2626 replies to this topic

[X_Danny_X]

I havent follow the thread for a while. Is Forskolin still an issue for downgrading ACH receptors. What happens when it does that, you find yourself going to sleep? also can Galantamine combat this?

[FrankMH]

I found a website that does have a 98% forskolin extract, however I don't see it as being for sale on the website anywhere. That said, I've just emailed them and I'm awaiting a response.

In the meantime, how about this?

http://www.sigmaaldr...blePage=9563801

Quite pricey, though.

[health_nutty]

Yup, chiming in with my hesperidin report here: I noticed that although it seemed helpful for the first few days for anxiety, I'm now about 5-6 days in and it just seems to make me...dumber. That's the best word for it. My creativity, cleverness, sense of humor, all seem to be lacking quite a lot. Didn't take it earlier today for the whole day up until 2 hours ago and felt great, took it 2 hours ago and now I feel like everything about me has been reduced again. Good to have been able to at least isolate it to the hesperidin, it has almost counteracted all the benefits I usually get from the CILTEP stack. Shame :/ So I'd suggest it be avoided. Such a pain in the ass that supplements need to be cycled, would be wonderful if the benefits from individual supplements could just remain and increase with time. Meh.

Yes, Hesperidin was great for anxiety the first couple of days. Drowsiness was there, but did not seem so bad. Then the drowsiness seemed to just get worse and worse until yesterday it was extreme (even with copious amounts of caffeine!)

[genghiz]

Ive been taking Forskohlii and Artichoke extract for a little more than a week now and its very subtle. (Still waiting for

L-Phenylalanine)

My forskohlili is in 26mg caps and the first few days taking that with 500mg artichoke extract gave me a very slight headache. Then i lowered forskohili to half capsule (~13mg) with 500mg artichoke extract and the result has been very slight but positive. I feel motivated to get stuff done where as before that would only happen on a good day.

Edited by genghiz, 06 July 2012 - 05:53 PM.

[owtsgmi]

Then the drowsiness seemed to just get worse and worse until yesterday it was extreme (even with copious amounts of caffeine!)

This CILTEP routine has progressively made me more and more tired also. I am down to 1/4 original dose...just one forskolin + 1 quercetin per day (down from 2 x 2 per day). I noticed I've been staying up later reading/watching movies though, so it could be that simple. It just seems like its harder and harder to wake up in the morning although the mood is just fine. The overall effects are still positive in the context of my overall regimen.

[health_nutty]

Then the drowsiness seemed to just get worse and worse until yesterday it was extreme (even with copious amounts of caffeine!)

This CILTEP routine has progressively made me more and more tired also. I am down to 1/4 original dose...just one forskolin + 1 quercetin per day (down from 2 x 2 per day). I noticed I've been staying up later reading/watching movies though, so it could be that simple. It just seems like its harder and harder to wake up in the morning although the mood is just fine. The overall effects are still positive in the context of my overall regimen.

I *think*, in my case it was the hesperidin. Today is my first day Hesperidin free, and my energy is 70% back.

[Rior]

Then the drowsiness seemed to just get worse and worse until yesterday it was extreme (even with copious amounts of caffeine!)

This CILTEP routine has progressively made me more and more tired also. I am down to 1/4 original dose...just one forskolin + 1 quercetin per day (down from 2 x 2 per day). I noticed I've been staying up later reading/watching movies though, so it could be that simple. It just seems like its harder and harder to wake up in the morning although the mood is just fine. The overall effects are still positive in the context of my overall regimen.

What's your dose of forskolin? I've been sticking with a solid 4mg or so, 2-3 times daily.

[health_nutty]

Then the drowsiness seemed to just get worse and worse until yesterday it was extreme (even with copious amounts of caffeine!)

This CILTEP routine has progressively made me more and more tired also. I am down to 1/4 original dose...just one forskolin + 1 quercetin per day (down from 2 x 2 per day). I noticed I've been staying up later reading/watching movies though, so it could be that simple. It just seems like its harder and harder to wake up in the morning although the mood is just fine. The overall effects are still positive in the context of my overall regimen.

What's your dose of forskolin? I've been sticking with a solid 4mg or so, 2-3 times daily.

10mg in the morning for me. Maybe I should split it into 5mg morning and 5mg afternoon?

[medievil]

5HTP increases cAMP and it may be a good addition.

[medievil]

Milk thistle, ginkgo and ginseng can be added to the list of PDE inhibitors.

[abelard lindsay]

5HTP increases cAMP and it may be a good addition.

Milk thistle, ginkgo and ginseng can be added to the list of PDE inhibitors.

Can you provide some links to studies?

[Nattzor]

5HTP increases cAMP and it may be a good addition.

Milk thistle, ginkgo and ginseng can be added to the list of PDE inhibitors.

Can you provide some links to studies?

Just found some stuff on pubmed, will highlight some "important" and some "weird" parts:
Ginseng:

Ginseng extract inhibits lipolysis in rat adipocytes in vitro by activating phosphodiesterase 4.
Elevated concentrations of plasma free fatty acids (FFA) may cause insulin resistance. Inhibition of lipolysis reduces FFA availability and improves insulin sensitivity. Ginseng extract (Panax spp., GE) was shown to improve glycemia in Type 2 diabetes. In the present study, the antilipolytic effect of GE in rat adipocytes and the signaling pathway for GE antilipolysis were investigated. Adipocytes were isolated from rat fat tissue by collagenase digestion. The ability of GE to inhibit lipolysis was assessed by measuring glycerol and FFA release into the incubation medium. Phosphatidylinositol 3-kinase (PI3-K) inhibitor and various phosphodiesterase (PDE) inhibitors were applied to investigate the signaling pathway for GE antilipolysis. The present study showed that insulin and GE inhibited lipolysis by 42.4 and 49% compared with basal, respectively (P < 0.05). Unlike insulin, the PI3-K inhibitor wortmannin did not reverse GE antilipolysis, and GE did not affect phosphorylation of protein kinase B (PKB). The nonselective PDE inhibitor enprofylline reversed both insulin and GE antilipolysis. The specific phosphodiesterase 3 (PDE3) inhibitor cilostamide reversed insulin antilipolysis completely, but did not significantly affect GE antilipolysis. The specific phosphodiesterase 4 (PDE4) inhibitor rolipram did not significantly affect insulin antilipolysis, but almost completely reversed GE antilipolysis. Moreover, the combination of PDE3 and PDE4 inhibitors completely reversed GE antilipolysis. None of the ginsenosides (Rb1, Re, Rg1, Rc, Rb2, and Rd) were responsible for GE antilipolysis. The results suggest that ginseng exerts its antilipolytic effect through a signaling pathway different from that of insulin. GE antilipolysis is mediated in part by activating PDE4 in rat adipocytes.

- http://www.ncbi.nlm....pubmed/16424109
Didn't really understand why they used rolipram and all the other stuff in the study. Activating the PDE4 wouldn't be something we want, or?

Ginsenoside Rg1 inhibits the brain cAMP phosphodiesterase activity in young and aged rats.
1. The in vitro effect of ginsenoside Rg1 from Panax ginseng on the low- and high-KM cyclic AMP phosphodiesterase (cAMP PDE) activity in the frontal cortex, striatum, hypothalamus and hippocampus of young (4-5-month old) and aged (22-month old) rats has been studied. 2. Administered in increasing concentrations (from 5 x 10(-5) M up to 5 x 10(-4) M), ginsenoside Rg1 exerted a pronounced inhibitory effect on the low- and high-KM enzyme activity in all brain structures studied in rats of both age groups. 3. Ginsenoside Rg1 exhibited inhibitory potency similar to that of theophylline. 4. The present results provide evidence for the CNS effects of ginsenoside Rg1 through inhibition of the intracellular level of cAMP.

- http://www.ncbi.nlm..../pubmed/8112520
Does that mean it's not good to take Ginsenoside (is it even the same thing as Ginseng?) together with the stack?

Ginko:

Inhibition of type 4 phosphodiesterase by rolipram and Ginkgo biloba extract (EGb 761) decreases agonist-induced rises in internal calcium in human endothelial cells.
The effects of Gingko biloba extract EGb 761 on 5 isolated, vascular, cyclic nucleotide phosphodiesterase (PDE) isoforms were evaluated. EGb 761 preferentially inhibited PDE4 (IC(50)=25.1 mg/L), the isoform that is mainly present in endothelial cells, in a competitive manner (K:(i)=12.5 mg/L). Because changes in cyclic nucleotide levels may affect intracellular calcium ([Ca(2+)](i)) levels in endothelial cells, we examined the effects of EGb 761 on both resting [Ca(2+)](i) levels and agonist-induced rises in [Ca(2+)](i) in single human umbilical vein endothelial cells (HUVECs) in culture. The effects of EGb 761 were compared with those of rolipram, a selective PDE4 inhibitor that increases cellular cAMP levels, and the cAMP analogue dibutyryl cAMP (db-cAMP). EGb 761 (20 and 100 mg/L), rolipram (50 micromol/L), and db-cAMP (100 micromol/L) significantly inhibited histamine-, ATP-, and thrombin-induced [Ca(2+)](i) increases in HUVECs without modifying resting [Ca(2+)](i) levels. Similar results were obtained by using a Ca(2+)-free bath solution. EGb 761 (100 mg/L), but not rolipram (50 micromol/L) or db-cAMP (100 micromol/L), also inhibited Ca(2+) influx into cells having thapsigargin-depleted internal Ca(2+) stores and bathed in a Ca(2+)-free external solution. Our results are consistent with an inhibition of PDE activity that causes a reduction of agonist-induced increases in [Ca(2+)](i) in HUVECs, mainly by inhibition of Ca(2+) mobilization from internal stores. It thus may be that the cardiovascular effects of EGb 761 involve inhibition of PDE4 activity and subsequent modification of Ca(2+) signaling in endothelial cells.

- http://www.ncbi.nlm....pubmed/10978267
Does that mean that Ginko is a PDE4 inhibitor and a cAMP increaser or have I misunderstod it?

Effects of an extract of Ginkgo biloba on the 3',5'-cyclic AMP phosphodiesterase activity of the brain of normal and triethyltin-intoxicated rats.
For clarification of the beneficial effects of the extract of Ginkgo biloba (EGB) on triethyltin (TET) toxicity in rats, the phosphodiesterase (PDE) activities of the cerebral tissue were measured under in vitro and ex vivo conditions. Under in vitro conditions, low concentrations of EGB (0.25-4.0 mg/L) activated the enzyme, whereas after higher concentrations (5-250 mg/L), dose-dependent inhibition of the enzyme activity was observed. In the lower concentration range, the extract also partially restored the high-affinity PDE activity (measured with 0.25 microM cyclic AMP) of the particulate fraction of the brain inhibited by TET in vitro. In contrast, the inhibitory influence of TET on the low-affinity PDE activity (measured with 50 microM cyclic AMP) of the particulate fraction was enhanced by the extract. Although treatment with a single large dose of EGB lowered the particulate PDE activities of the brain of normal rats, no effects of the extract could be detected in animals after repeated daily administrations of EGB during a 4-day period. Curative treatment of the TET-intoxicated rats with EGB during a 7-day period accelerated the recovery of the edematous state of the white matter caused by the intoxication and also normalized the lowered PDE activity of the particulate fraction of the edematous brain tissue. Furthermore, when preventively administered, EGB counteracted both the edema formation and the fall in PDE activity observed with treatment by TET alone. These observations strongly suggest that some beneficial effects of EGB might be due to its modulating influences on cellular cyclic AMP levels via activation of membrane-bound PDE.

- http://www.ncbi.nlm..../pubmed/3035090
Can't get much out of that as a layman.

Milk Thistle:

Milk Thistle may be useful in the treatment of psoriasis due to its ability to correct abnormal liver function, inhibit the synthesis of leukotrienes, lowering the cGMPlevels and raising the cAMP levels and it is noteworthy that if the liver is over burdened and cannot perform the basic tasks of detoxification of circulating endotoxins from gut bacteria, the psoriasis gets worse, therefore, the use of Milk Thistle preparations in psoriasis and other dermatoses seems prudent.

- http://www.doctormor...ew.rails?id=233
Not sure how reliable that site is, got sources but didn't look trough them that much.


Something else:

PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries.
Cyclic nucleotides (cAMP and cGMP) are the main second messengers linked to vasodilatation. They are synthesized by cyclases and degraded by different types of phosphodiesterases (PDE). The effect of PDE inhibition and cyclases stimulation on 5-hydroxytryptamine (5-HT; 1 microM) and histamine (10 microM) contracted arteries was analysed. Stimulation of guanylate cyclase or adenylate cyclase relaxed the histamine- and 5-HT-induced contractions indicating that intracellular increase of cyclic nucleotides leads to vasodilatation of the human umbilical artery. We investigated the role of different PDE families in the regulation of this effect. The presence of the different PDE types in human umbilical artery smooth muscle was analysed by RT-PCR and the expression of PDE1B, PDE3A, PDE3B, PDE4C, PDE4D and PDE5A was detected. The unspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX; 50 microM) relaxed histamine-contracted human umbilical artery on 47.4+/-7.2%. This effect seems to be due to PDE4 and PDE5 inhibition because among the selective PDE inhibitors used only the PDE4 inhibitor (rolipram; 1 microM) and the PDE5 inhibitors (dipyridamole and T0156; 3 microM and 1 microM respectively) induced significant relaxation (39.0+/-8.7, 30.4+/-6.0 and 36.3+/-2.8 respectively). IBMX, dipyridamole and T0156 produced similar relaxation on 5-HT-induced contraction. After forskolin, the addition of IBMX or rolipram increased the effect of the adenylate cyclase stimulator and almost completely relaxed the human umbilical artery contracted by histamine (92.5+/-4.9 and 90.9+/-4.7 respectively), suggesting a main role of PDE4. The data obtained with 5-HT contracted arteries confirmed this, because only rolipram and IBMX significantly increased the forskolin vasodilator effect. The administration of dipyridamole and T0156 after sodium nitroprusside (SNP) induced a significant increase of the SNP relaxant effect on histamine-contracted arteries, but PDE1 and PDE3 inhibition did not increase the effect of the guanylate cyclase stimulator. Similar effects were obtained in 5-HT contracted arteries, the SNP induced relaxation was increased by the PDE5 inhibition, but not by PDE1 or PDE3 inhibition. In summary, our results demonstrate that: 1) the increase of cAMP and/or cGMP levels induces relaxation of the human umbilical vascular smooth muscle; 2) four families of PDE are expressed in this smooth muscle: PDE1, PDE3, PDE4 and PDE5; 3) between these families, PDE4 and PDE5 are the key enzymes involved in the regulation of the relaxation associated to cAMP and cGMP, respectively.

- http://www.ncbi.nlm....pubmed/18234184
Does that mean that histamine is a PDE4 inhibitor?

Edited by Nattzor, 07 July 2012 - 08:10 PM.

[Raza]

Nice finds. I'm a layman too, but I'll give interpreting them a shot.

Didn't really understand why they used rolipram and all the other stuff in the study. Activating the PDE4 wouldn't be something we want, or?

I think that's the opposite of what we're doing. Might have some utility if we accidentally overdo it, though. One of the other studies you quoted appears to refer to drastic PDE4 inhibition by triethyltin as poisoning (although that bit isn't entirely clear to me), which might suggest that you can go too far.

Does that mean it's not good to take Ginsenoside (is it even the same thing as Ginseng?) together with the stack?

I think so. And gingsengosides are the active molecules in ginseng.

Does that mean that Ginko is a PDE4 inhibitor and a cAMP increaser or have I misunderstod it?

Can't get much out of that as a layman.

It appears to be a dose-dependent PDE4 inhibitor or activator (and through that, cAMP in- or decreaser). Low concentrations activate PDE4 (like ginseng), higher ones inhibit it.

If someone here is capable of translating those in vitro concentrations to human dosage, this could be a very useful find. The study claims it is highly selective to PDE4, and ginkgo is a dopaminergic as well - it could be a great complement to the stack, if the PDE4-inhibiting concentrations can be reached by reasonable levels of ginkgo supplementation.

Alternately, if we have anyone here sufficiently convinced of the recognizable effectiveness of CILTEP that they believe they can tell from taking it whether the combo is active, they could try skipping their usual PDE4 inhibitor that day and take forskolin with ginkgo instead, to see whether it works through experience. I do have all those supplements around, but I'm afraid I lack the confidence in my ability to tell.

Does that mean that histamine is a PDE4 inhibitor?

That's not how I read it. Histamine was one of the agents used to induce vasoconstriction, alongside serotonin. PDE4 and PDE5 inhibition, combined with Forskolin, counteracted this vasoconstriction in the umbilical artery specifically. This doesn't have much to do with our stack, that I can see.

Edited by Raza, 07 July 2012 - 09:53 PM.

[medievil]

"Silymarin: potent inhibitor of cyclic AMP phosphodiesterase.
Koch HP, Bachner J, Löffler E.
Abstract
Silymarin, the active principle of the Milk Thistle (Silybum marianum Gaertner), is a very potent inhibitor of cyclic AMP breakdown in vitro by a commercial beef heart phosphodiesterase preparation. Its main constituents, silybin, silydianin and silychristin, are 12.66 to 52.06 times more active than theophylline and 0.77 to 3.17 times more active than papaverine in this respect. Using a novel HPLC technique, the enzyme kinetical analysis can be performed much faster than by the classical methods."

Im taking forskolin with ginkgo and cafeine at the moment but dont really notice much difference perhaps i need a higher dose, unfortionally my smartpowders order took long and i ran out of quercetin before so cant really compare.

[nupi]

Interesting, I have been taking NOW Silymarin (which also has some Artichoke extract in it) since about 6 months for its hepatoprotective properties (initially because I had suspected Bupropion to affect liver function but I dropped that shortly after for its gastrointestinal upset and overall limited benefits) but I cannot say I noticed any direct nootropic effects from it. It apparently also works on some of the SIRT receptors, so might be quite useful for life extension purposes.


The report about hepatotoxicity with Forskolin makes my wary of the Forskolin supplement that is standing next to me...

Edited by nupi, 08 July 2012 - 05:46 PM.

[Brenjin]

http://www.ncbi.nlm....pubmed/12059045

Its also good in conjunction with anything that increases NGF.

[gizmobrain]

Coincidentally, I happen to have some Milk Thistle scheduled to be delivered tomorrow. I also have a whole container of powdered ginkgo that I have been trying to figure out what to do with, since it taste so bad and I don't have a capping machine (I really need to get a scale and capper).

I've got a lot of irons in the fire right now, so we will see if I can isolate the effects of the different supplements I've been trialing. Ultimately, I am looking for two stacks that increase motivation by different pathways, so that hopefully I can cycle them back and forth to avoid developing tolerances.

Edited by zrbarnes, 08 July 2012 - 06:49 PM.

[owtsgmi]

What's your dose of forskolin? I've been sticking with a solid 4mg or so, 2-3 times daily.

My forskolin pills are 20mg (200mg @ 10%). I am only taking one per day now with an activated quercetin pill (1g). Dropping to one pill per day has seemed to fix the tiredness issues I was having.

[medievil]

Coincidentally, I happen to have some Milk Thistle scheduled to be delivered tomorrow. I also have a whole container of powdered ginkgo that I have been trying to figure out what to do with, since it taste so bad and I don't have a capping machine (I really need to get a scale and capper).

I've got a lot of irons in the fire right now, so we will see if I can isolate the effects of the different supplements I've been trialing. Ultimately, I am looking for two stacks that increase motivation by different pathways, so that hopefully I can cycle them back and forth to avoid developing tolerances.

You can just scoop empty caps right before you take them, dont have a capping machine either works a charm for bad tasting powders.

[summertimex]

ive been taking the milk thistle also it doesnt cause drowsiness, but instead just an added effect to the artichoke. sylmarin is also pro-bdnf. it is a good add on, if youre worried about hepatoxicity from pills get the n-acetyl-cysteine. i havent found research on acai extract or those sorts of things on cAMP, but some sort of metabolic ATP increasing substance would do well

[CognitionCoefficient]

I'm currently taking:

- 10mg Forskolin
- 500mg Artichoke Extract
- Biphentin 15mg (or Concerta 18mg)
- CDP Choline 250mg
- Methylene Blue 60mcg (3x daily on weekdays)

... to treat ADHD-I.

I can't say I've noticed any significant effects from the first two supplements after >1 month of use. CDP choline seems to increase my vigilance. Methylphenidate provides modest relief of symptoms, but it's effects have long since waned since starting stimulant treatment in 2008.

Edited by CognitionCoefficient, 09 July 2012 - 12:38 AM.

[gizmobrain]

Lately, I've been learning about NMDA, and I've got a wild theory that needs to be tested. For those of us lacking motivation and are not anxious, I'm wondering if the issue at hand is hypo-NMDA activity.

That would go along nicely with this finding:

We have shown that the activation of adenylyl cyclase with forskolin enhanced the amplitude of EPSCs and abolished LTD. This finding is consistent with numerous studies showing that activation of adenylyl cyclase increases the probability of glutamate release (Chavez-Noriega & Stevens, 1994; Tzounopoulos et al. 1998).

Also, since I responded very well the motivating aspects of amphetamine (but couldn't take the side effects), I'm wondering if it's more because of this:

Systemic administration of d-amphetamine (4 mg/kg, ip) increased glutamate release by 500% in WT mice

[medievil]

How do you respond to other glutamate releasers? Like nicotine, nefiracetam, pregnenolone(even aspirin releases glut for a part) or other glutaminergics if you tried any.
Also nefiracetam helped several with adhd ive read and its highly glutaminergic.

[CognitionCoefficient]

It helps to isolate the sub-types of ADHD that supposedly benefit from this therapy, as you two seem to be doing. I self-experimented with this regimen knowing there was little in the way of high-quality studies showing efficacy in my subtype.

I'm not a fan of anecdotal reports, but I felt obliged to report my experience for the non-responders out there. I hope you find what you're looking for here.

Edited by CognitionCoefficient, 10 July 2012 - 08:37 PM.

[Raza]

You may want to try taking upping artichoke before you give up on this, especially if you've already paid for it. Too much Forskolin causes side effects, but the PDE4I seems to allow more leeway. Also, you could experiment with a dopamine precursor, which has 'activated' this combo for people before - being on methylphenidate means you'll want to start low, but dopamine excesses aren't as dangerous as serotonin's.

Also, aren't relaxants bad with ADHD (hearsay on my part)? Artichoke's been mentioned as anxiolytic (GABAergic?). Quercetin is the more upper-y of the PDE4Is, at east until we get Ginkgo to work.

Edited by Raza, 10 July 2012 - 09:03 PM.

[CognitionCoefficient]

Increasing the Artichoke Extract dosage is the last variation I've yet to try.

Edited by CognitionCoefficient, 12 July 2012 - 06:20 PM.

[Thorsten3]

I haven't read the last couple of pages but it was mentioned earlier in the thread that it's advisable to go with L-Phenylalanine instead of DL-Phenylalanine due to better efficacy???

Surely all of these dopamanergic precursers are going to be the same in that they fall victim to your body upregulating enzymes that deal with the increased amount of DA precursers in your body?

I have been taking Forskolin on its own and it seems to do most of the work (increased clarity, attention, focus). Adding Artichoke hasn't really done much, not that I can notice anyway.

I plan on trying Trivastal with this regimen when I finally get my order. It might compliment it.

[gizmobrain]

Just found an interesting study regarding Galantamine (and other acetylcholinesterase inhibitors):

Decreased glutamate toxicity through down-regulation of NMDA receptors, following stimulation of α7 nAChRs, could be another mechanism underlying neuroprotection by donepezil, in addition to up-regulating the PI3K-Akt cascade or defensive system.

Anyone care to take a look at it? If I read it right, Galantamine would be neuroprotective against the increased glutamate transmission caused by Forskolin, but it would not block the beneficial effects of such. However, I may be wrong.

Edited by zrbarnes, 13 July 2012 - 02:26 AM.

[medievil]

You dont want downregulation of nmda, pregnenolone for example makes nmda more sensitive so if you add that one factor of the neuroprotection will get lost but its not something you want anyway, there are better ways to offer neuroprotection, that with keeping nmda sensitive with preg is the way to go imo.

[X_Danny_X]

Where are trusted suppliers of D-serine? I want to add it to my CILTEP stack.