Dihexa Nootropics

Dihexa: The Story and Science of a Neurogenic Wonder-Drug

If you have spent any respectable amount of time studying the more extreme margins of nootropics lore, then you have likely stumbled upon accounts of Dihexa, the neigh-legendary Alzheimer’s drug that is purportedly “10,000,000 times stronger than BDNF for new synapse formation”.[1]

In the past Dihexa has been notoriously difficult to find, and even now it is far from accessible to budding body hackers, but with increasingly regular group buys and even a straightforward FAQ popping up, it would seem that Dihexa has made a stable arrival on the fringe of the Nootropics community, and is here to stay.

But despite the increase in access, Dihexa’s mechanism of action is still shrouded in a veil of mystery unperturbed by a mere Google search. Fortunately, the history and pharmacokinetics of Dihexa are as fascinating and tantalizing as the fabled experience reports and research studies purporting its potency.

History of Dihexa

As with many great drugs, the idea for Dihexa was conceived by the inspiration of serendipity and circumstance. In the early ‘90s, the laboratory of Joseph W. Harding was mainly focused on the cerebral control of vascular function, which is heavily influenced by the neuropeptide angiotensin. The lab’s work originally involved angiotensin blockers, specifically ACE inhibitors[2], as a novel means of cancer prevention through the lowering of prostaglandin[3] levels.

But in their tests was an anomaly: a specific sequence of angiotensin, specifically angiotensin IV (Val-Tyr-Ile-His-Pro-Phe), did not exert hypertensive effects unlike its precursor, angiotensin II. Harding’s interest in the compound was further piqued when a colleague’s paper on angiostatin, which is essentially the opposing hormone of angiotensin, had the angiotensin IV peptide sequence incorporated into its structure. Upon testing it for binding sites, Ang-IV was found significantly in the hippocampus, suggesting it had a potential connection to memory formation. With the acquisition of funding from the pharmaceutical giant Eli Lily & Co. (the same company responsible for Cialis, Prozac, and Cymbalta), Harding was able to synthesize an unlimited number of Angiotensin IV analogues for his work. Big Pharma had just given the hunt for Dihexa the huge boost it needed.

3D structure of Dihexa
The 3D structure of Dihexa, with labelled amino acid groups and modifications to encourage lipophilicity and stability.

Work with the Ang-IV analogues was nothing short of miraculous: in every model of cognitive decline, that the analogues of Ang-IV that Harding had developed were able to completely reverse impairment when intraperitoneally injected. (This even included such the reversal of damage from kainic acid brain injections that destroyed up to 60% of cerebral neurons![4]) Yet despite these remarkable findings, none of the tested analogues could pass the blood-brain barrier, and their half-lives in the brain lasted a handful of minutes, at most: none of these candidates could pass muster as a pharmaceutical drug. Unfortunately, before a more functional analogue could be found, Eli Lily was forced to cut off funding: the company had been plunged into a financial crisis when it failed to warn patients about the possible birth defects that can be caused by Prozac, launching a legion of lawsuits against the pharmaceutical giant. The strain and frustration of the period were so great that the company’s vice president actually resigned, and a happy byproduct of the resignation was the return of Harding’s intellectual property. The significant reduction of funds, however, had stopped progress with the Ang-IV analogues in its tracks.

In the early 2000s, the work began anew. Harding and his colleagues began to zero in on the precise peptides necessary for the procognitive properties of a particularly promising analogue, Nle-Angiotensin-IV and arrived at the tripeptide sequence Nle-Tyr-Ile. This sequence was then modified to increase its stability and lipophilicity. This progress attracted the attention of ADDF and WSU, which have been funding the project since. Eventually, one particular modified analogue, MM-201, later known as Dihexa, distinguished itself from the rest of the pack, even going as far as to boost the performance of impaired mice beyond that of non-impaired controls.

Dihexa compared with Ang-IV
Rodent hippocampal neurons were treated for 5 days in vitro with A) water B) Dihexa C) Nle1-Ang-IV. The images show the representative dendritic arbors from each sample, with glowing dots marking synapses. D) and E) show the number of dendritic spines per 50µm of dendrite following 5 days of stimulation and 30 minutes of stimulation with solutions, respectively. [5]
How does something this incredible happen on a chemical level? What miracles is Dihexa performing in our minds? The details are as complicated and interesting as anyone could hope for, and portray Dihexa as a very powerful drug that may also be very dangerous.

Dimerization: a novel mechanism of action

The major term to understand in comprehending Dihexa’s MOA is dimerization, coming from di-, or “two”, and -mer, or “part” (as in merman). Recent science has revealed that many growth factors actually come in two parts that remain apart in the cell, until conditions demand that they activate, at which point they will dimerize into a two-part complex that can then cause a signal cascade resulting in growth, survival, and regeneration of the factor’s target cells. Dihexa works with hepatocyte growth factor (HGF), which has been found in elevated levels in the cortex during the early stages of neurodegenerative disease, suggesting it is being released by the brain in an attempt to facilitate a recovery from damage.

The dimerization of hepatocyte growth factor involves the membrane-bound enzyme c-MET, a tyrosine kinase that is involved in the expression of certain genes by managing the proteins that bind onto DNA strands, preventing or enabling other enzymes to “read” the genes and produce the corresponding proteins from that code (this is the basis for changes in “gene expression”).

This is where the monumental potential of this drug becomes apparent: the current understanding that the dimerized form of growth factors is the activated form, Dihexa both increases HGF activity and lowers dimerization. This suggests that the allosteric modulation of HGF is actually producing an active monomer complex, theoretically doubling the capacity of the available factors to promote signaling cascades and exert changes on cell development. Here is the change in effect worked out as an equation:

Normal HGF/c-MET function: (HGF + HGF) + (c-MET) = Activation

HGF/c-MET function with Dihexa: (HGF + Dihexa) + (c-MET) = Activation

For analogy, imagine that the normal dimerized growth factor activity is like typing: you have to use both hands to do it properly. By allosterically binding to HGF, Dihexa is basically coming along and making it so you only need one hand to do a two-handed job, freeing the other hand to do another two-handed job.

c-MET pathway
An overview of the c-MET pathway. Note the dimerized c-MET complex protruding from the cell membrane.[6]
Before Dihexa, there were no drugs looking at managing the dimerization of growth factors to restore cognition. In fact, most contemporary dimerization work focuses on its prevention. This is where some very real concerns arise concerning the use of Dihexa in healthy subjects: the contemporary work to which I am referring is anti-cancer research. As much help as these performance-enhancing growth factors are for enhancing neuroplasticity and long-term potentiation, they give just as much of a leg up to any latent tumors developing in the body. The HGF/c-MET complex is actually an explicit target for antagonism in anti-cancer research, as this illustrative video reviewing the function of the factor shows.

Due to this implied cancer risk, one could liken the use of Dihexa to the use of nuclear power: rare but incredible power married to rare but incredible risks. But what power, indeed, we have yet to test the limits of. As suggested by its pro-tumor capacities, the HGF/c-MET pathway extends far beyond neurogenesis alone: c-MET receptors are expressed on the endothelial cells of many major organs, including the liver, kidneys, skeletal muscle, bone marrow, pancreas, and prostate. Dihexa could perhaps be used to accelerate wound healing, promote improvement of circulation, and perhaps even enhance anabolic development and prevent muscular atrophy from wasting disease. It could also facilitate recovery from diabetic neuropathy and circular dysfunction, liver cirrhosis/scarification, other types of organ damage, anemia, and perhaps even metabolic and mitochondrial disorders.

So why is such a remarkable drug so understudied and underdeveloped? The answer can be found in several endpoints, but the biggest one is the dollar: without the support of deep pockets like Eli Lily, there is no realistic scenario in which Dihexa becomes FDA approved, a process that can easily cost hundreds of millions, if not billions, of dollars. NIH, one of the major bodies giving research grants for Alzheimer’s treatments, only cares about working with amyloid beta to manage the disease.

The second reason is the sheer novelty of the drug means that it is not even on the radar for most organizations. In scientific research, being remarkable and unique is as much a blessing as a curse, because researchers prefer to build off of established knowledge bases, specifically the ones for which they have established a knowledge base. With the exception of some anti-cancer treatments, Dihexa is one of the only Alzheimer’s research chemicals that modulates HGF, an MOA most doctors know nothing about.

The pharmacology of Dihexa in animals is well-documented: in vitro, the synaptogenesis of Dihexa begins at T+30:00, maximizes at +48:00:00[7]. The overall half-life of the drug is currently charted at approximately a week: longer than just about any other neurogenic compound. While the major observed effect is synaptogenesis, in models of impairment the drug also revived production of tyrosine hydroxylase (the enzyme essential for the production of catecholamines such as dopamine and noradrenaline) in the substantia nigra (one of the largest concentrations of dopaminergic neurons in the brain).

Dihexa experiences

Discussion of history, MOA, pharmacokinetics, and obscurity aside, one question still remains: “What does it do when a healthy human takes it?” As with many neurogenic substances, the answer to such a question is predicted heavily on the existing neurochemical environment (including other drugs in the system), route of administration, and genetic predisposition. In the absence of neurological insult (science speak for “brain damage), which gives a firm basis for improvement, these conditions have a heavy bearing on whether such a substance will influence development at all. Formal testing of Dihexa in human trials has yet to even begin, due to the lack of funding for such research, and anecdotal reports are varied. Adventurous guinea pigs on different forums have listed dosages everywhere from 8 to 45 mg per day and report a variety of benefits, from increased mental stamina to heightened articulation. Users have reported increases in creative thinking, social intuition, and problem-solving skills. There has also been a fair deal of non-responders who haven’t felt anything at all.

Dihexa experienceThe author has personally experimented with a DMSO+Dihexa solution with a 16.67mg/mL concentration, applying .5mL to clean, exfoliated inner forearms every other evening for a week (3 doses, total). The experience was transformative in many of the ways purported by anecdote, including an increase in creativity, articulation, and problem-solving. What really distinguished the drug from other neurogenic substances in the author’s personal repertoire was how well it accelerated deliberation of social conflict. Remarkably large and fast leaps in logic allowed for prompt and thorough insight into the dynamics of ethical quandaries, suggesting a boost in critical thinking via the anterior cingulate cortex, the malfunction of which has been associated with such mental disabilities as ADHD[8] and ASD.[9]

Of course, this is only an informal study, complete with exposure to a multitude of confounding factors. Despite the promise already posed by Dihexa, poor funding and a lack of interest from much of the scientific community means that the chemical has a long way to go before human trials, let alone becoming an FDA-approved pharmaceutical, and if the view of the HGF/c-MET system as a vehicle for tumor growth persists, it may always be reserved for only the most severe cases of cognitive decline and physical distress. Still, for those determined few transhumanists willing to go to any lengths to transcend their normal limitations, Dihexa holds great promise and, despite its difficult procurement, doesn’t seem to be disappearing anytime soon. It is the imposing poster child of a new frontier in medicine, where the hopes of expectations met are to meet our expectations of ourselves.

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