A Critical Analysis of the Therapies for Narcolepsy and Hypersomnia Syndromes

Currently accepted treatment protocols for narcolepsy almost all address the sleep symptoms using stimulant drugs. This method is not even usually questioned.

I believe the evidence indicates an alternative approach may be more effective.

Narcolepsy is a neurological disorder resulting in excessive sleepiness and uncontrolled sleeping.  It is caused by a lack of the neurotransmitter Orexin (also known as Hypocretin), which promotes wakefulness.  Less well known is that orexin cells are glucose sensitive and regulate the feeding and metabolic processes of the gastrointestinal tract and pancreas.   Disruption of the orexin system not only results in abberrant sleep behavior- narcoleptics also exhibit eating disorders and obesity at about twice the rate of the normal population.

Those statistics may be explained by a number of recent experiments which show that Narcolepsy results in dysfunction of glucose/insulin metabolism.

Insulin Sensitivity in Narcolepsy and the effect of Sodium Oxybate as measured by a Hyperinsulinemic-Euglycemic Clamp

Donjacour C,Aziz A, Streefland TC, Orereem S, Lammers G, Pihl H    Sleep 2012 Abstract 0801

Introduction: Hypocretin deficiency causes narcolepsy, a condition characterized by excessive daytime sleepiness, cataplexy, and fragmented nocturnal sleep. Co-morbid obesity is present in more than half of narcolepsy patients. While a higher prevalence of the metabolic syndrome and Type 2 Diabetes Mellitus (T2DM) has been reported in narcolepsy, recent studies could not detect differences in insulin sensitivity between patients and controls. However, none of these studies applied the gold standard, i.e. the hyperinsulinemic-euglycemic clamp, to measure insulin sensitivity. Therefore, we performed a study using this gold standard to quantify insulin sensitivity in both narcolepsy patients and individually matched controls. Additionally, we investigated the effect on insulin sensitivity of three months of treatment with sodium oxybate (SXB).
Methods: Nine hypocretin deficient patients with narcolepsy-cataplexy (seven males), and nine sex, age, body mass index, and fat mass matched controls were enrolled. A hyperinsulinemic-euglycemic clamp was performed at baseline (40mU/m2/min insulin infusion for 2 hours to attain a
circulating insulin level of about 40mU/L). In seven patients (five males)a second hyperinsulinemic-euglycemic clamp was performed after three months of treatment with SXB.
Results: Glucose disposal rate per unit serum insulin was significantly higher in narcolepsy patients compared to individually matched controls indicating higher insulin sensitivity in patients. Narcolepsy patients lost a substantial amount of weight (mean of 5.2 kg) after 3 months of treatment with SXB. Moreover, SXB treatment lowered insulin sensitivity in narcolepsy patients to levels comparable to those of control subjects.
Conclusion: Our findings suggest that narcolepsy patients are actually more insulin sensitive than body weight and fat mass matched controls. Therefore, any potential tendency to develop T2DM probably stems from their propensity to grow obese. SXB decreased weight, and normalized insulin sensitivity.

Absence of the hypocretin peptide increases serum insulin without altering blood glucose or serum leptin levels in aged male mice.     

Ramanathan L, Siegel J  Sleep 2013 Abstract 0015

Introduction: We previously reported that both male and female Hcrt deficient mice showed increased body fat, although only the female mice showed increased body weight, compared to gender and genotype matched wildtype (WT) controls. In this study we compared blood glucose and serum leptin and insulin levels in male Hcrt deficient and WT mice. We also analyzed changes in the weight of the brain, heart, liver, spleen, pancreas, kidney, thymus, lungs, testes, bladder and stomach of these mice.
Results: Blood glucose levels were not significantly different between male Hcrt deficient and WT mice. However, male Hcrt deficient mice had significantly higher serum insulin levels compared to WT controls (129%, p= 0.02). Although serum leptin levels were higher in male Hcrt deficient mice compared to WT mice, this difference was not significant. Furthermore, the pancreas was significantly heavier in male Hcrt deficient mice compared to male WT mice. There were no changes in the size of any of the other internal organs studied here.
Conclusion: We conclude that aged male mice lacking the hypocretin peptide have decreased insulin sensitivity. Hence, they require higher insulin levels to maintain normal fasting glucose levels.  

Ingestion of glucose has been shown to increase narcoleptic symptoms.

Sugar induces insulin production. 

More conspicuously-  Narcolepsy symptoms mirror many of the symptoms of hyperinsulinema:

• Temporary muscle weakness

• Brain fog

• Binge eating

• Weight gain.

Many of the symptoms of narcolepsy may actually be effects of hyperinsulinemia caused by orexin depletion.

That mechanism is supported by the discovery that Narcoleptics have many more histamine cells than normal controls.

Hitstamine increases insulin levels.

And another experiment has shown that narcoleptics have significantly more GABA reactivity than controls.

GABA receptor sensitivity increases with insulin load.

Furthermore, an analysis of the specific drugs recommended for Narcolepsy shows that none of them claim to raise orexin levels, yet they all directly or indirectly affect glucose/insulin metabolism.

The pharmocology of these drugs supports this hypothesis. Narcolepsy drugs alter endocrine function. 

Current sleep testing and treatment completely disregards glucose/insulin metabolism. Despite all the studies detailing intricate metabolic involvement in narcolepsy, and widespread endocrine activity of orexin, all the diagnostic parameters are sleep related:  sleep latency and duration, REM onset, etc.

Paradoxically, even those patients who do experience syncope, and initially consult an endocrinologist- will elude diagnosis.  The standard glucose tolerance tests do not detect this activity.

Comprehensive Glucose and Insulin testing and verification of this phenomenon should be the First Priority of narcolepsy research.

The two experiments that have used Euglycemic Clamp Tests show definite abberent activity. But the specific alterations of insulin production, insulin resistance and glucose clearance are not evident from the limited data, and the researchers propose different mechanisms.

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If hyperinsulinemia is present in narcoleptics, it is possible syptoms may be greatly improved using existing protocols and drugs which target endocrine control directly instead of tangentially.

         Rats that have been depleted of insulin self-administer less amphetamine compared with those with normal insulin levels.

The standard treatment for hyperinsulinism is diet restriction and exercise. 

Sugar induces insulin production.  A low carbohydrate diet is very effective in reducing hyperinsulinism.

Low Carb dieting has been shown to improve narcoleptic symptoms.

My personal research (and many others) shows that maintaining a strict ketogenic diet is effective in reducing symptoms, but not completely. It is also restrictive, and rigorous conpliance is tedious. Drugs to reduce insulin levels are also clearly needed for lifelong maintenance.

Metformin is the drug most commonly used to normalize insulin sensitivity in hyperinsulinemic patients.

I have received anecdotal reports that it also reduces sleepiness and lowers weight in narcoleptics.

This drug's safety and efficacy has been documented for decades.  It should be investigated as soon as possible.

These drugs are also well established and show some very promising properties and effects-

Cimetidine blocks histamine-induced insulin secretion.

Amlexanox effectively induces weight loss in test animals.

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It may not be a cure, or even an Orexin replacement, but the data indicates that effective relief of narcolepsy symptoms may be achieved using drugs and methods which correct dietary endocrine function in patients.

In addition, Narcoleptics won't be the only ones to benefit- obese and depressed people also have low orexin levels. Targeted research into narcolepsy treatments has obvious implications for the affective disorders in general.