I think it’s important for people to know the mechanisms for why they are getting tired from carbs.  It turns out that the hacks that help post-meal carb fatigue fit nicely with my theories.

Orexin Suppression is Why You Feel Tired After Carbs

People want to know the underlying cause of why they get tired after meals – and carbs in particular.

I’ve spoken about orexin a lot on this blog.  Orexin is the most important wakefulness neuropeptide.

I am convinced that post-meal fatigue is mediated by orexin suppression (i.e. the neurons firing less), and this is backed up by studies and self-experiments.

Carbs and glucose in particular suppresses orexin.

The question then becomes why are your orexin neurons more easily suppressed by carbs (and you get tired) vs. other people who don’t get as tired from carbs.

In particular, people with chronic health issues are more likely to experience post-meal carb fatigue.

Read this post for a background on orexin: 29 Ways To Naturally Improve Mood and Motivation By Increasing Orexin/Hypocretin.

Why Health Issues Lead to The Suppression of Orexin

There are a variety of features of the CFS health issues that people deal with that lead to orexin being lower and more likely suppressed.

I’ve found six main reasons (theories) why CFS-like people get tired post carbs:

1) Lower mitochondrial function and ATP production

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ATP is the main energy-related molecule that we produce from out mitochondria in our cells.  It’s a form of stored energy.

Your hypothalamus senses energy-related molecules like ATP, and if it’s low, orexin neurons will be more likely to be suppressed to conserve energy.  This results in fatigue.

Increased ATP levels prevent the suppression of orexin from carbs (R), so if you have higher levels of ATP, you will less likely get tired after carb-filled meals.

ATP is the main energy-related molecule that we produce, and when they’re deficient, orexin is suppressed (R).

People with chronic fatigue health issues have lower ATP due to poor mitochondrial function, which will make them more likely to be fatigued after carbs.

My experiments in improving mitochondrial function confirm that this plays a significant role in lessening carb-induced fatigue.

2) Inflammation

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Elevated inflammation from cytokines like IL-1b (R) and TNF (R) cause fatigue by suppressing of orexin neurons (R, R2).

Il-1b is something that is more often than not localized in the hypothalamus.  If your nervous system is overactive, it means there’s a good chance you have higher IL-1b, which will predispose you to orexin suppression.

My experiments with reducing inflammation confirm that cytokines are a significant cause of orexin suppression.

3) Circadian Dysregulation

Sleeping

Orexin is controlled via a circadian rhythm and the SCN neurons (the command center for your circadian rhythm, found in the hypothalamus) directly connects to orexin neurons to stimulate wakefulness (R).

People who get tired after carbs tend to get less tired after carbs at certain times (such as the evening) or sometimes not at all.  This is because orexin is tied to your circadian rhythm.

If your SCN is firing on all cylinders when it’s supposed to, orexin will be more active when it’s supposed to, and you will be more awake in the day and tired at night.

Carbs will likely have less of an effect on orexin if your SCN is firing robustly.

People with chronic health issues tend to have more circadian rhythm problems.

4) Lower cyclic AMP

Cyclic AMP is one of the main communication molecules that transmits signals in the cell.

People with chronic health issues tend to have lower cyclic AMP because this is produced from ATP and when ATP is lower, cyclic AMP will be lower.

Forskolin is a well-known wakefulness promoter, and it certainly produces a noticeable effect on me.  Forskolin increases cyclic AMP in the whole body, including in the area where orexin neurons are.   This causes these neurons to activate (long-term potentiation), and the result is we’re more wakeful (R).

My experiments with Forskolin confirm that lower cyclic AMP is a significant contribution to the suppression of orexin.

5) Lower NAD+/SIRT1

SIRT1 is a protein that modifies other proteins, and it uses NAD+. So it’s important for epigenetic expression.

NAD+ and SIRT1 have a variety of protective functions in the body.

People with chronic health issues tend to have lower NAD+ and SIRT1 levels.

SIRT1 increases orexin receptors and makes you more sensitive to orexin peptides (R) and orexin activators like ghrelin (R).

Besides orexin, SIRT1 sustains other sets of neurons that are important for wakefulness.

Wake neurons in the basal forebrain and brainstem provide critical inputs to optimize alertness and attention.

In animals, SIRT1 serves as a critical neuroprotectant for these wake neurons.  Loss of brain SIRT1 in the adult mouse cause impairments in wakefulness.

Populations of wake neurons (including the orexinergic, locus coeruleus, mesopontine cholinergic, and dopaminergic-wake neurons) that don’t have SIRT1  show a loss of dendrites and neurotransmitter synthesis enzymes and develop an accelerated accumulation of cellular debris (lipofuscin), causing wake neurons to malfunction (R).

My experiments with increasing SIRT1 confirm these findings that it increases wakefulness in the long run.

6) Less Nitric Oxide Regulation

Nitric oxide is a complex story – it can be both good and bad.  The key point is that it needs to be regulated well.

Important factors are where it’s increased, for how long and how much is produced.

I’ll admit that I don’t fully understand all of the nuances of nitric oxide.

Nitric oxide regulation is off generally in people with chronic health issues, partly because iNOS (induced by inflammation) causes a dysregulation of nitric oxide.

Orexin-A’s effects are Nitric Oxide-dependent.  But you need this nitric oxide in specific parts of your hypothalamus (lateral hypothalamus).

In particular, nitric oxide is critical to the appetite-stimulating effects of orexin (R).

Too much and/or chronic nitric oxide can also cause orexin neurons to degrade (R).

Nitric oxide can cause both wakefulness (R) and sleep (R), depending on where it’s produced.

If nitric oxide isn’t regulated properly, it may cause fatigue/wakefulness at improper times.

Why Are Thin People More Prone to Orexin Suppression?

I see it all the time – people are either hungry and fat or have no appetite and can’t sustain their weight (or at the very least have no problems losing weight).

The people who are fat seem to have fewer issues with fatigue than the people who are thin, even though being overweight is symptomatic of health issues and you’d think they’d have it worse.

The thin people experience more fatigue from orexin suppression than the obese, in my experience.  This is because various factors cause less orexin function in the thin people.

There are many genes (and epigenetics) and environmental factors that interact in diverse ways that end up deciding your weight.

Th1 Dominance, Lower Orexin and Being Thin (Technical)

This will get technical.  Skip over if you aren’t a long-time reader of the blog or you don’t have a technical background.

I’ve noticed a cluster of traits in people (subjective):

  • Thin,
  • Th1 dominant,
  • More fatigued after carbs – i.e. more likely to have orexin suppressed.

The converse is also true:

  • Overweight,
  • Th2 dominant
  • More wakeful than the thinner people.

I can think of 4 reasons why these traits cluster together.

  1. Less SOCS3, which means less leptin resistance,
  2. Less PPAR gamma
  3. Less Ghrelin
  4. Less Cortisol.

Leptin causes the suppression of orexin (R).  Obese people are leptin resistance, which will likely prevent the suppression of orexin from leptin.  So obese people have one upside to leptin suppression – a lower likelihood of orexin suppression.

PPAR gamma preserves orexin neurons in response to insults (R), and this is lower in thin people.  Less PPAR gamma also causes Th1 dominance.

So less PPAR gamma will cause less orexin, less weight gain, and Th1 dominance.  This is one reason why these traits cluster together.

Ghrelin activates orexin.  Ghrelin is also an anti-inflammatory and inhibits Th1 dominance (R).

Ghrelin is known to stimulates hunger.  So if you have higher ghrelin, you will be more hungry, more awake (including after carbs) and suffer from less inflammation (especially Th1 inflammation).  The converse is also true.

Cortisol will increase orexin indirectly (by reducing inflammation, increasing mitochondrial function), but the thinner phenotype has lower levels of this.

So less cortisol=Th1 dominance, weight loss, and fatigue.

High POMC, Lower Orexin and Being Thin (Technical)

The POMC polypeptide causes a lower appetite, but they also lead to less orexin (mice lacking POMC have higher levels of orexin).  This is mediated by alpha-MSH, which suppresses orexin (R).

POMC also causes weight loss.

So thin people have higher POMC, and this leads to lower appetite/weight loss and less orexin.

Overweight people have lower POMC, more of an appetite and higher orexin.

How to Prevent The Suppression of Orexin From Carbs

I noticed these hacks prevent fatigue from carbs, without their main effect from decreasing blood glucose.  I hypothesize why these hacks help me when I need them.

References are found in my post:  29 Ways To Naturally Improve Mood and Motivation By Increasing Orexin/Hypocretin.

Circadian Rhythm Entrainment

Orexin is controlled via a circadian rhythm and the SCN neurons directly connect to orexin neurons to stimulate wakefulness (R).

I notice the more I take care of my circadian rhythm, the less tired I get after carbs.

Sun

Sun increases nitric oxide from UV and directly stimulates orexin with bright, blue light.

I’m more carb tolerant when I get more sun or when I use a Bright Light Device (which I only use if need be).  The effects are different, with the sun being better at increasing orexin for me because of the UV.

Infrared/UV from the sun could also improve mitochondrial function.

Note that some people get tired from the sun, perhaps also because of nitric oxide.  It used to make me sleepy.

Forskolin

Forskolin makes me more carb tolerant.

Forskolin increases cyclic AMP in the whole body, including in the area where orexin neurons are.   This causes these neurons to activate (long-term potentiation), and the result is we’re more wakeful (R).

Buy: Forskolin (IHERB)

Interval Exercise

Interval exercise increases orexin by increasing lactate, which prevents the suppression of orexin.

I’m more carb tolerant when I interval exercise.

DHA

A study found that in healthy people, there was a correlation between omega 3’s and orexin A (but not in the narcoleptics) (R).

I’m more carb tolerant when I increase DHA, whether from fish or fish oil.

Buy: Fish oil/DHA.

Resveratrol, Leucine, Niagen NAD+

I’m more carb tolerant when I use these, partly most likely because of SIRT1/NAD+’s effect on increasing orexin.

Buy:

Kombucha

Kombucha contains lactate and NAD+, in addition to tea polyphenols and some caffeine.

All of these will stimulate orexin (tea polyphenols indirectly).

I’m more carb tolerant when I drink kombucha.

Nicotine

Nicotine increases orexin, and this abolishes carb induced fatigue for me.

Apple Cider Vinegar

ACV decreases blood glucose, but besides that, anything acidic will increase orexin.  So ACV is good at decreasing fatigue after carbs.

Icariin

This works perhaps by increasing nitric oxide.  I’m not sure.

Buy: Epimedium (IHERB)

Berberine, Cinnamon, Rooibos,

Berberine and cinnamon will decrease blood glucose, which will help orexin.

These are also AMPK activators and anti-inflammatories, and I believe AMPK makes me more carb tolerant (no mechanism).

Buy:

Hi-Maize

Hi-maize produces butyrate, which is an energy-related molecule and should, therefore, block glucose-induced suppression of orexin (R).

Also, butyric acid is acidic and also increases ATP.  Therefore it may also increase orexin in these ways.

I’ve found that it does indeed increase wakefulness after a glucose challenge or a big meal.

It also increases GLP-1, which functions like orexin and works instead of it (R).

Hi-maize will also slow the absorption of glucose because it’s a fiber, so it works in multiple ways.

Buy:  Hi-Maize/Resistant starch (IHERB).

Chocolate

No clear mechanism, but I notice it increases carb tolerance.

ICES

ICES is a device that I have found to potently increase wakefulness.

There is no direct research showing ICES increases Orexin, but my personal experience leads me to think that it does.

I believe the main mechanisms by which ICES increases orexin is by decreasing  inflammation and potently increasing ATP production.   It does this better than every other thing that I have tried.

What This Post Excludes

Anything that will utilize blood glucose, slow the absorption of carbs, increase insulin sensitivity will make you less fatigued.

But I don’t really focus on these in this post because they revolve around lowering blood glucose.

Things like walks after meals, complex carbs, fiber, protein, fat, water, increasing insulin sensitivity, alpha-glucosidase inhibitors, will all help have a more steady blood level of carbs.

But that’s not the point of this post.  The point of this post is to directly combat the suppression of orexin with a given carb load.  I don’t include things that mainly work via decreasing blood glucose.

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19 COMMENTS

  • Natcha M

    Since I’m nerding out about this, I’m just gonna comment with my own experience. Maybe typing it out helps me think.

    There’s a timeline of how things happen after someone eats food, depending on digestion etc, right? Most of the carbohydrate digestion is in the intestine, so if someone is tired when food is still in the stomach, it’s likely because they have low HCl or low stomach enzyme.
    – What about LNAA receptors transporting tryptophan into the brain? High insulin levels increase LNAA receptor activity to import tryptophan into the brain. This increases serotonin levels and relaxes the said carb ingester. This only happens after the food is digested, amino acid absorbed, and circulate around the body. Because LNAA also transport leucine, valine, isoleucine, this might explain why a higher protein meal is less likely to result in fatigue after meals, but it can still raise insulin and cause the same effects.
    – I used to think that the fatigue is because of hypoglycemia, but I used a glucometer to track a few different meals 3 hours after eating. Surprisingly I found that sometimes I felt crashed in the middle of my blood sugar being ~120 – 140, so it definitely wasn’t because of hypoglycemia. It’s also possible to have brain insulin resistance but not be insulin resistant elsewhere in the body, but I gotta look into this.

  • Jake

    Fascinating post. I notice that after I eat chicken, the following 24 hours I’m significantly calmer/more energetic. I have the same effect after just 15 minutes of interval training. Considering chicken has decent levels of leucine, are these effects evidence that part of my fatigue is orexin suppression?

  • Robin

    Will you be writing a post on supporting BH4 production and nitric oxide regulation in the future?

  • andrew

    for the ICES theory on orexin, where do you put it on your body for max effectiveness in terms of insulin and carbs and gluten?

  • Nono

    Your blog are very interesting and intellectually smart but many of this recommendation about supplement are theory. In fact, many of them don’t work. Small% have a value

    1. Joseph M. Cohen

      Theory and validation based on my own experiments. Will this work for you? Maybe.

  • andrew

    whats your preferred nicotine delivery method?

    1. Joseph M. Cohen

      Snus or gum

  • Clóvis Valadares Junior

    Joseph, the spike of insulin when we eat carbs doesn’t matter in this case?

    1. Joseph M. Cohen

      No

  • Ahmad Awadallah

    I’m surprised no mention of Jasmine Green tea. It seems to help me after lunch and I don’t think it is because of the caffiene. If I drink coffee it does not help me against carb induced comma like jasmine green tea does. Especially if I make a strong one (2 tea bags of Numi Jasmine Green tea).

    1. Joseph M. Cohen

      I was thinking about adding tea and caffeine, but it actually used to make me tired for a bit…even though caffeine stimulates orexin…

  • Deane @ Be Brain Fit

    Orexin is actually a neuropeptide not a neurotransmitter. They are similar but don’t do exactly the same thing. You can read about the difference here: https://en.wikipedia.org/wiki/Neuropeptide
    Since you’re a science geek thought you’d like to know!

    1. Joseph M. Cohen

      True…

      “One major difference is that peptides are not recycled back into the cell once secreted, unlike many conventional neurotransmitters (glutamate, dopamine, serotonin). Another difference is that after secretion, peptides are modified by extracellular peptidases; in some cases, these extracellular cleavages inactivate the biological activity, but in other cases the extracellular cleavages increase the affinity of a peptide for a particular receptor while decreasing its affinity for another receptor. These extracellular processing events add to the complexity of neuropeptides as cell-cell signaling molecules.”

  • Robin

    Awesome post Joseph. I’m looking forward to what you figure out about nitric oxide regulation. As someone with NOS variations, and BH4 issues (in addition to many other wonderful variations) I know they contribute to my difficulties with headaches, fatigue, and systemic mast cell activation. I purchased ICES but have not started to use it.

  • ourgodisaconsumingfire

    Doesn’t it have to do with insulin resistance? After going very high in carbs and low in fat for a while, I don’t have this problem anymore, unless I stuff myself with sweets (excessive sugar, and especially the sugar-fat combo.)

    1. Joseph M. Cohen
  • Eddie Strike (@EddieStrike)

    Thanks for this write up Joe.

    Carbs often put me in a coma, and have done for a few years now. (even just low sugar berries, or something else low GI) Upon eating them, my energy completely tanks, I get depressed, fatigued, anxious, all while being fine prior to eating them.

    I haven’t been able to figure out the problem, no matter where I looked or who I asked, so I’m putting some hope to your Orexin Suppression theories.

    1. Pc

      Could be candida?

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