Intranasal Orexin/Hypocretin: The Ultimate Uptime Drug?

This cartoon was written before intranasal orexin was
developed, but
the same idea applies:







href="http://www.researchblogging.org/"> alt="Blogging on Peer-Reviewed Research"
src="http://www.researchblogging.org/public/citation_icons/rb2_large_gray.png"
height="50" width="80" class="inset"> title="Provigil.com" href="http://provigil.com/"
rel="tag">Provigil ( title="monograph about modafinil"
href="http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a602016.html"
rel="tag">modafinil) title="A Review of the Effects of Modafinil on Cognition in Schizophrenia"
href="http://schizophreniabulletin.oxfordjournals.org/cgi/content/abstract/33/6/1298">is
thought to act on the orexin system to promote wakefulness.
 Indeed, it has attracted title="Cognitive Enhancers in Academic Doping"
href="http://scienceblogs.com/retrospectacle/2007/12/cognitive_enhancers_in_academi.php">some
attention due to its potential to increase productivity.



Could the same effect -- perhaps greater -- be achieved with direct
administration of orexin?

Background: the terms orexin and hypocretin
both refer to the same entities.  They refer to a pair of
related small peptides that are found in the brains of vertebrates.
 Two labs discovered them simultaneously; each lab came up
with a different name.  The two terms are synonymous.
 I use the term orexin because I think it
sounds better.



This is the link to the Wikipedia entry for href="http://en.wikipedia.org/wiki/Orexin" rel="tag">orexin,
for what it is worth.  



Orexin is produced in the hypothalamus and is distributed widely in the
brain.  It tends to excite the neurons that it interacts with,
leading to wakefulness.



So why not simply take orexin, instead of modafinil?  Orexin,
being a peptide, tends to get digested in the stomach.  It's
like insulin.  So you can't take a pill. 



Dr. Sam A. Deadwyler, and colleagues at Wake Forest and UCLA decided to
find out if intranasal orexin would have a desirable effect.

 

href="http://www.jneurosci.org/cgi/content/abstract/27/52/14239">Systemic
and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of
Sleep Deprivation on Cognitive Performance in Nonhuman Primates

The Journal of Neuroscience, December
26, 2007,
27(52):14239-14247; doi:10.1523/JNEUROSCI.3878-07.2007



Hypocretin-1 (orexin-A) was administered to sleep-deprived
(30–36 h) rhesus monkeys immediately preceding testing on a
multi-image delayed match-to-sample (DMS) short-term memory task. The
DMS task used multiple delays and stimulus images and effectively
measures cognitive defects produced by sleep deprivation (Porrino et
al., 2005). Two methods of administration of orexin-A were tested,
intravenous injections (2.5–10.0 µg/kg, i.v.) and a
novel method developed for nasal delivery via an atomizer spray mist to
the nostrils (dose estimated 1.0 µg/kg). Results showed that
orexin-A delivered via the intravenous and nasal routes significantly
improved performance in sleep-deprived monkeys; however, the nasal
delivery method was significantly more effective than the highest dose
(10 µg/kg) of intravenous orexin-A tested. The improvement in
performance by orexin-A was specific to trials classified as high
versus low cognitive load as determined by performance difficulty under
normal testing conditions. Except for the maximum intravenous dose (10
µg/kg), neither delivery method affected task performance in
alert non-sleep-deprived animals. The improved performance in
sleep-deprived animals was accompanied by orexin-A related alterations
in local cerebral glucose metabolism (CMRglc) in specific brain regions
shown previously to be engaged by the task and impaired by sleep
deprivation (Porrino et al., 2005). Consistent with the differential
effects on performance, nasal delivered orexin-A produced a more
pronounced reversal of sleep deprivation induced changes in brain
metabolic activity (CMRglc) than intravenous orexin-A. These findings
provide strong evidence for the effectiveness of intranasal orexin-A in
alleviating cognitive deficits produced by loss of sleep.

They used both intravenous and intranasal orexin.  Both
worked; intranasal delivery actually was more efficacious.
 Notice that this was done in monkeys, not humans.
 (It is traditional to study a compound on other animals,
before trying it on humans.)  



Of course, it is way to early to know if this would work in people,
whether there would be deleterious effects, or whether there would be
any advantage over modafinil.  



If this works out as I expect, then it will work in people, it will not
have major deleterious effects, and some people will find it works
better than modafinil.  Others will not, since that is how
these things tend to go.  



If this stuff is brought to market, it will be very expensive at first.
 Modafinil will be available in generic form by then, so it
will cost a lot less.  



The really big question: will it really reduce or eliminate the need
for sleep?  This was discussed in an article in href="http://www.wired.com/science/discoveries/news/2007/12/sleep_deprivation">Wired:

"We have these other precedents, and it's
not clear that you can't use orexin A temporarily to reduce sleep,"
said Siegel. "On the other hand, you'd have to be a fool to advocate
taking this and reducing sleep as much as possible."

Sure, some people would try to use it to go without sleep, but it seems
highly unlikely that it would work very well.  Probably a
person could get by with less sleep for a day or two, but then would
become so sleepy that the drug would have no effect.  That
could be dangerous in the short term, if a person tried to exceed
whatever natural limits they had.  It also could be dangerous
in the long run, because chronic sleep deprivation does many bad things
to many body systems.