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Dopamine Metabolism for Optimal Performance


Dopamine is a neurotransmitter that is, among other things, associated with motivation, short-term memory, creativity and personality [1][2][3].  It is metabolized into epinephrine and norepinephrine to increase alertness and attention [4].  

It must be properly balanced and metabolized for optimal benefit.  Too much dopamine can result in manic states [5] and too little can cause depression and lack of motivation [6].

Dopamine metabolism can be metaphorically compared to a factory process where raw materials such as L-Phenylalanine and L-Tyrosine, which are amino acids present in foods, are transformed by various workers (enzymes) who use various materials (cofactors) in each transformation step.  

The intermediate products of this metabolism are used to transmit signals through the body and the brain [7].  Some are stored for later usage and some are actually harmful if they build up too much.  

After many different transformation steps they are transformed to chemicals such as homovanillic acid which are excreted in the urine.  Unlike a regular factory, the intermediate products are the useful aspects of production and are used primarily in signaling.

At the beginning of dopamine metabolism the dietary amino acid L-phenylalanine is converted into L-tyrosine by phenylalanine hydroxylase and L-tyrosine into L-dopa by tyrosine hydroxylase.  Studies suggest that tyrosine hydroxylase is upregulated by phosphorylated CREB which is activated during cAMP/PKA driven long-term potentiation [8].  

This is one of the theorized mechanisms of action of CILTEP.  Tyrosine hydroxylase can also be upregulated by nicotine for up to 48 hours [9].  The cofactors of these reactions are iron and tetrahydrobiopterin [10].  

Iron is available as a supplement but is not something I’d take as it can easily over accumulate and lead to toxicity [11]. I prefer to upregulate tyrosine hydroxylase activity, as its activity is the rate limiting step in this metabolic process [12].

Further down the metabolic chain from L-Tyrosine is L-Dopa, which is also available as a drug and in the supplement mucuna pruriens [13].  I don’t recommend it because of L-dopa’s association with tardive dyskinesia when taken long-term by parkinson's sufferers [14].  However, there is a study that suggests that mucuna pruriens might helps prevent some types of tardive dyskinesia [15].  L-dopa’s synthesis into dopamine is supported by the active form of vitamin B6, known as pyridoxal phosphate, commonly abbreviated as p5p , and the enzyme dopa-decarboxylase [16].

Some intermediate products of dopamine metabolism act as an agonist at the TAAR1 receptor [17].  This receptor is primarily targeted by ADHD drugs [18].  It causes increases in cAMP levels in the cell [19].  Forskolin also raise cAMP levels but through a different mechanism.  

Unlike forskolin, the aforementioned ADHD drugs cause efflux of stored dopamine into the synaptic cleft via modulation of the dopamine transporter protein known as DAT [20][21].   This efflux leads to increases in dopamine in the synaptic cleft producing fast increases in arousal.  

It’s my opinion, from reading through a lot of anecdotal experiences and research, that it might be undesirable to rapidly raise neurotransmitter levels in the synaptic cleft above a given baseline as it can lead to excessive arousal and unbalanced cognitive effects.

 In my opinion, it’s better to help the “factory” produce optimally by supplying co-factors and optimally helping and directing each intermediate reaction and post-synaptic metabolic pathways.

Another place that products in dopamine metabolism operate is in the dopamine receptors themselves.  The D1,D2,D3,D4, and D5 receptors all respond to dopamine in the brain and have various cognitive related effects.  D2 receptors modulate prolactin [22] which some studies suggest is linked to the male sexual refractory time [23].  

Direct agonists for these receptors are usually in the class of dopamine agonist drugs that are sometimes prescribed for parkinson's symptoms [24][25][26].  D1 and D2 are involved in novelty detection [27] and sexual desire [28].  While D1 and D5 are involved in memory formation [29].  D2 and D3 are associated with addiction [30] and compulsions [31].  D4 is involved with cognitive performance [32].

The various mood, addiction, compulsion and sexual influencing effects of dopamine agonists in the brain and various accounts of socially undesirable behavior under the administration of direct dopamine agonists [33], usually in parkinsons treatment, leads me to avoid the direct stimulation of these pathways.  Again, it is my humble opinion that it is better to provide cofactors to aid and assist in metabolism along dopaminergic pathways than to directly activate receptors with agonists.  However, direct agonists certainly have their uses.

Dopamine is converted into norepinephrine with vitamin C (ascorbic acid) as a cofactor via the enzyme dopamine b-hydroxylase.  That is further converted to epinephrine via phenylethanolamine n-methyltransferasewith SAM-e as a cofactor.  You can read more about SAM-e in my earlier essay “The SAM Cycle And The Brain”.  Dopamine can also be converted to the TAAR1 agonist 3-Methoxytyramine via the enzyme COMT [34].

COMT inhibition is an interesting area of exploration in cognitive enhancement.  There is a gene polymorphism, the val158met polymorphism, that influences the rate at which dopamine is processed into further metabolic intermediates via the COMT enzyme.  The quick processing polymorphism is called val/val and the more slowly processing polymorphism is called met/met.  

In one study, participants with the val/val gene had lower scores on a memory test known as dual-n-back [35].  Another study suggests that those with the met158 allele have better cognitive performance.  

To quote the study “The low activity met158 allele has been associated with improved working memory, executive functioning, and attentional control, but also with a higher risk of anxiety-related behaviors” [36]. It is interesting to note that Luteolin is a substrate for COMT [37] so variations in the COMT allele might account for different anecdotal effects of Luteolin from artichoke extract.

MAO inhibitors might be helpful for brain health by possibly preventing the degradation of dopamine into DOPAL via MAO, which, if it builds up, can cause oxidative damage if it is not detoxified into DOPAC [38].

Selegiline, which is a primarily MAO-B inhibiting drug is also known to extend lifespan in animals, possibly by protecting the dopamine producing regions of the brain [39]. Catechin and epicatechin present in green tea and chocolate also have MAO-B inhibition activity [40][41][42].

How we metabolize dopamine is a core contributor to mood and cognitive function. The reason studying it is so fascinating is that dopamine is. as some studies have suggested, responsible for fascination itself [43].  

In fact the more one delves into the interaction between dopamine and cognition, the more one wonders if moods and personality and life itself is a biochemical construction or if there is room for free will.  Regardless,  I prefer to have my dopamine metabolism well stocked and modulated so I have the motivation and energy to do whatever I focus my mind on and to help prevent the over accumulation of harmful metabolic byproduct.

Additional posts by Abelard Lindsay (@ciltep):

[expand title="References:"]

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