7 votes
Posted 17 May 2014 - 04:53 AM
Posted 17 May 2014 - 04:54 PM
Rodent studies have indicated that administration of HDAC inhibitors without successful exposure therapy actually worsens anxiety disorders significantly,[8] although the mechanism for this trend is unknown.[7] The most likely explanation is that exposure therapy works by a learning process, and can be enhanced by processes which increase neural plasticity and learning. However, if a subject is exposed to a stimulus which causes anxiety in such a way that their fear does not decrease, compounds which increase learning may also increase re-consolidation, ultimately strengthening the memory.
So if this is true, you better know what you're doing when you take a HDACi to facilitate fear extinction. That quote is from wikipedia and it seems a bit weird, because in the study that is cited on 8, they didn't even use HDACis, but rather d-cycloserine and some NMDA-antagonist. But if I'm not mistaken, the following abstract says more or less the same:
Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.
Posted 06 June 2014 - 03:52 PM
Please keep me posted about the studies of CL-994 and a group buy or whatever venue of treatment seems merited. I am definitely interested in a group buy should one manifest, as I have plenty of fear that needs to be eradicated.
Posted 06 June 2014 - 04:03 PM
Also, with the Cl-994 it might be worth asking Transhuman Technologies whether they are willing to synthesize it. They have been manufacturing other nootropics not otherwise available to individuals at prices far below the mean. Hopefully the stuff is of quality. There site is scheduled to be up and running in July so we could inquire then.
Posted 06 June 2014 - 11:07 PM
Has anyone here tried NSI-189. I had amazing recall of autobiographical events throughout my childhood and adult life. I was able to focus on old memories and re-evaluate them in an emotion-free manner. It took about 3 weeks but I worked through almost every old/annoying/traumatic memory I ever had. I don't get bothered by those issues anymore.
Reading this thread and the linked articles made me now realize what I went through. It is available now and cheaper than cl994. It starts to work in like a week at 10-20mg/day. May be worth doing first.
Posted 08 June 2014 - 09:54 AM
Has anyone here tried NSI-189. I had amazing recall of autobiographical events throughout my childhood and adult life. I was able to focus on old memories and re-evaluate them in an emotion-free manner. It took about 3 weeks but I worked through almost every old/annoying/traumatic memory I ever had. I don't get bothered by those issues anymore.
Reading this thread and the linked articles made me now realize what I went through. It is available now and cheaper than cl994. It starts to work in like a week at 10-20mg/day. May be worth doing first.
Yes, I'm going to start a new topic on this soon. There is a good deal of research which backs up its usability for such a purpose.
Posted 08 June 2014 - 10:14 AM
How often is the cl 994 to be taken once, once a month?
I doubt that would be sufficient. I'd plan with 8-10 sessions to be sure, and I wouldn't space them out to much (those who already tried it may prove me wrong). In addition to that, I think what's important is the time after the session, a hdaci can't just erase neuronal connections that were strenghtend for years by re-expierencing old, traumatic memories on a daily basis. What it can do is loosen the grip the epigenome dicates your brain to have on those memories. That means you won't get much less intrusive thoughts, feelings and pictures at first, but (if the hdaci theory is correct) it will matter how you react to them, as neuroplasticity is restored.
So I'd learn about CBT and mindfulness first, otherwise I don't see how taking a hdaci can make a huge difference for anyone suffering from anxiety or ptsd-like symptoms.
Edited by 5ht2a, 08 June 2014 - 10:16 AM.
Posted 08 June 2014 - 12:40 PM
Strong HDAC inhibitors are NOT a regime supplement! You take a dose to loosen the locks on mental pathways (and genes) and then take advantage of it by confronting your established mental responses and hopefully weaken or even delete them. Then you wait for say, 2-3 weeks or so (depending on the dose and how fit you are) before repeating if necessary.
HDAC inhibitors will temporarily prevent cell division, which is harmless with a single dose but dangerous if repeated continuously. That is why there are side-effects when HDAC inhibitors are used for cancer treatment; here they are given as a regime instead of a single dose.
Posted 19 June 2014 - 03:41 PM
Posted 21 June 2014 - 02:18 PM
I had wanted with sharing my experience tilll I had feedback from someone else who used vorinostat, but I think I should share the results now.
First I want to stress that up to this point I already got rid of panic attacks thanks to behavioural therapy/meditation, but what was left was a generally elevated level of restlessness, some remaining OCD and above all a type of strong nervousness/anxiety which occured whenever I mentally confronted myself with some triggers.
One of this triggers was very information rich texts such as scientific literature. Not too odd since my mental breakdown occured during studying.. my mind seems to have made the connection that text books are bad. Fair enough, but they are quite necessary to me nonetheless. Other triggers are the possibility that I might get yet *another* disease, or the possibility of failure etc. Basically the common things people are worried about except my conditioned response to this was extreme. The anxiety would clamp down my mind very quickly to the point were I was unable to properly continue until I gave my myself rest (f.i. meditate). It was like an anxiety induced mental block or fog which prevented even remotely clear thinking and made me feel terrible, which is probably what many of you experience. These triggered responses are what I tried to target with vorinostat.
I used low dosages, first of all because I suspected that not much was needed, secondly because I wanted to stay on the safe side and incrementally increase the dose untill I noticed effects, and thirdly because I might have a porous blood-brain barrier. Multiple prescribed medications (for diverse problems) needed to be discontinued because I am oversensitive to all side-effects which affect the central nervous system. A normal dose can equal an overdose for me. I have no idea if this is really due to a porous blood-brain barrier or that I might simply break down some medications slower, or have easily excitable nerves, but the first is a good possibility. In any case, I've learned to try small dosages first.
In this case that meant around 25mg of Vorinostat sublingual (under the tongue) to increase absorption. I thought it was important to clear my mind first using meditation, but I didn't go all out for this. Just enough so I could focus (as much as I can nowadays) on the mental trigger and the anxiety which it gives me, and how there really isn't anything to fear. The latter I added because it worked well in behavioural therapy. There clearly are some questions as to what the ideal therapy would be when HDAC inhibitors are involved. But it made sense that if you want the mind to re-condtition it's response to a trigger, that you also needed to inform it as to what the correct response should be like. It's difficult to know what goes on in the mind of mice, but it's fair enough to suggest that they do a lot less pondering and imagining compared to humans. I felt this adaptation from the animal studies was justified.
So basically, I cleared my mind for a few hours. I took the vorinostat out of the fridge, measured a dose and put it under the tongue while trying to read heavy scientific literature and, without tring to force or overthink anything, thought about how harmless this was. Normally my mind would get cramped up pretty quickly, but after meditation I had some buffer. I did notice it starting but tried to continue as described. I didn't pay attention tot the clock; my sense of time is pretty bad as is but I didn't want to distract myself. But I estimate about 20 minutes in I noticed that rather than feeling anxiety, I felt nothing. That wasn't really the right word for it since I didn't felt neutral. I VERY clearly noticed a lack of something which had been there previously, like there was a hole in my mind. I looked at the source of anxiety and very strongly anticipated something which didn't occur.
Strange as it is, I missed it. Not that I want anxiety but I was used to it, and was clearly aware that something that had been part of me was gone.
Naturally I assumed this might be placebo though nothing I ever did or tried (and that's a bloody lot) ever did this. So I waited a week, yet not once did I re-experience anxiety when reading information rich/scientific texts... I tried a second dose and focused on 3 other triggers, one after the other. I focused (passively, by clearing my mind and lightly think of the one thing I wanted to focus on rather than forcefully shuff more information in my mind as I used to do) on a trigger, waited till the response suddenly disappeared and moved on to the next.
I removed 1 trigger effectively. Strangely I don't recall what it was anymore. This might be more due to my post-breakdown memory than a side-effect of vorinostat. The second was fear for failure in general. This didn't seem to budge very much so I left it for what it was and went on to fear for getting sick. This worked almost perfectly, though there is a bit left. It was the strongest fear of them all and the last one I tried on a small dose. Perhaps the dose wasn't high enough. Still even this decrease was a great gain!
The fear for failure was an interesting one. During meditation I actually began to wonder if it really is failure that I fear. I've since then wondered further and come to the conclusion that there are deeper issues underneath. I suspect it's fear for disappointed others more than not succeeding at something. IF this is the real trigger, than it might be the reason I couldn't shake it loose like the other ones.
Again I waited several weeks to see if anything came back. What disappeared never resurfaced, and I mean really not even for a moment. Not even when I OCD-ishly stressed out that my therapy might have failed afterall and automatically began to try to retrieve the old fears as some sort of self-sabotage. Nada. The trigger which diminished didn't became stronger either, in fact it seems to have diminished further over time. Perhaps there was more effect than I thought.
In conclusion: vorinostat worked for me. It really, really worked for me.
I can't know if this would work for people who still have real panic attacks, and I don't know if other people need a higher dose than I used. I would disadvice this for people who are still under continued outward stress, as I suspect having a calm environment and a modicum of clarity are important for this kind of therapy. It might be necessary to have understanding of your own fear.
But I can't be certain of any of that, all I can honestly say is that it worked for me. Next thing to do is getting more insight into myself and use the remaining vorinostat to deal with what is left of the fear conditioning.
Posted 21 June 2014 - 02:59 PM
Thank you tree! Very interesting. I'm happy to hear it is working for you!
But what was left was a generally elevated level of restlessness, some remaining OCD and above all a type of strong nervousness/anxiety which occured whenever I mentally confronted myself with some triggers.
Did you experience anxiety/nervousness only after triggers or was it there all the time and just got worse from triggers? My question is: What has exactly changed?
1. The background anxiety, 2. The sheer quantity of mental triggers (how often a thought like "I might fail" or "I might get another disease" pops up in your mind). 3. Only the emotional response to such thoughts.
So it seems like what you did was some form of exposure... That was more easy in the case of the scientific literature, as it's a clear trigger in the outside world - you exposed yourself and let your brain learn that there is nothing to be afraid of. That's rather simple, of course nothing happens if you read a text and as long as your brain doesn't prevent neuroplasticity epigenetically, it will learn quick.
How did you proceed in the case of the mental obsessions? What did you recall - the traumatic situation itself (as far as that is possible) or only the triggers like "There is a possibilty to get ill". To me that sounds a bit more complicated, as in terms of probability, things like getting ill or failing in life is real possibilty.
I'm planning to take a hdaci soon. In my case, my brain remembers a traumatic memory about every 10 to 15 minutes. That memory entails an information, which my brain uses to predict a possible dangerous situation in the future. The possibilty of this situation is very real, so it's not that it's irrational in a strict sense, it just doesn't serve any purpose to think about it all day long and experience the life-shattering anxiety because of pure speculation.
Edited by scarredforlife, 21 June 2014 - 03:08 PM.
Posted 30 June 2014 - 06:04 PM
Thank you tree! Very interesting. I'm happy to hear it is working for you!
But what was left was a generally elevated level of restlessness, some remaining OCD and above all a type of strong nervousness/anxiety which occured whenever I mentally confronted myself with some triggers.
Did you experience anxiety/nervousness only after triggers or was it there all the time and just got worse from triggers? My question is: What has exactly changed?
1. The background anxiety, 2. The sheer quantity of mental triggers (how often a thought like "I might fail" or "I might get another disease" pops up in your mind). 3. Only the emotional response to such thoughts.
So it seems like what you did was some form of exposure... That was more easy in the case of the scientific literature, as it's a clear trigger in the outside world - you exposed yourself and let your brain learn that there is nothing to be afraid of. That's rather simple, of course nothing happens if you read a text and as long as your brain doesn't prevent neuroplasticity epigenetically, it will learn quick.
How did you proceed in the case of the mental obsessions? What did you recall - the traumatic situation itself (as far as that is possible) or only the triggers like "There is a possibilty to get ill". To me that sounds a bit more complicated, as in terms of probability, things like getting ill or failing in life is real possibilty.
I'm planning to take a hdaci soon. In my case, my brain remembers a traumatic memory about every 10 to 15 minutes. That memory entails an information, which my brain uses to predict a possible dangerous situation in the future. The possibilty of this situation is very real, so it's not that it's irrational in a strict sense, it just doesn't serve any purpose to think about it all day long and experience the life-shattering anxiety because of pure speculation.
Sorry, been very busy.. Anxiety was always there is some form or another, I suppose there still is. I've gotten used to it so much that it's difficult to know what normal is supposed to be, but yes. I almost always feels more stress-full than I should. But the triggers made it way worse, and also prevented me from every getting in a calmer state.
Most of those triggers are now either gone or diminished. It seems this also greatly helps to attain a more normal base line of calmness, but I clearly have some way to go before it's normal.
I confronted the source of current anxiety, not the memory of the initial traumas. Not sure how the 2 are linked in the memory, perhaps confronting either will affect the other. But I focused only on my current fears. I'm not denying the possibility of a negative event, but that doesn't mean I have to experience unhealthy levels of anxiety over it.
Posted 30 June 2014 - 06:10 PM
Sorry for the tldr, but where can this be purchased from?
Vorinostat? It's not on the open market, the only cheap and reliable source I found exclusively sells to research institutes. I used old ties to order it and doubt I will get away with it twice without some consequences. There are likely other, easier to access, HDAC inhibitors that work the same. But I already did *a lot* literature research on Vorinostat and didn't felt like researching every other compound as well.
Maybe there are Asian manufacturers who are willing to sell this.. but if you can find an alternative HDAC inhibitor that isn't produced by an obscure Chinese factory it would be better.
Posted 02 August 2014 - 01:10 PM
Interesting bit which shows one way in which epigenetic memory, through methylation, keeps the stress going...
"Within this mutation (which is pretty common), they looked for epigenetic modifications -- chemical triggers that modify DNA by turning genes on or off. These could alter the way SKA2 functions without changing the gene’s underlying DNA sequence. One type of modification is the addition of methyl groups (one carbon bonded to three hydrogen atoms) to a gene. The researchers found higher levels of methylation in those who committed suicide; it seems they were unable to “switch off” the effect of the stress hormone."
http://www.iflscienc...ct-suicide-risk
Posted 08 August 2014 - 07:08 PM
Very interesting experiences, tree. I wonder if an HDACi could help with more general emotional / behavioral plasticity.
If it does, than this class of drugs is going to change psychotherapy.
I've just taken a larger dose of vorinostat; 160mg. All I had left. I will come back in a week or so to report.
Posted 19 September 2014 - 07:40 PM
That took longer than a week, sorry. But at least I can be very certain now that I experienced a massive improvement that didn't just disappear over time.
As mentioned in the above post I took 160mg of vorinostat. I used the same set-up as before, namely meditation for a few hours until I was calm and as clear-minded as I can be. Which isn't very much post-nervous breakdown but there are obviously still gradations of (un)clarity.
As is so often the case with new therapies/meds I had the hope that it might remove all of the remaining brain-fog and anxiety. This didn't happen and I can't be surprised at that. But it DID improve for about 1/5th within a half hour or so of taking the vorinostat. More importantly my clarity has kept this improvement ever since without failing. It's clearly not placebo! A lot of stress would still increase the brain-fog as it does even with a healthy person, but the threshold has been seriously increased and the resulting brain-fog reduced. What surprised me was how easily I accepted the improvement. It was like a few cogs in my mind started moving again, I feel and think more like I should feel and think.
But 1/5th ain't enough. I'm going to order more, I wasn't certain I could get away with it as my source usually only sells to research institutes, but I'm going to risk it. If any one wants to participate in a group buy let me know.
-tree
PS It is important to note that this time, I took half sub-lingually (under the tongue) and the other half I snorted. I only desire the vorinostat to affect the brain, and snorting, as amateurish as it might seem, is a good manner of getting a med where it should go. This obviously can't be done with many drugs that cause side-effects when delivered quickly, but in the case of vorinostat I felt reasonably certain it would be safe. Still I decided to apply this method only to half of the vorinostat, just in case.
As said I experienced no side-effects. That might change when I take ever lager dosages, but judging from literature I doubt it will be anything other than a slight temporal fatigue at worst.
Edited by tree, 19 September 2014 - 07:49 PM.
Posted 22 September 2014 - 06:34 AM
Now I know there are a lot of people around here that don't trust in TLRs proprietary extracts - just giving a heads up that they appearantly carry a compound that works by the same mechanism, of wich they claim it's comparable to CL-994 - so maybe a group buy wouldn't be necessary...?
http://teamtlr.com/s...l-994&results=1
Posted 22 September 2014 - 04:05 PM
According to this site its a hdac 1,2,3 and 8 inhibitor
https://www.caymanch...1FDE95D8BFDFF84
What if the mechanism is not related to hdac1 ?
Posted 22 September 2014 - 05:23 PM
Vorinostat is a class I and II inhibitor and appears to work well, so either I or II or both are required.
Either way, I'm hesitant to order anything else since I already know vorinostat works (for me). I have no such certainty with anything else. That said it IS pricey and tricky to order, so if someone is planning to try out any other inhibitor on short term, please let me know! Then I'll wait with my order. Otherwise I'll likely order this or next week.
Posted 25 September 2014 - 12:59 PM
Vorinostat is a class I and II inhibitor and appears to work well, so either I or II or both are required.
Either way, I'm hesitant to order anything else since I already know vorinostat works (for me). I have no such certainty with anything else. That said it IS pricey and tricky to order, so if someone is planning to try out any other inhibitor on short term, please let me know! Then I'll wait with my order. Otherwise I'll likely order this or next week.
What would You roughly estimate for the costs of a group buy or by buying alone i.e. minimum-maximum price.
Edited by Flex, 25 September 2014 - 01:04 PM.
Posted 25 September 2014 - 07:08 PM
What would You roughly estimate for the costs of a group buy or by buying alone i.e. minimum-maximum price.
These are the costs per weight (LCLABS):
250 mg
41 $
32 €
500 mg
72
56
1 g
121
94
2 g
214
167
So it depends on how much you want to order. For 250 mg that would be +/- €80-85 / $105 in total. 500mg costs €104-109 / $136 in total. That's including shipping and customs. So shipping/customs etc alone was (the last time) +/- E50 / $64. I'll PM more details to you and anyone who wants to participate.
Edited by tree, 25 September 2014 - 07:09 PM.
Posted 17 October 2014 - 06:25 PM
I'd be up for a group buy
Send a PM
Has this groupbuy allready started
and do You distribute it or do everyone recieves directly ?
Its problematic for me to recieve something from outside the EU
Hi
The groupbuy hasnt concluded yet. I've send you a pm.
Posted 16 January 2015 - 07:47 AM
I would like to activate this thread by inserting some ideas/informations. Have you guys ever thought about the anti-anxiolytic mechanism of acetyl-L-carnitine? ALCAR works at the beginning of the treatment slightly anxiogenic, but after a while it is anxiolytic.
By inhibiting histonedeacetylases you reach some kind of hyperacetylation of histones. On the other side ALCAR does the some by being a donor for acetylgroups (1). The anxiolytic and antidepressant action of ALCAR is perhaps rather promoted by acetylation of other non-histone proteins like mGlu2 (2), but additionally L-carnitine also has an HDAC inhbitory potential (3).
ALCAR helps with neuropathic pain like HDACi.
To sum it up: ALCAR does donate acetyl groups and it also inhibits HDAC (L-carnitin does it). On the other side it works anxiolytic by acetylating other proteins, so this could suppress the fear to come up in special fear promoting situations and so hinder you to experience the fear again and to eradicate it or is this irrelevant?
Some thoughts on it?
(1) http://www.molecular...content/10/1/68
Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F, Battaglia G, Mathé AA, Pittaluga A, Lionetto L, Simmaco M, Nicoletti F.
Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4804-9. doi: 10.1073/pnas.1216100110. Epub 2013 Feb 4.
PMID:23382250
Huang H, Liu N, Guo H, Liao S, Li X, Yang C, Liu S, Song W, Liu C, Guan L, Li B, Xu L, Zhang C, Wang X, Dou QP, Liu J.
PLoS One. 2012;7(11):e49062. doi: 10.1371/journal.pone.0049062. Epub 2012 Nov 5.
PMID:23139833
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