Gluten Free PWN Updates

Hello, everyone!

I received an e-mail a few months ago that made me smile pretty big. It was from a reader who had come across the blog about a year ago, and then noticed I quit posting updates! She reached out to see if I was OK, and specifically to ask if I was “feeling so much better that [I] didn’t feel the need to post updates.” I hate it when blogs to un-updated for a long time, so I wanted to take the time to give an update on everything that’s been happening in the “Gluten Free PWN” community – and boy is it a LOT!

Around September of 2014, we launched, a website intended to be a central resource for happenings in the Gluten Free PWN community.

We’re working on buildScreen Shot 2015-12-28 at 12.24.48 PMing the site so that it’s easy for people interested in implementing a gluten free diet or other lifestyle changes in an attempt to mitigate narcolepsy symptoms to find active blogs, the Gluten Free PWN Facebook page and the basics of what our little movement is about.

We’re always looking for testimonials to publish – if you’re interested in sharing your story, please e-mail us at!

2014 Narcolepsy Network Conference in Denver

In October 2014, Heidi, Gina and I attended the 2014 Narcolepsy Network Conference and I gave a talk to a PACKED room of people about using dietary strategies to mitigate symptoms of narcolepsy. It was such an honor to be a part of the largest patient-oriented narcolepsy conference and to be able to present survey data we’ve generated from our groups showing the different dietary changes that PWN make and how it helps improve their symptoms.

Just before the conference, Paleo Movement Magazine published an article about the upcoming talk, entitled “Paleo Narco: Applying Paleo Principles to Narcolepsy.

BONUS: You can view the presentation below or on Youtube!

Kitchen Table Hypothesis

Hypotheses have been brewing over at the Kitchen Table. Earlier this year, Heidi L. published a paper entitled “An Evidence and Experience Based Mechanism for Narcolepsy.” Featured components include a detailed analysis on the role of infection and antibiotics, and the interplay of intestinal permeability in the pathogenesis of narcolepsy.

Madcap MissAdventures of a Narcoleptic

Gina (AKA Madcap Miss) has been busy launching her new site “Madcap MissAdventures of a Narcoleptic” and boy does she have some big things brewing! Recently she was busy with a very successful Sleep Walk in Dallas Forth-Worth – Dr. Todd Swick was a special guest! Gina also attended the 2015 Narcolepsy Network Conference to promote awareness of her new website, which is sure to be a great resource to the PWN community. Stay tuned, and follow her on Twitter and Facebook in the meantime!

Other News Adventures

My good friend Charrisa was featured in the newspaper for her school, Webster University in a piece titled “Battling Narcolepsy with Nutrition” in which she describes her journey with narcolepsy and nutrition and how since being properly diagnosed and making dietary (gluten free, of course!) and lifestyle changes she now says: “I’m not failing to thrive,” Martin said. “I feel healthy, and I have a drive. I feel like I can succeed now.” We love you, Charissa!

Personal Updates

Many of the e-mails I get are in reference to some of the specific things I’ve said help my narcolepsy: Am I still doing gluten free? Do I still take L-tyrosine and carnitine? One of the constants in my life health-wise is I am always trying to do the best thing for my body at the time. I’m not perfect, and I change it up a lot. I think that I’ll always identify as a “biohacker” and always be looking to improve what I can. My lifelines are nicotine and caffeine, and I still take tyrosine (although I found larger doses aggravated my anxiety). I’m currently working on biohacking anxiety and I’m prepping a blog post on that.

I’ve been finishing up my PhD at the University of Florida, and I’m slated to defend my thesis in January (hence my lack of recent updates)!

Retraction of Paper “Confirming” Narcolepsy as an Autoimmune Disease

Today is a disappointing day in the narcolepsy community.The scientific
manuscript reported to have “confirmed” narcolepsy as an autoimmune disease has been formally retracted.

The retraction notice states, “The researchers report that they have been unable to reproduce the paper’s key findings.” (source


The paper, entitled  “CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy,” and published by Science Translational Medicine in December 2013, caused more than media ripple.  Submitted by co-senior authors Mellins and Mignot and collaborators, the original article was highlighted in more than 100 news and press releases, and received featured articles and posts on major news sites including Nature News, Scientific AmericanThe Huffington PostMedical News Today, National Geographic, Psychology Today — it even made waves in The New Reddit Journal of Science

The article has been cited 4 times since it’s publication in Dec. 2013, according to PubMedCentral.

At the time of publication, the paper was reported to demonstrate immune cross-reactivity between a flu antigen and the orexin protein — so-called molecular mimicry. In layman’s terms, if an immune response was generated recognizing flu antigen (such as during natural infection or in a vaccine), that immune response could also target neurons in the brain expressing orexin. Specifically reported was (1) characterization of narcolepsy-specific auto-immune CD4+ T cells, (2) their corresponding epitopes, and (3) evidence of a mimicry-based mechanism potentially explaining the association between narcolepsy and influenza infection.

Orexin is a hormone critical for maintaining wakefulness. Loss of orexin-producing neurons is believed to be the primary cause of symptoms in many individuals with narcolepsy. You can learn more about narcolepsy here.

These results were poised to explain the increases in narcolepsy following Pandemrix vaccinations in Europe during the 2009 H1N1 influenza pandemic.  Earlier studies suggested that the adjuvant used in the Pandemrix vaccine, AS03 (which was not approved for use in the United States) may have been to blame.

The findings of the paper in question caused a stir because for many years studies have failed to demonstrate orexin immunoreactivity or a cell-specific immune response to orexin producing neurons, despite the fact that narcolepsy contains other “autoimmune signatures” including a high (90%) association with a specific HLA genotype (HLA-DQB1*0602), and a strong association with the T-cell receptor alpha locus, among others.

A quote from the Nature News article summarizes the general sentiment well:

“Thomas Scammell, a neurologist at Harvard Medical School in Boston, Massachusetts, says that the results are welcome after “years of modest disappointment”, marked by many failures to find antibodies made by a person’s body against their own hypocretin. “It’s one of the biggest things to happen in the narcolepsy field for some time.”


Co-senior author of the study Mellins is quoted:

“Up till now, the idea that narcolepsy was an autoimmune disorder was a very compelling hypothesis, but this is the first direct evidence of autoimmunity. I think these cells are a smoking gun,”


With many basic science manuscripts which make significant discoveries, the excitement is often confined to the scientific community. What is different about this paper is that the enthusiasm bubbled over into patient circles and prominent outreach organizations. Narcolepsy has been long suspected to be of immune origin, and the fact that this theory hasn’t been yet confirmed has meant the often stimatized patient population continues to struggle with being incorrectly diagnosed with mental and behavioral disorders, often up to 15 years before receiving a correct diagnosis. One of the important advancements that might have been made from the discoveries of this paper was the development of a new diagnostic test for narcolepsy, which could improve diagnosis and time-to-diagnosis for patients.

Interestingly, a letter written by inventors of Pandemrix was submitted in February 2014 stating that  “CD4+ T cell cross reactivity” was part of a “research plan.(update 9-9/30/14: the letter has since been retracted). The research plan, authored by GlaxoSmithKline researchers is entitled “Narcolepsy and A(H1N1)pdm09 vaccination: Shaping the research on the obeserved signal” was published in December 2013.  In it, they listed key areas of research needed to fill the information gap about how the Pandemrix AS03-adjuvanted influenza vaccine could have caused increases in narcolepsy:

Therefore, the following key areas of research can be identified, (1) characterization of hypothetical narcolepsy-specific auto-immune CD4+ T cells, (2) mapping epitopes of such T cells, and (3) evaluating potential mechanisms that would enable such cells to gain access to the hypothalamus. Addressing these questions could further our understanding of the potential links between narcolepsy and A(H1N1)pdm09 vaccination and/or infection. Of particular interest is that any evidence of a mimicry-based mechanism could also explain the association between narcolepsy and A(H1N1)pdm09 influenza infection.


As a reminder, the reported findings of the now retracted “CD4+ T cell cross reactivity…” paper were: (1) characterization of narcolepsy-specific auto-immune CD4+ T cells, (2) their corresponding epitopes, and (3) evidence of a mimicry-based mechanism potentially explaining the association between narcolepsy and influenza infection.

A timeline of events is shown below:

retraction timeline crop

It should be noted that the publications of GlaxoSmithKline researchers did not reportedly contribute to the rectraction of “CD4+ T cell Autoimmunity…”

According to, Mignot has said regarding the retraction:

Mignot tells us:

We were just continuing our work based on the finding, trying to establish it as a diagnostic test, but could not replicate it.  No other work is affected, and in fact the DQ binding studies of that article are perfectly fine.  Only the [Enzyme-Linked ImmunoSpot (ELISPOT)] results are in question.

The retraction notice first appeared on the mobile site of Science Translational Medicine on July 23, 2014, but linked to a “Content Not Found” page. The “Retraction” section was missing from the non-mobile version of the website, and no reply was received when the Editors of STM were contacted to clarify whether the article had been retracted or not.

In spite of this disappointing turn of events, the community is hopeful that we will continue to move forward in our pursuit of understanding the molecular mechanisms of narcolepsy and that these developments will lead to improved diagnostic tools and treatments.


A. K. De la Herrán-Arita, B. R. Kornum, J. Mahlios, W. Jiang, L. Lin, T. Hou, C. Macaubas, M. Einen, G. Plazzi, C. Crowe, E. W. Newell, M. M. Davis, E. D. Mellins, E. Mignot, CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci. Transl. Med. 5216ra176 (2013).

M. Brandt. “Narcolepsy is an Autoimmune Disorder, Researcher Says.”  Stanford Medicine News Center. (2009.)

K. Conger. “H1N1-triggered narcolepsy may stem from ‘molecular mimicry,’ study finds.” Standford Medicine News Center. (2013)

E. Yong. “Narcolepsy confirmed as autoimmune disease.” Nature News. (2013).

S. Harris. Notes on NarcolepsyPsychology Today. (2012).

J. Hallmayer et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics. 41, 708 – 711 (2009)

Narcoleptic with a Poor Memory?

For as long as I can remember, my sister has always impressed me with her ability to remember things that I never could. My memories of childhood are usually vague at best. As I became older and entered college, I realized that I required a LOT more studying than my colleagues. Where most people could get by on “cramming” material for a few hours before, I had to study all materials for several hours a day before I got it right. When it came to learning something new, it was like.. things just didn’t stick.

After I was diagnosed with narcolepsy, and I went to several patient conferences, I realized that complaints of poor memory were very common among us – yet, again, I was not alone. Indeed, it has been shown that memory and cognition are impaired in narcolepsy.

dendritic spineIt’s been suspected for a long time that sleep can help consolidate memories. So, for a disease like narcolepsy where the basic sleep architecture is disrupted, it makes sense that narcoleptics might have impaired memory.

A recent study reports that sleep promotes memory formation through the formation and maintenance of dendritic spines on neurons. It would be interesting to see if spine formation is impaired in narcolepsy.

Image credit:



The First Documented Case of Narcolepsy – Is the flu to blame?

Narcolepsy, as a documented disorder, first appeared in medical literature in 1880. Dr. Jean Baptiste Edouard Gélineau published an account of a 38 year old man with a two-year history of narcolepsy. The man experienced up to 200 sleep attacks a day, and also had cataplexy. Interestingly, Dr. Gélineau also describes the patient as having a “nervous, volatile temperament” and “histrionic personality” – an endearment many of u220px-Jean_Baptiste_Edouard_Gélineaus with narcolepsy can probably relate to. The patient also reports having conceived his child “in a moment when the illness came over him.” Cataplexy at orgasm is a phenomenon that has been largely discussed in PWN forums, and has been recently described in medical literature.

Narcolepsy has also been recently linked to influenza. Outbreaks of narcolepsy occurred after the 2009 Swine Flu pandemic and was apparently precipitated by the adjuvant used in the Pandemrix vaccines. However, it has been determined that there is potentially some molecular mimicry occurring between orexin proteins and specific proteins found in influenza itself and the influenza vaccines, confirming that type I narcolepsy is of autoimmune origin It begs the question, could this first case of narcolepsy have also been precipitated by influenza?

In Dr. Gélineau’s description, the abrupt onset of this particular case led to the suggestion of a potential head trauma in precipitating the disease. This phenomenon is still described today. In this particular report, the patient had been punched in the head and also had a log fall on his head about three years prior; it was determined that these probably did not contribute to his disease in the initial report, though.

What if it was actually precipitated by influenza? The 38 year old man described in the report was first seen by Dr. Gélineau in 1879.  Five years prior, he had “suffered acute rheumatism in the joints and Herpes tonsurans at the same time.” 

Rhuematism is an inflammatory inflammatory disease that occurs following a Streptococcus pyogenes infection. Importantly, patients with recent onset narcolepsy have demonstrated in increase in anti-streptococcal antibodies. Additionally, influenza infection boosts subsequent Strep pyogenes infection and invasion. For a more detailed perspective on this, check out one of Heidi L.’s most recent posts, H1N1 Flu Virus may cause Narcolepsy via Secondary Infection.

Interestingly, the patient’s symptom appearance is sandwiched between two influenza pandemics (the 1847-1851 pandemic and the 1889-1893 pandemic). Capture

If the patient had a childhood bout of influenza (a likely event, particularly during the pandemic), this might just have been the original trigger of his narcolepsy. To be sure, many people are now discussing respiratory events as predisposing factors in their own narcolepsy. Just check out how many times sinusitis is listed on this thread. Below is a timeline of documented events for that first patient.

influenza pandemic

So, could the influenza virus and Strep infection have a played a role in the first case of narcolepsy? Maybe, but maybe not. Share your opinions below!


Narco Track Bio Hack

January 1st

Narco Track Bio Hack

Use the link above to access the first page of a .PDF which will soon become a 365-day calendar to track your sleep quality.

The calendar is intended for individuals with narcolepsy or other sleep disturbances to be able to track:

  • Time and quality of sleep of the previous night upon waking. Specific sleep disturbances are noted, with an additional column so that you can add your own particular sleep disturbance (restless legs, how many times you awakened, auditory hallucinations, etc.)
  • Medication or vitamin regimen to track how certain vitamins or new prescriptions may be affecting your daily functioning; these are separated in to morning, noon, and night dosages.
  • Modifications or exercise. Many individuals have had a great deal of success in managing excessive daytime sleepiness (EDS) using an exercise routine. You can also note other “mods” here, including light box/blue light therapy, stretching, or whatever you do to help you wake up and stay awake.
  • A quick food log. While this isn’t a place to keep a detailed food diary, you can make quick notes about what you ate. It is also encouraged that you keep track of the carbohydrate content of each meal and snacks throughout the day; many narcoleptics note that carbohydrates in the diet significantly increase morning and daytime sleepiness.
  • Narcolepsy and cataplexy attacks.  You can note how many EDS/naps/cat attacks you have throughout the day. They are positioned strategically between meal times to help you pinpoint specific food triggers that you may be experiencing (for example, I have noticed that I will nap after meals containing more than 30g / carbohydrate).
  • Daily Epworth Sleepiness Scale. Use the Epworth Sleepiness Scale form at Narcolepsy to track how tired you are feeling on a day to day basis. Over time this can let you know how your changes in exercise, daily routine, diet, and medications  are affecting your symptoms of narcolepsy overall.
  • Red box summary. This is my favorite part of Narco Hack Bio Track. It has a one box summary of whether or not you had daily consumption (or potential exposure) to gluten, your alcohol consumption, and your total carb count for the day. For days you don’t have time to fill out the entire form, try just using this box (in combination with the Epworth Sleepiness Scale box) for a quick and dirty for your gluten/carb count.

Happy Tracking!

Wheat Woes: All In Your Head?

Gluten free is without a doubt, one of the newest “fad diets”, and the issue is being hotly debated in the blogosphere and medical communities alike [1,2].  Gluten free is being criticized as trendy, and as an option for individuals who “just want to lose weight,” or believe that a gluten free diet will make them feel better. “Self-diagnosis” of a gluten sensitivity igluten frees common and shunned upon by most of the medical community, even though a diagnosis by exclusion is still the best and only way to diagnose non-celiac gluten sensitivities. The reaction by some when you chose not to eat a particular food group is shock and concern for your health, as if not eating bread will cause you more harm and this concept that you could end up with “severe nutritional deficiencies“. Let’s be clear, so long as you replace the gluten in your diet with healthy alternatives, you are likely not going to “miss out” on any nutrients, which are usually artificially added to wheat, anyway.  Check out The Paleo Mom for a great article on the subject here.

When I first became gluten free, you either had biopsy-confirmed celiac disease or it was all in your head. I had the good fortune of having a doctor trained in Greece, who was more a fan of “if it made you feel better, then do it.” I did a rotation diet under his guidance, and discovered a severe sensitivity to wheat, although I was never diagnosed with “celiac disease,” (nor do I have the most commonly recognized susceptibility genes for it).

Initially in the literature, many scientists and practitioners argued if “non-celiac gluten sensitivity” was even a real thing. Apparently, many doctors had experienced people insisting they were sensitive to gluten, without any trace of official celiac disease on their medical records or diagnostic exams. For the last 3-5 yearsthe health community at large did, and still does to a considerable degree, consider non-celiac gluten sensitivity a fad-diet.  Even still, perception and opinion persists among the medical and scientific communities, that if people don’t have “markers” for celiac disease, “there’s no evidence that the protein can do any lasting harm,” and only individuals with biopsy-confirmed celiac disease can benefit from a gluten free diet. There are even some with biopsy-confirmed celiac disease who have grown resentful of the “gluten free craze” and can’t wait for it to end.

Fortunately, very recent literature has done two things for us. In the first case, a study was conducted to determine that individuals with non-celiac gluten sensitivity weren’t just a bunch of liars with personality problems — whew, what a relief!

Secondly, current literature has refuted the fad-hypothesis and identifies non-celiac wheat sensitivity as a distinct clinical condition, which may present as a spectrum of related complications — from migrane to skin rashes to psychosis or depression.  What’s more is that wheat/gluten sensitivity looks different in different individuals.  Moreover, you’re talking about a patient population of 18 million Americans (compare that to only 100,000 American narcoleptics)

That’s not to say that there are probably people adopting a gluten free diet that don’t necessarily need to. These people are otherwise healthy, are completely gluten tolerant, get no (obvious) positive benefits from removing gluten from their diets and are really getting ripped off by a lot of companies trying to make a buck.

However, there are many ways that gluten can cause ill-effects outside of classical celiac disease. Indeed, gluten sensitivity often lies outside of intestinal pathology, per se, and rather manifests with extra-intestinal symptoms, including neurological issues. Take the case of celiac and non-celiac gluten sensitivity in schizophrenia, for example.

Sleep architecture has also been shown to be impaired in those with celiac disease, but whether these same disturbances occur in “non-celiac” sensitivities are not yet fully reported. Anecdotal evidence would suggest yes. Reports of hypnagogic hallucinations, sleep paralysis, and nightmares are common in people who have discovered an underlying gluten intolerance.

So, how could this be?

Firstly, you can’t find what you aren’t looking for.

It is apparent that non-celiac disease gluten sensitivity is not celiac diseaseIn that way, if you go looking for classical diagnostic markers of celiac disease, they won’t be there. Does this mean that you aren’t still gluten intolerant or wheat-sensitive? Absolutely not.

At the end of the day, elimination diets are still the clinically best way to determine if you have a non-celiac gluten sensitivity. After you have determined with your doctor that you do not have celiac disease, remove gluten for three weeks. If you feel better after removing it, you are likely sensitive.

Narco Biohack – environmental modifications

A few weeks ago, I was scouring the internet for devices that could help narcolepsy.  stumbled upon a fake invention (presumably it’s a college website design class or something of that nature) advertising The Narco Ring,an anti-narcoleptic ring you wear to “The Narco-Ring – Helping Narcoleptics Remain Alert During Critical Awareness Moments.”  Although to my despair it turned out to be a fake product, you can see why I was excited:

mood ringFirst it had to be powered by some source. For a ring since it is small we knew something as double A batteries would not work. However the battery called coin cell or button cell battery that operates on small electronics such as wrist watches, calculators, hearing aids, or on the central printed circuit board we figured would do just fine to operate the Narco-ring.

Then what needed to be done is to figure out how much of the force of a vibration or shock is needed and for how long. For each person it would more than likely differ, because it would depend on how sensitive their finger is to the vibration and if they are a deep sleeper or not. Also the vibration may not be enough to wake them up with even the highest vibration, so then a shock would be used.

A new sensor would need to be created for this ring. Motion senors have been created where if someone or something moves then it triggers an alarm and it goes off letting someone or something know that there is something making motion. For our ring we need just the opposite of that where there is a sensor on the Narco-ring that detects when your finger isn’t moving.

Pretty clever, huh?

In all seriousness, though, there are a few devices that people are using to help narcoleptic symptoms.  I haven’t personally tried any of these yet, but have just placed an order, and very confident they work based on testimonials I’ve received.

Blue Light Blocking Glasses blue block

The idea behind using amber lenses to block blue light to improve sleep is basically that:

  • Blue wavelengths are important for circadian rhythms
  • When and how much light (especially blue light) you receive affects sleep
  • Blocking blue light mimics “physiological darkness” and could lead to improved sleep cycles, which is impaired in narcolepsy.

Blue light evolutionarily should only really come from the sun, fires, and other natural sources of light. So, your body has evolved to use these light cues to signal when it is appropriate to sleep, and when it is appropriate to wake up.

Much of the blue light we receive at inappropriate times (mainly when it is dark outside) are coming from not only articficial lighting systems within the home, but from electronic devices.  Even over the past 10 years, the number of people using the internet, and presumably using computers and surfing the web, phones, or iPads has increased dramatically. Internet adoptionIn the study linked above, patients (non-narcoleptic) wore blue light blocking glasses for three hours prior to bed time.  They demonstrated that those wearing blue light blocking glasses:

  •  had significant improvement in sleep quality compared to the control group
  •  had significantly improved mood relative to controls

Phototherapy a.k.a. Light Boxes

Light therapy is essentially waking up in the morning and sitting in front of a light box for about 1/2 an hour to “reset” your circadian clock. The idea is basically the exact same aslightbox the blue light blocking glasses, except this time you’d like to have it. Receiving cues that it is morning time (a time to be awake and alert) may be able to help, especially if delayed awakening is a problem.

These products can be a bit of an expense ($70-$140), but it might be worthwhile if you can rouse yourself enough to go take a walk outside, or if you don’t live in the Sunshine State.





Passive Transfer of “Narcolepsy” in Mice

J Autoimmun. 2013 Jul 5. pii: S0896-8411(13)00084-X. doi: 10.1016/j.jaut.2013.06.010. [Epub ahead of print]

Passive transfer of narcolepsy: Anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice.


Dept. Neurology and Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Israel; Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Affiliated to Sackler Medical School, Tel Aviv University, Israel.


Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy (a sudden weakening of posture muscle tone usually triggered by emotion) caused by the loss of orexin neurons in the hypothalamus. Autoimmune mechanisms are implicated in narcolepsy by increased frequency of specific HLA alleles and the presence of specific autoantibody (anti-Tribbles homolog 2 (TRIB2) antibodies) in the sera of patients with narcolepsy. Presently, we passively transferred narcolepsy to naïve mice by injecting intra-cerebra-ventricularly (ICV) pooled IgG positive for anti-TRIB2 antibodies. Narcolepsy-IgG-injected mice had a loss of the NeuN (neuronal marker), synaptophysin (synaptic marker) and orexin-positive neurons in the lateral hypothalamus area in narcolepsy compared to control-IgG-injected mice and these changes were associated with narcolepsy-like immobility attacks at four weeks post injection and with hyperactivity and long term memory deficits in the staircase and novel object recognition tests. Similar behavioral and cognitive deficits are observed in narcoleptic patients. This is the first report of passive transfer of experimental narcolepsy to naïve mice induced by autoantibodies and supports the autoimmune pathogenesis in narcolepsy.

Copyright © 2013 Elsevier Ltd. All rights reserved.


Anti-Tribbles homolog 2 (TRIB2) antibodies, Behavioral deficits, Narcolepsy, Orexin, Passive transfer


Histamine, narcolepsy and “idiopathic” hypersomnia

Histamine is critical for maintaining arousal and wakefulness. The sole source of histamine in the brain is a region called the TMN (tuberomammillary nucleus) in the posterior hypothalamus. The hypothalamus is also where orexin comes from in the brain. Like orexin, neurons which make histamine (called histaminergic neurons) have far-reaching projections in the brain. Because of this, again, like orexin, these neurons are implicated in many different physiological states including sleep-wake control, learning, emotional status, and memory formation.

Most of us have experienced the histamine wakefulness-promoting effect when we have taken anti-histamines (Benadryl, etc.). The #1 side effect that most people notice is drowsiness. This is due to the fact that anti-histamines bind and antagonize histamine receptors (H1 receptors). Anti-histamines block histamine signaling in the brain.

In health, histominergic neuron activity is highest during wakefulness, and is becomes nearly undetectable during sleep (REM and NREM).

It has been shown previously that  people with narcolepsy have low CSF histamine. In addition, the lower the corresponding orexin levels, the lower the histamine levels; indicating that proper orexin signaling in the brain is crucial for proper histaminergic signaling. The same trend has been shown for those with idiopathic hypersomnia.

Mouse models have also demonstarted a link between histamine and sleep impairment. Histamine deficient (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, a condition that sounds intriguingingly similar to narcolepsy. Moreover, sex differences in histamine deficiency have been demonstated in mice: female HDC KO mice demonstrated “hypoactivity, increased measures of anxiety, impairments in water-maze performance, but enhanced passive avoidance memory retention.”

Currently, it has been hypothesized that histaminergic neuron activity of the TMN may be reduced in individuals with narcolepsy.

Somewhat unexpectedly, researchers have also recently discovered an increase in the number of histaminergic neurons in people with narcolepsy. And, they didn’t find just a modest increase – they found narcoleptics had up to 94% more histaminergic neurons! They also confirmed their human findings using orexin knock-out mice, which displayed a similar increase.  It has now been suggested that this drastic increase in histaminergic neurons may be a compensatory effect of orexin loss.
It was recently demonstrated that, contrary to expectation, individuals with narcolepy may have more histaminergic neurons in the TMN.

It was recently demonstrated that, contrary to expectation, individuals with narcolepy may have more histaminergic neurons in the TMN.

It is important to note that just because there are more histaminergic neurons, does not mean that there is more histamine. This previously mentioned study has been incorrectly represented in mainstream media already. As mentioned before, we already know that narcoleptics have lower CSF histamine.
Histamine has been implicated in neuroinflammation. Experimentally, histamine has been demonstrated to be neuromodulatory/regulatory in multiple sclerosis (“EAE” is the murine experimental version of the human disease MS).  Unlike individuals with narcolpesy, people with active multiple sclerosis have higher levels of CSF histamine, although it is probable that elevated histamine is a feature of neuroinflammation in general.  If narcolepsy is a true neurological autoimmune disease, one would expect elevated CSF histamine. It’s important to note that how CSF histamine changes over time in narcolepsy is not known.
Histamine has also been implicated in neurogenesis. I’ve already discussed this concept to some degree here (although I should point out that was discussing a different region of adult neurogenesis).  This has been demonstrated largely in the subventricular zone (SVZ), which is a known area of adult neurogenesis and has implications for repair following injury. The image below shows the respective regions (SVZ) in relation to the hypothalamus (where orexin neurons are).CaptureWhat does it mean for narcolepsy?  Why would narcoleptics have low histamine and a compensatory increase in the number of histmaine-containing neurons?