Connective Tissue Disorders/Ehler Danlos, the ECM and Chronic Issues - MCAS, CIRS, POTS, CFS, IBS, Dystonias, Pain, Proprioceptive Disorders, ETC.!

[Persej]

I have been feeling moody like I have pms for weeks, melancholy, annoyed at things my partner does that aren’t even annoying worthy (poor dude) . The only thing that’s changed for me is the introduction of PEA.
So I’m going to stop the PEA which has done nothing notable in the 3 weeks I’ve been trying it- except may be making me a pseudo-premenstrual misery machine the whole time.

I’ll report back in after I actually enter then finish the luteal phase in a few weeks

It has been shown in experiments that high dose of Allopregnanolone can have opposite effects of low dose. Perhaps you have enough of it and you don't need more. Here you can see the graph of Allopregnanolone during the menstrual cycle:

Trajectories of Allopregnanolone and Allopregnanolone to Progesterone Ratio across the Six Subphases of Menstrual Cycle - PMC

Background: Allopregnanolone is one of the most studied neuroactive steroids; yet, despite its relevance to neuropsychiatric research, it is not known how it, as well as its ratio to progesterone, varies across all six subphases of the menstrual ...

pmc.ncbi.nlm.nih.gov

If you cannot tolerate PEA at all perhaps you can try Oleoylethanolamide (OEA) which has many similar effects.

 

[iamthatis]

Interesting @Persej
I have been feeling moody like I have pms for weeks, melancholy, annoyed at things my partner does that aren’t even annoying worthy (poor dude) . The only thing that’s changed for me is the introduction of PEA.
So I look up Allopregnanolone so see if has any adverse affects associated.

Ai says

Allopregnanolone, a neurosteroid derived from progesterone,
paradoxically induces anxiety, irritability, and negative mood at moderate, physiological levels (e.g., during the luteal phase), despite being a
GABAA
receptor sedative. This biphasic, inverted U-shaped effect is most common in individuals with Premenstrual Dysphoric Disorder (PMDD).

Key Aspects of the Allopregnanolone Paradoxical Effect:

• Biphasic Action (U-Shaped Curve): While high concentrations (as in late pregnancy or high-dose therapy) and low concentrations produce calming, anxiolytic, or neutral effects, moderate levels (1.5–2 nmol/L) cause adverse emotional symptoms.
• Mechanism of Action: Allopregnanolone acts as a positive modulator of the
  GABAA
  receptor. In specific individuals, it may act on different receptor subunits
  
  rather than calming, lead to paradoxical effects. It is thought to increase amygdala activity (associated with anxiety) at moderate levels, rather than decreasing it.
• Role in PMDD/PMS: The rise of allopregnanolone during the luteal phase (premenstrual) triggers these paradoxical symptoms, with symptoms, mood, and irritability, declining when allopregnanolone levels fall.
• Treatment Approach: Research suggests that using a
  GABAA
  modulating steroid antagonist, such as isoallopregnanolone (Sepranolone/UC1010), can counteract these effects and reduce negative mood in PMDD.
  ScienceDirect.com +4

Contextual Factors:

• Sensitivity Differences: Only 3–8% of the population experiences severe, and up to 25% experience moderate, negative mood changes, similar to the prevalence of PMDD.
• Neurodivergence: Individuals with ADHD, autism, or a history of mood disorders may be more susceptible to this effect.
• Contextual Stress: Chronic stress may play a role in increasing sensitivity to these paradoxical effects.

It’s me again. So I’m going to stop the PEA which has done nothing notable in the 3 weeks I’ve been trying it- except may be making me a pseudo-premenstrual misery machine the whole time.

I’ll report back in after I actually enter then finish the luteal phase in a few weeks

Another way of looking at it is that PEA is changing your physiology, and providing you with an opportunity to do the emotional work. If PEA is clarifying your system, which it probably is, it would also be improving your neuroception. So it may be that what you're now noticing was already there, just another layer of the onion. Generally this is how healing or deprogramming happens, OSIT - not by 'feeling better', but by increasing self-awareness, noticing our BS more, accepting it, and the lessons involved, and struggling with oneself to make the necessary emotional or mental changes. My two cents.

 

[Persej]

Such regenerative effect of Allo is dose-dependent and exhibits a classic U-shaped dose-response curve indicating that more is not better. Based on that principle high doses of Allo, that induce a sedative response, do not promote neurogenesis. The inverted-U shaped dose response profile of Allo is particularly important from a safety perspective. Greater than normal concentrations of Allo or continuous unrelenting exposure to Allo inhibit neurogenesis thereby protecting against uncontrolled cell proliferation.

Outcomes demonstrated that Allo was safe and well-tolerated after a single IV infusion and after weekly IV infusions for 12 weeks (G. D. Hernandez et al., 2020). A maximally tolerated dose of 6 mg was established using sedation as a threshold which interestingly demonstrated a sex difference in sedation tolerance. Women exhibited signs of sedation at doses ≥10 mg whereas men did at doses ≥ 6 mg. Therefore, to optimally target neurogenesis, the sub-sedative dose of 4 mg was chosen for the treatment regimen.

Allopregnanolone: Regenerative therapeutic to restore neurological health - PMC

Chronic stress has been proposed as a driver of altered brain structure and function, including the pathogenesis of neurodegenerative diseases and a driver of disease progression. A key outcome of stress in the brain is structural remodeling of ...

pmc.ncbi.nlm.nih.gov

Critical to success was a dosing and treatment regimen that was consistent with the temporal requirements of systems biology of regeneration in brain. A treatment regimen that adhered to regenerative requirements of brain was also efficacious in reducing Alzheimer's pathology. With an optimized dosing and treatment regimen, chronic allopregnanolone administration promoted neurogenesis, oligodendrogenesis, reduced neuroinflammation and beta-amyloid burden while increasing markers of white matter generation and cholesterol homeostasis.

(...)

However, the continuous release treatment paradigm was much different pharmacokinetically and pharmacodynamically than the “treat and excrete” approach wherein the neurobiological system is stimulated and then allowed to return to baseline over the period of 1 week or longer duration. (...)

Although the levels of Allo were higher in the single pulse dose experiments, the neurobiological system was able to respond in a proactive manner to induce neurogenesis and learning and memory improvements and return to homeostasis. Comparison of intermittent bolus dosing and continuous release treatment regimens further demonstrate the importance of precise neurosteroid treatment paradigms. (...)

In a series of studies, continuous subcutaneous osmotic pump infusion of Allo proved to be detrimental and decreased learning and memory performance while simultaneously exacerbating AD pathology markers (Bengtsson et al., 2012, 2013). Although not measured, neurogenesis possibly was inhibited in the continuous Allo exposure studies. From these tabulated studies we hypothesized that the dose and frequency of Allo are critical components of efficacy at neurogenic and pathological endpoints.

Allopregnanolone as regenerative therapeutic for Alzheimer’s disease: Translational development and clinical promise - PMC

Herein, we review a translational development plan to advance allopregnanolone to the clinic as a regenerative therapeutic for neurodegenerative diseases, in particular Alzheimer’s. Allopregnanolone, an endogenous neurosteroid that declines with age ...

pmc.ncbi.nlm.nih.gov

Remarkably, intermittent allopregnanolone treatment regimens have shown benefit in multiple preclinical neurodegenerative disease models including Niemann-Pick type C, traumatic brain injury, diabetic neuropathy, peripheral nerve crush injury, multiple sclerosis and Parkinson disease. By contrast, continuous infusion of allopregnanolone for several months is not efficacious and can worsen pathology in a preclinical model of Alzheimer disease (Figure 4). The benefit of intermittent treatment regimens might apply to other regenerative factors where constant infusion for extended duration has met with adverse outcomes.

Neurosteroids as regenerative agents in the brain: therapeutic implications - PMC

Regenerative therapeutics hold the promise of self-renewal and repair. Ageing and age-associated neurodegenerative diseases are marked by a decline in self-renewal and repair, but a capacity for regeneration is retained. The challenge faced by ...

pmc.ncbi.nlm.nih.gov

The long-lasting antidepressant effect observed in clinical trials, which outlasts the pharmacokinetics of the drug exposure, is not easily explained by the known mechanism of action of these compounds. One could envision that allopregnanolone acts on δ subunit-containing GABAARs to shift the network to a healthy network state that is more stable and can persist in the absence of the compound.

Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala - PMC

Brexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive ...

pmc.ncbi.nlm.nih.gov

Something to take into consideration.

 

[Persej]

I was reading this study where they gave people Pregnenolone because you cannot buy Allopregnanolone, and Pregnenolone converts into Allopregnanolone. I checked and you can buy Pregnenolone online.

Allopregnanolone Elevations Following Pregnenolone Administration Are Associated with Enhanced Activation of Emotion Regulation Neurocircuits

These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacologic intervention in the treatment of anxiety disorders and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(12)01093-1/abstract