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. Read on to learn about this neurotransmitter, the results of not having enough of it, and why you should attempt to increase it.
- 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 Resistant Starch
- 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 with Caution)
- 28) Neurotensin
- 30) Omega 3s
- Not Advised
- Avoid Orexin Inhibitors
- What Are Potential Downsides to Increasing Orexin?
- Disclaimer and Caveats
- Health Tools I Wish I Had When I Was Sick
What Is Orexin?
The brain contains about 10,000 to 20,000 neurons in the hypothalamus, but axons from these neurons extend throughout the entire brain and spinal cord, where there are also receptors for orexin.
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. 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. However, orexin is the central player in wakefulness.
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.
Top Ways to Increase Orexin
1) Get Rid of Inflammation
This is actually the most important factor in orexin being suppressed: chronic inflammation.
There are a few main reasons why your TNF/IL-1b is significantly elevated.
- 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.
Recently it’s been demonstrated that it increases orexin, and that’s the likely mechanism by which it’s effective for depression and SAD) [R].
A 2007 study found acidification of our blood increases excitability of orexin, whereas alkalinization depresses it [R].
Interval exercise especially leads to a surge in lactate, which is important for exciting orexin, regardless of acidity.
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 I’ve found to potently increase wakefulness.
There is no direct research showing ICES increases orexin, but my personal experience leads me to believe 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 I have tried.
ATP is the main energy-related molecule that we produce and when it’s deficient, orexin is suppressed [R].
5) Consume Fermented Foods for Lactate (and Pyruvate)
Supplying orexin neurons with lactate 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:
- Sauerkraut, pickles, and fermented foods
- Probiotics – Lactobacilli produce lactate
- Calcium lactate
- Calcium pyruvate
- Magnesium lactate
6) Drink Kombucha
I’ve found it to be 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
Nonessential amino acids were more potent in activating orexin cells than essential amino acids [R].
Amino acids blocked the glucose suppression of orexin because it tells the neurons that there’s enough energy around [R].
In order of most to least effective:
I just recommend taking glycine and NAC, though glycine is relaxing.
A different study gave 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)
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 20 g a day. Rather, just don’t eat high carb, and perhaps restrict your carbs to 200 g/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
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. This would be good news for people with narcolepsy [R].
12) Take Resistant Starch
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 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
I haven’t seen any studies about ketosis and orexin directly, but I have some theories about how it may stimulate orexin. I subjectively feel more awake when in 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.
However, human studies show that ketosis doesn’t increase ghrelin [R].
Fifth, ketosis results in elevated ATP in animals, which activates orexin [R].
15) Increase Dopamine
A study examined the ability of dopamine agonists to activate orexin neurons in the rat. The study found that both D1 and D2 agonists are sufﬁcient to activate orexin neurons [R].
However, when dopamine binds to other receptors, it can suppress orexin(alpha-2 receptor). So, it depends on the receptors.
Longvida curcumin can also activate dopamine receptors.
Forskolin is a well-known wakefulness promoter and it certainly produces a noticeable effect on me.
Orexin binds to orexin 1 receptors to stimulate neurons by activating cAMP [R].
However, another study did not find this to be true [R].
17) Pregnenolone and Other GABA Antagonists
GABA antagonists or ‘negative modulators’ block the effects of GABA.
GABA (both A and B) suppresses orexin, so blocking GABA helps activate it.
Here are a list of GABA antagonists:
- Pregnenolone – Potent; I use 25 mg, but you can start with a lower dosage. I and all of my clients find this helpful in promoting wakefulness (gamma2-subunit independent) [R]
- Progesterone – Pregnenolone converts to this [R]
- DHEA and DHEA-S – Pregnenolone converts to this [R, R]
- Ginkgo/bilobalide and ginkgolide – This extract should contain about 2% bilobalide [R]
- Zinc – Different mechanism than pregnenolone -gamma2-subunit [R]
- Wormwood/thujone – Thujone is also found in sage
- Muira Puama
- Theobromine and theophylline [R]
- Opioids/morphine – 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 twofold in the first 15 minutes.
Therefore, you want to expose yourself to cold by going outside in the winter or taking cold showers. This means 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 buy some TRH. You can additionally take Hypothalamus glandular, which probably contains some minute concentrations of TRH. I take 1,500 mg at a time under my tongue.
It can inhibit it simultaneously through a different mechanism, but it mostly increases it.
I recommend Alpha GPC.
21) Use LLLT/Increase ATP
Increasing ATP levels can increase orexin.
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.
Macronutrient profile aside, you can increase CO2 by breathing into a bag for as long as comfortable a few times a day.
You can also use the BreathSlim device.
I recommend getting your caffeine from tea.
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 6 hypothalamic regions that were examined [R].
In addition, long-term nicotine usage increases the orexin receptors, which makes you more sensitive to a given amount of orexin [R].
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 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 in orexin to drive you to consume nicotine [R, 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.
25) Consume Fructose
Also, 25% of fructose consumed turns into lactate, which has orexin-increasing effects [R].
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.
The structure of oxytocin is very similar to that of vasopressin. Due to its similarity to vasopressin, it can reduce the excretion of urine slightly.
In several species, oxytocin can stimulate sodium excretion from the kidneys (natriuresis), and, in humans, high doses can result in hyponatremia.
Falling in love, having sex, nursing, and positive social encounters all lead to increased oxytocin.
27) Vasopressin (Use with 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.
Vasopressin directly activates orexin/hypocretin neurons [R].
I can relate to this. When I’m really thirsty, I’m more awake. When we haven’t drank 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.
It also decreases our body temperature and pain levels, increases our energy (locomotor activity), and has important gut functions.
Neurotensin increases orexin.
30) Omega 3s
A study found that in healthy people, there was a correlation between omega 3s and orexin A (but not in narcoleptics) [R].
CRH or Corticotrophin Releasing Hormone is released by the hypothalamus and activates orexin. It’s released in response to stress, which is why we feel more awake at first when stressed.
Therefore, we don’t want to increase orexin in this manner.
Glutamate is an excitatory neurotransmitter that activates orexin.
Too much glutamate release is implicated in most chronic cognitive diseases.
CCK activates orexins; however, this is the only hormone I know of that is an orexin activator but also induces sleep.
A high-protein diet increases CCK. Chewing gum increases it a bit.
Avoid Orexin Inhibitors
The following inhibit orexin:
- Fasting – Very healthy, but it does decrease orexin [R]
- TNF-alpha, IL-1 [R]
- Excess glucose
- NPY – Although NPY stimulates wakefulness, it has wakeful-promoting and sedative effects, which depends on where it’s released [R, R]
- Dopamine (alpha-2 receptor)
- Opioids [R]
- Serotonin (5-HT1A)
- Cannabinoids – Although, orexins play a role in the addictive properties of cannabinoids. This is perhaps because CB1 receptors potentiate orexin 1 receptors [R, R, R, R]
- MSH [R]
- Chronic high-dose lithium (low doses are fine)
What Are Potential Downsides to Increasing Orexin?
Orexin plays a role in causing Alzheimer’s disease by increasing amyloid plaques.
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.
Indeed, orexin plays a role in food, drug, and sex addiction [R].
Blocking orexin also reduced cocaine-induced impulsivity [R].
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].
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 good f or your health.
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].
Health Tools I Wish I Had When I Was Sick
At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.
That’s why I decided to create tools that will help others cut down the guesswork:
- Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
- SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
- SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
- SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
- Selfhacked Inflammation course – a video course on inflammation and how to bring it down
- Biohacking insomnia – an ebook on how to get great sleep
- Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
- BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
- SelfHacked VIP – an area where you can ask me (Joe) questions about health topics
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