The patent office likely decided that the solution would be too obvious to give out a patent for it
This isn't an orexin-specific decision. Human genes and proteins can't be patented under EU and US patent law.
I remember Scott writing about MIT patenting melatonin some time ago. Was that before the laws changed and now such a patent wouldn't be given out anymore?
From Scott's article:
EDIT: Commenters, including a patent lawyer, have filled in the rest of the story. Because melatonin is a natural hormone and not an invention, patents can only cover specific uses of it. The MIT patent covered the proper way to use it for sleep; a broader patent might not have been granted. The patent probably guided supplement companies, but expired about five years ago. It’s now legal to produce melatonin 0.3 mg pills, but people are so used to higher doses that few people do.
So it seems possible that orexin could be patented for use in staying awake (or sleeping), which I had not considered, and which is perhaps what you meant when you wrote this? If so, that would be some helpful nuance to add to your OP as I didn't know enough about patent law going in to make this distinction, and thought you were talking about patenting orexin the protein, as opposed to the specific use.
I do speak about the patent after the paragraph of using orexin A for narcolpesy 1, so I don't see that I claimed patenting orexin as such. Besides that use case, registering a patent for using it for depression might be possible as well. Having a new depression meditation that uses a different pathway than the existing ones might plausibly be a drug that produces billions in revenue per year.
After reading https://www.reddit.com/r/Peptides/ I do think that there might be a longer post written about the general topic of medical use of peptides.
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.
Directed evolution of synthetic ligands is my research area. We can and do select for specificity as well as sensitivity.
It's easier than you might think to select against "good general binders." If a ligand has high affinity to a wide range of molecules, then you can use any of a wide range of molecules in your negative selection.
What's harder is to select for specificity to just one of two structurally similar binding sites.
It's been more than a decade since I was at university, so it's plausible that I'm not up to date anymore on how ligands get chosen.
Is the claim that you are making that ligands that are chosen as drug candidates these days generally don't bind anything off-target?
No :) I’m saying that the epitope the ligand binds may have bioactive analogs on other proteins in sites accessible to the ligand. This is where off-target binding mostly comes from, and it’s hard to prevent.
Contrast this with a ligand being good at “binding things in general,” ie without regard to structure. This problem is relatively easy to prevent.
I hate to be the bearer of bad news, but the methodology in the study you linked is just terrible.
99% of candidate gene studies do not replicate, and the first study you link uses an extremely error-prone P < 0.05 threshold to determine that orexin has an effect.
It may still have an effect, but there's no way to really know this without some kind of large sample GWAS.
The proper way to do this would be to get research access to a large genetic database like 23&Me or UK BioBank and pair that data with info from sleep trackers like Apple Watch, FitBit, or other devices to see which genes are involved in sleep duration and how large the effect of each is.
Depending on the sparsity of the trait, you'd probably need somewhere between 100k - 1 million genotype-phenotype pairs to make a good predictor.
Lastly, in the "Possible Actions" section you should include embryo selection. Genes obviously play some role in sleep needs. If at least some of them have no relevant downsides, selecting for those genes in embryos would probably be quite cost-effective. In fact, you could further reduce the odds of any unintended side-effects by selecting not just for shorter required sleep duration, but also for longer quality-adjusted lifespan.
1When doing gene studies if you look at all genes and see which one's have P < 0.05, that gets you a lot of false positives. That's however not what they did in the linked paper.
The linked paper looks at one gene because previous papers identified that gene as being significant in humans. The paper says that the gene has significance for sleep in mice.
The argument doesn't rest on a single experiment. I agree that it would be desirable to have 23&Me cooperate with Apple or Google to find genes that affect the metrics that the Apple watch / Fitbit measures. That's helpful to have a good overview of all the mutations that affect sleep length.
Lastly, in the "Possible Actions" section you should include embryo selection.
Yes, that's a valid action. I was thinking about actions that actually result push the field forward. You could have benefits for the child from such embryo selection but I wouldn't expect it to lead to knowledge generation.
Can you link the earlier studies showing the significance of BHLHE41 in humans? When I Google it all I find are other candidate gene studies with small sample sizes.
https://www.science.org/doi/abs/10.1126/science.1174443 seems to be the first paper. It does have a small sample size and thus is only able to produce candidates, but it results in the later paper not randomly searching over all possible gene mutations.
My main point is that there are papers that made independent observations and thus arguments that a single paper doesn't demonstrate the effect doesn't hold. I didn't copy the exact minute numbers that the EA cause report had because I was unsure about the exactness of the data.
I'm not sure if you have read the story of 5HTTLPR and all the independent studies which found it to have an effect, but if you haven't you should.
In the case of orexin, my argument doesn't just rest on the DEC2 gene.
The experiments that improved performance in sleep-deprived rhesus monkeys happened before the discovery of the link between the DEC2 mutation and orexin.
The observations in Astyanax mexicanus seem independent from my perspective. Attempts to make Astyanax mexicanus a model organism aren't driven by sleep researchers but because it's interesting for studying evolution.
Orexin deficiency causing Narcolepsy type 1 is independent of any findings about the DEC2 gene as well.
As far as the linked post of Scott goes, it says nothing about experiments on animals other than humans. Gene knockout studies in mice and Drosophila seem to me like a pretty good way to measure the influence of a gene.
Orexin is a signal about energy metabolism. Unless the signaling system itself is broken (e.g. narcolepsy type 1, caused by autoimmune destruction of orexin-producing neurons), it's better to fix the underlying reality the signals point to than to falsify the signals.
My sleep got noticeably more efficient when I started supplementing glycine. A key function of sleep appears to be clearing reactive oxygen species that accumulate during wakefulness, and glycine is rate-limiting for glutathione, the main antioxidant that does that clearing.
Most people on modern diets don't get enough glycine; we can make ~3g/day but can use 10g+, because in the ancestral environment we ate much more connective tissue or broth therefrom (see Balancing Methionine and Glycine in Foods). Glycine is both important for repair processes and triggers NMDA receptors to drop core temperature, which smooths the path to sleep.
I learned much of the info here from Amber O'Hearn's 2024 paper, Signals of energy availability in sleep: consequences of a fat-based metabolism.
ETA: I wrote this up in more detail here.
Unless the signaling system itself is broken (e.g. narcolepsy type 1, caused by autoimmune destruction of orexin-producing neurons)
"Broken" depends a lot on the perspective. How do we decide whether the person with short sleeper genes that sleeps four hours per day is more or less "broken" than the person who sleeps eight hours?
Why are the evolutionary pressures in the dark caves where blind Astyanax mexicanus lives structured in a way that in each separate cave that don't exchange individuals the all lead to short sleeping genes? If the key function of sleep is about reducing reactive oxygen species, why would the blind cavefish need less of that, so that the evolutionary pressures are so different?
Edit: Having looked at it a bit more, Astyanax mexicanus does seem to have increased glutathione production, so maybe increasing glutathione production is important to move in the reaction of needing less sleep.
My sleep got noticeably more efficient when I started supplementing glycine.
Picking Glycine in particular as supplementation target is interesting. I think most people who "supplement glycine" probably do it via collagen supplements. Do you believe hydroxyprolyl-glycine / prolyl-hydroxyproline not to be valuable?
How do we decide whether the person with short sleeper genes that sleeps four hours per day is more or less "broken" than the person who sleeps eight hours?
ROS clearance, mitochondrial health, and more generally whether recovery tasks that rely on sleep are happening or not.
My impression is that they're not similarly bottlenecks in people who consume enough protein from animal sources; if someone not on anabolic steroids is consuming at least 0.8g of protein per pound of ideal bodyweight, mostly from animal sources, most amino acids will not be bottlenecks, and glycine is unusual for being an exception, as is cysteine specifically when sick.
Just because hydroxyprolyl-glycine and prolyl-hydroxyproline might not provide necessary building blocks doesn't mean they have no effects. Both get released when collagen breaks down. Fibroblasts seem to take them as a signal that they should repair collagen.
Given that your reasoning is that paleo-people essentially supplemented collagen by eating more connective tissue, this would suggest that the normal person gets less signals that their Fibroblasts should repair collagen than paleo-people did.
As far as I understand the standard mainstream idea about how much we need of each amino acid comes from looking at milk. You expect milk to have an amino acid distribution that's optimized for what's needed. Do you have an idea why milk doesn't have more glycine that it has? Do you believe that humans that are older than three years need more glycine?
When Chris Masterjohn says "3-5 grams of glycine before a meal helps stabilize blood sugar" I'm not sure that's great. If you take a bit of glucose before a meal you get a bit of an insulin spike that helps stabilize the blood sugar from the meal. While good timing with effects like this might manage your insulin well, general nutrition advise is to reduce foods that cause direct insulin spikes. This is especially bad if you take the glycine directly before bed without a meal which seems to be what's suggested for the sleep benefits that he talks about.
I can't find good evidence that glutathione production for a healthy person with an average diet is bottlenecked by glycine availability.
I agree strongly that wording like "helps stabilize blood sugar" often reflects a totally backwards view of glucose management that implies that energy is a burden to be managed.
The evidence I’ve been able to find on those dipeptides is only that they serve a signaling function, not that we are rate limited on their components. So unless consuming collagen directly generates a signal that isn’t screened off by digestion, or we’re rate limited but haven’t demonstrated it yet, I don’t see the mechanism for dietary proline to matter on the margin like glycine does.
Milk is optimized for rapid growth, which is generally not what adults are doing.
So unless consuming collagen directly generates a signal that isn’t screened off by digestion
This is the read of the evidence that Gemini has.
Hydroxyprolyl-glycine and prolyl-hydroxyproline from supplements clearly pass through digestion and circulate in the blood. In cell and tissue culture we observe that they seem to have a signaling function. I think we still lack the exact pathway through which this happens, but the story is quite strong that this is how collagen peptides achieve their result to increase collagen production.
I looked into the dipeptide signaling more carefully. Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine activate fibroblasts on collagen gel in vitro, but dietary collagen seems unlikely to be enough to matter systemically. Fibroblast activation in vitro was reported at about 200 nmol/mL for linear Pro-Hyp, and a more potent cyclic form at 7 nmol/mL. After taking collagen orally, human plasma reaches about 6-33 nmol/mL of hydroxyproline peptides, most of which is some form of Pro-Hyp, while cyclic Pro-Hyp alone reaches only about 0.2 nmol/mL.
Gut effects are more mechanistically plausible than systemic fibroblast signaling, since collagen peptides hit the gut first before being diluted into the full blood volume.
One human exercise-GI study was null on permeability and injury markers, though it reported a suggestive attenuation of post-exercise LPS for the collagen-treated group.
Animal and cell studies are mixed:
- Caco-2 cell monolayers: collagen peptides (especially low molecular weight fraction) attenuated TNF-alpha-induced barrier dysfunction by protecting tight junction proteins ZO-1 and occludin
- Acetic acid-induced colitis in rats: bovine collagen peptides reduced disease activity and histologic damage, restored ZO-1 expression, and improved colon mucosal architecture, consistent with improved barrier integrity
- DSS-induced colitis in mice: walleye pollock collagen peptides worsened colitis, kept tight junction proteins low, increased pro-inflammatory M1 macrophage polarization, and shifted gut microbiota toward inflammation-promoting bacteria
The main good argument for collagen over pure glycine is a heuristic argument that favors whole foods over extracts since just because we don't know about a cofactor doesn't mean it isn't helpful.
There seems to be a lot that's confusing about collagen. I'm thinking about writing a post going deeper into it in the future.
There are five separate things you could eat: Full connective tissue (including collagen and hyaluronic acid) Full collagen as it appear in food, Gelatin (which is shorter collagen that you get by heating collagen), hydrolyzed collagen and straight glycine.
Even when it's not clear to me how hyaluronic acid is bioavailable, as a supplement it seems to have benefits against wrinkles, so somehow it does something.
After pure glycine hydrolyzed collagen seems to be the farthest away from whole foods. Given the report of glycine helping with blood glycose management by spiking insulin, you probably don't want to ingest 3 gram of glycine before sleeping without anything else. Spiking your insulin levels while consuming no carbohydrates at the same time, seems to be unwise because you don't want to develop diabetes. I would expect hydrolyzed collagen to have a similar insulin spike given that it also has a lot of free glycine.
Hydrolyzed collagen does contain more hydroxyprolyl-glycine and prolyl-hydroxyproline than you would get by normal digestion of gelatin or full collagen.
When it comes to collagen production it's also worth thinking about what we actually want. A core problem of normal aging is that you get accumulation of advanced glycation end-products (AGEs) in collagen. This is crosslinks between collagen that make the collagen more brittle. Ideally, you have macrophages eat the collagen that's contaminated with AGEs and then have the body produce new collagen to replace it. Under normal conditions you this process doesn't work well and you have more and more AGE accumulation over time in most collective tissue in humans and this drives a lot of effects of skin aging.
The whole business of breaking down collagen and recreating it does look pretty inflammatory but inflammation is complex and has a lot of complex interacting elements.
When it comes to the numbers you cited the tissue study was within an order of magnitude of what's available in blood. I would expect that in vivo, there are other regulatory factors that can move the point so, that's enough to have some effect.
The in vitro activation thresholds range from 6-35x the plasma concentrations I cited; 'within an order of magnitude' is a stretch. The rest of this feels too handwavy to respond to, but I'll look at your post going deeper if/when it's available.
Yes, I think in addition to the post about hyaluronan I will write another 2-3 posts in the space of bone broth and it's contents.
This is good but I'd want to see deeper dives into why this wouldn't have been selected for. Could it plausibly really just be a fat-burning thing? Why wouldn't that have been selected for by, say, agricultural humanity? (And why wouldn't this metabolic parameter be modulated adaptively/physiologically?) Does this mess with subtle neural processes with effects that researchers don't know how to measure, e.g. in a way that affects peak intelligence?
Maybe another reason why it might not have been such a great fitness advantage is that activity was effectively constrained by daylight availability?
1I think that calorie needs did matter to agricultural humanity. When there wasn't enough food, people could starve in winter.
I spoke about two hypotheses in my post, fat-burning is just one of them.
The cavefish are interesting because they exist in an environment that actually has strong evolutionary pressure for shorter sleep. They can mate with surface fish, so without any evolutionary pressure, the differences between them wouldn't be sustained. There are also multiple caves that all have evolved shorter sleep.
And why wouldn't this metabolic parameter be modulated adaptively/physiologically?
Parameters don't evolve directly. Evolution is about whether or not a given mutation is advantageous or isn't.
2Parameters don't evolve directly. Evolution is about whether or not a given mutation is advantageous or isn't.
Yeah... but I'm saying, why wasn't this modulated physiologically? Lots of stuff is modulated physiologically. Why wouldn't it be modulated by how much food there's been recently?
Reducing the amount of orexin in the body might be very well the way it's modulated physiologically. Plenty of animals hibernate in the winter when they sleep more and eat less.
Because evolution didn't had the time to select for the mutations that would result in that outcome.
Ok now I think you just didn't get what I mean by that. I mean how a bacterium will make lactase when there's lactose, but won't make lactose when there isn't lactose. That's a physiological adaptation as opposed to a genetic adaptation. It's of course mediated by genetically programmed mechanisms, but the variation is mediated by physiological changes, not by naturally selected changes in a gene pool. I'm asking why orexin wouldn't be physiologically adaptive to the amount of food that's generally around.
I mean how a bacterium will make lactase when there's lactose, but won't make lactose when there isn't lactose.
It's quite easy to have a receptor protein that binds to lactose and then leads to a protein being expressed that turns lactose into lactase.
"amount of available food in the environment" is not as simple to measure inside of a cell and as a result, the regulation is much more complex.
I'm asking why orexin wouldn't be physiologically adaptive to the amount of food that's generally around.
That assumes that orexin is independent of food that's around, which clearly isn't true. Fasting increases orexin levels, it's just that chronic food restriction that doesn't change it.
Hm. So orexin is increased initially during a fast, and also when eating high-caloric food? That's weird. Do people who eat high-caloric food need less sleep?
Modafinil is a wakefulness promoter, used as nootropic drug, and has a yet unknown mechanism of action linked to the orexinergic system. Since I've started using it (though confounded with a million other factors) my sleeping levels have roughly decreased from 8 to 6 hours a night, with a corresponding drop in stress - though to be fair I also just discovered the link while reading this. Its other side effects, higher body heat and (though n=1) risk tolerance, line up with how you describe orexin as functioning. Apparently, the patent on it is [expiring soon](https://www.pharmacompass.com/patent-expiry-expiration/modafinil), and enforcement of it is already anemic enough to make descheduling it a distinct possibility.
There are two plausible ways to cut sleep duration without harming cognition: increasing the proportion of slow wave sleep that is spent in deep sleep and reducing REM sleep.
Slow wave sleep is needed for synaptic homeostasis (e.g. see https://www.sciencedirect.com/science/article/abs/pii/S1087079205000420). There are evolutionary trade-offs between time spent awake, time spent in light sleep, and time spent in deep sleep. Deep sleep is more restorative than light sleep but an animal is more likely to be awakened from predators in deep sleep. Humans sleep less than other primates but spend more time in deep sleep than other primates - maybe because our ancestors took turns to stay awake and watch for predators at night?
I’m not so sure what the function of REM sleep is. Maybe something something emotion learning something something? There are cases of people on antidepressants going months with no REM sleep. There are also cases of people on antidepressants who say they have no emotions so I doubt that it’s possible to cut REM sleep without side effects.
>Function of REM sleep
https://en.wikipedia.org/wiki/Rapid_eye_movement_sleep#Deprivation_effects
I had a Zeo sleep monitor and I noticed that I had more REM sleep when doing hard intellectual work or deliberate practice, or after emotionally intense experiences. I had more deep sleep when exercising hard e.g. sprints or resistance training. This suggests to me that these forms of sleep are respectively associated with learning and body repair.
I also notice that I can learn a lot faster when I have naps and/or ample sleep. And that I recover from hard exercise more quickly.
OK this is all a bit uncertain but not just vacuous speculation.
I would like to see some evidence that orexin does not detract from these alleged effects before using it. Edit - the EA article does provide some evidence for this.
Slow wave sleep is needed for synaptic homeostasis (e.g. see https://www.sciencedirect.com/science/article/abs/pii/S1087079205000420).
The linked article speaks about a hypothesis and the abstract does not use language indicating certainty. In its text, it speaks about how the hypothesis might be validated which is basically an admission that it's not validated.
Deep sleep and REM sleep are not the only sleep phases. We spent half of our sleep in light sleep.
For completeness, I would add another (more general) Possible action:
develop a system that is able to investigate, develop and provide such cheap (probably not-patentable) treatments, therapies or improvements in general that are currently not pursued because they are not expected to be profitable.
(I know, much easier said that done!)
We want our farm animals to eat a lot...
What we "want" is that farm animals grow fast and big, not that they eat a lot. Actually we want them to eat the least possible and grow fast and big.
Ok so modulo @GeneSmith's comments about this gene potentially being red herring, if there were a genetic basis to this, we'd expect to see prevalance of this trait increase due to genetic drift and removal of the selection pressure right?
I don't have a good sense of how quickly we'd expect to be able to detect those population level differences with the rate at which calories have become more available and the rate of growth of the variant.
Figure 7 in @guzey's post shows that it's directionally been increasing but a lot has changed about our environments and lifestyles so it doesn't rule out that maybe people are in-fact less pre-disposed to sleep but something else is increasing it.
https://www.lesswrong.com/posts/HvcZmKS43SLCbJvRb/theses-on-sleep
Since the matter at hand is a genetic basis that could flip a switch to needing "a lot less sleep" we should still expect to see the variance in sleep duration increase in the population even if the mean is increasing. I have no idea what the data says about that though.
I don't see why genetic drift would increase this particular mutation. On average I expect genetic drift to destroy the body's ability to produce substances and not increase their production of them.
If the selection pressure is due to certain risk-taking behavior, it's not clear that we see a removal of selection pressure. In humans, we certainly don't have an environment which is similar to those cavefish as far as the selection pressures go.
I did wonder whether one reason it might be hard to commercialise orexins was because, being peptides, delivery would be difficult.
But, apparently not, nasal spray works just fine …
Aw man, I was wondering about that Takeda trial since it was supposed to report results a few months ago. I didn't see it was canceled due to safety problems!
I wonder if those are due to off-target or on-target effects. The latter would be quite disappointing.
I am currently 18-years-old and was diagnosized as type one narcoleptic, suspectedly from the Pandremix influenza vaccine, as 11-years-old.
Good things:
- Small compensation from Finnish government
- Introduced me to stimulants (metylphenidate)
- Superior lucid and subconscious dreaming skill
- LSD will be very interesting when I try next week
- Awoke huge genius EG reading textbooks for fun
- Uberman is feasible
- Drug addiction is harder
- Can remember things not experienced in this world
- Aella is relatable
- Deep philosophy is intuitive
- Mathemathics and computer science is easy
Neutral things:
- Facial cataplexy
- Minor risk of injury from other cataplexy
- Would like to try lisdexamphetamine
- Mild autism and edginess
- Decreased sadism
Sad things:
- Compensation is not serious
- Narcoleptic lifestyle => lenghtended lyceum studies + forgetting curve => competition on the Gauss-curve for top-university spot harder
- Masturbation addiction is easy
- OCD is easy
- Scizophrenia is always creepingly easy
I do not want to ever lose my narcolpesy because makes a part of my consciousness.
I am very open to all possible suggestions.
Aella is relatable
I would expect that Aella is relatable to many people and don't see a reason why narcolepsy would have a big effect here.
Deep philosophy is intuitive
Why do you believe that narcolepsy has an effect here?
Mathemathics and computer science is easy
Why do you believe that narcolepsy makes computer science easier for you?
Uberman is feasible
I'm not aware of anyone doing Uberman for more than a year. A decade ago I wrote https://skeptics.stackexchange.com/a/1007/196 and since then no other case came to my attention.
I do not want to ever lose my narcolpesy because makes a part of my consciousness.
Orexin A supplementation might mean that you can choose not to have it for a few days. If you don't like the changed state, you could easily stop taking the supplement.
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:
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:
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:
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.