Common Patterns In Anxiety, Depression, Aggression and Mood Swings
Updated: Jan 19
In chronic illness health circles, gut issues are more commonly in play than not. Perhaps not as a root or causal factor , but as a consequence sometimes too. However they often play a critical role in mood related issues. This article will explore some of the common patterns is in folks with mood related challenges across gut issues, genetics, diet, and nutritional status.
NEUROTRANSMITTER PATHWAYS FOR DOPAMINE AND SEROTONIN
When we think about mood balance, often neurotransmitters come to mind, specifically the more basic ones like dopamine and serotonin where this initial article will focus. The amino acid Phenylalinine is the first amino acid used in the formation of dopamine, it is converted into Tyrosine by the PAH enzyme with iron and BH4 as cofactors, and then into dopamine by the DDC enzyme using iron and BH4 again as cofactors. Dopamine either goes through COMT or through the DBH enzyme and gets turned into norepinephrine using copper as a cofactor. So the basic 'escape hatches' for dopamine are DBH and COMT. When either of these slow down, get blocked, or back up - dopamine can rise - which leads to more aggressive and impulsive behavior.
THE COMT DOPAMINE ESCAPE HATCH
COMT uses the cofactors SAMe and Magnesium, with SAMe being of product of methylation. COMT also processes all aldehydes, testosterone, tyramines (cheese), Phenols, histamine to name a few. Genetic mutations that slow down or speed up COMT are common. You can see how on one hand alot of dopamine input (from lots of phenylalinine and tyrosine) and slowed down release through COMT can lead to elevated dopamine. Elevated testosterone, high dietary phenol intake (berries, coffee, tea), lots of cheese, high histamine diet, and aldehydes from conditions like candida can slow down COMT. IF methylation is also compromised, which denies COMT its cofactor SAMe, trouble begins to stack up. Mutations on MTHFR c677 seem to be more impactful here than MTHFR1298c.
COMT releases the by products of the neurotransmitters, hormones, to get processed by phase 2 detoxification processes in the liver - using the glucuronidation pathway, namely UGT1A1, and UGT1A4. If phase 2 liver enzymes for glucuronidation are compromised these by products can get backed up. Further, if there isnt much fiber in the diet (note below about low fiber diet), then most of these by products will be re absorbed by the intestinal wall rather than excreted out into the toilet through stool.
THE DBH DOPAMINE ESCAPE HATCH
The enzyme DBH turns dopamine into norepinephrine which gives us adrenaline with the cofactor copper. Excess supplementation of zinc (common in the covid circles) can deplete copper. Genetic mutations on DBH can both speed it up and slow it down based on the specific mutations. However, perhaps most impactful is overgrowth in the GI tract of specific clostridia bacteria that emit a compound that shuts down DBH. Clostridia bacteria over growth is common , especially in diets with low fruit and vegetable intake, and other issues like SIBO and candida in play. There are 4 specific strains of clostridia that have been identified that lead to this issues, none are tested in commercially available stool kits, rather, only through Organic Acids testing can they be identified through some metabolyte markers. The markers are :
4-Cresol (for C. Difficile);
HPPA (C. sporogenes, C. caloritolerans, C. botulinum & others);
4-Hydroxyphenylacetic (C. difficile, C. stricklandii, C. lituseburense & others);
3-Indoleacetic (C. stricklandii, C. lituseburense, C. subterminale & others)
The above attempts to outline some of the factors that can lead to excess dopamine across gut issues, diet, and genetics involved in COMT, MTHFR, DBH, DDC, and Glucuronidation (UGT1A1, UGT1A4, etc). If any of the nutritional cofactors are depleted - this too can lead to excessive dopamine: copper, B9 folate for methylation, Magnesium, BH4, Iron, and B6 to name a few. Secondarily, the enzymes MAOA, and MAOB both also offer routes for escape for dopamine, with the cofactor B2.
On the flip side, low dopamine, can occur for many reasons as well - such as low dietary intake of phenylalinine, faster DBH activity, or faster COMT activity. Additionally, if pheynalinine isn't converted into tyrosine (TH gene) with iron and BH4, or converted from tyrosine into dopamine by DDC with B6 due to nutritional deficits in B6, iron, or BH4 or genetic mutations that slow TH or DDC down. Low dopamine often presents as lower motivation and mood.
BH4 Tretrahydrobopterin
BH4 is a critical compound, and several enzymes are involved in its formation and recycling - and this often gets depleted. Genes such as MTHFR 1298 C, Folate Receptors, (FOLR2, FOLR3, FOLR4, SLC19a1), QDPR, DHFR, are involved in the recycling of BH4. While the genes: SUCLA2, GCH1, PTS, SPR are involved in the production of BH4. Any compromise in BH4 is critical, as it is also used as a cofactor for making nitric oxide via NOS1, NOS2, and NOS3. BH4 is also used in the similar Serotonin pathway. BH4 is prioritized in the following order: Nitric Oxide, Tyrosine / Dopamine, and then Tryptophan / Serotonin. When BH4 is compromised, lower serotonin levels are usually seen first, and sometimes higher iron levels. GCH1 was identified by Martin Pall as the critical limiting factor in BH4 production, and also identified that it can be stimulated by Heat Shock Protein 90 (HSP90). HSP90
NOS2 Upregulation - Consumes Large Amounts of BH4 and NAD / NADPH
There are certain mutations on NOS2 (iNOS) that lead to its upregulation, and results in a significant amount of nitric oxide being produced, and released primarily in the GI tract (not its impact on gut micro biota). These upregulation mutations consume large amounts of BH4 as a consequence, and also large amounts of one of the most critical enzymatic cofactors NAD / NADPH. Depletion of NAD / NADPH often leaves people feeling tired. While depletion of BH4 effects mood. Wired (low serotonin , high dopamine) and tired (low NAD/NADPH) often results.
TRYPTOPHAN / SEROTONIN PATHWAY
The pathway for making serotonin is similar to the one that makes dopamine. Tryptophan is converted into 5 HTP by the TPH1 and TPH2 genes using iron and BH4, while 5 HTP is then converted into serotonin by the DDC enzyme and B6. Serotonin then has 3 main routes: a) turned into melatonin through ANNAT gene with b5, processed by MAOA / MAOB with b2, or hits the serotonin receptors through the transporters SLC18a1 - lithium orotate and SLC6A4 (sodium). Anxiety is seen commonly in cases of low serotonin.
GUT RELATED ISSUES
Above, we mentioned how the enzyme DBH can be blocked by excess clostridia bacteria leading to high dopamine. However other gut related issues can also be factors too. For example, a shortage of bifo bacteria, can lead to shortage in the availability of B vitamins which are vital cofactors for both the serotonin and dopamine pathways. A genetic mutation on the FUT2 gene can lead to a condition called 'non secretor status' which leads to a very problematic situation where it is very difficult to maintain bifo bacteria in the gut. Luckily, several folks have developed protocols to rectify the situation - aside from just taking bifo bacteria pro biotics the rest of your life. Gut infections or pathogens can also lead to un balanced gut microbiome and a shortage in synthesizing b vitamins, or in fact consuming too much of the b vitamins.
TESTING DOPAMINE AND SEROTONIN LEVELS - OPTIONS
There isnt a reliable way to measure neurotransmitter levels in the brain, but there are two basic options to assessing the situation:
1) Organic Acids Tests - reveal the basic metabolytes involved in the serotonin and dopamine pathways via a simple urine test. The organic acids test also looks for the metabolytes of the excess clostridia bacteria that block the DBH enzyme. I prefer Vibrant Americas organic acids test, its $238.
2) Blood levels of various amino acids (tryptophan, 5htp, tyrosine, glycine, etc), and neurotransmitter levels (dopamine, serotonin, etc). I like Vibrant America's and its around $200.
TRICKS AND TIPS ON ADJUSTING YOUR DOPAMINE LEVELS
There are many ways to alter your serotonin and dopamine levels, some are pretty obvious and straight forward, some are more nuanced and based in the gut, and some are based on some novel concepts with some limited non peer reviewed studies:
Increase dopamine by increasing Phenylalinine and or Tyrosine intake - straight forward.
Increase dopamine by ensuring necessary cofactors are available to produce dopamine (BH4, Iron, B6).
Increase dopamine by slowing down some of the 'escape hatches' like COMT, DBH, and MAOA/MAOB
Slow Down COMT by slowing methylation / SAMe, or loading COMT with other things it has to process: Phenols, hormones, histamine, aldehydes, tyramine, etc.
Slow down DBH: lower copper with zinc supplementation (dont recommend), increase clostridia in gut (dont recommend)
Slow down MAOA/MAOB: stop supplementing with B2, dont recommend
Lower Dopamine by lowering intake of Phenylalanine, and or Tyrosine
Lower Dopamine by increasing rates through 'escape hatches':
Increase throughput through COMT by: lowering histamine, tyramines, phenols, hormones
Increase throughput through COMT by: increasing methylation (B12, methyl folate, B2, Methyl Donors), SAMe, and Magnesium
Lower Dopamine by increasing throughput through DBH by increasing copper, and increasing throughput through MAOA/MAOB with B2
Lower Dopamine by taking an Amino Acid Powder that contains all 9 of the EAA EXCEPT Phenylalinine (and Tyrosine) - the body will scavenge excess Phenylalinine and Tyrosine to make a complete protein [10].
TRICKS AND TIPS ON ADJUSTING YOUR SEROTONIN LEVELS
There are many ways to alter your serotonin and dopamine levels, some are pretty obvious and straight forward, some are more nuanced and based in the gut, and some are based on some novel concepts with some limited non peer reviewed studies:
Increase serotonin by increasing tryptophan and 5htp intake - straight forward.
Increase serotonin by ensuring necessary cofactors are available to produce serotonin (BH4, Iron, B6).
Increase serotonin by slowing down some of the 'escape hatches' like COMT, and MAOA/MAOB
Slow Down COMT by slowing methylation / SAMe, or loading COMT with other things it has to process: Phenols, hormones, histamine, aldehydes, tyramine, etc.
Slow down ANNAT: lower B5, SAMe supplementation (dont recommend)
Slow down MAOA/MAOB: stop supplementing with B2, dont recommend
Lower Serotonin by lowering intake of Tryptophan and or 5 HTP
Lower Serotonin by increasing rates through 'escape hatches':
Increase throughput through COMT by: lowering histamine, tyramines, phenols, hormones
Increase throughput through COMT by: increasing methylation (B12, methyl folate, B2, Methyl Donors), SAMe, and Magnesium
Lower Serotonin by increasing throughput through SLC18A1 (using lithium orotate) and SLC6a4 (using Sodium) so serotonin gets to the serotonin receptors (HTR1, HTR2, HTR3)
Lower Serotonin by taking an Amino Acid Powder that contains all 9 of the EAA EXCEPT Tryptophan - the body will scavenge excess Tryptophan to make a complete protein [10].
One can begin to see how various factors can play into achieving a balanced mood across genetics, gut health, nutritional status, and diet makeup.