2626 replies to this topic

[health_nutty]

When I first started taking this stack, I went through the entire Khan Academy match exercise set. That's like 260 exercises... and it was fun. There is no way I would have done that without this. Math usually drives me nuts. This is some seriously good stuff and it's super cheap and all natural. I really can't express how blown away I've been by this stack. One other odd thing is it would make me get perfect scores on Lumosity memory match and over 7000 on Brain Shift which according to Lumosity is 1700 bpi or basically the highest you can score.

I agree that Threonate is pretty good stuff too. It makes me sleep well and then I get a stream of memories readily popping into my head throughout the day that would have been difficult to summon otherwise..

Have you tried pure Luteolin with forskolean? I wonder if the full spectrum artichoke powder is needed or luteolin itself will work.

[abelard lindsay]

When I first started taking this stack, I went through the entire Khan Academy match exercise set. That's like 260 exercises... and it was fun. There is no way I would have done that without this. Math usually drives me nuts. This is some seriously good stuff and it's super cheap and all natural. I really can't express how blown away I've been by this stack. One other odd thing is it would make me get perfect scores on Lumosity memory match and over 7000 on Brain Shift which according to Lumosity is 1700 bpi or basically the highest you can score.

I agree that Threonate is pretty good stuff too. It makes me sleep well and then I get a stream of memories readily popping into my head throughout the day that would have been difficult to summon otherwise..

Have you tried pure Luteolin with forskolean? I wonder if the full spectrum artichoke powder is needed or luteolin itself will work.

I tried Luteolin (Lutimax) but it didn't last that long and it's very expensive. Maybe if I used more it would have worked but a small bottle is $80. Artichoke Extract is far cheaper and seems to work. The only slight problem with this stack is that Luteolin and Artichoke are PDE5 inhibitors (e.g Viagra, Cialis) as well as being PDE4 inhibitors so easy spontaneous erections can be a slight annoyance. Interestingly, there is some research as to PDE5 Inhibitors ALSO improving memory.

Br J Pharmacol. 2011 Dec;164(8):2029-41. doi: 10.1111/j.1476-5381.2011.01517.x.

Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease.

Cuadrado-Tejedor M, Hervias I, Ricobaraza A, Puerta E, Pérez-Roldán JM, García-Barroso C, Franco R, Aguirre N, García-Osta A.

Source

Division of Neurosciences, CIMA, University of Navarra, Avenida Pio XII 55, Pamplona, Spain.

Abstract

BACKGROUND AND PURPOSE:

Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory-related behaviour were investigated.
EXPERIMENTAL APPROACH:

Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age-matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil.
KEY RESULTS:

Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin-dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain-derived neurotrophic factor (BDNF) and the activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden.
CONCLUSIONS AND IMPLICATIONS:

Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease.
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

PMID: 21627640 [PubMed - indexed for MEDLINE] PMCID: PMC3246665 [Available on 2012/12/1]

[health_nutty]

Well, I already ordered the Lutoelin and Forslean from BAC. I'll report back when they arrive. I'm hoping to use a fairly small dose of the luteolin.

Edited by health_nutty, 25 April 2012 - 05:17 AM.

[abelard lindsay]

Well, I already ordered the Lutoelin and Forslean from BAC. I'll report back when they arrive. I'm hoping to use a fairly small dose of the luteolin.

Yeah. Start with small dosages. This stack AFAIK just got invented on this thread by me and I'm only really familiar with how it works with NOW Artichoke Extract as the Luteolin source.

[vali]

Ordered. Will report back.

[abelard lindsay]

Caffeine I've found is also synergistic with this stack, even in reasonable amounts (200mg) because it blocks increased PDE4 activity due to endogenous adenosine acting on the A2A receptor.

J Neurochem. 1997 Sep;69(3):1300-9.

Activation of phosphodiesterase IV during desensitization of the A2A adenosine receptor-mediated cyclic AMP response in rat pheochromocytoma (PC12) cells.

Chang YH, Conti M, Lee YC, Lai HL, Ching YH, Chern Y.

Source

Institute of Neuroscience, National Yang-Ming Medical College, Taipei, Taiwan, R.O.C.

Abstract

Prolonged activation of an A2A adenosine receptor significantly inhibits the cellular response to subsequent stimulation (A2A desensitization). We have reported previously that activation of phosphodiesterase (PDE) contributes to A2A desensitization in PC12 cells. In the present study, we show that a type IV PDE (PDE4)-selective inhibitor (Ro 20-1724) effectively blocks the increase in PDE activity in desensitized cells. Thus, PDE4appears to be the PDE specifically activated during A2A desensitization in PC12 cells. Prolonged treatment of PC12 cells with an A2A-selective agonist (CGS21680) leads to increased PDE4 activity in a dose-dependent manner, which can be blocked by an A2A-selective antagonist [8-(3-chlorostyryl)caffeine]. Using two PDE4antibodies, we were able to demonstrate that the levels of two PDE4-immunoreactive bands (72 and 79 kDa) were increased significantly during A2A desensitization. Prolonged treatment with forskolin to elevate intracellular cyclic AMP contents also resulted in increased PDE4 activity. In addition, activation of PDE4 activity during A2A desensitization could be blocked by a protein kinase A (PKA)-selective inhibitor (H89) and was not observed in a PKA-deficient PC12 cell line (A123). Taken together, activation of PDE4 via a cyclic AMP/PKA-dependent pathway plays a critical role in dampening the signal of the A2A receptor.

PMID: 9282956 [PubMed - indexed for MEDLINE

Edited by abelard lindsay, 27 April 2012 - 05:22 AM.

[health_nutty]

Caffeine I've found is also synergistic with this stack, even in reasonable amounts (200mg) because it blocks increased PDE4 activity due to endogenous adenosine acting on the A2A receptor.

Nice! Can't wait for my shipment to arrive!

[kevinseven11]

Which studies point towards lutein/aritichoke being a PDE5 Inhibitor aswell? Couldn't Find it. Found it BTW its Luteolin not lutein I made that mistake...
Would you say a PDE4 Inhibitor would be a more cost effective approach rather than just cAMP supplementation?

Edited by kevinseven11, 29 April 2012 - 05:09 PM.

[kevinseven11]

Also another thing to add is, Luteolin has been show to reduce IGF1 and 2 (only in colon cells?) and IGF 2 is known to boost memory so is this not a good idea?

[abelard lindsay]

You have to take them both together to get the effect. It's like Piracetam/Choline. A reasonable amount of Caffeine also helps too (see study above). You can take whatever stack you want, but it won't have the effect that taking the Artichoke(Or other PDE4 Inhibitor)/Forskolin/Caffeine combo has.

BTW, I got an A on my MITx Circuits and Electronics Midterm today. I used to suck at this kind of stuff .

[health_nutty]

BTW, I got an A on my MITx Circuits and Electronics Midterm today. I used to suck at this kind of stuff .

Congrats! (are you at *the* MIT?) I got my luteolin and forskolin yesterday. I'll try to report more detail later.

[abelard lindsay]

BTW, I got an A on my MITx Circuits and Electronics Midterm today. I used to suck at this kind of stuff .

Congrats! (are you at *the* MIT?) I got my luteolin and forskolin yesterday. I'll try to report more detail later.

No I'm at https://6002x.mitx.mit.edu/info. This is their new online course offering. It's meant to be equivalent to the first year undergraduate electrical engineering course they teach at *the* MIT. Sadly my academic career has been decent but nothing special and is all in the past before I discovered nootropics and especially Artichoke/Forskolin. Since I started this combo I have just been watching Khan Videos and taking this online course, along with my full-time job and really enjoying learning in a way I never have previously.

Since I came up with this stack... I'm going to name it. Any Herbal PDE4 Inhibitor (Artichoke, Luteolin, etc) + Forskolin I shall name the CILTEP (Chemically Induced Long TErm Potentiation) stack. It's pronounced "sil-tep" stack. Nice and discrete sounding. Wouldn't even sound out of place if the words was snuck into casual conversations at dinner parties.

Edited by abelard lindsay, 30 April 2012 - 06:00 AM.

[noos]

What is the artichoke for?

[health_nutty]

What is the artichoke for?

Artichoke contains Luteolin, a PDE4 inhibitor.

[noos]

What is the artichoke for?

Artichoke contains Luteolin, a PDE4 inhibitor.

Thanks. How do chamomile or rosmarinus compare in luteolin content to artichoke?

[health_nutty]

What is the artichoke for?

Artichoke contains Luteolin, a PDE4 inhibitor.

Thanks. How do chamomile or rosmarinus compare in luteolin content to artichoke?

That is a good question, I don't even know how much luteolin artichoke extract has!

[kevinseven11]

I don't think artichoke is the most potent source, but it probably is the most cost effective source.http://www.wisegeek....is-luteolin.htm

[gizmobrain]

I don't know how much it has either, but adding Solaray's Rosemary Extract to the CILTEP stack causes a very interesting sensation... I kind of feel like I'm floating underwater, especially if I close my eyes. It's weird because you'd think it would cause nausea, but it does not. It definitely causes a sort of relaxation that Artichoke does not. I don't have anxiety, but it might be interesting for someone with anxiety to try rosemary + forskolin and let us know the results.

Rosemary has been show to increase well being, and memory accuracy.

Int J Neurosci.

2003 Jan;113(1):15-38.

Aromas of rosemary and lavender essential oils differentially affect cognition and mood in healthy adults.

Moss M, Cook J, Wesnes K, Duckett P.

Source
Human Cognitive Neuroscience Unit, Division of Psychology, Northumberland Building, University of Northumbria, Newcastle upon Tyne, NE1 8ST, UK. mark.moss@unn.ac.uk

Abstract
This study was designed to assess the olfactory impact of the essential oils of lavender (Lavandula angustifolia) and rosemary (Rosmarlnus officinalis) on cognitive performance and mood in healthy volunteers. One hundred and forty-four participants were randomly assigned to one of three independent groups, and subsequently performed the Cognitive Drug Research (CDR) computerized cognitive assessment battery in a cubicle containing either one of the two odors or no odor (control). Visual analogue mood questionnaires were completed prior to exposure to the odor, and subsequently after completion of the test battery. The participants were deceived as to the genuine aim of the study until the completion of testing to prevent expectancy effects from possibly influencing the data. The outcome variables from the nine tasks that constitute the CDR core battery feed into six factors that represent different aspects of cognitive functioning. Analysis of performance revealed that lavender produced a significant decrement in performance of working memory, and impaired reaction times for both memory and attention based tasks compared to controls. In contrast, rosemary produced a significant enhancement of performance for overall quality of memory and secondary memory factors, but also produced an impairment of speed of memory compared to controls. With regard to mood, comparisons of the change in ratings from baseline to post-test revealed that following the completion of the cognitive assessment battery, both the control and lavender groups were significantly less alert than the rosemary condition; however, the control group was significantly less content than both rosemary and lavender conditions. These findings indicate that the olfactory properties of these essential oils can produce objective effects on cognitive performance, as well as subjective effects on mood.

PMID: 12690999

Interestingly, the artichoke source I've been taking, Nature's Herbs Artichoke Extract, lists rosemary oil as a preservative. It's probably not much, but at some point I plan to try a different source in order to see if I notice a difference.

An update on my stack:

During the week days, I wake up, take 5mg Adderall, 2 Artichoke Extracts capsules, and 25mg Forskolin. I then go back to sleep for about 30 minutes, and then wake up ready to take on the world. Then, for lunch, I eat some eggs cooked in olive oil and take 5mg Selegiline.

On the weekends, I cut out the Adderall, and replace it with about 50mg of caffeine. If I wake up and take the artichoke + forskolin without it, it actually makes going back to sleep feel really, really pleasurable for some reason. Since going back to sleep keeps me from getting anything done with my day, haha, caffeine has been important for me to add on the weekend.

Eventually, I'm hoping to knock the Adderall out of my stack, and at least take a lower dose of Selegiline. I hope at some point in the future, Artichoke + Forskolin + Caffeine + cognitive training may be my cure for ADD/low motivation. I have yet to develop a tolerance to my current stack over the past month and a half, so I hope that I never do.

I should be getting in a Forskolin shipment soon from a different source. Significantly cheaper too (720 capsules x 20mg for $49).

Edited by zrbarnes, 01 May 2012 - 11:49 PM.

[gizmobrain]

Information regarding the bio-availability of artichoke extract constituents:

Phytomedicine.

2005 Jan;12(1-2):28-38.

Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans.

Wittemer SM, Ploch M, Windeck T, Müller SC, Drewelow B, Derendorf H, Veit M.

Source
Lichtwer Pharma AG, Berlin, Germany.

Abstract

Extracts from artichoke leaves are traditionally used in the treatment of dyspeptic and hepatic disorders. Various potential pharmacodynamic effects have been observed in vitro for mono- and dicaffeoylquinic acids (e.g. chlorogenic acid, cynarin), caffeic acid and flavonoids (e.g. luteolin-7-O-glucoside) which are the main phenolic constituents of artichoke leaf extract (ALE). However, in vivo not only the genuine extract constituents but also their metabolites may contribute to efficacy. Therefore, the evaluation of systemic availability of potential bioactive plant constituents is a major prerequisite for the interpretation of in vitro pharmacological testing. In order to get more detailed information about absorption, metabolism and disposition of ALE, two different extracts were administered to 14 healthy volunteers in a crossover study. Each subject received doses of both extracts. Extract A administered dose: caffeoylquinic acids equivalent to 107.0 mg caffeic acid and luteolin glycosides equivalent to 14.4 mg luteolin. Extract B administered dose: caffeoylquinic acids equivalent to 153.8 mg caffeic acid and luteolin glycosides equivalent to 35.2 mg luteolin. Urine and plasma analysis were performed by a validated HPLC method using 12-channel coulometric array detection. In human plasma or urine none of the genuine target extract constituents could be detected. However, caffeic acid (CA), its methylated derivates ferulic acid (FA) and isoferulic acid (IFA) and the hydrogenation products dihydrocaffeic acid (DHCA) and dihydroferulic acid (DHFA) were identified as metabolites derived from caffeoylquinic acids. Except of DHFA all of these compounds were present as sulfates or glucuronides. Peak plasma concentrations of total CA, FA and IFA were reached within 1 h and declined over 24 h showing almost biphasic profiles. In contrast maximum concentrations for total DHCA and DHFA were observed only after 6-7 h, indicating two different metabolic pathways for caffeoylquinic acids. Luteolin administered as glucoside was recovered from plasma and urine only as sulfate or glucuronide but neither in form of genuine glucosides nor as free luteolin. Peak plasma concentrations were reached rapidly within 0.5 h. The elimination showed a biphasic profile.

PMID: 15693705

[gizmobrain]

I think it might be significant to look not only at the effect that luteolin is causing, but also the caffeoylquinic acid that Artichoke extract is often standardized to contain higher amounts of.

Basic Clin Pharmacol Toxicol. 2006 Nov;99(5):374-8.

Neuropharmacological analysis of caffeic acid in rats.

Pereira P, de Oliveira PA, Ardenghi P, Rotta L, Henriques JA, Picada JN.

Source
Department of Pharmacy, Lutheran Univerity of Brazil, Av. Farroupilha, 8001, Bairro São José, Canoas, RS, Brazil. patipere@yahoo.com.br

Abstract
The aim of the present study was to investigate the effect of intraperitoneal administration of caffeic acid (0.5, 1, 2, 4 or 8 mg/kg) on elevated plus-maze and open field tasks in rats and its possible neuroprotection/neurotoxicity using the comet assay. Caffeic acid at 1 mg/kg increased the number of entries and the time spent in the open arms on plus-maze, suggesting an anxiolytic-like effect when used in lower doses without affecting locomotion and exploration on the open field. Furthermore, a protective effect against hydrogen peroxide-induced oxidative damage on brain tissue was observed through the treatment with caffeic acid at 1 and 8 mg/kg. However, in the highest dose, caffeic acid induced DNA damage in brain tissue.

PMID: 17076690

I hesitated posting this, because I figure that it would take a massive overdose to cause this, but anyone want to take a stab at calculating the dosage for a human?

By contrast, Rosmarinic acid does not have this problem:

Pharmacol Res.

2005 Sep;52(3):199-203.

Neurobehavioral and genotoxic aspects of rosmarinic acid.

Pereira P, Tysca D, Oliveira P, da Silva Brum LF, Picada JN, Ardenghi P.

Source
Universidade Luterana do Brasil, Curso de Farmácia, Rua Miguel Tostes 101, 92420-280 Canoas, RS, Brazil. patipere@yahoo.com.br

Abstract
Rosmarinic acid is a naturally occurring hydroxylated compound. It is present in many plants, for example, it occurs in Artemisia capillaris, Calendulla officinalis, Melissa officinalis, Salvia officinalis and in other several plant families. It also shows a number of interesting biological activities, e.g. antiviral, antibacterial, antiinflammatory and antioxidant. The aim of the present study was to investigate the effect of the i.p. administration of rosmarinic acid (1, 2, 4 or 8 mg kg(-1)) on elevated plus-maze, step-down inhibitory avoidance and open field task in rats. In addition, we evaluated its genotoxic effect on brain tissue using the comet assay. Rosmarinic acid (2 and 4 mg kg(-1)) increased the number of entries in the open arms, suggesting an anxiolytic-like activity when used in lower doses, without affecting the short-term memory (STM) and long-term memory (LTM) retention on inhibitory avoidance task. Eight milligrams per kilograms of this acid was enough to increase the locomotion and motivation of the animals, but not 1, 2 or 4 mg kg(-1), suggesting that in lower doses, this compound can produce anxiolytic-like effect without exerting locomotor alterations or DNA damage in brain tissue.

PMID: 16026713

And since we aren't just made up of our brains alone, high doses of caffeic acid has been shown to increase incidences of rat forestomach papillomas and/or carcinomas by 14.8%.
http://www.ncbi.nlm..../pubmed/9472713

Yet it potentially reduces the formation of inflammatory bowel diseases in humans.
http://www.ncbi.nlm....pubmed/18444659

I'm far beyond my area of expertise here, so take this post with a grain of salt. There are tons of studies related to caffeoylquinic acid (mostly positive), since it is found in coffee and has been studied for years.

I'm not even trying to stir up fear here. I think if you take/eat/drink just about anything in excess, it will cause some sort of problem. Let's look at the toxicity of H2O, shall we? The hard part is figuring out how much is too much, especially if I am looking at taking this long term. Artichoke extract has been shown to have numerous other health benefits, so looking at the extreme cases of a few overdosed rats isn't enough to deter me, unless someone with more experience can interpret these studies more accurately than I.

Edited by zrbarnes, 02 May 2012 - 01:00 AM.

[gizmobrain]

Also, if someone is interested in looking into Celery Seed extract as a potential source of luteolin for the CILTEP stack, and how it might differ in its cognitive/health effects, that would be great. I plan to get around to it eventually...

I've also combined this stack with Source Naturals, Activated Quercetin w/Bromelain, with an nice cognitive boost. However, I only had 3 days worth, so I didn't get a chance to fully investigate it. The cognitive boost may have (i.e. was probably) due to the fact that my nose wasn't half stuffed with mucus like it always seems to be. I tried to do a bit of scholarly look at the potential interaction of the CILTEP stack with Quercetin, however I couldn't decipher if it should be good or bad. Hopefully someone else can look into it. I was definitely pleasantly surprised about how effective it was against my seasonal and pet allergies.

I've tried to investigate a synergy of Berberine with the CILTEP stack, as well, however, it seems hit or miss. I'm not sure what's going on, but I don't consistently get the same result.

Edited by zrbarnes, 02 May 2012 - 12:52 AM.

[kevinseven11]

8-bromo-cAMP is a chemical used in many studies as an alternative to using pde4 inhibitors plus camp. 8bromo isnt degraded close as quickly as camp. Any comments?

[health_nutty]

I did some research and apparently too much cAMP can inhibit learning as can too little. I think I've been overdoing it with my 500mg of 10% forskolin split into 4 doses a day (along with 100mg of luteolin split 4 times a day). This was the recommended daily dose on the bottle (250mg twice a day).

I looked it up the original stack had 3.85mg of actual forskolin (385mg of 1% powder). I'm taking 50mg, which is causing a bit of light headedness and the opposite of what I want!

I'm going to lower the dose to 5mg of forskolin 4 times a day (200mg of powder).

[abelard lindsay]

I did some research and apparently too much cAMP can inhibit learning as can too little. I think I've been overdoing it with my 500mg of 10% forskolin split into 4 doses a day (along with 100mg of luteolin split 4 times a day). This was the recommended daily dose on the bottle (250mg twice a day).

I looked it up the original stack had 3.85mg of actual forskolin (385mg of 1% powder). I'm taking 50mg, which is causing a bit of light headedness and the opposite of what I want!

I'm going to lower the dose to 5mg of forskolin 4 times a day (200mg of powder).

Well you seem to be overdoing things a bit here. This stack works well at fairly low doses. I tried straight luteolin (Lutimax) but the effect only seemed to last for a hour or so. The artichoke extract seems to have a longer duration of action. You are also taking almost 13 times the Forskolin I was taking. I would expect some strange effects at that concentration. I would start on the low end of the dosage curve and work your way up. I get on the verge of feeling overstimulated when I take about 3 Artichoke Extract pills with 1 Forskolin.

I was looking at why Artichoke Extract seems to work so well. Artichoke extract contains apigenin which happens to inhibit CYP2C9 which is responsible for metabolism of some drugs. Maybe this increases the amount of time that the Luteolin hangs around?? Apigenin is also a monamine transporter and a benzo receptor ligand so would have a psychotropic effect. I would expect it to be more sedating though than helping with memory as it seems to.

Also Apigenin is a PDE 1-3 Inhibitor. Quercetin is a PDE 3 and 4 inhibitor.
http://www.sciencedi...006295204004770

Luteolin-7-glucoside exhibited dual inhibition of PDE2/PDE4with an IC₅₀ value of around 40 μM.
The same was true for quercetin, but we rather consider that it more-selectively inhibited PDE3 and PDE4 (IC₅₀ of <10 μM)

Hmm.. Guess I should try this with Quercetin and see if I get any effect since it's supposedly a better PDE4 inhibitor than Luteolin and is also present in decent quantities in Artichoke Extract. Maybe the Quercetin is why Artichoke works better.

http://en.wikipedia.org/wiki/IC50

The half maximal inhibitory concentration (IC₅₀) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC₅₀). It is commonly used as a measure of antagonist drugpotency in pharmacological research.

The synthetic PDE4 inhibiting research chemicals have IC50s that are in the nM ranges.

Edited by abelard lindsay, 04 May 2012 - 06:08 AM.

[health_nutty]

I lowered my dose to 200mg of 10% split into 4 doses. After the first dose, I feel absolutely fantastic. Finally getting the expected results and no side effects. The best part is complements the rest of my stack (working through a unique mechanism of action). Awesome stuff.

Well you seem to be overdoing things a bit here. This stack works well at fairly low doses. I tried straight luteolin (Lutimax) but the effect only seemed to last for a hour or so. The artichoke extract seems to have a longer duration of action. You are also taking almost 13 times the Forskolin I was taking. I would expect some strange effects at that concentration. I would start on the low end of the dosage curve and work your way up. I get on the verge of feeling overstimulated when I take about 3 Artichoke Extract pills with 1 Forskolin.

I was certainly overdoing it, but I overstated it a bit. The 50 mg of forskolin was split into 4 doses. So I was taking 12.5mg per dose compared to 3.85mg per dose (3 times the dose!). To my defense, I was taking the recommended dosage on the bottle.

I was looking at why Artichoke Extract seems to work so well. Artichoke extract contains apigenin which happens to inhibit CYP2C9 which is responsible for metabolism of some drugs. Maybe this increases the amount of time that the Luteolin hangs around?? Apigenin is also a monamine transporter and a benzo receptor ligand so would have a psychotropic effect. I would expect it to be more sedating though than helping with memory as it seems to.

Also Apigenin is a PDE 1-3 Inhibitor. Quercetin is a PDE 3 and 4 inhibitor.
http://www.sciencedi...006295204004770

Hmm.. Guess I should try this with Quercetin and see if I get any effect since it's supposedly a better PDE4 inhibitor than Luteolin and is also present in decent quantities in Artichoke Extract. Maybe the Quercetin is why Artichoke works better.

http://en.wikipedia.org/wiki/IC50

The half maximal inhibitory concentration (IC₅₀) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC₅₀). It is commonly used as a measure of antagonist drugpotency in pharmacological research.

The synthetic PDE4 inhibiting research chemicals have IC50s that are in the nM ranges.

I'll have to try the same brand of Artichoke extract to compare with pure luteolin. Let me know how the quercetin experiment goes. Quercetin is much much cheaper than luteolin.

[gizmobrain]

I can attest to Quercetin working well with this stack, but I'm waiting on a full bottle to figure out at which dose to take it. I think I was taking something like 600mg, in combo with the artichoke + forskolin.

Health_nutty, when I take forskolin in the 50mg range, things get weird, probably due to the massive vasodilation:
http://www.ncbi.nlm..../pubmed/1381777
http://www.ncbi.nlm..../pubmed/2434756

However, in the 20mg range, I see both the cognitive and physical benefits of the herb. I also only take it once a day. Redosing thoughout the day hasn't seemed to do much for me. I do plan to play around with splitting the doses once my new shipment arrives, though.

I was looking at why Artichoke Extract seems to work so well. Artichoke extract contains apigenin which happens to inhibit CYP2C9 which is responsible for metabolism of some drugs. Maybe this increases the amount of time that the Luteolin hangs around?? Apigenin is also a monamine transporter and a benzo receptor ligand so would have a psychotropic effect. I would expect it to be more sedating though than helping with memory as it seems to.

I've wondered if it was the Apigenin that was causing my 5mg of Adderall to work so well for all day, instead of 4 hours like it used to. I don't think amphetamines are effected by CYP2C9, though. Artichoke + Adderall alone turns me into a thoughtless zombie. If I add the Forskolin, everything gets amazingly better.

[abelard lindsay]

Hmm... I took some Activated Quercetion (http://www.sourcenat...roducts/GP1008/) 3 capsules or 1gram of Quercetin with good effect. I'm pretty sure the effect lasted most of the day with it being particularly strong in the morning. Bromelain that comes with this seems to be pretty benign. Probably better to keep it simple with pure Quercetin.

I find my days seem to last much longer, as if I were on vacation. This is probably the enhanced memory triggered by

Novel Stimulus (e.g Going to an unfamiliar place on vacation) -> Enhanced Dopamine -> Increased cAMP -> Increased CREB -> Increased LTP.

Except we're doing this


Inhibited PDE4 + Increased cAMP -> Increased CREB -> Increased LTP.

Without all the anxiety and weird personality/behavior effects of messing around directly with Dopamine.

More on Dopamine being coupled to cAMP/PKA signaling being attached to LTP-> http://www.ncbi.nlm....pubmed/20969573

I think what we're doing here is increasing the sensitivity of cAMP/PKA signaling so that the dopamine system can more easily modulate LTP.

Edited by abelard lindsay, 05 May 2012 - 06:16 AM.

[gizmobrain]

Hmm... I took some Activated Quercetion (http://www.sourcenat...roducts/GP1008/) 3 capsules or 1gram of Quercetin with good effect. I'm pretty sure the effect lasted most of the day with it being particularly strong in the morning. Bromelain that comes with this seems to be pretty benign. Probably better to keep it simple with pure Quercetin.

I find my days seem to last much longer, as if I were on vacation. This is probably the enhanced memory triggered by

Novel Stimulus (e.g Going to an unfamiliar place on vacation) -> Enhanced Dopamine -> Increased cAMP -> Increased CREB -> Increased LTP.

Except we're doing this


Inhibited PDE4 + Increased cAMP -> Increased CREB -> Increased LTP.

Without all the anxiety and weird personality/behavior effects of messing around directly with Dopamine.

More on Dopamine being coupled to cAMP/PKA signaling being attached to LTP-> http://www.ncbi.nlm....pubmed/20969573

I think what we're doing here is increasing the sensitivity of cAMP/PKA signaling so that the dopamine system can more easily modulate LTP.

I just ordered a huge bottle of Now's Quercetin w/Bromelain yesterday, so hopefully the Bromelain isn't a downfall. I had skimmed some abstracts about Bromelain, and how it was supposed to help with Quercetin, so I went ahead and got the combo, since it wasn't much more expensive.

Today I took my first dose of VRP's Forskohlii 100mg [20% Forskolin extract = 20mg], and it definitely works. I used a 50% off code, and bought a total of 14.4g forskolin extract (120 capsules x 6 bottles x 20mg extract). I'm going to try opening the capsules and doing some lower dosing testing, though I don't notice side effects at the 20mg dose. Even at 1 capsule a day, I have 2 years supply of forskolin for $45 shipped! I couldn't find a different source for anywhere near that price, and the quality "seems" to be top notch (though I don't have any lab tests to say so).

I've never been this close to getting my brain to work right. I'm starting to get excited.

I definitely feel more aware and in the moment, making days seem to last longer. Especially on days with caffeine instead of Adderall. Adderall can sometimes cause a bit of too much focus, and I can lose track of time. This occurs with much less frequency on the low dose stack I'm taking now then with the high dosage of Adderall by itself that I used to take.

Also, I've attempted to decipher that abstract you posted about Amphetamine and LTP, but I'll admit that I got a bit lost. I do know that Adderall by itself destroys my memory after taking it for a few weeks. However, I haven't seen a drop in memory since adding the CILTEP stack.

Edited by zrbarnes, 05 May 2012 - 07:33 AM.

[abelard lindsay]

Today I took my first dose of VRP's Forskohlii 100mg [20% Forskolin extract = 20mg], and it definitely works. I used a 50% off code, and bought a total of 14.4g forskolin extract (120 capsules x 6 bottles x 20mg extract). I'm going to try opening the capsules and doing some lower dosing testing, though I don't notice side effects at the 20mg dose. Even at 1 capsule a day, I have 2 years supply of forskolin for $45 shipped! I couldn't find a different source for anywhere near that price, and the quality "seems" to be top notch (though I don't have any lab tests to say so).

I've never been this close to getting my brain to work right. I'm starting to get excited.

I definitely feel more aware and in the moment, making days seem to last longer. Especially on days with caffeine instead of Adderall. Adderall can sometimes cause a bit of too much focus, and I can lose track of time. This occurs with much less frequency on the low dose stack I'm taking now then with the high dosage of Adderall by itself that I used to take.

Ain't it great that this stack is so cheap? All this hunting around chasing after obscure grey market research chemicals in this forum and this stack is maybe $100 a year, all natural and available at just about any supplement shop. I am trying really hard to not get too Isochroma about all this . I am starting to wonder if I should take a few days off. It's funny though, the pace of my life has sped up so much since I started taking this stack that going back to normal speed would require a vacation. I know I couldn't do the MITX course without it. I have also completed several significant life goals in just the past couple of months that I had been procrastinating about for years.

Anyway, back to the science:

http://www.ncbi.nlm....pubmed/21833500

Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex.

RATIONALE:

Alteration of dopamine neurotransmission in the prefrontal cortex, especially hypofunction ofdopamine D1 receptors, contributes to psychotic symptoms and cognitive deficit in schizophrenia. D1 receptors signal through the cAMP/PKA second messenger cascade, which is modulated by phosphodiesterase (PDE) enzymes that hydrolyze and inactivate cyclic nucleotides. Though several PDEs are expressed in cortical neurons, the PDE4 enzyme family (PDE4A-D) has been implicated in the control of cognitive function. The best studied isoform, PDE4B, interacts with a schizophrenia susceptibility factor, disrupted in schizophrenia 1 (DISC1).

OBJECTIVES:
We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4.
RESULTS:
Inhibition of PDE4 by rolipram induced activation of cAMP/PKA signaling in cortical slices and in vivo, leading to the phosphorylation of DARPP-32 and other postsynaptic and presynaptic PKA-substrates. Rolipram also enhanced DARPP-32 phosphorylation invoked by D1 receptor activation. Immunohistochemical studies demonstrated PDE4A, PDE4B, and PDE4D expression in DARPP-32-positive neurons in layer VI of frontal cortex, most likely in D1 receptor-positive, glutamatergic corticothalamic pyramidal neurons. Furthermore, the ability of rolipram treatment to improve the performance of mice in a sensorimotor gating test was DARPP-32-dependent.
CONCLUSIONS:
PDE4, which is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons in layer VI, modulates the level of D1 receptor signaling and DARPP-32 phosphorylation in the frontal cortex, likely influencing cognitive function. These biochemical and behavioral actions of PDE4 inhibitors may contribute to the hypothesized antipsychotic actions of this class of compounds.

So what is this interesting molecule DARPP-32 that's getting phsophorylated by D1?

First, what is D1? D1 receptor is the primary dopamine receptor. So your brain, going about its daily business activating D1 from time to time.

https://www.ncbi.nlm...pubmed/22339853

(ii) Local injection of the D1 /D5 dopamine receptor antagonist SCH-23390 into the auditory cortex after task acquisition caused a discrimination deficit of similar extent and time course as with pre-exposure. This effect was dependent on the dose and time point of injection. (iii) Injection of the D1 /D5 dopamine receptor agonist SKF-38393 into the auditory cortex after retraining caused a further discrimination improvement at the beginning of subsequent sessions. All three treatments, which supposedly interfered with dopamine signalling during conditioning and/or retraining, had a substantial impact on the dynamics of the discrimination performance particularly at the beginning of subsequent training sessions.

http://www.ncbi.nlm....pubmed/19520120

These results indicate that decreased dopaminergic functioning is correlated with increased activity levels in C57L/J mice and suggests thatD1-like receptors as well as tyrosine hydroxylase (an indicator of dopamine production), but not D2-like receptors may be associated with the regulation of physical activity in inbred mice.

So part of D1's function is triggering memory formation and in activity levels (e.g motivation) in general.

By going about its daily business of getting activated D1 is causing phosphorylation of DARPP-32. When we inhibit PDE4 and add cAMP this process is increased. The original signaling of the dopamine receptor is not affected. If it were, this would likely cause down regulation of the receptors which leads to tolerance and other bad things. It's just that the same signal has more effect downstream.

Now what is DARPP-32 Phsphorylation good for?
http://www.ncbi.nlm....pubmed/19520120

Phosphorylation of CREB and DARPP-32 during late LTP at hippocampal to prefrontal cortex synapses in vivo.

Specific patterns of stimulaion applied in the ventral hippocampus produce long-term potentiation (LTP) of postsynaptic synapses in the prefrontal cortex in vivo. The induction ofLTPis dependent on NMDA receptors and cAMP-dependant kinase (PKA) activation. Yet little is known concerning the cellular mechanisms underlying the expression of this neocortical form ofLTP. In the present study, we tested whetherLTPat hippocampal to prefrontal cortex synapses leads to activation ofDARPP-32 and CREB as well as defined the temporal regulation of the phosphorylation states of both proteins. Our data indicate a peak in CREB andDARPP-32 phosphorylation during the late phase of prefrontal LTP (2 h posttetanus). These findings support the hypothesis that prolonged expression of hippocampal-prefrontal cortex LTP depends on a synergistic mechanism involving phosphorylation of both CREB and DARPP-32 via activation of the cAMP/PKA-dependent pathway.

What about CREB? Don't we need that for LTP synergy too? Turns out it runs on the same cAMP/Dopamine pathway we've been optimizing

http://www.ncbi.nlm....pubmed/19812345

cAMP can stimulate the transcription of many activity-dependent genes via activation of the transcription factor, cAMP response element-binding protein (CREB). However, in mouse cortical neuron cultures, prior to synaptogenesis, neither cAMP nordopamine, which acts via cAMP, stimulatedCREB-dependent gene transcription when NR2B-containing NMDA receptors (NMDARs) were blocked.

So anyway, in summary, we are making the effects of normal dopamine function more effective at triggering desirable downstream processes that increase learning and memory. Thus, the chemical dynamics of the dopamine system are preserved, which avoids all the negative effects of traditional dopamine stimulation (e.g Adderall, Ritalin) while making normal receptor activation operate more effectively on the desirable LTP increasing metabolic pathways.

Edited by abelard lindsay, 05 May 2012 - 01:51 PM.

[Gamerzneed]

do you feel like you are on NZT with this combo or something? How does it improve mental clairity/logic reasoning for you, Do things that nomrally would've taken a lot of brainpower just make sense all of a sudden for you on this combo?