2626 replies to this topic

[hephaestus]

I've not been supplementing with Glutamine (though I do have some L-Glutamic Acid lying around)... but I have been trying to figure out if glutamate is the missing piece for me, since I have not been able to figure out how to perfectly replicate the motivating effects since I have dropped the final 5mg of Adderall out of my CILTEP stack.

Quoting myself from earlier in this thread:

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

CILTEP "increases the probability of glutamate release". Therefore, supplementing with a precursor to glutamate might be a good idea.

The problem is that I still don't quite understand how the brain deals with just spare glutamate floating around. Will it down-regulate Glutamate receptors? Will it restock the glutamate supply? Will it cause excitotoxicity? What about supplementing a glutamatergic agent and glycine (or another glycine receptor agonist) together? Would the effects cancel out or would it instead allow the brain to have all the raw material it needs to prevent damage? Then there is the pre-synaptic vs post-synaptic sites, kinate receptors, ion channels...

Dear sweet goodness, the brain is complex. I really need to just sit down and read an up-to-date "Neuroscience for amateurs" book.

Do you take any of the racetams? Methylphenidate could be an option as well, seems to be better understood and probably safer long term than amphetamines. I've never tried it but I am asking my doctor about getting a script, the piracetam/amphetamine combo kicked my ass.

[hephaestus]

Could always try rhodiola with n-acetyl-tyrosine or something like that too.

[hephaestus]

Don't smoke!

Brain Res. 2006 Mar 17;1078(1):80-91.
Nicotine reverses consolidated long-term potentiation in the hippocampal CA1 region.

Guan X, Nakauchi S, Sumikawa K.

Source

Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA.

Abstract

Long-term potentiation (LTP) has a memory-like consolidation period during which it becomes progressively stabilized. However, it is unknown how the consolidation is achieved. The present study demonstrates that nicotine reverses stabilized LTP in the hippocampal CA1 region, providing the first evidence that consolidated LTP can be reversed. The nicotine-induced reversal appeared to work by reversing cellular processes involved in stabilizing LTP, as LTP was readily induced again after reversal. The effect of nicotine was mediated, in large part, via desensitization of alpha7 nicotinic acetylcholine receptors (nAChRs), as an alpha7 nAChR-selective antagonist mimicked the nicotine effect. A non-selective N-methyl-d-aspartate receptor (NMDAR) antagonist completely abolished the nicotine-induced reversal, whereas an NR2B-containing NMDAR-selective antagonist had no effect. Furthermore, both the protein phosphatase 1/protein phosphatase 2A inhibitor okadaic acid and the protein phosphatase 2B (calcineurin) inhibitor cyclosporin A blocked the nicotine-induced reversal. Taken together, our results suggest that the reversal of stabilized LTP depends on the activation of NR2A-containing NMDARs and dephosphorylation. Thus, the consolidation of LTP appears to be the interruption of signaling leading to NR2A-containing NMDAR-dependent activation of protein phosphatases, which can be circumvented by nicotine-induced signaling. LTP induced in chronic nicotine-treated hippocampi contained a component that is immune to reversal, and thus acute nicotine was no longer effective to reverse consolidated LTP. These results demonstrate the differential effects of acute and chronic nicotine exposure on the cellular processes that are potentially involved in learning and memory.

This is from way back on page 5, but I thought I'd point out that it says chronic nicotine use isn't necessarily bad for LTP:

LTP induced in chronic nicotine-treated hippocampi contained a component that is immune to reversal, and thus acute nicotine was no longer effective to reverse consolidated LTP.

I recently quit smoking and purchased an e-cigarette, really like the short acting stimulant effects of nicotine.

Edited by hephaestus, 25 July 2012 - 07:22 PM.

[RS3RS]

Say I take MAO-B selective doses of Selegiline along with very low doses of phenylethylamine (less than 50mg 2x daily). Besides the already discussed dangers of this stack, is there any specific reason that this LTP stack would be a dangerous to add?

Edited by RS3RS, 25 July 2012 - 10:31 PM.

[brainslugged]

I am thinking about trying this stack now. I have had great improvements with my current stack where the primary components are piracetam, grape seed extract, and bacopa, but if I can get even better, I am all for it.

My concern, however is that I could potentially cause too much dopamine and go into a manic state. With just my current stack alone, I seem to be fairly stabilized at baseline or just above with occasional swings that approach hypomania or dysthymia compared to my previous stabilization around dysthymia with swings that approached baseline or Major depression, and although I don't think I am actually reaching hypomania, I think I am getting very close.

Judging from these effects, I am afraid that if I do this, I could stabilize at hypomania (a good thing), but have swings into full mania (which I don't want). I don't know if this is an accurate assumption, though. I don't know if mania is really just more hypomania or something different, or if these would have powerful enough mood effects to push me over, or even if they protect against mood disorder. If someone could reassure me, that would be great. Thanks for your time!

[Raza]

Posted in wrong thread.

Edited by Raza, 28 July 2012 - 08:29 AM.

[RS3RS]

Postman just came. I took 500mg Quercetin and 200 mg of 10% forskolin (20mg forskolin) with 100mg caffeine and 1.25 mg of sublingual Selegiline (which I take daily, so MAO-B is already inhibited) on an empty stomach. That was 2 hours and 20 minutes ago, from the time of typing this. It's hard to distinguish when the effects began (it's not something you feel "kick" in), but I'd say at around the 40 minute mark. I have ADHD-PI and possibly SCT.

This stack is certainly a unique feeling. I'm used to ADHD medications, which clear my head and allow thoughts to flow freely, accompanied by a stimulant surge. This provides the clear-headedness without the stimulant rush. I feel like I can focus much better and organize my thoughts better. I suppose I've never experienced enhanced dopamine activity without the boost of accompanying norepinepherine. It actually weireded me out a bit, so I took an additional 100mg caffeine and it feels a little more like a stimulant might.

Definitely interested in this one. On my to-do list is to try it before work, which I constantly struggle with. My job requires intense concentration, and I'm constantly being distracted, making a 4 hour project take me 7 hours+ to finish. Also on the list is to experiment with nicotine, as my access to dopaminergic drugs is quite limited. Based on clinical data posted, I'm unsure if nicotine will potentiate or hinder CILTEP.

Finally, I'm interested in combining a very, very low dose of Phenethylamine (which I still have to order) with this stack. Since I take selegiline, I wouldn't take more than ~50mg or so of PEA to begin with. With this stack, I would want to reduce that even more for my first time. Not sure where to begin? 10mg? Probably won't feel anything from that, but we'll see. A slow ramp-up is definitely in order.

Interested to know what results others have had with ADHD (specifically PI), brain fog, SCT, executive function disorder, and maybe dysthymia and social anxiety. Will keep update this thread as I experiment.

Edited by RS3RS, 28 July 2012 - 07:36 PM.

[RS3RS]

Forskolin is a diterpene derivative of the plant Coleus forskohlii that stimulates adenylate cyclase activity without interacting with cell surface receptors. Forskolin lowers the intraocular pressure of rabbits, monkeys, and humans. In rabbits, net aqueous humor inflow decreases, outflow facility remains unchanged, and ciliary blood flow increases. Tolerance to the intraocular pressure lowering effect did not occur in rabbits after topical doses given every 6 hr for 15 days. In vitro forskolin activates adenylate cyclase of crude particulate homogenates prepared from cultured human ciliary epithelia or from dissected ciliary epithelial processes of rabbit or human eyes. This activation is not blocked by timolol. The stimulation of adenylate cyclase by isoproterenol in vitro is potentiated in the presence of forskolin. Forskolin represents a potentially useful class of antiglaucoma agents differing in molecular mechanism of action from previously used drugs.

Is there any known way to counteract the decrease in intraocular pressure caused by Forskolin? This side-effect is a little annoying, it definitely makes it more difficult to read text.

[jayfoxpox]

Sorry if this has been answered , but after a quick wiki search on PDE3 inhibitors the adverse effects arearrhythmia, thrombopenia and increased transaminase levels.
PDE5 inhibitors
The occurrence of adverse drug reactions (ADRs) with PDE5 inhibitors appears to be dose related. Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis.^{[2] ( not really worried about these ones)}

On October 18, 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible sudden hearing loss would be added to drug labels of PDE5 inhibitors.^[3]
Since 2007 there is evidence that 5-phosphodiesterase inhibitors can cause an anterior optic neuropathy^[4]

http://en.wikipedia....verse_reactions
http://en.wikipedia....Adverse_effects

Because Luteolin is a non-selective inhibitor effecting 1-5 should we assume that it comes with all risks stated above?
If so , would it be safer is there any that avoids inhibiting pde3 and 5?

Thanks.

Edited by jayfoxpox, 29 July 2012 - 03:41 PM.

[jayfoxpox]

Also I don't want to get a constant erections from Luteolin inhibiting pde5 :p

[chroncile]

Sorry if this has been answered , but after a quick wiki search on PDE3 inhibitors the adverse effects arearrhythmia, thrombopenia and increased transaminase levels.
PDE5 inhibitors
The occurrence of adverse drug reactions (ADRs) with PDE5 inhibitors appears to be dose related. Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis.^{[2] ( not really worried about these ones)}

On October 18, 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible sudden hearing loss would be added to drug labels of PDE5 inhibitors.^[3]
Since 2007 there is evidence that 5-phosphodiesterase inhibitors can cause an anterior optic neuropathy^[4]

http://en.wikipedia....verse_reactions
http://en.wikipedia....Adverse_effects

Because Luteolin is a non-selective inhibitor effecting 1-5 should we assume that it comes with all risks stated above?
If so , would it be safer is there any that avoids inhibiting pde3 and 5?

Thanks.

Whoa. After waking up deaf in one ear and remaining deaf in that ear till this day, I can tell you that hearing loss concerns me greatly. I only have one good ear left and I have to take care of it.

Anyway, from my understanding the pharmaceutical drugs used for treating erectile dysfunction are potent. I haven't done much research, but Luteolin is found in green pepper, celery, carrots, olive oil, and other dietary sources. From this, I think it's clear that Luteolin is not the most potent compound for inhibiting PDE, otherwise we would all easily get erections after ingesting a simple meal.

Does Quercetin also inhibit PDE5?

Also, since PDE5 inhibitors seem to increase Nitric Oxide and since Panax Ginseng also increases Nitric Oxide, do you think there's a relationship between the two? I currently take Panax Ginseng and the thought of hearing loss in my only good ear frightens me.

[gizmobrain]

At the dosages that have been tossed around in this thread, PDE5 inhibition is not substantial. If it was, then you would know it immediately

Is there any known way to counteract the decrease in intraocular pressure caused by Forskolin? This side-effect is a little annoying, it definitely makes it more difficult to read text.

The only solution I have found is to reduce the dosage of Forskolin. I divided my 100mg (20%) pills into 3 or 4 doses. This reduces some of the other side effects as well.

Edited by zrbarnes, 29 July 2012 - 06:48 PM.

[jayfoxpox]

Anyway, from my understanding the pharmaceutical drugs used for treating erectile dysfunction are potent. I haven't done much research, but Luteolin is found in green pepper, celery, carrots, olive oil, and other dietary sources. From this, I think it's clear that Luteolin is not the most potent compound for inhibiting PDE, otherwise we would all easily get erections after ingesting a simple meal.

Although it may be found in the food we eat I'd argue that because the the stack consists of an artichoke extract , it's possible the amount of Luteolin is much higher than one would get from regularly consuming foods that contain luteolin.

Does Quercetin also inhibit PDE5?

Also, since PDE5 inhibitors seem to increase Nitric Oxide and since Panax Ginseng also increases Nitric Oxide, do you think there's a relationship between the two? I currently take Panax Ginseng and the thought of hearing loss in my only good ear frightens me.

no clue , I just started researching on nootropics like a week ago.

[Major Legend]

For everyone else following the thread up to this point, here is a summary so far:

- Concluded of effective Forksolin Doses are: 4mg (no side effects) or 10-20mg (with side effects of tiredness on the long term especially on the 20mg end)

- For PDE 4 Inhibition anywhere 400 to 1200mg of Artichoke Extract, or 500mg to 1g of Quercertin (Quercertin has a much longer half life than Artichoke extract)

- A source of dopamine precursor L-Phenylalanine or Tyrosine at 500 to 1000mg. This could be replaced by a stronger stimulant like caffeine or low dose amphetamine. Some other additions suggested or NOS or NAC.

Overall effect: improved long term learning, but no noticeable affect on working memory, intelligence or creativity. Some report increase motivation and focus (but could be due to stimulation refer to below)

Possible Contraindictions - Does not work with Aniracetam. Vasodilation chemicals.

Possible Problems : possible hepatoxicity at higher doses, desensitisation of acetylcholine receptors


I usually don't contribute to threads, since my working memory (or memory in general) or even intelligence is poor. So i'm not good at finding scientific backup for stuff...

I don't really understand the rationale behind taking stuff daily without breaks. In my experience/knowledge the brain/body is exceptionally good at returning processes to status quo via homeostasis. Meaning taking most things daily would probably ensure the body fighting back in some way (e.g. getting tired, because the body is probably trying to get sleep from all the potentiating). Cycling or taking breaks makes most sense for most regimens, unless some mechanism of tolerance can be alleviated.

Also some of the stuff that have longer half lifes linger in the body when taken daily and thus "stack up".

A lot of the effects on the thread regarding quercertin might not be due to PDE4 inhibition, but due to it being a COMT inhibitor. This would explain why less stimulants are needed (because they are being potentiated), thus increasing baseline dopamine levels could therotically temporarily improve focus, motivation and reduce anxiety.

Another point is : Caffeine is often underestimated as a stimulant because its so common, but at 100mg its actually pretty damn potent and could contribute significantly to a placebo effect (energy, motivation, better memory, performance). I mean looking at how most pre-workouts don't even work without caffeine says to me how damn effective caffeine actually is.

On a peronal note, I found the stack to not work with piracetam, it seems like whatever it does it counters piracetam's affinity for working memory and creativity improvements. I'm not 100% certain yet, but this stack seems to improve learning at the cost of short term awareness and problem solving, which kind of make sense as these might be two ends of the spectrum. People with bad memory have been found to be able to be more "present" and able to deduce/problem solve things in the moment (some article in the internet), this is due to the fact that their brains are not clogged up by all the recall associated with good long term memory.

Its plausible of course that short term awarness (piracetam effects) and long term learning (CILTEP) effects are two completely different systems, and it justs happens that Piracetam doesn't work with Ciltep, or rather Piracetam doesn't offset CILTEP enough to feel/see the benefits that I would normally associate with Piracetam alone. Either way it didn't feel as synergistic as I would have hoped it to be.

I'm also mildly confused about the MET/VAL gene thing. So lets get this straight or wrong: but VAL/VAL (Warrior) gene leads to high levels of COMT which means more enzymes to break down dopamine e.g. easier to have lower level of dopamines? and Worrier Met/MET leads to low levels of COMT which means dopamine stays elevated easier. So Val/Val is more likely to have poor working memory and ADHD, but this doesn't make sense to me as ADHD and Social anxiety are comorbid as well as a host of other problems, and how does that make sense. If any of the above is right (provided I haven't got the order confused), then warrior mentality and "being inattentive and so on" are the same side of the coin.

So I react strongly to stimulants, but I find my levels dip very very easily. If I take an amphetamine i'm out for a week, ritalin i'm out for the entire evening. It seems my dopamine runs out very quickly, even caffeine seems to run out on me quicker than most people, and it takes longer for my dopamine to go back to baseline. Am I warrior or worrier? I understand most people actually fall on Met/Val which mean they respond "normally", as I don't consider my responses normal I think i'm either Val/Val or Met/Met.

Regardless I have a interesting in quercertin also for its other effects, and the CILTEP stack i'm looking forward to being able to help me on my difficulties on learning one subject. Whilst I find it easy to learn multiple subjects and cross-pollinate them. I find it hard to be one of those "doctor" types and just gobble up information on one subject.

Edited by Major Legend, 29 July 2012 - 08:23 PM.

[jayfoxpox]

after looking through the net I found a couple sources that may have better value per serving

I found a source of forskolin significantly cheaper
10% forskolin 50 grams . With shipping $24
http://www.ebay.ca/i...#ht_1569wt_1393

its from india but I'm not sure if that's a good enough reason to look elsewhere

and artichoke extract here is 180 tablets - 500mg artichoke with 37 mg calcium
with shipping it costs $20.40

http://www.ebay.ca/i...#ht_1379wt_1136

My concern is the "Expiration Date: 10/2012 or later"
because I was hoping to take this stack once in awhile and last me for a year , but I guess it just loses a bit of potency and if I place it in a freezer it will prob keep good longer right?

Edited by jayfoxpox, 29 July 2012 - 11:46 PM.

[gizmobrain]

I found a source of forskolin significantly cheaper
10% forskolin 50 grams . With shipping $24
http://www.ebay.ca/i...#ht_1569wt_1393

its from india but I'm not sure if that's a good enough reason to look elsewhere

If you were going to go with them, I would consider buying the 20% instead. The less of the other parts of the herb, the better.

[jayfoxpox]

If you were going to go with them, I would consider buying the 20% instead. The less of the other parts of the herb, the better.

Sorry if this is a dumb question , but may I ask why?

[gizmobrain]

Sorry if this is a dumb question , but may I ask why?

Coleus' class='bbc_url' title='External link' rel='nofollow external'>http://www.ncbi.nlm.nih.gov/pubmed/22729658']Coleus forskohlii root extract (CFE) represented by its bioactive constituent 'forskolin' is popularly used as a natural weight-lowering product, but the association of its use with liver-related risks is very limited. In the present study, the effect of standardized CFE with 10% forskolin on liver function of mice was examined. Mice were given 0-5% CFE in an AIN93G-based diet for 3-5 weeks. Food intake, body weights, relative organ weights and liver marker enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] combined with histophatological analysis were assessed. CFE (0-0.5%) only had minimal effects on food intake and body weight whereas a significant difference was observed in mice receiving the highest dose (5% CFE). The extract 0.05-5% dose-dependently decreased visceral fat weight by between 16% and 63%, and a dose-dependent several folds increase was observed in liver weights and plasma AST, ALT and ALP activities with quick onset apparent after only 1 week of 0.5% CFE intake. The hepatic effect persisted throughout the 3-weeks course but was restored towards normalization within 1 week after withdrawal of treatment. Liver histology of mice fed 0.5% CFE for 3 weeks showed hepatocyte hypertrophy and fat deposition. In contrast, none of the hepatic responses measured were altered when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE. The present study clearly indicated that forskolin was not involved in the CFE-induced hepatotoxicity and was caused by other unidentified constituents in CFE which warrants further studies.

→ source (external link)

There is some compound in coleus forskohlii root extract that causes increased liver enzymes, but it isn't forskolin. So, while the liver enzymes returned to normal after a week of discontinuation (meaning that there probably not permanent damage), it is best to use as little as possible.

The 20% extract would have more forskolin, and less of whatever causes this issue.

Edited by zrbarnes, 30 July 2012 - 12:04 AM.

[jayfoxpox]

so then this 95% forskolin would be the the wisest choice then
http://www.bodybuild...2DA8F9E42210760

"when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE."
But if I'm reading the study right on the beggining it mentions nothing on 100% forskolin , but an extract with 10% forskolin as the standard.
I see many products labeled as pure forskolin but they are 10% and some are 20%

this lab offers 98%
http://www.boprocess...in-extract.html

And furthermore, lets say that the 20% and 10% are not "pure" and has the harmful compounds. I'm not convinced that 20% is that much safer since there is still 80% unknown substances.


just saying that I'd also stay away from the 20% extract if it comes with risk also.

Edited by jayfoxpox, 30 July 2012 - 01:30 AM.

[RS3RS]

so then this 95% forskolin would be the the wisest choice then
http://www.bodybuild...2DA8F9E42210760

"when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE."
But if I'm reading the study right on the beggining it mentions nothing on 100% forskolin , but an extract with 10% forskolin as the standard.
I see many products labeled as pure forskolin but they are 10% and some are 20%

this lab offers 98%
http://www.boprocess...in-extract.html

And furthermore, lets say that the 20% and 10% are not "pure" and has the harmful compounds. I'm not convinced that 20% is that much safer since there is still 80% unknown substances.


just saying that I'd also stay away from the 20% extract if it comes with risk also.

Fantastic, I was looking for a source higher than 20% earlier today but came up short. May have to try the 95% extract when this bottle runs out.

[gizmobrain]

These are actually the first non-imported forskohlii products I've seen to be higher than 20%:

USPowders - PureCAMP-95
Better Body Sports - C-Bolic

Anyone see any more currently on the market?

If anyone wants to buy my 20% capsules, I have 5 bottles of unopened 100mg (20mg Forskolin) x 120 capsules.

Edited by zrbarnes, 30 July 2012 - 07:34 AM.

[mait]

I found a really interesting take on PDE-4 and cAMP from here:

Wang and colleagues found that administration of the α2A-AR agonist guanfacine strengthened delay-related firing of PFC neurons, while a metabolically stable cAMP analog, Sp-cAMPS, not only weakened PFC firing, but reversed the effect of guanfacine. The findings support the idea that adrenergic stimulation supports working memory by attenuating cAMP. But how does lowering cAMP lead to better working memory? Wang and colleagues hypothesized that the cyclic nucleotide may attenuate PFC firing by opening a gated cation channel called the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel. “Activating HCN channels is like punching a big hole in the membrane because they allow both sodium and potassium to flow through, and since they greatly reduce membrane resistance when they are open, the effects at any synapse nearby are greatly reduced,” said Arnsten

The researchers extended these observations to other models of PFC circuitry. They found that, in tissue slices, reduction of HCN activity enhances network interactions, while reducing HCN activity in rats (by infusing low doses of ZD7288) improved animal performance in a T-maze model of spatial working memory. All told, the experiments suggest a model whereby cAMP disconnects neural networks in the PFC by opening HCN channels and shunting synaptic inputs out of the dendritic spine (schematically depicted in diagram below).

And now the cAMP with PDE-4 part of the story:

Ever since scientists found a translocation in the gene for DISC1 that strongly associates with schizophrenia and other psychiatric disorders, the gene and its protein product have come in for intense scrutiny. Though the biology of DISC1 has not been exhaustively explored, one path of investigation has suggested that DISC1 mutations compromise the transport of essential protein cargo down neuronal axons (see SRF related news story). Another posits that DISC1 modulates key signal transduction pathways that, if perturbed, might alter neuronal activity and circuitry (see SRF related news story). Finally, there is a very tentative link to working memory, in that researchers have found working memory deficits in mice with a naturally occurring DISC1 mutation (see SRF related news story).
These latest findings are then potentially relevant to schizophrenia and other major psychiatric disorders linked to DISC1, which can activate PDE4B. “During stress, cAMP levels increase and there is a loss of prefrontal function. This suggests that people with DISC1 mutations would be particularly susceptible to network collapse during exposure to stress,” said Arnsten. In fact, the researchers were able to demonstrate this experimentally in the primate model by administering etazolate, a phosphodiesterase inhibitor, which is similar to “having a DISC1 mutation,” said Arnsten. Etazolate suppressed delay-related PFC firing. If this model is confirmed by further experimentation, it might validate a new therapeutic approach (which the researchers have begun to patent) for cognitive deficits in schizophrenia, namely, blocking HCN channels.—Tom Fagan and Hakon Heimer.

And for general backround on PDE-4 and DISC1 an abstract from here:

Disrupted in schizophrenia 1 (DISC1) is one of the most convincing genetic risk factors for major
mental illness identified todate.DISC1interacts directlywith phosphodiesterase4B(PDE4B), an
independently identified risk factor for schizophrenia. DISC1–PDE4B complexes are therefore
likely to be involved in molecular mechanisms underlying psychiatric illness. PDE4B hydrolyses
cAMP and DISC1 may regulate cAMP signalling through modulating PDE4B activity. There is
evidence that expression of both genes is altered in some psychiatric patients.Moreover, DISC1
missensemutations that give rise to phenotypes related to schizophrenia and depression in mice
are located within binding sites for PDE4B. These mutations reduce the association between
DISC1 and PDE4B, and one results in reduced brain PDE4B activity. Altered DISC1–PDE4B
interaction may thus underlie the symptoms of some cases of schizophrenia and depression.
Factors likely to influence this interaction include expression levels, binding site affinities and
the DISC1 and PDE4 isoforms involved. DISC1 and PDE4 isoforms are targeted to specific
subcellular locations which may contribute to the compartmentalization of cAMP signalling.
DysregulatedcAMPsignalling in specific cellular compartmentsmay therefore be a predisposing
factor for major mental illness.

So it seems the gains in LTP are balanced by losses in working memory. Too bad - I was really close to trying CLITEP stack myself.

Edited by mait, 30 July 2012 - 08:23 AM.

[gizmobrain]

As one who has been on the stack for quite a while, I haven't seen a reduction of working memory... though I can say that my working memory has always been rubbish.

This may be unrelated, but maybe not: I do always take Melatonin and Magnesium L-Threonate at night, which may somehow offset the potential for reduced working memory?

Honestly, the only thing I have ever found to have a drastic effect on my working memory is alcohol (short term) and amphetamines (short to medium term); both in a negative way.

Edited by zrbarnes, 30 July 2012 - 08:29 AM.

[Major Legend]

I find working memory impaired, but noy on the level alcohol and other drugs do, almost a light tip of the tongue brain fog, anyone else getting these side effects? maybe it will clear after some time?

Edited by Major Legend, 30 July 2012 - 08:30 PM.

[RS3RS]

I find working memory impaired, but noy on the level alcohol and other drugs do, almost a light tip of the tongue brain fog, anyone else getting these side effects? maybe it will clear after some time?

It's funny how different everyone's biochemistry is. I have the exact opposite effect -- an improvement in working memory. Then again, I'm ADHD-PI and moderate amounts of alcohol or most dopaminergic substances tend to improve my working memory / brainfog over baseline. Maybe that's the difference -- those of us with low dopamine activity in the prefrontal cortex might respond differently to those who are normal? Just a theory.

[RS3RS]

Sorry if this has been answered , but after a quick wiki search on PDE3 inhibitors the adverse effects arearrhythmia, thrombopenia and increased transaminase levels.
PDE5 inhibitors
The occurrence of adverse drug reactions (ADRs) with PDE5 inhibitors appears to be dose related. Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis.^{[2] ( not really worried about these ones)}

On October 18, 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible sudden hearing loss would be added to drug labels of PDE5 inhibitors.^[3]
Since 2007 there is evidence that 5-phosphodiesterase inhibitors can cause an anterior optic neuropathy^[4]

http://en.wikipedia....verse_reactions
http://en.wikipedia....Adverse_effects

Because Luteolin is a non-selective inhibitor effecting 1-5 should we assume that it comes with all risks stated above?
If so , would it be safer is there any that avoids inhibiting pde3 and 5?

Thanks.

Whoa. After waking up deaf in one ear and remaining deaf in that ear till this day, I can tell you that hearing loss concerns me greatly. I only have one good ear left and I have to take care of it.

Anyway, from my understanding the pharmaceutical drugs used for treating erectile dysfunction are potent. I haven't done much research, but Luteolin is found in green pepper, celery, carrots, olive oil, and other dietary sources. From this, I think it's clear that Luteolin is not the most potent compound for inhibiting PDE, otherwise we would all easily get erections after ingesting a simple meal.

Does Quercetin also inhibit PDE5?

Also, since PDE5 inhibitors seem to increase Nitric Oxide and since Panax Ginseng also increases Nitric Oxide, do you think there's a relationship between the two? I currently take Panax Ginseng and the thought of hearing loss in my only good ear frightens me.

Since taking this stack, hearing in my left ear has been faded a couple of times then popped back. Not sure what to think of that, or if I should continue to take it.

edit: Upon further reading, I will no longer be taking this stack. The FDA website states hearing loss caused by PDE inhibitors is only temporary in roughly 1/3 of cases, and typically occurs in one ear. Hearing has faded out twice today in my left ear, and that tells me all I need to know. It's a shame, because this is the best I've felt in a very long time, but I know there are other ways to boost dopamine activity. Best of luck to those of you who continue.

Edited by RS3RS, 30 July 2012 - 10:54 PM.

[brainslugged]

Sorry if this has been answered , but after a quick wiki search on PDE3 inhibitors the adverse effects arearrhythmia, thrombopenia and increased transaminase levels.
PDE5 inhibitors
The occurrence of adverse drug reactions (ADRs) with PDE5 inhibitors appears to be dose related. Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis.^{[2] ( not really worried about these ones)}

On October 18, 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible sudden hearing loss would be added to drug labels of PDE5 inhibitors.^[3]
Since 2007 there is evidence that 5-phosphodiesterase inhibitors can cause an anterior optic neuropathy^[4]

http://en.wikipedia....verse_reactions
http://en.wikipedia....Adverse_effects

Because Luteolin is a non-selective inhibitor effecting 1-5 should we assume that it comes with all risks stated above?
If so , would it be safer is there any that avoids inhibiting pde3 and 5?

Thanks.

Whoa. After waking up deaf in one ear and remaining deaf in that ear till this day, I can tell you that hearing loss concerns me greatly. I only have one good ear left and I have to take care of it.

Anyway, from my understanding the pharmaceutical drugs used for treating erectile dysfunction are potent. I haven't done much research, but Luteolin is found in green pepper, celery, carrots, olive oil, and other dietary sources. From this, I think it's clear that Luteolin is not the most potent compound for inhibiting PDE, otherwise we would all easily get erections after ingesting a simple meal.

Does Quercetin also inhibit PDE5?

Also, since PDE5 inhibitors seem to increase Nitric Oxide and since Panax Ginseng also increases Nitric Oxide, do you think there's a relationship between the two? I currently take Panax Ginseng and the thought of hearing loss in my only good ear frightens me.

Since taking this stack, hearing in my left ear has been faded a couple of times then popped back. Not sure what to think of that, or if I should continue to take it.

edit: Upon further reading, I will no longer be taking this stack. The FDA website states hearing loss caused by PDE inhibitors is only temporary in roughly 1/3 of cases, and typically occurs in one ear. Hearing has faded out twice today in my left ear, and that tells me all I need to know. It's a shame, because this is the best I've felt in a very long time, but I know there are other ways to boost dopamine activity. Best of luck to those of you who continue.

Woah, that scares me quite badly. Isn't PDE inhibition quite common, though? I am guessing the hearing loss is not common. I don't like the idea of losing one of my senses.

[RS3RS]

Woah, that scares me quite badly. Isn't PDE inhibition quite common, though? I am guessing the hearing loss is not common. I don't like the idea of losing one of my senses.

Definitely, and I'm not in any way suggesting anyone in this thread shouldn't take this stack based on my single anecdotal experience. I'm sure my experience is a quite rare side effect occuring in a small percent of the population. I just happen to be one of those people, and I'm not willing to continue experimenting if it's affecting my hearing. But if I were experiencing no hearing issues (like you guys), I would definitely continue. Like I said, I'm sure this only affects a small portion of users.

Edit: For what it's worth, I was taking 500 mg Quercetin and 2x 100 mg Forskohlii (only 10% extract) once per day with 200 mg caffeine.

Edited by RS3RS, 31 July 2012 - 03:44 AM.

[abelard lindsay]

There's quite a bit of information about PDE5 Inhibitors (erectile dysfunction drugs) causing hearing loss

The mechanism of action seems to be caspase 3 immunoreactivity.

There isn't anything at all about PDE4 inhibition and hearing loss that I could find except some study suggesting Rolipram could be applied topically to downregulate mucus production in childhood ear infections thus preventing hearing loss.

Luteolin IC50s PDE 1 15.0 PDE 2 6.4 PDE 3 13.9 PDE 4 11.1 PDE5 9.5 (micromoles)
Quercetin has effects on PDE 1 through 4 only with selectivity for PDE3 and PDE4

Sildenafil (Viagra) - Sildenafil is a potent competitive inhibitor of PDE5 (IC50 3.5 nM)

So that's IC50 3.5 * 10^-9 for Viagra and 9.5 * 10^-6 for Luteolin or Luteolin is 2000 times weaker than Viagra.

Still, quercetin appears to be the better choice to cause a smaller amount of PDE5 inhibition than Luteolin.

There's still the issue with PDE3 inhibition with Quercetin. So we have left Hesperetin which is a bit weaker but more selective PDE4 inhibitor which people have had uneven results with and Genistein which supposedly messes with Rolipram High Affinity Binding Sites causing gastrointestinal distress and has been shown to cause NMDA inhibition and a lot of other inhibitory activity.

The PDE3 Ic50 of meribendan, a potent PDE3 inhibtior, are .05 micro Moles or about 100x more potent than Quercetin. So anyway, has anyone been taking Quercetin with this stack for a while? I find it a little strong. Sometimes I drink an energy drink with Quercetin in the afternoon if I'm starting to slow down and it has quite an effect. If I drink two of these energy drinks my stomach does not like it at all. Maybe I'll switch things up and try a dose of <500mg of Quercetin for a while and see how it goes.

Edited by abelard lindsay, 31 July 2012 - 04:21 AM.

[Major Legend]

I took just 500mg quercetin empty stomach this morning, and i'm certain its a pretty potent COMT inhibitor. I got all the telltales signs of a dopamine rise, more awareness in my body, sharper focuse, blunted abstract thinking, a little more insensitive than usual. I even felt a bit of a cotton mouth which is weird. Looks like I might be a Val/Val.

So there is a huge chance this stuff potentiates any stimulant taken, and the raised peripheral dopamine might also explain the sudden heart beat changes. I've been getting sudden heart beat rises myself too, but I also took 10mg forksolin later in the afternoon as well after feeling the isolated effect of Quercetin.

Now I'm curious whether there will be tolerance, or will there be a long come down?

My work isn't exactly a good measure of cognitive ability so I don't know how much my learning is improved from this stack, I work as an artist primarily so today with my raised dopamine levels i'm finding it hard to do anything, even watching my own work and feeling it is really hard. I have very little insight or inspiration, but this could also be due to the forksolin.

Think I should do an isolated full test on both of them. I'm starting to think this stack won't work for me, but i'd like to stick with it for a while just because I really need to study stuff to have more options in my future.