23andme & Chronic insomnia and family history of psychiatric/CNS disorders

[Valentijn]

10.6% of the general population is homozygous for rs1800497 and 43.9% are heterozygous. In some Asians populations, that goes up to 65% of the population being homozygous or heterozygous. Is it your belief that all of those people are also having problems similar to yours?

 

[futuritycarpaccio]

10.6% of the general population is homozygous for rs1800497 and 43.9% are heterozygous. In some Asians populations, that goes up to 65% of the population being homozygous or heterozygous. Is it your belief that all of those people are also having problems similar to yours?

That's not the point. In my previous post I showed there is a possible association of this polymorphism with extrapyramidal symptoms coming from neuroleptic usage, which is what happens whenever i use antidopaminergics and even after i use them.

It is linked to reduced dopaminergic activity in the striatum, which is linked to extrapyramidal symptoms, movement disorders, mood disorders, alcoholism, deficient reward,etc.

it's probably not the only polymorphism related to my problems. I think disease, maybe except for those very rare ones, are coming from the net effect of several polymorphisms.This polymorphism in people withouth symptoms, is probably being offset by something else, which is why their families have been able to propagate their genes.

However, this polymorphism, together with CYP2D6 polymorphism, explains most of my reactions to many of the medications I took. All the ones I reacted badly to, were heavily metabolised by CYP2D6 and reduced dopaminergic activity to some extent. So I have reason to believe that the low dopaminergic reactions I am having are also related to it. Of course,I have no way to prove this...I can only try dopaminergic substances and see if I feel better.

If it is the sole responsible? I don't think so. But it's one of the most obvious ones, together with CYP2D6. In me these two aren't being offset by other compensating polymorphisms, maybe in other people they are and hence why they don't have these issues.

 

[Valentijn]

That's not the point. Have you read what I wrote?

No, it was too long and poorly formatted.

There is a possible association of this polymorphism with extrapyramidal symptoms coming from neuroleptic usage, which is what I have suffered from a long timewhenever i use antidopaminergics.

So do 50-65% of the people taking those drugs have the same reaction? I'd assume such a common and severe reaction would be very obvious in the drug trials. And do you only have the reaction when taking those drugs, and no symptoms otherwise?

 

[futuritycarpaccio]

No, it was too long and poorly formatted.

So do 50-65% of the people taking those drugs have the same reaction? I'd assume such a common and severe reaction would be very obvious in the drug trials. And do you only have the reaction when taking those drugs, and no symptoms otherwise?

Valentijn, I'm sorry you found the post long and poorly formatted. I'm not too good at formatting as I don't always put an effort on it. i assume who is looking for this info will still read it.

No, the side effects are very rare. I can't possibly know for sure that my issue is in Taq1A A1 together the CYP2D6 polymorphism, anymore than a person with MTHFR mutation can. You'd have to make a study to know that... But judging by the studies I found, by my reactions to those meds, and by how these can affect one's biology, I strongly suspect they are causing issues in me. In other people maybe they are offset by something else.

Taq1A A1 said on promethease it has 5% frequency. I found other values, ranging from 20-40%in europe (where I am from).

What is the frequency of Taq1A A1 together with some specific CYP2D6 polymorphisms ? Maybe it's lower then 20-40%. What is the frequency of Taq1A A1 with CYP2D6 polymorphisms, together with other unidentified polymorphisms that would be able to offset the effects of the previous mentioned polymorphisms ? Probably very rare.

I have some movement symptoms off of the medicines too,but they are not bothersome nor are they so frequent. i've woken up to fingers moving, arms moving, muscle spasms, etc.. they just are very very exacerbated by these drugs

 

[Hip]

@xptriado
Thanks for your post.

I am coming to dopamine receptor function from a slightly different angle to you: in my case, I am looking to fix a condition I have called anhedonia, which is where the pleasure and reward circuits of the brain don't work so well, so that you don't get much enjoyment from the everyday activities that you once found pleasurable or rewarding.

There's not that much research in this area, but the dopamine D1 and D2 receptors may be involved.

I use very low dose amisulpride for D2 stimulation (when taken at very low doses, amisulpride blocks presynaptic dopamine autoreceptors, which then acts to increase dopamine production and thus D2 activation).

On my list to try are the potent D2 agonists cabergoline and bromocriptine.

The D1 receptor however seems to have very few agonist drugs, nothing that is available to buy. Cabergoline though does have some weak D1 agonism.



Methylphenidate (Ritalin) seems to have complex effects on dopamine receptors. This post mentions that in rats, methylphenidate can either increase or decrease the number of dopamine D2 receptors, depending on the age of the rat and the duration of treatment.

 

[futuritycarpaccio]

@Hip, I have this anhedonia too. I don't know what hascaused allthis mess. It gradually set in.Some symptoms were accute, others were gradual.

I have here methylphenidate and ropinirole. The first one seems to work as NRI and DRI and the last one as D2 agonist.

Uridine has impact on the D1-D2 heteromer as a modulator (i think). Don't know if that could help you.

i didn't know amilsupride blocks presynaptic receptors, I wonder if it could help me, as according to that Taq1A1 A1, I have too much L-Dopa at the presynaptic vesicles, which is lowering the D2 receptors.

I am quite afraid that methylfenidate and the D2 agonist could make me worse. especially since methylphenidate metabolizes through cyp2d6. I will have to start very very very slowly.

Do you feel high prolactin sides from amilsupride?

Have you tried any SERMs (estrogen receptormodulators) or steroids at some point, anabolic or other ?

Have you tried memantine?

 

[Hip]

@Hip, I have this anhedonia too. I don't know what hascaused allthis mess. It gradually set in.Some symptoms were accute, others were gradual.

In my case, my anhedonia, and also my blunted affect (emotional flatness), were both trigger by the virus I caught, which also precipitated my ME/CFS. And it was not just me; several acquaintances who caught the virus from me also developed some anhedonia and blunted affect. I detail the symptoms produced by my virus here.

Prior to catching this virus, I definitely did not have anhedonia; I found lots of everyday things in life very rewarding.

It is interesting that in ME/CFS, a small percentage (5%) of patients develop autoantibodies to the dopamine D2 receptor (ref: here), so possibly this may help explain my anhedonic symptoms.

I have here methylphenidate and ropinirole. The first one seems to work as NRI and DRI and the last one as D2 agonist.

I'd like to try methylphenidate, because I suffer from quite severe ADHD (my ADHD appeared after I had a nasty episode of viral meningitis). However, I read that in the UK, it is hard to get a doctor to prescribe this drug, if you are an adult. And being a controlled drug, it hard to find for sale online (and where it is for sale, it tends to be very expensive).

Uridine has impact on the D1-D2 heteromer as a modulator (i think). Don't know if that could help you.

I did do a brief trial with uridine monophosphate recently, at a dose of 120 mg sublingual daily. I found uridine had a good mental focusing effect, but in a subtle way (not like a strong stimulant), which allowed me to work on the computer more effectively. However, it caused a side effect of increase sound sensitivity, so I stopped it for the moment, but will be trying it again soon.

Interestingly, I found amantadine also causes this side effect of increased sound sensitivity, but usually after several days taking amantadine, this side effects gradually diminishes.

By contrast, very low dose amisulpride greatly reduces my sound sensitivity, which is one of the reasons I find this drug a great ME/CFS treatment.

i didn't know amilsupride blocks presynaptic receptors, I wonder if it could help me, as according to that Taq1A1 A1, I have too much L-Dopa at the presynaptic vesicles, which is lowering the D2 receptors.

The thing I like about very low dose amisulpride is that no tolerance builds up; it works as well for me now as when I first started taking it a few years ago.

Also, for me this drug feels very "natural." I have some depression as well as anhedonia, and I have tried out various antidepressants. Some, like tricyclic antidepressants (eg: amitriptyline), kind of alleviate my depression, but they feel unnatural and imbalanced in terms of how my mind feels. The mood is improved, but the minds feels a bit disturbed. Whereas amisulpride feels nice and balanced, more like a supplement than a drug.

Do you feel high prolactin sides from amilsupride?

Very low dose amisulpride does lower libido, I find, which may be a result of increased prolactin. However, the dose I use, just 12.5 mg daily, is about 100 times smaller that the full amisulpride dose (of 1200 mg) used for treating schizophrenia. So I would think that compared to the full dose, the very low dose I use will cause much less of a problem with prolactin.

Though note that with any anti-psychotic, even these second generation atypical anti-psychotics like amisulpride, there is a significant risk of developing diabetes. But again, using a very low does, I assume that the risk will be correspondingly reduced.

Have you tried any SERMs (estrogen receptormodulators) or steroids at some point, anabolic or other ?

I have seen selective estrogen receptor modulators (SERMs) for sale on body-building websites, but I am not sure what benefits these might have for my symptoms. Was there any benefit you had in mind?

On the subject of estrogens: a while ago I was trying low doses of transdermal estriol, the weakest of the three estrogens. Estriol has potent anti-autoimmune effects, and is being investigated as a treatment for multiple sclerosis. The very high levels of estriol found in pregnancy might also explain why some female ME/CFS patients find their symptoms significantly better during pregnancy.

Anyway, at the low doses I used (0.3 mg estriol daily), I found no specific benefits for ME/CFS, but I did find estriol noticeably improves my blunted affect (flat emotions), and makes me less irritable, more tolerant of people, and more inclined to social banter.

So now I use estriol now and then for this purpose. I don't take it all the time, because even though it is a very weak estrogen, it does still have some feminizing effects, and I don't really want to grow breasts.

Have you tried memantine?

Have not tried it, but I should do really. I often use high-dose transdermal magnesium (magnesium cream applies to the skin from head to toe), which like memantine is also an NMDA blocker. I definitely notice a calming, anti-anxiety effect from high-dose transdermal magnesium (anxiety may be linked to NMDA receptor over-stimulation).

But I guess you are referring to memantine's agonism of the dopamine D2 receptor.

 

[Darrin]

G6PC2
rs560887

Do you have any blood sugar issues with the mutation G6PC2
rs560887? I have that mutation and need to eat every hour and a half.

 

[futuritycarpaccio]

So I'm coming back to my thread after a few months to leave a testimonial.

As I thought, my D2 was an issue.

I tried ropinirole (0.25mg) and it felt like the cleanest drug I took, appart from dexametasone. It felt like it filled a hole. It instantly solved some depression i am facing , apathy, motivation, I got more pleasure. It was like i felt more like my old self. I had (odly) a worsening of the spasms at night and I was afraid that I would make things worse in the long run so I stopped using it and tried instead AGAIN to fix my sleep...I am probably giong to give it another shot again though because I have the feeling it would help my sleep had I increased the dosage.

I decided to give tianeptine a try. It messed my sleep up over the course of a few days...but again, my depression was fixed and only took one pill (7.5mg) to do it. Something is trumping my HPA axis big time!! I stopped it because of sleep issues and because I didn't find any evidence the HPA axis would settle down a little bit after the first days on tianeptine.

Maybe I need polypharmaceutical approach or maybe this won't work at all.

I also tried clonidine and the stuff ismuch better than any benzo I tried. More clean, more calming!! if tianeptine wasnt so agressive on the liver I would try both of them together

My fatigue improved a little bit since I got Vit D3 in range. I feel there is an issue with my red blood cells, since the median volume of the cells is on the low limit...i tried increasing it with strong iron dosages and C during 10 days. No difference..I will keep taking iron but at a maintenance dosage.

I find that my symptoms do belong in the PFS forum but I still would like to update my thread as there are some similarities between both diseases.

Im trying to remain the most natural possible and I still have to check my stool with PCR as it may give me some more info...But I feel My best shot at healing this is probably through D2 receptor agonism, and healthy lifestyle. Im thinking of starting enemas (maybe coffee), and following some variant of Gerson therapy...it seems the most important thing in PFS is to be consistent and I'm completely erractic at the moment.

 

[globalpilot]

Close. I do not just look for the rarest SNPs. I look at SNPs in the Methionine, Transulfuration, and Catecholamine pathways and a few others, like the Krebs cycle and Glucose Pathway. The rarity is just a way I use to know if a gene in those pathways are fast or slow. I do not treat all of the SNPs, but they give me a clue to the "flow" of this complex of pathways. That is the best way my mind can put it.

I do not see the a SNP as a problem on its own, but the combination of SNPs in all these pathways is just a way for me to see the way people express disease and what can help them.



Yes, the rest is correct.



Yes, I folcus on genes that effect methylation and de-methylation. I have about 200 SNPs I look at but will only treat four or five of them with supplements and a lot of them are the same supplements. I will list all the SNPs at the end of this post.

My self personally, with a change in diet a lot of days I take nothing. I take supplements if I feel symptoms or as preventives. For example, if I know I am going to eat dinner out I might take some FMN (B2) to help me process dietary amines.

[

Again, rarity is not the issue. I am afraid that was misinterpreted by another member. I take four supplements mostly. Biotin (BTD), FMN (MAOA, MAOB, MTRR, MTHFR), Magnesium (COMT) and P5P (GAD1). I also changed my environment. Low amine, low protein, low glutamate, low stress. The only one I take everyday is Biotin.

I also take on occasion Optizinc, molybedenum/thiamine, manganese, and selenium. But I try to get these from foods.

Note that I NEVER take the products of these pathways. Doing so creates issues like when the give levdopa to parkinsons patients.

[

I look at the receptor SNPs because that gives me a way to gauge the importance of the donator SNP. For example, my GAD1 SNPs are bad, leaving a lot of glutamate around and making me low in GABA. My GABA receptor SNPs (GABRA) are very bad as well, causing me to NEED more GABA. Knowing that, I see I might need more P5P to help me create more GABA than people who do not have as bad GABA receptor SNPs.

[

All the genes I look at have some influence in DNA methylation or de-methylation.
For example, MAO;
Histone H3 Lysine 4 Demethylation Is a Target of Nonselective Antidepressive Medications
http://www.sciencedirect.com/science/article/pii/S0014579305003376

Thank you for the detailed questions!

These are the SNPs I look at:


MTHFR
rs1801133
rs1801131
rs4846048
rs1476413
rs6676300
rs4846049
MTHFD1
rs2295639
rs10498514
rs2236225
rs2236224
MTHFD1L
rs803422
rs6922269
MTHFS
rs6495446
BHMT
rs651852
rs3733890
rs567754
PEMT
rs7946
rs4646406
MTRR
rs1801394
rs3776467
GCH1
rs4411417
rs752688
rs8007267
PTS
rs3819331
TPH2
rs4570625
rs17110690
rs4565946
rs10506645
rs1487278
rs11179002
TYR
rs1393350
rs1847134
rs1799989
TPO
rs1514687
rs732609
TH
rs6356
DDC
rs3735273
rs1451375
rs921451
rs2329340
rs11974297
rs1451371
DBH
rs77905
rs1108580
rs2007153
rs1611115
rs2283123
MAOA
rs909525
MAOB
rs2283729
rs1799836
COMT
rs4633
rs4680
rs165722
GAD1
rs769407
rs3791878
rs3791851
rs12185692
rs3828275
rs2241165
rs3749034
GABRA2
rs11503014
rs279845
rs279836
rs279858
rs279826
GABRA3
rs750841
GABRA4
rs17599416
SUOX
rs10876864
SOD1
rs2070424
rs1041740
SOD2
rs2758331
rs4880
SOD3
rs2536512
rs1799895
GPX1
rs1800668
rs1050450
GPX2
rs2071566
GPX3
rs3828599
rs8177447
rs8177404
rs8177406
GPX4
rs757228
rs2074451
GSTP1
rs1695
rs1871042
TTPA
rs35916840
CBS
rs1801181
rs2851391
rs4920037
rs234706
rs234709
rs6586282
rs234715
CTH
rs1021737
DAO
rs4623951
rs2070586
rs3741775
rs1935062
rs3916967
DAOA
rs3916967
rs2391191
rs3918341
rs947267
HNMT
rs1050891
FADS1
rs174549
rs174550
rs174546
rs174547
rs174548
rs174556
FADS2
rs482548
rs174575
rs174570
rs498793
rs1535
rs174576
GCK
rs730497
rs1799884
G6PC2
rs560887
GPT
rs1063739
PC
rs28940589
MCM6
rs4988235
rs182549
LCT
rs2322659
BTD
rs13078881
rs7651039
BCMO1
rs12934922
rs7501331

Has anyone performed the exercise of identifying the frequency of your allele for each of the above genes and locations ? I have and so far have identified I have the rare DBH
rs1611115
(3.6% of pop'n has this according to Prometheus). This results in lower activity of the enzyme which will result in lower epinephrine and norepiniprhine. Also I have a couple of DAO snps which have been shown to have lower activity. Interestingly, both of these SNPs use copper as a cofactor.

 

[futuritycarpaccio]

Has anyone performed the exercise of identifying the frequency of your allele for each of the above genes and locations ? I have and so far have identified I have the rare DBH
rs1611115
(3.6% of pop'n has this according to Prometheus). This results in lower activity of the enzyme which will result in lower epinephrine and norepiniprhine. Also I have a couple of DAO snps which have been shown to have lower activity. Interestingly, both of these SNPs use copper as a cofactor.

@globalpilot i have one rare snp which i thought would be responsible for some symptoms but then i took selenium for it, as seen in studies published, and it should have raised. well it prob did but i felt nothing at all.

i'm not looking so much into 23andme anymore, maybe i should change the title of my thread to "Xptriado's Journal" or smtg like that but i dont know if i can.

Last week my insomnia suddenly started getting better. I don't know if its a upper part my disease's cycle (it cycles it seems), or if indeed something i'm doing is working. I will know for sure this week...

 

[globalpilot]

@globalpilot i have one rare snp which i thought would be responsible for some symptoms but then i took selenium for it, as seen in studies published, and it should have raised. well it prob did but i felt nothing at all.

i'm not looking so much into 23andme anymore, maybe i should change the title of my thread to "Xptriado's Journal" or smtg like that but i dont know if i can.

Last week my insomnia suddenly started getting better. I don't know if its a upper part my disease's cycle (it cycles it seems), or if indeed something i'm doing is working. I will know for sure this week...

Thanks xptriado. I've done quite a bit of reading since I wrote this on the DBH gene. It turns out it is actually protective on some of the organs studied, including the heart. I don't see anywhere that it's a huge problem.

 

[heyitisjustin]

what is die off?

i took again dexa today, 0.25mg. i was feeling horrible and it changed me to feeling great

Did you ever figure out why dexamethasone made you feel better? I think dexamethasone raises cortisol.
Do you have low cortisol?

 

[futuritycarpaccio]

Did you ever figure out why dexamethasone made you feel better? I think dexamethasone raises cortisol.
Do you have low cortisol?

Well i got some of the benefits from dexametasone by taking testosterone gel, and by taking a dopamine agonist.

So i am supposing that i have some sort of estrogen dominance issue, or of some binding protein like cbg tbg or shbg, that dexametasone "cured"

I tried the equivalent amount of hidrocortisone but i felt nothing.

 

[heyitisjustin]

Well i got some of the benefits from dexametasone by taking testosterone gel, and by taking a dopamine agonist.

So i am supposing that i have some sort of estrogen dominance issue, or of some binding protein like cbg tbg or shbg, that dexametasone "cured"

I tried the equivalent amount of hidrocortisone but i felt nothing.

What does dexamethasone have to do with dopamine? I also have high estrogen sporadically. Is your estrogen always high? How is your Testosterone? Mine is high at least at times, but I seem to have a similar problem profile as you otherwise.

Is your shbg high? Have you seen an endo? My endo said something about estrogen/shbg being linked to liver problems. Why would dexamethasone help with any hormone binding globulin besides cortisol (I assume that is CBG)?

dexamethasone also made me sleep better so I am trying to figure out what we have in common if anything.

Has anything besides dexamethazone helped you sleep? CBD oil, magnesium,GABA,flax oil,hemp oil and methylation seem to be the biggest helps to me. I also used to sleep fine on fluronef (although I was much younger than so that could've been an age thing).

Had you taken something to raise cortisol in the past?

 

[heyitisjustin]

So i used 0.25mg dexametasone in the morning one day, and then the subsequent 3 days i used 0.125mg

Any idea why I felt normal the first 2 days?i felt like my old self. Its so frustrating that its gone now!

I seem to have retained better sleepm today i slept unassisted.

My doctor was so worried that i was doing that. She said i can get cushings from it. Even from licorice root...
I was very worried.

I felt like my old self.

An adaptogen like holy basil,rhodiola, or ashwaganda should be safer. Taking dexamethasone seems like it could easily pushing cortisol too high. Personally, I am taking adrenacalm, which I am worried is pushing mine too low so it might pay to be very careful here...

 

[heyitisjustin]

Well i got some of the benefits from dexametasone by taking testosterone gel, and by taking a dopamine agonist.

So increasing dopamine helped you sleep? Did I get that right?

 

[futuritycarpaccio]

Dexametasone cured me, it really did, with exception of sleep. It gave me really bad insomnia from the first dosage. But after quitting my sleep pattern seemed improved. I didnt retain any gains from it though

I am still messing with testo gel so i dont want to comment on it. The benefits i got where related to mood and surprisingly gynecomastia

 

[heyitisjustin]

Dexametasone cured me, it really did, with exception of sleep. It gave me really bad insomnia from the first dosage. But after quitting my sleep pattern seemed improved. I didnt retain any gains from it though

I am still messing with testo gel so i dont want to comment on it. The benefits i got where related to mood and surprisingly gynecomastia

If dex helped your sleep you might have too low cortisol. Have you seen an Endocrinologist? You might also have something that benefits from cortisol (I have histamine intolerance which cortisol regulates. I think it also modulates inflammation).

 

[futuritycarpaccio]

If dex helped your sleep you might have too low cortisol. Have you seen an Endocrinologist? You might also have something that benefits from cortisol (I have histamine intolerance which cortisol regulates. I think it also modulates inflammation).

lol not it didnt help my sleep, as i wrote in the former posts.

it cured me in every other aspect though