TRH and Rifaximin – an alternative to intranasal TRH or oral Taltirelin/Ceredist?

I think this is going to be one of my smarter posts. It may be more for our doctor readers and our motivated home-based researchers. It does remain a hypothesis and while it looks plausible it is certainly not 100% proven – so typical Peter stuff.

Many parents with autism regularly treat their child with the antibiotic Rifaximin. This drug is also the go-to therapy for SIBO (small intestine bacterial overgrowth) and is a key part of the Nemechek autism protocol to increase butyric acid production in the gut (and reduce propionic acid).

Some parents report that their child with completely normal GI function responds well behaviorally to Rifaximin.

Rifaximin is taken orally and stays in the gut, it does not enter the blood stream.

Our long-time reader Maja mentioned that she still uses Rifaximin in her now adult daughter.

I then did a quick Google and was surprised to see Rifaximin linked to the hormone TRH.

And, most surprising, you can use Rifaximin to treat prostate inflammation, via its effect on TRH.

TRH was the subject of an experiment I did 12 years ago. I suggested that an existing Japanese drug, an orally available TRH super-agonist, could be repurposed at a low dose to treat autism.

 https://www.epiphanyasd.com/2014/05/the-peter-hypothesis-of-trh-induced.html

I then noted that a well-known, but a little controversial, doctor in the US used intranasal TRH to treat his patients with chronic fatigue syndrome.

Another doctor had grant funding from the US military to develop intranasal TRH to reduce suicides in veterans.

In my old post I started by wondering why my son and some others with severe autism respond so well to sensory stimulation like standing on the upper deck of a ferry boat in the open sea on a windy day, or sitting in an open-top bus, driving in a convertible car etc.

Without be able to do any testing I looked for “similar” situations that haven been studied. The closest I found was people jumping out of a plan (with a parachute) where one of the key changes was a surge in the level of the hormone prolactin.

How to replicate the open-top bus effect? One of my doctor relatives suggested sitting Monty in front of a fan. Over course I wanted better than that. I found that stimulating TRH receptors in the brain would release prolactin.  It was already known that TRH is disturbed in autism.

It seemed to me that a Japanese orphan drug developed to treat spinocerebellar degeneration (SCD) – a group of progressive neurodegenerative disorders characterized by ataxia (poor coordination, gait disturbance, speech difficulties) could be repurposed.

I did discuss with a Japanese doctor in Osaka and he prescribed it.

It is a very expensive drug, even when bought with a prescription, and it has a very short expiry date. The idea was to use a micro-dose, to avoid undesirable side effects and this would also make the price less scary. I thought it provided a benefit without side effects, but was impractical. At the full dose it is potent and is the only drug I have trialed that had a near immediate profound effect on myself. I suddenly had hyper-acute vision. The micro dose had no effect on me.

Since Ceredist (taltirelin) is a TRH analogue, it could in theory affect the hypothalamic–pituitary–thyroid (HPT) axis.

TRH normally stimulates TSH release from the pituitary, which then increases thyroid hormone (T4/T3) secretion. Taltirelin was designed for CNS activity rather than endocrine use. Its clinical development in Japan for spinocerebellar degeneration focused on neurological symptoms, not thyroid stimulation. Animal studies showed that taltirelin has much weaker TSH-releasing activity than native TRH, but much stronger central nervous system stimulant effects (improved motor coordination, wakefulness).

Human data at therapeutic doses for spinocerebellar degeneration, significant changes in thyroid hormone levels (TSH, T3, T4) have not been a common clinical issue. Monitoring thyroid function is not part of standard Ceredist treatment.

 

So what is TRH?

TRH (thyrotropin-releasing hormone) serves as a master regulator of energy metabolism, mood, arousal, cognition, and immune balance.

Core Endocrine Role

Produced in the hypothalamus (paraventricular nucleus), but also found in other brain regions and peripheral tissues.

Main function is to stimulate the anterior pituitary to release TSH (thyroid-stimulating hormone), this increases thyroid hormone (T3, T4) production in the thyroid gland.

A secondary effect promotes prolactin release from the pituitary. TRH is a significant stimulator, especially when dopamine inhibition is reduced.

 

Effects on Other Hormones

Growth hormone & insulin: Some modulatory effects reported in stress and metabolism, though less central.

ACTH/cortisol: Minor indirect effects; TRH can modulate stress responses via cross-talk with the HPA axis.

 

Mood and Behavior

Antidepressant effects - TRH has rapid mood-elevating and activating effects in both animals and humans, independent of thyroid hormones. Some clinical studies have tested TRH or TRH analogs as rapid-acting antidepressants.

Arousal & vigilance - it increases wakefulness, motivation, and locomotor activity.

Anxiety - can produce mild anxiogenic effects at high doses, but generally associated with improved mood and alertness.

 

Cognition

Neurotransmitter modulation - TRH interacts with cholinergic, dopaminergic, and glutamatergic systems.

Memory & learning - TRH and TRH-like peptides enhance memory consolidation and counteract cognitive decline in animal studies.

Neuroprotection - shown to reduce neuronal injury in models of ischemia and trauma.

 

Inflammation & Immunity

 Anti-inflammatory - TRH dampens pro-inflammatory cytokine production (e.g., TNF-α, IL-1β).

Microglia modulation - TRH reduces microglial over-activation, relevant in neuroinflammation.

Systemic effects: TRH analogs show protective roles in sepsis and multiple organ injury in animal studies, likely via immune regulation and mitochondrial support.

 

Here is the recent study that showed the common antibiotic Rifaximin increases TRH in the brain and in peripheral tissues. Rifaximin itself stays within the gut when taken by mouth, it does not enter the blood stream. It changes the gut microbiota which then sends a signal via vagus nerve to the brain (clever, isn’t it?).

Caveat – rats are not humans.

 

Rifaximin modulates TRH and TRH-like peptide expression throughout the brain and peripheral tissues of male rats

 

The TRH/TRH-R1 receptor signaling pathway within the neurons of the dorsal vagal complex is an important mediator of the brain-gut axis. Mental health and protection from a variety of neuropathologies, such as autism, Attention Deficit Hyperactivity Disorder, Alzheimer’s and Parkinson’s disease, major depression, migraine and epilepsy are influenced by the gut microbiome and is mediated by the vagus nerve. The antibiotic rifaximin (RF) does not cross the gut-blood barrier. It changes the composition of the gut microbiome resulting in therapeutic benefits for traveler’s diarrhea, hepatic encephalopathy, and prostatitis. TRH and TRH-like peptides, with the structure pGlu-X-Pro-NH₂, where “X” can be any amino acid residue, have reproduction-enhancing, caloric-restriction-like, anti-aging, pancreatic-β cell-, cardiovascular-, and neuroprotective effects. TRH and TRH-like peptides occur not only throughout the CNS but also in peripheral tissues. To elucidate the involvement of TRH-like peptides in brain-gut-reproductive system interactions 16 male Sprague–Dawley rats, 203 ± 6 g, were divided into 4 groups (n = 4/group): the control (CON) group remained on ad libitum Purina rodent chow and water for 10 days until decapitation, acute (AC) group receiving 150 mg RF/kg powdered rodent chow for 24 h providing 150 mg RF/kg body weight for 200 g rats, chronic (CHR) animals receiving RF for 10 days; withdrawal (WD) rats receiving RF for 8 days and then normal chow for 2 days.

Results

Significant changes in the levels of TRH and TRH-like peptides occurred throughout the brain and peripheral tissues in response to RF. The number of significant changes in TRH and TRH-like peptide levels in brain resulting from RF treatment, in descending order were: medulla (16), piriform cortex (8), nucleus accumbens (7), frontal cortex (5), striatum (3), amygdala (3), entorhinal cortex (3), anterior (2), and posterior cingulate (2), hippocampus (1), hypothalamus (0) and cerebellum (0). The corresponding ranking for peripheral tissues were: prostate (6), adrenals (4), pancreas (3), liver (2), testis (1), heart (0).

Conclusions

The sensitivity of TRH and TRH-like peptide expression to RF treatment, particularly in the medulla oblongata and prostate, is consistent with the participation of these peptides in the therapeutic effects of RF. 

 

It turns out that other researchers have looked at Rifaximin’s effects on the brain, but they never understood the mechanism.

 

Effects of Rifaximin on Central Responses to Social Stress—a Pilot Experiment

Probiotics that promote the gut microbiota have been reported to reduce stress responses, and improve memory and mood. Whether and how antibiotics that eliminate or inhibit pathogenic and commensal gut bacteria also affect central nervous system functions in humans is so far unknown. In a double-blinded randomized study, 16 healthy volunteers (27.00 ± 1.60 years; 9 males) received either rifaximin (600 mg/day) (a poorly absorbable antibiotic) or placebo for 7 days. Before and after the drug intervention, brain activities during rest and during a social stressor inducing feelings of exclusion (Cyberball game) were measured using magnetoencephalography. Social exclusion significantly affected (p < 0.001) mood and increased exclusion perception. Magnetoencephalography showed brain regions with higher activations during exclusion as compared to inclusion, in different frequency bands. Seven days of rifaximin increased prefrontal and right cingulate alpha power during resting state. Low beta power showed an interaction of intervention (rifaximin, placebo) × condition (inclusion, exclusion) during the Cyberball game in the bilateral prefrontal and left anterior cingulate cortex. Only in the rifaximin group, a decrease (p = 0.004) in power was seen comparing exclusion to inclusion; the reduced beta-1 power was negatively correlated with a change in the subjective exclusion perception score. Social stress affecting brain functioning in a specific manner is modulated by rifaximin. Contrary to our hypothesis that antibiotics have advert effects on mood, the antibiotic exhibited stress-reducing effects similar to reported effects of probiotic

 

Effects of the antibiotic rifaximin on cortical functional connectivity are mediated through insular cortex

It is well-known that antibiotics affect commensal gut bacteria; however, only recently evidence accumulated that gut microbiota (GM) can influence the central nervous system functions. Preclinical animal studies have repeatedly highlighted the effects of antibiotics on brain activity; however, translational studies in humans are still missing. Here, we present a randomized, double-blind, placebo-controlled study investigating the effects of 7 days intake of Rifaximin (non-absorbable antibiotic) on functional brain connectivity (fc) using magnetoencephalography. Sixteen healthy volunteers were tested before and after the treatment, during resting state (rs), and during a social stressor paradigm (Cyberball game—CBG), designed to elicit feelings of exclusion. Results confirm the hypothesis of an involvement of the insular cortex as a common node of different functional networks, thus suggesting its potential role as a central mediator of cortical fc alterations, following modifications of GM. Also, the Rifaximin group displayed lower connectivity in slow and fast beta bands (15 and 25 Hz) during rest, and higher connectivity in theta (7 Hz) during the inclusion condition of the CBG, compared with controls. Altogether these results indicate a modulation of Rifaximin on frequency-specific functional connectivity that could involve cognitive flexibility and memory processing.

  

Probing gut‐brain links in Alzheimer's disease with rifaximin

Gut‐microbiome‐inflammation interactions have been linked to neurodegeneration in Alzheimer's disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut‐specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open‐label trial, we treated 10 subjects with mild to moderate probable AD dementia (Mini‐Mental Status Examination (MMSE) = 17 ± 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament‐light levels (P < .004) and a significant increase in fecal phylum Firmicutes microbiota. Serum phosphorylated tau (pTau)181 and glial fibrillary acidic protein (GFAP) levels were reduced (effect sizes of −0.41 and −0.48, respectively) but did not reach statistical significance. In addition, there was a nonsignificant downward trend in serum cytokine interleukin (IL)‐6 and IL‐13 levels. Cognition was unchanged. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo‐controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.

 

Rifaximin and the prostate

For some reason one of the main areas where Rifaximin triggers the production of TRH is in the prostate, in males. There are studies showing how Rifaximin can be used to treat prostatitis (prostate inflammation).

Symptom Severity Following Rifaximin and the Probiotic VSL#3 in Patients with Chronic Pelvic Pain Syndrome (Due to Inflammatory Prostatitis) Plus Irritable Bowel Syndrome

This study investigated the effects of long-term treatment with rifaximin and the probiotic VSL#3 on uro-genital and gastrointestinal symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) plus diarrhoea-predominant irritable bowel syndrome (D-IBS) compared with patients with D-IBS alone. Eighty-five patients with CP/CPPS (45 with subtype IIIa and 40 with IIIb) plus D-IBS according to the Rome III criteria and an aged-matched control-group of patients with D-IBS alone (n = 75) received rifaximin and VSL#3. The primary endpoints were the response rates of IBS and CP/CPPS symptoms, assessed respectively through Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) and The National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and performed at the start of therapy (V0) and three months after (V3). In IIIa prostatitis patients, the total NIH-CPSI scores significantly (p < 0.05) decreased from a baseline mean value of 21.2 to 14.5 at V3 , as did all subscales, and in the IIIb the total NIH-CPSI score also significantly decreased (from 17.4 to 15.1). Patients with IBS alone showed no significant differences in NIH-CPSI score. At V3, significantly greater improvement in the IBS-SSS and responder rate were found in IIIa patients. Our results were explained through a better individual response at V3 in IIIa prostatitis of urinary and gastrointestinal symptoms, while mean leukocyte counts on expressed prostate secretion (EPS) after prostate massage significantly lowered only in IIIa cases. 

Since SIBO is treated by rifaximin, some researchers linked SIBO with prostatitis: 

Chronic prostatitis and small intestinal bacterial overgrowth: is there a correlation?

Background: Clinical management of chronic inflammation of prostate and seminal vesicles is very complex. Among the causes of recurrent chronic prostatitis (CP), a possible malabsorption, such as lactose intolerance, in turn related to small intestinal bacterial overgrowth (SIBO), should be considered.

Methods: We have performed lactose and lactulose breath test (BT) in 42 patients with CP, in order to evaluate the prevalence of SIBO in this kind of patients and the concordance of the two tests.

Results: A positive lactulose BT was present in 33/42 patients and in 73% (24/33) was associated to lactose malabsorption. Five patients had positive response after lactulose, while only 4 had both negative tests.

Conclusions: Our data showed an association between lactose and lactulose BT positivity. They also indicated high prevalence of bacterial colonization of small bowel in patients with CP, possibly related to recurrence or chronicity of genitourinary tract inflammation. The research for these phenomena could be relevant in diagnostic route of infertile patients in whom slight gastro-enteric symptoms can be underestimated.

 

For those of you who still read books:

 

Betrayal by the Brain: The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders
This seminal work presents Dr. Goldstein's theory that CFS and fibromyalgia result from dysfunctions in neural networks. It integrates neuroscience research into the pathophysiology and treatment of these conditions.

A Companion Volume to Dr. Jay A. Goldstein's Betrayal by the Brain: A Guide for Patients and Their Physicians
Authored by Katie Courmel, this companion guide simplifies Dr. Goldstein's theories and treatment protocols for a broader audience, aiding patients and physicians in understanding and applying his methods.

 Tuning the Brain: Principles and Practice of Neurosomatic Medicine

In this book, Dr. Goldstein outlines the principles of neurosomatic medicine, a field he developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses.

In Tuning the Brain: Principles and Practice of Neurosomatic Medicine, Dr. Jay A. Goldstein discusses the use of thyrotropin-releasing hormone (TRH) in treating chronic fatigue syndrome (CFS) and related disorders. He describes TRH as a neuropeptide that can modulate neural network activity, particularly through the trigeminal nerve, which is involved in sensory processing. By stimulating this pathway, TRH may help "re-tune" the brain's response to sensory input, potentially alleviating symptoms associated with CFS and similar conditions.

The book outlines the principles of neurosomatic medicine, a field Dr. Goldstein developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses. It emphasizes the rapid modulation of neural networks through pharmacological means, aiming to restore normal sensory processing and alleviate symptoms.

 

Conclusion

It does look like Rifaximin has interesting effects beyond where it can reach itself.

Rifaximin → modifies gut microbiota → activates vagus nerve

Vagus nerve → signals to brainstem → hypothalamus → TRH release 

According to that rat study, TRH and TRH-like peptides are present in the prostate, and their levels change in response to rifaximin. The TRH (or TRH-like peptides) in the prostate is produced locally in the prostate tissue itself, not delivered there from the brain via the bloodstream. the level of production can be modulated by gut–brain signaling, such as after rifaximin treatment.

I have to say that this reminds me of using L-Reuteri probiotic bacteria to send a signal via the same vagus nerve to release oxytocin in the brain. Seems a better approach than intranasal oxytocin.

I think the study showing Rifaximin improves the response to social stress fits with Dr Goldstein’s use of intranasal TRH to “retune” the brain in the conditions he studied and the potential use to reduce suicide initiations. It is enough for me to see TRH as a possible common factor.

I think Goldstein and the US DoD scientists should have used the TRH super-agonist Taltirelin/Ceredist. It is 30x more potent and yet does not affect thyroid function. It also has a far longer half-life. The other alternative, we now see, would have been to use Rifaximin.

Goldstein has passed away and the US DoD gave upon TRH. Research indicates that intranasal esketamine can rapidly reduce suicidal thoughts. Esketamine was FDA approved in 2019.

Taltirelin was approved for use in humans in Japan in 2000 for spinocerebellar degeneration (SCD).

Note that spinocerebellar degeneration (SCD) has no drug therapy in the US/Europe, even though one has existed in Japan for 25 years. Looks pretty odd to me. In a perfect world low dose Taltirelin could be a useful add-on therapy for many neurological conditions and potentially even for prostatitis! Don’t hold your breath.

Taltirelin is now being researched in animal models of Parkinson’s and fatigue syndromes.

Unless you live in Japan and have a pal who is a doctor, I think autism parents are best off with Rifaximin.

As Maja just pointed out “Rifaximin is still very helpful. I repeat a ten-day course (2x400 mg) every two to three months”, in her adult daughter. We can never know for sure if increased TRH is mechanism, or reduced SIBO, or increased butyric acid, or something else. If it works, stay with it!