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

[forestglip]

In the correspondence discussed above, the authors helpfully linked some other dopamine-specific prolactin tests in migraine:

only two studies suggest DA hypersensitivity (17, 18), whereas the other four (19–22) suggest either normal or reduced DA sensitivity in migraine subjects between attacks.

Spoiler: References

17. Murialdo G, Martignoni E, De Maria A, Bonura ML, Sances G, Bono G, et al. Changes in the dopaminergic control of PRL secretion and in ovarian steroids in migraine. Cephalalgia 1986; 6: 43–9. Crossref. PubMed. Web of Science.

18. Calabresi P, Silvestrini M, Stratta F, Cupini LM, Argiro G, Atzei GP, et al. L-deprenyl test in migraine: neuroendocrinological aspects. Cephalalgia 1993; 13: 406–9. Crossref. PubMed. Web of Science.

19. Nappi G, Savioldi F, Bono G, Martignoni E. Reserpine – headache and PRL release in migraine. Headache,1979; 19: 273–7. Crossref. PubMed. Web of Science.

20. Nattero G, Corno M, Savi L, Isaia GC, Priolo C, Mussetta M. PRL and migraine: effect of L-dopa on plasma PRL levels in migraineurs and normals. Headache 1986; 26: 9–12. Crossref. PubMed. Web of Science.

21. Bussone G, Frediani F, Lamperti E, LaMantia L, Vescovi A, Peccarisi C, et al. Piribedil test in migraine: neuroendocrinological aspects. Headache 1986; 26: 482–5. Crossref. PubMed. Web of Science.

22. Capellan JIL, Dacosta CV, Garcia JMG, Servan PR, Cermeno JCA. Tuberoinfundibular dopaminergic tonus in common migraine. Headache 1990; 30: 282–4. Crossref. PubMed. Web of Science.

I already posted about refs 17 and 19. Taking a look at 18 now.

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L-deprenyl test in migraine: neuroendocrinological aspects (1993, Cephalalgia)
P Calabresi, M Silvestrini, F Stratta, L M Cupini, G Argiro, G P Atzei, G Bernardi

This was a study of prolactin and growth hormone response to L-deprenyl, also known as selegiline. It is an MAO-B inhibitor, so it increases dopamine signalling. It also affects some other chemicals like norepinephrine, though the paper says norepineprhine effects typically occur at higher doses than used here. Some info from Wikipedia:

It is a selective inhibitor of monoamine oxidase B (MAO-B) at lower doses but additionally inhibits monoamine oxidase A (MAO-A) at higher doses. MAO-B inhibition is thought to result in increased levels of dopamine and β-phenethylamine, whereas MAO-A inhibition results in increased levels of serotonin, norepinephrine, and dopamine. Selegiline is also a catecholaminergic activity enhancer (CAE) and enhances the action potential-evoked release of norepinephrine and dopamine. Through its active metabolites levomethamphetamine and levoamphetamine, selegiline acts as a weak norepinephrine and/or dopamine releasing agent.

Cohort
10 females with migraine (5 with and 5 without aura).

10 age and weight matched female healthy controls.

Tested during late follicular phase.

No use of specific anti-migraine drugs for at least 2 months prior, but use of non-steroidal painkillers was not exclusionary.

Test
L-deprenyl (5 mg, orally)

Findings
Baseline levels of prolactin and growth hormone were similar in the two groups.

There was a significantly different prolactin response between groups. In controls, prolactin remained stable up to the end of the test at minute 120, while in migraine patients, prolactin decreased over time.

There was no significant difference in growth hormone response between groups.

Author interpretation
The decrease of prolactin only in migraine patients after administration of a dopamine-enhancing agent may suggest altered sensitivity of dopamine receptors.

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The data are presented as raw prolactin and growth hormone values at each timepoint for each individual:


It's hard to conceptualize those raw numbers, so I plotted them.

Here is prolactin response, with migraine on the right. There appears to be a fairly clear difference in the trends between the groups:

Regarding prolactin:

Finally, the Group x Time interaction was significant (F = 13.8, p < 0.001 with 3 and 54 df). While in controls circulating prolactin remained stable, in migraine patients a significant and gradual decrease was observed after 1-deprenyl administration (Table 2).

No such difference for growth hormone:

* Note that I changed the table's prolactin value for migraine patient 8 at minute 90 from 32 to 3.2, as the former appears to be a typo or scanning error. Using the latter makes the values match the paper's provided mean value.

They note that l-deprenyl would make for a good test because of the lack of side effects:

Finally, the absence of side effects after the administration of this drug, due to the pharmacological selectivity of 1-deprenyl for MAO-B system, permits wide utility of this test.

It's interesting that they chose to use a dose so low that it has no effect on healthy people. I would have been worried it'd be so low it wouldn't affect migraine patients either. Maybe they had seen this effect in migraine patients at this dose previously. Or maybe it is known that a dose only slightly higher causes prolactin release in healthy people.

Edit: This plot that instead shows the change from baseline in prolactin for each individual makes the trends for each group much clearer:

 

[forestglip]

I haven't read this in detail, but I thought it was worth linking on the thread. This is Abdel Bakheit's thesis that includes the same study as the 1992 postviral fatigue syndrome prolactin challenge paper.

Hypothalamic Dysfunction and Neutrotransmitter Abnormalities in the Postviral Fatigue Syndrome (1992)

The final paper only included tables, but the thesis shows the prolactin response to buspirone as plots. Females and males, respectively:



The thesis also includes details about another study about vasopressin in postviral fatigue syndrome, which was published as: Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome 1993, Bakheit, Behan et al

 

[SugarSquared]

In the correspondence discussed above, the authors helpfully linked some other dopamine-specific prolactin tests in migraine:

You’ve been looking a lot at migraine papers (thank you very much!). I’m curious to know if you’ve noticed so far any difference between the different types of migraines, like with or without aura. Are there any consistent patterns so far, and are they shared with ME/CFS?

 

[forestglip]

I’m curious to know if you’ve noticed so far any difference between the different types of migraines, like with or without aura.

Of the ones I've looked at, I think only one suggested an abnormal response in migraine without aura but not migraine with aura.

Differing central amine receptor sensitivity in different migraine subtypes? A neuroendocrine study using buspirone (Cassidy 2003)

MA [migraine with aura] subjects did not differ in their PRL responses to buspirone compared to healthy controls. The MO [migraine without aura] group had a four-fold increase in mean ΔPRL responses compared to healthy controls. Mean ΔPRL was also increased in the CM [chronic/transformed migraine] group compared to controls, but the difference was less exaggerated.

But this one did not see a difference between the subtypes:

L-deprenyl test in migraine: neuroendocrinological aspects (1993, Cephalalgia)

The present study shows that in migraine patients, unlike control subjects, acute 1-deprenyl administration causes a significant reduction of circulating prolactin

Although the small number of our patients does not permit us to draw strong conclusions, no difference was apparent between patients with migraine with aura and those without aura

The following study is just on migraine without aura and found a difference from healthy for buspirone prolactin response:

Central 5-Ht Receptor Hypersensitivity in Migraine Without Aura (Cassidy 2003)

Twelve female subjects fulfilling International Headache Society (IHS) criteria for migraine without aura were evaluated.

serum prolactin was assessed at baseline and every 30 min for 3 h following a single dose of 30 mg oral buspirone

Subjects with migraine had a significantly increased prolactin response to buspirone (delta max) compared to controls (P < 0.001).

Another study just on migraine without aura with a significant difference for mCPP prolactin response:

5-HT1A Receptor hypersensitivity in migraine is suggested by the m-chlorophenylpiperazine test (Leone 1998)

the prolactin (PRL) and cortisol responses to m-chlorophenylpiperazine (mCPP), a selective 5-HT1A,-5-HT2A/C receptor agonist, were monitored in 12 patients suffering from migraine without aura and in 14 matched healthy controls.

Migraine patients had a greater PRL response to mCPP (p = 0.05)

Menstrual and non-menstrual migraine both showed similar differences from healthy controls in this study:

Changes in the Dopaminergic Control of Prolactin Secretion and in Ovarian Steroids in Migraine (Murialdo 1986)

 

[forestglip]

Are there any consistent patterns so far, and are they shared with ME/CFS?

It at least seems like buspirone appears to lead to an exaggerated prolactin increase in both ME/CFS / postviral fatigue syndrome (five studies listed in the previously posted table) and migraine without aura (two studies above). And several other drugs seem to also lead to an abnormal response.

I think of the studies I've looked at that showed a significant difference, most are directionally consistent with dopamine receptor or serotonin receptor hypersensitivity. But as the authors in the correspondence above said, at least one migraine study seems to show the opposite of what would be expected if the mechanism was dopamine receptor hypersensitivity. I haven't read this yet, but it's a test of L-DOPA on prolactin response:

Prolactin and Migraine: Effect of L-Dopa on Plasma Prolactin Levels in Migraineurs and Normals (Nattero 1986)

In migraineurs the inhibition of PRLsecretion was less marked than in normals, with a statistically significant difference at 30 and 60 minutes.This difference might suggest a reduced responsiveness of the pituitary lactotroph cells to the action ofdopaminergic agents.

 

[SugarSquared]

Thanks for the comprehensive responses @forestglip! I’m glad there’s a lot of migraine studies to chew on.

 

[Jonathan Edwards]

I emailed James Baraniuk.

 

[Kitty]

I emailed James Baraniuk.

Thank you!

 

[Hutan]

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.

From a NZ Medsafe (governmentdocument:

Renal Impairment
Buspirone should be used cautiously in patients with renal disease. Since buspirone is excreted by the kidneys the dose should be reduced in patients with renal impairment but administration of buspirone to patients with severe renal impairment cannot be recommended.

Hepatic impairment
Buspirone should be used cautiously, at reduced doses, in patients with impaired hepatic function or may be contraindicated (see section 4.3). Buspirone clearance is reduced in patients with hepatic cirrhosis. In one study, a single 20 mg oral dose led to 16 fold and 13 fold increases in mean peak buspirone blood levels and mean peak AUC respectively in cirrhotic patients compared to normal volunteers. Administration of buspirone to patients with severe hepatic impairment is not recommended.

I have some catching up to do with this interesting thread. But I want to flag one thought before I forget it. Look at the warning in the NZ Medsafe document - cirrhotic patients had 16 fold increases in mean peak buspirone blood levels!

A lot is made of how people with ME/CFS are more sensitive to drugs. I'm not sure I believe it, but it's said enough that perhaps there is some truth in it. There has been talk about low blood volume and people feeling better immediately after IV saline.

In migraine, dehydration is one trigger. IBS too could be a reason for low blood volume.


Could it be that the reported effect on prolactin is largely the result of inefficient clearance of the buspirone and/or higher concentrations due to low blood volume, resulting in a higher and longer effective dose?

If a study can be arranged, I think some thought might need to be given to ruling those possibilities out e.g. checking for kidney and liver function, checking for dehydration markers

 

[Jonathan Edwards]

I think a volume effect ect would be unlikely as an explanation of the time course. And I doubt volume is low enough in MECFS to make a big difference. But further analysis is clearly worth while.

 

[forestglip]

I've been reading the 1996 thesis that also reported increased prolactin response to buspirone. The author is Tahir Majid. The supervisor is Peter Behan, who was an author on the 1992 postviral fatigue syndrome prolactin paper.

Neuroendocrine Alterations in Chronic Fatigue Syndrome (Majid, 1996, Thesis)

Recall that there was a comment on Behan's 1992 paper pointing out that the abnormal prolactin response to buspirone in postviral fatigue syndrome may be dopamine mediated, as opposed to the author's claim about the abnormal response being serotonin-mediated. This thesis seems to partly be an attempt to resolve this question.

Majid performed multiple neuroendocrine challenges to assess different neurotransmitter systems. I was mainly interested in the serotonin and dopamine-related portions, and did not focus much on the other parts, such as those relating to norepinephrine or GABA.

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Study 1 was a test of 60 mg oral buspirone on prolactin response, to test serotonin function. The cohort included 15 male and 15 female ME/CFS patients based on Fukuda criteria, with depression excluded. There were also 30 age and sex matched healthy controls. Females were tested in the early follicular phase.

[p. 143] In the first study we extended the original work of Bakheit et al (1992) on buspirone induced prolactin (PRL) release.

[p. 92] The first study was designed to test the hypothesis that serotonergic neurotransmission is enhanced in CFS (Bakheit et al 1992). Hormonal responses to 5-HT1A agonist buspirone were examined in CFS, compared to a healthy control group.

There was a significant difference between groups for prolactin response. Here is delta prolactin, which is the difference between maximum prolactin and baseline prolactin for each individual:

[p. 114] [delta] Prolactin levels differed significantly between patients with chronic fatigue syndrome and controls (unpaired ttest: t = 2.7, d .f= 58, P < .009)

Also tested using two way ANOVA:

[p. 114] Using a repeated measures two-way ANOVA to compare responses over time between CFS and controls yields a significant group x time interaction (F = 3.59; d.f = 4 , 295; P = .007). Tukey comparisons reveal differences (P < 0.05) between the groups at +60, and +120 minutes (see fig. 4.1.2).

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Study 6 was a test of 2 mg oral bromocriptine on growth hormone response as a test of dopamine function. It included 6 males and 6 females with ME/CFS fulfilling Fukuda criteria. The controls were sex matched healthy volunteers. Females were tested in the first 10 days of their menstrual cycle.

[p. 92] Finally, dopaminergic and GABAergic function was examined by measuring growth hormone responses to the dopamine agonist bromocriptine and the GABA (B) agonist baclofen respectively, in patients with CFS compared with healthy controls.

The thesis says bromocriptine is a D2 agonist and D1 antagonist:

[p. 135] Bromocriptine is an ergot derivative, stimulates D2 receptors and antagonises D1 receptors. It is used in the treatment of Parkinson's disease, acromegaly and hyperprolactinemia.

The difference between groups was not significant:

[p. 135] In fact, two-way ANOVA with repeated measures disclosed no signficant differences between the two groups [F = 0.080, NS] and no significant group x time interaction (F = 0.308, NS) but it showed a significant effect for time (F = 12.44, P = .0001). Tukey's post-hoc analysis indicates that responses at +60, +120, +180 and +240 minutes are not different in both groups (see fig. 4.6.1).

No significant difference in mean [delta] growth hormone (Peak GH after bromocriptine baseline GH) is seen in CFS (8.93 + 1.32 mU/L) compared with the control group (8.53 + 1.95 mU/L) [unpaired t-test: t = 0.1, d.f = 22, P = 0.86] (see Figure 4.6.2).

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My commentary: it is not at all clear to me why they tested dopamine function using a bromocriptine challenge for growth hormone response, rather than using bromocriptine or another dopamine agent to test prolactin response instead.

Imagine you want to test dopamine function using a neuroendocrine challenge. You have two options: growth hormone or prolactin. Based on the author's own words, here is the involvement of dopamine with each of these:

Majid points out that dopamine inhibits both prolactin and, "under certain conditions", growth hormone:

[p. 59] The principal inhibitor of PRL secretion, dopamine, also inhibits TSH, gonadotropin and, under certain conditions, GH secretion.

He provides a table of anterior pituitary hormones and their regulators. Notice that for growth hormone, dopamine is not even listed, presumably because it plays a smaller role compared to the other hormones. While for prolactin, dopamine is the only regulator listed (prolactin-inhibiting hormone is another name for dopamine).


The details of how dopamine regulates growth hormone appear to be rather murky and indirect. It is stated that (probably) dopamine stimulates somatostatin neurons which then inhibit growth hormone release from the pituitary. And that a dopamine precursor, l-DOPA, has been seen to stimulate growth hormone. So dopamine may both stimulate GH through increasing secretion of growth hormone-releasing hormone, or inhibit GH through somatostatin. Neither of which is dopamine directly affecting the pituitary gland.

[p. 65] Dopamine agonists stimulate GH secretion in normal subjects by stimulating dopamine receptors.

[p. 67] There is substantial evidence that neurosecretary SS [somatostatin] neurons in the hypothalamus receive a catecholaminergic (probably dopaminergic) input (Arimura and Fishback 1981). Thus intraventricular dopamine stimulates SS secretion and inhibits the release of GH. However, circulating GH levels were increased following peripheral adminstration of L-DOPA or dopaminergic agonists. This paradoxical effect suggests that both SS and GHRH may be regulated by dopaminergic stimuli, and that the effects of dopaminergic agents on pituitary GH secretion may reflect a delicate balance between the effects of the release o f these two regulatory factors.

[p. 161] There is considerable evidence that dopamine is an important modulator of growth hormone release in man (Camanni et al 1977). Apomorphine and bromocriptine and potent GH secretogue (Wass 1983), and both enhance GHRH induced GH release (Delitala et al 1987), probably by inhibiting the release of endogenous somatostatin from the median eminence (Vance et al 1987). Others have suggested an inhibitory effect of DA on growth hormone release (Arce et al 1991) probably by decreasing noradrenergic mediated GH (Kuchel et al 1987). Therefore exact mechanism (s) of action for dopaminergic agents in stimulating the release of growth hormone in man are not entirely clear and requires further investigations.

On the other hand, dopamine is known to be the main regulator of prolactin directly through binding to the pituitary:

[p. 68] Its secretion is regulated by the hypothalamic prolactin-inhibiting hormone dopamine and by various prolactin releasing factors as shown in Figure 2.8. Prolactin is unique among the anterior pituitary hormones in that it is under tonic hypothalamic inhibition by dopamine produced by tuberoinfiindibular dopamine neurons. Dopamine acts by stimulating the lactotroph D2 receptors to inhibit adenylate cyclase and consequently inhibits both prolactin release and prolactin synthesis.

[p. 143] In general prolactin secretion from the anterior pituitary is likely to be mediated by many different pathways but is primarily under tonic dopaminergic (DA) inhibitory control (Kato et al 1985).

Figure 2.8 even includes the dopamine agonist they used for the growth hormone test in the chart of prolactin regulation, showing it inhibiting prolactin by binding to the pituitary:


And in the description of bromocriptine, it says that it is used clinically to lower prolactin:

[p. 99] It is used in the treatment of Parkinson's disease, acromegaly and hyperprolactinemia.

He did write that the plan was to use challenge tests that stimulate, not inhibit, all of the hormones of interest, in which case bromocriptine could not be used for a prolactin challenge, as it would inhibit prolactin.

[page 90] For the studies in this thesis we utilised stimulatory tests that were designed to increase the endogenous trophic factors in the hypothalamus through central neurotransmitter activation and to measure specific aspects of pituitary reserve.

But others have done prolactin tests with selective dopamine antagonists, so I would think that it would have been feasible to select a dopamine antagonist such as sulpiride for this study.

It seems to me that a dopamine agent would be much less likely to demonstrate a dopamine abnormality through GH secretion than through prolactin secretion, because of the indirectness of dopamine-GH regulation. I'm not positive of this, but I would think that adding involvement of another organ (hypothalamus) and other hormones (growth hormone-releasing hormone and somatostatin) along the pathway to regulation of a hormone would add more noise and more opportunity for the body to attenuate any differences related to dopamine.

Also, if the abnormality seen due to buspirone administration is based on prolactin secretion, why not continue testing prolactin? Why test dopamine function using a different hormone? Maybe the abnormality is relatively specific to prolactin regulation.

------

With regard to the author's interpretation: Majid finds it unlikely that abnormal prolactin increase from buspirone was dopamine-mediated, because of the null GH finding, and thus they think there is an abnormality in the serotonin system:

[page 145] If this increase in prolactin release [due to buspirone] is mediated through DA receptors it can be hypothesised that dopaminergic inhibitory tone on anterior pituitary lactotrophs for the release of prolactin is higher in patients with CFS compared with controls. This postulated altered DA neurotransmitter function in CFS was further tested by giving the patients dopamine agonist - bromocriptine and measuring growth hormone release, no difference was found between patients and controls. It is therefore unlikely that the increase in prolactin release in response to buspirone in patients with CFS is through dopaminergic receptors.

[p. 146] Finally, it is concluded that prolactin release in response to buspirone is mediated through 5-HT1a receptors in the hypothalamus and an augmented response suggest upregulation/increased sensitivity of central 5-hydroxytryptamine receptors in CFS.

[p. 161] We studied the post-synaptic DA receptor by means of a neuroendocrine strategy by quantitatively examining a DA mediated post-synaptic function. We have done this by determining the GH responses to a standardised dose of the DA agonist bromocriptine which acts both centrally and peripherally. We found no differences between patients with CFS and healthy controls. [...] On the basis of this, we concluded that buspirone-induced enhanced prolactin release as previously reported is mediated through serotonergic transmission rather than dopamine mediated.

[p. 161] To summarise, we found that plasma GH responses to bromocriptine challenge were normal and hence DA neurotransmitter function in patients with CFS is unaffected.

For the reason I gave previously about indirectness of regulation, I don't think the null bromocriptine-GH finding provides strong evidence dopamine is not involved in ME/CFS. I wonder if Majid would have same interpretation, except with regard to serotonin not playing a role, after seeing the 1996 paper from Sharpe finding that ME/CFS patients had an abnormal prolactin response but a not-significantly different growth hormone response after a buspirone challenge.

From Sharpe et al. 1996:

Animal experimental studies suggest that both prolactin and growth hormone release can be produced by activation of 5-HT1A receptors in the hypothalamus (Willoughby et al., 1987, 1988). If CFS is associated with an increase in the sensitivity of hypothalamic brain 5-HT1A receptors, we would therefore expect that both growth hormone and prolactin responses to buspirone should be greater in CFS patients than controls.

While buspirone-induced prolactin release appears to be increased in patients with CFS, our findings question whether this reflects an increase in hypothalamic 5-HT1A receptor sensitivity because the growth hormone responses to buspirone were not significantly raised.

Also, another study (study 2) from this same thesis, where ipsiparone, a selective serotonin agonist, produced less of an increase in ACTH in ME/CFS, seems to complicate the upregulated/hypersensitive serotonin receptor hypothesis suggested by the buspirone-prolactin study. Majid said the ACTH finding may suggest less sensitive serotonin receptors, and there is an ambiguous suggestion that there may be "differences" in 5HT1A responses.

[p. 148] Ipsapirone is a selective 5HT1A agonist and has been shown to produce a dose dependent increase in ACTH and cortisol which is blocked by 5HT1 antagonists (Lesch et al 1990 and Koenig et al 1988).

[p. 148] Blunted release of ACTH in response to ipsapirone challenge was demonstrated. [...] The abnormality may be attributed to a number of possible factors: 1. decreased responsivity of 5HT1A receptors at a hypothalamic level. 2. decreased responsivity of CRH receptors on the anterior pituitaty corticotrophs. 3. underactivity of anterior pituitary corticotrophs leading to decreased production and release of ACTH.

[p. 149] This might indicate that 5HT1A responses show anatomic differences with some responses enhanced and other attenuated in CFS. It is however possible that the differences may be due to differing drug selectivity.

He does say that the blunted ACTH response could be attributed to factors other than abnormal serotonin receptors. But then so could increased prolactin response to buspirone. Apart from increased responsivity of serotonin receptors, it could involve D2 receptors on lactotrophs (pituitary cells which release prolactin), or it could involve overactivity of lactotrophs, if using an analogous factor to that provided for ipsiparone and ACTH.

Therefore, I think the paper's final conclusion is stated too confidently:

[p. 164] In summary, in CFS, 5-HT receptors are upregulated and 5-HT function is increased. [...] Dopamine (DA) and GABA neurotransmitter systems are not involved in the pathophysiology of chronic fatigue syndrome.

 

[ScoutB]

Thanks for going through that so thoroughly forestglip. It is really frustrating that they had a possible lead here and the whole investigation of it seems to have been distorted and then forgotten.

Also, if the abnormality seen due to buspirone administration is based on prolactin secretion, why not continue testing prolactin? Why test dopamine function using a different hormone? Maybe the abnormality is relatively specific to prolactin regulation.

Agreed. And this is the sort of thing where I get the feeling (some of) these researchers might be misleading themselves a bit and taking receptor sensitivity very literally. It feels like because they only had a simple measurement tool that tests the sensitivity of all 5-HT/D2 receptors in the brain at once (not exactly correct but that's how they seemed to be thinking of it), the underlying problems they were envisioning were of the form "all 5-HT/D2 receptors in the brain are too sensitive or not sensitive enough."

 

[neophyte32]

A personal story—heads up.
I think my ME/CFS was triggered by low-dose Tramadol, which affects neurotransmitters. I took it in small doses for three years. I never needed to increase the dosage—my addiction specialist was actually very surprised by that.

Mixing alcohol and Tramadol triggered a very mild onset of the illness in January 2022. Then, a year later—when I was in remission and living normally—I started taking Tramadol again after another three-month withdrawal period (I’ve gone through about six cold-turkey withdrawals lasting a few months each over the past four years). I had a panic attack (I had taken cocaine a few days prior—a one-off thing, please don't judge me).

After that, my MECFS was mild, I was put on antidepressants, but they made my condition worse... so much so that after two weeks on paroxetine in June 2024, I developed postural tachycardia with orthostatic intolerance. I tried an antidepressant again in March 2025 and my condition instantly became very severe.

Low-dose abilify (LDA), on the other hand, improves my ME/CFS; it modulates my dopamine levels and reduces my postural tachycardia. However, the effect doesn't last long—only a few months.

In short, that’s the experience of a severe ME/CFS patient regarding neurotransmitter-related medications. Even before the onset of ME/CFS, I was extremely sensitive to Tramadol. Small doses were enough to keep me high for 12 hours... my addiction specialist had never seen anything like it.

 

[Axel]

these researchers might be misleading themselves a bit and taking receptor sensitivity very literally. It feels like because they only had a simple measurement tool that tests the sensitivity of all 5-HT/D2 receptors in the brain at once... the underlying problems they were envisioning were of the form "all 5-HT/D2 receptors in the brain are too sensitive or not sensitive enough."

But even then, I think they’d need to test 5-HT separately as well to demonstrate it.