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Thread: Stimulating dopamine production: NADH, L-tyrosine, NADH and B6

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    Stimulating dopamine production: NADH, L-tyrosine, SAM-e and B6 
    #1
    (I apologize if this is the wrong forum, I am new here and and after looking around decided this would be the best place to put it, though I may be wrong.)

    I know many people use the dopamine precursor l-tyrosine to pre- or post-load certain substances, and many also use it daily as a supplement for fatigue or attention problems or impulse control. It is also used with great success by some for combatting withdrawal.

    I was doing some research today and found two new dopamine precurors that I had not been aware of previously. At least one serves an essential and complementary (with l-tyro) role in dopamine production, and I was wondering if anyone has experimented with a cocktail.

    a) NADH (nicotinamide adenine dinucleotide). NADH stimulates tyrosine hydroxylase, the enzyme that converts l-tyrosine to l-dopamine.

    b) SAM-e (S-adensoyl-L-methionine). The mechanism of action is unclear (at least I couldn't find anything definitive) but it clearly does dramatically increase brain levels of dopamine and norepinephrine, indicating it may play some role in l-tyrosine conversion.

    So, has anyone used NADH + L-tyro? Or all three? Or just SAM-e and L-tyro? I am assuming, perhaps obviously, that B6 would be taken along with the tyrosine.

    If no one has experimented with combinations, what do people think about the best order in which to take these? L-tyro first? Or after the NADH? Or at the same time?
    Last edited by brandnewvibe; 23-04-2005 at 05:07.
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    #2
    Well personaly I take some Deprenyl (MAO-B inhibitor) and some DLPA together once every 2 days, and it`s really good for the mood

    I should probably add some L-tyrosine too, but it's illegal in canada and his hard to find
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    #3
    SAM-e (S-adensoyl-L-methionine). The mechanism of action is unclear (at least I couldn't find anything definitive) but it clearly does dramatically increase brain levels of dopamine and norepinephrine, indicating it may play some role in l-tyrosine conversion.
    S-Adenosylmethionine is the main methyl donor in dopamine synthesis... but I don't quite see why you're saying "it clearly does dramatically increase brain levels of dopamine " Why is this clear? SAM is known for producing symptomes of dopamine depletion when given to animals, in larger doses it is a dopaminergic neurotoxicant.
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    #4
    What about dopamine agonists like: Mirapex, Requip, Pronoran. Do they stimulate dopamine production? (I think yes). Would it be a good idea to combine dopamine agonist with selegiline or Enada NADH for even better effect? By "effect" I mean anti-depressant, motivation, energy, stimulation without jitterness.
    Last edited by bouncer; 24-04-2005 at 07:29.
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    #5
    It's highly unlikely dopamine agonists increase dopamine synthesis, it's more likely that they will inhibit it.
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    #6
    Bluelight Crew 5-HT2's Avatar
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    Anybody know offhand how much and by what mechanisms L-tyrosine supplementation increases dopamine release? This seems like the type of thing some of the larger dopamine-oriented PET/SPECT imaging groups may have looked at.
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    #7
    Originally posted by BilZ0r
    It's highly unlikely dopamine agonists increase dopamine synthesis, it's more likely that they will inhibit it.
    Inhibit? Why do you think so?
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    #8
    Because non-specific dopamine agonists bind to dopamine auto-receptors and inhibit tyrosine hydroxylase.
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    #9
    http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=9247319
    Life Sci. 1997;61(5):495-502. Related Articles,Links

    Depletion of nigrostriatal and forebrain tyrosine hydroxylase by S-adenosylmethionine: a model that may explain the occurrence of depression in Parkinson's disease.

    Charlton CG.

    College of Pharmacy, Florida A and M University, Tallahassee 32307, USA.

    The loss of nigrostriatal tyrosine hydroxylase (TH), dopamine and dopaminergic neurons are the major pathology of Parkinson's disease (PD). These catecholaminergic changes are responsible for the symptoms of tremor, hypokinesia and rigidity. Depression is also a major symptom in PD, but the cause is unknown. The impairments of catecholaminergic fibers in the frontal lobe may be involved, because the frontal lobe of the cerebrum is involved in the regulation of mood, and decreased catecholaminergic activity in the frontal lobe is related to behavioral depression. The changes that damage the nigrostriatal dopamine system and induce motor impairments may also damage the forebrain catecholamine fibers and induce depression. It means that manipulations that damage the nigrostriatum (NS) and induce parkinsonism may also deplete TH in the frontal cortex. Such an effect would suggests a basis for the depression seen in PD. The injection of S-adenosyl-L-methionine (SAM), the biological methyl donor, into the brain of rats damaged the NS, depleted TH and caused tremor and hypokinesia. SAM may interfere also with the forebrain TH, which may help to explain the occurrence of depression in PD. Experiments were designed to test such a hypothesis. The results showed that SAM caused a loss of immunoreactive nerve fibers and it decreased the intensity of TH-immunoreactivity (IR) in the frontal cortex. These changes were accompanied with the loss of cells and the depletion of TH-IR from nerve fibers in the SN and the caudate nucleus. Other studies showed that SAM depletes DA and since SAM induces PD-like changes the results may be relevant to the co-occurrence of PD symptoms and depression. A single biological manipulation may impair the nigrostriatal dopaminergic neurons as well as the frontal cortex catecholaminergic fibers.
    http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=7888091
    Mol Neurobiol. 1994 Aug-Dec;9(1-3):149-61. Related Articles,Links

    Substantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain. Support for an excess methylation hypothesis for parkinsonism.

    Charlton CG, Mack J.

    Department of Pharmacology, Meharry Medical College, Nashville, TN 37208.

    The major symptoms of Parkinson's disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by degeneration of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal dopaminergic terminals. Norepinephrine, serotonin, and melanin pigments are also decreased and cholinergic activity is increased. The cause of PD is unknown. Increased methylation reactions may play a role in the etiology of PD, because it has been observed recently that the CNS administration of S-adenosyl-L-methionine (SAM), the methyl donor, caused tremors, hypokinesia, and rigidity; symptoms that resemble those that occur in PD. Furthermore, many of the biochemical changes seen in PD resemble changes that could occur if SAM-dependent methylation reactions are increased in the brain, and interestingly, L-DOPA, the most effective drug used to treat PD, reacts avidly with SAM. So methylation may be important in PD; an idea that is of particular interest because methylation reactions increase in aging, the symptoms of PD are strikingly similar to the neurological and functional changes seen in advanced aging, and PD is age-related. For methylation to be regarded as important in PD it means that, along with its biochemical reactions and behavioral effects, increased methylation should also cause specific neuronal degeneration. To know this, the effects of an increase in methylation in the brain were studied by injecting SAM into the lateral ventricle of rats. The injection of SAM caused neuronal degeneration, noted by a loss of neurons, gliosis, and increased silver reactive fibers in the SN. The degeneration was accompanied with a decrease in SN tyrosine hydroxylase (TH) immunoreactivity, and degeneration of TH-containing fibers. At the injection site in the lateral ventricle it appears that SAM caused a weakening or dissolution of the intercellular substances; observed as a disruption of the ependymal cell layer and the adjacent caudate tissues. SAM may also cause brain atrophy; evidenced by the dilation of the cerebral ventricle. Most of the SAM-induced anatomical changes that were observed in the rat model are similar to the changes that occur in PD, which further support a role of SAM-dependent increased methylation in PD.
    http://www.ncbi.nlm.nih.gov/entrez/q...t_uids=8503824
    Behav Neural Biol. 1993 May;59(3):186-93. Related Articles,Links

    S-adenosyl-L-methionine decreases motor activity in the rat: similarity to Parkinson's disease-like symptoms.

    Crowell BG Jr, Benson R, Shockley D, Charlton CG.

    Department of Pharmacology, Meharry Medical College, Nashville, Tennessee 37221.

    S-Adenosyl-L-methionine has been shown to cause Parkinson's disease-like effects that include hypokinesia, tremor, rigidity, and abnormal posture. S-Adenosyl-L-methionine is the rate-limiting endogenous methyl donor. Its biochemical role, which includes the metabolism of dopamine and the synthesis of acetylcholine, also resembles the changes that occur in Parkinson's disease. Therefore, S-adenosyl-L-methionine may play a role in Parkinson's disease-like motor impairments. In this study we manipulated the levels of S-adenosyl-L-methionine in the brain of rats and quantified the changes in hypokinetic type motor activity that seems to occur also in Parkinsonism. Male Sprague-Dawley rats were anesthetized with chloral hydrate (400 mg/kg/rat), cannulated, injected into the lateral ventricle with S-adenosyl-L-methionine or saline, and their motor activity was measured in a Digiscan Animal Activity Monitor. Other behaviors were also observed. S-Adenosyl-L-methionine caused hypokinesia, tremor, rigidity, and abnormal posture in rats. Motor activity was significantly decreased within 2 min postinjection. The hypokinesia was maximal at 60 min, at which time a 65, 75, and 90% decrease for total distance, number of movements, and the ratio of total distance to the number of movements occurred, respectively. The hypokinetic effect of S-adenosyl-L-methionine was dose dependent. A 65.0 and 51.3% decrease in total distance and number of movements, respectively, were observed following 9.38 x 10(-9) mol. The 5.0 x 10(- mol caused a reduction of 73.42 and 57.66% and 4.0 x 10(-7) mol/rat caused a 94.9 and 78.43% decrease, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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    #10
    Bluelighter protovack's Avatar
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    a) NADH (nicotinamide adenine dinucleotide). NADH stimulates tyrosine hydroxylase, the enzyme that converts l-tyrosine to l-dopamine.
    Isn't NADH just an electron receptor in cellular respiration? I wasn't aware that it stimulated tyrosine hydroxylase. Does that lead to a measurable increase in tyro -> dopa conversion?
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    #11
    NADH indirectly supplies reducing co-facotrs to the rate-limiting tyrosine hydroxylase-catalysed step of dopamine synthesis. It is so fucking unlikely that oral NADH increases dopamine synthesis.
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    #12
    Bluelight Crew fastandbulbous's Avatar
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    ^ As the rate limiting step in dopamine synthesis is the action of tyrosine hydroxylase (addition of an OH group to the 3-position of the phenyl ring), which, as BilZ0r has pointed out, is inhibited by dopamine, eating huge amounts of L-tyrosine will make very little difference to dopamine production under normal circumstances (ie not a post amphetamine depletion state).

    L-DOPA, on the other hand, is downstream of the rate limiting step, and can vastly increase dopamine synthesis; this isn't a good thing though - large doses of L-DOPA in Parkinson's patients can cause uncontrollable writhing type movements.

    Best to just suppliment with a modest dose of tyrosine or phenylalanine (to counteract any delpetion), and leave it at that.
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    #13
    ^ Indeed, and it can cause serious peripheral side effects as most (95-99 l-DOPA, when given by itself, is converted into dopamine in the gut and blood.
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    #14
    Bluelighter
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    I agree with fastandbolus that more dopamine is not necessarily better. The whole idea that dopamine is what makes you feel good is such old science. It might increase reward seeking, but not the actual intensity of reward.
    In response to your question brandnewvibe: I believe if you wanted to increase dopamine levels you could use deprenyl or maybe high doses ghb to increase tyrosine hydroxylase. I have experimented with the combination of deprenyl/TMG (sam e precursor), deprenyl/niacinamide (should increase NADH), deprenyl/l-dopa, deprenyl/coca thee, niacinamide/TMG, and niacinamide/TMG/dl-phenylalanine. None of these combinations where pleasurable to me (anxious/agressive/pissed-off /jittery kind of feeling). even though any of these by themselves have a favorable effect on me.
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    #15
    "The whole idea that dopamine is what makes you feel good is such old science. It might increase reward seeking, but not the actual intensity of reward."

    Smartshop,
    I guess I'm behind on my science then. Could you possibly give a brief explanation of what it is, then, that increases 'actual intensity of reward'?

    Thanks.

    p.s. My question actually wasn't slanted towards increasing pleasure/intensity of reward. It was in the context of supplementation during amphetamine withdrawal.
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    #16
    Bluelight Crew fastandbulbous's Avatar
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    I agree with fastandbolus
    Another of my many aliases... (I've seen quite a few variations on my name)
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    #17
    Bluelighter TruthSpeaker's Avatar
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    Is F&B one of them?
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    #18
    Bluelight Crew fastandbulbous's Avatar
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    Yes, but that's one I chose to use myself, rather than ones from other people - BilZ0r thought I was 'fastandfabulous' for quite a while!
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    #19
    Bluelighter Blowmonkey's Avatar
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    lol.. sorry.
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    #20
    fast and bolus... lol... sounds like the shit I just had.
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    #21
    Effects of tyrosine, phentermine, caffeine D-amphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation.
    Magill RA, Waters WF, Bray GA, Volaufova J, Smith SR, Lieberman HR, McNevin N, Ryan DH.
    Nutr Neurosci. 2003 Aug;6(4):237-46.

    Cognitive and motor performance are critical in many circumstances and are impaired by sleep deprivation. We administered placebo, tyrosine 150 mg/kg, caffeine 300 mg/70 kg, phentermine 37.5 mg and D-amphetamine 20 mg at 15.30 h following overnight sleep deprivation and compare their effects on cognitive and motor performance in healthy young men. Tests of visual scanning, running memory, logical reasoning, mathematical processing, the Stroop task, four-choice serial reaction time, time wall take, pursuit tracking, visual vigilance, Trails (B) task and long-term memory were evaluated at standardized intervals before, during and after sleep deprivation and drugs. Performance decrements with sleep deprivation occurred in visual scanning, running memory, logical reasoning, mathematical processing, the Stroop test, the time wall test, tracking and visual vigilance. Interestingly, with sleep deprivation some tests improved and others did not deteriorate. Improvements with medication following sleep deprivation were seen in running memory, logical reasoning, mathematical processing, tracking and visual vigilance. Although less effective than D-amphetamine, tyrosine improved performance on several tests. We conclude that all drugs tested improved at least some aspects of cognitive and motor performance after sleep deprivation. As a naturally occurring amino acid, and thus amenable to nutritional strategies, tyrosine may deserve further testing.
    http://www.ncbi.nlm.nih.gov/entrez/q...140&query_hl=3



    So tyrosine seems to have some stimulant action by itself in high doses. Has anyone tested that high doses, ~10g?
    And can anyone post whole article?
    Any pharmacodynamic info about tyrosine would be very welcome too!
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    #22
    Tyrosine... Decarboxylated to tyramine and then it could hit up the Trace amine receptor, or cause noradrenaline release? *Shrug*
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    #23
    BUMP!

    Interesting

    I believe I have a big deficet in dopamine, I suffer from depression anxiety and have only ever responded to dopaminagenic drugs.
    However they always poop out.
    I would like to try from the other end, stimulating production. Anyone have anything new to add 5 years down the track?
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    #24
    Fuck me, this is horrifying! Thanks for bringing this to our attention.
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    #25
    N-Acetyl-L-Tyrosine is far more effective at rapidly producing dopamine than plain L-Tyr. and is readily available at prices not too much higher, FWIW.
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