CFS is so valuable. Plus, if it can be related to comorbidities like IBS and migraine, the better.

We’ll make sure to get this done. It’s so important.

 

[forestglip]

I’m simultaneously afraid of an exaggerated prolactin response being a part of many diseases, but also excited about it. Any replicable biological finding in ME/CFS is so valuable. Plus, if it can be related to comorbidities like IBS and migraine, the better.

Of the ones we've looked at so far, for the most part, it seems to be reported in diseases that are at least kind of related to ME/CFS, like IBS, dyspepsia (indigestion, so maybe similar to IBS), and migraine, so I think that's reassuring that this is uncovering some common thread to these illnesses.

IBS and migraine have some similarities to ME/CFS in their genetics:

Insights into Pathophysiological Pathways in ME/CFS Through Genetic Correlation and Mendelian Randomization, 2026, Wielscher et al

Across 22 auxiliary traits spanning five mechanistic domains, cellular energetics, neurovascular regulation, and barrier–microbiome function showed the strongest genetic overlap with ME/CFS, with migraine and irritable bowel syndrome contributing most to shared pleiotropy.

DecodeME showed high comorbidity of IBS in ME/CFS. For migraine comorbidity, I'm not sure of the quality of the studies, but these say they are comorbid more often than expected by chance:

Increased risk of chronic fatigue syndrome in patients with migraine: A retrospective cohort study (2015, J Psychosom Res.)

The current study demonstrated an increased risk of CFS in migraineurs.

Migraine headaches in chronic fatigue syndrome (CFS): comparison of two prospective cross-sectional studies (2011, BMC Neurol)

CFS subjects had higher prevalences of MO [migraine without aura] and MA [migraine with aura] than HC

Since the other conditions are not things like Alzheimer's and gout and celiac disease and a lot of other random diseases, I think that makes it more likely that it's not just a very nonspecific effect of being sick.

 

[forestglip]

I found very interesting data in a 1986 study on prolactin response in migraine: Changes in the dopaminergic control of prolactin secretion and in ovarian steroids in migraine (Cephalalgia)

According to the paper, there are even earlier papers about abnormal prolactin release in migraine from dopaminergic agents.

(The third quote repeats things from the first two quotes)

These observations confirm previous findings on sulpiride effects in migrainous subjects by Nappi et al. (5) and by Horowski (11).

A more prolonged PRL release but not higher peak levels have been observed after reserpine administration (9) and after benserazide (10). Bussone et al. (14) have reported an enhanced stimulatory effect on PRL by morphine. In their study, the trend was evident, but the data were expressed as the absolute values and did not reach statistical significance.

Reserpine induces a greater and more prolonged rise of PRL serum levels in this condition than in healthy subjects (9). Similar data have been obtained after the administration of sulpiride, a DA receptor blocker (5, 10, 11) and of benserazide, an aromatic amino acid decarboxylase inhibitor (5, 10).

Spoiler: References

5. Nappi G, Martignoni E, Bono G, Savoldi F, Murialdo G, Polleri A. THDA system function in migraine. In: Clifford Rose F, Zilkha KJ eds Progress in migraine research. London: Pitman 1981;1:110-23

9. Nappi G, Savoldi F, Bono G, Martignoni E. Reserpine: headache and prolactin release in migraine. Headache 1979;19:273-7

10. Polleri A, Nappi G, Masturzo P, Martignoni E, Murialdo G, Bono G, Testa E, Savoldi F. Neuroendocrine approach to headache. Adv Neurol 1982;33:173-82

11. Horowski R. Role of monoaminergic mechanisms in the mechanism of action of ergot derivatives used in migraine. In: Clifford Rose Fed Advances in migraine. New York: Raven Press 1982:187-98

14. Bussone G, Boiardi A, La Mantia L, Frediani F, Vescovi A, Parati EA. Long-acting ergot: clinical and neuroendocrinological aspects in migraine patients. Cephalalgia 1983;3(suppl 1):163-7

Continuing to check out the references to older papers.

Reference 10 about sulpiride and benserazide is also a book that isn't easily accessible. Google scholar citations.

Reference 11 about sulpiride is also a book. It's available to borrow on the Internet Archive. I'll take a look more closely later, but it looks like they tested prolactin response in migraine after separate tests of reserpine, fenfluramine, benserazide, and sulpiride.

Reference 14 about morphine is a paper:

Long-acting ergot: clinical and neuroendocrinological aspects in migraine patients (1983, Cephalalgia)

They gave morphine to 12 migraine patients and 10 age and sex matched healthy controls, and measured prolactin afterwards.

Twelve patients, 22-45 years of age, 7 women and 5 men

All subjects had a history of a least four years of migraine and they had been free of therapy for at least one month before participating in the study.

although the releasing effect is wider and greater in migraine patients than in control subjects, but without statistical significance (see Fig. 2).

 

[Kitty]

I really hope a good research group jumps on this soon.

It sounds as if a well designed study wouldn't need an enormous budget either. Maybe the sort of scale that would fit with the WE&ME grants scheme?

I wonder if the prolactin response research for migraine stopped as well.

If it did, it'd be interesting to know why. Did it begin to look like a dead end, or was it just not fashionable enough to attract funding so the researchers were forced to move on?

 

[forestglip]

Reference 11 about sulpiride is also a book. It's available to borrow on the Internet Archive. I'll take a look more closely later, but it looks like they tested prolactin response in migraine after separate tests of reserpine, fenfluramine, benserazide, and sulpiride.

Ok, this one, Polleri et al. 1982, is pretty interesting as well, as it showed increased prolactin response to sulpiride in migraine (both men and women separately), thus showing the same effect as the 1986 Murialdo study. (Three of the authors are the same.)

Recall that in Murialdo 1986, women with menstrual and women with non-menstrual migraine showed increased prolactin response to sulpiride, but only during follicular, not luteal phase.

------

Some more details about Polleri 1982:

This study separately tested several forms of headache, but neuroendocrine challenge tests were only done in migraine.

Reserpine: Men with migraines had delayed return of prolactin to baseline compared to healthy men. No difference for women.


Fenfluramine: There was little difference between migraine and healthy for prolactin response.


Benserazide: Women had delayed return of prolactin to baseline compared to healthy women. No difference for men.


Sulpiride: Increased prolactin response in both migrainous men and women (5 men with migraine, 5 healthy men, 6 women with migraine, and 5 healthy women).


From discussion:

differences observed indicate that they are most striking when the DA [dopamine]-dependent direct regulation at the pituitary level is challenged, as in the case of benserazide and sulpiride. To assess the relevance of the reported data, it may be useful to recall that neither drug crosses the blood-brain barrier.

The PRL [prolactin] increase due to the reserpine-induced DA depletion is a central and a peripheral effect as well, whereas the stimulatory effect of 5-HT due to fenfluramine occurs via hypothalamic serotonergic synapses.

An antagonism between estrogen and DA has been demonstrated at this site [pituitary gland], which explains the sex-dependent differences in PRL response.

-------

So one of my top picks currently for what to test in ME/CFS is the prolactin response to sulpiride.

 

[forestglip]

Ok, my vague understanding from the bits I've picked up so far is that serotonin can increase prolactin, but it is through signalling to the hypothalamus, and then the hypothalamus can tell the pituitary to release more prolactin either by releasing more thyrotropin-releasing hormone or less dopamine. But I don't think there is any direct action of serotonin on the pituitary gland.

So...if this is right, the debate about whether serotonin or dopamine is more involved in the abnormal prolactin response from buspirone, based on whether serotonin agonists cause the effect, or serotonin antagonists block the effect, seems to make little sense.

Hypothetically, if dopamine receptors are hypersensitive in ME/CFS, for example, and a patient takes buspirone: buspirone will increase serotonin signalling, which will decrease dopamine signalling, which will increase prolactin more than normal because of the sensitive dopamine receptors. Or buspirone will antagonize dopamine receptors directly, and thus increase prolactin more than normal.

Same thing if taking a selective serotonin agonist. Dopamine is a step in the prolactin-releasing process, so it could still show increased response even if the problem is only dopamine receptors.

I don't even know see how it'd be possible to directly test for a role of serotonin in a disease using a prolactin challenge, if dopamine is a main step in the chain to releasing prolactin.

On the other hand, the dopamine antagonists skip the serotonin step entirely, so if they show an increased response (as for sulpiride in migraine), then it would seem to suggest that the problem is not necessarily serotonin-mediated.

Please correct me if I'm wrong about the basic biology.

 

[ScoutB]

So one of my top picks currently for what to test in ME/CFS is the prolactin response to sulpiride.

A D2-antagonist that doesn't cross the bbb sounds promising. I'm curious how sulpiride is thought to help schizophrenia and depression in this case. Google is saying that a little crosses via an active transporter, so I guess it works at high enough doses. Sounds like maybe a recipe for hyperprolactinemia ..


What you've written on serotonin is my vague understanding of things as well.

I don't even know see how it'd be possible to directly test for a role of serotonin in a disease using a prolactin challenge, if dopamine is a main step in the chain to releasing prolactin.

Yea agreed. Some old papers really seemed to be thinking about it with a very broad black box approach and not really even having a framework to consider that dopamine could be mediating everything. But I need to look over them again when my brain stops being a slug.

I have a similar feeling about how they talk about serotonin and dopamine receptors being 'more sensitive'. Maybe this is a well understood concept and I just need to find it described -- but from the way I've seen it mentioned so far it's not clear to me if they mean something mechanistically specific that they just aren't diving into (e.g. that the receptors literally bind ligands more aggressively, there are more/less of them, they kick off a cascade inside the neuron more easily or something) or if they are leaving it as a black box because it'd require more research to figure out the details, or if they are operating in a framework which isn't as interested in questions like "what does D2 receptors in the pituitary being more sensitive to dopamine antagonists actually mean?"

 

[forestglip]

A D2-antagonist that doesn't cross the bbb sounds promising. I'm curious how sulpiride is thought to help schizophrenia and depression in this case. Google is saying that a little crosses via an active transporter, so I guess it works at high enough doses.

Oh yes, one more quote from that paper says "at the employed doses, benserazide and sulpiride do not cross the blood-brain barrier in sufficient amounts". The dose used was 15 mg/m^2 for sulpiride.

I used a calculator to get around 50 mg for an adult male. A pamphlet says starting dose of 400-800 mg for schizophrenia.

 

[forestglip]

I have a similar feeling about how they talk about serotonin and dopamine receptors being 'more sensitive'. Maybe this is a well understood concept and I just need to find it described -- but from the way I've seen it mentioned so far it's not clear to me if they mean something mechanistically specific that they just aren't diving into (e.g. that the receptors literally bind ligands more aggressively, there are more/less of them, they kick off a cascade inside the neuron more easily or something) or if they are leaving it as a black box because it'd require more research to figure out the details, or if they are operating in a framework which isn't as interested in questions like "what does D2 receptors in the pituitary being more sensitive to dopamine antagonists actually mean?"

I don't know either, but this Wikipedia page talks about dopamine receptor supersensitivity possibly being a consequence of long term D2 antagonist use, with the suggested cause of high sensitivity being greater numbers of D2 receptors or more of the D2 receptors being "active":

Dopamine supersensitivity psychosis

Dopamine supersensitivity psychosis may occur due to upregulation of dopamine D2 receptors. [...] The antagonizing of D2 receptors by antipsychotics may cause neurons to undergo compensatory changes to make up for the loss of activity at D2 receptors. [...] However, this is likely an oversimplification, as—despite differences in sensitivity to dopamine of around 3-fold in people that have taken antipsychotics chronically—there is a disproportionately low increase in the amount of D2 receptors in the brain in these people (around 1.4-fold in the striatum of the brain in people with schizophrenia).[3] Other hypotheses include increases in the "active" D2 receptors (termed D2High) relative to the "inactive" conformation (D2Low).[3]

As Murialdo 1986 said, receptor supersensitivity could be caused by decreased dopamine, so the receptors might not even be the interesting part. Just a consequence.

The postsynaptic receptor supersensitivity in migraine has been interpreted as the consequence of neurotransmitter depletion in the presynaptic neuron ('empty neuron' hypothesis) (6).

The decrease of the available neurotransmitter in the presynaptic neuron may induce a supersensitivity of the postsynaptic receptor. This may be true also for lactotrophic DA receptors, which may be considered postsynaptic.

It might fit nicely with the recent VMAT2 study which suggested some decrease in dopamine signalling in the striatum in long COVID.

 

[Turtle]

@forestglip I admire the work you and others are doing here.

Just a layperson's questions: How would insulin resistance interfere with a buspirone challenge test?
Would taking ropinirol for nerve pain, a dopamine agonist (mostly D3) influence such a test?

 

[forestglip]

Just a layperson's questions: How would insulin resistance interfere with a buspirone challenge test?
Would taking ropinirol for nerve pain, a dopamine agonist (mostly D3) influence such a test?

I'm not sure. Are you suggesting these might have affected the results?

At least for some of the studies, they say the patients didn't take any medications recently. Not sure if that'd be good enough to avoid a medication-induced effect.