36 replies to this topic

[pi-]

I'm trying to uncover how dihexa works.

 

View on Vimeo.

^ Inventor (Harding) gives a talk:

• AngioTensin IV agonises AT4 receptor
• causes allosteric modulation of HGF/c-MET system

Basically scientists found that agonising the AT4 receptor improves memory, and Harding&Wright managed to find a small molecule agonist (dihexa) capable of crossing the brain blood barrier (BBB).

 

But it would be nice to know how agonising AT4 improves memory.

 

The angiotensin IV/AT4 receptor <-- 10 year old paper that says "although we don't know how it works, here are three hypotheses", namely:

1. acting as potent inhibitors of IRAP, they may prolong the action of endogenous promnestic peptides
2. they may modulate glucose uptake by modulating trafficking of GLUT4;
3. IRAP may act as a receptor, transducing the signal initiated by ligand binding to its C-terminal domain to the intracellular domain that interacts with several cytoplasmic proteins.

What progress has been made since then? Is the mechanism of action known yet? Since that Harding video says "causes allosteric modulation of HGF/c-MET system" does this mean that these hypotheses have been superseded?

 

Also, I can't find any discussion about the risks.  If I understand correctly, there is some risk of cancer.

 

I will update this thread as I research the subject. If anyone can accelerate my progress, I am most grateful!

 

π

Edited by pi-, 03 September 2014 - 11:23 PM.

[Metagene]

pi do you have a working link for the video above? Impeccable timing btw.

 

The pro-cognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on 

activation of the hepatocyte growth factor/c-Met system 

 

http://jpet.aspetjou...5.full.pdf html

 

"Dihexa and Nle1-AngIV Act Synergistically with HGF to Augment c-Met Signaling and HGF-dependent Cellular Activity.The notion that Dihexa and Nle1 -AngIV allosterically activate HGF predicts that these analogs should potentiate HGF’s ability to activate its receptor and subsequent cellular responses. To evaluate this idea HEK-293 cells, which express c-Met, were stimulated with threshold levels of HGF in the presence of Dihexa and Nle1-AngIV and the impact on c-Met activation (phosphorylation) was accessed (Figure 2A-D). . While Dihexa at 10-10 M and 10-12 M alone did not  activate c-Met, Dihexa at both concentrations markedly augmented the capacity  activate c-Met, Dihexa at both concentrations markedly augmented the capacity of HGF at 1.25 ng/ml and 2.5 ng/ml to activate c-Met (Figure 2A and B). . Similarly these 

concentrations of Nle1-AngIV potentiated the ability of 1.25ng/ml and 2.5 ng/ml of HGF to activate c-Met (Figure 2A and B).-AngIV potentiated the ability of 1.25ng/ml and 2.5 ng/ml of HGF to 

activate c-Met (Figure 2C and D). However unlike Dihexa, Nle1-AngIV alone at concentrations of 10-10 M and 10-12 M was capable of activating c-Met, perhaps suggesting an even higher 

affinity for HGF than Dihexa."   

 

 

 

[Bateau]

Working link for video:

View on Vimeo.

[pi-]

Thanks MetaGene, surprised I can't locate that paper in PubMed or LibGen.

 

I've also found (2013) Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents which puts Dihexa through its paces.

 

Below I pull out interesting bits from the paper. Some of it goes over my head. It doesn't seem to indicate clearly the dosage and dosing pattern for optimal synaptogenesis. It looks as though a steady influx over a short period of time (a few days?) prompts new synapses to form. It doesn't seem to investigate the maximum effective dose.  i.e. There is probably some dose level where HGF receptors are getting fully agonised by dihexa and synaptogenesis peaks. I can't find that info.

 

As regards risks, it looks as though one would need to investigate the HGF/c-Met pathway.

 

π

 

- - - - - - -

Introduction

Multiple studies have documented the ability of angiotensin IV (AngIV) and several AngIV analogs to facilitate long-term potentiation, learning, and memory consolidation (Braszko et al., 1988; Wright et al., 1999; Kramar et al., 2001; Lee et al., 2004); increase cerebral blood flow (Kramar et al., 1997); and provide neuroprotection (Faure et al., 2006). [...]

 

[AngioTensin IV agonises AngIV receptor which activates HGF/c-Met pathway.]

 

Dihexa Has a Long Circulating Half-Life

To begin to evaluate the potential clinical utility of dihexa, adult male Sprague-Dawley rats were administered 10 mg/kg dihexa intravenously and in-vivo pharmacokinetics were determined. An example of the resulting plasma concentration/time profile is shown in Supplemental Fig. 2. Dihexa exhibited rapidly decreasing plasma levels from 0 to 4 hours, suggesting that both distribution and elimination occurred during this period. After 4 hours, the rate of clearance declined and plasma levels became more stable, exhibiting a relatively linear rate of decline, suggesting a phase of pure elimination from 4 to 120 hours.

[...]

Dihexa Exhibits Procognitive Activity

The essential test of the success of the structural modifications incorporated into dihexa was whether it possessed procognitive activity like its parent compound Nle¹- AngIV. Therefore, dihexa’s ability to reverse scopolamine-dependent deficits in the water maze performance was established. The initial study, which was simply tasked with verifying the procognitive activity of dihexa, entailed the direct brain delivery of dihexa via an i.c.v. cannula. The data presented in Fig. 3A confirm our expectation that dihexa would retain biologic activity. Both the low- and high-dose groups of dihexa yielded significantly improved performance when compared with the scopolamine group from day 2 of testing on (P < 0.001). The high-dose group was indistinguishable from the vehicle control group at all testing days (P > 0.05).

 

Since the ultimate goal of the project was to produce a clinically relevant molecule that could be delivered peripherally but still exhibit procognitive/antidementia activity, the effectiveness of both the intraperitoneal and oral delivery routes of dihexa administration were determined using the scopolamine model. As can be seen in Fig. 3, B and C, both delivery methods yielded the anticipated biologic activity. Furthermore, both studies indicated a clear dose-response relationship between the dose of dihexa and water maze performance. The high doses of each method of delivery (i.p. = 0.5 mg/kg per day; oral = 2.0 mg/kg per day) produced performances that were significantly improved over that seen in the scopolamine groups (P < 0.001) and indistinguishable from vehicle controls (P > 0.05).

Probe trials on day 9 were again used to evaluate the strength and persistence of the learned task. As can been seen in Fig. 4, A, B, and C, dihexa at its highest dose significantly (P < 0.001) increased the time spent in the target quadrant compared with the scopolamine-impaired groups, regardless of the delivery method used and was not different from nonscopolamine-treated controls (P > 0.05). In each case where multiple doses of dihexa were used, the probe trial data yielded a dose-response relationship similar to that observed for escape latencies.

[...]

Dihexa Induces Spinogenesis in Cultured Hippocampal Neurons

Recently, the procognitive effects of Nle¹-AngIV, the parent compound of dihexa, and several C-terminal–truncated analogs have been correlated with their ability to induce dendritic spine formation and the establishment of new synapses (Benoist et al., 2011). As such, the influence of dihexa on spinogenesis and synaptogenesis in high-density mRFP-β-actin–transfected rat hippocampal neuronal cultures was evaluated. Actin-enriched spines increased in number in response to both dihexa (Fig. 6, B and D) and Nle¹-AngIV (Fig. 6, C and D) following 5 days of treatment at 10⁻¹² M concentration that started on the seventh day in vitro (DIV7). The results revealed a near 3-fold increase in the number of spines stimulated by dihexa and a greater than 2-fold increase for Nle¹-AngIV. [...]

 

The i.c.v. water maze data with dihexa indicate a modest but significant improvement in spatial learning performance even on the first day of testing, thus suggesting that the underlying mechanism responsible for the behavior must be rapidly engaged. Therefore, the ability of both dihexa and Nle¹-AngIV to promote spinogenesis was assessed following an acute 30-minute application on the final day of culturing (Fig. 6E). The acute 30-minute application of dihexa and Nle¹-AngIV, on the 12th day in vitro (DIV12), reveals a significant increase in spines compared with 30-minute vehicle-treated neurons (dihexa mean spine numbers per 50-µm dendrite length = 23.9; Nle¹-AngIV mean spine numbers per 50-µm dendrite length = 22.6; vehicle control–treated neurons mean spine numbers per 50-µm dendrite length = 17.4; n = 60; P < 0.0001 by one-way ANOVA followed by Tukey post-hoc test).

Strong correlations exist between spine size, persistence of spines, number of AMPA-receptors, and synaptic efficacy. A correlation between the existence of long-term memories to spine-head volume has also been suggested (Kasai et al., 2010; Yuste and Bonhoeffer, 2001; Yasumatsu et al., 2008). With these considerations in mind, spine-head size measurements were taken following 5 days of drug treatment. Results indicate that the 10⁻¹² M dose of dihexa and Nle¹-AngIV both increased spine-head width (Supplemental Fig. 4). The mean spine-head width for Nle¹-AngIV was 0.87 μm, 0.80 μm for dihexa, and 0.67 μm for vehicle controls.

Dihexa and Nle¹-AngIV Mediate Synaptogenesis

To begin to assess the functionality of the newly formed dendritic spines, mRFP-β-actin–transfected neurons were immunostained for three synaptic markers. Hippocampal neurons were stimulated for 5 days in vitro with 10⁻¹² M dihexa or Nle¹-AngIV (Fig. 7). Since glutamate synaptic transmission is known to involve receptors that reside on dendritic spines, neurons were probed for excitatory synaptic transmission by staining for the glutamatergic presynaptic marker vesicular glutamate transporter 1 (VGLUT1) (Balschun et al., 2010). The universal presynaptic marker synapsin was also visualized to assess the juxtaposition of the newly formed spines with presynaptic boutons (Ferreira and Rapoport, 2002). Finally, PSD-95 served as a marker for the postsynaptic density (El Husseini et al., 2000).

 

Again, dihexa and Nle¹-AngIV treatment significantly augmented dendritic spinogenesis (Fig. 7, B, D, and F) in each of the three studies [mean spine numbers for the combined studies for Nle¹-AngIV = 39.4, for dihexa = 44.2 and for vehicle-treated neurons = 23.1 (mean ± S.E.M., P < 0.001)]. The percent correlation for the newly formed spines with synaptic markers VGLUT1, synapsin, or PSD-95 is shown in Fig. 7, D, and E. Dihexa and Nle¹-AngIV treatment-induced spines did not differ from control-treated neurons in the percent correlation to VGLUT1, synapsin, or PSD-95 (P > 0.05), indicating that the newly formed spines contained the same synaptic machinery as already-present spines. The previous results suggest that the newly formed dendritic spines produced by dihexa and Nle¹-AngIV treatment create functional synapses.

[...]

Dihexa and Nle¹-AngIV Induce Spinogenesis in Hippocampal Organotypic Cultures

To further assess the physiologic significance of the spine induction witnessed in dissociated neonatal hippocampal neurons, the effects of dihexa and Nle¹-AngIV on spine formation in organotypic hippocampal slice cultures were evaluated. These preparations, while still neonatal in origin, represent a more intact and three-dimensional environment than dissociated neurons. Hippocampal CA1 neurons, which have been functionally linked to hippocampal plasticity and learning/memory, were easily identified based on morphologic characteristics and were singled out for analysis. Dihexa and Nle¹-AngIV significantly augmented spinogenesis in organotypic hippocampal slice cultures when compared with vehicle-treated neurons. There were no differences in spine numbers between the dihexa and Nle¹-AngIV treatment groups (Supplemental Fig. 5). Spine numbers measured for control slices were 7 per 50-µm dendrite length versus 11 spines per 50-µm dendrite length for both Nle¹-AngIV- and dihexa-treated neurons (mean ± S.E.M., n = 13–20 dendritic segments; P < 0.01).

 

DISCUSSION

The goal of this study was to develop an AngIV-derived molecule that retained the procognitive/antidementia activity of AngIV and Nle¹-AngIV but possessed improved pharmacokinetic properties, thus allowing it to penetrate the BBB in sufficient quantities to reach therapeutic levels in the brain. The culmination of this effort was dihexa, a hydrophobic, N- and C-terminal–modified, AngIV-related peptide. The cursory pharmacokinetic characterization of dihexa included in this study indicated that it was stable in serum, had a long circulating half-life, and penetrated the BBB. Data from behavioral studies using scopolamine amnesia and aged rat models, where dihexa was able to reverse cognitive deficits, indicated that the metabolic stability and BBB permeability of dihexa were apparently high enough to attain therapeutic brain levels after oral administration. Additional mechanistic studies demonstrated that both dihexa and Nle¹-AngIV, its parent compound, were effective stimulators of hippocampal synaptogenesis, thus providing a rational explanation for their procognitive activities.

 

[...]

 

Although not the focus of this study, an obvious question relates to the identity of the molecular target responsible for the procognitive and synaptogenic activity of dihexa and other AngIV-related compounds. Hints to the answer to this question can be found in four recent articles (Yamamoto et al., 2010; 2012; Kawas et al., 2011; Wright et al., 2012), which clearly demonstrate that both the peripheral and central nervous system actions of AT₄ receptor antagonists depend on their ability to inhibit the hepatocyte growth factor (HGF)/c-Met (HGF receptor) system by binding to [HGF] and blocking HGF activation. Conversely, we (C. C. Benoist, Kawas LH, and Harding, JW, unpublished data) have recently demonstrated that both Nle¹-AngIV and dihexa bind HGF, leading to its activation, and that the procognitive and/or synaptogenic actions of these compounds are blocked by both HGF and c-Met antagonists. With this knowledge in hand, a library of N-acyl-Tyr-Ile-(6) amino-hexanoic amide analogs was screened for their capacity to potentiate the biologic activity of HGF. This screen identified the hexanoic N-terminal substituent as the most active compound.

 

The ultimate goal of this project was to produce a clinically useful pharmaceutical for the treatment of dementia, including Alzheimer’s disease. At its core, dementia results from a combination of diminished synaptic connectivity among neurons and neuronal death in the entorhinal cortex, hippocampus, and neocortex. Therefore, an effective treatment would be expected to augment synaptic connectivity, protect neurons from underlying death inducers, and stimulate the replacement of lost neurons from pre-existing pools of neural stem cells. These clinical endpoints advocate for the therapeutic use of neurotrophic factors, which mediate neural development, neurogenesis, neuroprotection, and synaptogenesis. Not unexpectedly, neurotrophic factors have been considered as treatment options for many neurodegenerative diseases, including Alzheimer’s disease (see reviews: Calissano et al., 2010; Nagahara and Tuszynski, 2011). The realization that activation of the HGF/c-Met system represents a viable treatment option for dementia should be no surprise. HGF is a potent neurotrophic factor in many brain regions (Ebens et al., 1996; Kato et al., 2009), while affecting a variety of neuronal cell types. [...]

[Metagene]

Thanks MetaGene, surprised I can't locate that paper in PubMed or LibGen.

That's because it was released online yesterday ahead of the finalized print version.

http://m.jpet.aspetj...jpet.114.218735

Edited by Metagene, 04 September 2014 - 10:53 PM.

[pi-]

Ha! Good timing indeed!

Good to see you have your finger on the pulse, Metagene!

 

Great! They have finally figured out how it works!

 

"Dihexa and Nle1-AngIV Act Synergistically with HGF to Augment c-Met Signaling and HGF-dependent Cellular Activity.The notion that Dihexa and Nle1 -AngIV allosterically activate HGF predicts that these analogs should potentiate HGF’s ability to activate its receptor and subsequent cellular responses."

 

So, HGF must be some extra cellular messenger molecule that agonises the HGF-receptor (HGFr, also known as C-Met).  And Dihexa (or Nle1-AngIV, its parent compound) catalyses this.  This makes me wonder whether it is also possible to boost HGF through noots.

 

http://en.wikipedia.org/wiki/C-Met <-- "MET induces several biological responses that collectively give rise to a program known as invasive growth"

 

That page answers my question about cancer risk. Overactive HGFr assists development of tumours by encouraging growth of blood vessels, nerves, etc. It is called invasive growth. However, there doesn't seem to be any suggestion that increasing HGFr activity actually causes tumours. So as far as I can see, anyone with tumours should steer clear of dihexa.  But dihexa would just be a catalyst. Not a cause.

 

Edited by pi-, 05 September 2014 - 12:31 AM.

[Flex]

 

http://en.wikipedia.org/wiki/C-Met <-- "MET induces several biological responses that collectively give rise to a program known as invasive growth"

 

That page answers my question about cancer risk. Overactive HGFr assists development of tumours by encouraging growth of blood vessels, nerves, etc. It is called invasive growth. However, there doesn't seem to be any suggestion that increasing HGFr activity actually causes tumours. So as far as I can see, anyone with tumours should steer clear of dihexa.  But dihexa would just be a catalyst. Not a cause.

 

Really dont want to be a downer but our Eyes are just able only to see how far the horizon goes

( excuses if this sound too wise-guy like)

Consider that that this simple fact, what You´ve said, is not done, since we are not scientists and even scientist must admit that they sometimes dont know or are mistaken

( ok I had a beer)

In short:

Spontaneous Cancer Cells Killed by Immune System Every Day

http://guardianlv.co...stem-every-day/

 

What if dihexa would help them to stay alive ?

Edited by Flex, 05 September 2014 - 11:50 PM.

[pi-]

Certainly, this is a good point. Life is more complex than our scientific models.

 

This is of course why several stages of FDA approval are required. And experience weighs more heavily than all the theories in the universe.

 

But we currently don't have that luxury. Only time will tell.

 

But what we can do is use the science we have to make the best possible predictions.

 

That's what I'm fishing for here. From the information available, I'm trying to assess the likelihood of bad things happening.

 

π

[resveratrol_guy]

So with respect to the risk: how does Dihexa compare with nerve growth factor (or lion's mane mushroom, which appears to be a good agonist thereof)? Specifically, would there be any reason to take dihexa at all, if one has the cheaper and better studied alternative of supplementing or agonizing NGF? On the other hand, is there room for synergy between them without dangerously raising the cancer risk?

If there is a case for dihexa now, then I think the reasoning goes like this, if I understand the science correctly: Dihexa acts rapidly to stimulate dendritic spine formation among existing neurons, resulting in comparably rapid significant mental improvements (at some "high" dose), in spatial memory and perhaps other functions. NGF takes a month to act, and agonizes neurogenesis but does not particularly impact connectivity; moreover, the mental benefits achieved therefrom are transitory, and vanish to control levels within a month or so of cessation of (lion's mane) supplementation in the presence of advanced Alzheimers (but might persist longer in a healthy brain); whereas the spines resulting from a few high doses of dihexa (presumably and hopefully) survive as long as new spines would be expected to survive in its absence, achieving long term reversal of dementia.

My naive impression is as follows:

1. Dihexa stimulates connectivity among neurons, moreso than neurogenesis. NGF stimulates only the latter, but has been proven effective in a Japanese Alzheimers study mentioned on this forum.

2. The rodent studies with dihexa are very promising, but no human trials seem to have been done, controlled or otherwise.

3. Dihexa's interactions with HGFr would be supportive of (but not conducive to) cancer. But more to the point, we don't even have long term rodent data on the risk differential here.

4. NGF, although angiogenic and neuroprotective, was taken ocularly by its discover for over 40 years, who was mentally sharp (and even simply alive!) at 100 (Wikipedia). She died at 103, at which point the question of cancer would have been moot. This is one very significant data point. From what I gather, it's also taken by glaucoma sufferers to prevent retinal decay. It stimulates some cancer cells but suppresses others, so perhaps eye drops are indeed the way to go because NGF might diffuse through the eye sockets and into the brain, thereby bypassing general circulation for the most part (is this possible?). NGF vs. cancer:

5 strains of pancreatic:

https://www.ncbi.nlm...pubmed/11205897

Breast:

http://www.nature.co...l/1206805a.html
 

Edited by resveratrol_guy, 06 September 2014 - 07:46 PM.

[sk_scientific]

bump

[DonManley]

I've found some user on reddit claiming that s/he is worked with Joe Harding (link) The message is below.  Tl; dr; version: Joe Harding alarms that one can expect to develop autistic like symptoms and the drug will be "stimulating the growth of any hidden brain tumors 10,000,000 fold". In the end he says that "you're crazy if you're under 60 and use it deliberately".

 

I actually worked with Joe Harding some time ago so I have some experience with the drug. However, it was only for a few months. I'll cut/paste some PM's....

Oh yeah and proof: http://imgur.com/QeQCeFt

About a year ago you wrote about a drug, MM202, that was able to "able to stimulate the regrowth of exactly half of the substantia nigra of a rats brain within 2 weeks-- to 140% of its original density." Do you have any more information about this compound, even the name of the professor would be useful. permalinkreportblock usermark unreadreplyfull comments [–]to ****** sent 18 days ago This is more commonly referred to as Dihexa, and if you use it, expect to develop autistic like symptoms as a result of excessive connection formation. If you could get a reasonable dose, and you weren't worried about contributing to the growth of a formerly-dormant brain tumor, then you could go nuts conceivably to great permanent effect. It's an extremely small BDNF agonist that acts as the other half of the otherwise quite large dimer, produced via computer-aided design in Joe Harding's lab. I can tell you that accidental exposure (it's quite skin permeable) also results in absurdly accelerated fibroblast activity, such that a cut across a finger to the bone, without stitches, will be effectively healed in 3 days, and any residual inflammation or any indication of injury will be gone before next week. And falling off of a cliff while climbing and splitting your face open on a rock a month later? Yeah, that ridiculously long half life will put your face back together before your plastic surgeon can say WTF. Helluva drug =) permalinkfull comments

[–]from ****** sent 18 days ago So, I'll be a savant Wolverine? You're not doing the best job of talking me out of this, doc. permalinkreportblock usermark unreadreplyfull comments

[–]to ****** sent 17 days ago Savant... eventually if you get perfect dosage. But you won't, so you'll be a savant who has a variety of confounding symptoms some of which seem to be related to excessive excitation, too many connections (esp. large dendritic trees) and inadequate inhibition. So these include synesthesia, ironically intermittent mild tremors, random memory loss during simple task completion, inability to properly recognize certain objects or features of objects (e.g. perceive edges or other features that aren't actually there) and others. If you get it just right though, you could end up with significantly increased learning potential for both explicit and motor/spatial tasks. Really, I'd jump on using it if I had less than 20 years of predicted lifetime left and had any sort of neurodegenerative symptoms. But, you'll be stimulating the growth of any hidden brain tumors 10,000,000 fold, so that sucks, and you're crazy if you're under 60 and use it deliberately. Interesting aside, I never remembered my dreams until Dihexa... now I remember most of them. And those negative symptoms mentioned earlier are not my own, those are from chronically exposed idiots who had it manufactured overseas for ~$1,000/gram. This is highly unethical, but I am quite curious what Dihexa would do if administered during development, as many inappropriate connections are trimmed during development. TL;DR: Psycho Wolverine with a giant brain tumor, in all likelihood. But if you're very lucky with dosage, Aaron Cross. permalinkfull comments

[–]from****** sent 17 days ago Interesting. I had no idea it was that dangerous. I tend to stick to drugs that have been used extensively in humans, so I won't actually try it untill quite a few other people have. But of all the nootropics, it does look like the best shot for an actual IQ increase. Shame it's so dangerous. I know some people were taking it everyday, combined with the short half-life I could see why that would be an issue. Do you think you, personally, have come of better or worse for your exposure to the stuff? permalinkreportblock usermark unreadreplyfull comments

[–]to ****** sent 17 days ago Better. I spilled ~300mg worth of fairly concentrated solution on my hand and wiped it off almost immediately, then flushed with water for several minutes. I feel that I can definitely focus better than I used to-- or rather, I can tune out distractions more easily. Dreams are cool too, as I feel remembering them (and they're always relevant to the past day or just random) seems to help me remember things better. Opposite of the effect I would have guessed. Those people on Longecity are nuts and the daily administration is nuttier. You mean long half-life, right? It's just over a week. A fucking week! Excuse me, but seriously. Badassest computer design ever. I hope we can find more critical dimers to apply the model. permalinkfull comments

[–]to ****** sent 17 days ago It would be much safer if we could determine a good dosage, but since it works by making BDNF active until it's broken down, regardless of pairing with another subunit, and since BDNF levels vary by a number of factors and are typically vanishingly low anyway, dosage therefore varies by a number of factors. You can't form too many connections too quickly or you're asking for lifelong seizures, though that hasn't happened yet... it's only made our rats smarter. Every last one of them. permalinkfull comments

[–]from ****** sent 17 days ago Yes. I meant long half-life. You should post some these comments to the main forum. It's super interesting. It's only made our rats smarter. Every last one of them. How often were they treated? Just once? permalinkreportblock usermark unreadreplyfull comments

[–]to ****** sent 17 days ago I didn't actually administer so I'm not perfectly sure, but, I believe we did 3 administrations 4 days apart. I don't remember the dosage but it was ridiculously low, and we think still too high for some of them. I think those were listen in the paper. Also worth noting that while we have decent (and very statistically significant) measures for these improvements they are all behavioral and there's more individual variance than you'd expect (but everyone improved). It's such a complex change and the consequences are hard to understand. They're not really the same rats.

 

 

 

[Metagene]

That was posted on reddit six months ago. I can't believe we all missed it.

[sparkk51]

I find that post extremely hard to believe. That picture he gave as "proof" isn't a clear-cut confirmation.

[Metagene]

I find that post extremely hard to believe. That picture he gave as "proof" isn't a clear-cut confirmation.

It is consistent with his post history regardless of said "proof". I still find it a little hard to believe myself.

[DonManley]

I find that post extremely hard to believe. That picture he gave as "proof" isn't a clear-cut confirmation.

 

However, the user does not give any reasons to doubt the story either. His account is very consistent with the story. He talks a lot about the brain, mentions multiple times that he works in a lab. So I would use the Occam's razor in this case. Of course, it's entirely possible that as a brain researcher he was worried about people using a drug like that so he fabricated the story to make users more cautious. But I think that is a less likely explanation.

[sparkk51]

Heal a cut to the bone in 3 days with no post scarring? You guys don't actually believe that right?

[DonManley]

Below is the email that I'm going to send to Joe Harding. English is not my native language, so if somebody can look at it and point mistakes, brain farts or just give any feedback, I would be grateful. Also, perhaps sending it from an edu email is more likely to get a response? Perhaps somebody who is also interested in the response should send it from a credited email domain of some university?I'm afraid that it's going to get swallowed by spam / email filters if a peasant like me sends it.

 

Dear Professor Harding,

The essence of this inquiry is kept short because we're aware that your time is valuable. Many people in our community are considering to use or are already using the drug MM-201, also known as Dihexa. A student of the university where you teach posted a conversation that he claimed took place with you. The conversation contained some unique information, which we can't find in your published work. However, we are concerned whether this conversation actually took place and thus whether this information is credible. Can you please confirm that those messages are yours?

Here is the link to that message: http://www.reddit.co...a_again/cl1b751

It might be possible that you expected the conversation to be private and it was made public without your consent. Thus, it is understandable if you don't not want to comment on whether that conversation took place. If that is the case, then perhaps you can instead comment on possible side effects of this substance, especially if it's used by healthy individuals for nootropic effects?

It's also possible that you don't want to make any "official" comment. In this case, it would be great if you could just reply from another email address to this email or make an "unofficial" comment in some other way that you find suitable.

Last but not least, we don't know whether you'll take your time to respond, so we would like to proactively express our gratitude in this message. Thank you for your published work and fascinating research!

Sincerely,
Longecity Community

 

 

Edited by DonManley, 13 April 2015 - 07:37 PM.

[RobbieG]

DON MANLEY.  YOU DID A GREAT JOB.  I MADE A FEW EDITS FOR YOU TO CONSIDER. GOOD LUCK: 

 

Dear Professor Harding,

I am writing to you on behalf of the Longecity Community.  If you are not familiar with us, we are a global online community of people all interested in life extension technologies.  Many of the community live on the edge as early adopters.  Recent a post of Reddit came to our attention with many claims about Dihexa attributed to you.    Here is the link to that conversation: http://www.reddit.co...a_again/cl1b751.  The conversation contained some unique information, which we can't find in your published work. So we are concerned whether this conversation actually took place and thus whether this information is credible. Can you please clarify if these are your thoughts on Dihexa or not?  

 

It is understandable if you don't not want to comment on whether that conversation took place. If that is the case, then perhaps you can instead comment on possible side effects of this substance, especially if it's used by healthy individuals for nootropic effects?  In the event you do not want to make any comment, it would be great if you could just reply from another email address to this email or make an "unofficial" comment in some other way that you find suitable.

On behalf of the Longecity community we appreciate your effort and research in this field and will be watching for news on Dihexa with intense interest.  

Sincerely,
Longecity Community

[pi-]

Great stuff everyone!

 

By the way I'm in the process of putting up my neuroscience research (sneak preview: http://46.101.38.186...hp/Neuroscience -- currently it's read-only but if anyone would like write-access let me know --  anyway, I will create a new forum thread in due course).

 

I like the idea of contacting Prof. Harding, and I like the look of the letter. It would be rather nice if those of us that are interested in the issue put our names (or handles if we prefer) at the bottom. I would like to sign. 

 

May I have a go at making a third draft?

 

Dear Professor Harding,

We write to you on behalf of the Longecity Community (http://www.longecity.org/).  If you are not familiar with us, we are a global online community of people interested in life extension/enhancement technologies.  Your molecule MM-201 (Dihexa) has caused much excitement.  Many of the community live on the edge as early adopters, some of whom have (for some time) been experimenting with Dihexa and reporting back their experiences.  Recently a post on Reddit (http://www.reddit.co...a_again/cl1b751) came to our attention containing claims about Dihexa attributed to you; strongly worded cautions on the dangers of the substance.  We cannot find matching statements in your published work, and are hence naturally concerned whether this information is credible.  

Would you care to verify that this conversation took place?

Might you be willing to offer any comment on the potential risks and side-effects of this molecule if used by healthy individuals for nootropic purposes that we might disseminate to the community?  Your thoughts would be of great value to us.

The above notwithstanding, it remains for us, on behalf of the Longecity community, to thank you wholeheartedly for the work you do.  Those of us that attempt to follow modern developments in neuroscience at a technical level, through the difficulty of following the trail acquire the greatest respect for those that blaze it. We will be following the progress of Dihexa through the FDA approval process with intense interest, and eagerly await future publications.  

Sincerely,

 

Don Manley, Major Woody, π, ...?

On behalf of the Longecity Community

Edited by pi-, 13 April 2015 - 10:00 PM.

[DonManley]

Great edits, guys! You're so great that I want to outsource the rest of the work to you as well . It sounds silly, but can somebody also brainstorm the clickbait subject for the email?  The best  I can come up with is "A small question about MM-201 (Dihexa) from the Longecity Community". Otherwise, I think it's great and I just want to send it, as I don't think any more polishing will increase the likelihood of the reply by any significant amount.

 

Has anybody PMed xenodius (that user on reddit), yet? If not and we get no reply from Joe Harding himself, then I'll try to contact xenodius to see whether he can help us to resolve suspicions in any way and whether he is willing to do that.

[di36]

On the part where you ask for comment on risks,use etc i would suggest that you should inform him that in case he is ethically unable to give such advices for human lab rats,he should give anyway as people already are using or have already ordered.So he is not helping in any risky decision making, just minimizing the already taken risks.

Edited by di36, 16 April 2015 - 02:31 PM.

[not nostalgic]

Soo? what happened? Did the guy respond?

 

BUUUMPP

[DonManley]

Soo? what happened? Did the guy respond?

 

BUUUMPP

 

Unfortunately, no. I doubt he will. It's been one month already (I've send the email on 19 April).

[not nostalgic]

Fuck him then, give me a year and $200 and I'll make a HGF CRISPR gene therapy plasmid that'll make me famous and then he'll talk to me.

 

Seriously guys, if you want to help fund this it would be really helpful. I'm dropping out of school to do *this* so if anyone wants to join and help out or just help out with funding the more the merrier right? Or if you have a better biological circuit that you can think of

 

[Ark]

Any thoughts on extra risk of using DMSO with Dihexa. I've noticed a pattern, in the logs of Dihexa, where DMSO was used in conjunction had a higher incidents of blowback. Could this be the culprit causing all the mayhem?

Edited by Ark, 20 May 2015 - 03:07 AM.

[Ark]

I've found some user on reddit claiming that s/he is worked with Joe Harding (link) The message is below. Tl; dr; version: Joe Harding alarms that one can expect to develop autistic like symptoms and the drug will be "stimulating the growth of any hidden brain tumors 10,000,000 fold". In the end he says that "you're crazy if you're under 60 and use it deliberately".

I actually worked with Joe Harding some time ago so I have some experience with the drug. However, it was only for a few months. I'll cut/paste some PM's....
Oh yeah and proof: http://imgur.com/QeQCeFt
About a year ago you wrote about a drug, MM202, that was able to "able to stimulate the regrowth of exactly half of the substantia nigra of a rats brain within 2 weeks-- to 140% of its original density." Do you have any more information about this compound, even the name of the professor would be useful. permalinkreportblock usermark unreadreplyfull comments [–]to ****** sent 18 days ago This is more commonly referred to as Dihexa, and if you use it, expect to develop autistic like symptoms as a result of excessive connection formation. If you could get a reasonable dose, and you weren't worried about contributing to the growth of a formerly-dormant brain tumor, then you could go nuts conceivably to great permanent effect. It's an extremely small BDNF agonist that acts as the other half of the otherwise quite large dimer, produced via computer-aided design in Joe Harding's lab. I can tell you that accidental exposure (it's quite skin permeable) also results in absurdly accelerated fibroblast activity, such that a cut across a finger to the bone, without stitches, will be effectively healed in 3 days, and any residual inflammation or any indication of injury will be gone before next week. And falling off of a cliff while climbing and splitting your face open on a rock a month later? Yeah, that ridiculously long half life will put your face back together before your plastic surgeon can say WTF. Helluva drug =) permalinkfull comments
[–]from ****** sent 18 days ago So, I'll be a savant Wolverine? You're not doing the best job of talking me out of this, doc. permalinkreportblock usermark unreadreplyfull comments
[–]to ****** sent 17 days ago Savant... eventually if you get perfect dosage. But you won't, so you'll be a savant who has a variety of confounding symptoms some of which seem to be related to excessive excitation, too many connections (esp. large dendritic trees) and inadequate inhibition. So these include synesthesia, ironically intermittent mild tremors, random memory loss during simple task completion, inability to properly recognize certain objects or features of objects (e.g. perceive edges or other features that aren't actually there) and others. If you get it just right though, you could end up with significantly increased learning potential for both explicit and motor/spatial tasks. Really, I'd jump on using it if I had less than 20 years of predicted lifetime left and had any sort of neurodegenerative symptoms. But, you'll be stimulating the growth of any hidden brain tumors 10,000,000 fold, so that sucks, and you're crazy if you're under 60 and use it deliberately. Interesting aside, I never remembered my dreams until Dihexa... now I remember most of them. And those negative symptoms mentioned earlier are not my own, those are from chronically exposed idiots who had it manufactured overseas for ~$1,000/gram. This is highly unethical, but I am quite curious what Dihexa would do if administered during development, as many inappropriate connections are trimmed during development. TL;DR: Psycho Wolverine with a giant brain tumor, in all likelihood. But if you're very lucky with dosage, Aaron Cross. permalinkfull comments
[–]from****** sent 17 days ago Interesting. I had no idea it was that dangerous. I tend to stick to drugs that have been used extensively in humans, so I won't actually try it untill quite a few other people have. But of all the nootropics, it does look like the best shot for an actual IQ increase. Shame it's so dangerous. I know some people were taking it everyday, combined with the short half-life I could see why that would be an issue. Do you think you, personally, have come of better or worse for your exposure to the stuff? permalinkreportblock usermark unreadreplyfull comments
[–]to ****** sent 17 days ago Better. I spilled ~300mg worth of fairly concentrated solution on my hand and wiped it off almost immediately, then flushed with water for several minutes. I feel that I can definitely focus better than I used to-- or rather, I can tune out distractions more easily. Dreams are cool too, as I feel remembering them (and they're always relevant to the past day or just random) seems to help me remember things better. Opposite of the effect I would have guessed. Those people on Longecity are nuts and the daily administration is nuttier. You mean long half-life, right? It's just over a week. A fucking week! Excuse me, but seriously. Badassest computer design ever. I hope we can find more critical dimers to apply the model. permalinkfull comments
[–]to ****** sent 17 days ago It would be much safer if we could determine a good dosage, but since it works by making BDNF active until it's broken down, regardless of pairing with another subunit, and since BDNF levels vary by a number of factors and are typically vanishingly low anyway, dosage therefore varies by a number of factors. You can't form too many connections too quickly or you're asking for lifelong seizures, though that hasn't happened yet... it's only made our rats smarter. Every last one of them. permalinkfull comments
[–]from ****** sent 17 days ago Yes. I meant long half-life. You should post some these comments to the main forum. It's super interesting. It's only made our rats smarter. Every last one of them. How often were they treated? Just once? permalinkreportblock usermark unreadreplyfull comments
[–]to ****** sent 17 days ago I didn't actually administer so I'm not perfectly sure, but, I believe we did 3 administrations 4 days apart. I don't remember the dosage but it was ridiculously low, and we think still too high for some of them. I think those were listen in the paper. Also worth noting that while we have decent (and very statistically significant) measures for these improvements they are all behavioral and there's more individual variance than you'd expect (but everyone improved). It's such a complex change and the consequences are hard to understand. They're not really the same rats.

http://www.longecity...-dmso-toxicity/

[Junk Master]

You would think with that report of accelerated healing Dihexa would already be in use by the P.E.D guru's and their multi-millionaire athlete clients...then again, if it's such a potent molecule that it can produce Autistic (like) symptoms, then maybe not...lol..

 

I'm really curious if anyone here as tried applying a small amount topically, and if so what was their experience?

 

 

[nightwolfz]

Tried it on a small wound. Nothing out of ordinary happened. Tested with both Nyles and the latest group buy batches.

[playground]

Where are they up to with Dihexa ?

Have they started stage 1trials yet ?

 

Howabout animal work ?

Has this work been done but not published ?

 

There's something suspicious (and dangerous) about Dihexa being a synthetic drug.

 

They can't patent natural drugs.  They can only patent synthetic ones.

So drug companies routinely ignore 'effective' drugs, because they're natural.

 

Interesting case occurred with valium (diazepam). Hoffman La-Roche were impressed

with the effects of niacin on mood, feelings of wellbeing etc.

Niacin is vitamin B3. 

There's an abundant literature on niacin's positive, anti-depressant

and neuro-protective effects (with virtually no toxicity profile).

However, niacin is natural, Hoffman La-Roche isn't going to make much money

advertising it since almost anyone can sell it. 

 

So Hoffman La-Roche created a synthetic version of niacin and called it

valium (aka diazepam).  It doesnt work quite as well as niacin, and it has a

very definite toxicity profile.  It also costs several hundred times more.

 

Probably, something similar has happened here.

Dihexa has to be synthetic, not because of half lives or the blood brain barrier, but

because the people sponsoring this research want a return on their investment.

 

Someone with a good knowledge of this area could probably figure out

which chemicals have shown similar efficacy and are natural.

Those chemicals are the ones you 'really' want.

Those chemicals will have a better toxicity profile.

Those chemicals will be cheaper.

 

playground

[Fenix_]

Edited by Fenix_, 28 May 2015 - 05:12 AM.