NeuroNootropic:
Interestingly, I tried Life Extension brand methylfolate a while back, and I distinctly recall feeling that it was less effective than other brands that I had tried. Why this would be, I am not sure. Poor quality perhaps? I don't think the amount of "elemental" folate would be any different between two equivalent doses of quatrefolic.
The other experiences you describe appear consistent with my own experiences. I find that modest doses of methylfolate and methylcobalamin can be beneficial in terms of mood and cognition, but after a certain threshold my mood and energy take a nose dive. I tend to think it is due to excess SAM-E overdriving the COMT enzyme and breaking down too much dopamine and norepinephrine in the prefrontal cortex, though I can't say for sure. It appears that moderation is key for benefitting from methyl donors, at least for some people.
I think personal experimentation is key, and I question how constructive it is to get too hung up on labels like "undermethylator" vs. "overmethylator" that you see bandied around by the so-called methylation authorities (like Amy Yasko) out there on the internet.
I don’t know too much about SAM-e and COMT relationship (don’t know too much about them too) but I did a search and I’ve found something for you:
“S-adenosyl-methionine (SAM-e), functions as a primary methyl group donor for several metabolic compounds. Since SAM-e is involved in several metabolic processes, its administration may have a role in the amelioration of several disorders. In addition, SAM-e increases catechol-O-methyltransferase (COMT) enzyme activity, which may ameliorate aggressive symptoms in certain patients.”
http://www.ncbi.nlm....pubmed/18824331
You are right, SAM-e can decrease norepinephrine, epinephrine and dopamine through COMT, but it’s used for many reactions, including “phenylethanolamine n-methyltransferase” (that converts norepinephrine to epinephrine) – so here may balance the loss of epinephrine by COMT but it “double” the loss of norepinephrine (which we know that’s involved in mood disorders like depression). And since COMT can breakdown dopamine – and dopamine is used to convert into norepinephrine, it’s going to be a “triple” loss of noradrenergic tonus. Too much norepinephrine and you will get anxiety by overactive sympathetic nervous system (SNS) something that’s know to impair your cognitive functions (like executive one). Too less and you won’t maintain alertness and arousal.
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.
1. 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/THDDC (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.
Hi Chadwick,
I am a 35 year old male who feels lack of motivation (low dopamine?) despite being very motivated in the past.
I have searched through my Promethease report for these SNPs you mentioned and found only 3:
rs1801131(C;C) - MTHFR (good).
rs27072(C;C) - DAT - remove dopamine the sybaose so it can't bind its receptors
rs1800497(C;T) - DRD2 - social functioning, extraversion and social status
2. What kind of supplementation would you recommend?
1. I just don’t know nothing about it, but I did some research too. I don’t know how I get into this post, since I don’t have hangover benefits, but maybe I can help a little. First of all, if you guys have some benefit from HANGOVER instead of drunkenness we have to understand what’s going on in this situation.
Pathophysiology
Alcohol flush reaction as a result of the accumulation of acetaldehyde, the first metabolite of alcohol
After being ingested, ethanol is first converted to acetaldehyde by the enzyme alcohol dehydrogenase and then to acetic acid by oxidation process. These reactions also convert nicotinamide adenine dinucleotide (NAD+) to its reduced form NADH in a redox reaction. By causing an imbalance of the NAD+/NADH redox system, alcoholic beverages make normal bodily functions more difficult. Consequences of the alcohol induced redox changes in the human body include increased triglyceride production, increased amino acid catabolism, inhibition of the citric acid cycle, lactic acidosis, ketoacidosis, hyperuricemia, disturbance in cortisol and androgen metabolism and increased fibrogenesis.The metabolism of glucose and insulin are also influenced.[9] However, recent studies showed no significant correlation between hangover severity and the concentrations of various hormones, electrolytes, free fatty acids, triglycerides, lactate, ketone bodies, cortisol, and glucose in blood and urine samples.[3]
Alcohol also induces the CYP2E1 enzyme, which metabolizes ethanol and other substances into more reactive toxins. In particular, in binge drinking the enzyme is activated and plays a role in creating a harmful condition known as oxidative stress which can lead to cell death.[10]
So “ethanol” first is transformed to “acetaldehyde” by “alcohol dehydrogenase” (ADH).
wtf is ADH?
Alcohol dehydrogenases (ADH) (EC 1.1.1.1) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+ to NADH).
RH2 + NAD+ → NADH + H+ + R;
I won’t go futher, I think these informations will - hopefully - give you some clues.
https://en.wikipedia...ns_and_symptoms
2. You should give more information for us to make easier to help. But, I’m going to recommend you something to start – C4 Extreme from Cellucor. It’s not cheap, but if you want to be sure about your “dopamine” statement, you should try it. If you need I’ll explain why I’d recommend it.
I really feel for you and can strongly relate to almost every single symptom you describe: ADHD-PI diagnosis, dysphoria, lethargy, bad short-term memory, rigidity/awkwardness, "cognitively fried," significant cognitive boost from alcohol consumption, trouble with eye contact, the feeling that all this does not reflect who you really are, ALL OF IT. One minor difference is that where you experience dysphoria from dexamphetamine, I experience a marked mood boost. In any event, it does not sound like a dopamine issue.
Me too - especially the emotional things, rigidity and social anxiety but also lethargy, chronic dysphoria and restlessness (this is awful when you're tired at the same time), also have inattentive adult ADD diagnosed ... but the strange thing is that I get great relief from NMDA antagonists. Sometimes that antidepressant afterglow ketamine has become so famous for works, but usually it's really that I feel just better while actually being on the dissociative. So I heavily suspect a NMDA dysfunction too, but with overactive and/or too many receptors.
I've tried AMPAkines, both sunifiram and unifiram, despite that uni is said to be gentler, I found the suni to be better but both were intensifying the tension and somewhat speedy. So more AMPA activity is a part (antagonizing NMDA actually leads to more glutamate output, I suspect because of auto receptor antagonism, and this glutamate will then preferably bind to the AMPAR's which aren't blocked) but less NMDA is more crucial.
Currently I'm using ketamine daily (threshold dosages, 2-3x 10mg's or so). This is not sustainable, because of laws and money, but I also fear of tolerance and long-term toxicity.
We really are in the dark ages of mental health in some ways.
This is so sad and so true. We have this very promising riluzole out there for example, but getting a script for it is impossible despite of a shitload of well done studies. The same for ketamine. And I have one of the best doctors in town, next to all my other experiences were disappointing to say the least. I've heard repeatedly that taking memantine when you don't have Alzheimer's is like 'taking smarties' - they forced me to go off it cold turkey and wanted to start fucking antipsychotics. They know shit about their matter and get such high salaries.
As far I know, memantine doesn’t improve cognitive function in healthy people. But it’s not used only for Alzheimer disease – I can be used for anxiety and ADHD as well.
Memantine as an Augmentation Therapy for Anxiety Disorders
4. Discussion
Glutamate is felt to play a role in the development of anxiety. Glutamate, an excitatory neurotransmitter, is often in balance with an inhibitory neurotransmitter, GABA. This GABA-glutamate balance (when GABA is low and Glutamate is normal to high) is also felt to play a role in the development of generalized or social anxiety disorders. Sometimes, GABA activity increasing sedative drugs, such as diazepam, are used to raise GABA and create a better balance between the stimulatory glutamate and inhibitory GABA. Given memantine's ability to lower glutamate activity, it may be able to also lower anxiety without the need for a sedative medication. Lowering glutamate this way may allow a patient's own GABA concentrations to be more effective in lowering generalized or social anxiety disorder symptoms.
Memantine may be an effective augmentation therapy in patients with anxiety who remain symptomatic despite adequate treatment with conventional antidepressant anxiolytics.
In regards to limitations, this was an open-label consecutive patient case series. As such, these data are open to referral and investigator bias. Future investigations would benefit from placebo-controlled clinical trials to further investigate the true benefits of memantine for the treatment of anxiety.
Attention Deficit Hyperactivity Disorder
Glutamatergic dysfunction in ADHD was reported more than ten years ago (Carrey, MacMaster, Sparkes, Khan, & Kusumakar, 2002). Initially, from a study of the available literature, ADHD was considered as a hypoglutamatergic condition affecting primarily prefrontostriatal pathways, (Carlsson, 2000). Later, using short echo magnetic resonance spectroscopy, Carrey et al. provided initial evidence that glutamate concentrations were, in fact, raised in the left striatum of male ADHD (combined subtype) subjects at baseline as compared to controls, with no increase in the prefrontal cortex (Carrey, MacMaster, Gaudet, & Schmidt, 2007). In 2009, elevated glutamate levels were again reported, this time, both in the prefrontal cortex and striatum of untreated ADHD children (Kavirajan, 2009). Recently, decreased NMDA-mediated transmission was again reported in ADHD, with caution that further reducing it with an NMDA receptor antagonist could worsen the condition (Sani et al., 2012). Whether ADHD is a hyper or hypoglutamatergic condition is not clear. Treatment with a glutamatergic agonist was inconclusive (Carlsson, 2000) but an eight-week, open-label, dose finding trial with memantine in 16 children, 6–12 years of age, diagnosed with ADHD (combined type), using a dose of 10 mg/day in eight children and 20 mg/day in the other eight children, reported a dose dependent benefit in both the inattention and the hyperactivity/impulsivity domains (Findling et al., 2007). The response was minimal at 10 mg/day and significantly better on the 20 mg/day dosage.
http://www.ncbi.nlm....les/PMC3420624/
https://www.ncbi.nlm...les/PMC3647634/
I really feel for you and can strongly relate to almost every single symptom you describe: ADHD-PI diagnosis, dysphoria, lethargy, bad short-term memory, rigidity/awkwardness, "cognitively fried," significant cognitive boost from alcohol consumption, trouble with eye contact, the feeling that all this does not reflect who you really are, ALL OF IT. One minor difference is that where you experience dysphoria from dexamphetamine, I experience a marked mood boost. In any event, it does not sound like a dopamine issue.
It all sounds like the hallmarks of NMDA/glu receptor dysfunction to me, maybe with some added effects from chronic alcohol consumption. I believe you stated that you don't benefit from NAC, though I wonder if you'd see a benefit from continued use or upping your dosage. I also wonder if you'd benefit from glycine, which has become a staple of my stack. Glycine can be beneficial for NMDA-receptor hypofunction in two ways: 1) required (along with the cysteine from NAC) for synthesis of glutathionine, which has been shown to benefit compromised NMDA-receptor function; and 2) glycine is a co-agonist (along with glutamate) for the NMDA receptor and directly stimulates it. I have read some fairly convincing arguments that the modern diet may not contain enough glycine for optimum health, and maybe it could be depleted further by alcohol consumption? Not sure. In any event it is very cheap and 10 grams a day gets me one step closer to where I want to be.
Also, alcohol consumption can deplete glutathione which can contribute to NMDA receptor dysregulation, so supplements that increase it could be a reasonable approach to explore (the trifecta is NAC, glycine, glutamine, though NAC is the most important).
Other potentially beneficial supplements could include sarcosine (blocks the re-uptake of glycine and enhances NMDA-receptor stimulation), and anything that is beneficial for inflammation (hell, I get a mental boost from ibuprofen). BH4 may not be a viable option since it seems almost impossible to get your hands on though I would absolutely love to try it.
Again, I feel for you. It is a crime that so many of us have to turn to internet forums for help. We really are in the dark ages of mental health in some ways.
When you said about having benefit from dextroamphetamine “hangover/withdraw” the first thing that came in mind was something like “NMDA receptor hypofunction” because the fact that most people have bad side effects from it (mostly it becomes overactive after amphetamines – something similar happens with alcohol hangover). Maybe energetic beverages may help (caffeine) to improve your excitatory neurotransmission, just try one time.
Hey guys,
I posted in this thread earlier about the hangover phenomenon and have gotten significantly worse. The hangovers been my lifeline for a while now. Anytime i'd get in this extremely depressed, confused, awkward, cognitively fried mood, i'd drink to experience a hangover and get on with my next couple of days really well. I'd self medicate to feel normal. That is until about a month and a half ago when I pooped it out. I tried a few times getting drunk but for the first time in my life, i'd have the typical hangover regular people experience. I'd vomit (which i never used to do), I would be slightly negative and extremely lethargic.
So since about a month ago, I've stopped drinking entirely. I've gone from professional to professional and was finally diagnosed with ADHD-PI. The psychiatrist described it as ethanol igniting my neurons to fire up and that other people have different catalysts such as marijuana etc. I started my introductory dose of adderal and it felt really strange. I became really quiet and dysphoric. This is off two doses of 5mg dexamphetamine, four hours apart. I tried supplementing tyrosine a couple of weeks prior to my diagnosis and that made me feel really irritable. Also, it's worth noting that smoking makes me dysphoric too?
Oh and I wanted to experiment with DXM to see if that did anything and 80mg literally put me in this strange, hypnotic and mute state. I was in a dysphoric mood where I brain fog, a mental block and wasn't talkitive. I think I got the rebound effect because I was in an okay mood the next day but that could've been placebo. I tried again the next week and had 30mgs. Same hypnotic, strange and untalkative mood. On second thought, I think it was after the whole experience with experimenting with DXM where I stopped experiencing those hangovers where I feel normal.
I'm finding it harder to regulate thoughts, feelings and emotions. I've become rigid and awkward. Can hardly look at people in the eye. Short terms memory has tanked. I feel really trapped, I know this isn't me and i'm a really light and easy going person but something in my cns is happening that's making me extremely depressed and stupid. Above all, I feel really dumb at the moment.
I'm in a really dark place. I'm a stones throw away from handing myself over to a clinic. But i doubt they'll take me or even know whats going on.
My country subsidizes BH4 if you can prove through some pretty expensive testing that you're deficient. Could my cns fuckups be a product of a bh4 deficiency?
Could I just have an extremely hypo-active nmda neurotransmitter? What could potentially be causing this?
Could it be a faulty glu neurotransmission?
I'm extremely lost. I've quit my job and studies, living a dormant life till I become functional again. Any help would be an absolute god send. Please.
I want to chat with you in real time. I may have some useful information.
Has any of you tried one of the AMPAkines (sunifiram, unifiram) yet, or colouracetam? The latter is said to be effective for ADHD but my primary interest are the AMPAkines. Indeed they should be able to replicate this 'glutamate rebound' you are experiencing after alcohol, but without the drunken period and the headache.
I found sunifiram to be somewhat interesting but also speedy and it intensified my tension. But I seem to be a bit atypical in that I do need NMDA antagonism for cognition to flow easily - I get exactly that enormous improvement in cognitive, verbal and emotional fluency with NMDA antagonists (resulting in less NMDA and more AMPA activity).
Also dopamine is definitely a central mediator, but I really believe now that glutamate is just as essential. Maybe they are tightly coupled together too, I know yet too little about it all but there is some evidence. Dopamine does modulate and limit glutamate trafficking, this is a supposed mechanism for why antipsychotics lower the seizure threshold if I'm right (have to search the source if you're interested, I moved recently and am just on my travel notebook now). NMDA antagonism appears to disinhibit dopamine, and consequently will too much glutamate lead to little dopamine.
Methylphenidate has worked well for me, but only in combination with a mild NMDA antagonist (memantine - unfortunately it's hard to get a prescription for because of off-label) and it has some rough edges on the body. The currently RC-only cousin isopropylphenidate is miles better, if it's legal in your country, you might consider to give it a try.
Or, what I'm currently trying out myself is rasagiline, a MAO-B inhibitor that lowers the degradation of dopamine and phenethylamine. Am just on day 2 now, there is a definite improvement not unlike methylphenidate but completely without any body load or speediness - truly appreciable. It makes a nice synergy with tobacco and 2-fluoroamphetamine (low dose! it potentiates that).
I already took selegiline, but I didn’t like too much. Specially because you must be careful mixing IMAO (even reversible ones) with monoamine transporters inhibitors (like methylphenidate).
