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Chemically induced LTP?

ciltep pde4 forskolin ltp

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#2311 row1

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Posted 11 January 2014 - 10:16 AM

The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected.

Download the Study: http://download.cell...67407003443.pdf

It seems that you guys are dead right about cAMP in the PFC being a very big problem. This is not going to be peculiar to Forskolin/Artichoke, but rather to anything which indiscriminately increases cAMP production, as mere exposure to high levels of cAMP locks open the HCN channels. This can lead to LTP, or it can lead to a dysfunction in the brain's ability to moderate itself and engage in necessary inhibitory actions from run-away neurotransmission.

Incidentally, it also explains why I simply have not noticed any of these working memory deficits that people have been describing. You see, I am solidly diagnosed as ADHD, and as such elevated cAMP levels in the Prefrontal Cortex, and thus low working memory, involuntary hyperfocus, and higher stress levels in general are a normal part of my everyday mental state.

In other words, and not to put too fine a point on it, I think that CILTEP might actually be inducing partial symptoms of ADHD! It's ADHD-memetic!

But don't fret, there is hope! A lot of research has been put into this angle of ADHD-type disease, and there are treatments. That would be a great place to start when looking for a possible cure for this working memory deficit.

The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical norepinephrine or by medications like guanfacine.


There are already chemicals that work on these channels, which are primarilly focused in the Amygdala and the Prefrontal Cortex.

"Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."


But wait, it gets better.

Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.


Stress seems to be a related function, here. And there has been a lot of mention about irritability and stress from some people on this stack (and some of the even polite conversation seems strained, at times, by worry, anxiety, and bravado. I am not exempt.)

There is a downside to Guanfacine, however: It is a prescription medication. But it's function is as a Central α2 adrenergic receptor agonist. And as it turns out, some of our fellow Longecity members have looked into this, quite extensively: http://www.longecity...lpha-2-agonist/

Another angle to look at, here, is intracellular Mg+ levels, which is one of the cofactors in closing those HCN channels, albeit in a voltage dependant way. And when researching this, I found a very troubling study:

Caffeine has been extensively used to study intracellular Ca2+ control and contraction-relaxation in cardiomyocytes. The effects of caffeine on intracellular free Mg2+ concentration, [Mg2+]i, were studied in isolated adult rat ventricular myocytes by fluorescent techniques using mag-fura-2. Basal [Mg2+]i was 0.62 +/- 0.02 mM, n = 54, in quiescent cells and 0.73 +/- 0.02 mM, n = 23, in electrically-stimulated adult rat ventricular myocytes. Caffeine, 20 mM, significantly decreased [Mg2+] in both quiescent (-0.17 +/- 0.01 mM) and electrically-stimulated (-0.16 +/- 0.01 mM) adult ventricular myocytes. Ryanodine, a blocker for Ca(2+)-release channels of the sarcoplasmic reticulum, did not have any effect on basal [Mg2+]i, 0.67 +/- 0.02 mM nor on caffeine-induced reduction in [Mg2+]i, -0.16 +/- 0.01 mM in quiescent cardiomyocytes or electrically-stimulated cells; 0.74 +/- 0.03 mM and -0.11 +/- 0.03 mM, respectively. Ruthenium red, an inhibitor of mitochondrial Ca2+ uptake, also failed to alter basal [Mg2+]i, or caffeine-induced reduction in [Mg2+], in either quiescent or electrically-stimulated cells. The effects of caffeine on [Mg2+]i, may be important in considering the use of this drug to study contraction/function studies in heart cells.

http://www.ncbi.nlm..../pubmed/9030202

Some previous studies have reported the involvement of magnesium (Mg) deficiency in children with ADHD syndrome. In this work, 40 children with clinical symptoms of ADHD were followed clinically and biologically during a magnesium-vitamin B6 (Mg-B6) regimen (6 mg/kg/d Mg, 0.6 mg/kg/d vit-B6) which was set up for at least 8 weeks. Symptoms of ADHD (hyperactivity, hyperemotivity/ aggressiveness, lack of attention at school) were scored (0-4) at different times; in parallel, intraerythrocyte Mg2+ (Erc-Mg) and blood ionized Ca2+ (i-Ca) were measured. Children from the ADHD group showed significantly lower Erc-Mg values than control children (n = 36). In almost all cases of ADHD, Mg-B6 regimen for at least two months significantly modified the clinical symptoms of the disease: namely, hyperactivity and hyperemotivity/aggressiveness were reduced, school attention was improved. In parallel, the Mg-B6 regimen led to a significant increase in Erc-Mg values. When the Mg-B6 treatment was stopped, clinical symptoms of the disease reappeared in few weeks together with a decrease in Erc-Mg values. This study brings additional information about the therapeutic role of a Mg-B6 regimen in children with ADHD symptoms.

http://www.ncbi.nlm....pubmed/16846100

So basically, so sum that all up, it seems that Caffeine, specifically, aggrivates the same situation that the increased cAMP does, in reguards to the stuck-open HCN channels, and that increased Mg2+ may be a possible method of amelioriating that issue.

Anecdocally, I have been supplementing a product called "Krebs Cycle Chelates", from Enzymatic Therapy, along with fairly high doses of activated B-Complex. Fundimentally, what these contain are a very broad spectrum mineral supplement, the highest by weight being Magnesium and Calcium (both involved in nerve transmission potentials), all chelated to citrate, fumarate, maleate, succinate, and alpha ketoglutarate, along with complexed B-vitamins in their active forms. If those names don't ring a bell, they should. They are part of the Citric Acid Cycle in generating ATP, which is located in the mitochondria of cells, and could most definitely be considered as "intracellular". This could also be one of the reasons, in addition to already suffering from increased PFC cAMP levels, that I am not experiencing the noticeable working memory deficits that others seem to be. I thought this substance to be just a general mediator of ATP synthesis, but more and more I am finding that it has other effects that I had not anticipated.

Also, guess what mineral is present in Cocoa in high amounts?



Jeoshua

Very interesting finding...

The thing is that I don't have good result with this stack like other people dicribe.
Maybe some more energy and focus but slight.

But I have ADHD-PI (ADD)

Low Serotonin & Dopamine Levels I think?


That means too much inhibition of my one?? and maybe that only need to increase cAMP production?

Thus no architchoke...

But after reading:

"as mere exposure to high levels of cAMP locks open the HCN channels. This can lead to LTP, or it can lead to a dysfunction in the brain's ability to moderate itself and engage in necessary inhibitory actions from run-away neurotransmission."

I thing is better to wait :)

I must say that caffeine by itself is a pretty good nootripic (0,1gr)

Are there other people with ADD here? With no effect with ciltep.

And if you have good results...what your secret :laugh:

Edited by row1, 11 January 2014 - 10:18 AM.


#2312 Jeoshua

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Posted 11 January 2014 - 03:23 PM

In the interest of continuously improving on the CILTEP concept I did some more research and came up with another idea for manipulating cAMP levels in the CNS in a beneficial manner:

The idea is to find a herbal D1 agonist and a D2 antagonist with a good safety profile. D2 antagonists and D1 agonists raise cAMP in the CNS and I'm pretty sure nowhere else. This would help focus CILTEP in the CNS.


Dopamine receptors are definitely present, however, in more than just the Central Nervous system. I am almost positive that their end effects are different than in the brain, of course, but their function still likely hinges upon cAMP modulation. Just as Serotonin has different effects in the brain and on the digestive system, this is likely to have some kind of side effects (as all things do).

Cardio-pulmonary system
In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasodilatory effects of dopamine in the blood.[12] In rats, D1-like receptors are present on the smooth muscle of the blood vessels in most major organs.[13]
D4 receptors have been identified in the atria of rat and human hearts.[14] Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.[2]
Renal system
Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density.[13] In rats, D1-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D2-like receptors are present on the glomeruli, zona glomerulosa cells of the adrenal cortex, renal tubules, and postganglionic sympathetic nerve terminals.[13] Dopamine signaling affects diuresis and natriuresis.[2]

https://en.wikipedia.org/wiki/Dopamine_receptor#Non-CNS_dopamine_receptors

These side effects may be good ones, but they will not be the intended ones.

As far as the distribution of D1 receptors in the brain, it seems that they are tightly associated with the core of the brain:

The DRD1 gene expresses primarily in the caudate putamen in humans, and in the caudate putamen, the nucleus accumbens and the olfactory tubercle in mouse.

https://en.wikipedia...r_D1#Production

The nucleus accumbens angle is worrisome, since that is often involved in drug addiction and reward, and its activation has been shown to be related to the placebo effect. It is very likely that activation of these receptors will definitely feel like a good idea.

These findings are consistent with the hypothesis that this system is involved in the encoding of the ‘incentive value’ of the placebo, possibly acting as a gate or permissive system for the formation of placebo effects.

http://www.eurekaler...p-brc071607.php

On the other hand, the D2 receptor seems to be highly expressed primarilly in the Frontal Cortex, secondarilly in the Cingulate Cortex, Pareito-Occipital Cortex, and Amygdala, with weak expression in any other system of the brain. Having learned that cAMP accumulation is bad in the Pre-Frontal Cortex, this is definitely worrisome for the working memory angle: http://www.brain-map...t&e_ag=t&e_tr=t

Overall, I think this combination might be worse for working memory, but it would feel great and seem to be highly self-reinforcing.

Edited by Jeoshua, 11 January 2014 - 03:29 PM.

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#2313 Droplet33

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Posted 11 January 2014 - 07:08 PM

I ordered some leaft extract of Schinus Molle and the possible blood pressure effects are interesting :)!

Not a problem for me since i'm in the upper half of the green zone on automated blood pressure machines available in pharmacies (mind you, the heartbeats are slightly higher than what i'd like to, i don't do much exercise lately).

Still, i'll try to find one of those, test my blood pressure and take measurements at different dosage to see what happen. It could be useful to someone here :).

#2314 magta39

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Posted 11 January 2014 - 07:57 PM

Very interesting finding...

The thing is that I don't have good result with this stack like other people dicribe.
Maybe some more energy and focus but slight.

But I have ADHD-PI (ADD)

Low Serotonin & Dopamine Levels I think?


That means too much inhibition of my one?? and maybe that only need to increase cAMP production?

Thus no architchoke...

But after reading:

"as mere exposure to high levels of cAMP locks open the HCN channels. This can lead to LTP, or it can lead to a dysfunction in the brain's ability to moderate itself and engage in necessary inhibitory actions from run-away neurotransmission."

I thing is better to wait :)

I must say that caffeine by itself is a pretty good nootripic (0,1gr)

Are there other people with ADD here? With no effect with ciltep.

And if you have good results...what your secret :laugh:

I have never been officially diagnosed with ADHD but I do fall somewhere in that spectrum.....CILTeP has helped stabilize my moods but I notice decreased working memory on it...I think it is somewhat mitigated by taking small amount of galantamine with it...but now I am re-evaluating the whole stack....maybe I don't need forskolin at all....maybe some PDE inhibition from artichoke and vinpocetine is all I really need....I have noticed that artichoke (with or without coffee) in the afternoon on a non-CILTeP day really helps me focus....or maybe experiment with even smaller doses of forskolin, cutting back from 2mg to 1mg or less.

Edited by magta39, 11 January 2014 - 08:09 PM.


#2315 norepinephrine

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Posted 11 January 2014 - 11:42 PM

Jeoshua - fascinating insights about PFC cAMP, ADHD, cacao, magnesium, etc.

One mineral that I don't see brought up often in dialogue is zinc. In the personal sphere, I've noticed benefit in terms of increased libido and ability to focus, and a number of studies have been published in regards to the relationship it may play with ADHD:

Lower levels of zinc and iron seen in children with inattentive ADHD; lower levels of zinc, iron and magnesium seen in children with hyperactive ADHD - http://www.ncbi.nlm....pubmed/22206662

'Apparent improvement' noted in children who co-supplemented MPH with zinc - http://www.ncbi.nlm....pubmed/22696891

Zinc inhibition of forskolin-mediated cAMP signaling - http://www.ncbi.nlm....pubmed/11805091

Zinc regulates DAT in a membrane potential and chloride dependent manner - http://www.ncbi.nlm....pubmed/19000913

Additional food for thought - converts B6 into active form, aids in serotonin and melatonin production, etc. - http://adhd-treatmen...ombat-adhd.html

I've always considered magnesium a pretty crucial co-requisite to extended stimulant use; zinc certainly appears to be another.
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#2316 Jeoshua

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Posted 12 January 2014 - 04:17 AM

I must amend one of my prior assertions about the D2 receptor being specific to the Frontal Cortex. It seems I do not fully understand how to read the DNA Database's data correctly. There have been more STUDIES about it's presence in the Frontal Cortex, not that it was actually found there more often. I apologize (and if any moderators are able to excise that paragraph and the conclusion from my post, please do so).

Also, I was able to come across an interesting study, which deserves a bit of scrutiny:

Attention deficit/hyperactivity disorder (ADHD) is characterized by inattention, impulsivity, and motor hyperactivity. Several lines of research support a crucial role for the dopamine transporter (DAT) gene in this psychiatric disease. Consistently, the most commonly prescribed medications in ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-cocaine insensitive (DAT-CI)] has been generated carrying a cocaine-insensitive DAT that is functional but with reduced dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular dopamine levels and basal motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal dopamine turnover, altered basal phosphorylation state of dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D(2) receptor (D(2)R) function. However, although we demonstrated that striatal D(1) receptor (D(1)R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) treatment induced paradoxical motor calming effects, and (3) SKF 81297 administration failed to increase cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected dopamine D(1)Rs since haloperidol, by blocking the tonic inhibition of D(2)R, unmasked a normal activation of striatal adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that amphetamine, nomifensine, and bupropion, through increased striatal dopaminergic transmission, are able to revert motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D(1)R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular dopamine levels.

http://www.jneurosci.../11043.full.pdf

It seems that the D1 Agonism will preferentially increase cAMP levels in the Striatum and Caudate Putamen, along with weaker activity in the Hippocampus and Prefrontal Cortex (our other two targets/problem children), which would actually have the effect of inhibiting the Frontal Cortex. In the case of elevated whole-brain cAMP levels, as seen in ADHD and CILTEP-Forskolin/Artichoke, this may actually have an Amphetamine-like effect on increasing focus and being antispasmodic. It doesn't eliminate the possibility that it may also activate the Nucleus Accumbens, which certainly is activated with other D1 Agonists, and thereby stimulate the "reward" circuit. But just as Amphetamine has its uses, if not taken too far, so should Schinus Molle when used with a PDE4 Inhibitor.

------------------------

I don't mean to derail the thread with too much discussion about ADHD, it is just that the specific pharmacology of whole-brain cAMP increase along with PDE4 Inhibition have generated a lot of effects that are classically associated with ADHD, and a lot more reasearch has been done into how it operates than on Forskolin, In Vivo. I applaud any attempts to make the effects more specific to the Hippocampus, where cAMP and LTP have been extensively studied.

The minerals angle has a lot of potential in this area. Nearly everything involving nerve cell transmission along the neuron has to do with some mineral, or another. Ca+, Mg+, Mg2+, etc. And as such, I decided to try an experiment, on myself. I decided to forego my usual Mineral supplements and take just Forskollin/Luteolin. No Multivitamin, no minerals, no B6. It was a very disappointing experience, slightly buzzy and I felt like I could focus a bit more than baseline... until I got stressed out from something at work. My brain seemed to physically shut down! It was like the worst brain fart I had ever experienced. Thinking back, it was almost as if, at the time of the accute stressor, I could almost feel the nerves in my brain lock completely open, and was overwhelmed to the point of speechlessness.

Tommorow, I am going to perform the opposite trick. No cAMP or PDE inhibition. No coffee, even. Just the minerals and b-complex. We will see how far it goes around, on the other side of the equation (and it will likely be a lot safer to test).

Edited by Jeoshua, 12 January 2014 - 04:18 AM.


#2317 Jeoshua

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Posted 13 January 2014 - 12:06 AM

Today was rather lackluster, in a good way. No major stress, no hyperfocus, ADHD seemed well managed. I did notice a serious lack of verbosity and a tendency to just say what I felt instead of supporting it with facts and diagrams and the like. There were a few annoying stressors, all met with very calm and level-headed indifference... which is somewhat unlike my normal mental state. Overall it's been pretty boring... again, in a good way.

And thus, tommorow, I am going to try just PDE inhibition with the minerals and b-complex, and see how I fair.

#2318 Sholrak

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Posted 13 January 2014 - 01:20 PM

Jeoshua - fascinating insights about PFC cAMP, ADHD, cacao, magnesium, etc.

One mineral that I don't see brought up often in dialogue is zinc. In the personal sphere, I've noticed benefit in terms of increased libido and ability to focus, and a number of studies have been published in regards to the relationship it may play with ADHD:

Lower levels of zinc and iron seen in children with inattentive ADHD; lower levels of zinc, iron and magnesium seen in children with hyperactive ADHD - http://www.ncbi.nlm....pubmed/22206662

'Apparent improvement' noted in children who co-supplemented MPH with zinc - http://www.ncbi.nlm....pubmed/22696891

Zinc inhibition of forskolin-mediated cAMP signaling - http://www.ncbi.nlm....pubmed/11805091

Zinc regulates DAT in a membrane potential and chloride dependent manner - http://www.ncbi.nlm....pubmed/19000913

Additional food for thought - converts B6 into active form, aids in serotonin and melatonin production, etc. - http://adhd-treatmen...ombat-adhd.html

I've always considered magnesium a pretty crucial co-requisite to extended stimulant use; zinc certainly appears to be another.

That doesn't seem surprising anyway: Mg and Zn are two crucial minerals whose supplementation can be positive. Another would be selenium.

#2319 Jeoshua

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Posted 13 January 2014 - 02:00 PM

That doesn't seem surprising anyway: Mg and Zn are two crucial minerals whose supplementation can be positive. Another would be selenium.


It's not a surprise to find that we need these minerals, but it is interesting to find an increased need for them, and at least in my case, such a drastic change in the level of effect of the other supplements and overall effectiveness depending upon the specific level of the mineral. Other people had touched on taking a multivitamin and just considered it something they do. But it actually seems to be necessesary to supplement it in higher than usual amounts to have the stack work without breaking.

Edited by Jeoshua, 13 January 2014 - 02:00 PM.


#2320 basicallyyes

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Posted 16 January 2014 - 05:37 PM

Hey guys, this thread is massive, anyone tried these solar ray products from Vitamin Shoppe and had CILTEP success (or do you see any reason why they wouldn't work)? I've done a comparison with the OP's original suggestions and they look like a good comparison but maybe something was discovered in the middle of the thread that I don't know about...

http://www.vitaminsh...41#.UtgVI_RDuPs

http://www.vitaminsh...40#.UtgYT_RDuPs

Edited by basicallyyes, 16 January 2014 - 05:37 PM.


#2321 Rumpelstiltskin

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Posted 16 January 2014 - 06:18 PM

I always thought that zinc has a negative effect on calcium absorbsion. So I never took those two at the same time. But I came across this study that states its okay to take them together if the calcium amount is normal.

#2322 hephaestus

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Posted 16 January 2014 - 07:39 PM

That artichoke extract is about 2.5x as expensive as the jarrow product on amazon, and the forskolin is about 5x as expensive as the nutrigold product on amazon.

#2323 basicallyyes

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Posted 16 January 2014 - 11:14 PM

That artichoke extract is about 2.5x as expensive as the jarrow product on amazon, and the forskolin is about 5x as expensive as the nutrigold product on amazon.


Whoa, CILTEP enhances your math skillz

Edited by basicallyyes, 16 January 2014 - 11:15 PM.


#2324 magta39

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Posted 17 January 2014 - 12:30 AM

Here is some food for thought....could adding vinpocetine help those with ADHD?
Acute administration of vinpocetine, a phosphodiesterase type 1 inhibitor, ameliorates hyperactivity in a mice model of fetal alcohol spectrum disorder.

Nunes F, Ferreira-Rosa K, Pereira Mdos S, Kubrusly RC, Manhães AC, Abreu-Villaça Y, Filgueiras CC.

Author information

Abstract

BACKGROUND:

Maternal alcohol use during pregnancy causes a continuum of long-lasting disabilities in the offspring, commonly referred to as fetal alcohol spectrum disorder (FASD). Attention-deficit/hyperactivity disorder (ADHD) is possibly the most common behavioral problem in children with FASD and devising strategies that ameliorate this condition has great clinical relevance. Studies in rodent models of ADHD and FASD suggest that impairments in the cAMP signaling cascade contribute to the hyperactivity phenotype. In this work, we investigated whether the cAMP levels are affected in a long-lasting manner by ethanol exposure during the third trimester equivalent period of human gestation and whether the acute administration of the PDE1 inhibitor vinpocetine ameliorates the ethanol-induced hyperactivity.
METHODS:

From postnatal day (P) 2 to P8, Swiss mice either received ethanol (5g/kg i.p.) or saline every other day. At P30, the animals either received vinpocetine (20mg/kg or 10mg/kg i.p.) or vehicle 4h before being tested in the open field. After the test, frontal cerebral cortices and hippocampi were dissected and collected for assessment of cAMP levels.
RESULTS:

Early alcohol exposure significantly increased locomotor activity in the open field and reduced cAMP levels in the hippocampus. The acute treatment of ethanol-exposed animals with 20mg/kg of vinpocetine restored both their locomotor activity and cAMP levels to control levels.
CONCLUSIONS:

These data lend support to the idea that cAMP signaling system contribute to the hyperactivity induced by developmental alcohol exposure and provide evidence for the potential therapeutic use of vinpocetine in FASD.

#2325 Jeoshua

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Posted 17 January 2014 - 03:25 PM

Another D1 Agonist/D2 Antagonist to look into is (-)Stepholidine
https://en.wikipedia...ki/Stepholidine

It is found in Stephania intermedia, and is actually a fairly well known herb in Chinese medicine. In addition to the dopaminergic effects, it also has weak 5-HT1A agonism, which is not exactly unhelpful, here (downstream, modulating the α2-adrenergic receptors).

Overall it's a promising candidate, but I am having problems finding a source for it that is reasonably priced, as is the case with most ingredients from TCM.

#2326 Jeoshua

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Posted 18 January 2014 - 02:48 PM

Agmatine is a promising looking adjunct to the stack:

Acute agmatine (2.5-10mg/kg, s.c.) treatment facilitated hippocampal LTP.

http://www.ncbi.nlm....pubmed/20451544

Agmatine (0.1-100 microM) failed to activate pre-junctional alpha 2-adrenoceptors regulating transmitter release in the guinea-pig isolated ileum and rat isolated vas deferens, nor did it activate postjunctional alpha 2-adrenoceptors of the porcine isolated palmar lateral vein which mediate contraction or inhibition of forskolin-stimulated cyclic AMP formation.

http://www.ncbi.nlm..../pubmed/7715734

Among it's many effects, Agmatine seems to replace NO2 as a neurotransmitter, inhibiting its release and acting in its stead. It's effects on increasing specifically Hippocampal LTP over any other kind is also of use, here. It also seems not to interfere with the basic mechanism by which Forskolin works, at least not directly, and it seems to potentiate at least some of its effects while eliminating some of its side effects. I have been trying the whole stack + Agmatine and have noticed a marked improvement in the working memory aspect and overall calm.

Also, some of the things that people may be overlooking in the stack are actually of vital importance, such as Acetyl-L-Carnitine:

The beneficial effects of acetyl-L-carnitine may occur through amelioration of oxidative stress because it effectively decreases the levels of oxidative products and increases the activity of superoxide dismutase; this leads to a recovery in the suppressed activity of p53 caused oxidative stimuli, which in turn restores levels of insulin-like growth factor II, an important hormone for learning and memory.

http://www.ncbi.nlm....pubmed/24012657

Here we report that treatment with acetyl-l-carnitine (ALCAR), a substance which has been shown to prevent some impairments of the aged CNS in experimental animals as well as in patients, is able to increase the levels and utilization of nerve growth factor (NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be attained when ALCAR is given either for long or short periods to senescent animals of various ages, thus indicating a direct effect of the substance on the NGF system which is independent of the actual degenerative stage of the neurons.

http://www.ncbi.nlm..../pubmed/8187841

By increasing NGF expression, ALCAR grows the dendritic spines and prevents them from wasting away. This is of vital importance in LTP, as without healthy dendritic spines there are less synapses to potentiate.

So armed with Forskolin, Luteolin, Tyrosine, ALCAR, B-Complex, Minerals, and Agmatine, I have started on this new regimen. Results yesterday were stellar. I could think clearly, remember things I didn't think I even learned in the first place, an handled every challenge thrown at me with a clear and level head. No hint of mania, but a definite elevation of mood that was steady, insistent, and lasted throughout the day. Working memory was good, episodic memory good, long term memory excellent. I also recommend Methylxanthines of any kind (Caffeine, Theobromine, etc) to extend out the life of the enhancement. Once the initial Forskolin-dependant phase of cAMP increase is over (around 3 hours), the PDE inhibititory quality works to extend out the effects, as the initial phase of cAMP increase is over and done with, and levels just need to be maintained.

Edited by Jeoshua, 18 January 2014 - 02:51 PM.

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#2327 kai2

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Posted 18 January 2014 - 10:42 PM

Also, some of the things that people may be overlooking in the stack are actually of vital importance, such as Acetyl-L-Carnitine:

The beneficial effects of acetyl-L-carnitine may occur through amelioration of oxidative stress because it effectively decreases the levels of oxidative products and increases the activity of superoxide dismutase; this leads to a recovery in the suppressed activity of p53 caused oxidative stimuli, which in turn restores levels of insulin-like growth factor II, an important hormone for learning and memory.

http://www.ncbi.nlm....pubmed/24012657

Here we report that treatment with acetyl-l-carnitine (ALCAR), a substance which has been shown to prevent some impairments of the aged CNS in experimental animals as well as in patients, is able to increase the levels and utilization of nerve growth factor (NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be attained when ALCAR is given either for long or short periods to senescent animals of various ages, thus indicating a direct effect of the substance on the NGF system which is independent of the actual degenerative stage of the neurons.

http://www.ncbi.nlm..../pubmed/8187841

By increasing NGF expression, ALCAR grows the dendritic spines and prevents them from wasting away. This is of vital importance in LTP, as without healthy dendritic spines there are less synapses to potentiate.

So armed with Forskolin, Luteolin, Tyrosine, ALCAR, B-Complex, Minerals, and Agmatine, I have started on this new regimen. Results yesterday were stellar. I could think clearly, remember things I didn't think I even learned in the first place, an handled every challenge thrown at me with a clear and level head. No hint of mania, but a definite elevation of mood that was steady, insistent, and lasted throughout the day. Working memory was good, episodic memory good, long term memory excellent. I also recommend Methylxanthines of any kind (Caffeine, Theobromine, etc) to extend out the life of the enhancement. Once the initial Forskolin-dependant phase of cAMP increase is over (around 3 hours), the PDE inhibititory quality works to extend out the effects, as the initial phase of cAMP increase is over and done with, and levels just need to be maintained.


Hi Jeoshua,

Do you believe there to be a cumulative benefit from supplementing with ALCAR?

Also, Abelard chose to go with L-Phenylalanine in his NaturalStacks product, whereas you have chosen to use Tyrosine instead. Are you using L-Tyrosine or N-Acetyl-L-Tyrosine? Why did you choose it over L-Phenylalanine?

#2328 chung_pao

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Posted 19 January 2014 - 12:31 AM

Jeoshua,
Great posts you've been putting out lately. Just make sure they add to the discussion (Which they do so far) and they'll be appreciated!
I have some questions though,
Are you using pure luteolin or artichoke?

I love the stack. But artichoke is messy.... I don't want a 12h+ duration, and using isolated Luteolin might have better effects, with less positive GABA modulation and less MAO-transporter activation (due to an exclusion of apigenin, among others).

Also, do you notice the reduction in working memory? Or do you mitigate this somehow?
For me, it's less pronounced when using only forskolin + artichoke, but becomes much worse when adding artichoke.
The problem isn't so much the abstract notion of "working memory" - but verbal skills & comprehension of fast communication.
I have to plan the stack only on days when I have no important social interactions - since the stack basically makes me a hyperfocused, staring mute.
The PDE-inhibition is also something you have to be careful with, since it potentiates not only dopamine, but also adrenaline, i.e. anger.

I would appreciate the reply.

Edited by chung_pao, 19 January 2014 - 12:31 AM.


#2329 Jeoshua

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Posted 19 January 2014 - 04:51 AM

Hi kai2.

Do you believe there to be a cumulative benefit from supplementing with ALCAR?


Absolutely. They their use together is at least cumulative, in my experience, if not synergistic in it's effects with cAMP/PDE Inhibition for the purposes of encouraging potentiation. Acetyl-L-Carnitine helps growing dentritic spines (http://www.ncbi.nlm....les/PMC3515484/), giving more prime surface area for LTP to occur, which isn't exactly a bad thing. The Agmatine then narrows the playing field of most of the effects to just the hippocampus, and by it's effects on the HCN channels, keeping the lines of communication across the neuron's length out of the equation, since side-channel synapses tend to be more inhibitory and re-uptake related, if I recall correctly.

Also, Abelard chose to go with L-Phenylalanine in his NaturalStacks product, whereas you have chosen to use Tyrosine instead. Are you using L-Tyrosine or N-Acetyl-L-Tyrosine? Why did you choose it over L-Phenylalanine?


The rate limiting step in normal catchecholine synthesis is L-Tyrosine -> L-DOPA, and so creates a ready pool for synthesis, and Phenylketoneutrics are deficient in Tyrosine Synthase and cannot convert L-Phenylalanine -> L-Tyrosine safely and can quickly OD on Phe. Call it an attempt to reach a broader market.

Also I could only find DLPA when I went to the Vitamin Shoppe, so had to find a sensible alternative.

---------------

Are you using pure luteolin or artichoke?


I am using Swanson Ultra Luteolin Complex, which is confounded with Rutin, but is nevertheless the purest source of Luteolin I could reliably find for a reasonable price. Plus, it is ~50% Luteolin, in comparison to ~5-10% depending on which Artichoke Extract you choose, so far fewer confounding factors. I was previously using a Supercritical extract of Holy Basil, clocking in by most assays with around 2 times the amount of luteolin and similar esters thereof. It worked, but it also has some other aromatase inhibition co-factors that might be useful, but did make me a bit grumpier than usual as well as theoretically working against the rest of the stack, in the long term.

Also, do you notice the reduction in working memory? Or do you mitigate this somehow?


I did notice it, very profoundly, until recently. I could not remember two things at once, but somehow could remember complex knowledge from long term memory just fine. It led to a lot of "Hey Joe.... Uh, nevermind" moments. With the Agmatine (500mg, twice a day, but once is before bed since it is a bit sedating at 1g/day, but 500mg is fine for the day), I feel a tiny bit less "sharp" and a lot more "here".

The PDE-inhibition is also something you have to be careful with, since it potentiates not only dopamine, but also adrenaline, i.e. anger.


Well quite a lot of the different substances in CILTEP cause increase in neurotransmitter turnover (ie. metabolism), it would naturally cause this. I have thought of looking into inhibition of that system, but it seems like I would have to think long and hard about throwing in wrench in those works.

Edited by Jeoshua, 19 January 2014 - 04:57 AM.


#2330 row1

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Posted 19 January 2014 - 09:38 AM

Hi

I have been off ciltip for a while, beceause of no/little effect :(

But after hearing Abelard has read the book The Egde effect I was curious....and read the book

The book is interesting. In the book there is a "Braverman Nature Assement" test

also find it af: http://www.pintochir...m/PHP/sec1a.php

this is the outcome

This is my dominant nature (dopa and cholin)
1a total dopamine nature = 25
2a total acetylcholine nature = 26
3a total gaba nature = 18
4a tot serotine nature = 20


this is my deficiency (gaba and serotonin)
1b dopamine deficiency = 14
2b acetylcholine deficiency = 14
3b gaba deficiency = 16
4b serotonin deficiency = 15



Im wondering how I can modify the stack. Any ideas hear?

book suggest for gaba def
gaba :)
inositol
glutamic
melatonin
thiaimine
niacinamide
pyroxine
valarian rood
passioflower

for serotonin
cacium
fish oil
5htp
magn
mela
passoinfl.
pyridoxine
sam-e?
johns worth
trypto
zinc



Maybe for people who hasnt responding good. Try this test maybe you can adjust your stack.

Edited by row1, 19 January 2014 - 09:40 AM.


#2331 Nordmann

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Posted 19 January 2014 - 09:50 AM

Just want to add that a choline "depression" trumps the effect of this stack. I had two weeks with little to no effect, I had increased the amount of Alpha GPC in my Pre-workout. Dropped the Alpha GPC, and is back to full effect now, feels like when I first started the stack :)

#2332 cat@

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Posted 19 January 2014 - 11:39 AM

But after hearing Abelard has read the book The Egde effect I was curious....and read the book

The book is interesting. In the book there is a "Braverman Nature Assement" test

also find it af: http://www.pintochir...m/PHP/sec1a.php


Thanks. Has anyone read his latest book, Younger Brain, Sharper Mind: A 6-Step Plan for Preserving and Improving Memory and Attention at Any Age from America's Brain Doctor? Does it compare?

#2333 Jeoshua

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Posted 19 January 2014 - 04:44 PM

Just want to add that a choline "depression" trumps the effect of this stack. I had two weeks with little to no effect, I had increased the amount of Alpha GPC in my Pre-workout. Dropped the Alpha GPC, and is back to full effect now, feels like when I first started the stack :)


Personally I have been eating a few eggs, sunny side up, for years, so I never ran into choline problems, but that does bring up a good point. One of the biggest supplements that had a potentiating effect on CILTEP, for me, was L-Tyrosine. For you, the limiting factor was Choline. For others it might be Serotonin. And Agmatine is a neurotransmitter, as well.

Given that Luteolin causes an increase in neurotransmitter turnover, and the facts that for me Dopamine was a limiter and for you Acetylcholine was a limiter, it might be advisable to find an adjunct to the stack that increases neurotransmitter synthesis across the board. I have halfway done that, with the B-Complex and C (2 Oranges a day, usually). But there are other ways to go about this. A lot of people talk about mood problems, and Serotonin might have an effect, as well.

L-Tryptophan: Synthesis pool for Serotonin.
L-Tyrosine: Synthesis pool for all Catecholamine precursors (Dopamine, Noradrenaline, etc).
CDP-Choline: Metabolized in the body into Choline and Uridine.
- Choline: Synthesis pool for Acetylcholine and precursor to all phospholipids (major component of dendritic membranes).
- Uridine: Part of the Kennedy Cycle, helps in creating phospholipids, encourages neurite outgrowth and release of Dopamine.
ALCAR: Assists with conversion of Choline -> Acetylcholine, encourages neurite outgrowth.
B-Complex: General enzymatic assistance in molecular conversions and cellular metabolism.
Vitamin C: General enzymatic assistance and cellular metabolism.

So instead of Alpha-GPC, using CDP-Choline would be cheaper and more effective, due to the presence of increased Uridine levels due to that little quirk of metabolism. Alpha-GPC is good, but for the purposes of increasing Acetylcholine, it is not the perfect ideal candidate that it's price would suggest.

As far as the Aminos outlined above, and the vitamins, the most useful way to supplement them may be through food. Protein powders (all kinds) contain plenty of those Aminos, in the right proportions. And any multivitamin worth it's salt has a fairly complete B-Complex component, along with Vitamin C. So downing a good multivitamin with a glass of protein powder about an hour after dosing could go a long way towards increasing the effects of the stack.

I am going to fine tune my stack:

-CILTEP Base
Forskolii extract (5mg forskolin)
Luteolin Complex (50 mg Luteolin)

-Vitamin and Mineral Support
Mineral supplement (100% all essential minerals)
Multivitamin (lots of stuff, really)

-Neurotransmitter Support
Acetyl-L-Carnitine (400mg)
CDP-Choline** (200 mg)
L-Tryptophan* (500 mg)
L-Tyrosine (500 mg)
Agmatine (500 mg)

* I take the L-Tryptophan at night and on weekends, already.
** Still yet to source.

Edited by Jeoshua, 19 January 2014 - 05:44 PM.

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#2334 hephaestus

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Posted 19 January 2014 - 06:28 PM

He said removing the AGPC potentiated this stack.

#2335 Jeoshua

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Posted 19 January 2014 - 09:15 PM

He said removing the AGPC potentiated this stack.


And Alpha-GPC is known for being too much of a good thing, and inducing depression in large doses. CDP-Choline is not, due to being far enough back in the chain of synthesis of both Acetyl-Choline and Phospholipids to provide a pool for replenishing these substances, rather than flooding the brain with them. Even tho CDP-Choline as a chemical is pretty far along the biosynthetic pathway towards Phospholipid synthesis, it has an oral halflife of only a few minutes in that form, instead raising plasma levels of Choline and Uridine.

Plasma choline exhibited dose-related increases in peak values and areas under the curves (AUCs), remaining significantly elevated, after each of the three doses, for 5, 8, and 10 hr, respectively. Plasma uridine was elevated significantly for 5– 6 hr after all three doses, increasing by as much as 70 –90% after the 500 mg dose, and by 100 –120% after the 2000 mg dose. Plasma cytidine was not reliably detectable, since it was less than twice blank, or less than 100 nM, at all of the doses. Hence, it seems likely that the circulating substrates through which oral citicoline increases membrane phosphatide synthesis in the brains of humans involve uridine and choline, and not cytidine and choline as in rats

http://web.mit.edu/d...www/pdf/972.pdf

I would use CDP-Choline for the same reason I chose to go with L-Tryptophan and L-Tyrosine, rather than 5-HTP or L-Dopa.

Edited by Jeoshua, 19 January 2014 - 09:18 PM.


#2336 Nordmann

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Posted 19 January 2014 - 10:54 PM

I was using Alpha GPC mainly because of the Power Output, Growth Hormone spike and Focus.

But my last workouts have been a lot more fun and energized after I stopped Alpha GPC and the Ciltep stack started working again.

I have experienced choline "depression" earlier with CDP Choline, but this time it was hard to discover the "depression" as I think the ciltep stack sort of masced it, I wasn`t feeling down, but I wasn`t feeling hapy either.

I now eat two eggs everyday for the nutrients as I`m dieting/calorie restriction to a upcoming fight. I will stop all choline intake, and only use in small doses if I feel deficient.

#2337 abelard lindsay

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Posted 21 January 2014 - 07:41 PM

So I got my Schinus Molle from InkaNatural. I put a drop or two on a q-tip and applied it to my skin. I figured this would be a good way to test it as it is used in cosmetics and such for improving skin and is also a potent anti-microbial. I had also taken CILTEP that morning. The effect was certainly noticeable. I went through my usual round of cambridgebrainsciences and the results were below average except for grammatical reasoning, where I got one of my highest scores. Grammatical Reasoning always seems to benefit the most from CILTEP in my experience. What I really noticed was the image streaming of events since I took it. I can play back things I was doing earlier in the day in a very movie like fashion. Anyway, I'm going to take 2 grams of ALCAR to see if I can counteract what feels like an Acetylcholine dip.

#2338 p3x888

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Posted 21 January 2014 - 08:41 PM

So I got my Schinus Molle from InkaNatural. I put a drop or two on a q-tip and applied it to my skin. I figured this would be a good way to test it as it is used in cosmetics and such for improving skin and is also a potent anti-microbial. I had also taken CILTEP that morning. The effect was certainly noticeable. I went through my usual round of cambridgebrainsciences and the results were below average except for grammatical reasoning, where I got one of my highest scores. Grammatical Reasoning always seems to benefit the most from CILTEP in my experience. What I really noticed was the image streaming of events since I took it. I can play back things I was doing earlier in the day in a very movie like fashion. Anyway, I'm going to take 2 grams of ALCAR to see if I can counteract what feels like an Acetylcholine dip.


Is this the one you got? I don't know if I am allowed to post this, I just want to confirm that this is the right one -

http://www.inkanatur...s.html#comprarm

#2339 basicallyyes

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Posted 21 January 2014 - 11:03 PM

how quickly do you guys feel the effect? It took me a couple of hours

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#2340 abelard lindsay

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Posted 22 January 2014 - 03:36 AM

Is this the one you got? I don't know if I am allowed to post this, I just want to confirm that this is the right one -

http://www.inkanatur...s.html#comprarm


Yeah that's the one I got but I don't know if I would recommend it. It was certainly an interesting experience. Everything got very pretty, I was listening to audio books at 3x and enjoying it and I can vividly image stream a lot of my day. However! My stomach was generating a lot of acid and I felt faint at times, something wasn't right. I measured my blood pressure when I got home later that day and it was fine and all the while I was drinking a lot of caffeine to keep the blood pressure up just in case. However, I know Schinus is an ACE inhibitor (http://www.ncbi.nlm....pubmed/20185303) and can thus lower blood pressure. Schinus is also somewhat of a d1 agonist(http://informahealth...i.41.1.45.14695) and dihydrexidine, a strong full D1 agonist was rejected because of hypotension problems (http://www.ncbi.nlm..../pubmed/9844789). Maybe at some point someone could create a way to reliably microdose this but for now I'd recommend against it because I did feel kind of faint and disturbingly off about 5 hours after applying it.

In conclusion, the therapeutic window is probably narrow here and thus I would *NOT* recommend Schinus Molle at this time in combination with CILTEP.

What I can take away from this is that there's plenty of room for improvement in the PDE4 Inhibition/cAMP effect... just not this way.





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