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12 Natural Factors that May Increase Orexin & Wakefulness

Written by Puya Yazdi, MD | Last updated:
Medically reviewed by
Genius Labs Science Team | Written by Puya Yazdi, MD | Last updated:

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Orexin, also called hypocretin, is a neurotransmitter that regulates arousal, wakefulness, and appetite. Scientists suspect that 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 and factors that may naturally increase it.

What Is Orexin and Why Is It Important?

Definition

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.

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

What Does it Do?

Orexin is not just any molecule in our body. Some scientists say that whenever we’re tired or fatigued, orexin is suppressed [2].

It’s not like orexin is one of the many systems that stimulate wakefulness. It’s considered to be by far the most significant stimulator of wakefulness. Histamine is also involved, but orexin activates the histamine system [2].

Researchers suspect that there are many hormones and other systems in the body that interact with orexin.

Therefore, the orexin system seems to be central to productive human functioning and good mood. However, orexin’s role is a relatively recent discovery. Larger human studies are needed to better understand its effects on health [2].

Narcolepsy

There are two main types of narcolepsy: type 1 and type 2. Measuring orexin levels helps diagnose type 1 narcolepsy [3].

Doctors need the following to diagnose type 1 narcolepsy [4]:

  • Hypersomnia (extreme sleepiness)
  • Cataplexy (episodes of muscle weakness in response to emotional stimuli), and/or
  • Orexin (hypocretin-1) concentrations in the CSF (cerebrospinal fluid) of 110 pg/mL or less

The exact cause of narcolepsy is still unknown. Unproven, experimental theories suggest that narcolepsy may result from immune imbalance, specifically an elevated Th2 immune system, in some people. Another study found elevated TNF and IL-6 [5, 6].

Beyond Wakefulness

Limited research suggests that orexin also increases metabolism and body temperature. According to this theory, people that feel cold and tired may, among other factors, have low orexin [7].

Orexin also seems to increase hunger via increased neuropeptide Y expression in the arcuate nucleus of the hypothalamus [8].

Animal models suggest that low levels of orexin cause obesity, even when fewer calories are consumed. This hasn’t been confirmed in humans [9].

One hypothesis posits that orexin is a significant factor in why consuming sugar makes people fat. They claim that this is because people feel tired after eating sugar, since it causes blood sugar levels to spike and orexin to fall. So, instead of burning calories, people go to sleep. Although plausible, this hypothesis has yet to be tested [9].

Another team of researchers claimed that higher levels of orexin-A cause people to be happier. They’re still lacking solid data, though, since this theory is mainly based off the fact that the incidence of depression is higher in narcolepsy.

Yet another stream of research found that orexin and its receptors may decline with age. Plus, orexin may cause people to increase oxygen use because it might increase metabolism. Future research has yet to clarify and solidify all these findings [9, 10].

Factors that May Increase Orexin

When to See a Doctor

If your goal is to increase orexin to improve your fatigue – or extreme exhaustion-related issues – including those of chronic fatigue or depression – it’s important to talk to your doctor, especially low energy levels are significantly impacting your daily life.

Your doctor should diagnose and treat any underlying conditions causing your symptoms.

Precautions & Limitations

Remember that the existing evidence does not suggest that low orexin causes fatigue or mood disorders.

There’s also no precise way to measure orexin levels outside of research studies and diagnosing type 1 narcolepsy. For narcolepsy, a healthcare professional has to take a person’s cerebrospinal fluid, which is an invasive procedure reserved only for specific cases.

Complex disorders like chronic fatigue syndrome always involve multiple possible factors – including brain chemistry, environment, health status, and genetics – that may vary from one person to another.

Additionally, changes in nerve tone and brain chemistry are not something that people can change on their own with the approaches listed here. Instead, the factors mentioned in this article are meant to improve energy levels and support overall mental health and well-being. Most are backed up only by limited human or animal studies.

Therefore, you may try the strategies listed below if you and your doctor determine that they could be appropriate. Read through the approaches we bring up and discuss them with your doctor before trying them out. This is particularly important if you plan to take any dietary supplements.

Supplements have not been approved by the FDA for medical use and generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective.

Finally, have in mind that none of these strategies should ever be done in place of what your doctor recommends or prescribes.

1) Resolving Chronic Inflammation

Research suggests a link between orexin and chronic inflammation. Persistent, low-grade inflammation also seems to be tightly tied to fatigue and low cellular energy, according to recent scientific findings [11, 12].

Elevated inflammation from cytokines like IL-1b and TNF is hypothesized to cause fatigue by the suppression of orexin neurons [13, 14, 15, 16].

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. This hasn’t been verified in humans, though [17].

If you are experiencing chronic inflammation, work with your doctor to resolve the underlying issue causing your symptoms.

2) Exercise

Getting regular, moderate exercise is good for overall health. We know from experience that it makes us feel energized, and some scientists think orexin might be one of the reasons.

Limited human studies back this theory up: exercise was able to increase orexin levels in the human bloodstream [18].

Additionally, exercise seems to increase orexin in the cerebrospinal fluid of rats, dogs, and cats [18].

Researchers think that the source of orexin might be directly released from the pituitary into the bloodstream, leaked from the cerebrospinal fluid, or produced by the gut or pancreas. More research is needed [18].

Exercise temporarily acidifies our blood (increases lactate), which is hypothesized to increase the firing of orexin neurons [19].

Interestingly, orexin A may cross the blood-brain barrier. Theoretically, if it’s elevated in the blood after exercise, it may also be elevated in the brain [20].

3) Natural Light – Get Outside

Bright light (for example, from the sun) increases orexin, and animal research suggests that this is the likely mechanism by which it’s effective for depression and seasonal affective disorder (SAD). Proper human data are still lacking to back up this mechanism, though [21].

4) Fermented Foods

We spoke about lactate as a “backup generator” before.

Lactate is a critical energy source and a likely regulator of the orexin system. Scientists think that lactate release from astrocytes plays an integral part in balancing brain activity and energy supply [22].

According to one theory, supplying orexin neurons with lactate can stop glucose from blocking orexin neurons. Lactate might disinhibit and sensitize these orexin neurons for future excitation. This hasn’t been proven in humans, however [1, 22].

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].

Here are some fermented foods that likely contain lactate:

  • Kombucha
  • Sauerkraut
  • Pickles

Kombucha has lactate, pyruvate, butyrate, ATP. Studies are investigating whether it has other “energy-related molecules” as a result of the fermentation process. Anecdotally, many people say this fermented Eastern drink refreshes and energizes them [1].

Additionally, certain probiotics like Lactobacilli produce lactate.

On the other hand, various minerals can be formulated into lactate salts, such as Calcium lactate and Magnesium lactate.

5) Protein

It’s a good idea to get adequate amounts of healthy protein foods on a daily basis. Various amino acids are hypothesized to affect orexin signaling, but there are no clinical studies to determine their impact.

Researchers believe that amino acids excite orexin neurons through a few mechanisms, though this has yet to be confirmed in humans [23].

An animal study gave branched-chain amino acids (BCAAs), which are precursors to glutamate synthesis, to brain-damaged mice. BCAAs reinstated activation of orexin neurons and improved wake deficits in mice with mild brain injury. Human data are lacking [24].

In the lab, nonessential amino acids were more potent in activating orexin cells than essential amino acids [23].

One theory states that amino acids may block glucose suppression of orexin because they tell the neurons that there’s enough energy around [23].

In cells, scientists ordered them this way – from most to least effective:

  • Glycine
  • Aspartate
  • Cysteine (NAC)
  • Alanine
  • Serine
  • Asparagine
  • Proline
  • Glutamine [23]

However, we have no way to know how each one affects orexin activity in complex beings. This hasn’t been researched.

6) Carb and Caloric Restriction

Theoretically, elevated glucose concentration might block or silence the activity of orexin neurons [1].

In lab animals, the principal way to activate orexin is by restricting glucose [25].

The hypothesis is that under low-energy conditions such as starvation, 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].

In addition, scientists think that orexin neurons are stimulated by falling glucose levels [25].

Hypothetically, people who eat less or practice some degree of caloric restriction may have higher orexin because their body senses they’re not getting enough calories, which activates this system. Proper human data are needed, though [9].

7) Maintaining Healthy Weight

Some researchers consider that losing extra weight may help increase orexin and energy levels.

This is based on the theory that Leptin inhibits orexin. High leptin levels are characteristic of being overweight, while leptin levels tend to drop as a result of weight loss [26].

However, many other factors also affect leptin levels and weight and the exact role of orexin has yet to be determined.

8) Fiber

GLP-1 is a gut hormone that can activate/excite orexin neurons in the hypothalamus (which increases orexin). Scientists think it might be useful in making us feel satiated as well, which may make us eat less and further activate orexin.

It’s possible that GLP-1 functions like orexin and sometimes works instead of it, though this hasn’t been confirmed in humans [27].

Resistant starch may increase GLP-1 and also produces butyrate. It’s also acidic. Hypothetically, this might block glucose-induced suppression of orexin [28, 29, 1].

Anecdotally, people say high-butyrate foods or drinks (like kombucha) increase energy levels after a big meal.

9) Having Fun

A study in dogs found having fun or play was able to increase orexin, while the same level of exercise wasn’t able to [30].

The study concluded that motor and cardiovascular changes might not sufficient to elevate orexin, so they hypothesize that the emotional aspects of yard play account for the observed increase in orexin [30].

Research hasn’t yet measured the effects of fun activities on orexin in humans.

10) Vagus Nerve Stimulation

Vagus nerve stimulation seemed to decrease daytime sleep and rapid eye movement in epilepsy patients with traumatic brain injury in limited studies. More clinical trials are needed and whether or not vagus nerve stimulation affects orexin signaling is still unknown [31].

In comatose rats after traumatic brain injury, vagus nerve stimulation promoted the recovery of consciousness [31].

The effects were thought to be, in part, mediated by the increase of orexin-A and its receptor (OXR1) in the prefrontal cortex [31].

11) Green Tea

Caffeine was found to activate orexin, which isn’t surprising given that it’s the most widely-consumed stimulant worldwide. It’s found in both coffee and green and black tea, but green tea is the highest in antioxidants among the three [32, 33].

12) Omega 3s

A study found that in healthy people, there was a correlation between omega 3s and orexin A (but not in narcoleptics) [34].

Experimental (Lacking Evidence)

The following factors are theoretical or anecdotal. They aren’t backed up by solid science, and some are not generally associated with well-being.

For example, we recommend against bag breathing and high fructose intake but think that they’re interesting to mention for informational purposes.

We also highly recommend against the use of nicotine for any indication other than smoking cessation. Nicotine is highly addictive and its harms outweigh any benefits.

Keto diets and cold exposure are not harmful as long as you get a green light from your healthcare provider.

Bag Breathing/CO2

CO2 increases after eating carbohydrates. Macronutrient profile aside, CO2 increases after breathing into a bag [35].

Fructose

Animal studies suggest that long-term fructose consumption (bingeing) increases orexin [36].

Also, 25% of fructose consumed turns into lactate, which is hypothesized to have orexin-increasing effects [37].

Fructose, fructans, and FOS might also excite orexin neurons by increasing GLP-1, thereby potentially increasing wakefulness [38, 39].

Raw honey has some fructose. However, heavy fructose consumption is not healthy.

Cold Exposure

In rats, 30 min of cold stress increased the expression of orexin [40].

Although the effects of cold showers on orexin activity and wakefulness haven’t been studied, many people advocate for this traditional cooling method.

It usually takes a while to get accustomed to fully cold showers, though. Some people say it’s good to dip your face in cold water for starts.

Remember to consult your healthcare provider first, though. Most doctors recommend against cold showers in people with heart disease or in those at risk. That’s because sudden cold exposure can restrict blood vessels, which may raise heart rate and blood pressure.

Keto Diet

No studies about ketosis and orexin specifically have been published.

Nonetheless, some people claim that a keto diet may stimulate orexin since they report feeling subjectively more awake.

Keto advocates say that if they get into ketosis, glucose levels will likely be low, which is more likely to activate orexin. This hasn’t been proven, though.

Second, advocates claim that ketones are “energy-related molecules” that would theoretically signal to the brain that there’s not a famine, which should activate orexin… in theory. This is thought to be the underlying logic for why lactate allegedly prevents orexin suppression.

Third, ketones are acidic, so people say that this will also increase orexin. Remember that no human data back them up, though.

In animals, ketosis increases ghrelin. Ghrelin activates orexin [41]. However, human studies show that ketosis doesn’t increase ghrelin [42].

Ketosis results in elevated ATP in animals, which activates orexin. Human data are lacking [43].

Ketogenic diet changes

Forskolin

Although forskolin is a popular “wakefulness promoter,” its effects on sleepiness and orexin levels in humans haven’t been proven.

Forskolin is hypothesized to increase cyclic AMP, including in the area where orexin neurons are. This might, in theory, activate these neurons (long-term potentiation) and increase wakefulness [44].

Orexin binds to orexin 1 receptors to stimulate neurons by activating cAMP [45].

However, another study did not find this to be true [46].

Dopamine

A study examined the ability of dopamine agonists to activate orexin neurons in the rat. The study found that both D1 and D2 receptors may be sufficient to activate orexin neurons [47].

However, when dopamine binds to other receptors, it can suppress orexin (alpha-2 receptor). So, it seems to depend on the receptors and much more research is needed.

Mucuna, tyrosine, Rhodiola, and SAM-e allegedly increase dopamine, but their effects on orexin are unknown [48].

Investigational Supplements

These data can’t be applied to humans.

Nicotine

Nicotine is addictive and its harms outweigh any benefits. The only acceptable indication for its use is smoking cessation therapy.

Scientists think that nicotine activates orexin neurons. They are investigating whether it increases [53]:

  • Orexin-A (in the dorsomedial hypothalamic nucleus)
  • Orexin B (in the paraventricular nucleus)
  • Orexin receptors [54, 55].

Nicotine and orexin seem to excite the same synapses of the arousal pathway within the prefrontal cortex (thalamocortical). Researchers wonder if orexin pathways are also involved in addiction [56].

The increase in orexin seems very significant with regard to nicotine addiction. Withdrawal causes an increase in orexin to drive people to consume nicotine [57, 58].

Galantamine

Galantamine is a drug that has been studied as a treatment for Alzheimer’s disease. In the US, it’s available with a doctor’s prescription.

Scientists claim that it may increase orexin activity indirectly by increasing a receptor or activating nicotinic receptors involved in orexin [a4b2 nicotinic receptor – 59, 60].

Other Hormones, Neurotransmitters, and Pathways

This section summarizes the science behind hormonal, cellular, and drug-related factors that may increase orexin. Our aim is to discuss the research findings.

Some of the substances listed here can have detrimental health effects if used inappropriately. Be sure to discuss all your medications, supplements, and lab results with your doctor.

  1. Acetylcholine [61] (may inhibit it simultaneously through a different mechanism, but it mostly seems to increase it)
  2. Norepinephrine [62]
  3. Glutamate
  4. TRH [63]
  5. Estradiol and phytoestrogen [64, 65]
  6. DHEA [66]
  7. DHT [66]
  8. Ghrelin [41, 67]
  9. Oxytocin [68]
  10. Vasopressin [68] is a hormone that makes people 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 [68].
  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. Some scientists think this might be 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 identified so fat that is an orexin activator but also induces sleep.
  14. Follicle Stimulating Hormone – increased orexin 1 receptor in testes [69]
  15. Cortisol (animal version) [70]
  16. Endomorphin-2 [71]
  17. SIRT1 [72, 73, 74]

Potential Orexin Inhibitors

Many unhealthy habits may disrupt energy balance in the body.

It’s always a good idea to avoid unhealthy behaviors – such as not getting enough sleep, smoking, fast food, overeating, being under a lot of stress, and drinking too much coffee or alcohol – that can reduce your energy levels in the long run and make you feel exhausted.

Look to get regular exercise, enough nutrients, sleep, and set a healthy circadian rhythm.

In addition, below are some factors that may inhibit orexin in animals and cells. Human data are lacking

The Following May Decrease Orexin

  • Fasting [75]
  • TNF-alpha, IL-1 [76]
  • Excess glucose
  • Alcohol [77]
  • LPS – causes loss of orexin neurons from inflammation [78]
  • Melatonin [79]
  • Leptin
  • NPY – Although NPY stimulates wakefulness, researchers believe it has wakeful-promoting and sedative effects, which depends on where it’s released [80, 81]
  • Prolactin [82]
  • Opioids – may inhibit orexin neuron activity via mu opioid receptor [83]
  • Adenosine (A1 receptor) [77]
  • Serotonin (5-HT1 receptor)
  • Cannabinoids – orexins may play a role in the addictive properties of cannabinoids (possibly because CB1 receptors potentiate orexin 1 receptors, but more research is needed) [84, 85, 86, 87]
  • MSH [88]
  • Chronic high-dose lithium
  • Alkalinization
  • Nociceptin

What Are the Possible Downsides to High Orexin?

Some studies suggest that orexin may play a role in Alzheimer’s disease by increasing amyloid plaques. It was found that the mechanism by which lower orexin reduced plaque was by the animals sleeping longer [89]. Scientists say that this also highlights the important role of sleep in brain health, not orexin per se.

Too much orexin at night may also lead to insomnia, which is no surprise since orexin is viewed as a wakefulness-promoting signal [90].

Orexin and Addiction

Recent science suggests that many of the same systems in the 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. Orexin is hypothesized to play a role in food, drug, and sex addiction [91].

In one study, blocking orexin reduced cocaine-induced impulsivity [92].

Too much orexin was linked with anxiety, panic attacks, and depression in animals [93].

Human studies are needed to determine the link between orexin and addiction.

Orexin Balance

According to one experimental hypothesis, too much or too little orexin may cause emotional imbalances. This might mean that orexin balance is important. However, human data are still lacking [94].

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About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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