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S14: relief from anhedonia and induction of dopaminergic neurogenesis

pde7 s14 anhedonia dopamine depression 18741-24-7

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#1 MentholFlavoring

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Posted 22 April 2019 - 01:28 PM


In this post, I'd like to share with you the amazing therapeutic potential of PDE7 inhibitors, and my own experience with the small molecule S14. I was a little surprised to see that there is not much discussion on this forum about these substances, and I hope to see this increase with my post.
 
Recently, it was discovered that PDE7 inhibitors are strong inducers of dopaminergic neurogenesis, as well as having protective effects on dopamine neurons in the brain. This 
opens up new potential for diseases that are implicated with dysfunction of the dopamine system.
 
Some elucidation about the mechanism: phosphodiesterases are enzymes that break down intracellular cAMP and cGMP, which are second messengers. PDE is divided into 12 families with many subfamilies, which break down these substances in different tissues. 
 
There are some drugs that block other PDE families, such as:
 - Ibudilast, an anti-inflammatory drug, which blocks PDE4, used for post-stroke complications
 - Sildenafil (Viagra), a PDE5 inhibitor used for erectile dysfunction
 
Increasing cAMP levels in the brain excite broad anti-inflammatory, neuroprotective and regenerative effects. This is beneficial for chronic brain inflammation, not uncommonly seen in depression and highly present in neurodegenerative disorders.
 
The target of PDE7 inhibitors is to selectively block the PDE7 enzyme (PDE7A and PDE7B), which will raise cAMP in certain places and regions of the brain. Particularly, PDE7 inhibition will provide protection to the dopamine system, and even dopamine neurogenesis, supposedly more potent than 9-Me-Bc with very few side effects (if any). 
 
The potential seems huge for sufferers of Alzheimer's, Parkinson's, brain injury, schizophrenia, anhedonia, and even addiction. Recently, Omeros discovered the link between PDE7 inhibition and addictive behaviors, and now they're doing clinical trials with PDE7 inhibition. Even in healthy brains, I suspect that there is nootropic potential from the induction of dopamine neurogenesis.
 
There are some experimental PDE7 inhibitors out there. Most have been designed by Omeros, but then there is S14. It is a selective, potent PDE7 inhibitor with a good safety profile, which passed toxicology tests and is ready for Phase I trials. For a Parkinson's trial, a daily oral dose of 800 mg has been suggested. Effective doses have been defined as low as 10 mg/kg in rats, but mainly it would be most effective at higher doses. While it is rather simple to synthesize, it is still cost expensive to experiment with high doses. Ideally, a group buy could effectively reduce the cost of this. I would be very excited to see others discover the potential of this substance.
 
References/studies regarding PDE7
Targeting PDE7 by the small molecule S14: a potential disease-modifying Parkinson's disease therapy ready to start clinical trials
 
PDE7 inhibitors as new drugs for neurological and inflammatory disorders
 
Amyloid β-induced impairments on mitochondrial dynamics, hippocampal neurogenesis, and memory are restored by phosphodiesterase 7 inhibition
 
Phosphodiesterase 7 Inhibition Induces Dopaminergic Neurogenesis in Hemiparkinsonian Rats
 
Omeros Elucidates Mechanism of its PDE7 Inhibitors in Addiction
 
Dual inhibitor of PDE7 and GSK-3-VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice.
 
Personal experience with S14
It had been a while that S14 was sitting in my storage before I decided that I'd want to cycle this. Initially, I purchased it because the effect on dopamine neurogenesis hyped me up. But a while after, I theorized that my anhedonia was caused by downregulation rather than any damage, and I did not expect any effect. To my own surprise, it worked out better.
 
Dosing in the morning, my anhedonia lifts for the rest of the day, and depersonalization improves. Being able to feel again is amazing. My sense of smell is restored, scents enter my mind and play around with my emotions. Colors are brighter and visual acuity is improved, which I suspect is an effect of the relieving depression. Reliving memories induces many emotions. To some point, I even experience positive events in a child-like way, which makes life just much more beautiful. It's a non-stimulating effect, with a lack of side effects.
 
I've been dosing 10 mg daily for a week now (oral), which is micro-dosing, but I already perceived powerful effects from this dose. I suppose higher doses will achieve better effectiveness. Effects are consistent when taken with my daily stack or isolated. There seems to be a modest chronic improvement in my symptoms, but it's still too early to speak. Going to continue taking this and see how the effects will turn out. My daily stack consists of Vit B, Vit C, Vit D, ALCAR, Longvida, Ibudilast & Lion's Mane.
 
Thanks for reading! Excuse me for any bias, as I'm merely doing research in my free time and I'm pretty new to science. Leave anything in the comment section
 

Edited by MentholFlavoring, 22 April 2019 - 01:43 PM.

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#2 Immutabledestiny

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Posted 24 April 2019 - 12:54 AM

Thank you for posting such a comprehensive review of this substance, it seems really promising. I’m suffering from anhedonia and dementia like symptoms after a viral brain infection.

Are there any other sources for s14 or other PDE7 inhibiting compounds besides the link you provided to medkoo? Is that where you acquired yours?

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#3 ceridwen

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Posted 24 April 2019 - 12:27 PM

What other PD7 inhibitors are there?
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#4 Pereise1

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Posted 24 April 2019 - 04:39 PM

So from this study (https://journals.sag...087057110362100), I found the following:

 

In comparing the structures of the 24 compounds that conferred the highest average OD600 values (>0.821), 2 related compound families were immediately obvious. Two compounds are the steroids androsterone acetate (Microsource 00107113) and canrenone (Microsource 01505248), whereas another 3 are podocarpanes, which possess the same arrangement of three 6-carbon rings as found in steroids (Fig. 2A). Previously, Lee and coworkers23 described the PDE7A inhibitor IC242 as being a steroid-like compound; thus, these compounds are related in structure to at least one previously identified PDE7 inhibitor. On the other hand, they bear no resemblance to a variety of purine-based,24 pyrimidine-based,25 or thioxoquinazoline-based26 PDE7 inhibitors described in the literature

 

 

So a neurosteroid and a mineralocorticoid inhibitor. Unfortunately, although there are several studies that have screened thousands and thousands of compounds for PDE7 selectivity, they don't name the compounds for the most part. I can't recognize the molecular structure either. At least I found this little interesting tidbit about PDE7:

 

 
Conclusions

When taken together, the results reported here provide new evidence that demonstrates that PDE7 inhibitors can also be considered as potent indirect inhibitors of GSK-3 through the cAMP/PKA signaling pathway and through phosphorylation of GSK-3 at Ser9 and subsequent inactivation of this enzyme. As such, PDE7 inhibitors represent a class of drugs with a dual mechanism of action and with therapeutic potential for regulating neuroinflammation processes in different brain injury paradigms. We have shown the in vivo efficacy of several chemically diverse PDE7 inhibitors in different murine models of neurodegenerative diseases such as Alzheimer’s disease,13 Parkinson’s disease,7 stroke,10 and multiple sclerosis43 and also the pharmacologic potential of dual GSK-3/PDE7 in a mice model of schizophrenia.44The PKA-dependent stimulation of GSK-3 phosphorylation by these cAMP-enhancing agents should be considered in their therapeutic translation to the clinic. Our results provide new insights into the mechanism of action of PDE7 inhibitors, and corroborate their potential as new therapeutic agents for the treatment of neurodegenerative disorders.

 

 


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#5 jacobjerondin

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Posted 24 April 2019 - 09:29 PM

Excellent work OP, these types of posts are exactly why I'm on this forum. This is more advanced and promising than the vast majority of stuff people are trying for anhedonia and dopamine system improvement in general. I've looked into PDE7 inhibitors before and thought they looked quite excellent for exactly the reasons you described in your post. I'm highly interested in a group buy and I'm sure a bevy of other members would be as well given that this stuff could be even better than 9-me-bc!!

 

I too am very much interested in where exactly you got yours! If it was from medkoo, how difficult was the process of corresponding with them, how long did it take you to get it from your first inquiry with them, and how much did you pay? Also, how much did you receive based on how much you paid? Lots of questions I know haha, it just seems like it tends to be very difficult to order from these professional chemical suppliers so I'm wondering if that was the case for you and how you managed it exactly.

 

How is ibudilast for anhedonia by the way? I've had some sitting around for a couple months now but I got scared of trying it after reading about how it made people sweaty and nauseous for hours on end, sometimes with few positive effects. I already tend to sweat a lot and sometimes struggle with nausea since I've been dealing with some Phenibut PAWS for a couple months now. What effects exactly do you notice from it?

 

Finally, is there any sort of downregulation or dependence potential that we need to worry about with this stuff or PDE inhibitors in general? For example, could PDE upregulate if we are blocking it regularly? I don't really understand this mechanism of action very well so just trying to be careful here.


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#6 Donald Trumpet

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Posted 27 April 2019 - 02:31 PM

This is interesting. Please update again in a few weeks.



#7 anonymousdino

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Posted 27 April 2019 - 08:03 PM

Keep us updated please. Where did you source it? 9-me-bc stopped working for me

#8 BasicBiO

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Posted 27 April 2019 - 09:33 PM

Very interesting. 9-me-bc has worked the best for me out of all the dopaminergics I've tried and I have used it for about 2 years in small doses. I'm fearful of continuing this due to the concerns about carcinogenicity, so a superior replacement would be great.

 

Also, I've had decent success with various extracts of Coleus forskohli to raise cAMP levels. Wondering if using it in conjunction with other PDE inhibitors would be useful.


Edited by BasicBiO, 27 April 2019 - 09:35 PM.


#9 jacobjerondin

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Posted 28 April 2019 - 03:26 AM

Very interesting. 9-me-bc has worked the best for me out of all the dopaminergics I've tried and I have used it for about 2 years in small doses. I'm fearful of continuing this due to the concerns about carcinogenicity, so a superior replacement would be great.

 

Also, I've had decent success with various extracts of Coleus forskohli to raise cAMP levels. Wondering if using it in conjunction with other PDE inhibitors would be useful.

 

Sorry if this a dumb question but raising cAMP boosts dopamine right? How exactly does that work? I've tried reading about cAMP but the fact that I have no background in biology makes it difficult to understand what it does exactly for dopamine. I know forskolin is one the very few dopamine receptors upregulators out there and so should be helpful for anhedonia, do you have anhedonia and do you find it helpful if so?

 

And yeah I'm sure forskolin would go great with PDE inhibitors especially PDE4 like kanna or ibudilast, that was the whole idea behind CILTEP right?



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#10 BasicBiO

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Posted 28 April 2019 - 05:55 PM

Sorry if this a dumb question but raising cAMP boosts dopamine right? How exactly does that work? I've tried reading about cAMP but the fact that I have no background in biology makes it difficult to understand what it does exactly for dopamine. I know forskolin is one the very few dopamine receptors upregulators out there and so should be helpful for anhedonia, do you have anhedonia and do you find it helpful if so?

 

And yeah I'm sure forskolin would go great with PDE inhibitors especially PDE4 like kanna or ibudilast, that was the whole idea behind CILTEP right?

 

 

Don't feel bad...I do have a background in biology and struggle to understand the cAMP process and all of it's downstream effects on dopamine etc. Bear in mind that upregulation of dopamine may occur because of an overall increase of DA, an increase in DA receptor(of which there are many kinds) density and sensitivity, and that either of these two basic factors can occur in greater concentrations in any part of the body or any region of the brain. 

 

So, I don't have an answer to your question unless I go down the rabbit hole of research out there, but perhaps someone else here has a better handle on it.


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#11 anonymousdino

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Posted 12 May 2019 - 02:36 AM

Update????


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#12 MentholFlavoring

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Posted 13 May 2019 - 02:43 PM

Hey there again, here's my update.
 
I've currently stopped the S14 trial, which resulted in anhedonia coming back the next day. Overall I'm really impressed with the efficacy of this compound. A great deal of the benefits may come from strong neuroprotection.
 
Just like with Ibudilast, I experienced the effect fading a bit to the background. That might have something to do with upregulation as @BasicBiO suggested. It seems that the dopamine system adjusts to the situation
However it's different from tolerance, the effect does not completely diminish. It's definitely much better than my emotional flat baseline.
 
The following effects are consistent every day:
 - Improved visual acuity
 - Restored sense of smell (especially when being outside)
 
Somewhat less consistent is the way emotions come back, which are sometimes either more peaking or less pronounced. Still much better than baseline 
 
(Also to note, Ibudilast doesn't help with anhedonia for me)
 
Also to note is that it's not a stimulating effect. I've tried 9-Me-Bc as well which does have a distinguishable stimulating effect, but I run into tolerance issues pretty quick. (Only the first day it works)
 
I did not source from Medkoo but provided the link as a reference to the chemical properties.
I sourced from a personal manufacturer who has done several synths for me. Unfortunately, I cannot disclose their details, but sourcing shouldn't be a big problem if a group buy is organized.
 
Also, someone mentioned in a PM that the human dosage seems to be between 50 - 100 mg instead of 800 mg. That would explain the good efficacy of a low dose of 10 mg
 
Another thing to investigate is the role of PDE7 in T cells. In one study, it was shown that PDE7 knockout in mice does not impair T cell function (source), but PDE7 seems to have a regulatory function on T cells. Could immunosuppression become a problem? This is important to find out (sources: https://www.ncbi.nlm...les/PMC1906253/https://www.pnas.org...nt/114/30/E6240)

 


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#13 khalidnt

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Posted 28 June 2019 - 03:55 AM

PDE7 is interesting substance.

 

What is your plan now to stop or to continue? what are the alternatives you have found.



#14 jacobjerondin

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Posted 28 June 2019 - 05:18 PM

 

Hey there again, here's my update.
 
I've currently stopped the S14 trial, which resulted in anhedonia coming back the next day. Overall I'm really impressed with the efficacy of this compound. A great deal of the benefits may come from strong neuroprotection.
 
Just like with Ibudilast, I experienced the effect fading a bit to the background. That might have something to do with upregulation as @BasicBiO suggested. It seems that the dopamine system adjusts to the situation
However it's different from tolerance, the effect does not completely diminish. It's definitely much better than my emotional flat baseline.
 
The following effects are consistent every day:
 - Improved visual acuity
 - Restored sense of smell (especially when being outside)
 
Somewhat less consistent is the way emotions come back, which are sometimes either more peaking or less pronounced. Still much better than baseline 
 
(Also to note, Ibudilast doesn't help with anhedonia for me)
 
Also to note is that it's not a stimulating effect. I've tried 9-Me-Bc as well which does have a distinguishable stimulating effect, but I run into tolerance issues pretty quick. (Only the first day it works)
 
I did not source from Medkoo but provided the link as a reference to the chemical properties.
I sourced from a personal manufacturer who has done several synths for me. Unfortunately, I cannot disclose their details, but sourcing shouldn't be a big problem if a group buy is organized.
 
Also, someone mentioned in a PM that the human dosage seems to be between 50 - 100 mg instead of 800 mg. That would explain the good efficacy of a low dose of 10 mg
 
Another thing to investigate is the role of PDE7 in T cells. In one study, it was shown that PDE7 knockout in mice does not impair T cell function (source), but PDE7 seems to have a regulatory function on T cells. Could immunosuppression become a problem? This is important to find out (sources: https://www.ncbi.nlm...les/PMC1906253/https://www.pnas.org...nt/114/30/E6240)

 

 

Can you sell some to us from your personal manufacturer, something like what Strangelove did with nsi-189 and more recently vorinostat? I get that that might be a bit of work for you but you could make some money if you wanted and it still might be a lot cheaper, definitely at least easier, than us organizing a group buy and then having to get hlpc testing and all that.

 

So are you permanently less anhedonic? What did you get anhedonia from and how great is the acute relief from using s14? I'm maybe 20 - 50% anhedonic right now, improved from 100% anhedonic by using syrian rue extract! I'd still like to improve a lot more so any details about your motivation and enjoyment from doing things would be greatly appreciated. My emotions are less of an issue since I used nsi-189 but anhedonia is an ongoing struggle for me and it's very stubborn sadly.


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#15 John250

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Posted 20 July 2019 - 08:47 AM

Very interesting. I take it this could be beneficial for amphetamine tolerance/withdrawal/etc..

Amphetamine is the only FDA prescribed medication with no FDA prescribed medication for withdrawal/tolerance despite trying for 20+years.

Perhaps science has focused too much on dopamine and not on specific inhibition of phosphodiesterase,histone deacetylase,etc.. or even more so ways to antagonize transcription factors like FOSL2 and agonize Delta JunD and G9a.
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#16 Andersen

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Posted 06 August 2019 - 10:41 PM

In high school I abused stimulants. Mdma and adderall hard for two years.Now I have thesenintense cravings for pleasure, caffeine and sugar. I’ve tried dieting, exercising , and I have sleeping problems. I don’t know what to do anymore. I abused mdma and prescrip stimulants for like 2 years in high school hard and have tried to get better for like 3 years since. I can’t stick to anything. I can’t hold down a job. I’m unmotivated and can’t feel anything(anhedonia). I binge eat sugar and caffeine till I’m sick. What do I need to do? See a psychiatrist, or just get on say like keto and stick to it? I just want to get better? I feel like it had to do with either brain damage or down regulated seratonin and dopamine receptors. I’m slow and sluggish. I don’t react to anything, and I explode and get upset sometimes because I let things boil up. What do I need to do to get better? It’s like I just can’t get satisfied, and have no drive for anything. Is this even from the drug abuse or am I just fucked in the head. I over think things and worry yet feel so numb. Do you know of anything that might help?

#17 khalidnt

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Posted 07 August 2019 - 06:02 AM

In high school I abused stimulants. Mdma and adderall hard for two years.Now I have thesenintense cravings for pleasure, caffeine and sugar. I’ve tried dieting, exercising , and I have sleeping problems. I don’t know what to do anymore. I abused mdma and prescrip stimulants for like 2 years in high school hard and have tried to get better for like 3 years since. I can’t stick to anything. I can’t hold down a job. I’m unmotivated and can’t feel anything(anhedonia). I binge eat sugar and caffeine till I’m sick. What do I need to do? See a psychiatrist, or just get on say like keto and stick to it? I just want to get better? I feel like it had to do with either brain damage or down regulated seratonin and dopamine receptors. I’m slow and sluggish. I don’t react to anything, and I explode and get upset sometimes because I let things boil up. What do I need to do to get better? It’s like I just can’t get satisfied, and have no drive for anything. Is this even from the drug abuse or am I just fucked in the head. I over think things and worry yet feel so numb. Do you know of anything that might help?

 

Hello Andersen,

 

Hope is the most powerful drug that we need to take it everyday; Hope always looks forward to the future and never backwards.

When we are at stimulants hopes, dreams, and happens are driving by the chemicals and disappear after sometime and they are not sustainable. We have to learn to build them by ourselves and make them at the center of our heart.

 

Feeling deep in your heart that you are fine and in good health will boost your brain chemicals and spark the cells to fix itself. 

 

We are glade you have joined LongeCity and I hope you will find the answers for all your questions.


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#18 MentholFlavoring

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Posted 18 August 2019 - 12:30 PM

Hey there once again, I'm sorry for the delay in update.

 

Recently, I got caught up with a viral infection which lasted a month and caused the skin on my hands and feet to peel off. Overall it was very unpleasant and I was bedridden for 6 weeks.

Now this may or not correlate, but I was using S14 for 2 - 3 weeks before this event happened. Whether S14 is the cause remains unclear but it could be a strong indication that S14 does suppress the immune system, as there is some controversy about that.

 

Since this cannot be confirmed, I would NOT recommend anyone to try this substance.

If PDE7 inhibition does indeed cause immunosuppression, then it is very unfortunate as the compound has favorable and promising effects. I would also feel like I handled careless since I did not study the papers about the role of PDE7 in the immune system.

Aside of this: I did not perceive any long term improvements from my trial.


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#19 MichaelFocus22

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Posted 23 August 2019 - 03:14 AM

In high school I abused stimulants. Mdma and adderall hard for two years.Now I have thesenintense cravings for pleasure, caffeine and sugar. I’ve tried dieting, exercising , and I have sleeping problems. I don’t know what to do anymore. I abused mdma and prescrip stimulants for like 2 years in high school hard and have tried to get better for like 3 years since. I can’t stick to anything. I can’t hold down a job. I’m unmotivated and can’t feel anything(anhedonia). I binge eat sugar and caffeine till I’m sick. What do I need to do? See a psychiatrist, or just get on say like keto and stick to it? I just want to get better? I feel like it had to do with either brain damage or down regulated seratonin and dopamine receptors. I’m slow and sluggish. I don’t react to anything, and I explode and get upset sometimes because I let things boil up. What do I need to do to get better? It’s like I just can’t get satisfied, and have no drive for anything. Is this even from the drug abuse or am I just fucked in the head. I over think things and worry yet feel so numb. Do you know of anything that might help?

 

 

1. I know this feeling all to well, I also feel NOTHING either..No joy, no sorrow, No NOTHING. You probably have ADHD-PI which is the hardest type to treat.   No your not fucked in the head your brain isn't REWARDING you or you could be around toxic people. I've had thoughts of ending my own life just this evening, maybe hanging or getting a stroke would be nice both are instant death.  The emptiness you speak of will never go away never ever, stimulants only help remove it for a bit.  Again, most things are simply pseudoscience, so I'm not sure what to tell you. I've had thoughts of going into the Woods to the most isolated location and never returning, maybe they could find my dead body somewhere, where I've finally been put out of my misery like an old dog.







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