260 replies to this topic

[tree]

Obviously vorinostat also has anti-cancer properties since that's its original use and they are pretty strong. Whether there are other health benefits of butyrate is a bit besides the point though. I'm not looking for a supplement to a health regimen.

The cost of vorinostat from lclabs (see earlier posts) is not that much, not more than $50 for 1 dosage including s&h. More than butyrate per mg but that won't cost a lot less to order since there are minimum amounts. There is no way you can encapsulate butyrate yourself; it smells like hyper concentrated vomit and can induce blindness at contact with the eyes.

So I'd need to order capsules, which means ordering an entire bottle, which can't be done in my country which mean I will end up ordering abroad and paying almost as much as for a single dose of vorinostat.

But the real problems are this:

1] Butyrate is very irritating, more so then vorinostat. And a much larger dose is required of butyrate (around 6 gram) as opposed to vorinostat (400mg). I did want to try a lower dose (say half) but that still leaves a large dose of a strong irritant. I got the gut feeling that this won't sit well in my stomach. In the studies the compounds got injected in the mice, not eaten (but I do know for certain that vorinostat has good oral absorption).

2] The second problem is the notion that butyric acid can do all that vorinostat and cl-994 can do yet it was never discovered before! That is what literature is saying, and yet... it's a bit like claiming carrots is as good as prozac yet nobody ever noticed. I guess it's *possible* but... it sounds too much like all the other hyped claims I read about supplements.

3] Third issue is that I'm considering sniffing the compound rather than swallowing it to maximize absorption into the brain. That would be a lot easier with a few hundred mg of vorinostat than several gram of blinding stinkbomb acid. To say the least.

[Phoenicis]

"Valproic acid may cause serious or life threatening damage to the liver and is most likely to occur within the first 6 months of therapy. The risk of developing liver damage is greater in children who are younger than 2 years of age and are also taking more than one medication to prevent seizures, have certain inherited diseases that may prevent the body from changing food to energy normally, or any condition that affects the ability to think, learn, and understand. ; Tell your doctor if you have a a certain inherited condition that affects the brain, muscles, nerves, and liver (Alpers Huttenlocher Syndrome), urea cycle disorder (an inherited condition that affects the ability to metabolize protein), or liver disease. Your doctor will probably tell you not to take valproic acid. If you notice that your seizures are more severe or happen more often or if you experience any of the following symptoms, call your doctor immediately: excessive tiredness, lack of energy, weakness, pain on the right side of your stomach, loss of appetite, nausea, vomiting,, dark urine, yellowing of your skin or the whites of your eyes, or swelling of the face.
[...]
Valproic acid may cause serious or life-threatening damage to the pancreas. This may occur at any time during your treatment. If you experience any of the following symptoms, call your doctor immediately: ongoing pain that begins in the stomach area, but may spread to the back nausea, vomiting, or loss of appetite."

Alas, why must these meds always have such extreme side effects?! Eating stinks bombs (Na butyrate) sounds alot more reasonable now.

Edited by Phoenicis, 07 April 2014 - 05:46 PM.

[tree]

Do you guys communicate telepathically or something?

Yes. Yes we do.

This abstract seems to suggest sodium butyrate only affects genes with "butyrate response elements" but who knows what that implies
http://www.ncbi.nlm....ubmed/12840228/

Sodium butyrate is a semi-endogenous substance, it's produced by gut bacteria. So that would be 1 major benefit over vorinostat; at low dosages it's bound to be safer since it's a naturally (and freely) occurring substance in the human body. But at very large amounts that won't matter much... peroxide isn't safe to drink either after all.

Alas, why must these meds always have such extreme side effects?! Eating stinks bombs (Na butyrate) sounds alot more reasonable now.

Well valproic acid was never an option for this exact reason. There are many other safer HDAC inhibitors. Mind you, nothing that erases your epigenome is safe to take as a regimen. You have to take it once, not daily for months like a supplement. The body does need the epigenome to keep information stored.

I like to think of it as resetting my internal pc.

[Phoenicis]

A patent on vorinostat runs out in July 2015, so generics may follow.

[Phoenicis]

Obviously vorinostat also has anti-cancer properties since that's its original use and they are pretty strong. Whether there are other health benefits of butyrate is a bit besides the point though. I'm not looking for a supplement to a health regimen.

The cost of vorinostat from lclabs (see earlier posts) is not that much, not more than $50 for 1 dosage including s&h. More than butyrate per mg but that won't cost a lot less to order since there are minimum amounts. There is no way you can encapsulate butyrate yourself; it smells like hyper concentrated vomit and can induce blindness at contact with the eyes.

So I'd need to order capsules, which means ordering an entire bottle, which can't be done in my country which mean I will end up ordering abroad and paying almost as much as for a single dose of vorinostat.

But the real problems are this:

1] Butyrate is very irritating, more so then vorinostat. And a much larger dose is required of butyrate (around 6 gram) as opposed to vorinostat (400mg). I did want to try a lower dose (say half) but that still leaves a large dose of a strong irritant. I got the gut feeling that this won't sit well in my stomach. In the studies the compounds got injected in the mice, not eaten (but I do know for certain that vorinostat has good oral absorption).

2] The second problem is the notion that butyric acid can do all that vorinostat and cl-994 can do yet it was never discovered before! That is what literature is saying, and yet... it's a bit like claiming carrots is as good as prozac yet nobody ever noticed. I guess it's *possible* but... it sounds too much like all the other hyped claims I read about supplements.

3] Third issue is that I'm considering sniffing the compound rather than swallowing it to maximize absorption into the brain. That would be a lot easier with a few hundred mg of vorinostat than several gram of blinding stinkbomb acid. To say the least.

How many dosages are you considering to use?

[tree]

1 dose

That is what is used in literature. If there are partial results I'll see from there.

[Jbac]

Well valproic acid was never an option for this exact reason. There are many other safer HDAC inhibitors. Mind you, nothing that erases your epigenome is safe to take as a regimen. You have to take it once, not daily for months like a supplement. The body does need the epigenome to keep information stored.

I like to think of it as resetting my internal pc.

Why do you believe HDAC inhibitors permanently "erase" your epigenome, as opposed to increasing epigenomic plasticity and allowing you to modify it more easily? Are you suggesting the long-term side effects of CL-994 in the rat study are caused by epigenome erasure, when they could instead be caused by an unknown MOA of the drug?

Your theory seems to be that short-term HDAC inhibition erases the bad parts of the epigenome that code fear behavior, and long-term inhibition erases everything else, like good behaviors. That sounds too convenient to be true.

Also, how easy is it to order from your supplier; do you have a research lab front set up?

[socialpiranha]

sounds like a mix of neuropeptide s and y would be a nice combo, i wonder if aloradine modulates these in some way

[Jbac]

How much does it cost to get a 20 aa peptide synthesized in china? $200 for 120 micrograms of neuropeptide S from every supplier. According to the one study on neuropeptide S they got results injecting 0.1 to 1 nmol into mouse brains, which equals 0.22 to 2.2 micrograms, which translates to who knows what in humans.

[celebes]

2] The second problem is the notion that butyric acid can do all that vorinostat and cl-994 can do yet it was never discovered before! That is what literature is saying, and yet... it's a bit like claiming carrots is as good as prozac yet nobody ever noticed. I guess it's *possible* but... it sounds too much like all the other hyped claims I read about supplements.
 

I don't understand how you get from an established property of a compound seen in study after study to... supplement hype. Oh right: how can a relatively "ordinary" substance have any effect on something as powerful as plasticity. Comparing two things that have the exact same effect at different doses to the difference between carrots and prozac is pretty ridiculous. You seem to need to believe that HDAC inhibition is somehow "special" in order to feel hopeful about it. 

 

 

i. Butyrate producing bacteria have the exact same effect on plasticity vorinostat does: 

 

Heijtz et al. showed that SPF mice had higher central expression of neurotrophins, such as nerve growth factor (NGF) and BDNF. Furthermore, there was differential expression of multiple genes involved in the secondary messenger pathways and synaptic long-term potentiation in the hippocampus, frontal cortex and striatum. Similarly, Neufeld et al. demonstrated increased expression of NMDA receptor subunit NR2B in the central amygdala and serotonin receptor 1A (5-HT 1A) expression in the hippocampus in SPF mice compared to germ-free mice.

 

ii. And almost exactly the same effect on Histone H3 acetylation and GDNF that Valproate does:

 

http://www.ncbi.nlm....9941/figure/F4/

http://www.ncbi.nlm....9941/figure/F3/

 

 

iii. And is the only other HDAC inhibitor shown to facilitate complete fear extinction (apart from vorinostat and valproate):

 

http://www.ncbi.nlm....port=objectonly

 

 

The others are prescription drugs so they must be more effective, all evidence to the contrary? More than a little irrational.

 

 

Also, you need to realise that neither vorinostat, butyrate nor valproate cause fear extinction. They increase plasticity allowing other therapies to overcome the imprinting. To my mind, increasing plasticity over time scales that neurogenesis operates over should be more effective than ramping up plasticity for a few hours and hoping whatever you do in that period sticks. You can get 2 months of RS(butyrate), magnesium threonate and baclofen (all shown to either promote plasticity and/or fear extinction) for the price of 1 (half) dose of vorinostat and without any risk of customs seizure. I know what I'm going for.

Edited by celebes, 07 April 2014 - 11:42 PM.

[Phoenicis]

Regarding butyrate producing bacteria, this guy illustrates (using studies) that potato starch may not be the best fermentation source for major butyrate producing bacteria (Firmicute). Instead scFOS is pointed out as being the best:

 

http://mrheisenbug.w...ed-not-so-fast/

Edited by Phoenicis, 08 April 2014 - 12:03 AM.

[neuroatypicow]

FOS is an ingredient in many probiotic supplements as well. i try to get it from all three sources - resistant starch, a probiotic, fermented and real food sources. and not just for butyrate-producing bacteria, but as many benevolent colonies and cross-feeders as i can make from my hybrid mediterranean/paleo diet.

[celebes]

Yeah, I'm aware of that and have started some GOS at 3g a day while I wait, but 20g will get very expensive very fast. Potato starch costs $5 for 1-2 months worth, plus shipping. I can't find the chart but it causes higher relative production of butyrate than FOS does. I think the combination will be synergistic and still economical. Even Lactobacilli increase F. prausnitzii proliferation: http://www.ncbi.nlm....pubmed/20181862

 

Anyway, the particulars might be irrelevant. The other SCFAs are HDAC inhibitors too and the combination is fully 50% more potent than butyrate alone.: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499459/ 

Edited by celebes, 08 April 2014 - 01:26 AM.

[Phoenicis]

I went out and bought some fruit, realised I wasn't eating enough and feel quite calm and relaxed after 2 bananas, 4 kiwis and 2 big clementines. I still have lots left so may go for more now. I'm also vegan so I eat lots of vegis. 

 

I might give the potato starch a try but by forcing myself to eat fruit and vegis for the fiber I feel like I'm doing myself a bigger favour. I wonder if hemp protein/fiber works well?

[tree]

That's now what I was saying. But if you want to know how it works then read the links in this thread. I'm repeating myself over and over with these questions... I understand the people interested in this thread probably have concentration problems like I have, but it's getting too time consuming for me.

 

Your theory seems to be that short-term HDAC inhibition erases the bad parts of the epigenome that code fear behavior, and long-term inhibition erases everything else, like good behaviors. That sounds too convenient to be true.

 

 

Edited by tree, 08 April 2014 - 08:48 AM.

[tree]

 

I don't understand how you get from an established property of a compound seen in study after study to... supplement hype. Oh right: how can a relatively "ordinary" substance have any effect on something as powerful as plasticity. Comparing two things that have the exact same effect at different doses to the difference between carrots and prozac is pretty ridiculous. You seem to need to believe that HDAC inhibition is somehow "special" in order to feel hopeful about it.

 

No I don't.

 

 

The others are prescription drugs so they must be more effective, all evidence to the contrary? More than a little irrational.

 

Did I say that? Can you stop being defensive already? You made a suggestion and I'm sceptical. That happens.

Also, you need to realise that neither vorinostat, butyrate nor valproate cause fear extinction. They increase plasticity allowing other therapies to overcome the imprinting.

 

I was the one to first mention this in the thread. Yeah, I still remember.

 

Here is an idea: rather than discussing at infinitum, how about you use butyrate and I use vorinostat and we'll see if either of us experiences improvement. Real improvement, not improvement which disappears over a month time. That might actually make this thread worth while.

 

 

[stolpioni]

So what you guys are saying is that by taking any of these drugs they will permanently eliminate the fear response in my brain?

 

That would be some awesome stuff. I'd easily pay $100k for that.

[Jbac]

I understand the people interested in this thread probably have concentration problems like I have, but it's getting too time consuming for me.

Haha yea, I tl;dr'd most of your posts. I came here for the magic peptide not a powerpoint lecture on genetics. Let's just order the damned thing already

[celebes]

Actually I wasn't being defensive at all. I guess I can see how it would read like that.

 

But you did say a few things that were simply false and I tried to address them.

 

 

 HDAC inhibitors....... erase your epigenome.

 

You have to take it once, not daily for months like a supplement. The body does need the epigenome to keep information stored.

I like to think of it as resetting my internal pc.

 

 

That is not at all what HDAC inhibition does. So you don't actually understand.

 

HDACi increases epigenome plasticity. The studies universally combined that window of plasticity with fear extinction training. What mechanism for fear extinction are you planning to use?

 

 

 

 

You made a suggestion and I'm sceptical. That happens.

 

I was the one to first mention this in the thread. Yeah, I still remember.

 

Here is an idea: rather than discussing at infinitum, how about you use butyrate and I use vorinostat and we'll see if either of us experiences improvement. Real improvement, not improvement which disappears over a month time. That might actually make this thread worth while.

 

The point I was making was your scepticism doesn't seem to based on the evidence or a proper understanding of the mechanisms involved. Discussing it once is not ad infinitum but I do agree that once is more than enough.

Edited by celebes, 09 April 2014 - 02:10 AM.

[tree]

 HDAC inhibitors....... erase your epigenome.

 

You have to take it once, not daily for months like a supplement. The body does need the epigenome to keep information stored.

I like to think of it as resetting my internal pc.

 

 

That is not at all what HDAC inhibition does. So you don't actually understand.

 

HDACi increases epigenome plasticity. The studies universally combined that window of plasticity with fear extinction training. What mechanism for fear extinction are you planning to use?

 

 

Information is stored in the epigenome in several forms, among them are methyl and acetyl groups. HDAC inhibition forces the removal of methyl groups in favour for acetyl groups. This unlocks genes but some are locked for a good reason. If you take a lot of HDAC inhibitiors, it will start to unlock *all* locked genes. Which can cause cancer or other problems.

 

Whether you call this resetting is semantics. Since the epigenome carries information of your entire life (and some of those of your ancestors) which gets erased when you start to inhibit HDACs I think it is an appropriate term.

 

That window of learning you mentioned is caused by the removal of the off-switches in your epigenome. Especially fear and anxiety is under protective lock; the bran doesn't want them removed easily. Once the read/write protection is gone you can change the memory.

 

So my statement was correct and so is yours.

 

 

Anyway: I ordered 2 dosages of vorinostat in a group buy yesterday. Will come back when I used it.

Edited by tree, 09 April 2014 - 09:17 AM.

[dijital]

Thank you tree for keeping up the good work. I'm really looking forward to hear about your experiences. Celebes question about the mechanism of fear exitinction that is needed for vorinostat to work is quite important, but relatively easy to answer. Or is there another known method other than plain exposure therapy?

 

 

[High_Probability]

 

2] The second problem is the notion that butyric acid can do all that vorinostat and cl-994 can do yet it was never discovered before! That is what literature is saying, and yet... it's a bit like claiming carrots is as good as prozac yet nobody ever noticed. I guess it's *possible* but... it sounds too much like all the other hyped claims I read about supplements.
 

I don't understand how you get from an established property of a compound seen in study after study to... supplement hype. Oh right: how can a relatively "ordinary" substance have any effect on something as powerful as plasticity. Comparing two things that have the exact same effect at different doses to the difference between carrots and prozac is pretty ridiculous. You seem to need to believe that HDAC inhibition is somehow "special" in order to feel hopeful about it. 

 

 

i. Butyrate producing bacteria have the exact same effect on plasticity vorinostat does: 

 

Heijtz et al. showed that SPF mice had higher central expression of neurotrophins, such as nerve growth factor (NGF) and BDNF. Furthermore, there was differential expression of multiple genes involved in the secondary messenger pathways and synaptic long-term potentiation in the hippocampus, frontal cortex and striatum. Similarly, Neufeld et al. demonstrated increased expression of NMDA receptor subunit NR2B in the central amygdala and serotonin receptor 1A (5-HT 1A) expression in the hippocampus in SPF mice compared to germ-free mice.

 

ii. And almost exactly the same effect on Histone H3 acetylation and GDNF that Valproate does:

 

http://www.ncbi.nlm....9941/figure/F4/

http://www.ncbi.nlm....9941/figure/F3/

 

 

iii. And is the only other HDAC inhibitor shown to facilitate complete fear extinction (apart from vorinostat and valproate):

 

http://www.ncbi.nlm....port=objectonly

 

 

The others are prescription drugs so they must be more effective, all evidence to the contrary? More than a little irrational.

 

 

Also, you need to realise that neither vorinostat, butyrate nor valproate cause fear extinction. They increase plasticity allowing other therapies to overcome the imprinting. To my mind, increasing plasticity over time scales that neurogenesis operates over should be more effective than ramping up plasticity for a few hours and hoping whatever you do in that period sticks. You can get 2 months of RS(butyrate), magnesium threonate and baclofen (all shown to either promote plasticity and/or fear extinction) for the price of 1 (half) dose of vorinostat and without any risk of customs seizure. I know what I'm going for.

 

 

In the last article stated above under section iii:  Can anyone comment on the study showing fear extinction effects in rats fed a Zinc Restricted Diet.  Can anyone break down the study and explain what it means.

Edited by High_Probability, 11 April 2014 - 11:16 PM.

[mikey]

There are several options to lower the price further.

There are Chinese labs which are open for negotiation and can produce a chemical at request. It may be worth checking their price ranges. We could also try to get more people in on it; there certainly isn't a shortage of anxiety sufferers.

Another option is to lower the dose. The authors focused on 30 mg/kg, but showed that 10 mg/kg resulted close to the same values of compound in the brain as 30mg/kg. Because of the high cost I wanted to test 10mg/kg. But the authors also tested the bio-availability at 1 mg/kg and it does show up in the brain, though of course at one tenth of the concentration. It's not clear to me whether the authors tested if these lower concentrations can also remove emotional trauma's, they only published results with 30mg/kg. However since it can travel to the brain and the effect was strong enough to remove the artificial trauma's to the mice completely, I suspect that we may also get result from 1mg/kg.

If bought in bulk from the cheapest source I could find, it would cost $1350 for 5 gram, that would mean a mere $0,27/kg or $10-20 for an adult! Quite the difference with a full dose from Sigma! Even if it doesn't work as well, it may still give people some results and an indication if the compound is worth investing in further.

Luckily Cl-994 (aka N-acetyl dinaline aka tacedinaline) has been used a lot in both cancer research and epigenetics. Some further look into publications might help to answer how research and dosages in mice translates in humans. But for now I assume the dosages are only weight dependent.

 

Mice are about six times more bio-active than humans, thus there's a 1/6th bioequivalence. We need less by 6 times.

 

[dijital]

Any updates on this?

[tree]

The stuff arrived. Looks very silky white. Tested a little bit and it has no discernible taste or smell.

 

During meditation I occasionally get moments of bliss so I'm waiting for such a moment to try the rest. Perhaps more of it will stay afterwards. A stuffy nose is going to make it difficult to sniff it so I might have to put it under the tongue or encapsulate it.

[StevesPetRat]

This is a very interesting topic. I noticed my anxiety really started going out of control after taking methylB12 during a very stressful time thanks to a "great recommendation" by my doctor. This was followed by a situation in which I had a viral heart infection which went undiagnosed until after the fact. My pulse was above 100 all day and night for 3 weeks and my startle reflex was elevated for over a month. Now I am in what appears to be the late stages of adrenal fatigue (3C or D on Dr. Lam's scale if you buy into that sort of thing), and I have fear conditioning to so goddamn many stimuli-- including the basic idea of trying to accomplish anything.

So, uh, yeah, if I took this or say high dose NaButyrate for a few weeks in conjunction with some potent anxiolytics while trying to live my life and experience a bunch of stuff that now makes me anxious, do you think it might work?

I am also concerned about the viral reactivation issue.... hmmm... CMX001 group buy?

[noveltyaddict]

This is a very interesting topic. I noticed my anxiety really started going out of control after taking methylB12 during a very stressful time thanks to a "great recommendation" by my doctor. This was followed by a situation in which I had a viral heart infection which went undiagnosed until after the fact. My pulse was above 100 all day and night for 3 weeks and my startle reflex was elevated for over a month. Now I am in what appears to be the late stages of adrenal fatigue (3C or D on Dr. Lam's scale if you buy into that sort of thing), and I have fear conditioning to so goddamn many stimuli-- including the basic idea of trying to accomplish anything.

So, uh, yeah, if I took this or say high dose NaButyrate for a few weeks in conjunction with some potent anxiolytics while trying to live my life and experience a bunch of stuff that now makes me anxious, do you think it might work?

I am also concerned about the viral reactivation issue.... hmmm... CMX001 group buy?

 

No, I don't think this would work. Even if NaButyrate can do the trick, you simply can't take potent anxiolytics in your exposure training if you want to experience fear extinction.

 

Maybe I undstand what your plan was: If you remember the fearful memory under the influence of anxiolytics, your brain might learn "Hey, there is the memory, I have no fear - everything is safe - so anxiety is bullshit in that case". Or do you want to use anxiolytics to get in situations you'd be too scared for otherwise?

 

The fearful memory must be activated - this gives you a timeframe in which modification of that memory can take place. But as far as I know, anxiolytics prevent an adequate activation of the fear memory, which would make extinction or modification during reconsolidation impossible. It seems like you actually NEED to feel the anxiety that comes with the memory. Correct me if I'm wrong.

 

 

 

 

[Phoenicis]

 viral reactivation issue?

[...]

I am also concerned about the viral reactivation issue.... hmmm... CMX001 group buy?

 

[noveltyaddict]

Is there any study indicating how much Sodium Butyrate (which contains 0,6 g Butyric Acid per capsule) would be needed for fear extinction? And does anyone know if taking larger amount of that chemical might cause bad smell?

 

Edited by noveltyaddict, 05 May 2014 - 12:42 AM.

[celebes]

Is there any study indicating how much Sodium Butyrate would be needed for fear extinction?

 

 

6g of butyrate is roughly equivalent in potency to 250mg of Vorinostat in terms of HDAC inhibition. SCFA's in combination though inhibit HDAC 50% more potently than Butyrate alone. There aren't any studies that quantify the precise amount of plasticity required and I doubt there will be.

 

Edited by celebes, 05 May 2014 - 03:05 AM.