Link post for Orexin and the Quest for more Waking Hours

A week ago I was skeptical about the prospect of radically reducing human sleep needs. After reading John Boyle’s Cause area: Short-sleeper genes, I decided to research the area more deeply and updated to believe that it’s more likely that we can reduce human sleep needs without significant negative side effects. It might increase risk-taking which has both positive and negative effects. The one friend I have that has short-sleeper genes is a startup founder.

Boyle suggested that one of the best actions to attempt would be using orexin or an orexin agonist as a drug, but that there’s currently a lack of funding for doing so.

Given the way the FDA and EMA work, drugs only get approved when they are able to cure illnesses, with an illness being anything that has an ICD code. According to that notion, people who suffer from having to sleep more than four hours don’t have an illness and thus drugs can’t be approved for that purpose. In practice, this results in the NIH not being interested to fund the research of Ying-Hui, about people who need a lot less sleep and are still well rested, that Boyle discussed.

DEC2-P384R and orexin biology

The DEC2 gene produces prepro-orexin, which is 131 amino acids long. People with the DEC2-P384R mutation produce more prepro-orexin and have a reduced need for sleep. From prepro-orexin our body generates orexin A, which is 33 amino acids long, and orexin B, which is 28 amino acids long. Orexin A is highly conserved and has the same molecular structure in humans, mice, rats, and cows, while human orexin B differs from rodent orexin B. While orexin B doesn’t cross the blood-brain barrier, orexin A does. I didn’t find information on whether or not prepro-orexin passes the barrier, but it likely doesn’t given its size.

According to Uniprot:

Orexin-A binds to both OX1R and OX2R with a high affinity, whereas orexin-B binds only to OX2R with a similar high affinity.

The literature is sometimes unclear when they use the term orexin about whether the author means prepro-orexin, orexin A, and orexin B or a mix of them. Hypocretin is an alternative name in the literature for orexin, hypocretin-1 for orexin A, and hypocretin-1 for orexin B.

Do we get a free lunch?

From an evolutionary perspective, it seems beneficial to have a lower sleep requirement, so we have to ask ourselves why DEC2-P384R didn’t provide a significant enough advantage to spread the mutation to the whole human population.

Energy expenditure hypothesis

In the search for evolutionary disadvantages, I found an article by Dyan Sellayah et al where they say:

Here, we review a fat-burning mechanism that is turned on by the brain hormone orexin during high-caloric food consumption. Remarkably, the same hormone also induces feeding, and its levels correlate with lean body mass in both rodents and humans. Intriguingly, loss of orexin prevents thermogenic energy expenditure while inducing obesity in the face of hypophagia. Thus, orexin is a unique neuropeptide that promotes both feeding and energy expenditure, conferring resistance to weight gain.

Evolutionarily, for most of human history, a mutation that caused someone to eat more while burning their fat reserves for thermogenic energy, instead of using the energy for necessary metabolic processes, was a clear disadvantage.

This makes me hopeful that in our current world, where we have access to as much food as we want, DEC2-P384R comes without clear negative side effects.

Stress hypothesis

The cavefish Astyanax mexicanus has evolved to need 80% less sleep compared to related surface fish, while having a similar lifespan. Astyanax mexicanus have OX2R receptors that are more sensitive, and have an increased blood level of orexin.

A key environmental difference for Astyanax mexicanus is that they live in an environment without predators. This makes them less anxious, and it’s plausible that increasing orexin will make people less anxious and more willing to take risks.

If that’s what comes with reducing human sleep needs, we might be okay with it. Sleeping less, having a stronger drive for action, and willingness to take more risks sounds like a good package in today's environment for most people. It might be negative for individuals with high aggression or low IQ who are more likely to commit crimes if they feel less inhibition.

If we need sleep to deal with the effects of stress, it makes sense for genes that reduce stress to lead to less sleep. This hypothesis would also be supported by some people who need less sleep after meditating a lot, given that meditation is another way to reduce stress.

Orexin and narcolepsy

Lucie Barateau et al write in Treatment Options for Narcolepsy:

Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy and is associated with hypocretin-1 deficiency. On the other hand, in narcolepsy type 2, cerebrospinal fluid hypocretin-1 levels are normal and cataplexy absent.

Given that orexin A (hypocretin-1) passes the blood-brain barrier while orexin B doesn't, it's possible to measure orexin A deficiency in the blood but not measure whether or not someone is orexin B deficient. Narcolepsy type 1 patients are likely both orexin A and orexin B deficient. Narcolepsy type 1 is estimated to have a prevalence of 25 to 50 per 100,000 people according to UpToDate. In a double-blind experiment intranasal orexin A supplementation of patients with Narcolepsy type 1 helped them with having faster reaction times and making fewer errors.

If you are a naive reader, you might expect that we give people with narcolepsy type 1 orexin-A as a supplement because that would be obvious. We don’t. You might expect that someone tried to bring it to market as a drug and ran a clinical trial. They didn’t.

The problem seems to be that the solution is too obvious. The patent office likely decided that the solution would be too obvious to give out a patent for it, and thus the narcoleptic patients are without orexin-A supplementation unless they go through efforts to procure it themselves.

Clinical trials

Instead of giving patients orexin-A, multiple companies recently invested in clinical trials for orexin agonists. An orexin agonist is a substance that binds to the orexin receptors just like orexin does. Unfortunately, when you select a molecule for binding to a certain receptor you are generally choosing molecules that easily bind in general, which often leads to off-target effects where other receptors are also affected.
Scott Alexander's post on how his hospital pharmacy didn’t have any melatonin but only what’s effectively an expensive melatonin agonist is worth reading to understand the problem of how hard it is for unpatented natural substances to exist in our medical system.

Researchers at Takeda got breakthrough therapy status for their oral orexin agonist to treat narcolepsy type 1, but their trial ended prematurely because a safety signal emerged in the trial. The likely hypothesis for the safety signal is that their drug not only binds to the orexin receptors but also has other interactions, which is a common problem when developing artificial agonists instead of the natural substance to which the body is already adapted.

Fortunately, there are more clinical trials underway for orexin agonists for narcolepsy type 1.

Possible actions

We can hope that the clinical trials for orexin agonists find a drug that gets approved for Narcolepsy type 1 patients, and then non-narcoleptics can use that drug off-label.

We could fund studies for orexin-A supplementation with philanthropic money with the hope of both helping Narcolepsy type 1 patients, and using the drug after it got FDA approval off-label to reduce sleep needs in the general population. Given that there’s a market failure because of the inability to patent orexin-A as a treatment, using philanthropic money has justification. This approach has the benefit that orexin-A would be available without patent protection, and thus a lot cheaper to procure.

Daring individuals might buy orexin-A from a nootropics store and experiment themselves. It helped rhesus monkeys to deal better with sleeping less than their normal amount of hours. If you think about it, then I would recommend that you do additional research in addition to what you read from me. This post is very much not medical advice.

The cavefish seem to eat more in an environment with plenty of food than the surface fish and have less stress. We want our farm animals to eat a lot and have less stress. From an animal welfare standpoint, replacing the orexin system of chicken, pigs, or cows with the orexin system of cavefish might help them be happier and be economically beneficial. This might make sense as an EA startup. You get more happy animals and potentially show that reducing sleep needs in a nonhuman species works well enough to motivate us to invest research dollars into reducing human sleep needs.

Invest more into researching the other short sleeper genes that interact with different systems than the orexin system.