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Chemically induced LTP?

ciltep pde4 forskolin ltp

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#2281 Droplet33

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Posted 07 January 2014 - 03:10 AM

Which form would be the most potent and useable?

If we believe the inkanatural website, the fruits have the most essential oils (5%) versus the leaf (2%), can't say for the bark. For ease of administration, wouldn't be the oil extract be easier to control in regards to quantity?

For all we know, the leaf extract from Healing Herbs might be a big pot of leafs.

#2282 abelard lindsay

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Posted 07 January 2014 - 03:23 AM

Which form would be the most potent and useable?

If we believe the inkanatural website, the fruits have the most essential oils (5%) versus the leaf (2%), can't say for the bark. For ease of administration, wouldn't be the oil extract be easier to control in regards to quantity?

For all we know, the leaf extract from Healing Herbs might be a big pot of leafs.


The study I referenced said that it was the leaf extract that had the most powerful D1/D2 cAMP activity.

There's also evidence for an anti-depressant effect in the leaf extract.

http://www.ncbi.nlm....pubmed/17182164

Abstract


Schinus molle L. (Anacardiaceae), among other uses, is popularly employed for the treatment of depression. In this study, the antidepressant-like effect of the hexanic extract from leaves of S. molle was investigated in the mouse tail suspension test (TST), a predictive model of depression. The immobility time in the TST was significantly reduced by the extract (dose range 30-600 mg/kg, p.o.), without accompanying changes in ambulation when assessed in an open-field test. The efficacy of extract was found to be comparable to that of fluoxetine (10 mg/kg, p.o.). The anti-immobility effect of the extract (100 mg/kg, p.o.) was prevented by pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), NAN-190 (0.5 mg/kg, i.p., a 5-HT(1A) receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), MDL72222 (0.1 mg/kg, i.p., a 5-HT(3) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a D(1) receptor antagonist) or sulpiride (50 mg/kg, i.p., a D(2) receptor antagonist). It may be concluded that the hexanic extract of S. molle produces an antidepressant-like effect that seems to be dependent on its interaction with the serotonergic, noradrenergic and dopaminergic systems. These results provide evidence that the extract from S. molle shares with established antidepressants some pharmacological effects, at least at a preclinical level.


This looks like powerful stuff. I'm going to way underdose and be super careful!!

Edited by abelard lindsay, 07 January 2014 - 03:40 AM.

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#2283 Droplet33

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Posted 07 January 2014 - 03:48 AM

And probably stay away from Zembrin as well ;) !

I suppose you're ordering from Healing Herbs, how much did you order?

#2284 Jeoshua

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Posted 07 January 2014 - 04:31 AM

Just something to add to the pile of evidence here:

Functional activation of monoamine transporters by luteolin and apegenin

Monoamine transporters playing major roles in regulating normal and abnormal synaptic activity are associated with various neuropsychological disorders. In spite of the discovery of a series of structurally different monoamine transporter antagonists for the therapy approach, no practical pharmaceutical can act as a transporter activator. Here, we isolated luteolin and apigenin from the fruit of Perilla frutescens (L.) Britt by using an activity-guided extraction technique, and proved that the two compounds possess actions of enhancing monoamine uptake either upon monoamine-transporter transgenic Chinese hamster ovary (CHO) cells or upon wild dopaminergic cell lines, with higher specificity for dopamine (DA) uptake than for norepinephrine (NE)- and serotonin (5HT)-uptake, as well as with more potency and greater efficacy for luteolin than for apigenin. Further, in the transgenic cells, the principal NE/DA uptake activation by luteolin was significantly prevented by respective transporter inhibitor, and the transmitter-uptake-enhancing action was independent of its ligands, which is in support of the compounds as monoamine transporter activators. Furthermore, luteolin evoked a marked disinhibition of cocaine-targeted effect in CHO cells overexpressing dopamine transporter. Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity.

http://www.ncbi.nlm.nih.gov/pubmed/19815045

#2285 BioFreak

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Posted 07 January 2014 - 11:45 AM

Antagonizing d2 receptors may be a bad idea. Specifically, it could reduce spartial working memory. Enhancing d2 are connected to spartial working memory.
http://msurj.mcgill....Liggins2009.pdf
http://www.ncbi.nlm....pubmed/14764884

And there seems to be inconsistent knowledge of d2 antagonism on working memory...

However...

Sulpiride and mnemonic function: effects of a dopamine D2 receptor antagonist on working memory, emotional memory and long-term memory in healthy volunteers.

(...)After dopamine D2 receptor blockade, performance was not impaired on the spatial WM (SWM) task, but was impaired on the auditory counting task with distraction. Sulpiride did not impair, but rather appeared to enhance trial-and-error learning overall. Thus, we were unable to support the notion that dopaminergic modulation preferentially influences spatial over non-spatial processing during learning. In addition, recognition was impaired in the emotional memory task after encoding on drug compared to placebo.

http://www.ncbi.nlm.nih.gov/pubmed/15671126

I guess I'll personally pass on d2 receptor antagonists though, I don't want to trade enhancement in one area for decreased performance in another. And seems like literature is pretty inconclusive on this one, so it might be a matter of personal genetics if it works or not.

Plus, it seems like neurogenesis is enhanced when neurotransmitters are activated properly, and atrophy happens when receptors are not used enough. Meaning this would result in atrophy in any part of the brain that has lots of d2 receptors.

Specifically,

Neurospheres have been demonstrated to express D1- and D2-like DAergic receptors.[143145] Treatment of neurospheres with bromocriptine and apomorphine, significantly increased cell proliferation[143,144] which was blocked by the D2-like antagonist sulpiride,[143,144] suggesting that it was indeed mediated via the D2-like receptors.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312696/

So d2 antagonism at least inhibits cell proliferation. And I am pretty sure that is not because of the specific drug, but because of its antagonistic action on d2. Decreased neurogenesis(or even potential atrophy) in some parts of the brain is a huge price to pay for better learning capabilities while on a stack.

#2286 Jeoshua

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Posted 07 January 2014 - 01:50 PM

Myself, I'm going to see if Forskolin's effect can be replicated by CORDYCEPS.
Studies suggest it's also an agonist at adenosine receptors (A2), while having other cool properties.
http://www.ncbi.nlm......7229422<br />

whereas the NO-sensitive guanylyl cyclase inhibitor ODQ did not alter the cordycepin-induced up-regulation of cGMP, the adenylyl cyclase inhibitor SQ22536 completely blocked the cAMP enhancement mediated by cordycepin, indicating that cordycepin had different modes of action.

http://www.ncbi.nlm......1512251<br />
But I'm still testing Cordyceps + Artichoke out of curiosity. At least, it'll probably have some cool effects on fertility.


Keep us posted on that. One of my first thoughts on how to possibly improve the CILTEP stack was how one could increase cGMP, as well, and is one of the things that let me to looking into Holy Basil. Not that I found any studies suggesting that it increases it, but cGMP also pulls up herbal supplements when using Google Searches (certificate of Good Manufacturing Practices).

Also, Luteolin is a PDE 1-5 inhibitor (Affinities being for 4, 2, 1, 3, and 5, in that order, descending), so we are basically halfway there in having a cAMP/cGMP increaser with Cordyceps + Luteolin.

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

Although, after doing a little research:

Cordycepin Inhibits Protein Synthesis and Cell Adhesion through Effects on Signal Transduction

3′-Deoxyadenosine, also known as cordycepin, is a known polyadenylation inhibitor with a large spectrum of biological activities, including anti-proliferative, pro-apoptotic and anti-inflammatory effects. In this study we confirm that cordycepin reduces the length of poly(A) tails, with some mRNAs being much more sensitive than others. The low doses of cordycepin that cause poly(A) changes also reduce the proliferation of NIH3T3 fibroblasts. At higher doses of the drug we observed inhibition of cell attachment and a reduction of focal adhesions. Furthermore, we observed a strong inhibition of total protein synthesis that correlates with an inhibition of mammalian target of rapamycin (mTOR) signaling, as observed by reductions in Akt kinase and 4E-binding protein (4EBP) phosphorylation. In 4EBP knock-out cells, the effect of cordycepin on translation is strongly reduced, confirming the role of this modification. In addition, the AMP-activated kinase (AMPK) was shown to be activated. Inhibition of AMPK prevented translation repression by cordycepin and abolished 4EBP1 dephosphorylation, indicating that the effect of cordycepin on mTOR signaling and protein synthesis is mediated by AMPK activation. We conclude that many of the reported biological effects of cordycepin are likely to be due to its effects on mTOR and AMPK signaling.

http://www.jbc.org/content/285/4/2610.full

As I understand it, this would get in the way of the long-term, protein synthesis dependent portion of LTP. By being so very close in structure to Adenosine, the Cordycepin can and will be incorporated into DNA/RNA synthesis reactions, thereby terminating the synthesis chain and causing the whole nucleic acid to be aborted (as well as the Cordycepin lost). This might be part of its function, as it would lead to increased intracellular levels of Adenosine and Guanosine from the now catabolized RNA strain, and by that stroke increase the raw materials for cAMP and cGMP. It does make sure that any LTP gained from it's concomitant usage with Luteolin would be short lived, and would be only the initial stages, thereof, with chronic usage.

Edited by Jeoshua, 07 January 2014 - 02:49 PM.


#2287 leoben

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Posted 08 January 2014 - 05:46 AM

Anyone tried CILTEP with alpha brain?

Ive tried combining these supplements over the last couple of days and I feel like I have rock solid focus throughout the day.

Ive observed that using only CILTEP makes me pretty well focused but also gets me somewhat introverted and effects my speech and verbal abilities. Like I just want to sit and focus on one thing all day.

Using Alpha brain alone did not do much for me in terms of focus but I felt more confident in general and boosted my verbal skills beyond baseline. Almost as if I could form very coherent sentences without any prior think. Very spontaneous in a sense.

Combining the two gave me the benefits of each of them and I feel extremely well balanced. Haven't noticed an issues with sleep or tiredness either.

Any thoughts?

#2288 chung_pao

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Posted 08 January 2014 - 03:45 PM

This study explains the problem with the mechanism of ciltep: reduced working memory.
This affects speech, executive function and spatial senses.
http://www.sciencedi...092867407003443

Etazolate is a PDE4 inhibitor that increases cAMP levels by inhibiting the breakdown of endogenously produced cAMP. Iontophoretic application of etazolate (25 nA) had highly consistent suppressing effects on spatial mnemonic activity in 10 of 12 PFC neurons.


Recent studies indicate that elevated cAMP signaling in PFC impairs behavioral measures of WM, and that α2A-AR stimulation improves WM performance via Gi suppression of cAMP intracellular signaling. In contrast to long-term memory consolidation which is facilitated by cAMP signaling, WM performance at short delays is impaired by increased cAMP signaling, e.g., following infusion of the cAMP analog, Sp-cAMPS, into the rat PFC (Taylor et al., 1999). Similarly, WM performance of aged monkeys is impaired by systemic administration of the phosphodiesterase 4 (PDE4) inhibitor, rolipram, which increases endogenous levels of cAMP (Ramos et al., 2003). The enhancing effects of guanfacine on WM can be blocked by coinfusion of low dose Sp-cAMPS in the rat PFC (Ramos et al., 2006). Conversely, inhibition of cAMP with Rp-cAMPS infusions improved WM performance (Ramos et al., 2003). These findings indicate that excessive cAMP actions in PFC impair WM. Importantly, dysregulated cAMP signaling may contribute to WM deficits in schizophrenia, as a gene linked to this disorder, DISC1, has been found to upregulate PDE4B activity under conditions of high cAMP production (Millar et al., 2005). Thus it is key to understand how elevated cAMP signaling impairs PFC cognitive operations.


Now if we could only avoid cAMP accumulation in the PFC, that'd be great. But would also require very selective PDE inhibition. (?)

Edited by chung_pao, 08 January 2014 - 03:49 PM.

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#2289 Droplet33

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Posted 08 January 2014 - 04:15 PM

So d2 antagonism at least inhibits cell proliferation. And I am pretty sure that is not because of the specific drug, but because of its antagonistic action on d2. Decreased neurogenesis(or even potential atrophy) in some parts of the brain is a huge price to pay for better learning capabilities while on a stack.


Food for thoughts : Could the neurogenesis coming from a dose of uridine/DHA MrHappy stack, taken before going bed, help to mitigate the side effects of d2 antagonism ?

Just saying, i'm waay out of my league here :)!

#2290 leoben

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Posted 08 January 2014 - 05:28 PM

This study explains the problem with the mechanism of ciltep: reduced working memory.
This affects speech, executive function and spatial senses.
http://www.sciencedi...092867407003443

Etazolate is a PDE4 inhibitor that increases cAMP levels by inhibiting the breakdown of endogenously produced cAMP. Iontophoretic application of etazolate (25 nA) had highly consistent suppressing effects on spatial mnemonic activity in 10 of 12 PFC neurons.


Recent studies indicate that elevated cAMP signaling in PFC impairs behavioral measures of WM, and that a2A-AR stimulation improves WM performance via Gi suppression of cAMP intracellular signaling. In contrast to long-term memory consolidation which is facilitated by cAMP signaling, WM performance at short delays is impaired by increased cAMP signaling, e.g., following infusion of the cAMP analog, Sp-cAMPS, into the rat PFC (Taylor et al., 1999). Similarly, WM performance of aged monkeys is impaired by systemic administration of the phosphodiesterase 4 (PDE4) inhibitor, rolipram, which increases endogenous levels of cAMP (Ramos et al., 2003). The enhancing effects of guanfacine on WM can be blocked by coinfusion of low dose Sp-cAMPS in the rat PFC (Ramos et al., 2006). Conversely, inhibition of cAMP with Rp-cAMPS infusions improved WM performance (Ramos et al., 2003). These findings indicate that excessive cAMP actions in PFC impair WM. Importantly, dysregulated cAMP signaling may contribute to WM deficits in schizophrenia, as a gene linked to this disorder, DISC1, has been found to upregulate PDE4B activity under conditions of high cAMP production (Millar et al., 2005). Thus it is key to understand how elevated cAMP signaling impairs PFC cognitive operations.


Now if we could only avoid cAMP accumulation in the PFC, that'd be great. But would also require very selective PDE inhibition. (?)


chung_pao,

That makes a lot if sense. I've also noticed that reducing my caffeine intake helps while on this stack.

#2291 Droplet33

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Posted 08 January 2014 - 05:32 PM

This looks like powerful stuff. I'm going to way underdose and be super careful!!


What might be your starting point, in regard to dosage :)?

#2292 BioFreak

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Posted 08 January 2014 - 07:19 PM

So d2 antagonism at least inhibits cell proliferation. And I am pretty sure that is not because of the specific drug, but because of its antagonistic action on d2. Decreased neurogenesis(or even potential atrophy) in some parts of the brain is a huge price to pay for better learning capabilities while on a stack.


Food for thoughts : Could the neurogenesis coming from a dose of uridine/DHA MrHappy stack, taken before going bed, help to mitigate the side effects of d2 antagonism ?

Just saying, i'm waay out of my league here :)!


And I thought no one here reads my posts. :laugh: I would not go into the d2 antagonism direction in the first place. And, it is still unclear to me why uridine and forskolin do not play well with each other. A dopamine depleting effect has been proposed, but I am not sure if this is the (only) reason.

For anyone trying to increase cGMP... quercetin has an effect on it too, I haven't looked into it so I can't say its good or bad, just pasting it here FYI:

http://www.ncbi.nlm....les/PMC2828021/

Quercetin and quercetin 3′-sulphate inhibited endothelin and U46619-induced contractions with greater potency (three- to fivefold) against the former, while quercetin 3-glucoronide was inactive. Quercetin enhanced both the cyclic GMP content of the artery (threefold) and cyclic GMP-dependent relaxations to GTN and SNP (two to threefold), but forskolin-induced relaxations were unaffected. Although the effect of quercetin was qualitatively similar to that noted for UK-114,542, a selective inhibitor of phosphodiesterase 5, it was still evident against SNP-induced relaxations in the presence of 10 nM UK-114,542. Quercetin and quercetin 3′-sulphate significantly reduced the development of GTN-associated ‘tolerance’.


And food for thought for mega dosing quercetin:
From own experiments it seems that it does increase neurotransmitters at moderate dosages(and has some other very benifical action), while at high dosages it seems like it does massively decrease neurotransmitters. So its a double edged sword really... And it might even be contraindicated for bipolar disorder... if anyone is interested, pm me, and I'll write a post about why quercetin behaves this way.
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#2293 rikelme

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Posted 08 January 2014 - 11:18 PM

This is interesting, seeing as drugs like caffeine and modafinil do the opposite.
This is also evident on forums, as modafinil usually produces "wall of texts"-long posts, while CILTEP-posts are more succinct.

It seems you edited your post in the meantime, but anyways a question: a google search does show that both modafinil and caffeine either slow down degradation or increase levels of cAMP, meaning that they should impair WM, which seem counter-intuitive to me... I'm not addicted nor have tolerance to either of them but when I take them I really have razor sharp focus and am VERY productive. It might be related to motivation, but I feel that I solve problems much more easily while on them.

Edited by rikelme, 08 January 2014 - 11:22 PM.


#2294 Jeoshua

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Posted 09 January 2014 - 04:34 AM

For anyone trying to increase cGMP... quercetin has an effect on it too, I haven't looked into it so I can't say its good or bad, just pasting it here FYI:

http://www.ncbi.nlm....les/PMC2828021/

Quercetin and quercetin 3′-sulphate inhibited endothelin and U46619-induced contractions with greater potency (three- to fivefold) against the former, while quercetin 3-glucoronide was inactive. Quercetin enhanced both the cyclic GMP content of the artery (threefold) and cyclic GMP-dependent relaxations to GTN and SNP (two to threefold), but forskolin-induced relaxations were unaffected. Although the effect of quercetin was qualitatively similar to that noted for UK-114,542, a selective inhibitor of phosphodiesterase 5, it was still evident against SNP-induced relaxations in the presence of 10 nM UK-114,542. Quercetin and quercetin 3′-sulphate significantly reduced the development of GTN-associated ‘tolerance’.


That would be me! And I thought nobody reads MY posts!

The reason for increasing cGMP being that when hearing the reasoning behind the CILTEP stack, I was intrigued and began to do my own research into the phenomenon. It appears that LTP has its mediators and its modulators, like any other biological process, and the cAMP angle did not seem sufficient to do what the stack was trying to do. Certainly it is one part of the puzzle, but not the whole of the story.

Specifically:

Proposed modulators of LTP; Modulator Targets
β-Adrenergic receptor; cAMP, MAPK amplification
Nitric oxide synthase; Guanylyl cyclase, PKG, NMDAR
Dopamine receptor; cAMP, MAPK amplification
Metabotropic glutamate receptor; PKC, MAPK amplification

As described previously, the molecules that underlie LTP can be classified as mediators or modulators. A mediator of LTP is a molecule, such as the NMDA receptor or calcium, whose presence and activity is necessary for generating LTP under nearly all conditions. By contrast, a modulator is a molecule that can alter LTP but is not essential for its generation or expression.

In addition to the signaling pathways described above, hippocampal LTP may be altered by a variety of modulators. For example, the steroid hormone estradiol may enhance LTP by driving CREB phosphorylation and subsequent dendritic spine growth. Additionally, β-adrenergic receptor agonists such as norepinephrine may alter the protein synthesis-dependent late phase of LTP. Nitric oxide synthase activity may also result in the subsequent activation of guanylyl cyclase and PKG. Similarly, activation of dopamine receptors may enhance LTP through the cAMP/PKA signaling pathway.


That's all from Wikipedia by the way, which I figured was a good place to start. So honestly with the CILTEP stack, as it stands, there are a few issues. Some of the substances used are Armoatase inhibitors, which would decrease estradiol levels, leading to less dendritic spine growth and phosphorylation. For this reason I suggest finding something other than Forskolin, for the increasing of cAMP.

The reason I was looking into increasing cGMP is that it would naturally increase both nNOS, eNOS, and Guanylyl cyclase activity, adding another piece to the puzzle.

For both of these reasons, and at the suggestion of a previous post, I was looking into Cordycepin. It does have the property of potentially inhibiting late-phase LTP by inhibiting long chain DNA and RNA synthesis, but that is only at very high levels, in vitro, and there is no real evidence that I could find that it had ever been tested in that sense in vivo. There is also the interesting property of Cordycepin, being very close in structure to Adenosine, to actually be phoshoporylated and become something akin to cyclic Cordycepin Monophosphate. The molecule's physical structure (a kind of deoxyadenosine) allows it, and its properties should be close enough to cAMP to allow it to be used by the cell in the same way, yet far enough away from cAMP to be harder to break down.

Cordycepin also seems to increase Free Testosterone levels in a way that does not involve Aromatase inhibition, so that is also a plus.

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

A google search does show that both modafinil and caffeine either slow down degradation or increase levels of cAMP, meaning that they should impair WM, which seem counter-intuitive to me...


Endogenous chemicals can be increased in a few different ways: by increasing their production, by inhibiting their breakdown, on by inhibiting their function in the case of chemicals which change upon being used up (like ATP). There is also the difference between intracellular amounts of chemicals and extracellular amounts.

If you antagonize dopamine receptors, for example, you will increase the extracellular levels of dopamine while not activating the receptor, basically by plugging up the hole. The intracellular levels of dopamine, in the receptor part of the neuron, will not likewise be increased. On the other hand, if you supplement L-Tyrosine or L-Dopa, you can increase the amount of intracellular AND extracellular dopamine without changing how it functions in the brain on a basic level.

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

As far as the effects of caffeine on this stack:

The adenosine triphosphate-dependent calcium uptake by endoplasmic reticulum elements of lysed synaptosomes from rat brain cortex was studied. Caffeine exhibited a biphasic effect on this calcium uptake activity: concentrations of 1, 2, 5, 10 or 30 mM caffeine stimulated calcium uptake by 62, 111, 73, 88 and 60% respectively, whereas calcium uptake was inhibited by 55% at a 60-mM concentration of caffeine. Calcium release from endoplasmic reticulum elements of lysed brain synaptosomes was stimulated by 10 mM caffeine. Cyclic adenosine 3′,5′-monophosphate stimulated calcium uptake in the lysed synaptosome preparation: exogenous concentrations of 0.05, 0.5, 5, 50 of 500 μM stimulated uptake by 67, 67, 95, 38 or 67% respectively. To explore the possibility that caffeine stimulated calcium uptake through inhibition of phosphodiesterase and consequent preservation of cyclic adenosine 3′,5′-monophosphate, we have tested whether caffeine retained its ability to stimulate calcium uptake under conditions of maximal stimulation by cyclic adenosine 3′,5′-monophosphate. The combined presence of 10 mM caffeine and 5 μM cyclic adenosine 3′,5′-monophosphate resulted in an approximate doubling of the calcium uptake as compared to the uptake in the presence of the cyclic nucleotide alone, indicating that the stimulation due to caffeine does not occur via cyclic adenosine 3′,5′-monophosphate.

http://www.sciencedi...006899387904252

It seems that in addition to its PDE inhibition, it also increases the Ca+ metabolism, which is a bit part of LTP. It also has effects on the β-Adrenergic receptor. It also does all of this completely separately in it's method of effect from cAMP. I would almost say that Caffeine, or some other kind of Methylxanthine, should be considered as a canonical part of CILTEP's LTP Chemical Induction.

Edited by Jeoshua, 09 January 2014 - 05:15 AM.

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#2295 Vindex

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Posted 09 January 2014 - 04:35 PM

I know it sounds pretty far-fetched - the last quote isn't even a study.
But I'm still testing Cordyceps + Artichoke out of curiosity. At least, it'll probably have some cool effects on fertility.

In addition, I found Artichoke had much stronger effects when combined with EGCG.
Turns out, the concentration of Luteolin is increased by COMT-inhibitors (such as egcg), because COMT metabolizes Luteolin.
It's a very strong difference, and using 900 mg artichoke extract with egcg definitely makes the stack too strong.


http://www.ncbi.nlm....pubmed/23386290
[

Luteolin was a rare substrate of human COMT favoring a para-methylation, but further demethylation by human CYP1A2 and CYP3A4/5 caused a preference of accumulation in meta-methylated luteolin in vivo.


This makes me wonder if perhaps there's an association between a person's specific COMT Val158Met polymorphism and his response to the CILTEP, or at least luteolin. Back when I used to drink some 1.5L/day of green tea concomitantly with the stack it always left me feeling weird, almost overstimulated, even though caffeine alone doesn't do that. I have the met/met genotype correlating with lower COMT activity.
Could be that a val/val (more COMT) carrier who happens to not respond to the stack would benefit from either more luteolin, a different PDE4 inhibitor or some egcg.



#2296 kai2

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Posted 09 January 2014 - 09:02 PM

That would be me! And I thought nobody reads MY posts!

So honestly with the CILTEP stack, as it stands, there are a few issues. Some of the substances used are Armoatase inhibitors, which would decrease estradiol levels, leading to less dendritic spine growth and phosphorylation. For this reason I suggest finding something other than Forskolin, for the increasing of cAMP.

For both of these reasons, and at the suggestion of a previous post, I was looking into Cordycepin. It does have the property of potentially inhibiting late-phase LTP by inhibiting long chain DNA and RNA synthesis, but that is only at very high levels, in vitro, and there is no real evidence that I could find that it had ever been tested in that sense in vivo. There is also the interesting property of Cordycepin, being very close in structure to Adenosine, to actually be phoshoporylated and become something akin to cyclic Cordycepin Monophosphate. The molecule's physical structure (a kind of deoxyadenosine) allows it, and its properties should be close enough to cAMP to allow it to be used by the cell in the same way, yet far enough away from cAMP to be harder to break down.

Cordycepin also seems to increase Free Testosterone levels in a way that does not involve Aromatase inhibition, so that is also a plus.

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

A google search does show that both modafinil and caffeine either slow down degradation or increase levels of cAMP, meaning that they should impair WM, which seem counter-intuitive to me...


Endogenous chemicals can be increased in a few different ways: by increasing their production, by inhibiting their breakdown, on by inhibiting their function in the case of chemicals which change upon being used up (like ATP). There is also the difference between intracellular amounts of chemicals and extracellular amounts.

If you antagonize dopamine receptors, for example, you will increase the extracellular levels of dopamine while not activating the receptor, basically by plugging up the hole. The intracellular levels of dopamine, in the receptor part of the neuron, will not likewise be increased. On the other hand, if you supplement L-Tyrosine or L-Dopa, you can increase the amount of intracellular AND extracellular dopamine without changing how it functions in the brain on a basic level.

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

As far as the effects of caffeine on this stack:

It seems that in addition to its PDE inhibition, it also increases the Ca+ metabolism, which is a bit part of LTP. It also has effects on the β-Adrenergic receptor. It also does all of this completely separately in it's method of effect from cAMP. I would almost say that Caffeine, or some other kind of Methylxanthine, should be considered as a canonical part of CILTEP's LTP Chemical Induction.


Your posts are definitely getting read, Jeoshua, and they are particularly thought-provoking. Thank you for keeping them coming.

Are you suggesting that decreasing one's estradiol level is not a positive? I was under the impression that an aromatase inhibitor is a positive, so that we reduce the tendency for testosterone to be converted into excess estradiol. This is the first I've heard that lowering estradiol would reduce something we want, like dendritic spine growth. Is this a matter of estradiol being decreased below an optimal level, whereas the usual discussion relates to estradiol being decreased from an excess level caused by an artificially-increased testosterone level?

Re: your statement that L-Tyrosine increases the amount of intracellular AND extracellular dopamine without changing how it functions in the brain. Would that hold true if supplementing with N-Acetyl-L-Tyrosine?

I'm unsure how to interpret your use of the word canonical in your final sentence. Are you saying that caffeine should be considered an essential part of the CILTEP stack?

#2297 Jeoshua

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Posted 09 January 2014 - 10:04 PM

Are you suggesting that decreasing one's estradiol level is not a positive? I was under the impression that an aromatase inhibitor is a positive, so that we reduce the tendency for testosterone to be converted into excess estradiol. This is the first I've heard that lowering estradiol would reduce something we want, like dendritic spine growth. Is this a matter of estradiol being decreased below an optimal level, whereas the usual discussion relates to estradiol being decreased from an excess level caused by an artificially-increased testosterone level?


There is a bit of evidence I was able to come across that Estrogens are essential to dendritic spin growth, and therefore Aromatase Inhibition would potentially be detremental to long term, sustainable LTP:

Estrogens regulate dendritic spine density, but the mechanism and significance of this effect for brain networks remain unknown. We used repetitive imaging over several days to investigate how 17β-estradiol affected the turnover and long-term behavior of dendritic spines in CA1 cells of hippocampal slice cultures. We find that 17β-estradiol and serum in the culture medium tightly regulated spine density by promoting an increase in the rate of new spine formation and their transformation into synapses, without affecting spine elimination or stability. New spines formed during a transient 17β-estradiol application were preferentially eliminated upon removal of the hormone, in contrast with pre-existing spines that remained unaffected. Our results reveal that 17β-estradiol transiently regulates the complexity of hippocampal circuits without causing major alterations of pre-existing networks.

http://www.ncbi.nlm....pubmed/20928832

Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.

http://www.ncbi.nlm....pubmed/22699893

Neurosteroids are synthesized de novo from cholesterol in the brain. In rodents, the Purkinje cell actively produces several kinds of neurosteroids including estradiol during neonatal life, when cerebellar neuronal circuit formation occurs. Estradiol may be involved in cerebellar neuronal circuit formation through promoting neuronal growth and synaptic contact, because the Purkinje cell expresses estrogen receptor-β. To test this hypothesis, in this study we examined the effect of estradiol on dendritic growth, spinogenesis, and synaptogenesis in the Purkinje cell using neonatal wild-type (WT) mice or cytochrome P450 aromatase knock-out (ArKO) mice. Administration of estradiol to neonatal WT or ArKO mice increased dendritic growth, spinogenesis, and synaptogenesis in the Purkinje cell. In contrast, WT mice treated with tamoxifen, an ER antagonist, or ArKO mice exhibited decreased Purkinje dendritic growth, spinogenesis, and synaptogenesis at the same neonatal period. Estrogen administration to neonatal WT or ArKO mice increased the expression of brain-derived neurotrophic factor (BDNF) in the cerebellum, whereas tamoxifen decreased the BDNF level in WT mice similar to ArKO mice. BDNF administration to tamoxifen-treated WT mice increased Purkinje dendritic growth. These results indicate that estradiol induces dendritic growth, spinogenesis, and synaptogenesis in the developing Purkinje cell via BDNF action during neonatal life.

http://www.ncbi.nlm....pubmed/22198873

It seems that the effects of this occuring are mainly in infant or female subjects, and not so much in adult males. This might not affect me or any of my elder Y chromosomal buddies, out there, but it certainly doesn't bode well for well over half of the population that would potentially be using CILTEP. It is still food for thought. LTP is such a complex system, and much work has still yet to be done in trying to understand how many systems of the whole body may be involved in it's modulation, mediation, promotion, and inhibition. Until some lab does an In Vivo study of Forskolin + Artichoke and takes note of both Dendritic Spine Growth and Estradiol levels, we really can't know for sure. For me, it is enough to look for a source of cAMP increase and PDE Inhibition that does not involve the Aromatase Inhibition.

And, as luck would have it:

There is increasing evidence that 17β-estradiol (E2) directly influences the quality of maturing oocytes and thus the outcome of assisted reproduction treatment. Although Cordyceps sinensis (CS) mycelium, a Chinese herbal medicine, is believed to enhance libido and fertility in both sexes, the mechanism of its effect in women has not been determined. The aim of the present study was to evaluate the effects of CS on steroidogenic enzyme expression and E2 biosynthesis in human granulosa-lutein cells (GLC). We found that CS induced E2 production by GLC in a dose- and time-dependent manner and that a 3-h treatment with CS induced increased levels of mRNAs coding for the P450 side chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD), and aromatase. Western blot analysis demonstrated that, after treatment with CS for 3 h, protein levels of steroidogenic acute regulatory protein (StAR) and aromatase were upregulated while P450scc and 3β-HSD levels showed no substantial change. New protein synthesis was required for CS-induced E2 production because it was abrogated by cycloheximide pretreatment. Addition of 22®-hydroxycholesterol, thus bypassing the need for StAR protein, did not induce as much E2 production as CS treatment, indicating that upregulation of StAR protein was not the only factor contributing to CS-induced steroidogenesis. Cotreatment of GLCs with CS and aminoglutethimide, an aromatase inhibitor, completely abolished CS-induced E2 production. In conclusion, treatment of GLCs with CS results in increased E2 production due, at least in part, to increased StAR and aromatase expression. These data may help in the development of treatment regimens to improve the success rate of in vitro fertilization.

http://www.biolrepro.../70/5/1358.long

Cordycepin (3'-deoxyadenosine) is isolated from Cordyceps militaris, a species of the fungal genus Cordyceps. Cordycepin is an ingredient used in traditional Chinese medicine and is prescribed for various diseases, such as cancer and chronic inflammation. In this study, we investigated the novel effect of cordycepin (3'-deoxyadenosine) on collagen-induced human platelet aggregation. Cordycepin inhibited dose-dependently collagen-induced platelet aggregation in the presence of various concentrations of exogenous CaCl(2). Of two aggregation-inducing molecules, cytosolic free Ca(2+) ([Ca(2+)](i)) and thromboxane A(2) (TXA(2)), cordycepin (500 microM) blocked the up-regulation of [Ca(2+)](i), by up to 74%, but suppressed TXA(2) production by 46%. Subsequently, Ca(2+)-dependent phosphorylation of both 47-kDa and 20-kDa proteins in collagen-treated platelets was potently diminished by cordycepin. However, upstream pathways for producing these two inducers, such as the activation of phospholipase C-gamma2 (PLC-gamma2) (assessed by the phosphotyrosine level) and the formation of inositol 1,4,5-trisphosphate (IP(3)), were not altered by cordycepin. Cordycepin increased the level of second messengers adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) in collagen-stimulated platelets. Whereas the NO-sensitive guanylyl cyclase inhibitor ODQ did not alter the cordycepin-induced up-regulation of cGMP, the adenylyl cyclase inhibitor SQ22536 completely blocked the cAMP enhancement mediated by cordycepin, indicating that cordycepin had different modes of action. Therefore, our data suggest that the inhibitory effect of cordycepin on platelet aggregation might be associated with the down-regulation of [Ca(2+)](i) and the elevation of cAMP/cGMP production.

http://www.ncbi.nlm....pubmed/17229422

The stimulatory effect of Cordyceps sinensis (CS) on MA-10 mouse Leydig tumor cell steroidogenesis was previously demonstrated in our laboratory. In the present studies, we further determined the effect of CS on steroidogenesis in purified normal mouse Leydig cells. Different concentrations of CS (0.1-10 mg/ml) were added to Leydig cells without or with human chorionic gonadotropin (hCG) (50 ng/ml), and the steroid production was determined by radioimmunoassay (RIA). The results illustrated that CS stimulated normal mouse Leydig cell steroidogenesis in a dose-dependent relationship. CS at 3 mg/ml significantly stimulated testosterone production (p<0.05). Concerning the temporal relationship, CS at 3 mg/ml stimulated maximal testosterone production between 2 to 3 hr. Interestingly, hCG-stimulated testosterone productions were suppressed by CS in a dose-dependent relationship. CS also reduced dbcAMP-stimulated testosterone productions, which indicated that CS affected signal transduction pathway of steroidogenesis after the formation of cyclic AMP. Moreover, cycloheximide inhibited CS-treated mouse Leydig cell testosterone production, suggesting that new protein synthesis was required for CS-stimulated steroidogenesis.

http://www.ncbi.nlm....pubmed/11712663

Cordycepin is a bioactive component of the fungus Cordyceps militaris. Previously, we showed that cordycepin can alleviate hyperlipidemia through enhancing the phosphorylation of AMP-activated protein kinase (AMPK), but the mechanism of this stimulation is unknown. Here, we investigated the potential mechanisms of cordycepin-induced AMPK activation in HepG2 cells. Treatment with cordycepin largely reduced oleic acid (OA)-elicited intracellular lipid accumulation and increased AMPK activity in a dose-dependent manner. Cordycepin-induced AMPK activation was not accompanied by changes in either the intracellular levels of AMP or the AMP/ATP ratio, nor was it influenced by calmodulin-dependent protein kinase kinase (CaMKK) inhibition; however, this activation was significantly suppressed by liver kinase B1 (LKB1) knockdown. Molecular docking, fluorescent and circular dichroism measurements showed that cordycepin interacted with the γ1 subunit of AMPK. Knockdown of AMPKγ1 by siRNA substantially abolished the effects of cordycepin on AMPK activation and lipid regulation. The modulating effects of cordycepin on the mRNA levels of key lipid regulatory genes were also largely reversed when AMPKγ1 expression was inhibited. Together, these data suggest that cordycepin may inhibit intracellular lipid accumulation through activation of AMPK via interaction with the γ1 subunit.

http://www.ncbi.nlm.nih.gov/pubmed/24286368

It seems that Cordycepin hits all the sweet spots: 17β-estradiol, cAMP, cGMP, Ca+, Guanylyl Cyclase, AMPK, and Testosterone to balance out the estrogen. It is certainly a promising avenue of research. The only issue I can see is the science is never too specific on the exact chemicals responsible for the actions they are seeing. Mycellium is, of course, a very generic part of the body of the mushroom, whereas Cordycepin is one specific molecule the can be found therein (3'-deoxyadenosine). The science thus far is very unclear as to whether this is the only active ingredient in the mushroom, and many of the studies I have seen to not specify if they are using whole Mycellia, or just the Cordycepin extract/synthase.

For a proper test of this, I propose that there are 5 test groups required:
  • Cordycepin + Luteolin
  • Cordycepin + Artichoke Extract
  • Cordyceps + Luteolin
  • Cordyceps + Artichoke Extract
  • Control
I suggest the following as a "pure" source of Luteolin: http://www.swansonvi...-mg-30-veg-caps
It does have another chemical in it, but being 50% luteolin by weight is a lot more pure than Artichoke Extract

Re: your statement that L-Tyrosine increases the amount of intracellular AND extracellular dopamine without changing how it functions in the brain. Would that hold true if supplementing with N-Acetyl-L-Tyrosine?


The addition of the Acetyl group would change the pharmacokinetics of the process, somewhat. The question would be "Where does that Acetyl group get cleaved off the molecule?". It could be in the brain, thereby increasing the intracellular amounts of acetylcholine and, further downstream, dopamine. Or it could be any of the thousands of other situations where Acetyl groups are used by other systems in the body, primarilly in the mitochondria and nuclei.

I'm unsure how to interpret your use of the word canonical in your final sentence. Are you saying that caffeine should be considered an essential part of the CILTEP stack?


Yes. As in "In the Canon", when refering to an accepted fact within a particular work of fiction, and not just a fan theory. Or, alternatively, as the Catholics would see it as meaning "straight from The Book". And I officially denounce and object to any conflation and discussion comparing the "work of fiction" and "Catholic" angles, for the record ;)

The effects of Caffeine (and by extension, other Methylxanthines) are too good to pass up as just a possible adjunct to the stack, in my experience. They synergize so well with the cAMP and potential cGMP, Ca+, and β-Adrenergic effects that early-phase LTP induction relies upon, and their normal methodology of usage, being in drink or food form (coffee, hot cocoa, tea), give a natural tool by which one can modulate the specific intensities of the effects in play, extend the length of their effects, and allow one to fight off the effects of withdrawl once the half-lives of the other chemicals in effect wear off.

Personally I have been using Theobromine, which is potentially less stimulating, and therefore a bit more useful for me, in the form of:
  • Raw Cocoa powder fortified with Chocamine (40+ mg Theobromine per 8 fl oz, 20 mg Caffeine, 20 mg Theophylline)
  • Lightly salted (Himalayan Pink Salt) and lightly sugared (Just the white shit, until I determine if Glucose would be more suitable)
  • A dropper-full of Green Tea extract (EGCG delays the breakdown of Luteolin, also L-Theanine and more Methylxanthines)
  • A gram of Creatine Monohydrate (Protects ATP transport, which is a possible benefit to the stack, as well)
  • A tablespoon of Coconut Cream (Some fat for fuel, and it gives a nice color and mouth-feel)
  • In 24 oz piping hot, filtered water
  • Topped with a pinch of Ceylon Cinnamon (This is just for taste, not for any specific effects of Cinnamon)
As another benefit, Cocoa also contains non-trivial amounts of L-Tyrosine and L-Phenylalanine, which also are potential adjuncts to the stack. I down the rest of the stack in pill form, washing it down with this Cocoa mix, and sip on the remainder for the next few hours. I have noticed no crashes, no late-day drowsiness, and it's really fucking tasty, to boot.

But of course, I digress. Honestly, this drink has such specific and special effects, it could almost warrant it's own thread discussing them. It is a kind of stack, on its own. But, I have tried the CILTEP stack with, and without, this drink in the mix, and it definitely works in a very similar direction, and the effects synergize very strongly.

Edited by Jeoshua, 09 January 2014 - 10:54 PM.

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#2298 kai2

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Posted 09 January 2014 - 11:06 PM

I'm unsure how to interpret your use of the word canonical in your final sentence. Are you saying that caffeine should be considered an essential part of the CILTEP stack?


Yes. As in "In the Canon", when refering to an accepted fact within a particular work of fiction, and not just a fan theory. Or, alternatively, as the Catholics would see it as meaning "straight from The Book". And I officially denounce and object to any conflation and discussion comparing the "work of fiction" and "Catholic" angles, for the record ;)

The effects of Caffeine (and by extension, other Methylxanthines) are too good to pass up as just a possible adjunct to the stack, in my experience. They synergize so well with the cAMP and potential cGMP, Ca+, and β-Adrenergic effects that early-phase LTP induction relies upon, and their normal methodology of usage, being in drink or food form (coffee, hot cocoa, tea), give a natural tool by which one can modulate the specific intensities of the effects in play, extend the length of their effects, and allow one to fight off the effects of withdrawl once the half-lives of the other chemicals in effect wear off.

Personally I have been using Theobromine, which is potentially less stimulating, and therefore a bit more useful for me, in the form of:
  • Raw Cocoa powder fortified with Chocamine (40+ mg Theobromine per 8 fl oz, 20 mg Caffeine, 20 mg Theophylline)
  • Lightly salted (Himalayan Pink Salt) and lightly sugared (Just the white shit, until I determine if Glucose would be more suitable)
  • A dropper-full of Green Tea extract (EGCG delays the breakdown of Luteolin, also L-Theanine and more Methylxanthines)
  • A gram of Creatine Monohydrate (Protects ATP transport, which is a possible benefit to the stack, as well)
  • A tablespoon of Coconut Cream (MCTs, Polyunsaturated Fats, and it gives a nice color and mouth-feel)
  • In 24 oz piping hot, filtered water
  • Topped with a pinch of Ceylon Cinnamon (This is just for taste, not for any specific effects of Cinnamon)
As another benefit, Cocoa also contains non-trivial amounts of L-Tyrosine and L-Phenylalanine, which also are potential adjuncts to the stack. I down the rest of the stack in pill form, washing it down with this Cocoa mix, and sip on the remainder for the next few hours. I have noticed no crashes, no late-day drowsiness, and it's really fucking tasty, to boot.

But of course, I digress. Honestly, this drink has such specific and special effects, it could almost warrant it's own thread discussing them. It is a kind of stack, on its own. But, I have tried the CILTEP stack with, and without, this drink in the mix, and it definitely works in a very similar direction, and the effects synergize very strongly.


Thanks for the quick response, Jeoshua. Your comments are intriguing. I'm going to focus on the caffeine/chocolate piece for a moment, as this makes one want to try to isolate variables...

I generally consume almost zero caffeine, so for the purpose of this discussion, lets treat my baseline as zero caffeine. Then, I start CILTEP...

I took the NaturalStacks CILTEP formulation, and took 1 capsule on Day 1, 2 capsules on Day 2, and 3 capsules on Day 3...all immediately after waking.

Day 1 on the CILTEP stack, I found myself craving dark (90%+) chocolate (a craving I fed) late in the afternoon. My mood seemed to elevate significantly in the hour or two after consuming the dark chocolate.

Then, the amount of dark chocolate craved increased significantly from Day 1 to Day 2, and Day 2 to Day 3, without subsequent mood elevation.

Perceived cognitive benefit was significant on Day 1, much less on Day 2, non-existent on Day 3.

Could the NaturalStacks CILTEP formulation be depleting something that dark chocolate provides. The formulation contains L-Phenylalanine, so unless it doesn't include enough, would it be reasonable to rule that out?

Could it be L-Tyrosine? Could it be something that caffeine boosts?

Part of the reason this might be useful anecdotal information is because my guess is that most participants here would not be starting from a baseline of zero caffeine.

#2299 Jeoshua

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Posted 10 January 2014 - 03:13 AM

Could the NaturalStacks CILTEP formulation be depleting something that dark chocolate provides. The formulation contains L-Phenylalanine, so unless it doesn't include enough, would it be reasonable to rule that out?

Could it be L-Tyrosine? Could it be something that caffeine boosts?


Monoamine transporters playing major roles in regulating normal and abnormal synaptic activity are associated with various neuropsychological disorders. In spite of the discovery of a series of structurally different monoamine transporter antagonists for the therapy approach, no practical pharmaceutical can act as a transporter activator. Here, we isolated luteolin and apigenin from the fruit of Perilla frutescens (L.) Britt by using an activity-guided extraction technique, and proved that the two compounds possess actions of enhancing monoamine uptake either upon monoamine-transporter transgenic Chinese hamster ovary (CHO) cells or upon wild dopaminergic cell lines, with higher specificity for dopamine (DA) uptake than for norepinephrine (NE)- and serotonin (5HT)-uptake, as well as with more potency and greater efficacy for luteolin than for apigenin. Further, in the transgenic cells, the principal NE/DA uptake activation by luteolin was significantly prevented by respective transporter inhibitor, and the transmitter-uptake-enhancing action was independent of its ligands, which is in support of the compounds as monoamine transporter activators. Furthermore, luteolin evoked a marked disinhibition of cocaine-targeted effect in CHO cells overexpressing dopamine transporter. Thus, luteolin and apigenin function as monoamine transporter activators, which would improve several hypermonoaminergic neuropsychological disorders, especially cocaine dependence, through up-regulating monoamine transporter activity.

http://www.ncbi.nlm....pubmed/19815045

Luteolin increases turnover of all monoamines, which means basically they shuttle back and forth into and out of the cells. While inside the cells they would be subjected to various metabolic functions, and while outside the cell they would be subject to action by extracellular forces as well, so this increase would lead to a depletion over time of all monoamines. Monoamines, of course, are Serotonin, Dopmine, and Norepinephrine. Therefore, supplementing them is ideal, and that is the reason for the L-Phenylalanine in NaturalStacks' formulation. But see below:

Posted Image

There are quite a lot of steps involved, a lot of enzymes and cofactors, and many byproducts. Supplementing a specific precursor may not be enough to truly raise it in an effective and sustainable way. Food supplements that contain a large amount of one or more precursors to a substance, however, will usually contain all the relevant co-factors and modulators required to create these substances since in order for the organism to use these substances, it must also have all these co-factors present, as well.

If one were to use pure chemical supplementation to increase the monoamine levels, it would be preferable to do so with a balanced approach of L-Phenylalanine, L-Tyrosine, and L-Tryptophan, in decreasing amounts, respectively. (Phe > Tyr > Trp). They are all being depleted by the stack, and they are all required for a healthy and balanced mind. And guess what three amino acids are present in Cocoa, and in what proportions? (http://nutritiondata...s/sweets/5471/2)

In short, the Dark chocolate works better than L-Phenylalanine, alone.

Edited by Jeoshua, 10 January 2014 - 04:00 AM.

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#2300 bzyb

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Posted 10 January 2014 - 03:38 AM

Hi, I'm a big fan of the thread and the stack. I'm a previously poor student, with some situational anxiety, minor ADD, among other issues that caused me to be unemployed for a while. I've been using artichoke-CILTEP ever since I started this IT Networking bootcamp work/study program and it's really helped me to pass exams :)

Now I'm in the work part where I'm usually over caffeinated and sleep deprived. Anyway work requires me to be sociable, team-oriented, upbeat, and of course know my stuff...oh and not anxious either. So CILTEP is of course great for motivation, focus, and getting your brain churning. I'm just wondering since I'm new to neuroscience unlike all you geniuses in here and wondering what would help for a bit of impatience, minor irritability, and some jitters? Three/four mornings a week taking 25mg zembrin, 900 mg artichoke, 5mg of Forskolin, 500mg ALCAR, 500mg Phenylalanine, fish oil/vita D/theanine/l-glutamine and copious quantities of coffee while fasting.

For instance, if I'm waiting in line to speak to my manager who's taking his time and my brain wants to yell, "hurry up boss I got work to do!" (famous last words). I've tried excess amounts of theanine/GABA/L-Glutamine and they don't seem to help much. The only things that seem to work so far are ashwagandha (for jitters but might put the brain brakes on too much), zembrin (which seems to need multiple redoses), and propranolol (which seems to slow brain activity). I've read ScienceGuy's anxiolytic thread so I'm guessing I should try to avoid gaba-agonists, so guessing ashwagandha, GABA, etc should be off the list then? Besides more sleep, what could I add to my stack...more water/choline/tryptophan/piracetam/mucuna/anxiolytics? I like the effects of the stack and am wondering if I should shift to an IT sector where I could just enjoy my CILTEP and work in my cubicle :laugh:. I've been experimenting on my own and come across some dead ends, any thoughts would be appreciated thanks :-D .

Edited by bzyb, 10 January 2014 - 04:04 AM.


#2301 abelard lindsay

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Posted 10 January 2014 - 05:12 AM

Also, Luteolin is a PDE 1-5 inhibitor (Affinities being for 4, 2, 1, 3, and 5, in that order, descending), so we are basically halfway there in having a cAMP/cGMP increaser with Cordyceps + Luteolin.


Might not want to increase cGMP. Let me explain:

PDE1,2,3 and 10,11 work on both cAMP and cGMP.

PDE3 is also inhibited by cGMP
http://www.ncbi.nlm....pubmed/22922149

PDE3 is a dual-substrate phosphodiesterase responsible for hydrolyzing both cAMP and cGMP whilst being simultaneously inhibited by cGMP.


and is massively upregulated by forskolin

http://www.ncbi.nlm..../pubmed/9031467

HEL cells grown for 24 h in the presence of 50 microM forskolin, an adenylate cyclase activator, demonstrate further increase in PDE3A of 274% of control (p = 0.03).


so forskolin may mitigate PDE3 inhibition to some extent by increasing the amount of PDE3 available.

Now cAMP is hydrolyzed by 4,7 and 8 specifically and 5,6 and 9 work on cGMP. This is why CILTEP doesn't do a whole lot for erections. It's working mainly on cAMP's interaction with 4 because that's the intersection of artichoke/zembrin inhibition and forskolin's activity. 1 and 2 might also being doing something but they partially hydrolyze cGMP so forskolin's effects on them are partial as well and PDE3 acting partially is upregulated by forskolin so that may mitigate the effect on its inhibition.

Now if you got a 7 or 8 inhibitor you'd have interesting stuff going on because that's intersecting with forskolin.

However, if you increase cGMP you are switching around the activity of luteolin so 5 and 3 are emphasized and then combined with forskolin you are going to be disabling PDE3 with cGMP and you could be looking at a very different set of effects which makes it a really different stack and probably not what you wanted. Now if you want to create real herbal erectile dysfunction stack that might be something to look at but you probably should do that with Icarin (in Horny Goat Weed) as that is a PDE5 inhibitor with some small amount of PDE4 inhibition.

This is why I'm more focused in on d1/d2 manipulation with schinus molle in order to increase cAMP in the CNS more specifically.

Edited by abelard lindsay, 10 January 2014 - 05:40 AM.


#2302 Jeoshua

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Posted 10 January 2014 - 06:30 AM

I was looking into cGMP specifically because of the effects of Guanylyl Cyclase in LTP. It may be due to it's effects in turning cGMP into normal GMP, which can then be turned into GDP and thereby used in reactions that power the cell, specifically being used as a phosphoryl donor for the ADP->ATP transition. By inhibiting Adenylate Cyclase, that would naturally be reducing the amount of free Adenosine Monophosphate for the cell's power systems to play with.

However, cGMP itself does seem to be inextricably linked to LTP:

First, brief perfusion with 8-Br-cGMP before weak tetanic stimulation produced long-lasting potentiation in the CA1 region of hippocampal slices, but more prolonged perfusion with 8-Br-cGMP before the tetanus did not produce long-lasting potentiation. Second, the activity-dependent long-lasting potentiation by cGMP analogs was reduced when NMDA receptors were completely blocked, indicating that NMDA receptor activation contributes to, but is not required for, the potentiation. The amount of reduction of the potentiation differed with different protocols, and in some cases could be complete. Third, LTP produced by strong tetanic stimulation in the stratum radiatum of CA1 (which expresses eNOS) was blocked by inhibitors of soluble guanylyl cyclase or cGMP-dependent protein kinase, but LTP in the stratum oriens (which does not express eNOS) was not.

http://www.ncbi.nlm....pubmed/10454367

And Cordycepin seems to produce it's cyclic nucleotidal effects in ways other than merely inhibiting their breakdown:

NO-sensitive guanylyl cyclase inhibitor ODQ did not alter the cordycepin-induced up-regulation of cGMP, the adenylyl cyclase inhibitor SQ22536 completely blocked the cAMP enhancement mediated by cordycepin, indicating that cordycepin had different modes of action. Therefore, our data suggest that the inhibitory effect of cordycepin on platelet aggregation might be associated with the down-regulation of [Ca(2+)](i) and the elevation of cAMP/cGMP production

http://www.ncbi.nlm....pubmed/17229422

In short, it seems worth more than just a cursory look and brushing off as just another ED medication.

Besides, PDE 3 Inhibition is a therapeutic target for bronchial problems, not erectile disfunction (which is PDE 5).

I have looked somewhat into PDE 7 Inhibition, but the only medications I can see which even touch on this are highly experimental, hard to synthesize, and prohibitively expensive.

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

I actually did have a thought, re: bzyb's comment.

...while fasting.


While this may increase focus somewhat, and one's body will naturally use energy from the body stored in the adipose tissue, this also gets in the way of neurotransmitter renewal. Animals do not have the ability to generate several essential amino acids, the ability seemingly lost when we switched away from photosynthesis. Those Amino Acids include L-Phenylalanine, L-Tyrosine, and L-Tryptamine (along with everything that we declare to be a 'Vitamin'). Long story short: Supplement these essential neurotransmitter precursors if you plan on fasting and don't wish to deplete your brain's stores of monoamine neurotransmitters, and take a C and B-Complex vitamin as a matter of course.

Edited by Jeoshua, 10 January 2014 - 06:59 AM.


#2303 chung_pao

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Posted 10 January 2014 - 03:04 PM

If you're not convinced of Abelard's point that you either focus on cAMP or cGMP, try upping your theobromine intake.
Artichoke extract and Yerba maté tea, for example, turns my awesome CILTEP-focus into a Nitric Oxide-haze of boners and erotic daydreams.

A note on the experience with CORDYCEPS: it wasn't very successful. It was short in duration and low in intensity, with a noticeable crash after 3.5 hours.
I suspect it had some cool effects on hormones though, as I became very hungry.
It didn't synergize with Forskolin and artichoke either.

In short: It was not a step up and Forskolin + Artichoke remains superior.
Also a note on caffeine: If taken together with forskolin, this inhibits cAMP accumulation in the brain and causes drowsiness instead of the desired effect.
Caffeine can be taken after Forskolin and Artichoke though, when cAMP-levels have already increased from Forskolin.

http://www.ncbi.nlm..../pubmed/2172772

Caffeine potently inhibited forskolin-stimulated cyclic AMP accumulation in slices of rat cerebral cortex, with an IC50 of 21 +/- 3 microM.


I'm right now more interested in how we could mitigate the decrease in working memory with this stack.
This would require decreasing cAMP accumulation in the PFC. Not sure if this is even possible though.
This side effect is very significant, since working memory also involves speech, spatial abilities and creativity.

Edited by chung_pao, 10 January 2014 - 03:10 PM.


#2304 brainstorm11

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Posted 10 January 2014 - 04:32 PM

Hey guys, I just published a post about CILTeP including mostly information from experiences / anecdotes of other people (in this thread) and my own.

I combined taking CILTeP with intermittent fasting (always taken on empty stomach) and I felt hungry a lot later. A lot of the formula improve fatty-acid oxidation, which I speculate might be going on in that situation.

http://www.purenootr...nd-experiences/

#2305 Jeoshua

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Posted 10 January 2014 - 07:28 PM

If you're not convinced of Abelard's point that you either focus on cAMP or cGMP, try upping your theobromine intake.
Artichoke extract and Yerba maté tea, for example, turns my awesome CILTEP-focus into a Nitric Oxide-haze of boners and erotic daydreams.



I haven't noticed any untoward effects at 40 mg Theobromine in my Cocoa, or any random sexual side effects.

A note on the experience with CORDYCEPS: it wasn't very successful. It was short in duration and low in intensity, with a noticeable crash after 3.5 hours.
I suspect it had some cool effects on hormones though, as I became very hungry.
It didn't synergize with Forskolin and artichoke either.

In short: It was not a step up and Forskolin + Artichoke remains superior.



Well that is certainly unfortunate. It seemed a promising avenue of research. I might try to procure a pure source of Cordycepin, and see if the situation is at all improved.

#2306 kai2

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Posted 10 January 2014 - 07:53 PM

If you're not convinced of Abelard's point that you either focus on cAMP or cGMP, try upping your theobromine intake.
Artichoke extract and Yerba maté tea, for example, turns my awesome CILTEP-focus into a Nitric Oxide-haze of boners and erotic daydreams.

In short: It was not a step up and Forskolin + Artichoke remains superior.
Also a note on caffeine: If taken together with forskolin, this inhibits cAMP accumulation in the brain and causes drowsiness instead of the desired effect.
Caffeine can be taken after Forskolin and Artichoke though, when cAMP-levels have already increased from Forskolin.

http://www.ncbi.nlm..../pubmed/2172772

Caffeine potently inhibited forskolin-stimulated cyclic AMP accumulation in slices of rat cerebral cortex, with an IC50 of 21 +/- 3 microM.



Hi chung_pao,

Would your comment about theobrine intake mean that we would *not* want to be consuming chocolate while on CILTEP?

How much time after taking CILTEP before consuming caffeine? Also, if we were to multi-dose CILTEP, then how long after consuming caffeine before taking second dose of CILTEP?

#2307 row1

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Posted 10 January 2014 - 09:17 PM

Hi there,

Anyone also experianced constipation withs restults in hemorrhoids :(

I have been taken for PDE-4 Inhibition 2x artichoke from now with only whater.

after 25 min for increasing my camp cAMP: 4mg cbolic, 100phyn, 1cap b50 vit, caff 0,1 grams with whater.

After 30 minutes bread.

Can artichoke cause this? Or second part of the stack?

I'm not wanting to eat first beceause I think it will diminish the efect.

Anyone here eating with ciltep and having good results, what are you eating :).

I though maybe artichoke 2x with 2 eggs? and whater

en the rest of the stack with oat flakes and milk.

The thing is that 0,04 of forskoling wil be not prober digested with the oat an milk? I think.



Also how long will it take for PDE-4 Inhibition?

#2308 kai2

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Posted 10 January 2014 - 11:09 PM

Hi there,

Anyone also experianced constipation withs restults in hemorrhoids :(

I have been taken for PDE-4 Inhibition 2x artichoke from now with only whater.

after 25 min for increasing my camp cAMP: 4mg cbolic, 100phyn, 1cap b50 vit, caff 0,1 grams with whater.

After 30 minutes bread.

Can artichoke cause this? Or second part of the stack?

I'm not wanting to eat first beceause I think it will diminish the efect.

Anyone here eating with ciltep and having good results, what are you eating :).

I though maybe artichoke 2x with 2 eggs? and whater

en the rest of the stack with oat flakes and milk.

The thing is that 0,04 of forskoling wil be not prober digested with the oat an milk? I think.



Also how long will it take for PDE-4 Inhibition?


Hi row1,

When you say that you ate bread, do you mean that you are eating gluten??

#2309 row1

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Posted 11 January 2014 - 12:10 AM

Hi

yes gluten.

But must of the times i eat speltbread (nongluten)

I want to try the stack with food, but do know not wich food stacks the best.

Edited by row1, 11 January 2014 - 12:10 AM.


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#2310 Jeoshua

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Posted 11 January 2014 - 03:44 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.nih.gov/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.nih.gov/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?
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