3 Day Fast Experiment

In a previous post, Starving Yourself Awake, I wrote on the eating = asleep phenomenon (i.e. postprandial somnolence) experienced by many people, including those with narcolepsy.

In conducting research for the article, I discovered several key links between orexin activity (orexin expression and orexin receptor expression) and fasting.  A few of the important connections are summarized below:

1) Orexins stimulate arousal and wakefulness.

2) Orexins are found in the hypothalamus as well as the gut, and are up regulated during starvation/fasting, and inhibited during feeding (particularly in response to glucose).

3) Women with anorexia have been demonstrated to have higher levels of circulating orexin, while narcoleptics (with cataplexy) have little to no orexin in their CSF.

In addition to the specific effects of fasting on orexin and orexin receptor expression in the brain, fasting has been demonstrated to be effective in management of other autoimmune diseases, including MS, rheumatoid arthritis, and lupus (SLE). To my knowledge, no one has yet scientifically demonstrated this effect in narcoleptic patients. 

In light of these findings, I am conducting a 3 day fast to determine it’s effects on wakefulness and energy levels. The last time I ate was 9:00 PM 6/17/2012, and I slept 7 hours last night with no memorable sleep disturbances or hypnogogic hallucinations. I will post daily with reports on energy levels and wakefulness, and hope to provide anecdotal evidence to support (or refute) the use of fasting in narcolepsy.
——–UPDATE – 38 hours———

I have now been fasting for 38 hours. So far so good.

I do not have any remarkable changes in mood or energy level, as of yet. Last night I was less sleepy than I normally am upon laying down, but I didn’t have any trouble falling asleep. Only have had 2 short (less than 5 minute) periods of hunger (complete with tummy grumblings), but otherwise have not felt hungry.

I am hoping to see changes in energy levels and beginning about the 48/60 hour mark. My goal is to do a complete 3 day (72 hour) fast, but would be happy to make it to 48 hours. More updates tomorrow!

—–Update 48 hours——

Because I didn’t see any remarkable changes in energy level or alertness, I broke my fast at 48 hours.

I promptly went to sleep, and have been sleepy since breaking my fast.

That said, becomming sleepy after eating doesn’t really account for the fact that I didn’t feel dramatically more awake on the fast, as I had expected. Now, I did have coffee during the fast – maybe that was what kept me from feeling any better than I did?

Most people who fast for autoimmune therapies do a water only fast, and also may fast for up to two weeks! Especially because I was so dramatically tired after breaking my fast, I would like to reattempt the fast, this time for longer and to do a complete water fast.

I also think that a ketogenic diet (i.e. a diet from only fat and protein) may be more beneficial to narcolepsy than by fasting alone. 

In the first place, the benefits of fasting arise from your body’s ability to use fat and protein stores for fuel; carbohydrate metabolism (other than those arising from gluconeogeneis) are not utilized. Secondly, it was recently demonstrated that a diet of amino acids activates orexin producing neurons, and that the excitatory effect of dietary amino acids outweighed the inhibitory effect of glucose.

The best dietary “prescription” to be then would seem to be a gluten-free (benefits covered in other posts), low-carbohydrate ketogenic diet, coupled with bouts of intermittent fasting.

Anyone out there with fasting experience and narcolepsy? Or other low-carbers? What about for the treatment of other autoimmune diseases?


Starving yourself awake

One day when I was in college, about my second year, I suddenly realized I felt awake. At the time, I had just been diagnosed with narcolepsy, and hadn’t yet discovered gluten free, so to feel actually awake was mind-blowing. After a few days of thinking about it, I realized I was feeling awake because I wasn’t eating. Not only that, but I found several other people talking about not being able to eat without going to sleep, too.  Apparently it was a common experience for some of us.

There is a good blog article documenting this, as well as comments from many other sufferers at N is for Narcolepsy.  While the author describes the opposite of what I previously stated (eating = asleep vs. no eating = awake), the concept is exactly the same.  There’s something about eating that makes many of us tired. Maybe it has to do with glycemic control, carbohydrate content, insulin spikes, and maybe it is a food intolerance, but the it is clear that the orexin/hypocrein system plays a role in controlling postprandial somnolence.

All of this brings me to these four articles:

  1. Sleepiness after glucose in Narcolepsy,
  2. Widespread Distribution of Orexin in Rat Brain and Its Regulation upon Fasting
  3. Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting, and
  4. Plasma levels of leptin and orexin A in the restrictive type of anorexia nervosa.

In the first paper, Sleepiness after glucose in narcolepsy, the authors investigated the anecdotal claim (such as those from N is for Narcolepsy shown above), that narcoleptic patients were more tired after ingesting glucose. In this study, they gave 12 narcoleptics (and 12 controls) an additional 50g of glucose in a punch just before allowing them to take a nap.  Overall, they found that narcoleptic patients who ingested glucose had increased sleepiness and decreased wake duration. Additionally, 11 of 12 demonstrated increased REM. This also corroborates the effect of low-carbohydrate diets on sleepiness in narcolepsy demonstrated by Husain et al. covered elsewhere on Autoimmune Patient.com. So, in response to N is for Narcolepsy, I would say that there is good evidence that eating (especially sugar and carbohydrates) makes us narcos sleepy. 

I’m not going to review the second paper, but allow it to serve as a segway to the third paper (Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting). In it, the authors examined expression of the orexin 1 and orexin 2 receptor subtypes (OX1R and OX2R; i.e.  receptors for orexin) in the brain. They looked at where the receptors were, and if they were upregulated in different areas of the brain in response to fasting. It should be noted here that OX1R has a moderate specificity for Orexin A, and OX2R can respond probably equally well to both Orexin A and B. Overall, the found that the different receptors had different distribution patterns, but they had some overlapping areas in their expression as well.  I’ve uploaded a graphic below summarizing where the receptors were found and in which areas of the brain.

The importance of differential expression of orexin receptors in different structures of the brain suggests that they play novel roles in multiple circuits, each of which do different things.

For example, expression of these receptors in the lateral hypothalamic and dosomedial hypothalamic regions implicates orexin involvement in feeding behavior, circadian activity, and body-weight regulation.  

Expression in the hippocampal regions suggest orexins are also involved in regulating the monoaminergic systems (for example, histamines, dopamine, serotonin, melatonin, norepinephrine, epinephine and others).  These systems are of obvious importance, particularly because this is the only region of the brain which produces histamine. Histamine has been shown to be critical for wakefulness, and ablation of histamine in the CNS results in hypersomnolence, sleep fragmentation, and increased REM. Additionally, low levels of histamine are found in the CSF of narcoleptics, and is also reduced in animal models.

Additionally, expression of these receptors in the amygdala implicates partial orexin-regulation of memory, attention and emotion. 

In addition to the receptors, orexin itself has also been shown to be upregulated during fasting (and, interestingly, also by insulin-induced hypoglycemia).  

In another interesting study that investigated circulating orexinA levels in recovering anorexic women, found that as anorexic women who began a recovery program and gained weight (as shown by an increase in BMI and leptin levels), their circulating levels of orexin decreased significantly at every time point during the course study.

So what does this all mean? In the first place, it means that the sleepiness exhibited by narcoleptics after eating is real. For some, this may mean that not eating all day, in order to maintain wakefulness.  While certainly this doesn’t seem optimally healthy, it may be a legitimate alternative method to controlling daytime sleepiness for some, particularly in younger patients who may still have functioning hypocretin neurons that have not yet been destroyed by autoimmune attack.  In the second place, it means that dietary restriction can modulate expression of orexin/hypocretin and their receptors in the brain (and speculatively in the gut and pancreas as well).

While it is certain that more literature on the gut/brain axis and the role of the enteric nervous system in narcolepsy is sure to come, it is an exciting time to theorize major players of the disease that may extend beyond the hypothalamus, which may also pave the way for novel treatments or palliative care.



Eating Disorder and Metabolism in Narcoleptic Patients

In the recent article, Eating Disorder and Metabolism in Narcoleptic Patients, it was shown that the energy balance of narcoleptic individuals was impaired compared to healthy individuals.

It had been long reported by doctors that their narcoleptic patients tended to be overweight compared to other patients, and that patients tended to have a higher BMI (body mass index) “regardless of whether they were treated with drugs increasing appetite, and regardless of whether they had cataplexy.” More importantly, not only are narcoleptics more overweight than the “healthy” control population, but they are also more overweight than their family members, suggesting that the etiology of obesity and narcolepsy extends beyond a familial predisposition to be a little bit thicker.

In the hypothalamus, hypocretin neurons are found in the region of the brain called the feeding center, and when it was found that narcoleptics have a reduction in hypocretin-producing neurons in the brain, it was then suggested that metabolic functioning may also be impaired.  In the paper reviewed here, the authors set out to determine energy expenditure in more than 500 narcoleptic patients. Some patients had cataplexy, while some did not, but all were not taking any treatments at the time of the study for their narcolepsy.

Overall, they found that:

1) Narcoleptics tended to have a higher median BMI.  That is to say, we narcos are usually fatter.

2) Narcoleptics have lower rest energy expenditure.  This means that, when not moving, we burn calories at a lower basal rate than non-narcoleptics.

3) Typical, but not atypical narcoleptic patients tended to eat less.  In the study, they separated narcoleptics with cataplexy (“typical”) and those without (“atypical”) and found that typical patients ate less than “healthy controls.”  While there was no food intake difference between typical and atypical narcoleptics, overweight narcoleptic patients ate 1/2 as much as narcoleptic patients with a healthy weight.

4) Narcoleptic patients demonstrate a higher rate of eating disorders, particularly bulemia. Narcoleptic patients tended to demonstrate impaired eating behaviors, including the use of binge eating to control daytime sleepiness. There was no difference between typical and atypical narcoleptic patients, and they found that 1/2 of narcoleptic patients suffered from a mild form of eating disorder.

Narcos are fat.

No offense, but we narcoleptics are fat [1].  In fact, of all of the narcoleptics I have met, I have only met two people (both young men, mind you) that were even remotely in shape.  For me, the fact of obesity and narcolepsy is one of the most unfair aspects of the disease. In the first place, people who don’t know anything about narcolepsy, assume that we are lazy. “Just make your bed and sleep less!” seems to be their cure-all answer.

Indeed, the official stance of The Standford Center for Sleep Sciences and Medicine (home to the famous Dr. Mignot) appears to be: “Many patients with narcolepsy also gain weight as the result of inactivity and sleepiness.”

For years, narcoleptics have fought a huge social stigma that we are somehow lazy sloths that just want to sleep and eat all day, despite the facts that we actually sleep less efficiently than other people, and still gain weight on diets that work for other people!   

Fortunately for us, there is a body of research linking metabolic dysfunction and narcolepsy.  The excitement about these advances (for me, at least) is overwhelming, and there are several reviews on the site summarizing them.

Recently, it was shown that we narcos don’t produce a lot (if any) hypocretin.

hypocretin A

Structure of hypocretin

Our brains are simply deficient in the production hypocretin (also called orexin), and it is hypothesized, though not proven, that we may have a complete loss in the neurons of the hypothalamus responsible for producing hypocretin.  For everyone, hypocretin controls arousal, wakefulness and appetite. A deficiency in hypocretin impairs sleep as well as metabolism, and in addition to being sleepy, narcoleptics have a lower basal metabolism than other people. Because of this, narcoleptics tend to gain weight in spite of eating fewer overall calories than most people. 

Orexin is not only active in the central nervous system, but it has wide ranging action throughout the periphery.  Indeed, mice that lack orexin gain weight as a result of brown fat hypoactivity and reduced energy expenditure. Remember, brown fat is good fat. White fat is the “bad fat” that makes you appear fat.

So what does this mean? Surely, it doesn’t mean that we are now allowed to sleep and eat as much as we want. But it does mean that WE ARE NOT JUST LAZY!  For me, the problem of metabolism and narcolepsy (in addition to the metabolic problems that stem from my hypothyroidism), is an ongoing battle. On the one hand, I am able to harness the power of diet and nutrition to help control my symptoms, but on the other, I am always fighting. Even when I exercise, I can’t eat more than 1,000 – 1,200 calories a day without gaining weight (very quickly, I might add)!

It is clear that narcolepsy is more than just a disease of sleepiness. It is a disease with many faces, encompassing tiredness as well as impaired metabolic homeostasis. In fact, it was recently reported that obese individuals had lower circulating levels of orexin A. The results from the study indicate orexin doesn’t only work in your brain, but that the receptors for orexin (specifically in the gut and pancreas) contribute to systemic effects of orexin itself, and that a deficiency in orexin not only can have neurological effects, but systemic ones as well.