- What is Orexin?
- Why Should We Increase Orexin?
- Top Ways To Increase Orexin
- 1) Get Rid of Inflammation
- 2) Use A Bright Light Device Or Get Outside
- 3) Exercise
- 4) ICES/PEMF
- 5) Consume Fermented Foods For Lactate (and Pyruvate)
- 6) Drink Kombucha
- 7) Eat More Protein/Take Amino Acids
- 8) Restrict Glucose
- 9) Eat Less: Caloric Restriction
- 10) Lose Weight
- 11) Take Fibers and GLP-1 Agonists
- 12) Take Hi-Maize
- 13) Have Some Fun
- 14) Get Into Ketosis
- 15) Increase Dopamine
- 16) Forskolin
- 17) Pregnenolone and Other GABA Antagonists
- 18) Thyroid Releasing Hormone (TRH)
- 19) Ghrelin
- 20) Acetylcholine
- 21) Use LLLT/Increase ATP
- 22) Bag Breathing/CO2
- 23) Caffeine
- 24) Nicotine
- 25) Consume Fructose
- 26) Oxytocin
- 27) Vasopressin (Use Caution)
- 28) Neurotensin
- 30) Omega 3’s?
- Not Advised
- Avoid Orexin Inhibitors
- What Are Potential Downsides to Increasing Orexin?
- Disclaimer and Caveats
What is Orexin?
Orexin, also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite. Narcolepsy is caused by a lack of orexin in the brain due to the destruction of the cells that produce it (R).
Why Should We Increase Orexin?
Orexin is not just any molecule in our body.
Whenever we’re tired or fatigued, orexin is suppressed.
It’s not like Orexin is one of the many systems that stimulate wakefulness. It’s BY FAR the most significant stimulator of wakefulness (and it could be the only system). Histamine is also involved, but orexin activates the histamine system.
As you’ll see there are many hormones and other systems in the body that interact with orexin. But orexin is the central player in wakefulness. I can’t stress this enough.
Therefore, the orexin system is central to us functioning as productive human beings and being in a good mood.
This orexin system interacts with so many other systems of the body, which makes it so important.
This is a significant factor in why consuming sugar makes us fat. When we eat sugar it causes our blood to spike in sugar. This suppresses orexin, which makes us fatigued and inactive. So instead of burning the calories, we go to sleep. (R)
Orexin and its receptors decline with age. (R)
Orexin is particularly important in people with narcolepsy, which is an autoimmune condition that destroys orexin neurons. While this isn’t a cure, if you have narcolepsy you can optimize the orexin neurons that you have left.
Narcolepsy is significant as a result of an immune imbalance, specifically an elevated Th2 immune system. (R) Another study found elevated TNF and IL-6. (R) (Click on the links to see how to balance these out.)
Top Ways To Increase Orexin
1) Get Rid of Inflammation
This is actually the most important factor in orexin being suppressed: chronic inflammation.
- Food sensitivity or inflammation from food antigens.
- You have a chronic infection.
- You have a really unhealthy diet and lifestyle.
- You’re sleep deprived.
I also recommend exploring the following substances:
2) Use A Bright Light Device Or Get Outside
Bright light is used for seasonal affective disorder (SAD) and depression.
Buying a bright light device was one of the best purchases I’ve ever made. It increases BDNF and is stimulating.
I use this Bright light device. It’s one of the best investments I’ve ever made. I find it more stimulating than being outside.
A 2007 study found acidification of our blood increases excitability of orexin, whereas alkalinization depresses it. (R)
Exercise can increase wakefulness even without the orexin system, so it’s good anyway. (R)
Even the increases in CO2 in the atmosphere from increased pollution can increase orexin activation, which means people have slightly more orexin activation than in the past (all other things constant) (R).
(The effects of pH involve acid-induced closure of leak-like K+ channels in the orexin cell membrane. (R))
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.
ATP is the main energy-related molecule that we produce and when they’re deficient, orexin is suppressed. (R)
5) Consume Fermented Foods For Lactate (and Pyruvate)
Supplying orexin neurons with lactate and can stop glucose from blocking orexin neurons (R).
The effect of lactate on firing activity is concentration dependent. Also, lactate disinhibits and sensitizes these orexin neurons for future excitation (R).
One study hypothesized that orexin neurons only ‘see’ glucose changes when the levels of other energy molecules are low, whereas high energy levels can stop glucose from regulating orexin cells (R).
My main source of lactate is kombucha and interval exercise. Here are my recommendations:
- Sauer kraut, pickles, and fermented foods
- Probiotics – lactobacilli produce lactate
- Calcium lactate
- Calcium pyruvate
- Magnesium lactate
6) Drink Kombucha
Kombucha has lactate (R), pyruvate, butyrate (R), ATP (R) and perhaps other “energy-related molecules” as a result of the fermentation process, which increases orexin (R). I’ve found it to be the most powerful in increasing wakefulness because it has all of these in one drink.
In addition, it has tea polyphenols, which inhibit TNF-alpha.
7) Eat More Protein/Take Amino Acids
Amino acids blocked the glucose suppression of orexin because it tells the neurons that there’s enough energy around (R).
From most to least effective:
A different study gave mice a dietary supplement of branched-chain amino acids (BCAAs) to brain-damaged mice, which are precursors to glutamate synthesis in the brain. BCAA therapy reinstated activation of orexin neurons and improved wake deficits in mice with mild brain injury. (R)
(Works by inhibition of KATP channels and activation of system-A amino acid transporters. (R))
8) Restrict Glucose
Elevated glucose concentration can block or silence the activity of orexin neurons (R).
The principal way to activate orexin is by restricting glucose (R).
The hypothesis is that under low-energy conditions such as starvation or anorexia, it could be advantageous for ingested glucose to suppress the orexin-driven net energy expenditure, thereby ensuring that more fundamental processes (such as keeping the brain alive) receive enough glucose. Conversely, when the brain has plenty of fuel (perhaps signaled by high levels of pyruvate and/or lactate), there may be little advantage in coupling glucose fluctuations to orexin activity, since under these conditions, acute changes in glucose levels would be compensated by other energy molecules (R).
The best way to do this is to eat less sugar and carbs. This doesn’t mean to go low carb and eat less than 20g a day. Rather, just don’t eat high carb and perhaps restrict your carbs to 200g/day, most of which should be low glycemic index carbs.
9) Eat Less: Caloric Restriction
Orexin neurons are stimulated by falling glucose levels (R).
If you eat less or practice some degree of caloric restriction you will increase orexin because our body senses we’re not getting enough calories and activates this system. (R)
10) Lose Weight
(Works by presynaptic inhibition of excitatory neurotransmission and the opening of K ATP channels (R).)
11) Take Fibers and GLP-1 Agonists
GLP-1 is a gut hormone that can activate/excite orexin neurons in the hypothalamus (which increases orexin). It’s useful in making us feel satiated as well, which will make us eat less and activate orexin even more.
It’s possible that GLP-1 could function like orexin and work instead of it.(R) This would be good news for people with narcolepsy.
12) Take Hi-Maize
Also, butyric acid is acidic and increases ATP and therefore may also increase orexin in these ways.
I’ve found that it does indeed increase wakefulness after a glucose challenge or a big meal.
As discussed above, it also is a GLP-1 agonist, so it can increase orexin in multiple ways.
13) Have Some Fun
A study found having fun or play was able to increase orexin, while the same level of exercise wasn’t able to (R).
The study concludes that motor and cardiovascular changes are not sufficient to elevate orexin, so they hypothesize that the emotional aspects of yard play account for the observed increase in orexin (R).
14) Get Into Ketosis
First, if you get into ketosis, glucose levels will likely be low, which is a significant factor in activating orexin.
Second, Ketones are “energy-related molecules” that would theoretically signal to our brain that there’s not a famine, which should activate orexin (in theory). This is thought to be the underlying logic for why lactate prevents orexin suppression.
Third, Ketones are acidic and they increase our blood acidity, which in turn increases orexin.
Fifth, Ketosis results in elevated ATP in animals (R), which activates orexin.
15) Increase Dopamine
L-Dopa, Mucuna, Amphetamines, Modafinil, Tyrosine, and SAM-e all increase dopamine in the brain. Rhodiola specifically increases it in the hypothalamus (R– in the body of the study.) Longvida Curcumin can also activate dopamine receptors.
Forskolin is a well known wakeful 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)
17) Pregnenolone and Other GABA Antagonists
GABA antagonists or ‘negative modulators’ block the effects of GABA.
Here are a list of GABA antagonists:
- Pregnenolone (R, R2). ‘Potent’. I use 25mg, but you can start with a lower dosage. I and all of my clients find this helpful in promoting wakefulness. (gamma2-subunit independent)
- Progesterone (R) – Pregnenolone converts to this.
- DHEA (R) +DHEA-S (R) – Pregnenolone converts to this.
- Ginkgo/Bilobalide and Ginkgolide (R, R2). This extract should contain about 2% bilobalide.
- Zinc (R) (different mechanism than pregnenolone -gamma2-subunit)
- Wormwood/Thujone (R)…Thujone is also found in sage.
- Muira Puama (R)
- Theobromine and Theophylline (R)
- Opioids/Morphine (R) – inhibits GABA release (R)
- Antibiotics -β-Lactams (penicillins, cephalosporins, carbapenems), Fluoroquinolones…Not recommend unless you have a bacterial infection
18) Thyroid Releasing Hormone (TRH)
In rats, exposure to 4 degrees C or 39 degrees F increased TRH release by 2 fold in the first 15 min.
Therefore you want to expose yourself to cold by going outside in the winter or taking cold showers. This means to completely turn off the hot water. I can only do this one minute or else it’s too annoying.
If cold exposure isn’t your thing then you can buy some TRH. You can additionally take Hypothalamus glandular, which probably contains some minute concentrations of TRH. I take 1500mg per a time under my tongue.
21) Use LLLT/Increase ATP
Increasing ATP levels can increase orexin. (R)
My favorite way to do this is to put this LLLT on my brain. It also decreases inflammation and has a lot of other benefits.
22) Bag Breathing/CO2
CO2 is one of the methods to increase orexin (R).
Macronutrient profile aside, you can increase CO2 by breathing into a bag for as long as comfortable a few times a day.
You can use the BreathSlim device.
Nicotine is addictive. However, in all of the research I’ve read, nicotine is not harmful to most people.
Nicotine activates orexin neurons. (R)
Nicotine increases both Orexin A and B and ALSO increases orexin receptors. Chronic exposure seems to have better effects.
Specifically, it increases the levels of orexin A in the dorsomedial hypothalamic nucleus (DMH) and orexin-B in the DMH and paraventricular nucleus (PVN) among the six hypothalamic regions that were examined. (R)
In addition, long-term nicotine usage increases the orexin receptors (R), which will make you more sensitive to a given amount of orexin.
In addition, nicotine and orexin excite the same synapses of the arousal pathway within the prefrontal cortex (thalamocortical). (R) So in addition to increasing orexin, it increases wakefulness independently by activating the same neural pathways.
Nicotine addiction depends, in part, on leptin and orexin (R) and in particular orexin-1 receptors in the lateral hypothalamus. The increase in orexin seems very significant with regard to nicotine addiction. Withdrawal causes an increase orexin to drive you to consume nicotine. (R)
If you’re thin and experience significant fatigue in the day, it’s likely that you have low levels of both orexin and leptin, so addiction is less likely for you – or will be less severe.
And if you do become addicted, at least it will increase wakefulness at the same time, so it’s not actually so bad.
25) Consume Fructose
Heavy fructose consumption may not be the most healthy way to increase orexin, but based on my experience, it’s effective.
Raw honey is my preferred source.
27) Vasopressin (Use Caution)
Vasopressin is a hormone that makes us absorb more water and decrease urination.
Animals show increased activity when dehydrated, a behavior that improves the likelihood of locating new sources of water.
I can relate to this. When I’m really thirsty, I’m more awake. When we haven’t drunk for a while, vasopressin is released and this activates orexin so that we look for water (R).
Vasopressin is also used as a nootropic/smart drug.
30) Omega 3’s?
A study found that in healthy people, there was a correlation between omega 3’s and orexin A (but not in the narcoleptics) (R).
Therefore we don’t want to increase orexin in this manner.
Glutamate is an excitatory neurotransmitter that activates orexin. (R)
Too much glutamate release is implicated in most chronic cognitive diseases. (R)
Avoid Orexin Inhibitors
The following inhibit orexin:
- Fasting (R) – very healthy, but it does decrease orexin.
- TNF-alpha, IL-1 (R)
- Excess glucose (R)
- Leptin (R)
- NPY (R, R2) – although NPY stimulates wakefulness. (R) NPY has wakeful-promoting and sedative effects, which depends on where it’s released. (R)
- Gaba (R)
- Dopamine (R) (alpha-2 receptor).
- Opioids (R)
- Adenosine (R)
- Serotonin (5-HT1A) (R)
- Noradrenaline (R)
- Cannabinoids (R, R2)…Although orexins play a role in the addictive properties of cannabinoids. (R) This is perhaps because of CB1 receptors potentiate orexin 1 receptors. (R)
- MSH (R)
- Chronic high dose Lithium (R) (low doses are fine)
- Alkalinization (R)
- Nociceptin (R)
- Enkephalin (R)
What Are Potential Downsides to Increasing Orexin?
In my opinion, this isn’t significant. This is because it was found that the mechanism by which it prevented plaque was by the animals sleeping longer. This highlights the important role of sleep in preventing Alzheimer’s, not orexin per se.
Many of the same systems in our brain that are responsible for hunger are also responsible for addiction and pleasure seeking. Orexin is one such molecule that plays a role in both.
I have a friend who is never tired, always hungry and is addicted to pleasure – food, drugs, sex, anything. He needs less sleep, too. This is indicative of an overactive orexin system.
Too much orexin can also cause anxiety, panic attacks, and depression. (R)
Orexin can cause depression if there’s too much or too little. (R)
I’ve experienced both states and I can say both cases cause worse mood, but it’s different.
One kind of depression is when you’re tired and lethargic, without much energy. You are kind of just ‘down’. The other is more where you experience a boredom-based depression as if nothing is stimulating enough.
The point is an overactive or underactive orexin system is not either good.
Disclaimer and Caveats
Almost all of the studies referenced in this post come from animal studies, so keep that in mind.
Orexins are exclusively synthesized in the Lateral hypothalamus (LH), derived from a single protein precursor named prepro-orexin. Prepro-orexin is enzymatically matured into two peptides, orexin-A, and orexin-B which bind to the G-protein coupled receptors OX1 and OX2 (HCRT1 and HCRT2) (R).
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