Most of us have that drive to push ourselves hard each workout. We try to go “all out” each workout.
We have to demolish the PRs of the previous workouts, right?  And so we do everything possible to squeeze every bit out of our training.

But is this the right thing to do?
It sure feels like the right thing to do and feels like it will result in the best gains ever.

But that is actually not the case.
The key is just to continually overload the muscle and training to failure isn’t even any better for hypertrophy and can even be detrimental to hypertrophy by causing too much muscle damage and fatigue.

If we dig a little deeper, destroying ourselves in the gym, to the point where we have to drag ourselves out of the gym (although fun in the short term), is very counterproductive to our metabolism, health and (potential) longevity. So in the long run we’re doing more harm than good.

In this article I specifically want to talk about exhaustive exercise and it’s effect on serotonin, dopamine, cortisol and carbon dioxide (CO₂).

During low intensity exercise, we primarily use fats and some glucose for energy; the amount of glucose we use increases as the intensity goes up. Brief intense exercise uses glucose almost exclusively.

Proper glucose oxidation yields CO₂ and ATP.

Dragging the sets on for too long will lead to an increase in lactate production and a reduction in ATP and CO₂ production.

ATP drops when lactate production increases because with extensive lactic acid production, the total amount of ATP produced from the stored glycogen is lower than with complete oxidative phosphorylation; each glycosyl unit gives 3 ATP when lactic acid is produced and 39 ATP when it is completely metabolized in the mitochondria to CO₂ and water. Thus the glycogen stores are more rapidly depleted when large amounts of lactic acid are produced and muscle performance is severely depressed at low glycogen levels.

Also, as CO₂ drops, serotonin rises. CO₂ is a potent serotonin antagonist and prevents it from rising in the blood.

Serotonin has many side effects when chronically elevated. It’s anti-metabolic, anti-androgenic, anti-thyroid, pro-cortisol, pro-prolactin, pro-disease, pro-fatigue, etc.
So it’s definitely not something you want elevated all the time.

The thing is, the more exhaustive the exercise, the higher serotonin goes and the longer it stays elevated.
Our goal is to minimize serotonin and optimize CO₂ and dopamine.

So we primarily want to focus on:

1. Optimizing glycogen stores.
2. Maximizing glucose oxidation – we want to burn glucose during exercise to produce CO₂.
3. Keeping dopamine high and serotonin low – a high serotonin to dopamine ratio is a primary cause of fatigue and elevated prolactin.

Let’s focus on these one by one.

#1 Optimize glycogen stores

This one is easy – just consume a lot of carbs before and after each training session and glycogen stores should be topped up.

Consuming ketones, caffeine, fructose and salt with your glucose will speed up carbohydrate absorption and glycogen storage.

#2 Maximize glucose oxidation

As long as the sets are not too long, glucose will mainly be oxidized and minimal amounts of lactate will be produced. ATP and CO₂ are the end-products of proper glucose oxidation and CO₂ is a fascinating, gaseous molecule that’s very beneficial to your health.

During strenuous exercise, O₂ consumption and CO₂ production can increase 20-fold (R).

CO₂ promotes blood flow, vasodilation, tissue oxygenation, fat loss, muscle growth, exercise performance, 1RM strength, endurance, mitochondrial mass and capillarization. It also speeds up the metabolism, wound healing and injury recovery, prevents catabolism and so much more (R, R, R, A, R, R, R, R, R, R).

As CO₂ levels go up, more glucose is being used and the RQ increases. This is seen with altitude training where lactate levels drop (lactate paradox) and glucose oxidation increases.

And we want to rely on glucose for energy because exercise performance is positively correlated with carbohydrate metabolism (R). The better our glucose utilization and oxidation is, the better our exercise performance will be.

Serotonin however, has the opposite effect and that’s why we want to minimize its effect.

In order to maximize glucose oxidation we want to:

• Inhibit excess lipolysis.
  Free fatty acids inhibit proper glucose oxidation (Randle cycle), and waste it to lactate. Niacinamide and aspirin are perfect for this, but I’d stick to only niacinamide as aspirin might interfere with training adaption, although aspirin is also pro-metabolic, anti-cortisol and anti-serotonin.
• Inhibit lactate dehydrogenase (LDH).
  LDH is the enzyme that converts glucose to lactate. Vitamin B1 and methylene blue (R) will do this for us.
• Increase pyruvate dehydrogenase (PDH).
  PDH is the rate-limited enzyme that shuttles pyruvate (glucose breakdown product) into the mitochondria for oxidation. Caffeine, fructose, palmitic acid and vitamin B1 will increase the activity of this enzyme.
• Increase pyruvate carboxylase.
  This biotin dependent enzyme converts pyruvate to oxaloacetate for use in the mitochondria. Low biotin levels can lead to a buildup of pyruvate and elevate lactate levels. Supplementing biotin will help increase pyruvate carboxylase.
• Optimize electron transport chain (ETC) activity. Lastly, the ETC determines CO₂ and ATP production. If there is a kink in the chain CO₂ and ATP production is reduced. Methylene blue, vitamin K2 and CoQ10 is perfect for this and will optimize electron flow as well as CO₂ and ATP production.

#3 Lower serotonin and optimize dopamine

Although keeping serotonin low is ultimately the goal, by boosting CO₂ levels, we can also directly lower serotonin to boost CO₂ levels in turn.

A quick distinction between what dopamine and serotonin does to the body.

Dopamine increases:

• Mechanical efficiency
• Motor control
• Motivation
• Reward
• Energy expenditure

Serotonin:

• Decreases cutaneous heat loss, which decreases heat loss.
• Increases core temps, which reduces exercise performance
• Lowers motivation
• Increases lethargy and fatigue
• Speeds up glycogen depletion and wastes it to lactate, thus reducing exercise performance (R, R, R). Blocking the enzyme that produces serotonin and/or using serotonin receptor antagonists increases exercise performance (R, R).

“Exhaustion appears to set in when dopamine levels start to drop while serotonin levels are still elevated.” (R)

Doing exhaustive exercise all the time and not giving your body enough time to recover can lead to chronically elevated serotonin. The harder and longer we push ourselves, the higher serotonin goes and the longer it stays elevated; chronically elevated serotonin leads to chronic fatigue.

So what is the main cause of elevated serotonin?

A reduction in glucose oxidation and CO₂ production are two of the major reasons.

“Aerobic exercise is known to activate the body’s stress response, the hypothalamic-pituitary-adrenal (HPA) axis, and yet many people engage in sports like running because they perceive its effects as relaxing.” (R)

So our focus is to lower serotonin and increase dopamine to prevent fatigue as well as the anti-metabolic effect of elevated serotonin.

As a side note, not all serotonin is created in the brain and actually 95% or more of the serotonin is created in the gut. There is also some evidence which shows that lowering the permeability of the intestine prevents fatigue (R). Keeping the gut healthy is key to keeping serotonin low.

Let’s look at a few ways to keep serotonin low and dopamine high.

• Exercise – Yep, exercise if done correctly, can actually help to reduce the sensitivity of serotonin receptors and keep serotonin low by increasing the serotonin autoreceptor 5-HT1A (which when bound to, reduces serotonin production). Exercises also increases the activity of the enzyme that produces dopamine, tyrosine hydroxylase.
• Block lipolysis. An increase in lipolysis floods the body with free fatty acids (FFAs). These FFAs lower albumin, the transporter protein in the blood that shuttles tryptophan around (tryptophan is the precursor to serotonin), and this causes an increase in free tryptophan. More free tryptophan leads to more serotonin synthesis. Blocking excess lipolysis with niacinamide (Niacinamide is much better at this than niacin (R)) and aspirin will help lower free tryptophan and serotonin.
• Dopamine agonists. Using a dopamine agonist can actually help to lower serotonin (R). BCAAs, tyrosine and/or phenylalanine and gelatin are anti-catabolic and will provide dopamine precursors and no tryptophan.
• Increase CO₂ production with vitamin B1, methylene blue (R), caffeine and sodium bicarbonate (R).
• Keep cortisol and estrogen low. Both are potent inducers of serotonin and their activity should not be chronically elevated. Read here to lower cortisol and here to lower estrogen.
• Use various substances that lower serotonin production during exercise.
  • Caffeine inhibits the exercise-induced elevation in tryptophan hydroxylase (TPH) expression (R).
  • Red ginseng acts the same as caffeine (R, R).
  • Colostrum does the same (R).
  • Shi Chang Pu (R).
  • Vitamin B1. A deficiency in thiamine also increases serotonin synthesis and decreases its uptake, resulting in a stronger action of serotonin, which antagonizes dopamine further (R). Increased intake of thiamine increases serotonin disposal and inhibits dopamine reuptake, thus resulting in a stronger action of dopamine.
  • Salt/sodium bicarbonate. The serotonin re-uptake protein, SERT, is sodium dependent.

My pre-workout to boost CO₂ and lower serotonin:

• 1 cup water
• 4 tbsp sugar
• 10-15mg methylene blue
• 1 tbsp sodium bicarbonate (this tastes awful, but the 4 tbps sugar masks it a lot and it’s essential for boosting CO₂)
• 100mg vitamin B1
• 500mg niacinamide
• 200mg caffeine
• 1 tsp coconut oil (provides MCTs that are synergistically oxidized with glucose)

Products:

• Vitamin B1 – (Amazon, iHerb)
• Caffeine – (Amazon, iHerb)
• Niacinamide – (Amazon, iHerb)
• Biotin – (Amazon, iHerb)
• Methylene blue – (Amazon, IdealabsDC (product: Oxidal))
• Red ginseng – (Amazon, iHerb)
• Colostrum – (Amazon, iHerb)
• BCAA – (Amazon, iHerb)
• Tyrosine – (Amazon, iHerb)
• Phenylalanine – (Amazon, iHerb)
• Gelatin – (Amazon, iHerb)

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