Provigil (modafinil) is
thought to act on the orexin system to promote wakefulness.
Indeed, it has attracted 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 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.
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 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.
Brain & Behavior
Comments
Great post. Typo in your title: It reads Oxerin, but should read Orexin.
Posted by: Jerry | December 30, 2007 1:16 PM
Thanks. Corrected.
Posted by: Joseph j7uy5 | December 30, 2007 5:25 PM
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.
Interesting post! Not only would the physiology be adversely effected but I have heard of studies that draw parameters on how long it takes without REM sleep to go psychotic! Whatever drugs they come up with, I think it is wise to try to stick as closely to the old deal of one day and one night's sleep.
Dave Briggs :~)
Posted by: Dave Briggs | December 31, 2007 11:53 AM
Fascinating. I don't think the need for sleep would ever be eliminated by a chemical, to me the question seems to be: will the drug enhance waking action and thought? While the military (and World of Warcraft players) might be interested in the first one, 90% of people are more concerned with the second.
Posted by: Shelley Batts | January 3, 2008 12:59 PM
reat post about kanser. Typo in your title: It reads Oxerin, but should read Orexin.
Posted by: kanser | March 30, 2008 10:01 AM