Dihexa: A Deep Dive on the Synapse Building Nootropic Peptide
I'll be honest. I'm not a huge nootropic guy. When you're hormonally optimized and running peptides, you usually have all the brain function you need. But Dihexa is different. It sits in this perfect middle ground where you feel it working without losing your personality or empathy. Today I want to do a real deep dive on what it is, how it works, and how I actually use it.
Why Dihexa and not other nootropics
I've never tried modafinil. Maybe that makes me a weak biohacker, but I'm okay with that.
For me, life is a marathon. I do consistent work day in and day out, and I don't want a compound that turns me into a robot or strips away social empathy. Some nootropics do that.
Cerebrolysin and Semax are great, but with those you can't always tell if they're working. Dihexa I feel every time. It pushes me without pushing me too far.
What is Dihexa
Dihexa is a synthetic peptide developed over two decades at Washington State University. It's derived from angiotensin IV.
In lab assays it induced new synapse formation at picomolar concentrations, reportedly seven orders of magnitude more potent than BDNF. Big caveat. That was in vitro, not in humans. So don't take that 10-million-times claim and run with it as clinical reality.
What makes Dihexa interesting is that instead of just tweaking neurotransmitter levels, it physically rebuilds synaptic architecture.
The scandal you should know about
In 2013, the Washington State team co-founded M3 Biotechnology, later rebranded as Athira Pharma. They went public in 2020 and raised over $200 million.
They developed ATH-1017, a prodrug of Dihexa for Alzheimer's and Parkinson's trials. In 2021, the CEO was found to have manipulated images in her doctoral dissertation and at least four co-authored papers. Washington State revoked her PhD. Multiple papers were retracted. Athira paid $14 million in settlements for securities fraud and false claims act violations.
This doesn't mean Dihexa doesn't work. But a lot of the early research is now flagged, and no company is going to invest big money getting plain Dihexa approved when they can't patent it.
How Dihexa rewires the brain
Dihexa binds HGF and facilitates dimerization. That activates c-Met tyrosine kinase, which triggers PI3K/AKT signaling and a cascade through MAPK and ERK. The end result is synaptogenesis at picomolar concentrations.
Translation. Dihexa binds a receptor, kicks off a signaling cascade, and your brain starts building new synapses.
Pharmacokinetics
Oral bioavailability is around 38 percent. It crosses the blood-brain barrier via passive transcellular diffusion thanks to engineered lipophilicity.
Here's the interesting part. The half-life is roughly 12.7 days after IV administration in rats. That's extraordinarily long. It reflects metabolic stability and sustained synaptic effects.
What that means for you is there's a cumulative effect with daily dosing, and it takes a while to clear. That's not bad. It just means you probably don't need to take it every day. Two or three times a week works great in my experience.
It also has anti-neuroinflammatory effects. In APP/PS1 mice it reduced IL-1 beta and TNF-alpha, increased IL-10, and decreased astrocyte and microglial activation.
What the studies show
A 2013 study showed 2 mg/kg/day restored Morris water maze performance in cholinergic amnesic rats to the level of unimpaired controls.
Another 2013 study showed 24-month-old rats treated with oral Dihexa performed like young rats. This is one of the papers tied to the data integrity issue, so take it with a grain of salt.
A 2021 independent study confirmed oral Dihexa over three months improved spatial learning, increased neuronal counts, elevated synaptophysin, and reduced neuroinflammation. No integrity concerns with that one.
A 2025 Rowan University study showed Dihexa dose-dependently improved working memory after repeated mild traumatic brain injury. An HGF antagonist blocked the effects. First external confirmation of HGF/c-Met dependence and first evidence of cognitive TBI recovery via this pathway. As someone with a lot of football concussions, that one hits home for me.
The human trials were on the prodrug ATH-1017, not Dihexa itself. Phase 1 looked fine, no serious adverse events, just injection site reactions. The 2022 trial in 77 mild to moderate Alzheimer's patients failed its primary endpoint. The 2024 trial showed no significant benefit either. Athira has now pivoted to a different oral c-Met modulator.
So the prodrug doesn't seem to do what Dihexa itself does. From a pharmaceutical standpoint it might be a dead end.
Dosing
Oral capsules are what I use and recommend. Common doses run 5 to 40 mg. My sweet spot is 10 mg. At 5 mg I notice a little. Past 10 mg I don't need more.
Sublingual runs 10 to 20 mg held under the tongue.
Subcutaneous injection, if you go that route, I'd stay in the 1 to 3 mg range two to three times per week. Oral works great so I don't bother injecting.
Transdermal in DMSO runs 10 to 20 mg per day. I've never done this.
Intranasal runs 2 to 5 mg. Least common.
My protocol is 10 mg oral, Monday, Wednesday, Friday. Or on days I know I have heavy cognitive demand.
Cycling and safety
Run 8 to 12 weeks, then take 2 to 4 weeks off. Same rule of thumb as most peptides.
Dihexa is banned by WADA for competitive athletes, so be aware.
On safety, the HGF/c-Met pathway is implicated in tumorigenesis in lung cancer, glioblastoma, gastric, breast, and liver cancers. Does that mean Dihexa causes cancer? No. A lot of things can theoretically drive cancer pathways. We don't have data showing increased cancer prevalence in users. But that's why you cycle and dose intelligently.
Anecdotal side effects with overuse include vivid dreams, headaches, irritability, anxiety, sleep disruption, and mood swings. That's pretty endemic to all nootropics if you abuse them.
Best use cases
Age-related cognitive decline. If you have a parent showing early memory loss, this is a solid candidate.
TBI recovery. I wouldn't use it alone. Stack it with Cerebrolysin, BPC-157, and TB-500.
Neurodegenerative disease support.
Healthy biohackers who want a cognitive bump for demanding work or a test.
A useful stack tip
If you're running Dihexa Monday, Wednesday, Friday, take Alpha-GPC on the off days. It helps replenish neurotransmitters. Alpha-GPC is great in general. I need to do a whole video on it.
My take
Dihexa is real and it works. I use it 10 mg orally, two or three times a week, and that's plenty. Start low and slow. Don't jump to 40 mg because someone online told you to.
We're probably never getting big clinical data on plain Dihexa. The economics don't support it. So this is going to stay an underground tool that we figure out together through smart experimentation and conversation.
For me it's the perfect middle ground nootropic. Strong enough to feel, gentle enough that I still feel like myself. That's exactly where I want to be.
Full transcript click any paragraph to jump video
Hey everybody, this is Hunter Williams. I hope you're doing amazing wherever you might be in the world. Today, I am going to do a deep dive video on Dihexa. Di Hexa is a nootropic peptide. It is very cool. You guys don't know if you listen to me, but I do like to dabble from time to time. And I will say of all the ones I've tried, actually never have tried modafinil and maybe that makes me a very weak and inexperienced biohacker, but that's okay.
For me, nootropics are not something that I really like to push the gas pedal to for a couple of reasons. One, I don't feel like I need to. And so when you do what I do, you're hormonally optimized. You take peptides. The most part I say I have all the brain function that, um, really desire, which is I'm very blessed and fortunate to have that. But with some of these nootropic compounds, even ones that I've taken that are not really like as far, I have never taken modafinil, that don't push you that hard.
For me, i don´t necessarily always like the feeling. I kind of like to exist in this realm of able to have a lot of critical thought, but then also kind of existing as a normal person, if that makes sense. Meaning that I don't want to take something that is a neutropic that really stimulates my brain to the point of, one, where I become like a robot, or two, I where don t have as much social empathy, which I'm not saying every neutropic does that because some are kind But when it comes to nootropics, I love how I work and what I get to do to work.
And there's a time and place where you can work really, really hard and maybe you need to push it for 12 or 16 hour days. But fortunately for me, kind of like to exist in the form of life is a marathon, not a sprint. And I like doing my work. I'm very good at doing consistent work day in and day out.
over six years. And it definitely has not been a meteoric rise in the least. It's been one of those things that are slow and steady. So not to get off topic, but that is kind of my view around nootropics. However, that being said, I would say dihexa for me is the perfect middle ground. it's not so strong that I feel like I'd lose my personality or I lose who I really am because some noootropic I think can do that. but it's also not so weak. They don't really feel anything from it.
And I will say, although I love CMAX, I loved C-LINK, to me, those are more of kind of like, you can't tell in every case if they're working or not. In some cases they do, but sometimes it just like eh, don' t know how much I got out of that. Now, that being said, they are still very beneficial and there's things that are probably going on that we don t see with Cmax and CELINK. Whereas the Hexa, every time I take it I get a good effect, it doesn't push me too far. And so for me, Dihexa is a really good one. I kind of looked back and I was like, have I done a deep dive on it?
Not anyone that I could have found recently. You know, I've talked about it a lot in other videos, but anyway, that's what we're going to cover today. Just kind to kind go over the background of it. There's a little bit of an interesting story with DiHexa that we'll cover. But I love Di Hexa. It's one that everyone can relatively benefit from. especially as diverse as many people's neurochemistry are. So strap up. That's what we're going to talk about today. Before I go into it, as always, make sure you're signed up for the email list. I have had my Spotify account terminated. Luckily I was able to get it back.
But just know that some of these things, I kind of have to go with the view now that they're temporary, meaning that as much as I can publish and do really well on one platform, which Spotify has been going well since my YouTube got deleted, it probably is all temporary. And I hate to say that, you know, knock on wood, but it's one of those things I just don't know. I could wake up one day and all my content could be gone, at least from the public side of the internet. So that's why the email list is so important because I can stay in touch with you and send out if I do have to go to new places. And I did my best job not to spam you guys.
Just send information either that I'm working on from a content perspective or just other things that come across in my reading that like to share with my audience. So make sure you're signed up for that. And also too, check out the Action Collective. That's my private group. If you want direct access to be able to ask me questions and know that they're going to get answered. Also too the best part of that is there are over 200 other members in there and we have a really good time. We do live calls on Thursday nights. I think you'd enjoy it if you like this stuff. But anyway, without further ado, I'm gonna share my screen and today we're gonna go into Dihexa.
All right, today's gonna be a deep dive on a DiHexa, say that 10 times fast. Let's get into it and start with what is Di Hexa? Basically, it's a synthetic peptide developed over two decades, actually at Washington State University. It was derived from angiotensin force and it stunned neuroscience by inducing new synapses for nation at picomolar concentrations, which were seven orders of magnitude more potent than BDNF in lab assays. Now, I will caveat and say that that was in vitro, not in real persino.
So, When we talk about these things, if it's happening in those things doesn't necessarily mean it is going to have that same effect that BDNF would, like seven times the strength of BdNf to a human. But rather than tweaking neurotransmitter levels, dihexa aims to physically rebuild synaptic architecture, which is what makes it so powerful. And we're going to see kind of what's going on inside the brain today and how that works. So it was discovered in 1998. In 1992, they were able to analyze how it worked at the receptor level. 2001, They identified how to actually get it into a usable form.
And then 2007, 2011, it wasn't engineered for human use or the ability to be used as a compound. Now, here's a little bit of the scandal. So in 2013, the Washington State team co-founded M3 Biotechnology, later rebranded as Athera Pharma. And the company went public in 2020, raising over $200 million, not a chump change. They developed this product called Fosgonamantan or ATH 1017, which was a pro drug of dihexa for Alzheimer's and Parkinson's trials.
So what it was is a prodrug of Dihexa, so you take this and then the body would naturally increase dihexal levels. And in 2021, CEO lean chaos was found to have manipulated images in her doctoral dissertation, at least in atleast four co authored papers. So Washington state revoked her PhD, and multiple papers were retracted or flagged you can actually see this. When I get to the reference and slide. If you look up some of those references you could see in pub that it was actually retract it. And so Athera paid $14 million in settlements for securities fraud and for false claim act violations.
Now, all that to say, it does not change that dihexa actually works, but I did think that was interesting to include, because when we look at this research, a lot of this is gonna be around this, particularly in humans. And you have to understand, no company is going to invest a ton into getting diheexa to become an approved drug, cause it's really just a peptide. So when you look it, the risk to reward of spending a tone of money on taking this to market, to when your not gonna really be able to patent it in a way. And so that's why they made a pro drug, because it would be something they could patent that they were hoping would have the same effect.
But anyway, the best thing to do is to not fake data and fake papers when you're doing that. Let's look at how dihexyl rewires the brain. If you see this, if you watch the video, you'll see the diagram I have here. So it binds HGF, which then facilitates dimerization. Then in the process of doing this it activates C-Met tyrosine kinase. And then that creates this PI3K AKT pathway signaling, which then leads to a cascade via MAPK and ERK.
And ultimately that leads us to synaptogenesis at picomolar concentrations. Lots of scientific data to say when we take dihexa, it's going to bind HEF and then it ends up leading to Synaptogensis. And then again, the 10 million times more potent than BDF claim refers strictly to the molar concentrations, efficiency and vitro, not clinical superiority. But that's kind of the cycle of how dihexyl works in the brain to actually give us therapeutic benefits. So we look at the pharmacokinetics, it has around 38% oral bioavailability.
It does cross the blood brain barrier via passive transcellular diffusion enabled by engineered life illicity. The half-life, and this is where it's interesting with dihexa, the half life is around 13 days, 12.7 days. And so it is an extraordinarily long circulating halflife after IV administration in rats, which reflects metabolic stability and sustained synaptic effects. Now what that means is that one, there's going to be like a cumulative effect if you're taking it every day and also it was going take a while to get out of the body. No, that doesn't necessarily make it bad. It's just something to conscious of.
So maybe you don't need to take it everyday. Like I have found that if you take dihexa two or three times a week, you pretty much get really good benefit. But when we look at it as well, it has anti-neuroinflammatory. So in APP and PS1 mice, reduced interleukin-1-beta, TNF-alpha, increased inter-leucin 10, decreased astrocyte and microglial activation, and confirmed via PI3K inhibition. And so we do get some antiinflammatories benefits specifically in the brain around di-hexap.
Let's look at some of these animal studies. So 2013 dihexate 2 milligrams per kilogram per day restored Morris water maze performance in cholinergic amnesic rats. to the level of unimpaired controls confirming oral bioavailability and pro-cognitive efficacy. In another 2013 study, 24-month-old rats treated with oral dihexa performed like young rats. Again, this is one of the papers though that I believe that author was involved with, so who knows how much of that data is actually accurate.
2021 study independent study Confirmed that oral dihexa for three months improved spatial learning, increased neuronal counts, and elevated synaptophysum and reduced neuroinflammation. And there were no, obviously, integrity concerns with that one. Then we have a 2025 study at Rowan University. Dihexadose-dependently improved working memory after repeated mild traumatic brain injury. An HEF antagonist hinge block the effects in the first external confirmation of HEF and CMED dependence and first evidence of cognitive TBI recovery via
this pathway. And so we do see some bit of dihexa actually helping with recovery from traumatic brain injury, which for me, if you know me is near and dear to me as someone that has had a lot of concussions via playing football. So you can kind of see the route there. There was a phase one These are actually human trials in the ATH 1017, but I did want to include these. And so phase one, we had 88 participants on the pro-drug of dihexa, dose proportional pharmacokinetics, no serious drug related adverse events.
The primary side effect was injection site reaction. So just be aware of that. If you are injecting di hexa, which I don't think you need to do, you can do it, Joony 22 studies 77 mild to moderate Alzheimer's patients, 40 to 70 milligrams per day for six months, failed primary endpoint. So they didn't really get anything out of that one. 2024 study, same thing, no significant benefit. And then 2024 and beyond, the biotech company actually pivoted to another product, which is an oral small molecule HEF modulator,
and that is in phase one testing. last we were able to look that up. And so point being is that it does not seem that the prodrug actually does what dihexa itself actually, does and so from a pharmaceutical perspective, it might be kind of a dead end, least in terms of them trying to get approved as a drug. So let's look at dosing, and I put dosage in the nootropic underground. And so when we look the oral capsules, typically you're going to receive five to 40 milligrams being the most common dose. For me personally, I love 10 milligrams.
Ten milligrams is my perfect sweet spot. Five milligrams, notice a little bit, but beyond 10mg I really don't need any more than that. If you're doing a sublingual 10 to 20 milligrams, obviously got to hold that under your tongue. Then if you do a SubQ injection, if your doing the injection because I know there are companies that sell the Injection form, I would say stay around like the 1 to 3 milligrams 2 to three times per week. You could go higher, but I think given the oral bioavailability relative to obviously injection being 100%, available, I would say in the one to three
milligrams for that and just kind of, you know, use caution because it is going to be stronger. Transdermal in DMSO. I've never done this, but there are transderma versions. You do 10 to 20 milligrams per day. And then obviously lastly, intranasal. If you do it intrasnasal, it does work intransnasally two to five milligrams. This would be the least common. A lot of companies sell a spray. But again, just always take the oral capsules and they work great for me. So I know I inject with the best of. Injecting is no problem for me, but I would say that this, I just do the capsules.
And I like the three times per week. So Monday, Wednesday, Friday is good. Or if you just know you're going to have a cognitive demanding day to do it on those days. Um, and again, you can work your way up from five milligrams to 10 milligrams and then people really want to push it. Uh, if want really feel something, go up to 40 milligrams per day. But Hey, like I said, more conservative when it comes to some of the I would say just to add in the cycling of that, I like eight to 12 weeks. So if you are going to do continuous use, um, use it more as, as needed. I never have continuous used for eight weeks, but I say for continuous, uh, go to age 12, take a two to four week break.
If you really want to stay on it and use. Uh, it is banned by WADA for competitive athletes. Just thought I'd put that in there. But from a cycling perspective, kind of with the rule of thumb of every other peptide, eight to 12 weeks and then two to four weeks off, just to be safe because again, it's not one of those things that we have extensive data around. Now, when we look at safety, the pathway dihecta activates drives tumor genesis and lung cancer, glioblastoma, gastric breast and liver concerns. Does that mean the dihexyl will cause cancer? No, we don't know.
It's kind of like saying BPC-137 can cause cancers. Well, a lot of things can cost cancer. And so when we look at this, can we definitively say it doesn't cause a cancer, no, but it does seem like in any of the data that we have that there was ever a prevalence of cancer but again, when you look pathways, that's why we want to cycle and we wanna be smart about dosing because the possibility exists just like the possibilities exists for anything. Anecdotal side effects, some people have vivid dreams, headaches, irritability, and mounting attention deficits with daily use,
anxiety, sleep disruption, mood swings. And again, I think this is kind of endemic to lots of nootropics. If you overuse them, there is going to be bad side-effects. So just be careful when you're doing noootropic. That's why I'm not the biggest noosropic head, because I like my brain, the way it is, how I operate, so I don't want to necessarily alter that to a point that I can't come back from. And obviously we had that research integrity thing. So now why would we use Ditexel? What are the best use cases? I think obviously for H-related decline.
If you have a parent, it seems like they are starting to lose some of their memories. You kind of see that coming in a lot of cases where they have Alzheimer's. I that would be a really good case for it. There's a lotta clinics that will give it to people. TBI recovery, it definitely would be something that would throw in there. It wouldn't be the first thing or the only thing I would use, but alongside cerebellicin, BPC, TB 500, I will use that to help. Neurodegenerative disease, obviously it can definitely help with that. And then healthy biohackers, this is going to exist. When we look at the therapeutic benefit of helping with neurological disease.
that side of things. I think it definitely can help, but there's stronger things out there. Cerebral Iosin being probably the best one, P21 being a really good one. When we look at the performance side, I don't think we're going to get more of a performance push out of this relative to some of those other things and so healthy biohackers, again, that just want to kind of take up their cognition a little bit. So overall, it's very real. Will we ever have a lot of clinical data on it? I don't think so. And so we could, it'd be nice to say like, Hey, we'd love to see more clinical date on.
I just don' think it's coming. It's one of those things that's going to have to be worked out kind of in the underground of people using it, experimenting, talking about what the doses are, and then hopefully this helps contribute to that. But I think it's, again, like anything, it is a tool and we want to use it intelligently to get the benefit and the intended end result, which in this case, I thing is going to be just more cognitive capacity for people to able to push their work a little bit harder, focus a bit more, and kind of stay on task with the things they are doing. But, i think works great to do all those things.
And those are the references if you want to screenshot that and then just copy and paste them in a Google search to look up. And that is it for slides. As with everything, we want to use it in moderation. It's not something that I would abuse. I will not try to us it to basically kind of hack your way around mental performance. But hey, if you have a test coming up or you something you really need to be locked in for, you can definitely use.
to get to the point of abuse. I know just mechanistically and strength-wise, it's not going to be something as strong as modafinil, but for me, I feel more comfortable doing dihexa on an infrequent basis to kind of use it when I need it for performance, rather than pushing modaffinils, to which I'm going have to have a protocol of helping because I am pushing neurogenesis so hard sometimes and synaptogenesis, then I have have the protocol to help with recovery. I will add this in just as a little side note.
If you're going to do dihexa, say you were doing on that three day a week schedule, Monday, Wednesday, Friday, I like using AlphaGPC in between those days just to help replenish neurotransmitters. So on the off days, you could take it on days two, but on offdays, use some Alpha GPC to replenished neurotranmiters. And I think Alpha-GP is just great to take in general. It's something that actually, now that I've think about it, uh, need to work on a video on. That's kind of my thoughts around it. But I love di-hex-a. Again, my only thing would just be Make sure you're doing the right dose.
Don't jump to 40 milligrams a day because the people out there will tell you to do that. I would be with the opinion, start, you know, low and slow. And then if you want to work your way up to four milligrams, that's totally fine to. Do I don't see any safety concerns around that, but be intelligent about it, make sure your cycling it. So that's for this one. Just in closing, I want you guys to know I am so grateful for the support I've been getting from everyone out there. You know, censorship seems to be on the rise again. Who knows one day again, and I hope this doesn't happen, but I just kind of have realized now I have to go in understanding that there could be a time
to which my content will get wiped from the internet and that is okay. I'm totally fine with that because I chose to exist in this world. But I'd just say that to make sure you're on that email list because it's not fun when you are out making content and it gets deleted. But that being said, thank you guys so much. All the support I get makes this so worth doing. And I love what I do and to get to do this every day. But whatever shape or form or fashion it is that you support me, using my code at places, being in my private group, be on the email list, and even just sharing this with friends and family that think it will help, that goes so further than you know, because this will really be one of those
things that gets driven by the community. It's not going to be driven algorithms and big media, big pharma and things like that. I really will be a grassroots movement. Thank you guys and I will see you in the next one. Peace.
