There are quite a few effective ways to treat orexin deficiency naturally. You may want to read first this article about orexins: The Link Between Orexin Deficiency And Fatigue, Muscle Weakness, Neurodegeneration and MS

Let’s start with diet and other lifestyle changes and therapies, then you will learn about vitamins for tiredness and lack of energy and some of the best energy supplements for chronic fatigue- including MS chronic fatigue.

  1.  Diet

  2.  Vagus Nerve Stimulation

  3. Light Therapy

  4. Exercise

  5. Cold Therapy

  6. Supplements For Fatigue and Sleepiness Associated With Orexin Deficiency

 

1.Diet

Orexin neurons are activated by fasting and low sugar levels [1]. This means that low carb diets including ketogenic diet, as well as fasting will stimulate orexins. Technical: the high concentrations of glucose and leptin tend to hyperpolarize orexinergic neurons, while low concentrations of glucose and ghrelin depolarize them [2]. 

Allowing your body to use alternate sources of energy for cells- ie pyruvate or lactate instead of glucose, does activate orexins. These alternate sources seem to stop glucose from blocking orexin neurons [3].You can increase lactate levels with fermented foods (pickled foods, kombucha, kefir, etc), olives and exercise (particularly high intensity exercise and resistance training).

Orexins are activated by high protein diets [4]. The top three aminoacids that activate orexins are glycine, aspartate and cysteine [5]. BCAA (Branched Chain Amino Acids) leucine, isoleucine, and valine also seem helpful, as they can restore orexin levels after brain injury [6].

Fats, specifically triglycerides stimulate orexins as well [7].

Coffee: If you like coffee, you can have a few cups a day. Caffeine specifically activate orexin neurons, especially in perifornical region where orexin neurons are most concentrated [8].

2.Vagus Nerve Stimulation

Vagus nerve stimulation promotes wakefulness through activating orexin system (this is one mechanism of action, as vagal nerve stimulation involves multiple mechanisms of action) [9]. A few ways to stimulate vagus nerve include: deep breathing, yoga, meditation, exercise, cold showers, fasting, acupuncture, exercise, fish oil and probiotics.

3.Light Therapy

Day light exposure stimulates orexins and has antidepressant qualities, and orexinergic system mediates the effects of light on mood [10]. First thing in the morning, when you wake up you can  go outside and spend few minutes in the sun. This helps boost your serotonin levels as well. Alternatives: special lamps like SAD lamps.

4.Exercise

Exercise induces a significant increase of orexin A blood levels, with a peak at 30 min after the exercise bout [11],[12]. There are many benefits of exercise. Exercise enhances neurogenesis (the formation of new brain cells) in the hippocampus and the brain function, improves cognition and regulates mood. The underlying mechanisms include the boost in BDNF and the stimulation of orexins [13].

5.Cold Therapy

Cold therapy (via stress) can improve orexins levels [14]. You can take a quick cold shower or try cryotherapy. 

Good to know: orexin neurons are happy when you are happy. Being happy increases orexin levels, as I was explaining in my other article.

6.Supplements For Fatigue and Sleepiness Associated With Orexin Deficiency

In other words, what are the best energy supplements for chronic fatigue ? A bit more tricky when it comes to natural supplements for treating orexin deficiency. Truth is, there is not too much research available, as orexins had been discovered only a couple of decades ago.  In addition, it is not easy to test orexin levels (they have to be obtained from cerebrospinal fluid), thus many studies had been done in animal studies. Even conventional medicine has to catch up with the research and create new drugs. When I looked at specific supplements for treating orexin deficiency, I considered the following:

I.Studies that found supplements that specifically boost orexin levels- I mentioned caffeine, but there is some evidence that: 

  • Nicotine [15] (nicotine stimulates orexin A and B, and improves the sensitivity of orexin receptors; to be use only in nicotine patch form)

  • Forskolin [16]  (but should be used cautiously, can be too strong for some)

  • Noni [17] 

  • Berberine [18] 

  • Zinc [19] could also increase orexin levels

II. I think that most “stimulating “ supplements would improve orexin levels, as this neurotransmitter is sensitive to stress- remember its role in “fight or flight reaction”-the sympathetic nervous system.  However, stimulating supplements (and drugs) can also overstimulate the immune system (which is already overactive in MS).

III. The relationship between orexins and other neurotransmitters (dopa, norepi, serotonin, acetylcholine, GABA) is quite complex [20],[21]. The goal is to help balance all of them.

So what are the best choices ?

In my opinion, the adaptogens. They have great anti fatigue effects, while acting on various neurotransmitters and overall bring them in balance.

  • Rhodiola

  • Ashwagandha

  • Amla

  • Licorice

  • Holy Basil are all great choices [22].  Other adaptogens like ginseng and astragalus may be to strong and overstimulate the immune system- should be used cautiously.

IV.Supplements with strong anti-inflammatory qualities could be more important than those specifically targeting orexin system- since inflammation is the underlying problem. The inflammation drives the damage and death of orexin neurons.Supplements with strong anti-inflammatory qualities:

  • Omega 3

  • Vitamins D, A, E

  • Quercetin

  • Curcumin [23], [24]

V.Improving sugar metabolism ( which is a significant problem in MS and many brain conditions) and avoiding high sugar levels with diet/ supplements is also important- as orexin neurons are stimulated by low sugar levels and suppressed by high sugar levels. Supplements to consider :

  • Chromium picolinate

  • Cinnamon

VI. Supplements that support the health of brain cells (ie antioxidants, supplements that improve blood flow to the brain) can offer a nourishing environment for the hippocampus and thus would support healthy orexin neurons as well. Consider the following:

  • Ginkgo biloba

  • Resveratrol

  • Blueberyy Extract

  • Omega 3 (and exercise)

VII. I also looked at specific supplements and prescription drugs that had been found helpful to manage narcolepsy- because orexin deficiency is the main issue in this condition. If the symptoms of narcolepsy improve with these drugs and supplements, it is very likely they improve orexin system as well. Off note, they are also used for managing MS related fatigue

Drugs used for managing narcolepsy  include modafinil, armodafinil, methylphenidate and various amphetamines , as well as antidepressants:SSRIs, SNRIs and Sodium oxybate (which is a GABA derived drug)- I wrote about natural alternatives to SSRIs, SNRIs and natural GABA agonists.

Prescription drug modafinil: modafinil has an impact on a few neurotransmitters (dopamine, histamine, norepinephrine, serotonin, GABA, glutamate, acetylcholine), and of course orexins. Best natural alternatives to modafinil:

  • Ginseng (remember, ginseng may overstimulate the immune system thus be too strong for someone with MS)

  • Bacopa [23],[24]

  • Mucuna pruriens

  • 5 HTP

  • SAMe

  • Ginkgo biloba

This would be the best energy supplements for chronic fatigue. Consider lifestyle changes, too, not just supplements.  A recent meta-analysis in people with MS showed that exercise (ie physical and exercise therapy) and education (cognitive behavioral therapy, patient education, and self-management programs) are more effective as Modafinil or Amantadine for treating fatigue [25].

Natural alternatives to methylphenidate and other amphetamines:

  • Essential oils: vetiver essential oil and cedar wood [26]

  • Omega 3

  • Magnesium and B6

  • Zinc

  • Melatonin (short term use only)