1569 replies to this topic

[sk_scientific]

 

 

 

no problem xks, i do appreciate you not wanting me to waste my sample, this stuff is(maybe?) worth its weight in gold ^_^

 

Probably worth a lot more than that as 154mg of 99.9% (24k) pure gold is $6.48.

 

 

$20.02 per my calculations

 

 

I just found a random online calculator for gold prices. I might very easily be wrong. Even $20 isn't very expensive, though.

 

 

I was quoting the value of the Dihexa in hand, not gold prices.

[therein]

 

 

 

 

no problem xks, i do appreciate you not wanting me to waste my sample, this stuff is(maybe?) worth its weight in gold ^_^

 

Probably worth a lot more than that as 154mg of 99.9% (24k) pure gold is $6.48.

 

 

$20.02 per my calculations

 

 

I just found a random online calculator for gold prices. I might very easily be wrong. Even $20 isn't very expensive, though.

 

 

I was quoting the value of the Dihexa in hand, not gold prices.

 

 

Oh, okay. It's more expensive than gold for sure then.

[therein]

On a sidenote, I've just ingested 15mg sublingually. I'll keep you guys updated. It tastes like chalk and it is very hard to get it absorbed. Creates an odd burning sensation when administered sublingually.

Edited by therein, 23 July 2014 - 01:25 AM.

[Nemo888]

We need some baseline tests on you guinea pigs before this gets too far along.

Any ideas? Like these but with a finer calibration.

http://www.psychologytoday.com/tests

http://psychcentral.com/quizzes/

 

[therein]

Having ingested 15mg, I can say with absolute certainty that I am still very much alive. No side effects or discomfort at all.

 

I can say that I am more in the moment than I was the entire day. When I took Dihexa sublingually, I was crashing from 40mg of Vyvanse that I took in the morning. This crash normally lasts until I smoke cannabis later that night but the crash is nowhere to be seen right now. I am noticing a slight improvement in verbal fluency and I feel wide awake even though I think I have been chronically sleep deprived lately. There is definitely some psychoactivity, I just can't put my finger on it. Similarly to how Ritalin felt years ago when I took it for the first time, my peripheral vision feels more comprehensive. 

 

I'll take another 15mg when I wake up tomorrow morning and see where this takes me.

[therein]

While it is probably not a very smart thing to do, I vaporized a small amount of Cannabis while under the influence of Dihexa. As one would expect from a molecule that reverses Scopolamine-induced cognitive impairment almost completely, Dihexa was able to alter the high quite interestingly. I am feeling elevated like I normally would but I am not cognitively impaired at all. Thinking isn't any harder and sporadic thoughts reminiscent of being high are absent.

[mindpatch]

Just a quick update:  Are these experiences from another, separate group buy for dihexa?  There's quite a few of us who have been waiting for months after having paid a chunk of money for the synthesis to be completed and to finally try something that might hopefully help alleviate issues we've been having.  I've been patient, but I have to admit, it's a little hard to stomach waiting when there are people taking it to alter their cannabis intoxication.  

[neuroatypicow]

haven't you been staying current with this thread? if you go back to post #615, and read forward. it will catch you up. before the group buy yields product, we have an opportunity to try it out thanks to poster #615.

[therein]

Just a quick update:  Are these experiences from another, separate group buy for dihexa?  There's quite a few of us who have been waiting for months after having paid a chunk of money for the synthesis to be completed and to finally try something that might hopefully help alleviate issues we've been having.  I've been patient, but I have to admit, it's a little hard to stomach waiting when there are people taking it to alter their cannabis intoxication.  

 

Not from a separate group buy but from a third party individual that managed to get it synthesized on his own and was kind enough to offer samples to a small amount of people.

 

 

UPDATE: I woke up about 30 minutes ago and I wanted to provide some input. I haven't taken my second dose because I want to feel more comfortable with the chemical first. I'll take a second dose tomorrow morning if I don't notice anything alarming today.

 

Dihexa is definitely still active in my body and it's effects haven't diminished a bit. In fact, they might have even gotten stronger. One characteristic that I'm noticing is I'm showing symptoms similar to Restless Leg Syndrome. I tend to move my limbs a lot during quiet and calm times but Dihexa is certainly amplifying it.

 

I am also noticing an increase in blood pressure and a slight increase in the need for oxygen, or at least it feels that way. I find myself yawning a lot and being outside and getting fresh air makes me feel a lot better than it normally would. I almost feel a little under-oxygenated indoors. 

 

Normally I have a hard time reading long chunks of text. I normally skip sentences because "my brain doesn't feel like reading them" but yesterday reading was a breeze no matter how long the text was. I even joyfully read uninteresting pieces of text last night. I am noticing a significant change in the way that I write as well. I pick words that I normally wouldn't pick and I structure my sentences rather differently than I would before Dihexa.

 

I've observed some interesting non-cognitive effects as well. Since Dihexa is related to Angiotensin, I guess most of the following makes sense to a certain extent. I am more thirsty, drinking more water for sure. Despite the increased water intake, it seems I have to urinate less than usual. I'll have a more accurate representation of that today but yesterday definitely made me think that Dihexa is increasing water retention.

 

Now I am on my way to work as a software developer. Let's see how it affects my job. I am just thirsty all the time! I wish I had some water right now.

Edited by therein, 23 July 2014 - 03:35 PM.

[neuroatypicow]

daily update: day 4. 7:30am. Dihexa dose. 15mg., sub. no noticeable positives, no change in sleep last night from yesterday's dose.

11:00am. NSI dose. 25mg., sub. Side effect noticed: a half hour following my NSI dose (25mg., sub.) feel slight cranial vascular pressure on right temporal area.

 

 

[xks201]

Cow try it not sublingually.

[sk_scientific]

Cow try it not sublingually.

 

Did you lay the pills out for him?

Edited by sk_scientific, 24 July 2014 - 03:21 AM.

[neuroatypicow]

Cow try it not sublingually.

 

can i ask if you've felt anything at your dose and method? i'm amenable to changing my routine, i just would like a rationale for it.

i'll be dosing 20mg. tomorrow morning.

[FW900]

Cow try it not sublingually.

 

Sublingual administration usually results in increased bioavability.

 

You accused cow earlier of "wasting it" by taking too small of a dosage and taking it sublingually. In all reality, her smaller sublingual dosages may have been more effective than your large oral dosages.

 

http://www.dissertat...ccoy_020110.pdf

 

PHARMACOKINETIC
CHARACTERIZATION OF ANGIOTENSIN IV ANALOGS WITH THERAPEUTIC POTENTIAL FOR CANCER AND DEMENTIA.
By
ALENE MCCOY

 

The validated method was used to determine the pre-clinical pharmacokinetics of Dihexa after intravenous and intraperitone
al dosing. Dihexa exhibited a long half life in-vivo compared
to other angiotensin IV analogs
(18,256.48 minutes based in IV dos
ing data) and was not cleared
rapidly by the kidneys, which appear to play a minor
role in the total body elimination of Dihexa
based on evaluation of urine concen
trations. The bioavailability of
Dihexa after intraperitoneal
dosing was 8.32%, suggesting that Dihexa may ha
ve undergone extensive first-pass metabolism.
However this conclusion is not well supported
by studies with hepatic microsomes from adult
male Sprague-Dawley rats, which indicated that
Dihexa is not highly metabolized by phase I
metabolic enzymes. Dihexa exhibited minimal phase I enzymatic degradation compared to low,
moderate and highly metabolized reference compounds. It is possible that Dihexa was
extensively metabolized by phase II or other hepatic
enzymes. Another possibility is that Dihexa
precipitated out of solution upon injection in the intraperitoneal cavity and a large fraction of the
administered dose remained within the intraperitoneal cavity.

 

 

Dihexa exhibited low intraperitoneal bioavailability and no oral bioavailability. This was
surprising given its oral activity in behavioral studies. We hypothe size that Dihexa may be orally bioavailable to a very small degree and that resulting plasma concentrations, though below our limits of detection, are nevertheless adequate to induce a physiological response. Given that our first sample in the study using the largest dose of Dihexa was at one hour, it is possible that we have missed time points in which Dihexa concentrations were highest and might have been within our detectable range for that dose. This idea is supported by the fact that, after intraperitoneal dosing, plasma levels reached maximum concentrations within 10 minutes, indicating a very rapid absorption. It is possible that the low oral bioavailability of Dihexa can be attributed to first-pass metabolism, although this idea was not well supported by the low rate of phase I metabolism exhibited by Dihexa in the study using rat liver microsomes. However, the susceptibility of Dihexa to phase II or other metabolic enzymes has not yet been investigated.

Edited by FW900, 24 July 2014 - 03:47 AM.

[DHEXA]

Day 18 ~27mg QD

Visual perception seems to have become progressively sharper. Noticing details in my environment which I've never payed attention to before. Let's hope I don't develop a cleaning OCD or something.

The alertness is still very noticeable. Once I get out of bed I feel energized and focused for the entire day.
Still no sleep disturbances. If anything, I'm sleeping better now than before the trial. Not necessarily longer, but more deeply.

I had caffeine the other day, not much - just a cup of black tea (probably under 100mg?). Maybe It's just because I have no tolerance, but I was absolutely wired. I Definitely landed on the downward slope of the efficacy curve though. It was overstimulating and not at all helpful for my productivity. This may be an anecdote to keep in mind if you are using stimulants regularly.

 

If anyone's interested, I attempted to dissolve a small amount today. Effectively none of it was soluble in water. The compound clumped or floated.

[therein]

I am definitely noticing positive effects from sublingual dosing. Granted I ended up swallowing some of it but I don't think that makes a big difference as by the time I swallowed, most of the powder had dissolved.

 

I am mainly experiencing increased verbal fluency, anxiolysis, increased mental stamina and full prevention of dopaminergic stimulant crash. 

[sk_scientific]

 

In the intestine, where pH values are generally 

between 5 and 8, Dihexa is likely to be unionized, which should allow penetration of membranes 

there, especially given that it should be dissolved coming from the stomach. It is possible, 

however, that due to its high hydrophobicity, Dihexa may tend to precipitate out of solution in 

the intestine when its charged state is lost. Still, these properties prompt us to predict that some 

Dihexa should penetrate the lining of the intestine. This conclusion is supported by the 

appearance of enterohepatic recirculation after intravenous dosing. Gastric secretions after meals, 

which contribute to enterohepatic recirculation, lower intestinal pH, which may provide the right 

conditions for Dihexa solubility and absorption. Thus, we conclude that the fraction of Dihexa 

orally absorbed and transported into the systemic circulation at therapeutic doses is simply below 

our limit of detection. 

 

One wonders if exposed capilaries due to the presence of highly acid, and tissue deteriorating chewing tobacco like snus would impact sublingual absorbtion given that according to what I am reading, Dihexa is likely so utlimately potent that it doesn't matter if a vast majority of the molecule is passed straight through the digestive system it still seems to exhibit significant behavioral effects.

 

Additionally, Dihexa had a serious and immediate effect upon first dosing that was profound and unmistakable for me.  I think Alene's dissertation leaves a lot of "what ifs", which I am curious to see if have been answered in subsequent publications.

Edited by sk_scientific, 24 July 2014 - 04:26 AM.

[sk_scientific]

 

As mentioned briefly above, our recent studies 

show that Dihexa exhibits cognitive enhancing activity when administered orally. Implicit in the 

manifestation of oral activity is the assumption that the molecules not only penetrate the 

gastrointestinal tract, but also the blood-brain barrier. 

 

Maybe it goes to the brain and largely stays there some how, or maybe it's that protein binding thing.

 

This is puzzling.

[DHEXA]

Thanks for that FW900, good find!

I dug this out of the 2013 paper. It could possibly lend credence to the hypothesis that they waited too long to take the first data point? 
 

Dihexa appeared to be extensively distributed outside

the central blood compartment and/or bound within the

tissues as evidenced by its large V d . These results, which

suggest thatdihexa is very hydrophobic (logP), are in agreement

withtheoutcomeofQuantitativestructure–activityrelationship

(QSAR) modeling estimates generated by the ADMET Predictor

(Simulations Plus, Inc.; Lancaster, CA) that calculated an

octanol/water partition coefficient of 177.8 for dihexa (Table 4).
 

Not surprisingly because of its stability, hydrophobic

character, and small size, dihexa was predicted to be orally

bioavailable. The predicted effective human jejunal perme-

ability (P eff ) value represents the predicted effective human

jejunal permeability of the molecule (Table 4). The predicted

P eff value for dihexa (1.78) is intermediate between the

predicted P eff values for enalapril (1.25) and piroxicam (2.14),

two orally bioavailable drugs. Dihexa was also predicted to be

22.59% unbound to plasma proteins in circulation, thus

making it available for distribution into the tissues.

http://jpet.aspetjou...1.full.pdf html

 

 

It seems like there may be either a contradiction or a bit of deception in the published piece.

Do we know if MCCOY had access in 2010 to the same data that was used for the 2013 publication?

[FW900]

 

Thanks for that FW900, good find!

I dug this out of the 2013 paper. It could possibly lend credence to the hypothesis that they waited too long to take the first data point? 
 

Dihexa appeared to be extensively distributed outside

the central blood compartment and/or bound within the

tissues as evidenced by its large V d . These results, which

suggest thatdihexa is very hydrophobic (logP), are in agreement

withtheoutcomeofQuantitativestructure–activityrelationship

(QSAR) modeling estimates generated by the ADMET Predictor

(Simulations Plus, Inc.; Lancaster, CA) that calculated an

octanol/water partition coefficient of 177.8 for dihexa (Table 4).
 

Not surprisingly because of its stability, hydrophobic

character, and small size, dihexa was predicted to be orally

bioavailable. The predicted effective human jejunal perme-

ability (P eff ) value represents the predicted effective human

jejunal permeability of the molecule (Table 4). The predicted

P eff value for dihexa (1.78) is intermediate between the

predicted P eff values for enalapril (1.25) and piroxicam (2.14),

two orally bioavailable drugs. Dihexa was also predicted to be

22.59% unbound to plasma proteins in circulation, thus

making it available for distribution into the tissues.

http://jpet.aspetjou...1.full.pdf html

 

 

It seems like there may be either a contradiction or a bit of deception in the published piece.

Do we know if MCCOY had access in 2010 to the same data that was used for the 2013 publication?

 

 

I really wouldn't trust the 2010 piece, I mainly highlighted it to point out that it does not have 100% oral bioavailability so people realize that sublingual administration is the superior RoA for this substance. McCoy may have, but even if she did, it seems like she was just speculating from conflicting sources. Keep in mind it is an dissertation; many of which are done to satisfy the completion of a doctoral program. A lot of it is her speculation based on various studies.

[xks201]

I just don't understand how everyone here assumes something is going to absorb sublingually. There are multiple factors going into whether or not something absorbs sublingually. The study used oral dosing therefore I see no real reason to deviate without trying it how they said to take it first. You can't just assume some custom synth is going to absorb sublingually.

Edited by xks201, 24 July 2014 - 05:27 AM.

[therein]

I just don't understand how everyone here assumes something is going to absorb sublingually. There are multiple factors going into whether or not something absorbs sublingually. The study used oral dosing therefore I see no real reason to deviate without trying it how they said to take it first. You can't just assume some custom synth is going to absorb sublingually.

 

If it doesn't absorb, it will just make its way to the GI tract. That's why I am assuming sublingual is okay.

[xks201]

 

I just don't understand how everyone here assumes something is going to absorb sublingually. There are multiple factors going into whether or not something absorbs sublingually. The study used oral dosing therefore I see no real reason to deviate without trying it how they said to take it first. You can't just assume some custom synth is going to absorb sublingually.

 

If it doesn't absorb, it will just make its way to the GI tract. That's why I am assuming sublingual is okay.

 

Not necessarily. The molecule will have interacted with a lot of enzymes in the mouth and by the time what is left of it makes it to the gut who knows how much is really left. Metabolism is a zero sum game. It's like saying, airplanes land on land, but I am going to land my jet on water because sea planes land on water. The logic just isn't there. In the study they used oral administration, so I recommend oral administration first. 

 

I have experience with this. Saying that whatever sits in your saliva and half absorbs across a membrane is going to equate to the amount that ends up getting swallowed in the same form just is not true with most things. 

 

If you don't believe me, take your dose orally and tell me. 

 

If the enzymes in the mouth don't interact with it the particles will distribute around the mouth and not equate to any real dose as they slowly mix with food or dissolve there...

Edited by xks201, 24 July 2014 - 04:28 PM.

[neuroatypicow]

but none of the enzymes secreted by the salivary glands are of comparable strength with the potency of stomach juices and acids and pepsin, so i don't get your argument either. at least with sublingual dosing, you're giving a certain percentage of the compound to absorb directly into the bloodstream without becoming victim to the other problem with oral administration - mechanical digestion - the fact that a percentage of a substance escapes absorbtion by becoming intermingled with food matter that carries it through the g.i. tract, never becoming absorbed.

i try to take my nsi and dihexa on a near empty stomach for this reason.

maybe we can compromise - take 15 mg. sub., and 15 oral. = 30 mg./day, with a chance given for greater absorbtion in the sub. batch.

Edited by neuroatypicow, 24 July 2014 - 05:22 PM.

[sk_scientific]

If I'm not mistaken, Dihexa demonstrated little to no Phase I metabolism in the 2010 studies.  

 

'To avoid first pass metabolism a drug can be administered sublingual and buccal routes. These routes lead to drugs being absorbed by the oral mucosa. During sublingual administration the drug is put under the tongue where it dissolves in salivary secretions. An example of a sublingual drug is nitroglycerine. During buccal administration the drug is positioned between the teeth and the mucous membrane of the cheek. Both of these routes avoid destruction by the GI fluids and first pass effect of the liver. Drugs may also be administered via other routes to avoid first-pass metabolism, for example; rectal, inhalation, transdermal, intravenous.' [1]

I'm still going with the possibility that sublingual is an acceptable route of administration.  I know I felt effects more immediately than could be explained by interaction in the stomach, and especially the intestines.  Although it was hypothesized by the researchers that the intestines were likely to have an appropriate environment for absorbtion in their study, it takes many hours for drugs to get there, typically.

 

 

 

1. Essays, UK. (November 2013). The Drug Metabolism. Retrieved from http://www.ukessays....lism.php?cref=1

Edited by sk_scientific, 24 July 2014 - 05:15 PM.

[DHEXA]

Small non-polar compounds (like dihexa) are theoretically ideal for sublingual absorption. By the same token, if the compound is non-polar enough that it precipitates out of solution, then absorption will be hindered (both sublingually and in the small intestine - assuming its uncharged there). The researchers don't believe this is the case with dihexa - but they have provided no evidence one way or the other. MCCOY does give reason for us to question oral bio-availability in the dissertation.

I'm interested in transdermal administration. Dissolving dihexa in DMSO followed by topical application should push the molecule into circulation. Does anyone have direct experience with this?

[sk_scientific]

In 2010, I was approached by a friend who had Vitiligo.  I  recall that I used OHV Topical Solution as a transdermal vehicle for Pharmaceutical Grade Piperine.  I remember that as I was doing my research on the options, this one was largely used by body builders to transdermally deliver their 'roids'.  I think the company that made it was seized by the FDA, as I'm digging around...

 

Anyhow, It worked.

 

From my old notes here were the INGREDIENTS: 

 

Distilled water, grape spirits, aloe vera, ethoxy diglycol, dimethyl isosorbide, butylene glycol, jojoba oil, emu oil, squalene, tocopherol acetate, chamomile extract (matricaria recutita), isopropyl myristate, green tea extract (camellia sinensis), cetyl palmitate, sorbitan palmitate, sorbitan olivate, glyceryl stearate, PEG 100 stearate, glycerin, dimethicone, strontium nitrate, hydroxypropyl methylcellulose, d-Limonene, tetrahydropiperine, potassium sorbate, sodium benzoate, sodium PCA, sodium hydroxide.

 

This looks like it MIGHT be similar: http://centurysupple...-solution-225ml

 

However, you may want to tap some of your professional colleagues on this one.

 

Edited by sk_scientific, 24 July 2014 - 07:38 PM.

[DHEXA]

In 2010, I was approached by a friend who had Vitiligo.  I  recall that I used OHV Topical Solution as a transdermal vehicle for Pharmaceutical Grade Piperine.  I remember that as I was doing my research on the options, this one was largely used by body builders to transdermally deliver their 'roids'.  I think the company that made it was seized by the FDA, as I'm digging around...

 

Anyhow, It worked.

 

From my old notes here were the INGREDIENTS: 

 

Distilled water, grape spirits, aloe vera, ethoxy diglycol, dimethyl isosorbide, butylene glycol, jojoba oil, emu oil, squalene, tocopherol acetate, chamomile extract (matricaria recutita), isopropyl myristate, green tea extract (camellia sinensis), cetyl palmitate, sorbitan palmitate, sorbitan olivate, glyceryl stearate, PEG 100 stearate, glycerin, dimethicone, strontium nitrate, hydroxypropyl methylcellulose, d-Limonene, tetrahydropiperine, potassium sorbate, sodium benzoate, sodium PCA, sodium hydroxide.

 

This looks like it MIGHT be similar: http://centurysupple...-solution-225ml

 

However, you may want to tap some of your professional colleagues on this one.

Looks like the 'active' ingredient there is probably dimethyl isosorbide. Interesting that you were able to clear up vitiligo. I wonder have much of that had to do with vasodilation (and consequent photo-sensitivity) and how much had to do with piperine itself.

Completely unrelated, but i stumbled on a study you all might be interested in.

Increased Expression of Brain-Derived Neurotrophic Factor Preserves Retinal Function and Slows Cell Death from Rhodopsin Mutation or Oxidative Damage
http://www.jneurosci...0/4164.full.pdf

BDNF slows macular degeneration.
This might help explain the visual changes I've been experiencing.

[sk_scientific]

The course of treament was Tetrahydropiperine & piperine (topically) in the suspension, combined with UVR treatment and daily intake of 3-4 grams of L-phenylalanine.  So yes, you're right that was the objective.

 

 

Also in my notes (regarding the transdermal vehicle):

 

Only use compounds with a molecular weight (MW) of less than 500. Best results will be obtained from using ingredients with a MW of less than 300. Generally, the lower the MW, the better the absorption. Only use the pure ingredients, without other binders, fillers, oils, or solvents. Most compounds with a MW of less than 300 will be absorbed at a 30-40% rate over 12 hours. 

 

 

Tetrahydropiperine itself is purportedly known to enhance absorption of many compounds through the skin (it just happened to have efficacy in this repigmentation scenario). An unrelated fact is that when researching the poor efficacy of Curcumin (this was prior to the advent of J147), it was found that when food grade piperine was added to Curcumin, it significantly enhanced the oral bioavailability of curcumin.

 

Edited by sk_scientific, 24 July 2014 - 10:09 PM.

[sk_scientific]

 

Increased Expression of Brain-Derived Neurotrophic Factor Preserves Retinal Function and Slows Cell Death from Rhodopsin Mutation or Oxidative Damage
http://www.jneurosci...0/4164.full.pdf

BDNF slows macular degeneration.
This might help explain the visual changes I've been experiencing.

 

 

 

It may also imply that Dihexa is having an effect on synapses in the optic nerve, or even the occipital lobe.