450 replies to this topic

[Chadwick]

amazing thread. when i saw the dopamine and alcohol words together in the title, i knew its going to be interesting and boy what a trip it is to read it.

chadwick, i find it amazing how when you started this thread you were still figuring out whats wrong with you and by the end of the thread, not only did you find out and fix yourself, now you are like a teacher to the rest of us! which is amazing. most people start threads and cry all the time asking for answers and usually people cannot give them any. i have noticed no thread ever gives a topic starter their best solutions EVER but its like a road down the thread to find out whats best yourself and you suprised me to do just that contrary to other people on this forum. i must say, you are a pretty smart guy, except mentioning the defects in genes associated with dopamine, did you also see any expression in genes involved in intelligence?

but i have to ask this, its main reason i reply though i love the thread, im not sure i have the same problem to follow your regime and im not sure what problem i have anyway so this is why i reply now to ask this; if order the gene test from 23andMe, how much do they really tell you and explain in detail to you whats wrong and right with you ? i have never done this gene test, i have no clue how to read it! and you are smart enough to have figured it out by yourself without them telling you i assume ? i have to take this test but if they cannot help me with information, ill waste money on something i dont even really understand at all. but i assume you can read those tests and help me out ? i dunno if you self taught yourself all that biochemistry and knowledge on genetical problems, but you know what you are talking about so i put trust in you. perhaps you even have a job related to this ?
anyway any help much appreciated!!

I took me two years of medical school as well as a lot of thinking and reading on my own to figure out what my own problem really was. And now than I've done that and learned how to treat it, I can tell you that it was so, so worth it. I changed my life for the better, and I would be glad if I could help other people with similar problems to do the same.

I'm curious about how you see your problem subjectively - is it lack of motivation, depression, fatigue, or how would you describe them?

23and me will tell you some basic information about disease risks, but if you want to find out about you're genes relating to neurotransmission I'm afraid you'll have to download the raw data and analyze it yourself. The easiest way to do this is to use Promethease (https://promethease....ondemandlicense) which is an easy analytic tool, GeneticGenie Methylation Analysis (https://geneticgenie...ation-analysis/) which will give some info about genes relating to methylation, and SNPedia (http://www.snpedia.c...dex.php/SNPedia) which is a wiki-site that explains various genes. The easies ways to see your polymorphisms (gene variations) is to download your raw data from 23andme and upload it to Promethease, and then download the files you get from them. In the "report_ui2.html" file you can then search for certain SNPs (point mutations), that have names like Rs123456 and so on below. For the genes with many important SNPs you can just search for the gene name in Promethease and it will tell you if it finds something unusual.

These are the genes and SNPs I believe are the most important to look at when it comes to dopamine:

MTHFR - A gene involved in producing the active form of folate, which is needed to make several neurotransmitters.
Rs1801133 aka C677T. C is good to have, T is bad.
Rs1801131 aka A1298C. A is good, T is bad.

DHFR - Another gene involved in folate metabolism AND BH4 recycling. Not quite as important but still relevant. It's not know which SNPs are important here. Personally I'm homozygous Rs1650697 which is somewhat uncommon. C is good to have here, and T is bad.

GCH1 - Involved directly in BH4 synthesis. Many SNPs that are important, see http://snpedia.com/index.php/GCH1.

PCBD1 - Involved in BH4 synthesis. Many SNPs, see http://snpedia.com/index.php/PCBD1.

PTS - Involved in BH4 synthesis. Many SNPs, see http://snpedia.com/index.php/PTS.

QDPR (aka DHPR) - Involved in BH4 synthesis. This enzymes uses NADH, which I believe is the reason that NADH can raise BH4. Many SNPs, see http://snpedia.com/index.php/QDPR.

SPR - Involved in BH4 synthesis. Many SNPs, see http://snpedia.com/index.php/SPR.

TH (tyrosine hydroxylase) - Converts tyrosine to L-DOPA, which then is used to make dopamine. TH is an iron-containing enzyme, which is the reason that iron deficiency can lead to lower dopamine levels. Many importants SNPs, see http://snpedia.com/index.php/TH

DDC (aka AADC, dopa decarboxylase) - Turns L-DOPA into dopamine, and 5-HTP into serotonin. Several important SNPs, see http://www.snpedia.com/index.php/DDC.

COMT - Breaks down dopamine and other neurotransmitters.
Rs4680 aka the warrior/worrier SNP. The Met version (A) will give you lower COMT activity and therefore more dopamine. This will lead to higher pleasure response and higher extraversion, but also lower threshold for stress. The Val version (G) will give you higher COMT activity and therefore less dopamine. This will lead to lower pleasure response, lower extraversion but also higher threshold for stress. Val will make you calm and collected while Met will make you motivated and outgoing.

MAO - Breaks down dopamine and several other neurotransmitters.
Rs6323 - G will lead to higher enzyme activity and lower dopamine, and T to lower activity and higher dopamine.

DAT (aka SLC6A3, dopamine transporter) - removes dopamine from the synapse so it can't bind its receptors.
Rs27072 is onvolved in alcohol withdrawal as well as ADHD. C increases risk for ADHD and alcohol withdrawal, T lowers it.

DRD1 (dopamine receptor D1) - Involved in neuronal development and various behavioural responses. Several semi-important SNPs, see http://www.snpedia.com/index.php/DRD1.

DRD2 (dopamine receptor D2) - Involved in social functioning, extraversion and social status. Low D2 binding correlate with social phobia.
Rs1800497 aka Taq1a polymorphism. C is good to have, T is bad.

DRD3 (dopamine receptor D3) - Low activation is involved in cognitive problems and depression. See http://www.snpedia.com/index.php/DRD3.

DRD4 (dopamine receptor D4) - Links to lots of psychiatric conditions, including ADHD.
Rs1800955 is linked to personality. T is the normal variant, and C increases novelty seeking.

DRD5 (dopamine receptor D5)http://en.wikipedia.org/wiki/DRD5 - Not sure if it's involved in anything unique. See http://en.wikipedia.org/wiki/DRD5.

If you're main focus is how low dopamine connects to social phobia or lack of social drive/motivation, I believe that MTHFR, DHFR, MAO, COMT and DRD2 are the most important. And yeah - I personally have bad versions of them all.

If you wanna do more reading I suggest this article. Also if you want pictures explaining the reactions connecting folate metabolism with BH4 and dopamine, you can check this out.

[Chadwick]

theres a few anecdotes and a little bit of evidence suggesting that glutathione binds to active b12 and depletes it from the body. You can read about people talking about it here:

http://forums.phoeni...tory.142/page-2

This may be a problem for anyone on here taking glutathione, glutathione precursors, and/or glutathione promoting substances. These may be interfering with your methylation and B12 use. I have been successfully boosting glutathione with l-cysteine, l-glutamine, glycine, vitamin c, sustained release alpha lipoic acid, and more. I found that sublingual methyl B12 in a dose of 4mg and oral 5-MTHF gave me that sudden energy. I felt motivated and alive. It came on within 20 mins of the B12. I also have lost my social drive and energy which I think is related to dopamine and this brought it all back. I was 100%. But then I took my morning mix of supps and the effect of B12 was gone. I think the glutathione boosting substances took the B12 right out of me from active use preventing methylation. I'm looking into using B2 and NAD+ to prevent this. beware people

For how long did the effects from the B12 last? When I started using B12 and folate I took sublingual methyl B12 and oral methylfolate and felt great for half and hour or so before the effect faded. This might have been an increase in BH4 and methylation at first, that then turned into mainly methylation and less BH4, but it's only a guess. With hydroxocobalamin I don't have this problem.

[normalizing]

amazing thread. when i saw the dopamine and alcohol words together in the title, i knew its going to be interesting and boy what a trip it is to read it.

chadwick, i find it amazing how when you started this thread you were still figuring out whats wrong with you and by the end of the thread, not only did you find out and fix yourself, now you are like a teacher to the rest of us! which is amazing. most people start threads and cry all the time asking for answers and usually people cannot give them any. i have noticed no thread ever gives a topic starter their best solutions EVER but its like a road down the thread to find out whats best yourself and you suprised me to do just that contrary to other people on this forum. i must say, you are a pretty smart guy, except mentioning the defects in genes associated with dopamine, did you also see any expression in genes involved in intelligence?

but i have to ask this, its main reason i reply though i love the thread, im not sure i have the same problem to follow your regime and im not sure what problem i have anyway so this is why i reply now to ask this; if order the gene test from 23andMe, how much do they really tell you and explain in detail to you whats wrong and right with you ? i have never done this gene test, i have no clue how to read it! and you are smart enough to have figured it out by yourself without them telling you i assume ? i have to take this test but if they cannot help me with information, ill waste money on something i dont even really understand at all. but i assume you can read those tests and help me out ? i dunno if you self taught yourself all that biochemistry and knowledge on genetical problems, but you know what you are talking about so i put trust in you. perhaps you even have a job related to this ?
anyway any help much appreciated!!

I took me two years of medical school as well as a lot of thinking and reading on my own to figure out what my own problem really was. And now than I've done that and learned how to treat it, I can tell you that it was so, so worth it. I changed my life for the better, and I would be glad if I could help other people with similar problems to do the same.

I'm curious about how you see your problem subjectively - is it lack of motivation, depression, fatigue, or how would you describe them?

23and me will tell you some basic information about disease risks, but if you want to find out about you're genes relating to neurotransmission I'm afraid you'll have to download the raw data and analyze it yourself. The easiest way to do this is to use Promethease (https://promethease....ondemandlicense) which is an easy analytic tool, GeneticGenie Methylation Analysis (https://geneticgenie...ation-analysis/) which will give some info about genes relating to methylation, and SNPedia (http://www.snpedia.c...dex.php/SNPedia) which is a wiki-site that explains various genes. The easies ways to see your polymorphisms (gene variations) is to download your raw data from 23andme and upload it to Promethease, and then download the files you get from them. In the "report_ui2.html" file you can then search for certain SNPs (point mutations), that have names like Rs123456 and so on below. For the genes with many important SNPs you can just search for the gene name in Promethease and it will tell you if it finds something unusual.

These are the genes and SNPs I believe are the most important to look at when it comes to dopamine:

MTHFR - A gene involved in producing the active form of folate, which is needed to make several neurotransmitters.
Rs1801133 aka C677T. C is good to have, T is bad.
Rs1801131 aka A1298C. A is good, T is bad.

DHFR - Another gene involved in folate metabolism AND BH4 recycling. Not quite as important but still relevant. It's not know which SNPs are important here. Personally I'm homozygous Rs1650697 which is somewhat uncommon. C is good to have here, and T is bad.

GCH1 - Involved directly in BH4 synthesis. Many SNPs that are important, see http://snpedia.com/index.php/GCH1.

PCBD1 - Involved in BH4 synthesis. Many SNPs, see http://snpedia.com/index.php/PCBD1.

PTS - Involved in BH4 synthesis. Many SNPs, see http://snpedia.com/index.php/PTS.

QDPR (aka DHPR) - Involved in BH4 synthesis. This enzymes uses NADH, which I believe is the reason that NADH can raise BH4. Many SNPs, see http://snpedia.com/index.php/QDPR.

SPR - Involved in BH4 synthesis. Many SNPs, see http://snpedia.com/index.php/SPR.

TH (tyrosine hydroxylase) - Converts tyrosine to L-DOPA, which then is used to make dopamine. TH is an iron-containing enzyme, which is the reason that iron deficiency can lead to lower dopamine levels. Many importants SNPs, see http://snpedia.com/index.php/TH

DDC (aka AADC, dopa decarboxylase) - Turns L-DOPA into dopamine, and 5-HTP into serotonin. Several important SNPs, see http://www.snpedia.com/index.php/DDC.

COMT - Breaks down dopamine and other neurotransmitters.
Rs4680 aka the warrior/worrier SNP. The Met version (A) will give you lower COMT activity and therefore more dopamine. This will lead to higher pleasure response and higher extraversion, but also lower threshold for stress. The Val version (G) will give you higher COMT activity and therefore less dopamine. This will lead to lower pleasure response, lower extraversion but also higher threshold for stress. Val will make you calm and collected while Met will make you motivated and outgoing.

MAO - Breaks down dopamine and several other neurotransmitters.
Rs6323 - G will lead to higher enzyme activity and lower dopamine, and T to lower activity and higher dopamine.

DAT (aka SLC6A3, dopamine transporter) - removes dopamine from the synapse so it can't bind its receptors.
Rs27072 is onvolved in alcohol withdrawal as well as ADHD. C increases risk for ADHD and alcohol withdrawal, T lowers it.

DRD1 (dopamine receptor D1) - Involved in neuronal development and various behavioural responses. Several semi-important SNPs, see http://www.snpedia.com/index.php/DRD1.

DRD2 (dopamine receptor D2) - Involved in social functioning, extraversion and social status. Low D2 binding correlate with social phobia.
Rs1800497 aka Taq1a polymorphism. C is good to have, T is bad.

DRD3 (dopamine receptor D3) - Low activation is involved in cognitive problems and depression. See http://www.snpedia.com/index.php/DRD3.

DRD4 (dopamine receptor D4) - Links to lots of psychiatric conditions, including ADHD.
Rs1800955 is linked to personality. T is the normal variant, and C increases novelty seeking.

DRD5 (dopamine receptor D5)http://en.wikipedia.org/wiki/DRD5 - Not sure if it's involved in anything unique. See http://en.wikipedia.org/wiki/DRD5.

If you're main focus is how low dopamine connects to social phobia or lack of social drive/motivation, I believe that MTHFR, DHFR, MAO, COMT and DRD2 are the most important. And yeah - I personally have bad versions of them all.

If you wanna do more reading I suggest this article. Also if you want pictures explaining the reactions connecting folate metabolism with BH4 and dopamine, you can check this out.

thats a lot of information, thanks. it will take me a while to deal with all those things and process it most properly. starting first, dealing with the test which is kind of expensive for me and until i can afford it i cant move further. but the whole reading of genes, oh boy that is going to be a while. also, the whole bad news section of it is not fun to read how you will catch this or that disease and die of this or that :S but overall this can actually be fun to interprate....
anyway, i dont believe i suffer from same problems unless im in depression mode where i isolate myself and that happens a lot usually because of my addiction problems. that is the reason i need to take the test, i suspect i have some errors with dopamine genes, im a severe form of an addict. i cant remember NOT being an addict throughout my life. it costs me a lot! once i start i cant stop and its always "seeking novelty" type of behavior where you need more and more and more of pleasure to feel better. even if its less than ordinary, you still feel like you need more and more. it eats you inside. a person just cannot stop or control it. seems i have some severe form too compared to other addicts i met who try and manage it at least. anyway, novelty seeking has always been a problem with dopamine one way or another, i suspect its some error that i have to get an idea of.

[Mr Serendipity]

Does Zinc, Magnesium, Copper, or B6 relate to any of these cycles?

 

I've been taking zma for around 2 weeks, and felt pretty darn happy and motivated in life; a general sense of ease that it only gets better from here on out. This feeling is happening regularly, and I feel like a new kind of person, more confident. Rather than how I use to be, apathetic, going through the motions, frustrated but lacked feeling and emotions of depression, just frustrated. Now I feel much less like this because of zinc, magnesium, copper, and b6.

Edited by manny, 11 April 2014 - 07:22 PM.

[Chadwick]

Does Zinc, Magnesium, Copper, or B6 relate to any of these cycles?

 

I've been taking zma for around 2 weeks, and felt pretty darn happy and motivated in life; a general sense of ease that it only gets better from here on out. This feeling is happening regularly, and I feel like a new kind of person, more confident. Rather than how I use to be, apathetic, going through the motions, frustrated but lacked feeling and emotions of depression, just frustrated. Now I feel much less like this because of zinc, magnesium, copper, and b6.

 

B6 is used for converting 5-HTP to serotonin, L-DOPA to dopamine, norepinephrine and epinephrine, and some other stuff.

 

Zinc is used by a lot of enzymes, including methionine synthase, the same enzyme that is using B12.

[Lufega]

I believe this thread is going to help a lot of people figure out their dopamine related issues.  Folic acid doesn't seen to be the only issue for some of us, though.

 

I found a couple of interesting mutation in my profile that affect dopamine homeostasis.  It's seem that my problems are mostly centered around B12, vitamin D and to a lesser extent, vitamin B6.  

 

This is what I have:

 

MTHFR - No mutations

COMT - Val/Val - higher enzymatic activity

Taq1A - C;T - less D2 receptor density.

MAO - "T" allele. - lower mao enzyme activity

 

Now, this is where is gets interesting:

 

Homozygous for MTRR A664A rs1802059 (A;A).  This codes for methionine synthase reductase, an enzyme that helps methylate B12 so it can be used by methionine synthase (MS catalyzes the conversion of homocysteine to methionine).  With this mutation, the MTRR enzyme is less active and the activity of methionine synthase slows down.  This places a higher need for methyl-B12.  How much?  I have no idea.

 

Heterozygous for MTRR A66G rs1801394 which is similar to #1 meaning I need more B12.

 

Heterozygous for MTR A2756G rs1805087, which increases the activity of methionine synthase (to generate from methionine) and methylB12 is used up faster.  This is made worse is you have an MTRR mutation that can't methylate B12 fast enough.

 

Rs4654748(C;T)  There's a 1.45 ng/mL lower Vitamin B6 blood concentration for every C allele.  According to Niner, normal levels of B6 are 5-24 ng/ml so I don't yet know the relevance of this.

 

Rs2282679 (C;C) Associated with Lower vitamin D levels and thus, vit. d insufficiency.  There's 3 other SNP's but the 23andme chip used to profile my genome didn't look for those.

 

So my body uses up more methylated B12 and cannot regenerate enough of it to keep up with the demand.  This I assume has downstream effects including less conversion of homocysteine to methionine, less SAMe production (and all the downstream effects) and a decrease in formation of methylfolate.

 

I'm not sure I got the science right but this can partly explain some of my dopamine issues (little motivation or desire to go out, social anxiety, etc.) over the years combined with severe fatigue, depression and memory problems.

 

I have tried using methyl donors in the past and I am very sensitive to them.  TMG gave me an instant migraine, 125 mg DMG almost made me manic, SAMe causes horrible anxiety and choline causes depression.  So, I will add methylcobalamine in the lowest dose I could find (500 mcg) to start and 25 mg P5P and see if this has any positive effect.

 

I also want to add folic acid to balance the B12.  Not sure if I should use regular folic acid, since I have no MTHFR issues or just go with methylfolate?

Edited by Lufega, 24 April 2014 - 11:56 PM.

[Chadwick]

I believe this thread is going to help a lot of people figure out their dopamine related issues.  Folic acid doesn't seen to be the only issue for some of us, though.

 

I found a couple of interesting mutation in my profile that affect dopamine homeostasis.  It's seem that my problems are mostly centered around B12, vitamin D and to a lesser extent, vitamin B6.  

 

This is what I have:

 

MTHFR - No mutations

COMT - Val/Val - higher enzymatic activity

Taq1A - C;T - less D2 receptor density.

MAO - "T" allele. - lower mao enzyme activity

 

Now, this is where is gets interesting:

 

Homozygous for MTRR A664A rs1802059 (A;A).  This codes for methionine synthase reductase, an enzyme that helps methylate B12 so it can be used by methionine synthase (MS catalyzes the conversion of homocysteine to methionine).  With this mutation, the MTRR enzyme is less active and the activity of methionine synthase slows down.  This places a higher need for methyl-B12.  How much?  I have no idea.

 

Heterozygous for MTRR A66G rs1801394 which is similar to #1 meaning I need more B12.

 

Heterozygous for MTR A2756G rs1805087, which increases the activity of methionine synthase (to generate from methionine) and methylB12 is used up faster.  This is made worse is you have an MTRR mutation that can't methylate B12 fast enough.

 

Rs4654748(C;T)  There's a 1.45 ng/mL lower Vitamin B6 blood concentration for every C allele.  According to Niner, normal levels of B6 are 5-24 ng/ml so I don't yet know the relevance of this.

 

Rs2282679 (C;C) Associated with Lower vitamin D levels and thus, vit. d insufficiency.  There's 3 other SNP's but the 23andme chip used to profile my genome didn't look for those.

 

So my body uses up more methylated B12 and cannot regenerate enough of it to keep up with the demand.  This I assume has downstream effects including less conversion of homocysteine to methionine, less SAMe production (and all the downstream effects) and a decrease in formation of methylfolate.

 

I'm not sure I got the science right but this can partly explain some of my dopamine issues (little motivation or desire to go out, social anxiety, etc.) over the years combined with severe fatigue, depression and memory problems.

 

I have tried using methyl donors in the past and I am very sensitive to them.  TMG gave me an instant migraine, 125 mg DMG almost made me manic, SAMe causes horrible anxiety and choline causes depression.  So, I will add methylcobalamine in the lowest dose I could find (500 mcg) to start and 25 mg P5P and see if this has any positive effect.

 

I also want to add folic acid to balance the B12.  Not sure if I should use regular folic acid, since I have no MTHFR issues or just go with methylfolate?

 

Yeah - methylation in itself can impact dopamine and other cathecolamines. So BH4 isn't the only connection between folate and neurotransmitters. 

 

I've experimented a lot with B vitamins over the past few months, and increasing or decreasing methylation has several noticeable effects on me:

 

Low methylation: Low mood, fatigue, increase in salivation, increase in perspiration, increased acne, poor wound healing, flaky skin around fingernails (ths is my earliest warning sign that methylation is low), skin histamine reactions and low tolerance to high histamine foods (such as tuna).

 

High methylation: Increase in mood, high energy, low-normal salivation, low-normal perspiration, smooth skin, fast wound healing, low histamine.

 

You can always try methyl B12 to see if it helps you. 500 is a good starting dose, but it has to be taken sublingually. This will increase methylation, but it might also decrease BH4.

 

I'd use methylfolate with it even if you don't have any MTHFR mutations. This is because methylfolate will regenerate methyl B12 from its inactive form after it's been used for methylation. Also, using folic acid instead of methylfolate can actually lower methylation by using methyl groups to form methylfolate out of the non-methylated folic acid.

Edited by Chadwick, 26 April 2014 - 12:02 PM.

[chris106]

First of all, I agree with many others that this is an amazing thread.

I will get myself tested with 23&me as soon as possible, since I suspect a MTHFR mutation might be the root of my problems.

Anyways, I have a question, Chadwick:

Is this product a legit form of MTHF?

http://www.ebay.com/...=item233980761f

It seems odd to me that it is so much cheaper than any other MTHF product I can find, and it's the only one that uses this "quatrefolic" branding.The ingredients-description makes it seem as though it could be a lower form of Folate masked as MHTF...?


Also, I can only seem to find few sources of hydroxocobalamin - the only one that seems affordable comes as nasal spray:

http://www.ebay.de/i...=item4ac81c02b5


Do you have any other/ cheaper sources you would be willing to share?


 

[Chadwick]

First of all, I agree with many others that this is an amazing thread.

I will get myself tested with 23&me as soon as possible, since I suspect a MTHFR mutation might be the root of my problems.

Anyways, I have a question, Chadwick:

Is this product a legit form of MTHF?

http://www.ebay.com/...=item233980761f

It seems odd to me that it is so much cheaper than any other MTHF product I can find, and it's the only one that uses this "quatrefolic" branding.The ingredients-description makes it seem as though it could be a lower form of Folate masked as MHTF...?


Also, I can only seem to find few sources of hydroxocobalamin - the only one that seems affordable comes as nasal spray:

http://www.ebay.de/i...=item4ac81c02b5


Do you have any other/ cheaper sources you would be willing to share?


 

 

The folate you linked to is legit - I have that one as well at home but I currently don't use it since it has 400 mcg of folate in capsules, that are difficult to split to get the 200 mcg I want. Quatrefolic is another form of methylfolate and I'm not exactly sure of the (tiny) difference between it and Metafolin that I use, but both work well for me and many others. This is the one I personally use: http://www.iherb.com...40&sr=null&ic=3

 

For hydroxocobalamin I use this one: http://www.iherb.com...=4&sr=null&ic=1 It doesn't seem to matter if I skip a day or two every now and then when it comes to the B12, and it might even be possible to just take it every other day. It's somewhat more expensive than the foalte, so if that works it could be a way to keep expenses down. 

 

Edit: also, www.iherb.com is a good site to buy supplements, regardless of where you live. I pay $8 for 4-day shipping to Sweden.

Edited by Chadwick, 03 May 2014 - 09:38 PM.

[Mr Serendipity]

Well we might start getting confused on what folate to buy very soon in the future if the FDA has its way.

http://www.anh-usa.o...ther-b-vitamin/

[normalizing]

why are they banning it? also you are in UK, interesting concern though...

[xks201]

Majority of people have methylation mutations if not everyone has at least 1 or a few. Personally a blood test showed b12 over 3 times the top reference number and that told me I needed mb12 because it wasn't converting to mb12 obviously

[Lufega]

Funny thing about mb12. Every time i take it, it makes me very sleepy and groogy. I was expecting an abundancy of energy. I read something about increasing conversion of serotonin to melatonin or it could be that its increasing methylation or decresing bh4. All in all, im not feeling a boost in motivation but it does help with focus some.

I can try to take it at night but im afraid i'll get a wired, sleepy effect.

[Chadwick]

Funny thing about mb12. Every time i take it, it makes me very sleepy and groogy. I was expecting an abundancy of energy. I read something about increasing conversion of serotonin to melatonin or it could be that its increasing methylation or decresing bh4. All in all, im not feeling a boost in motivation but it does help with focus some.

I can try to take it at night but im afraid i'll get a wired, sleepy effect.

 

I personally know of one possible reason for this, but there are probably several other explanations as well:

 

People with a very high heavy metal burden, mainly mercury, can have a paradoxical reaction to methyl B12. The reason for this is that methyl B12 reacts directly with elemental mercury in the body and forms methylmercury, a MUCH more toxic substance than elemental mercury. When this methylation takes place the mercury is also mobilized from intracellular storage to the blood and from there distributed in the body, including passing the blood-brain barrier. 

 

Ironically, mercury, and especially methyl mercury since it's so much more toxic, acts as a strong inhibitor of methionine synthase, the same ezyme that methyl B12 is used by. The end result is that methyl B12 in mercury toxic people DECREASES methylation and gives symptoms of undermethylation, like fatigue and brain fog. Somewhat of a paradoxical reaction. 

 

So, the theory is that having a high heavy metal load (due to industrial exposure, amalgam fillings etc) could possibly be a reason for methylation problems in people who have a genetic predisposition for it, such as unfortunate polymorphisms in the genes relating to methylation (MTHFR, DHFR, MTRR, MTR and so on). These people will be undermethylated but will react poorly to methylation supplements.

 

Do you currently have any amalgam fillings, or have you had any in the past?

 

But as I said - there might be other more likely explanations 

[Lufega]

I had a few amalgam fillings but I had them all remove (the correct way) back in 2008.  

[monttt3]

Hello, nice to make your acquaintance. I've experience the same after-effects as you and find it horrible that these effects don't last. It's tormenting to know what you can achieve and be unable for the majority of the time to be at that level. It consumes way too much of my time... I find that GABAergic drugs like phenibut and gabapentin produce similar effects, though nothing so insightful and life-changing as those gained from the hangover. What's been killing me lately is knowing that each time I produce this state (through alcohol consumption), I destroy more of my limited number of brain cells. For the time being, I will decrease my alcohol consumption to three times a month, and in the meantime search for a healthy and wholesome fix. My methylated B12 will arrive some time today. 

 

Products that elevate my cognition significantly but inconsistently: Phenibut and Caffeine combination, and Marijuana. If I mix pheni with alcohol, the cognitive enhancements from the hangover are significantly increased. It leads me to wonder whether the effects we gain is a result of our unique neurochemistries, or if this is an effect that anyone can gain. If the latter is correct, it seems we will be forever fruitless in our pursuit of a solution (which is in fact non-existant). I, however, will not stop trying. I'm at my wits end as to how to proceed. I suppose a psychiatrist may be able to work through this problem with me. If it is the dopamine deficiency that is causing the cognitive defects, then what drug might I ask my psych to prescribe?

 

Also, an update by you would be nice. Have you found a new remedy? Have you been using the hangovers for enhancement lately? It's certainly unsustainable in my opinion. Also, someone should try a day of phenibut and alcohol. Use 2 grams of phenibut throughout the day (if you already have a tolerance) and consume alcohol that night (I use 8 shots). The next day may come with a hangover, sometimes the hangover doesn't come. YMMV. 

 

It sucks, because I made so much progress professionally using this combo, and I'm afraid I won't be able to live up to that reputation I established. Ah... Let's work out a solution please.

[Dichotohmy]

My experience, as a longtime heavy drinker, is that there's nothing pleasant about the hangover following acute alcohol intoxication. Nothing at all.

 

On the other hand, immediate cessation from just the right amount of ongoing alcohol intoxication, whether it be a day or two of binge drinking, or a weeks/months/years-long bender, results in the wonderful clarity described in this thread. It can also result in depersonalization and derealization and other elevated anxiety as the day(s) of cessation go on, but that's another matter entirely.

 

If I were to guess, I'd pin it on erratic gluaminergic rebound, or dopamine rebound following the sensation of alcohol's GABA-induced dopamine downregulation. Unfortunately, the positive effect is short lived because the neurotransmitter rebounds are so erratic - as any alcoholic going through withdrawal can attest to. 

 

5-MTHF and Me-B12 don't emulate the alcohol cessation effect for me, at all, but do help with physical energy.

 

 

Edited by Dichotohmy, 21 June 2014 - 05:57 PM.

[Vision]

Methylfolate (800-3200µg), Uridine UMP (2x250mg) and St. John's Wort (3-5x 300mg, 0.2-0.4% Hypericins, 2-4% Hyperforins) seems to emulate this hangover effect for me. ~5 days on this stack, will report if effects diminish.

[Lufega]

500 mcg mb12 wasn't doing anything for me so I increased it to 5,000 mcg sublingual.  At this dose, I'm having a surge of motivation and it's allowed me to get a whole lot done today.

 

I'll repeat this dose for the upcoming week to see if the effects are permanent.  Once that is done, I'll titrate down using 1,000 mcg to see if I can duplicate that effect with a smaller dosage. 

[Area-1255]

So, I got my 23andme results back. There are a few interesting things relating to dopamine that I've found so far. I'm homozygous Val/Val for the Val158Met in COMT, which means I'm breaking down dopamine, norepinephrine and epinephrine fast. I'm heterozygous for the Taq1A form of DRD2/ANKK1, which means my D2 dopamine receptors are less sensitive to dopamine. I'm also heterozygous for two mutations in the MTHFR enzyme: 1298 and 677. This means I'm producing less MTHF than the average person.
 

I took my first 500mcg dose of 5-MTHF last night. Within a half hour I started feeling anxiety, so I went for a jog, the anxiety wore off.

One interesting effect is my senses seemed to be heightened, when I listed to music I felt like there was subtle sounds I heard in the music I never had before, making it a more enjoyable experience. When I went to sleep I usually leave my pc on, ,but I heard a sound which almost sounded like a fly buzzing around, but in fact it was simply the echo of something in my computer running, when I shut the computer off obviously the noise went away and I fell asleep.I

I also did feel a lift in mood. I have read on here that if you have been deficienct in something for a while when you first take it you may feel some unpleasent feelings at first which could be the initial anxiety. So I am going to start slow using this every other day and see how it goes.

Personally I had an amazing time on 4 mg MTHF per day, without side effects, but that only lasted a week. After that anxiety and brain fog set in. After doing some googling I found this site which describes my experience quite well. It seems as if some people does not exerience any side effects, some get side effects after a week and some never have any trouble. This can be explained by the fact that MTHF has a methyl group, and therefore increases methylation which in turn can cause anxiety and brain fog.

For me this resolved after lowering my dose to 800 micrograms x2 per day, and adding 250 mg time-release niacin (vitamin B3). Niacin is broken down by methylation, and can therefore decrease excessive methylation. Sadly, the amazing results I felt the first week wore off, but I'm still doing better than I did before.

 

That's interesting, overmethylation tends to produce ahedonia by causing both low histamine and high serotonin (bad combination for nerves as well). In regards to your DRD2/ANKK1 - that is an unfortunate predicament - does it involve only the D2 short allele or the long strand as well? I haven't looked much into that particular gene, but if you have less sensitivity to dopamine at the D2S - you would have more dopamine due to less autoreceptor activity - so I am going to assume based on your symptoms that can't be the case - and that D2L is most certainly cross-interacting with that gene.

 

In addition, please remember there is a range of complex interactions when speaking about NMDA, for example, low NMDA activity is associated with elevated Zinc status, low serum histamine levels and possibly elevated magnesium as well - in addition to having significantly LESS reuptake of dopamine (leading to more dopamine activity) - ironically people still get ahedonia - but because of different reasons. Some commonly tied to overmethylation - and here is why.

 

When you are overmethylated, as said, serotonin continues to elevate - so no matter how much your raise dopamine, it is always going to be blunted to an extent --> or placed into the wrong area's, by the wrong receptors. In addition, overmethylation leads to LOW HISTAMINE - which leads to less dopamine being produced. Reason? 

 

Same reason clenbuterol and albuterol BOOST dopamine synthesis - the activation of adenylyl cyclase which leads to TYROSINE HYDROXYLASE activation - which leads to MORE dopamine being produced from Tyrosine - and increased sensitivity (more of a stimulant effect) from protein containing foods. Especially nuts and other foods that contain high amounts of tyrosine.

 

What this means is overmethylation may cause increased dopamine in the synapse, but that is short-circuited and irrelevant because the enzymes necessary for production of dopamine are Decreased dramatically.

 

 

Forskolin and Beta-Agonist usage is a good way to determine if this is your problem. If you respond well or get euphoria off of albuterol, clenbuterol, forskolin or similar cAMP boosting chemicals, then you are most likely OVERMETHYLATED.

 

If you are undermethylated, you would have the opposite effect, with increased rates of dopamine production, but less utilization and increased reuptake.

 

High Histamine is associated with low serum norepinephrine,dopamine and serotonin...  {UnderMethylation}

 

 

Read my article for more information --> http://area1255.blog...t=1408892625677

 

Also ...one of the symptoms shared by both low NMDA-activity and low histamine - is feeling like people can read your thoughts and a state of constant racing mind.

 

 

Signs and Symptoms of Low NMDA Activity

Edited by Area-1255, 26 August 2014 - 01:19 AM.

[Guardian4981]

When I do well on forskolin in terms of the mental benefit.  My issue with forskolin is I believe it lowers blood sugar, and my blood sugar tends to get to low to begin with.  What other supplements could work?

 

I have read niacinimide, but doesn't niacinimide raise serotonin?

[Area-1255]

When I do well on forskolin in terms of the mental benefit.  My issue with forskolin is I believe it lowers blood sugar, and my blood sugar tends to get to low to begin with.  What other supplements could work?

 

I have read niacinimide, but doesn't niacinimide raise serotonin?

Niacin can certainly raise serotonin. You need all B-Vitamins in colab though for proper NT synthesis. 

If you have low serotonin in bloodwork, you should also check for norepinephrine and dopamine - if these are also low, then you are probably undermethylated / high histamine. But then again not always, there is a such thing as low histamine and low serotonin, especially if an estrogen imbalance is apparent. Also things are never that clear-cut, because some people have low serotonin genetics or in particular, with people with OCD, genetically inherit SERT mutations/polymorphisms  - leading to increased serotonin reuptake and very strong serotonin loss - another one is the 5-HT1Dbeta gene - http://www.nature.co...s/4001059a.html

 

Keep in mind, these very same genes/polymorphisms are also involved in BiPolar and Major Depressive Disorder.

http://www.ncbi.nlm..../pubmed/1351684

 

 

 

The 5HT1Dβ receptor gene has at least three polymorphisms known: G861C, T-261G, and the functional T371G (Phe-124-Cys). The aim of this study was to investigate for the presence of linkage disequilibrium between the 5HT1Dβ receptor gene and BP. Two hundred and ninety probands with DSM-IV BPI, BPII, or Schizoaffective Disorder (Bipolar type) with their living parents were recruited. Genotyping data for the G861C and T371G polymorphisms were analyzed using the Transmission Disequilibrium Test (TDT). One hundred and sixty triads were informative for the TDT on the G861C polymorphism, which showed no preferential transmission of either allele (chi-square = 0.438, df = 1, p = .508). Only four triads were suitable for the analysis on the T371G variant, with the T allele transmitted once and the G allele transmitted four times to the affected. These findings validate further the results of pharmacological studies excluding a direct involvement of the 5HT1Dβ receptor in the pathogenesis of BP. Further investigations combining genetic and pharmacological strategies are warranted.

 

http://www.nature.co...l/1395702a.html

https://www.wikigene...ene/e/3352.html

Edited by Area-1255, 26 August 2014 - 03:20 PM.

[Anewlife]

Sounds like you MIGHT benifit from psychoanalysis and cbt.
I suspect you MAY have issues in your subconscious playing on your mind. Your post hints at a need for internal stimulation. Do you feel strong emotions in romantic relationships or have a narrow direction in life?

[Chadwick]

theres a few anecdotes and a little bit of evidence suggesting that glutathione binds to active b12 and depletes it from the body. You can read about people talking about it here:

http://forums.phoeni...tory.142/page-2

This may be a problem for anyone on here taking glutathione, glutathione precursors, and/or glutathione promoting substances. These may be interfering with your methylation and B12 use. I have been successfully boosting glutathione with l-cysteine, l-glutamine, glycine, vitamin c, sustained release alpha lipoic acid, and more. I found that sublingual methyl B12 in a dose of 4mg and oral 5-MTHF gave me that sudden energy. I felt motivated and alive. It came on within 20 mins of the B12. I also have lost my social drive and energy which I think is related to dopamine and this brought it all back. I was 100%. But then I took my morning mix of supps and the effect of B12 was gone. I think the glutathione boosting substances took the B12 right out of me from active use preventing methylation. I'm looking into using B2 and NAD+ to prevent this. beware people

 

I actually tried protandim, a supplement said to increase glutathione synthesis, a few weeks back, and ended up with extreme fatigue. The fatigue felt exactly the same as when I tried high doses of niacin a year ago, which also decreases methylation.

 

Sounds like you MIGHT benifit from psychoanalysis and cbt.
I suspect you MAY have issues in your subconscious playing on your mind. Your post hints at a need for internal stimulation. Do you feel strong emotions in romantic relationships or have a narrow direction in life?

 

I'm not sure if those questions were directed towards me, but if they were then the answers are yes, I feel strong emotions in a relationship and no, I don't have a narrow direction in life. 

[Anewlife]

Yeah at you Chadwick. You are still young so it's hard for me to draw a conclusion but I recommend you at least do some mindfulness meditation for now, get Book on it. Please try it for 10mins twice a day for 2 months before making a judgment along with fish oil and NAC. also a multi, roughly 800iu d3, Vit b6 and zinc. High dose magnesium.

I don't follow here too much anymore as i kicked a 10 year heavy internet addiction but please pm me after those 2 months as I am very curious about you. If it does work I can suggest further improvement.

[Anewlife]

Mainly focus on breathing and secondly feeling textures for mindfulness. You should try do it to fulfill your need for stimulation and prevent worrying about supplements. Any psych people here seeing where I am going please don't conclude a Dx of anything in a 22 year old over the net.

Edited by Anewlife, 28 August 2014 - 09:14 PM.

[Lufega]

Chadwick,

 

From your genetic genie report, do you have have any of the following mutations that affect methylcobalamin metabolism? (MTR or MTRR)

 

 

[Chadwick]

Mainly focus on breathing and secondly feeling textures for mindfulness. You should try do it to fulfill your need for stimulation and prevent worrying about supplements. Any psych people here seeing where I am going please don't conclude a Dx of anything in a 22 year old over the net.

 

To be honest I don't have any problems that needs to be solved anymore. But thanks for your concern!

 

Chadwick,

 

From your genetic genie report, do you have have any of the following mutations that affect methylcobalamin metabolism? (MTR or MTRR)

 

Yeah, but only heterozygote ones:

 

MTR A2756G rs1805087 AG +/-

MTRR A66G rs1801394 AA -/-

MTRR H595Y rs10380 CT +/-

MTRR K350A rs162036 AG +/-

MTRR R415T rs2287780 CC -/-

MTRR A664A rs1802059 AG +/-

Edited by Chadwick, 03 September 2014 - 12:28 PM.