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 and Why Is It Important?

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.

Brain orexin/hypocretin neurons stimulate wakefulness, alertness, eating, reward-seeking and healthy glucose balance [1].

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 wakefulnessHistamine 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.

Orexin also increases our metabolism and body temperature, so if you’re feeling cold and tired, low orexin is partly at fault [2].

Orexin also increases hunger, and this works via increased neuropeptide Y expression in the arcuate nucleus of the hypothalamus [3].

This orexin system interacts with so many other systems of the body, which makes it so important.

High levels of orexin-A cause us to be happier. The incidence of depression is higher in narcolepsy.

Animal models show that low levels of orexin cause obesity, even when fewer calories are consumed [4].

This is a significant factor in why consuming sugar makes us fat. When we eat sugar, it causes our blood sugar levels to spike. This suppresses orexin, which makes us fatigued and inactive. So, instead of burning the calories, we go to sleep [4].

Orexin and its receptors decline with age [4].

Orexin causes us to increase oxygen consumption because it increases metabolism [5].

Narcolepsy and Orexin

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 [6].

Another study found elevated TNF and IL-6 [7].

Top Methods of Increasing Orexin

1) Get Rid of Inflammation

This is actually the most important factor in orexin being suppressed: chronic inflammation.

Elevated inflammation from cytokines like IL-1b and TNF cause fatigue by the suppression of orexin neurons [8, 910, 11].

Just before the normal time of sleep onset for rats, TNF levels in brain tissue were shown to be 10-fold higher than their daily minimum [12].

There are a few main reasons why your TNF/IL-1b is significantly elevated.

  1. Food sensitivity or inflammation from food antigens
  2. You have a chronic infection
  3. You have a really unhealthy diet and lifestyle
  4. You’re sleep deprived

My favorite way to decrease inflammation is by putting a device called ICES on my head. My second favorite way to decrease inflammation is by putting LLLT on my brain.

2) Bright Light: Get Outside

Bright light(for example, from the sun) increases orexin, and that’s the likely mechanism by which it’s effective for depression and seasonal affective disorder (SAD) [13].

3) Exercise

Exercise can also increase orexin in the cerebrospinal fluid of rats, dogs, and cats [14].

Exercise was able to increase orexin levels in the human bloodstream [14].

The source of orexin might be directly released from the pituitary into the bloodstream, or leaked from the cerebrospinal fluid, or produced by the gut, pancreas, etc. [14].

Interestingly, orexin A can probably cross the blood-brain barrier, so if it’s elevated in the blood after exercise, it will probably be elevated in the brain [15].

Mechanism:

  • Exercise temporarily acidifies our blood, and through that method, can increase the firing of orexin, whereas alkalinization depresses it [16].
  • Things that increase blood acidity will help increase orexin.
  • Exercise increases lactate, which makes our blood more acidic.
  • 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 [17].
  • 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) [18].

4) Consume Fermented Foods for Lactate (and Pyruvate)

I spoke about using lactate as a backup generator before.

Lactate is a critical energy source and a regulator of the orexin system. Lactate release from astrocytes plays an integral part in balancing brain activity and energy supply [19].

Supplying orexin neurons with lactate can stop glucose from blocking orexin neurons [1].

The effect of lactate on firing activity is concentration dependent. Also, lactate disinhibits and sensitizes these orexin neurons for future excitation [19].

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 [1].

My main source of lactate is kombucha and interval exercise. Here are my recommendations:

    • Kombucha
    • Sauerkraut, pickles, and fermented foods
    • Probiotics – Lactobacilli produce lactate
    • Calcium lactate

Kombucha has lactate, pyruvate, butyrate, ATP, and perhaps other “energy-related molecules” as a result of the fermentation process, which increases orexin [1].

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.

5) Eat More Protein

Amino acids excite orexin neurons through a few mechanisms [20].

Nonessential amino acids were more potent in activating orexin cells than essential amino acids [20].

Amino acids blocked the glucose suppression of orexin because it tells the neurons that there’s enough energy around [20].

In order of most to least effective:

  • Glycine
  • Aspartate
  • Cysteine (NAC)
  • Alanine
  • Serine
  • Asparagine
  • Proline
  • Glutamine [20]

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 [21].

6) Eat Fewer Carbs

Elevated glucose concentration can block or silence the activity of orexin neurons [1].

The principal way to activate orexin is by restricting glucose [22].

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 [1].

The best way to do this is to eat less sugar and carbs.

7) Eat Less: Caloric Restriction

Orexin neurons are stimulated by falling glucose levels [22].

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 [4].

8) Lose Weight

Leptin inhibits orexin. High leptin levels are characteristic of being overweight and come down as a result of weight loss [23].

9) Consume Fiber

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 [24 ].

Resistant starch is a good way to increase GLP-1 [25, 26].

Resistant starch also produces butyrate, which is an energy-related molecule and should, therefore, block glucose-induced suppression of orexin [1].

Also, butyrate 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.

10) 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 [27].

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 [27].

11) Stimulate Your Vagus Nerve

Vagus nerve stimulation has been shown to decrease the amounts of daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury [28].

In rats with traumatic brain injury, vagus nerve stimulation promoted the recovery of consciousness in comatose rats after traumatic brain injury [28].

The effects were in part mediated by the increase of orexin-A and its receptor (OXR1) in the prefrontal cortex [28].

12) Increase Dopamine

A study examined the ability of dopamine drugs to activate orexin neurons in the rat. The study found that both D1 and D2 receptors are sufficient to activate orexin neurons [29].

However, when dopamine binds to other receptors, it can suppress orexin (alpha-2 receptor). So, it depends on the receptors.

L-DOPA, mucuna, amphetamines, modafinil, tyrosine, and SAM-e all increase dopamine in the brain. Rhodiola specifically increases it in the hypothalamus [30].

Modafinil is the most powerful of these and it works by increasing LTP in orexin neurons (via Dopamine D1) [31].

13) Forskolin

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 wakefulness [31].

Orexin binds to orexin 1 receptors to stimulate neurons by activating cAMP [32].

However, another study did not find this to be true [33].

14) Caffeine

Caffeine was found to activate orexin, which isn’t surprising [34].

I recommend getting your caffeine from tea.

15) Nicotine or Galantamine

Nicotine is addictive.

However, nicotine activates orexin neurons [35].

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 [36].

In addition, long-term nicotine usage increases the orexin receptors, which makes you more sensitive to a given amount of orexin [37].

Nicotine and orexin excite the same synapses of the arousal pathway within the prefrontal cortex (thalamocortical) [38].

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 [3940].

Galantamine may increase orexin activity indirectly by increasing a receptor or activating nicotinic receptors involved in orexin [a4b2 nicotinic receptor – 41, 42]. This could be used as an alternative to nicotine.

16) Omega 3s

A study found that in healthy people, there was a correlation between omega 3s and orexin A (but not in narcoleptics) [43].

17) Bag Breathing/CO2

CO2 is one of the methods to increase orexin.

You can increase CO2 by eating carbohydrates, but if you are trying to increase orexin you’re likely lectin sensitive, so you don’t want to have a high-carb diet [44].

Macronutrient profile aside, you can increase CO2 by breathing into a bag for as long as comfortable a few times a day.

18) Fructose

Studies have found that long-term fructose consumption (bingeing) increases orexin [45].

Also, 25% of fructose consumed turns into lactate, which has orexin-increasing effects [46].

As mentioned before, fructose, fructans, and FOS can also excite orexin neurons by increasing GLP-1, thereby increasing wakefulness [47, 48].

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.

19) Cold Exposure

In rats, 30 min of cold stress increased the expression of orexin [49]. You can get cold stress by taking a cold shower.

20) Keto Diet

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.

Fourth, ketosis increases ghrelin in animal studies. Ghrelin activates orexin [50]. However, human studies show that ketosis doesn’t increase ghrelin [51].

Fifth, ketosis results in elevated ATP in animals, which activates orexin [52].

Sixth, high saturated fat diets can increase orexin in rats [53].

Ketogenic diet changes

Other Hormones/Neurotransmitters That Increases Orexin

  1. Acetylcholine MOSTLY increases orexin [54]. It can inhibit it simultaneously through a different mechanism, but it mostly increases it
  2. Norepinephrine [55]
  3. Glutamate is an excitatory neurotransmitter that activates orexin.
  4. TRH [56]
  5. Estradiol (body of study) and phytoestrogen [57, 58]
  6. DHEA [59]
  7. DHT [59]
  8. Ghrelin increases orexin, and this is part of the mechanism by which ghrelin increases hunger [5060]
  9. Oxytocin [61]
  10. Vasopressin [61] 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. When we’re thirsty, we become more awake because vasopressin is released and this activates orexin so that we look for water [61].
  11. Neurotensin is a hormone found mostly in the hypothalamus that regulates luteinizing hormone and dopamine pathways. It also decreases our body temperature and pain levels, increases our energy (locomotor activity), and has important gut functions.
  12. 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.
  13. CCK is a gut hormone that causes nausea, anxiety, and satiation. However, this is the only hormone I know of that is an orexin activator but also induces sleep.
  14. Follicle Stimulating Hormone – increased orexin 1 receptor in testes [62]
  15. Cortisol (animal version) [63]
  16. Endomorphin-2 [64]

Pathways

Supplements

Orexin Inhibitors

The Following Things Decrease Orexin

  • Fasting [72]
  • TNF-alphaIL-1 [73]
  • Excess glucose
  • Alcohol [74]
  • LPS – causes loss of orexin neurons from inflammation [75]
  • Melatonin [76]
  • Leptin
  • NPY – Although NPY stimulates wakefulness, it has wakeful-promoting and sedative effects, which depends on where it’s released [77, 78]
  • Prolactin [79]
  • GABA
  • Opioids – inhibit orexin neuron activity via mu opioid receptor [80]
  • Adenosine (A1 receptor) [74]
  • Serotonin (5-HT1 receptor)
  • Cannabinoids – Although, orexins play a role in the addictive properties of cannabinoids. This is perhaps because CB1 receptors potentiate orexin 1 receptors [81, 82, 83, 84]
  • MSH [85]
  • Chronic high-dose lithium (low doses are fine)
  • Alkalinization
  • Nociceptin
  • Enkephalin

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.

Too much orexin at night can also cause insomnia, which is no surprise [86].

Orexin and Addiction

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 [87].

Blocking orexin also reduced cocaine-induced impulsivity [88].

Too much orexin can also cause anxiety, panic attacks, and depression [89].

The Orexin Balance

Orexin can cause depression if there’s too much or too little [90].

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 for your health.

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