450 replies to this topic

[Chadwick]

For as long as I can remember, I've felt that something is wrong with me. I'm 22 now, and what I'm feeling is somewhat difficult to put into words. It's as if I lack an inner drive and desire to be social, combined with an almost complete inability to be spontaneous. It's kind of like a light version of the negative symptoms of schizophrenia. However, I don't have any anxiety, and no major concentration difficulties.

During the last two years I've been thinking a lot and experimenting around with supplements, and I've noticed two things. The first thing is that this feeling goes away whenever I use dopaminergics. The second thing is that this feeling also disappears during hangovers the day after I've drunk a lot of alcohol (7 beers or more). The alcohol in itself makes me feel great, but strangely I feel even better while I'm hungover. I become clear-headed, I get back my desire to be social and I feel like myself in a way that is very rare for me. I often try to make the hangovers last as long a possible, simply because I enjoy it. After a lot of thinking I've come up with three possible explanations for this:

1. NMDA receptor hypoactivity. Low NMDA receptor signaling has been implicated in some forms of ADHD/ADD as well as schizophrenia. Since alcohol is an NMDA receptor antagonist, heavy alcohol consumption should upregulate NMDA signaling. I've tested this possible cause by using sarcosine (an NMDA co-agonist) and glutamine for a few days, but without improvement. If anything, I felt slightly overstimulated in a non-dopaminergic way, as well as somewhat derealized.

2. Increased NADH. Alcohol needs NAD+ for it's breakdown by alcohol dehydrogenase, and thereby produces an excess of NADH. NADH stimulates dopamine production by increasing the recycling of BH4, a cofactor for tyrosine hydroxylase. I've tried a NADH supplement, 10 mg a day for a few days, but without any effect.

3. Excess acetylcholine. Alcohol decreases acetylcholine synthesis and release, and too much acetylcholine seems to interfere with dopamine signaling. I haven't tested this one yet as I'm not sure how to do it. Ideas?

These are the supplements I've tried so far without effect: Zinc, manganese, vitamin D, vitamin C, vitamin A, NADH, fish oil, sarcosine, glutamine, magnesium, ALCAR, CDP-choline (makes me depressed sometimes, but not always), phosphatidylcholine, B complex, inositol, curcumin, MSM, SAMe (gives me a very uncomfortable feeling), caffeine (should give me a boost but it doesn't).

And these are supplements that have a subtle or limited effect: Uridine (worked amazingly well for two weeks, and then it stopped working - during this time I felt like myself for the first time for months), green tea extract (possibly a subtle effect), quercetin (subtle effect), CILTEP, tyrosine (works great, but I build tolerance quickly), dl-phenylalanine (tolerance), n-acetyl tyrosine (tolerance), phosphatidylserine (does nothing in itself, but combined with caffeine it gives me a boost for 30 minutes or so), grape seed extract (had an effect for a while, but then stopped working - not sure why it had an effect in the first place).

The best thing I've tried so far is uridine+fish oil, but the effects only lasted for two weeks. Selegiline in small doses (1.25 mg or less) works ok, but gives me a very flat mood and slight derealization that lasts a few hours to a day. Not worth it.

I'm not sure how to figure this out or what to try next. Any ideas? Is there any safe way to lower acetylcholine that doesn't require a prescription?

[dannyfc]

I share a lot of the same symptoms, and can definitely relate to the positive effects of hangovers, and similarly after effects of GBH.

[Keynes]

Piracetam lowers (or redirects?) Acetylcholine, maybe try that?

Naltrexone

Naltrexone's mechanism of action in alcohol dependence is not fully understood, but as an opioid-receptor antagonist is likely to be due to the modulation of the dopaminergicmesolimbic pathway (one of the primary centers for risk-reward analysis in the brain, and a tertiary "pleasure center") which is hypothesized to be a major center of the reward associated with addiction that all major drugs of abuse are believed to activate.

Suppose it's dopamine related since l-tyrosine and alcohol works well for you (and other dopaminergics like you stated). The anhedonia might stem from some issue with the above mentioned pathway, which alcohol stimulates. Suppose people with anhedonia are more prone to drinking since it relieves their symptoms. Now in comes Naltrexone, stimulating their reward pathways and improving their anhedonia, drinking is no longer necessary. Ergo, no more drinking.

//total speculation and most likely wrong. Naltrexone is rather benign though, I'm going to try it myself for similar problems. Alcohol personally makes me social, but also quite retarded so I don't drink much.

Might also be depression-related.

[dannyfc]

Piracetam lowers (or redirects?) Acetylcholine, maybe try that?

Naltrexone

Naltrexone's mechanism of action in alcohol dependence is not fully understood, but as an opioid-receptor antagonist is likely to be due to the modulation of the dopaminergicmesolimbic pathway (one of the primary centers for risk-reward analysis in the brain, and a tertiary "pleasure center") which is hypothesized to be a major center of the reward associated with addiction that all major drugs of abuse are believed to activate.

Suppose it's dopamine related since l-tyrosine and alcohol works well for you (and other dopaminergics like you stated). The anhedonia might stem from some issue with the above mentioned pathway, which alcohol stimulates. Suppose people with anhedonia are more prone to drinking since it relieves their symptoms. Now in comes Naltrexone, stimulating their reward pathways and improving their anhedonia, drinking is no longer necessary. Ergo, no more drinking.

//total speculation and most likely wrong. Naltrexone is rather benign though, I'm going to try it myself for similar problems. Alcohol personally makes me social, but also quite retarded so I don't drink much.

Might also be depression-related.

Low Dose Naltrexone sounds extremely interesting. I've been reading up on it most of this evening and there's tonnes of both anecdotal adn scientific evidence to support it's effectiveness. Unfortunately there's a lot of exploitive quack-like websites who try and sell it as an all encompassing miracle drug for all diseases, that just devalues it's validity.

Would you know of any reliable European sources of it?

It seems to come in both liquid and caspule form, some websites require a prescription, others don't. There seems a lot of shadey websites offering online prescriptions which I feel a bit uneasy about. I don't think my GP would be willing to write me a letter of support so I'm a little stuck.

[Alphatrial]

Anyone knows a good address for Naldrexone? LDN might be easier is available. I'm looking for a supplier to The Netherlands. Thx

Edited by Alphatrial, 29 July 2013 - 10:32 AM.

[nowayout]

Almost all people wil function better temporarily from dopaminergic stimulants. It does not mean everyone has a dopamine deficiency. Just like feeling good from ecstacy does not mean you gave an ecstacy deficiency.

Unfortunately the scientific understanding of neurotransmitters is not nearly advanced enough to be able to even remotely speculate whether your symptoms are from any neurotransmitter deficiency. That kind of speculation is really folk beliefs, nothing more. For all we know your problem might just as easily have to do with neurocircuit wiring, for example.

Edited by nowayout, 29 July 2013 - 10:41 AM.

[Galaxyshock]

You could try Kava as a substitute for alcohol. You may find it more pleasant for inducing sociability and feeling good without the drunkenness.

[Keynes]

Almost all people wil function better temporarily from dopaminergic stimulants. It does not mean everyone has a dopamine deficiency. Just like feeling good from ecstacy does not mean you gave an ecstacy deficiency.

Unfortunately the scientific understanding of neurotransmitters is not nearly advanced enough to be able to even remotely speculate whether your symptoms are from any neurotransmitter deficiency. That kind of speculation is really folk beliefs, nothing more. For all we know your problem might just as easily have to do with neurocircuit wiring, for example.

This is of course true, but imo also a rather pessimistic outlook. The issue might be dopamine related, and it might be resolved addressing this. It's all trial and error.

But personally I'm all for the holistic approach (I do meditation, work outs, rejection therapy etc).

To the others: I don't know any legit sources of naltrexone, but I'm sure there might be some good suggestions on this forum! I'll talk with my doc tomorrow about it, and hopefully be able to try it out. I'll update here with the results.

[Chadwick]

Almost all people wil function better temporarily from dopaminergic stimulants. It does not mean everyone has a dopamine deficiency. Just like feeling good from ecstacy does not mean you gave an ecstacy deficiency.

Unfortunately the scientific understanding of neurotransmitters is not nearly advanced enough to be able to even remotely speculate whether your symptoms are from any neurotransmitter deficiency. That kind of speculation is really folk beliefs, nothing more. For all we know your problem might just as easily have to do with neurocircuit wiring, for example.

I too believe that it's too easy reduce mental problems to a simple balance between neurotransmitters, when in reality the brain is infinitely more complicated. Neurotransmitters have kind of become the modern version of the four temperaments. However, I also believe that there are cases where neurotransmittor deficiency is a real problem (or a part of the problem), and there are a few reasons why I've assumed I'm one of these cases:

What I lack seems to correlate pretty well with what is commonly associated with dopamine: drive, motivation, sociability and so on.

Last year I developed an iron deficiency that aggrevated my problems very very much, to a point where I barely could maintain a conversation with friends because my social drive was so low. Iron deficiencies can cause anemia-like problems such as tiredness and depression before anemia is developed, mainly through a decrease in dopamine (as iron is needed for tyrosine hydroxylase). This I believe is also the reason why iron deficiency is involed in the pathology of restless legs syndome. The subjective effects of an iron deficiency are however usually small, but for me they were extreme. To me this would make sense if I already had an underproduction of catecholamines.

I've tried a lot of supplements, and a few of them have helped me. All of those have been catecholamine-raising (tyrosine, phenylalanine, phosphatidylserine+caffeine, uridine) and no other supplements have made any difference.

[Chadwick]

So, today I tried 10 mg sublingual NADH instead of oral. It worked like a charm and put me in the same state of mind that I have when I'm hungover. Suppose a change in NAD+/NADH ratio might be it then.

That's a kind of a pity though as NADH seems to build tolerance for a lot of people.

Edited by Chadwick, 31 July 2013 - 06:39 PM.

[tritium]

So, today I tried 10 mg sublingual NADH instead of oral. It worked like a charm and put me in the same state of mind that I have when I'm hungover. Suppose a change in NAD+/NADH ratio might be it then.

That's a kind of a pity though as NADH seems to build tolerance for a lot of people.

Interesting discovery. I also noticed the same clear mind the day after moderate drinking. I seen that NADH is also involved in cellular respiration, so there may be a deeper mechanism and root cause which I would be very interested in finding out.

Mind sharing where you purchased NADH?

Edited by tritium, 31 July 2013 - 11:32 PM.

[tritium]

NADH is involved in thousands of reactions, but seems to be most commonly used in oxidative phosphorylation:

http://biocyc.org/ME...UND&object=NADH

[Chadwick]

The NADH i used is from NOW Foods, purchased at iHerb.com. Using the supplement as inteded (swallowing the capsule) didn't produce any effects, but opening it up and keeping the contents under my tounge for ~10 mins did.

Edited by Chadwick, 01 August 2013 - 08:39 AM.

[nowayout]

Iron deficiencies can cause anemia-like problems such as tiredness and depression before anemia is developed, mainly through a decrease in dopamine (as iron is needed for tyrosine hydroxylase). This I believe is also the reason why iron deficiency is involed in the pathology of restless legs syndome.

Didn't know this, thanks for the heads up.

Testosterone deficiency also causes similar symptoms (among other things via dopamine) and anemia, so you might do well to have your T tested. T has a large effect on dopamine in men, and the effect on TRT is often dramatic on dopamine-related symptoms.

Edited by nowayout, 01 August 2013 - 08:59 AM.

[machete234]

Did you try not sleeping for a night and see if you feel like hungover the next day?

[Thorsten3]

I get euphoric (borders on mania/extreme excitement) from hangovers as well. I always put it down to excessive glutamate release. Some sort of rebound reaction from how it interacts with the GABA receptors (similar to GHB, but different - less brutal).

Although the hangover always feels nice, it also feels kind of toxic (like my brain has been ramped up). I wouldn't be surpised if what you were feeling was actually neurotoxcity. Perhaps, adding magnesium or even some memantine (if you have it), the following day, might yield some protection.

Although I will confess that I do enjoy the feeling, after a while this stimulation starts to grate on me and I start to crave going to bed and sleeping it off. I couldn't be like that every day, i'd go insane I think.

I wonder if it is only a few of us that get this reaction, though? I've been aware of it for years. Ever since I started experimenting with alcohol.

Saying that, I don't even drink nowadays. I'll get drunk, perhaps, 3 or 4 times per year.

To ease a hangover, I will take a b-complex and 2 pints of water, before hitting the pillow.

A source for naltrexone is: all day chemist (in the US). I've used them a few times. Cheap worldwide shipping.

Edited by Thorsten2, 06 August 2013 - 09:45 AM.

[machete234]

I get really depressed during my hangovers and I have no clue how people can enjoy it.
I did have some positive effects with GHB the next day though while I dont feel like I have perfect motor control I feel kind of in a good mood.
Im talking about something like 4g a night, with less than that I feel nothing the next day.

[Chadwick]

Did you try not sleeping for a night and see if you feel like hungover the next day?

I haven't tried that, do you have any theory on what would happen? All I personally know is that lack of sleep downregulates dopamine receptor D2 signaling, and I believe that should have the opposite effects of what I'm looking for.

My current theory of the whole hangover/euphoria connection is this: Alcohol increases the body's levels of NADH. This increases the recycling of BH4, a major cofactor in dopamine (and serotonin+norepinephrine) synthesis. The people who feel this effect are people who have insufficient BH4 production, which can be caused by either mutations in the genes coding for the enzymes involved in BH4 synthesis (uncommon) or a lack of folate in its bioavailable form, 5-MTHF (more common). A lack of 5-MTHF can be caused by a lack of folate (due to poor diet, malabsorption etc) or a low 5-MTHF synthesis due to mutations in the gene coding for the enzyme MTHFR, which is fairly common. 30% have one defect copy of the gene, and 10% have two defect copies.



The only way to know for sure if you have some kind of genetic defect is of course to test for it. I'm waiting for my results from 23andme, which should come in 4-6 weeks.

Edit: If anyone's interested, there's more info on BH4/dopamine here.

Edited by Chadwick, 07 August 2013 - 09:59 PM.

[Keynes]

Earlier tonight I was at the club (drank quite a bit), and I got a serious urge to run. So when I got back I did that.

So here's what's strange = my performance was great. Usually running is a pain in the ass for me, but I actually did an extra lap and an extra sprint just for the fun of it. I felt amazing. My pace was far superior than normal (definitely not imagined). About 40 minutes @ 4:20 min/k is a rough estimation. Next time I'll get my garmin gps watch to measure properly.

But wtf. I'd very much like to get this effect without the alcohol per se. Anybody's got an idea?

After club running is a new staple in any case.

Another thing, I don't get hung over anymore since starting my regimen, which is sweet (I'll post it if anyone's interested). Not really sure why though.

Edited by Keynes, 10 August 2013 - 01:47 AM.

[machete234]

In my crazier times I ran home drunk as hell for over 10-20km catching a train when I could for some part of the distance its like your body doesnt care and feels no pain.

Once I drank 5 pints of beer and missed my transport to the club, I then had to run 7km in 30 minutes or so, which I managed, the alcohol didnt hurt at all but probably gave me some energy.

[Galaxyshock]

You guys are idiots. First dehydrate yourself by drinking and then you run with the alcohol still in your system? that's really fucking unhealthy. And 10-20 kilometers or with a great pace? sure, this isn't something the drunken mind could make up. I once got high and flew home it must have been like 2000 kilometers (definitely not imagined). My wings were flapping better than normal. Next time I'll use my pilot glasses so I can better see the unicorns.

Edited by Galaxyshock, 12 August 2013 - 05:54 AM.

[rwac]

Another possible explanation is that your serotonin levels are too high. Serotonin and Dopamine go inversely to each other.
Might be worth trying some BCAAs or gelatin, both of those are low in tryptophan so should decrease serotonin.

[machete234]

You guys are idiots. First dehydrate yourself by drinking and then you run with the alcohol still in your system? that's really fucking unhealthy. And 10-20 kilometers or with a great pace? sure, this isn't something the drunken mind could make up.

Of that distance I was running 5km and staggering 5km thru some woods because it was like the opposite of a full moon with total darkness.
And the rest of the 20km I took an early morning train.

But 5km is really easily done when trained and as I said the alcohol makes you feel less exhaustion and probably gives you strength like sugar would give you strength.

I drink zero these days because it really fucks me up every time.

Edited by machete234, 12 August 2013 - 02:36 PM.

[Galaxyshock]

Well that's more believeable. I once walked 10km after a night of drinking and it felt like forever but not physically exhausting at all. It's true alcohol eases pain and can make you feel strengthful, probably the calories help too.

[Keynes]

You guys are idiots. First dehydrate yourself by drinking and then you run with the alcohol still in your system? that's really fucking unhealthy. And 10-20 kilometers or with a great pace? sure, this isn't something the drunken mind could make up. I once got high and flew home it must have been like 2000 kilometers (definitely not imagined). My wings were flapping better than normal. Next time I'll use my pilot glasses so I can better see the unicorns.

What I said about it being a new staple was kind of a joke.

I am very aware of my performance though, alcohol or not, like I said. It's apparently not unheard of in the running community that alcohol has this effect, and before races some drink a bit (understandably this is not something people brag about!). I did hydrate heavily before running, and since I am young (21) and rather fit I doubt this affected me in a bad way, as it was a one time thing. As mentioned I had no hangover the next day.

An interesting thing, running seems more enjoyable after doing this. Pavlovian conditioning perhaps?

[Psionic]

hey Chadwick, whats your progress with NADH, still same effects?

[Chadwick]

hey Chadwick, whats your progress with NADH, still same effects?

I used NADH for a few days with great results. Clear thinking, great mood, sociability, motivation and drive. I don't use it anymore, however, since I don't need it.

After coming up with the theory that low dopamine that goes away during hangovers could be caused by MTHFR mutations I bought some 5-MTHF (methylated folate) from iherb.com. Within a day from the first 4 mg dose the low dopamine symptoms I've had my whole life (I'm 22 now) was completely gone. An absolutely mind-blowing feeling. It has been 5 days now, and I'm still feeling great. It will take a few more weeks for my 23andme.com genotyping results will come, so I don't know if I actually have an MTHFR mutation, but that would make so much sense.

It's difficult of course to quantify well-being, but I'd say the quality of my life have improved by 25-30% over the last week. I don't feel euphoric in any way, I just feel... great. Like the best possible version of myself.

[Guardian4981]

I too find that the day after drinking while I may have some bodily aches and fatigue I feel much better mentally. I am going to order some 5-MTHF today.

In the past I tried folic acid and it gave me harsh anxiety, however I know that the form of vitamins can play a big role. When I took pyrodixine B6 I also got anxiety but when I take p-5-p I get a mood boost.

[Guardian4981]

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.

[Chadwick]

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.

Edited by Chadwick, 23 August 2013 - 01:13 PM.