you seem to know a lot about CRH/CRHR1, can you maybe give me some advice? I happen to have a mutation in my CRHR1 gene no idea what they mean but here they are:
SelfDecode | Genome Analysis
SelfDecode | Genome Analysis
SelfDecode | Genome Analysis
on CRHR1-IT1 it says valproate decreases it but the other two mgc57346-crhr1 and normal CRHR1 it doesent mention that valproate can decrease it how come?
Hi, sorry to disappoint but unfortunately I'm not the Joe from self hacked! Although I do read self hacked quite a bit and think he's got some good information. I think it relies a bit too much on animal studies, but reading some of those studies has helped me work out various underlying mechanisms, which is useful. I'm not in America, but actually in Italy, and half way through a degree in naturopathy - so that is why my focus is on herbs and the environment - either emotional or physical.
I'm not an expert on the CRHR1 receptor, but I'll tell you what I know... and I can't access those links you sent me...feel free to send me them as PDfs if you like.
A gene mutation will mean either more or less of the protein generated than average. In animal models I've read on CRHR1 mutations, they are usually dealing with less - so less receptor density > less CRH activity and less anxiety. In your case, going by your posts, I am assuming that your mutation may be responsible for more protein, meaning greater receptor density, and so greater CRH activity, which could lead to more anxiety.
The research I've read has only been looking at animal models, so it's difficult to make decisions based on this. And it is also worth remembering that all mutations are positive because they survived - even though they might make life uncomfortable when the environment changes. An example: I'm homozygeous COMT, so I tend to have more adrenaline floating around. This helped my ancestors survive, but it's a pain in the ass in today's chronically stressed modern world. The broad takeaway would be that yes - the mutation may make you more sensitive to anxiety, but even though you are predisposed to a higher production, the internal and external environment will likely have a much bigger effect on the expression of the gene. That is why the signals going in are so important.
I'm not sure if valproate would help. It's predominantly a gabanergic agent, so it would surely be anxiolytic - but it wouldn't be getting to the root of the problem. There are also side effects to consider. Some herbs with CRH antagonist activity:
Tulsi (Holy basil / ocimum sanctum): reduced cortisol by reducing CRHR1 receptor density
Anti-stress Activity of Ocimum sanctum: Possible Effects on Hypothalamic-Pituitary-Adrenal Axis. - PubMed - NCBI
Alleviation of Heat Stress by a Polyherbal Formulation, Phytocee™: Impact on Zootechnical Parameters, Cloacal Temperature, and Stress Markers
Xiao Yao San (traditional Chinese liver formula) usually used for liver health, but has also been found to lower CRH. research indicates it acts more on CRHR2, but there is limited research, and I wouldn't be surprised to find out it interacts with CRHR1 as well. Anything helping the liver to work more effectively will reduce inflammatory cytokines and reduce CRH.
Xiao Yao San Improves Depressive-Like Behavior in Rats through Modulation of β-Arrestin 2-Mediated Pathways in Hippocampus
Rhodiola Rosea and Schisandra have a noticable effect on CRH
Schisandra chinensis and Rhodiola rosea exert an anti-stress effect on the HPA axis and reduce hypothalamic c-Fos expression in rats subjected to repeated stress
Withania, as mentioned in the post.
It also depends on what symptoms you have - do you have any histamine - like symptoms? Rashes / reflux / tinnitus / blood pressure drops / tachycardia / insommnia?
As above I would emphasise looking at the input signals - the environment. To find out what is triggering the CRH release. This can be hypoxia, chronic cold exposure, fasting or caloric restriction, anything that increases inflammatory cytokines like IL-1, IL-6, TNF (poor gut health, poor liver health, oxalate issues, bacteria or viral challanges, candida), oxidative stress, histamine issues, and emotional issues. Trauma has been well proven to raise CRH. Trauma also causes muscle tension, which feeds back to the hypothalamus to increase CRH. As well as physical muscle issues like poor posture.
This is where the TRE exercises come is: the tremouring reduces adrenaline in the muscles, reduces muscle tension and reduced the feedback to the hypocampus.
The reason I mention these is that there is often a feedback loop between brain and body which elevates CRH as brain listens to body and body listens to brain. Any receptor mutation becomes a lot less important if the source of the CRH stimulation can be discovered and reduced.
Phosphatidylserine also deserves a mention, as in the post, because of it's ability to reset the off switch: cortisol feeds back to the hippocampus, which then signals the hypothalamus to stop producing CRH - but with chronic stress, the hippocampus stops signaling - either because it becomes resistant / reduces cortisol receptors - or it gets overridden by the amygdala. I think Phosphatidylserine somehow resets the abiity of the hippocampus to signal the hypothalamus to reduce CRH production.
Again, the emotional environment comes into play: the reason I mentioned EMDR is that the technique aims to use the frontal cortex to intervene in the limbic brain and reprogram the amygdala so that it no longer reacts quite so strong to traumatic events.
Sorry I can't be clearer, but the research is limited, and I can only give general suggestions because I don't know your specific case. I am also still training. What I've detailed above is more from my own personal experience as I've had a difficult few months with symptoms that kept me off work. I've found significant relief using this approach, but everyone is different, so please consider this before trying stuff out. It's always worth working with a doctor / naturopath if you can find someone who knows their stuff. Hope this helps and all the best, Joe
The names of the CRHR1 mutations are CRHR1-IT1 (CRHR1 intronic transcript 1) & MGC57346-CRHR1. I believe this somehow overactivates my CRHR1 receptors or produce too much CRHR1 mRNA?. I was told once you are born with a mutation it is in every cell, so I assume this mutation is universal ie all over my brain. The site I use SelfDeDode mark these two as red (meaning there is a mutation) and also just the regular CRHR1 gene is mutated also, I guess becuase of those previous two? I can't find much info on these they seem to be rare but I can assure you the anxiety is horrifying, it is like no other, there is no positive, my health is in very bad shape becuase of the stress I experience, every sound makes me scared, im dizzy, headache, feel like im drunk, all symptoms of CRH release. I know CRH binds to CRHR1 which is how the receptor gets activated, so my plan was to take Clomipramine which has shown to reduce CRH mRNA in the PVN, but I found out also other places produce CRH, like the amygdala,hippocampus,prefrontal cortex. On Wikipedia it states CRH secreted in the PVN, so I don't know how that works, is CRH produced in the amygdala in response to stress which is then sent to the PVN and released? Or does the PVN produce CRH that then releases to the amygdala and binds to CRHR1 receptors? I found out that CRH neurons also create glutamate which is released together, so now im in a situation like I don't know what to do. There is also something called paraventricular thalamic nucleus which produce CRH and I'm not sure which place I am supposed to target. My intuitions tell me that the hypothalamus PVN is the best place to reduce CRH which will balance all other brain regions and reduce CRHR1 receptor activity. But I don't know if those mutations I have what those are. Are they different CRHR1 receptors? Does my body see them as something important that needs to be activated so my PVN produces extra CRH? I have tried tianeptine which reduced CRH in the amygdala, it worked okay-ish, I have tried zyprexa which inhibits CRH in the hippocampus, not as good, I doubt the problem is PFC producing too much CRH, it is either the PVN or PTN or any other brain region im not familiar with that produce CRH that is involved in stress. If I had to guess , I think my PVN produces too much CRH which signals other brain regions to produce CRH and which overactivates CRHR1 receptors all over. I mean there's gotta be a reason Wikipedia only mentions that the PVN produces CRH and not all other places. Now I don't know if I need to inhibit CRH release or reduce the CRH mRNA which leads to less CRH being made, becuase I could lack enzymes regulating CRH but I doubt it. Cortisol does inhibit CRH in the hypothalamus but in the amygdala it increases CRH which leads to more CRHR1 activity. Also glutamate can't activate CRHR1 receptors so I don't think thats the issue now that I think about it.What do you think based off what I've said? Would it be as easy as just reducing CRH mRNA in the PVN? Or inhibiting CRH release in the PVN?(probably doesen't matter). I have read something about hypermorphic mutation (increased gene activity) but I don't know if this is my issue, and there's also tumors which produce CRH. Other than that im perfectly fine, besides all the health problems that come with excess stress.
A few general questions came to mind:
So did the anxiety start at a particular time? Or have you always had it?
Do you notice if these symptoms are linked in any way to lifestyle factors? Worse in the morning / evening? Do you feel better at night? Is feeling anxious linked to specific foods? Or better when fasting? Specific situations, like in shopping malls or busy restaurants? Do you react badly to alcohol? Is your sleep disturbed? How long does it take you to get to sleep, and do you wake up during the night? Do you have the need to eat frequently or do you have poor appetite? Do you get frustrated easily? How do you feel after eating - tired or energetic?
Have you tested your salivary cortisol or blood ACTH?
The symptoms you mention have a lot of overlap with histamine release - which is triggered by CRH. So, I don't know whether it would be CRH directly, or CRH triggering the mast cells. Dizzyness is often due to histamine receptors in the inner ear being activated. Have you ever tried taking mast cell stabilisers to see? Things like luteolin / quercetin / rutin with vitamin C? If it is more about CRH triggering histamine, then that could give you more options in breaking the feedback loop. Because histamine triggers CRH release, and CRH triggers histamine.
With regards to the receptors: CRH is primarily produced in the PVN (but also in T-lymphocytes). It then drifts around and binds to receptors all over the nervous system, but the receptors (CRHR1) are concentrated in the amygdala, pituitary, cerebellum and hippocampus. Basically the limbic brain.
The amount of receptors determine the effect of the CRH. If there are no receptors, it can't bind and cause an effect.
Receptors are proteins, and genes encode proteins. So a genetic mutation means that either more or less protein is created. In your case, it sounds like the genetic mutation causes more of the CRHR1 protein to be created, which means that there will be a greater number of CRHR1 receptors concentrated in the areas mentioned above.
Imagine a person walking through a house turning on all the light switches. The more light switches (receptors) there are, the more lights will be turned on - even though there is only one person (signal).
With regards to the mRNA - don't worry too much about this. It's just part of the process - like wiring in the light switch. When you get down to the microscopic, there is less research, and it's more difficult to affect change. It's more effective to concentrate more globally - like the number of light switches (receptor density), and who is turning on the switch (signal).
So the average person may have '10X' CRHR1 receptors on their amygdala, and you may have '12X' CRHR1 receptors.
That means that even if the amount of CRH made in the PVN is the same, you may have more receptors listening to that signal, so the signal causes more effect. More lights get switched on.
So there are 2 approaches: 1) reduce the signal 2) reduce the receptor density or block the receptors with an antagonist.
Number 2) is the modern pharma way, or modern herbal way. Number 1) seeks to find the underlying cause. What is it that is pushing the system. I believe both approaches are necessary.
1) So that is why I suggested Tulsi and XiaoYaoSan - they both act as antagonists to the CRHR1 receptor - meaning they bind, but do not trigger the receptor. Like chewing gum on the light switch. That is how they exert their calming effect. The dose for the XiaoYaoSan was high in the study, but it shows an effect. They also used antalarmin, a drug with similar antagonist properties.
https://www.hindawi....m/2016/1238426/
Importantly: your genes are not the boss that determines the receptor density. Your genes are taking signals from the environment. There are lots of environmental factors that upregulate and downregulate expression of the CRHR1 receptor. Having a mutation just means you need to work a bit harder. For example, hypoxia causes a greater CRHR1 receptor density in rats: Upregulation of PVN CRHR1 by gestational intermittent hypoxia selectively triggers a male-specific anxiogenic effect in rat offspring. - PubMed - NCBI
So under hypoxic conditions, an average person may go from 10X to 14X - and you may go from 12X to 15X, for example.
Alcohol consumption seems to downregulate CRHR1 expression - but it is not a recommended intervention for obvious reasons. But perhaps that is one reason why some people drink heavily and others do not.
2) Reduce the signal. Anything that lowers inflammation will lower CRH. Anything that reduces histamine will lower CRH. Exploring and finding peace with trauma and emotional issues will lower CRH. The herbs I mentioned - schisandra and Rhodiola - have a well studied effect on reducing CRH. The hypothalamus also adjusts CRH output based on muscle tension, so the TRE exercises can be useful for this.
But above all, think back in time: have you had this forever, or did it start / get worse at a particular time or after a particular event? That will be key.
I think it set in during puberty so the age of 9-12 for me. Before that I had my mothers genes they were more dominant and she doesen't have this anxiety problem. My father has this issue and once I reached puberty when my fathers gene took over more then this anxiety set in. I don't know if this makes even sense but thats what I think happend. So I think I got the mutation later becuase DNA does have tiny changes during once lifetime that happens in one cell. Or maybe I did have the mutation all along but I just since I was a child I didn't experience anxiety as much, You know how when you are a child you don't care so much about social stuff etc so that could also be it so it wasn't until I got older when you care more that I actually felt the effects, who knows. I have tried Alcohol and it did have an effect on my anxiety more than anything else, I read alcohol triggers CRH release, so it could have disregulated the normal rhytm of my CRH activity thus affecting my mood even tho it releases more CRH. My upbringing has been good, no problems, I eat healthy, work out, do the nessecary things but I still have this feeling, It is like im in a constant fight-flight feeling. I have tried various SSRIs and other drugs (maois) none of which worked. I have tried increasing GABA and that worked a little, becuase GABA-A inhibits CRH release. So I guess I have too many CRHR1 receptors? thus reducing CRH mRNA in the PVN wouldn't work as good? Clomipramine has been shown to reduce CRH mRNA in the PVN up to 74%. I have also tried ginkgo biloba which has been shown to reduce CRH mRNA and CRH secretion in the hypothalamus and it worked pretty good actually. This feeling I have is 24/7 even when im alone in my room, but of course it is not as bad but even I go out in public it gets even worse, I feel like freezing and I feel so scared and I have no reason to be. I think I feel better at night becuase it is more silent but it is still pretty bad, no food or fasting makes a difference,I feel nothing after eating and Yes I get very frustrated/annoyed easily about silly things. My apetite is weird I dont crave food but I still know I need to eat so I do. My sleep is horrible, I can sleep when I get tired but I sleep like 10 hours and still feel like crap when I wake up. I think it is this CRHR1 mutation which for years has caused a havoc on my health due to the stress. My anxiety is not caused by thoughts at all, it is just this feeling I have which makes my brain be so alert of everything and notice eveerything and things that shouldnt cause anxiety do. I have not tested cortisol or ACTH but I think they are dysfunctional due to the excess CRH-CRHR1 activation so they are no longer working optimal (they are low). I might give Tulsi and XiaoYaoSan combo a try, I have heard about antlarmin, are they as effective as that? and what dosages do I use? (English is my 3rd language so I have difficult reading studies).
From what I can tell, even tho I use clomipramine to reduce CRH, the CRHR1 receptors will still be turned on the same... So I just need to decrease CRHR1 receptors mRNA basically? so less desnity of them. It says Xiaoyaosan decrease CRHR1 in the amygdala, what about tulsi where does it decrease CRHR1? there are so many parts of the brain involved in anxiety idk where to target. Here is a intresting article I found that tells about CRHR1 mutation in rats Researchers discover how the brain turns chronic stress into pathological anxiety
CRF1 receptor binding was decreased in both the basolateral amygdala and cortex by Valproic acid.
Valproic acid decreased CRF concentrations in the median eminence and raphe nuclei. Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus.
Furthermore, repeated administration of VPA has been reported to decrease receptor binding of CRH/CRF1 in the amygdala and CRH/CRF2A mRNA in the paraventricular nucleus of the hypothalamus.
Carbamazepine has been shown to inhibit hypothalamic CRH release.
Clomipramine of course reduces CRH mRNA in the PVN up to 74%. So less CRH.
But I need something that decreases CRHR1 mRNA or the amount that CRH binds to CRHR1 receptors? How would I do that and where would I need to do this?
If you go here Hypothalamus - Wikipedia
you can see hypothalamus has role in fear, is it possible that these parts are activated by CRH binding to CRHR1 receptors there? or CRH being released into the HPA axis?
''Social defeat is a source of chronic stress in animals and humans, capable of causing significant changes in behaviour, brainfunctioning, physiology, neurotransmitter and hormone levels, and health (Bjorkqvist, 2001; Rohde, 2001; Allen & Badcock, 2003).''
''Research also implicates that the referred behavioral effects are moderated by neuroendocrine phenomena involving serotonin, dopamine, epinephrine, norepinephrine, and in the hypothalamic-pituitary-adrenal axis (CRH triggers this), locus ceruleusand limbic systems (Bjorkqvist, 2001; Rygula et alli, 2005; Selten & Cantor-Graae, 2005; Marinia et alli, 2006; Huhman, 2006).''
''Anatomical connections between brain areas such as the amygdala, hippocampus, prefrontal cortex and hypothalamus facilitate activation of the HPA axis'' (does that mean these areas signal the PVN to produce CRH which activates the HPA axis or can they activate the HPA axis on their ownn?)
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So either I have problem with my locus ceruleus or somewhere in the limbic system and I would guess these parts: amygdala,hippocampus,hypothalamus..
I think it is my hypothalamus recieving excess signals due to the amount of CRHR1 receptors I have or different CRHR1 receptors which react differently when CRH binds - then which produces and releases excess CRH from the PVN and overactivates HPA axis and in turn the locus ceruleus gets turned on a lot which = fight/flight 24/7
what are T-lymphocytes is that something I should keep in mind?
also some urocortin (which ones? 1,2,3?) has high affinity for CRHR1 receptors. But I don't think it activates the HPA axis, Only CRH does that. CRH > ACTH > Cortisol
But it can bind to CRHR1 receptors (urocortin can).
So decreasing CRH mRNA or secretion in the PVN would only help somewhat.
I would need to decrease CRHR1 binding or mRNA in important places so the PVN would recieve less signals, or is it the PVN that gives out signals?..Can't you decrease CRHR1 binding by decrease CRH? atleast to some extend but urocortin will still bind and have an effect, and like you said even tho my CRH has decreased the amount of CRHR1 receptors the CRH will still have a big effect even tho I reduced it. So how do I reduce the amount of CRHR1 receptors? I guess Tulsi/holy basil and XiaoYaoSan can bind to the CRHR1 receptors and deactivate them?
It says XiaoYaoSan decreases CRHR1 somewhere in the amygdala? and Tulsi decrease CRHR1 somewhere in the HPA axis?
check this out The Paraventricular Thalamus Encodes the Salience of Stimuli and Regulates Associative Learning thoughts?
btw what's emblica officinalis?
Hi farshad, sorry I didn't replied sooner...it's been a tricky few weeks. A few symptoms returning and exams as well. But some interesting learning going on too luckily...
Reading through what you wrote, I find it interesting that it started around 9 - 12 years old. We can acquire mutations during life, but only in a few cells as a result of environmental insults, so I'd say you were born with this mutation. Did you find it with 23andme?
The interesting thing is that it didn't become a problem until puberty. Of course, there are different stresses being an adult - and children are more resistant - but one other thing to consider is that our immune systems change a lot around puberty. In fact, research has identified puberty as a time when many anxiety conditions come out - potentially because of changes in the immune system.
The question is how? Certain inflammatory cytokines are important CRH triggers. They activate the HPA axis through CRH. The most well-researched are IL-1 beta, IL-6 and TNF. And they can cause local hypothalamic inflammation without raising general inflammation markers such as CRP.
Some of them have also been linked to appetite suppression, which you mention is the case for you. This can also be histamine - which also causes insomnia.
The problem is that we get into a cycle, where CRH triggers cytokine / histamine release, and these then stimulate CRH release - and it goes round. Cortisol is supposed to turn all this off, but we become resistant to it after chronic exposure, as I've mentioned quite a bit.
So, considering the CRHR1 mutation - it is useful to have ways to reduce the activation so you can stop this cycle. And that's what you've been exploring and experimenting so far. But it is also useful to look at other triggers. like these inflammatory cytokines. Imagine a sink in the bathroom. The receptor is a bit like the plug, in that the size regulates the amount of water that can flow away. But it also depends on how much the taps are turned on. We need to switch off the taps and unblock the plug.
If, for example, the liver is overwhelmed, it will be producing lots of cytokines which will trigger CRH regardless of any receptor mutations. An overwhelmed liver, according to TCM, produced feelings of frustration, anger, irritability - because we now know that inflammation activates the HPA axis. But in reality, it is valid for inflammation anywhere in the body.
Maybe you've heard of PNEI - which is the study of how the immune, endocrine, nervous systems and the psyche all interact together. Because CRH is also produced by certain immune cells around the body - not just in the PVN.
So this could give you some other things to try - another avenue to explore - because there are plenty of herbs and supplements that will modulate the immune system.
I've been trying various anti-inflammatory herbs, like frankincense, and noticed some positive results. On the Self-hacked site, you'll find lots of info about IL-1 / IL-6... maybe you've already seen it? There's a product I'm about to try by ATP Science called Resilience, which helps to re-balance the immune system and contains many of the herbs that dampen the cytokines above. And they also do Cort Rx which I've used and contains some of the herbs mentioned in previous posts for reducing the stress response in general. Andrographis is a popular herb there, and very effective at reducing the cytokines mentioned according to some studies. I haven't tried it yet as I saw one negative study on a particular extract.
I found it interesting you said it was a physical feeling more that a mental one. I get that too. That makes me think more of the immune response. Any histamine release would also increase glutamate, which may give the over-stimulation symptoms when outside. I've noticed this when in a busy restaurant, or a supermarket, or anywhere with too much going on. I take frankincense, turmeric and some taurine when I feel this, and it helps - which suggests, at least for me - that cytokines are part of the problem.
Another thing you might like to try are the TRE exercises or some Qi Gong meditation to specifically lower the stress response. Here is a video of the TRE exercises - its the best explanation I could find even though it is aimed at caregiver mothers... and also a dropbox link to a meditation I use. (You don't need dropbox - you can download direct) If you give them a try, just take note of how you feel afterwards.
Dropbox - Ken Cohen Qi Gong Meditation.mp3
In summary: I don't know about anything that is going to reduce the expression specifically of the CRHR1 protein by reducing the messanger RNA - it's something very specific, and any studies that demonstrate this will likely be rat studies which may not transfer to humans. If I find interesting animal studies, I look for traditional evidence as well - such as with the XiaoYaoSan and tulsi. Personally, I believe the immune system interaction is big - and I have seen anti-anxiety results from adding in some of the herbs that directly target some of these cytokines - as well as addressing the underlying issues of gut health, liver health and oxalates. For you, it may be different - but it is definitely worth exploring the immune angle and gut / liver health in any case.
In answer to your questions: Tulsi will act wherever it can get to I guess. We know it can cross the blood brain barrier. It is a CRHR1 receptor antagonist - so it binds and inactivates the receptor - but I haven't seen specific studies identifying wher it has the effect. It also increases acetylcholine, so that may be a factor.
Emblica officianalis is Amla - indian gooseberry. It is also contained in the resilience product, but I don't know about a relation to CRH. As far as I saw it had an anti-stress effect, but the mechanism was unclear. It's mostly taken for it's anti-cancer / antioxidant properties and high vitamin C.
Urocortin - I don't know much but it's part of the CRH family. It has been shown to suppress appetite, and to activate the stress response in mice / rats. It is linked with anxiety.
Ps well done for your language skills. You're English is really good considering it's your third language. My other job here is an English teacher. I'm studying my naturopathy degree in Italian, so I know how tough these subjects are if not in the mother tongue.
All the best and good luck, Joe
Puberty and Adolescence as a Time of Vulnerability to Stressors that Alter Neurobehavioral Processes - anxiety onset in puberty - immune
Cytokines and feeding suppression: an integrative view from neurologic to molecular levels. - PubMed - NCBI - cytokine appetite suppression
Ocimum sanctum Linn. stimulate the expression of choline acetyltransferase on the human cerebral microvascular endothelial cells - Tulsi
Corticotropin Releasing Hormone And The Immune/Inflammatory Response - Endotext - NCBI Bookshelf - Periferal CRH and the immune system
https://atpscience.c...uct/resilience/ - ATP Resilience (australia but available in other countries)
https://atpscience.c...roduct/cort-rx/ - Cort RX
Hi again, I ordered some Holy Basil on monday and it arrived today I took 2 capsules and I actually feel something.. My headache is gone, the pressure I had in the front of my head is gone, I do feel less anxiety and more alpha if you will.
Thanks for suggesting this, it's only day 1 and working excellent can't wait the next upcoming days if it gets any better.
I have also ordered Xiao yao San which I believe contains 8 different herbs , and it has antagonism in the Basal amygdala, the basal sends information to the central amygdala which stimulates fear. I think the Holy Basil antagonism is in the prefrontal cortex , either that or in the pituitary. Do you know what the equivalent dosage for the xiao yao san would be for humans? The study mentioned chronic treatment of this formula. I don't think holy basil on it's own will cure my anxiety, I believe I have high CRHR1 receptors in multiple places, my goal is to block these: amygdala(basal and central),hippocampus,prefrontal cortex and hypothalamus (pituitary has most CRHR1 receptors) becuase they facilitate activation of the HPA axis. Do you know of any more herbs with CRHR1 antagonism?
I don't think my issue is high CRH, I know for sure it is CRHR1 -too many receptors or my CRHR1 receptors react differently when ligands bind to it possibly?, I have tried clomipramine for the past 10 days and it's supposed to reduce CRH mRNA in the PVN up to 74%, It calmed me a little bit but my anxiety is very much there, Holy basil had a stronger effect.
Yes I uploaded my 23andme to selfdecode, here are the CRHR1 mutations.
LINC02210-CRHR1 LINC02210-CRHR1 readthrough [Homo sapiens (human)] - Gene - NCBI
LINC02210 long intergenic non-protein coding RNA 2210 [Homo sapiens (human)] - Gene - NCBI
If you have too many CRHR1 receptors you are more prone to stress and HPA axis overactivates and eventually it breaks and you are left with CRHR1 activated 24/7.
Does it matter if you decrease CRHR1 mRNA,expression,activity etc or decrease CRHR1 binding? I believe it has the same outcome right?
I have tried various supplements and things to improve my immune system it didn't really do much.
My goal is to get on valproate/valproic acid + prozac, even tho I hate the former drug, valproate is a disgusting drug with many side effects and I hate that it is an anti-androgen, do you know any herbs that balances the androgen receptor?
Valproate decrease CRHR1 in many places ;basolateral amygdala ,cortex , decreases CRF mRNA expression in the central nucleus of the amygdala and probaly a lot more and stronger than these herbs.
It's the only drug I have found with these properties. Prozac decreases CRHR1 binding in the hippocampus.
right now im looking for something that decreases CRHR1 binding in the central amygdala and pituitary (hypothalamus) and im set. Unless holy basil decreases in the pituitary but I dont think so it feels in the pfc. Is the pituitary in the hypothalamus ?? it says on wiki it is on the bottom of the hypothalamus but i dont understand if its in the hypothalamus or just under it.
''(chronic) Lithium administration decreased CRF(1) mRNA expression in both the amygdala(where in the amygdala I'm curious) and frontal cortex, but CRF(1) receptor binding also remained unchanged'' The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems. - PubMed - NCBI
What does that mean CRF1 receptor binding remained unchanged? surely if you have less CRHR1 mRNA expression it would mean less CRHR1 binding/activation too? since you have less CRF1 receptors.
Also Tianeptine has been good for my anxiety it reduces CRH mRNA in the Central amygdala.
Do you know of any drugs/ssri etc that reduce CRHR1?
So the article you linked about Xiao Yao san says
''Although it has been demonstrated that the levels of CRF1R mRNA transcripts were elevated in the hypothalamic paraventricular nucleus (PVN) and amygdala after exposure to immobilization stress in rats''
So PVN , central and basal amygdala are the areas I need to decrease CRHR1 binding/activity/mRNA etc? So forget the Cortex(PFC?), hippocampus and pituitary?
I'm currently taking Prozac which supposedly decrease CRHR1 in hippocampus or am I understanding it wrong?:
- ''Results In saline-treated LH animals, CRF expression in the BLA(what's BLA?) increased, while hippocampal CRF1 expression and ERK1/2 activation decreased -Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation.''
(PDF) Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm
Anyway prozac isn't working which is weird. I have taken zyprexa in the past and it decrease stimulated CRH in the hippocampus while prozac decrease CRHR1 directly , yet the zyprexa worked but the prozac doesen't . Unless again, I understand the study wrong and it says prozac increase CRHR1 expression.
I'm still waiting on the xiao yao san to arrive but I hope it works, im sure it will. Not sure what dosages I need to take that would be equivelent of the chronic dosage in the study.
So from what I understand the areas I need to decrease CRHR1 are in the hypothalamus PVN and amygdala, I assume the Basal & Central amygdala?
It would make sense in the hypothalamus becuase like I mentioned earlier it has a role in social defeat.
Hypothalamus - Wikipedia
''The medial zone of hypothalamus is part of a circuitry that controls motivated behaviors, like defensive behaviors.''
Since CRHR1 increases anxiety and according to the xiao yao san study that said CRHR1 was increased in hypothalamus of stressed rats. I can only assume that if you have increased CRHR1 in this area it means you are more prone to anxiety and not so defensive.
this would make sense, becuase I have very bad anxiety but im not Defensive at all..
''Likewise, the hypothalamus has a role in social defeat: Nuclei in medial zone are also mobilized during an encounter with an aggressive conspecific''
So its the Medial zone not the PVN like the study said? I have tried clomipramine like mentioned earlier which decreases CRH up to 74% in PVN which would mean less crh binding to CRHR1 but didnt work. but like you said its depends how many CRHR1 receptors are listening to that signal...
The closest thing I have found that might do all this is valproic acid.
Decreases CRHR1 in basal amygdala, CRH in central (unfourtunaly not CRHR1) and possibly CRHR1/CRH in the hypothalamus somewhere.......https://onlinelibrar....1111/cns.12598
(edit) Oh the PVN is in the medial zone...Hypothalamus - Wikipedia
that's weird, how come I didn't feel any anti anxiety effect at all from using clomipramine then? I know it depends on the crhr1 receptors listening but you would think i would feel a big difference anyway . hmm im confused, on the link above lists different nuclei in the hypothalamus but there's like 3 different medial.... which ones the medial zone
holy basil made me a little more confident but not much, it mostly gets rid of my headache in the front of my head so i believe it decreases crhr1 in the pfc.
so after doing a little bit of reading.. was a bit lazy but I came to the conclusion that these areas I need to decrease CRHR1: Valproate decrease CRHR1 in basolateral & CRH in central amygdala and Lexapro decrease CRH in hippocampus & sertraline decrease CRH in the BNST..
The basolateral amygdala (BLA) or basolateral complex, consists of the lateral, basal and accessory-basal nuclei of the amygdala. The lateral nuclei receives the majority of sensory information, which arrives directly from the temporal lobe structures, including the hippocampus and primary auditory cortex. The information is then processed by the basolateral complex and is sent as output to the central nucleus of the amygdala.
Extended amygdala - Wikipedia
This is the best I could find, ideal would be if they decreased CRHR1 binding rather than just CRH but it should be good enough.
I don't think I need the sertraline... or the lexapro.. I bet valproate alone decrease CRH or CRHR1 binding in the hippocampus and BNST.. But Valproate + Lexapro should be it....
when you get back could you answear these two questions?
the dose for the XiaoYaoSan was chronic in this study on rats:
https://www.hindawi....m/2016/1238426/
what would the equivalent be for humans?
and same question for valproate
Effects of sodium valproate on corticotropin-releasing factor systems in rat brain. - PubMed - NCBI
Hi,
So I'm glad you saw a positive effect with the Holy Basil. The XiaoYaoSan dosage in the rat study was high, but that doesn't mean it should be high in humans as well. More is not necessarily better. I followed the dosage on the bottle, which was 6 a day - but yours might be different. Sometimes herbs show a decreased effect at high dosages. For the valproate I don't know - I have no experience with it and not medically trained...
A note about sourcing: herbs are less controlled than drugs, so it's a good idea to get them from a reputable source. Sometimes products with very little or none of the active ingredients make their way onto the market.
Other herbs that I suspect interact with the CRH receptor might be Gotu kola (Centella asiatica), which also has a notable GABAergic effect - as well as lowering several cytokines which directly raise CRH.... Reishi and Ziziphus jujuba might also be interesting, but specific research on interactions with the CRH receptors are not so common because of funding and revenue barriers unfortunately. I'm sure well see a lot more in the future.
What herbs did you try for your immune system and what was the goal?
You also asked about a herb that modulated androgen receptors, and Tribulus does that. It doesn't boost testosterone as previously believed ( like tongkat ali, nettle root or pine pollen etc) - but it does increase androgen receptors in the brain.
One thing to keep in mind is that the majority of these studies are animal studies that can only provide a general idea of what is going on. The stress of modern life on the human brain is different to the stimulated stress of a rat in a lab. This is both annoying - because we don't have answers yet - as well as exciting because there are many possibilities not yet discovered. This is why I also consider traditional uses of herbs - both give us different perspectives.
I encourage you to look beyond the specific pharmacology to environmental and emotional effects on the CRH system. For example, one thing that raises my stress hormones is a sense of duty and responsibility relating to other people - and I know there would be no way to recreate this in a lab study. I also know that drugs and herbs will never fix this, but behavioural change will, which is why I am exploring EMDR. For me, addressing this exaggerated sense of responsibility is fundamental, because it puts a lot of stress on the CRH system which drugs and herbs can only lessen. It's like driving with one foot on the accelerator and one on the brake.
So which is more important: CRHR1 expression, CRH binding or CRH production? The answer is they are all important because they work together as a system - and systems behave differently to their individual components. The details are fascinating, but a zoom out every now and then is also very useful.
Environmental causes of CRHR1 expression:
Not only do environmental factors increase and decrease CRH production, they also change CRHR1 gene expression. It's not only the gene that controls this. An example:
- Alcohol reduces CRHR1 expression - that explains one of it's anxiolytic properties. But it also increases CRH by dysregulating the glucocorticoid feedback system, providing a stimulating effect. The predominant effect depends on the person drinking - and explains why some people who drink feel more relaxed while others want to fight. The terrain of the person is important.
This explains why herbs and drugs may not work how you expect: one study might focus on the first effect, while another might focus on the second.
One of the main ways genes get affected by the environment is through methylation and acetylation.
Hypomethylation and hyperacetylation is associated with increased CRHR1 expression.
Panic Disorder Might Have an Epigenetic Explanation | What is Epigenetics?
CRHR1 promoter hypomethylation: An epigenetic readout of panic disorder? - PubMed - NCBI
The effect may be local or general - so I'm not sure at this point how relevant general methylation symptoms are for this. For an idea, have a look at the general picture: Methylation Disorders | Under and Over Methylation | Tao Integrative Medicine | www.taoinstitute.com
Methylation status may also have an effect on how effective drug or herbal treatments are:
DNA methylation levels are associated with CRF1 receptor antagonist treatment outcome in women with post-traumatic stress disorder
And it starts before we are even born: here, a study showing that gestational hypoxia may increase CRHR1 expression in males - Gestational hypoxia induces sex-differential methylation of Crhr1 linked to anxiety-like behavior. - PubMed - NCBI
Hypoxia is also key because it plays into metabolism. Overactive stress metabolism causes a decrease in CO2 production, which causes relative hypoxia through vasoconstriction, which drives CRH production and CRHR1 expression even more. This may be one reason why people who start healing their metabolism start feeling less anxious - and perhaps one reason why you were drawn to the Ray Peat Forum, as I was. I know my metabolism leans towards anaerobic glycolysis.
Another cause could be Lactic acid. The effects on the CRH system are unclear from the studies - but when injected into anxious people, it can bring on a panic attack.
The regulatory feedback loop is also important for this reason:
The ability of cortisol to turn off CRH production is also linked not only to CRH production but also CRHR1 expression:
https://www.research...ed_AtT-20_Cells
So chronic cortisol elevation may lead to increased CRHR1 expression (whereas acute might decrease it)
This is why phosphatidylserine may be effective - because it re-sensitises this negative feedback mechanism.
So, to summarise: it's not just the genes that affect how much CRHR1 protein is made. It is part of a dynamic system reacting to the world around us. Making some changes to your environment may well have some of the same effects you are looking for from herbs and medication.
As well as your current protocol, you could consider:
- phosphatidyleserine. Most people start with 100mg twice a day, and go up to 300mg twice a day. At this dose it can be too stimulating for the brain, so I stick to 100mg twice a day and get some insomnia if I go higher.
- trialing breathing exercises, such as box breathing or Buteyko - to increase oxygen delivery.
- methylation. Do you identify with either hypo or hypermethylation?
- meditation. 8 weeks of meditation has been shown to shrink the amygdalae and weaken the signal from there to the rest of the brain. I am trialing EOC Institute – Access Deep Meditation Quickly, Safely, & Easily at the moment.
All the best, Joe
I ordered this Xiao Yao San 2x https://www.amazon.c...e/dp/B001MAVEV6 still waiting on it should arrive soon 1-2 weeks.
Gotu kola & Reishi and Ziziphus jujuba do they interact with the CRH or CRHR1 receptor? I don't think my issue is CRH but CRHR1 made in excess levels (double the average?).
What herbs did I try for my immune system? well I tried various: ashwagandha, rhodiola rosea, ginkgo biloba and some more, and I just wanted to feel better, I took them for weeks and I did feel different I could tell they were having an effect but I quit becuase for some reason one of the herbs was making me spit out blood....
I tried phosphatidylserine but I dont think it had any effect,
I read something about Phosphatidyserine:
''phosphatidylserine has been sourced from cow brain tissue, which carries a risk of contamination and disease transmission [R, R].
It is now usually sourced from soy extracts, which is not associated with the same risks''
Does it have the same effect on the cortisol system no matter where it is sourced from? cause I read someone saying phosphatidylserine from soy is not as good or doesent work as well as the one from cow brain tissue.
Do I identify with either hypo or hypermethylation? Well hypo is less CRHR1 right? So I would identify with hypermethylation but im not 100% sure what that is I know you provided some links but my English is not good so, either that or as I previously said I have hypomorphic mutation which sounds the same and is:
''A hypermorphic mutation causes an increase in normal gene function.[1] Hypermorphic alleles are gain of function alleles. A hypermorph can result from an increase in gene dose (a gene duplication), from increased mRNA or protein expression, or constitutive protein activity.
The phenotype of a hypermorph is worsened by increasing the wildtype gene dose, and is reduced by lowering wildtype gene dose.[2]
m/Dp > m/+ > m/Df''
Muller's morphs - Wikipedia
When I search hypomethylation and on wiki theres a little info it says:
''(genetics) an increase in the epigenetic methylation of cytosine and adenosine residues in DNA.''
Not sure what that means or what cytosine or adenosine is... but it does have similar words as the mutations I have on CRHR1: epigenetic means not genetics but caused by enviromenment which turns on genes more?
Heres all the info I got on the CRHR1 mutations I got from SelfDeCode (Joe's site)
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Here's all the info I got:
[ Homo sapiens (human) ]
LINC02210-CRHR1 readthrough also known as MGC57346-CRHR1, What does the 2.35 in the title stand for? It came with a genotyped I uploaded, probably nothing. ''This locus represents naturally occurring readthrough transcription between neighboring genes CRHR1-IT1, CRHR1 intronic transcript 1 (Gene ID: 147081) and CRHR1, corticotropin releasing hormone receptor 1 (Gene ID: 1394) on chromosome 17. The readthrough transcript encodes a protein that shares sequence identity with the product of the CRHR1 gene. [provided by RefSeq, Dec 2016] Expression Broad expression in brain (RPKM 3.0), testis (RPKM 2.3) and 23 other tissues''
(non-protein coding) LINC02210 long intergenic non-protein coding RNA 2210 also known as CRHR1-IT1. ''Ubiquitous expression in skin''
the dates on these are recent (2018):
LINC02210-CRHR1 LINC02210-CRHR1 readthrough [Homo sapiens (human)] - Gene - NCBI
LINC02210 long intergenic non-protein coding RNA 2210 [Homo sapiens (human)] - Gene - NCBI
MGC57346-CRHR1 SNPs: rs393152 AA & rs11655470 TC
CRHR1-IT1 SNPs: rs393152 AA & rs393152 AA
Intronic RNAs constitute the major fraction of the non-coding RNA in mammalian cells?
ADP-ribosylation factorP?
Alternative splicing/intronic transcript (not typically protein coding) as well as a read-through to the neighboring gene MGC57346?
Alternative splicing results in multiple transcript variants, one of which represents a read-through transcript with the neighboring gene MGC57346?
CRHR1-IT1 is a non-coding transcript of the CRHR1 gene (which its function is unknown but could maybe regulate gene expression) and MGC57346-CRHR1 is a fusion transcript between CRHR1-IT1 and CRHR1.
Hypermorphic Mutation? (A type of mutation in which the altered gene product possesses an increased level of activity, or in which the wild-type gene product is expressed at a increased level)
CRHR1 Hypomethylation and hypermethylation ?
-------------------------------------------
Protein names (CRHR1 mutations)
Recommended name:
Putative uncharacterized protein encoded by CRHR1-IT1
Alternative name(s):
CRHR1 intronic transcript 1
MGC57346
The following transcription factors affect gene expression ®:
CUTL1
HNF-4alpha1
HNF-4alpha2
GATA-1
GATA-2
GATA-3
Sox9
GCNF-1
GCNF-2
GCNF
CRHR1
The following transcription factors affect gene expression ®:
deltaCREB
CREB
AP-1
c-Jun
Max
c-Fos
Max1
NRSF form 1
NRSF form 2
---------------------------------------------------------
Hypermorphic list (increased gene function):
constitutive protein activity - "Constitutive" activity means that the regulation of the enzyme's activity is gone, it's been mutated or something to allow it to always be active.
Consider an enzyme: An mRNA molecule is translated to make a protein, which has enzymatic activity on some substrate, and can be regulated.
Expression is a readout for the translation of the mRNA into stable protein.
protein expression - DNA > mRNA > Protein expression(CRH) , it is possible to have low mRNA but high protein expression becuase a single mRNA molecule can stick around and be translated many times. And protein has longer half-life.
CRH-gene duplication - gene duplication, if the promoter regions (the DNA that communicates with proteins that tells the mRNA synthesis machinery when and for how long to make that particular gene's mRNA) and/or the enhancer regions (the DNA that adds nuances to what the promoters do) are copied along with the gene, you can predict that the expression of the duplicate will mirror that of the original. If not, maybe the duplicate is just turned off, maybe it picks up signals from promoters/enhances in the new region it gets duplicated into? All options.
Additionally some genes are tightly regulated so that the "dose" of that particular protein doesn't get to high or to low. If this is the case of a gene that gets duplicated, feedback mechanism may kick in and change the total amount of protein that gets made.
CRH-Secreting tumor - a tumor secreting a certain substance, if that substance is a protein or peptide, then yes, it has to go through transcription (DNA --> RNA), and translation (RNA--> protein) (fortunately CRH is a Peptide hormone). Since cortisol is not a protein, or peptide, it is a steroid hormone, it is synthesized (by proteins in the cell that did have to follow the DNA --> RNA--> Protein route), from other molecules that the cell takes up. The ability to synthesize these molecules is not unique to tumor cells, although the regulation of the synthesis may be drastically altered.
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The last one regarding tumor at first I thought I had a tumor in my brain that secrets CRH but thats not the case cause I had a brain scan and it was fine. But then I thought maybe the tumor is outside the brain and secrets CRH but No someone told me if the tumor is outside the brain it cant get to the brain and have an effect cause it needs certain proteins to get there or something along those lines my memory is fuzzy.
The huge paragraph(s) above is just information I have collected regarding my situation from other peoples help.
