young man asleep at wheel in car

Hypocretin Supplements & How To Increase Orexin Naturally

[toc]Unless you suffer from narcolepsy, there’s a good chance the words in the title are foreign to you.

But regardless of whether or not you have that disease, this neuropeptide is vitally important to your health.

It regulates your wakefulness, sexual arousal, and even influences your appetite.

This holds true for both humans and animals.

In your brain, there are only 30,000 to 70,000 neurons which make orexin (1). That may sound like a lot, but there are an estimated 100,000,000,000 neurons total, meaning these represent less than one out of every million brain cells.

orexin neuropeptide
What the orexin neuropeptide looks like.

Orexin and hypocretin are actually the exact same thing. Why two names then? The reason is bizarre…

Despite its importance, the discovery of it didn’t happen until 1998. Interestingly enough, two different groups of scientists discovered it that very same year.

One group decided to name the neuropeptide hypocretin, since it is made in the hypothalamus part of the brain. Those scientists were from Scripps, Stanford, Yale, and the University of Oslo (2).

The other group called it orexin. They were influenced by the Greek word for appetite, which is orexis. But they weren’t Greek, as they were all at the University of Texas (3).

Hypocretin and orexin are not different. For now, the terms can be used interchangeably, at least until one is designated the official name.

What causes narcolepsy?

This disease causes overwhelming drowsiness during waking hours, which can trigger uncontrollable episodes of falling asleep. For a long time, what causes narcolepsy was completely unknown. After discovering hypocretin, it was soon found that sufferers had much lower levels in their brain (4).

It may be premature to officially deem this chemical as being the one and only culprit, but Dr. Jerome M. Siegel, professor of psychiatry and biobehavioral sciences at UCLA, has stated the following (5):

“The findings end a 120-year search for the cause of narcolepsy and open new paths for treating this incurable disease.”

This newly discovered substance may also play a part in the side effects of other diseases, too.

In late-stage Parkinson’s, researchers have found that patients have a 38% to 45% less of the hypocretin-producing neurons. Perhaps that is one reason why sleepiness is a common complaint among people with Parkinson’s (6).

Does orexin deficiency cause low energy?

can of red bull energy drinkNarcolepsy and Parkinson’s are both major diseases of the brain.

How about the average Joe or Jane who is perfectly healthy, but no matter what he or she does, experiences bouts of unexplained tiredness and lack or energy. Is it possible that low orexin levels may be responsible?

Being that this neuropeptide was discovered barely 20 years ago, the research on this topic is in its earliest days. But consider some of the things we do know about it.

Sleep-deprived monkeys were “cured” of exhaustion with orexin injections (7).

Why you feel sleepy after a sugar crash may be explained by the research which has found that after eating high-glycemic foods, the orexin-producing cells are suppressed (8).

Lower carb, higher protein meals correlate with better cognitive performance. As evidenced by research, such as a study which looked at this during the AM hours after people ate different types of breakfast (9). Since lower carb/sugar intake has been linked to higher orexin levels, that may be the reason for the mental boost.

Obesity often correlates with excess carb intake, consisting of refined sugars like sodas, Red Bulls, and other “fixes” to maintain enough energy to get through the workday. The chronically elevated blood sugar would be the opposite of how to raise orexin levels, because it would be suppressing production! That may further contribute to weight gain, based on the next point…

Metabolism is boosted in mice when they are injected with orexin (10). They had increased physical energy and their respiratory exchange ratio (RER) shot up. That means they burned more calories, even when they weren’t doing extra physical activity.

It’s far too early to know if hypocretin replacement therapy may offer a solution for those with chronically low energy. However the research does suggest that we should all do what we can to avoid or minimize suppressing levels, when possible.

woman yawning at sporting eventBefore you make this neuropeptide your scapegoat for having low energy, skipping the gym, lack of libido, and unexplained bouts of yawning, know that it appears a significant suppression is needed to have an effect.

In the study with mice, where the orexin supplements boosted metabolism, the scientists played around with their levels by injecting chemicals to “turn off” the orexin neurons. They said that “70% ablation had almost no effect” on food and water intake.

It took an 83% destruction of these neurons before their metabolism and feeding behavior changed.

Since a 70% reduction didn’t alter things, it would suggest their brains are well adapted at compensating for when there is a lower number of active neurons.

Think of them like muscles. For an in-shape athlete or bodybuilder, if you could wave a magic wand and reduce their muscle mass by 50%, they would still be able to walk around and do normal activities just fine. Perhaps that is what’s going on in the brain.

Of course, mice are not people. Perhaps as humans we are more sensitive to smaller changes.

How to test hypocretin levels

lab experimentAll the research suggests that having subpar amounts of this neuropeptide will only produce adverse side effects, not health benefits.

Of course that’s not to imply higher than natural levels is good or better, but what if you have sub-optimal levels that may need some assistance just to get them up to normal?

Your first inclination may be to check your levels of hypocretin if you suspect a deficiency.

Unfortunately, testing orexin levels in humans is difficult. Currently there is not a blood test you can take at home and send away to a lab for results. Your primary care physician probably can’t test you, either.

Even if he or she could, you may not want them to.

Why? Because this lab test does not involve blood, it requires a sample of cerebrospinal fluid (CSF).

The lab requires a 2 ml CSF specimen. At Oxford University Hospitals in the UK, the turn-around time for this test is 4 to 6 weeks after the sample has been submitted (11).

In the United States, CSF testing for hypocretin is rare. Given that the test involves sticking a needle into your spine – which could be quite dangerous if something goes wrong – it’s no wonder so few doctors order it. Most diagnose narcolepsy without it.

There is something called the HLA blood test for narcolepsy.

It looks at your HLA-DQB1 gene. If the allele DQB1*06:02 is found, the test is positive. If not, it’s negative (12).

Even with a positive, this does not mean someone has narcolepsy. This is only a genetic marker which has a high correlation with the disease. It is not an orexin test, as levels aren’t even measured with it.

  • 25% of people who have DQB1*06:02 do not have the disease.
  • 90-95% of Caucasians, African Americans, and Japanese with narcolepsy type 1 will test positive for DQB1*06:02.
  • 40-50% with narcolepsy type 2 will test positive.

How to get more hypocretin

For starters, it’s important to point out that if you can increase your levels, you probably are doing so by stimulating your existing hypothalamic neurons which are responsible for creating it.

The process of growing new brain cells (adult neurogenesis) is something that was believed to be impossible.

Until recently, scientists believed that in humans, you could only grow brain cells during the embryonic and perinatal stages of life. In the 90’s, research started popping up which went against that theory. It wasn’t until this century when scientists firmly established that yes, grown men and women can indeed experience neurogenesis (13).

In humans, we now know this takes place in at least two areas of the brain:

  • The subgranular zone (SGZ) of the hippocampus (14)
  • The striatum, however in this region only interneurons are produced, which means they don’t communicate to other areas of the brain (15).

diagram of endocrine CNS and where hormones are made in brain

Where is hypocretin produced in the brain? Those neurons are found in the lateral hypothalamus. This is a different region than the hippocampus and striatum, which means there is no evidence to date to support the idea that humans can grow hypocretin producing neurons during adulthood.

Even though orexin is not a hormone, it is produced in a part of the brain which is responsible for making many, including the thyrotropin-releasing hormone. That hormone has been found to directly stimulate the orexin neurons, so they may be interrelated in some some aspect. (16).

Since this is an evolving field, perhaps in the future scientists will discover that these rare neurons also regenerate. As for now, based on the evidence, one would have to conclude they don’t. Naturally, that would also mean there is no drug, supplement, or food which can trigger new growth of these neurons.

However there are things you can take, eat, and do which might stimulate your orexin receptors and/or the orexin-producing neurons that you already have. They are often called precursors, even though they don’t technically meet that definition.

Prescriptions vs. supplements

prescription bottle with pillsFor decades now, the most popular sleeping pills, like the prescription Ambien, have all worked in similar ways.

They are believed to slow brain activity through activating the neurotransmitter GABA, then binding it to GABA receptors.

In 2015 a new prescription was launched called Belsomra (suvorexant) which works in a different manner; it decreases orexin, which helps you fall asleep faster. This new class of drugs is called orexin receptor antagonists (ORA).

When it comes to doing the opposite, an orexin prescription to increase levels, there is only one on the market and it has major drawbacks.

Provigil (modafinil) has been on the market since 1998, so it’s been around since the history of hypocretin. You cannot buy modafinil without a prescription and many doctors are hesitant to prescribe it, given that it is classified as a Schedule IV controlled substance in the United States. The only approved marketing for this prescription is for narcolepsy patients, not as a nootropic or any other disease.

Some doctors still prescribe Provigil to their patients for off-label purposes to reduce fatigue in multiple sclerosis, depression, chronic fatigue syndrome, fibromyalgia, Parkinson’s disease, and yes, even as a nootropic.

The side effects of modafinil can be awful (17):

“Modafinil is known to have less or no adverse effects than those found in traditional psychostimulants such as amphetamine, methylphenidate or cocaine. It can be applied as an anti-psychotic or anti-fatigue agent. However, the waking mechanism of modafinil is yet to be fully revealed. Recent studies reported that modafinil may be subject to abuse and addiction. In addition prolonged sleeplessness induces stress responses and impairs immune function.”

They don’t even know how modafinil works, at least not fully. Without knowing that, obviously it raises questions if there might be unknown side effects taking place which have yet to be discovered. Not like they need more either, because the Provigil symptoms of impaired immune function and comparison to “traditional psychostimulants” is bad enough.

As far as the known side effects, how long does modafinil last in the human body? Its half-life is 15 hours. After it kicks in, you could argue it stays in your system too long if you’re on a 24 hour cycle.

Can you sleep on Modafinil given its 15 hour half-life? Well consider that the half-life of the caffeine is only 3 to 9 hours.

man with insomniaFor many people, having strong coffee in the early afternoon is enough to cause insomnia at night, even when they go to bed at 11 pm or later.

Because of how long modafinil stays in your system, sleeplessness is a problematic side effect even for those with narcolepsy.

For healthy individuals, those without a disease who simply want an over-the-counter dietary supplement to support their natural hypocretin levels, are there any good options for replicating the so-called sleep replacement drug?

Back in 2007, the U.S. government’s Defense Advanced Research Projects Agency (DARPA) funded the development of an orexin nasal spray for humans, which could “replace sleep” or more accurately said, delay the need for it (18).

Here we are a decade later and you won’t be able to find a nasal spray for sale that does this. You might never be able to buy it, as the military was/is developing it for soldiers.

If you can buy hypocretin in the future, can you imagine how something like that would be abused if sold over-the-counter? Civilian workaholics would buy it for extra energy. If it boosts metabolism and suppresses appetite, you would have people popping pills (or snorting sprays) like crazy for weight loss. If it increases sex drive and arousal, who knows where that could lead!

So whether it’s a spray or a pill, as of today there are no companies marketing hypocretin supplements for sale (as in a product which contains the actual neuropeptide). A natural form of orexin is not present in any plant and harvesting it from the brains of animals to make dietary supplements would theoretically be possible, but quite difficult.

That being said, there are common foods and activities which have been suggested by research as being hypocretin neuropeptide precursors – meaning they may stimulate these neurons and/or their receptors. That’s how Provigil works too, as it is only a precursor and not the actual peptide.

We have already discussed one precursor – lower glycemic foods – which can increase orexin in the brain and central nervous system, at least relative to the opposite diet; high glycemic foods.

Here are 7 other ways you might be able to influence this neuropeptide.

1. Omega 3 fatty acids

seed and supplement sources of omega 3A study was done to find out if omega 3 supplements would have any effect on the plasma levels of orexin A (19).

  • All participants were male, ranging in age from 22 to 55 years old.
  • 14 were healthy.
  • 17 had narcolepsy.
  • Each person was given 1,400 mg of omega 3 fatty acids to take daily for a period of 2 months.

The results?

In the control group (those without narcolepsy) there was “a correlation between the plasma orexin A levels and plasma n-3 fatty acids.” The same effects were not seen in the narcolepsy patients, which would suggest omega 3’s might offer orexin benefits for healthy people only.

Here’s more info about the recommended omega 3 dosage per day for general health. As you will see, the amounts vary by country, gender, and age.

2. Caffeine

Starbucks coffee cupsOf course we all know caffeine is the most popular CNS stimulant in the world, yet believe it or not, its exact mechanism of why it works is not fully understood.

Research published in medical journal Neuroscience suggests that caffeine may work, at least in part, by causing c-FOS activation in orexin containing neurons.

That was based on findings from a rat study. They were administered dosages of 10, 30 and 75 mg of caffeine per kg of body weight. There was also a placebo group for comparison (20).

“These results indicate that systemically administered caffeine preferentially activates orexin neurons over non-orexin neurons in the same field, and that this activation is most pronounced in the perifornical region where orexin neurons are most concentrated. The activation of orexin neurons might play a role in the behavioural activation by caffeine.”

Green tea is often cited as a good source, but that’s a fallacy. According to the USDA National Nutrient Database, an 8 ounce serving has only 29 mg of caffeine (21). They list 95 mg for a serving of coffee which is the same size (22). The best natural source of caffeine is coffee.

Sure, you may be doubling or even tripling the number of tea bags in your mug, but the same can be said about coffee, too.

You can bet that old entry in the USDA database was back when people only used a half scoop per cup. Today, many brew it at double that strength – one scoop per cup.

So yes, your cup of Joe in the morning might actually be one of the best natural supplements for orexin.

Check out the lowest acrylamide coffees, which includes the highest antioxidant brands, too.

3. Natural sunlight or bright light device

dock on calm lake with sunny blue skyGetting some sunshine might be all it takes to boost your levels.

Researchers developed an animal model using the diurnal grass rat species, to replicate seasonal affective disorder (appropriately abbreviated as SAD).

That’s a disorder where depression is linked to the changing of seasons; the gloom of winter and fall causes it. During the sunny spring and summer months, SAD treatment is not needed.

The treatment often used for this disorder is light therapy. That’s also what the researchers used in this rat model. Their findings were that the orexinergic system is affected by light, which in turn positively influenced the mood of the animals (23).

The catch-22 though with getting more sun is the premature aging of the skin and increased cancer risk which correlates with it.

You can slather on sunscreen, but that may contain dubious chemicals which could create other problems.

old woman with wrinkles and sun damage
Please don’t rely on the sun for it like this lady did!

The natural sunscreens like ThinkSport leave a white-pasty appearance, due to the type of sunblock they use; 20% zinc oxide. Fine for the body, but not ideal for the face.

It’s not clear either whether sunscreen would interfere with light therapy. Why? Because even though it’s hypothesized that it is the visual effect (the light entering your eyeballs) which has the positive effect, it remains unproven.

It is at least possible that the sun may also be stimulating the skin and nerves underneath it in different ways, which in turn stimulates biological reactions in the body. If that’s happening, does it still happen when there’s sunscreen on top?

Because we hate the idea of accelerating the aging of skin, rather than sit outside in the sun, our recommendation is the NatureBright SunTouch Plus light and ion therapy lamp.

Plus if you work indoors for long hours, you really have very little opportunity to get natural sunlight anyway. Try setting this therapy lamp on your work desk and see if you experience benefits. Please share your reviews with us after you do.

4. Exercise

male and female curling weightsWe all know exercise is important for cardiovascular health and in today’s world, weight management too, since many of us sit around on our butts all day in front of a computer.

Recent research is finding some of the best benefits of exercise may less obvious, like activating AMPK, which is coined the youth enzyme.

For years, exercise has been considered a beneficial treatment for helping depression, but it was never understood why it would help.

In 2015, a cohort of scientists from various universities in South Korea reported they may have found the explanation. Exercise is one of the few methods for how to increase orexin levels naturally. In their experiments with mice, they claimed the antidepressant effects from exercise were due to the changes it produces in the levels (25).

A year prior to that, researchers from The Centre for Brain and Mental Health Research (University of Newcastle, Australia) and the Neurobiology of Stress and Addiction Laboratory (UMass Amherst) found that exercise might reverse the negative effects that early life stress (ELS) has on orexin cells reactivity. That was based on a study they did with rats (26).

What is early life stress? It plays an important part in many psychiatric disorders. Examples include emotional, physical, and sexual abuse when it occurs early on in childhood. Both physical and emotional neglect during that time are also considered forms of ELS. One or more of these may cause or worsen the severity of psychiatric problems later on, during adulthood (27).

Whether it’s running, bodybuilding, or playing sports, you may have one more reason why all of these physical activities are beneficial for your health.

5. Nicotinamide riboside

NAD+ effects on young vs. old monkeys
Will sirtuin activation be the key to increasing longevity in humans or not?

If you haven’t yet heard of this, it’s being hailed as “the next resveratrol.” But unlike that compound which is highly unstable and has a short half-life, nicotinamide riboside appears to demonstrate much greater potential for activating the Sirtuin 1 (SIRT1) enzyme which has been linked to youth and longevity.

While nictonamide riboside has not been directly researched as a supplement for hypocretin, it is interesting to consider the following (24):

“In the DMH and LH [dorsomedial and lateral hypothalamic nuclei], SIRT1 upregulates expression of the orexin type 2 receptor…”

Perhaps someday, researchers will be able to add hypocretin support to the long list of suspected nicotinamide riboside benefits.

6. Lactate and Lactobacillus probiotics

If you want to eat something rather than take supplements, then the best hypocretin foods may be those which are fermented. Why? Because they are among the top natural source of lactate. Listen to what researchers from Cambridge and Oxford had to say about this “intracellular fuel” (28):

We found that supplying orexin neurons with other energy-related molecules, such as pyruvate and lactate, can stop glucose from blocking orexin neurons. We hypothesize 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.”

That was based on a study they did using slice of brain taken from orexin-eGFP transgenic mice. Those are mice who show sugar sensing in these neurons, thanks to the use of a green fluorescent protein.

graph of how lactate and pyruvate boost orexin neurons
Responses of orexin cells to glucose with different concentrations of pyruvate and lactate. As you see, the adverse effect is less dramatic when lactate is higher.

Top dietary sources of lactic acid

During fermentation, pyruvate gets converted to lactate if oxygen is missing or limited (such as when pickles are in a sealed jar). Therefore it’s best to focus on supplementing with lactate as an orexin booster, rather than pyruvate, since that’s only the precursor. The chart above supports this.

dish of kimchi
Kimchi, the Korean traditional fermented side dish of veggies, is quite popular right now. Be careful though because it’s loaded with salt.

Sourdough breads

With the exception of a couple niche regional brands, most vegan and gluten free breads won’t work, because they don’t involve the use of fermentation from a sourdough starter.

Any regular sourdough bread – whether it’s a loaf, biscuit, or something else – will have lactic acid. This isn’t the best source though, because most breads are simple carbs which can dramatically raise your blood sugar (which as you will recall, is bad for hypocretin stimulation).

probiotics on intestinal wall
What probiotics look like on your intestinal wall

Pickled and fermented foods

Aside from the namesake mini cucumbers, this category can also include olives, onions, and other vegetables which are mixed with brine and put in a jar.

Sauerkraut and kimchi are popular right now, but do keep in mind that those – as well as all picked foods – contain high amounts of sodium. Even low salt olives have too much for daily consumption, if you want to be on a heart healthy diet.

Hypocretin probiotics

No, you won’t see any probiotics branded as such, but certain types produce lactic acid in your gut. The one specifically you will want is Lactobacillus.

A good broad spectrum like Garden of Life probiotics will contain some strains of it. However if you want a more concentrated source of over a dozen different Lactobacillus strains, your best bet is this Nexabiotic product.


Yogurt, cheese, and milk are all high lactate foods.

7. More protein (but the right kind)

grilled whole chickenWhen you hear you should eat more protein, what’s your first inclination? Go eat a slab of grilled chicken?

That might be the absolute worst choice you could make.

Grilled chicken tests out as one of the highest sources of heterocyclic amines (HCAs), a category of advanced glycation end products (AGEs).

These HCAs include known carcinogens and are linked to the acceleration of aging, including cosmetically, like the signs seen on one’s face.

The bad news is that cooked meats in general are potent sources of HCAs, as well as the similar category of PAHs. The latter actually includes benzo(a)pyrene – a Group 1 carcinogen, which is the most dangerous ranking.

Steamed and boiled meats produce very little, but the trend these days is to grill and fry everything, which are the two worse cooking methods for producing these compounds. They’re the opposite of anti-aging.

Overloading on some plant-based sources like black beans and lentils can be a bad idea for a different reason… flatulence.

protein powder scoopTo really amp up your amino acids, your best option is to use a properly formulated protein powder.

Natural supplements for narcolepsy rarely mention protein, but the concept of greater amounts being beneficial has been supported by research.

Duke University’s study found that a low-carbohydrate, ketogenic diet offered “modest improvements in daytime sleepiness” for those with the disease (29).

There is research suggesting the ketogenic diet (and low carb/high protein diets) might offer some benefits for not just narcolepsy, but also ALS, Parkinson’s, and Alzheimer’s (30).

Research is far too preliminary to draw any conclusions one way or another, but it’s a fascinating possibility considering that some of those diseases, like Parkinson’s, seem to benefit from boosting hypocretin. Is this all just a coincidence?

To be clear, we are not recommending supplementation for any disease/disorder, as that is something only your doctor can advise.

However for healthy individuals trying to augment their natural orexin production, using a scoop or two of powder per day is a wise idea, especially in the morning, given the human study which demonstrated that a lower carb/higher protein breakfast provided the most benefit.

Our favorite is Warrior Blend chocolate, because it tastes great even with plain water and doesn’t cause excess gas.
These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.