Medication and Vaccine Adverse Reactions and the Orexin – Hypocretin Neurons

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A paper published in Science Translational Medicine, provides preliminary evidence that the H1N1 Flu Vaccine Pandemrix can evoke immune system mediated damage to the orexin – hypocretin neurons and induce narcolepsy in individuals with a particular genetic variant. The orexin – hypocretin neurons were only recently discovered in the mid 1990s, by two separate research groups, hence, the two names for the same molecule. For this paper, we’ll be utilizing the orexin nomenclature.

Initially, the orexin neurons were thought to be involved only in feeding behavior, as damage elicited hypophagia in animals. Soon it was learned that more severe damage to the orexin neurons induced narcolepsy and the orexin system became a key focus in narcolepsy related research. With time, however, it became quite clear that these neurons were involved in regulating a myriad of hormone and neurotransmitter systems and their consequent behaviors. Narcolepsy or rather the ability to sustain wakefulness, is but one of the many functions regulated by the orexin system.

In a previous paper, I touched briefly on the possibility that the orexin neurons might be damaged and have diminished functionality in individuals suffering from post Gardasil side effects. In particular, I suspected these neurons were indicated in post-Gardasil hypersomnia, a derivative of narcolepsy. That may be only the tip of the iceberg. As I soon learned, the hypocretin/orexin neurons are brain energy sensors and may be involved in array of post medication or vaccine adverse reactions. Indeed, they may be central to the ensuing state of sickness behaviors that emanate once an organism becomes overwhelmed.

The Orexin – Hypocretin Basics

Orexin nuclei are located in the lateral hypothalamus, the section of the hypothalamus that is most known for regulating feeding, arousal and motivation. The hypothalamus is the master regulator for all hormone systems and hormone related activity including feeding, sleeping, reproduction, fight, flight, energy usage – basically every aspect of human and animal survival. It sits at the interface between the central nervous system functioning and the endocrine system functioning.

From the lateral hypothalamus, orexin neurons project across the entire brain with its two receptors (OXA and OXB) differentially distributed throughout the central nervous system and even in the body, including in the kidney, adrenals, thyroid, testis, ovaries and small intestine. The orexin neurons also modulate local networks of adjacent neurons within the hypothalamus that in turn influence a myriad of behaviors.

The most densely innervated brain regions include the thalamus, the locus coeruleus, dorsal raphe nucleus, accounting for the hormone’s role in arousal, feeding and energy management. At the most basic level release of the orexin induces wakefulness. When orexin neurons are turned on and firing appropriately, arousal is maintained. When orexin neurons are turned off, diminished or dysfunctional, melatonin, the sleep promoting hormone, is turned on. The two work in concert to manage wakefulness and sleep.

Orexin receptors are also located in the amygdala, the ventral tegmental area (VTA) and throughout the limbic system accounting for its role in emotion and the reward system. Orexin directly activates dopamine in the VTA. The VTA is the reward, addiction and in many ways, the pleasure center of the brain. All drugs of addiction, all pleasurable activities, activate dopamine in the VTA. Through the release of dopamine, here and elsewhere, orexin modulates the motivation to sustain pleasurable activities. When orexin is diminished, not only does dopamine diminish, but the motivation to sustain behaviors decreases and dysphoria increases.

That’s not all, orexin influences the release of many other neurotransmitters and hormones, several of which are co-located on the orexin neurons themselves. For example, the neuropeptide dynorphin is co-located on orexin neurons. Dynorphin is an endogenous opioid involved in the perception of pain and analgesia. It has dual actions that can both elicit analgesia or pain depending upon dose and length of exposure. Stress activates dynorphin. Dynorphin then inhibits orexin firing by as much as 50%.  Illness is a stressor, a vaccine is a stressor, either could activate dynorphin and inhibit orexin. After the initial activation of dynorphin, and the ensuing decrease in orexin, the presence of chronic stressors and chronic pain could begin a continuous feedback loop of diminished arousal, and increasing pain.

Other Neurochemical Connections

  • Consistent with orexin’s role in arousal, orexin neurons contain glutamate vesicles. Glutamate is the brain’s primary excitatory neurotransmitter. Drugs that increase glutamate, also increase orexin. Drugs that block glutamate, via its NMDA receptor, decrease orexin. Common migraine medications block glutamate and thereby may also diminish orexin.
  • Serotonin and norepinephrine decrease hypocretin/orexin firing (suggesting if one is concerned with hypersomnia, anti-depressants might not be a good option).
  • As one might expect, orexin neurons are inhibited by GABAα agonists – sedatives. From a women’s health perspective, consider that cycling hormones would also affect orexin neurons through the GABAα pathway. Progesterone is a GABAα agonist – a sedative, while DHEA and its sulfated partner DHEAS are GABAα antagonists, anxiolytics that block GABAα, reduce sedation, and thereby increase anxiety and wakefulness. There may be a cyclical nature to orexin firing that has yet to be investigated.
  • The hypocretin/orexin neurons also influence galanin, a GI and CNS hormone that seems to inhibit the activity of a variety of other neurons in those regions.

These are but a few of the brain systems that the orexin neurons touch in some way or another. Damage to this system would have serious health consequences by initiating a cascade of biochemical changes within the brain and body. Many of which, we have yet to fully understand.

How Might the Orexin Neurons Become Inhibited?

Quite easily, apparently. In addition to the orexin’s vast interconnected pathways with a myriad of neurotransmitters and neuropeptides, the orexin neurons act as energy and activity sensors with some unique intracellular mechanics that make them especially sensitive to the changing dynamics of the extracellular milieu. Disruptions in ATP, glucose and temperature, elicit reactions in orexin functioning.

Orexin neurons require as much as 5-6X the amount of intracellular ATP to maintain firing, and to maintain a state of wakefulness or arousal. This extreme sensitivity to reduced ATP makes the orexin neurons uniquely positioned to sense and monitor brain energy resources, early, before ATP levels become critical in other areas of the brain. The orexin neurons cease firing when ATP stores become low, thereby allowing the reallocation energy, perhaps to those cells required for survival, breathing and heart rate. As Hans Selye observed many decades ago, one of the first, and indeed, most consistent of the sickness behaviors, no matter the disease, is lethargy, fatigue and sleepiness. Orexin is at the center of this behavior.

Orexin neurons react to extracellular glucose levels, though perhaps not as one might expect. When extracellular glucose levels are high, orexin neurons stop firing via what is called an inward rectifying potassium (K+) channel that is ATP dependent. That means that when extracellular glucose is high, intracellular ATP is allocated to open K+ channels and flood the cell with the inhibitory K+ ions. K+ hyperpolarizes the cell, prohibiting it from firing. This mechanism reminds me of Dr. Peter Attia’s talk about the nature of Type 2 Diabetes and our approach to treatment. He proposes that the body’s metabolic response – the conservation of energy – to Type 2 Diabetes is not something aberrant but is exactly as it should be with a disease state. We’re just not treating the correct disease state.

Another way we can shut down the orexin neurons is via increased temperature. The orexin neurons are very sensitive thermosensors. Increased temperatures shut down orexin firing via the inward K+ flow. Again, this is consistent with sickness behaviors and the reallocation of resources.

Orexin – Hypocretin Neurons in Migraine and Seizures

Diminished orexin has been linked to migraine and seizure activity. With migraines specifically, orexin may contribute to the early warning, hours to days, of impending cortical disruption via changes in feeding and sleep patterns that often precede migraine onset. Orexin may also be linked to the pre-migraine aura mediated by changes in brain electrical activity that prelude the migraine pain itself by minutes, called cortical spreading depression or more appropriately, cortical spreading depolarization – the massive spreading change in ion balance of the neurons. Initially the wave is excitatory, neurons are firing, but that is soon followed by a period of neural silence. Finally, orexin is also connected to the vasodilation of the trigeminal nerve, the nerve responsible for migraine pain. These findings have led some to call orexin a migraine generator.

Diminished cerebral spinal concentrations of oxerin have been found in patients generalized tonic-clonic seizures. Conversely, in rodent studies, injections of orexin elicit seizure activity. Despite the somewhat contradictory findings in seizure activity versus migraine activity, it is likely that the orexin system is involved both disease processes.

Pulling it all Together: Orexins Monitor and Mark Disruptions in Brain Homeostasis

Here’s where it gets really interesting. Although some have argued orexin, particularly diminished orexin functioning, is the cause and culprit of disruptions in brain homeostasis, leading to narcolepsy, excessive sleepiness, migraine, seizures and other diseases, I think this system represents merely a marker of a disease process. I think the orexin system is the stopgap, the final barrier of disrupted cellular energetics, of mitochondrial function. Mitochondrial ATP is the key.

When we consider orexin’s role in migraine, in particular, we see clearly how environmental changes (diet, stress, illness, medication/toxin exposure) can lead to changes in the extracellular milieu where orexins reside. The orexin sensors adjust to these changes, mostly by reducing neural firing in attempt to counteract damages. The reduction in orexin then elicits the premonitory phases of the impending brain disruptions, sleep and hypophagia – the sickness behaviors. If it progresses, the massive waves of electrical disruption ensue, and migraine, perhaps even seizures are evoked. When the extracellular environment become chronically disrupted, so too does the diminishment of orexin activity, thereby initiating a perpetuating loop of dysregulated brain activity. We can hypothesize that similar progressions exist with disease processes marked by aberrant electrical activity, such as epilepsy.

We know that mitochondrial dysfunction is often generated by genetic polymorphisms and can predispose individuals to an array of seemingly unrelated conditions like migraine and fibromyalgia, dysautonomias and cognitive deficits. At the root of the dysfunction is a error of some sort in mitochondrial energy processing – ATP.

What has become increasingly clear, is that the production of cellular energy, can be disrupted environmentally, by diet, illness and exposures, if co-factors necessary for the production ATP like thiamine are diminished. It is via diminished ATP production, that I think some medications and vaccines evoke adverse reactions in some individuals. The orexin system, because it is so exquisitely sensitive to changes in cellular energy, is our warning system; first by subtle changes in neurochemistry, then by changes in arousal and feeding behavior, and finally, by an all-out reallocation of resources – excessive sleeping. If ATP remains deficient chronically, and an individual is so disposed, then the cortical misfiring we see in migraine and seizure ensues, along with autonomic dysregulation and the syndromes associated therewith. It is not the orexin – hypocretin system that is at root of many of these diseases, but rather, the causes are deeper yet and reside with mitochondrial health.

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This article was published originally on January 29, 2014.

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14 Comments

  1. Dr. Marrs:
    You wrote:
    “Damage to this system would have serious health consequences by initiating a cascade of biochemical changes within the brain and body. Many of which, we have yet to fully understand.”

    Serious health consequences is absolutely correct! I firmly believe my husband was injured by the barrage of vaccinations given to him in a single afternoon during his induction into the U.S Army in 1984 at 18 years of age—and we are just now beginning to understand the root cause of his suffering over the past two years. Within a few short weeks after the vaccinations he developed excessive daytime sleepiness, finally diagnosed as Narcolepsy 7 years later during a two day sleep study. Other than being born with a low amount of Melanin Concentrating Hormone (very fair skinned but not albinism; green eyes, Nystagmus; cataracts in his early 40’s), and a mild bout with childhood mumps, his medical history up to 1984 was unremarkable: no major illnesses, injuries or hospitalizations. However, I’ve recently discovered that MCH and orexins are both important regulators of arousal, feeding, and metabolism:
    http://www.eneuro.org/content/4/5/ENEURO.0013-17.2017#abstract-1

    Possibly this also has something to do with his loss of sense of smell, which he noticed in his early twenties.
    Interestingly, my husband’s oldest brother had the same physical features and above average intelligence as my husband, including character traits and behaviors I would classify as odd. l now often wonder if he was also afflicted with a similar condition, but instead was misdiagnosed and sent down the death-care systems’ rabbit hole before his untimely death in a car accident a few years ago. Now that this article has helped me to begin connecting the dots, it seems to me that the cascading effects of the loss of the orexins’ neurochemical interactions in the body parallels my husbands symptoms (those “serious health consequences” you mentioned), which began worsening two years ago when, after deciding to see a GP for a tremor that had suddenly developed in his right thumb along with newly onset orthostatic hypotension, he was diagnosed with “hypo-thyroidism”. Now 26 months and a myriad of new symptoms later—- including multiple food sensitivities, pins-and-needles pain in his extremities, ataxia, anemia, and much more— and he has declined to the point of being unable to work, drive or perform any type of activity that requires energy, along with being [mis]diagnosed with possible Multiple System Atrophy. I knew there was more to his story than what all the specialists were separately diagnosing, but not a single one of his doctors cared to delve deeper and connect the dots or do anything outside the norm of referring him back to his neurologist. We have yet to find a local healthcare provider who will work with us beyond offering referrals or prescription drugs (which my husband politely refuses to try, based on their short-term effectiveness and long-term, horrendous side-effects), but we’re never giving up. We still have faith and are hopeful, as within the past few months he has been taking a high dose of vitamin B1 (thiamine hcl) and beginning to see a little improvement. (This was after a short, 4-week course of a fat-soluble version, Alithiamine, afforded him only minimal improvement). We’re optimistic.
    And very thankful for your research.
    God bless you and your efforts with this website!

    1. I am glad that things are beginning to improve. You might consider our book: Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition. It will provide of the details to navigate thiamine deficiency and recovery.

  2. Dr,
    I’m sorry to bother you again. If the woman you referred to over the phone is uncomfortable talking to me I would be interested in knowing the following if you recall from your notes.

    Did she actually test for orexin deficiency?

    How did the dr justify the test? I don’t think I would be able to convince a Dr even though our circumstances are similar.

    How low was she ?

    How severe was her daytime sleepiness ?

    For how long did it last?

    I read TBI victims suffer a long time (if not permanently) with deficiency.

    And a question for you is orexin even tested for in the US?

  3. Hi Dr,

    Thank you for your time today. I wrote the article so whenever you are ready send me the link or email address to post this to. There are many like me so if you need more people for a research piece let me know.

  4. Dr Marrs,

    I would like to correspond with you directly if that is a possibility. This piece you wrote is incredibly insightful. Unfortunately, I believe it applies to me. I had an adverse reaction to Lexparo. It triggered all kinds of head pain, gait issues, fear, anxiety and stress. I find it interesting that I read the hypothalamus controls these emotions. I suffered this chemical stress for 60 days. I am a father of two. I was a reasonably successful consulting sales person as well. I never had a psychiatrist. I went on the med to help with pre-client meeting jitters. After the anxiety settled I started to become more and more tired. It was a sedated feeling that got increasing worse over 8 months. It is not to the point I cant walk straight, follow TV, or read books. I took neuro psych testing which the neuro psych didnt believe my story or the validity of my results. He said so in a letter to my work disability in which I was terminated. I also had an MRI which was normal. An EEG which said I said I slept the whole time when I was awake the entire time. Coffee or Provigil does nothing for me. I am seeing my 3rd neurologist and going to beg for a hypocretin test which I am sure he will decline. It is the only test that will medically prove my disability. As you can see I am quite desperate and dont mean to scare your readers. But if you know of any neurologists that are open to the idea of neurotoxicity please let me know. I am in Chicago. There are no other writeups on orexin deficiency except in regards to narcolepsy which doesnt apply to me. I know this is a big request. But my story is too unbelievable to be made up. Thank you for your consideration.

    1. Sorry one more thing. If you dont feel comfortable reaching out to me directly any advice would be welcome. I am not sure how you can help. But if you have any ideas please let me know. roof

  5. It will take me hours to read all those most intersting enclosed publications on nutritional deficiencies and a host of medical conditions.

    Well, vaccines are the primary cause of deficiencies of all kind; they upset the biological balance on all levels.

    Interestingly, when vaccinated babies with serious reactions are given sufficient doses of sodium ascorbate, their first response is falling deeply asleep. I am still getting emails from those parents who some 20 years ago listened and gave their babies reacting badly to vaccines sodium ascorbate (a non-acidic form of vitamin c). Their babies, now celebrating their birthdays as young adults, recovered without any residual damage.

  6. Excellent piece illustrating that we know so little about the body on a chemical level, and how artificial manipulations can cause a host of unknown and untoward events!

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