260 replies to this topic

[tolerant]

Steve, 

 

Thanks a lot to heeding my request and sharing your experience. To touch on what dijital said, maybe vorinostat is not supposed to work in this way, but I think it's heartening that it does. That it can extinguish conditioned fear without the need for formal extinction learning. This in a certain way gives hope to people who suffer from generalised anxiety and cannot point to specific triggers, or to whom almost everything can become a trigger. 

 

My question to Steve is along the lines of the question I asked tree about his joy of learning: when you stopped being flustered and stupefied by the girl you dated, did some calm sort of joy of having had that relationship/memories feelings of being in love remain/resurface? Or was it like there was just nothing was left and that's what made you feel easier?

 

Also, can Steve or someone someone knowledgeable provide advice on how Ach (which I assume stands for acetylated histones) can be boosted with diet and supplements? Is this basically contained the information collated by Flex?

 

Thanks,

 

tolerant

Edited by tolerant, 19 April 2016 - 03:18 AM.

[StevesPetRat]

It's hard for me to make sense of your experience Stevepetrat, because from theory that is not how Vorinostat is supposed  to work. When you're revisiting the traumatic memory on a HDACi for the first time, you shouldn't feel calm. It's not like Vorinostat should have immediate calming effects, but rather restore neuroplasticity in fear extinction processes. Fear extinction and memory reconsolidation needs some time, and in that time frame, reprocessing the traumatic memory doesn't feel good, most of the time it is a rather painful experience. So my guess is that your first reaction sitting on the poker table was the result of the propranolol + some placebo effect. I'm not saying the Vorinostat didn't do its work, but that's something you should test the next time playing poker, without propranolol.

Yes, I've gone back and played several times without propranolol. The adrenaline response is gone, except for one time where I was already stressed out about something else to begin with. I got excited a couple times, but it was after something good happened, not in anticipation of losing money. But I did think about what you said, because I was sort of surprised that it went that way, too. So I went back and looked at what Tree wrote about his experience and noticed this part:
 

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...

 
So this is actually, now that I go back and look at it, pretty similar to what I experienced. Sit down, experience the "trigger", and then... nothing... and then notice that there's nothing. Then just [i[think[/i] of another trigger, it too becomes nothing. Too bad more people haven't taken it. My guinea pig wasn't very articulate, but she seemed to also feel something along those lines. I also tried to steer her towards thinking about something that she wasn't even experiencing.
 

My question to Steve is along the lines of the question I asked tree about his joy of learning: when you stopped being flustered and stupefied by the girl you dated, did some calm sort of joy of having had that relationship/memories feelings of being in love remain/resurface? Or was it like there was just nothing was left and that's what made you feel easier?
 
Also, can Steve or someone someone knowledgeable provide advice on how Ach (which I assume stands for acetylated histones) can be boosted with diet and supplements? Is this basically contained the information collated by Flex?

Yeah, I still feel really, really strongly about her, but it doesn't make me stressed out / stupid. I ran into her a week or two after this post and she either didn't see me or acted like she didn't, and it did hurt my feelings, but again, no real stress response.

ACh is acetylcholine, I wrote about my stack for that in this thread.

 

Hope that helps...

[tolerant]

Thank you to StevesPetRat for the answer. It's very encouraging as far as vorinostat is concerned. However, I have a few concerns as follows:

 

1. If a person does not have a choline deficiency but decides to use your stack, which contains numerous precursors and inhibitors at megadoses in comparison to the amounts of those substances a person would ordinarily consume, doesn't the person then risk getting that "acetylcholine surge" and in turn developing new symptoms? For a person with no choline deficiency, would your stack be equivalent to "nootropic abuse"?

 

2. How does this all relate to vorinostat? Is success with your stack a bit of a predictor to success with vorinostat? Or is taking vorinostat a different thing altogether?

[StevesPetRat]

Thank you to StevesPetRat for the answer. It's very encouraging as far as vorinostat is concerned. However, I have a few concerns as follows:

 

1. If a person does not have a choline deficiency but decides to use your stack, which contains numerous precursors and inhibitors at megadoses in comparison to the amounts of those substances a person would ordinarily consume, doesn't the person then risk getting that "acetylcholine surge" and in turn developing new symptoms? For a person with no choline deficiency, would your stack be equivalent to "nootropic abuse"?

 

2. How does this all relate to vorinostat? Is success with your stack a bit of a predictor to success with vorinostat? Or is taking vorinostat a different thing altogether?

1. Yes, definitely, but fisetin inhibits the gene (cFOS) that is activated by an ACh overload, so in principle this should protect against the generation of long-term symptoms. This might have been a useful dietary adjunct for those who were routinely exposed to AChEI's while in the military...

 

2. Vorinostat works by a totally different mechanism. I found my stack effective in eliminating the subjective experiences of anxiety (actually... my dietary changes alone more or less fixed that along with my IBS... but that's another entire post), but I still had "conditioned stress responses" that were physically similar to what would trigger anxiety attacks in those predisposed to them. Vorinostat (seems to have) fixed that. This is consistent with the few other human anecdotes available.

[tolerant]

I think I tried a modified version of your stack based second part of you post in this thread, which I could relate to (my stress started after beginning a relationship I wasn't ready for; my belief that (at least in a subset of people including myself) all symptoms of all disorders such as fibromyalgia, chronic pain, ME/CFS, depression/anxiety are fear-conditioned responses). I didn't read the disclaimer in your actual thread and the symptoms you describe there, which I don't have. Now I understand that your stack was for a different set of symptoms.

[Lunast]

New

[Lunast]

In.

[musicman4534]

My friend and I are interested.

[David Middlemiss]

Interested,

[Lunast]

I'm desperately interested in hearing more positive success stories with this chemical.  I have been suffering all my life with repressed trauma that all seems to be coming to a head.  My parasympathetic nervous system is perpetually stuck in fight, flight, or freeze mode and as a result am never able to relax and enjoy life.   Looking for hope here, people.  Looking for hope.

[Lunast]

Can someone PM me a cheap and reliable source for Vorinostat?

[Groundhog Day]

I'm interested as well.

 

How in the world would one get vorinostat? Do doctors prescribe it off label?

[musicman4534]

Hi everyone!

 

If you can wait until October I'll be organizing a fairly large group buy so we can all get a good price. I'll be making a separate thread for Vorinostat/SAHA and it's studies soon since CL-994 has gone by the wayside.

 

Uses of vorinostat for nootropic purposes include:

 

- Fear extinction. This is due to vorinostat keeping chromatin open so epigenetic changes can be made to our DNA, which has the effect of strongly extinguishing fear when a normally fear-inducing event is experienced or thought about.

- Child-like learning abilities. The effect of chromatin being open gives us the ability to use or memory as a small child would. Studies have shown HDAC inhibitors allow adults to learn things like perfect pitch and language as a small child would.

- Recent studies on HDAC inhibitors show that they affect neuroplasticity in a unique and novel manner, affecting zinc finger proteins including early growth response 1, as well as CREB-mediated transcription, eliciting unique and novel mechanisms of adult neurogenesis.

 

- Conventional uses of vorinostat include arresting the cell cycle through repeated dosing to halt the growth of cancers and tumors. I think it's interesting that vorinostat's fear extinction properties lead to much less physical stress, which can lead to cancer. I think the mental effects are intimately linked to its anti-cancer effects.

 

Mainly! Vorinostat has shown the most promise with FEAR EXTINCTION, even when an actual situation is not experienced and only the thought is brought up.

 

Useful dosage for fear extinction is around 150mg.

 

In the meantime you may look into crebinostat, which tht sells. It is another HDAC inhibitor meant specifically for nootropic purposes, but is hard to come buy for a good price from chemical suppliers, and I'm not sure about tht's crebinostat quality. I, personally, am going for vorinostat this fall because it has been around longer, has had a few more studies done on it, has more anecdotal evidence from the nootropic community, and can be found from a few chemical suppliers at a reasonable price. Vorinostat is also meant more for fear extinction, whereas crebinostat is meant more for novel mechanisms in learning.

 

Stay tuned!

Evan

 

P.S. Notable natural HDAC inhibitors include:

- EGCG (take with Magnesium and Fish Oil to increase bioavailability)

- Curcumin (taken with piperine to enhance bioavailability)

- Cocoa, although weaker

- fisetin is not a pan-HDAC inhibitor outright, but I am listing it because it modulates HDAC, DNMT, and SIRT

Edited by musicman4534, 01 September 2016 - 12:15 PM.

[Lunast]

I am definitely interested in a future group buy. I'm sure you already have the intention to, but please announce the title of the new thread in this one (once you create it), so people can find it.

[David Middlemiss]

I'm very interested too If you canb keep me uptodate, I think if Dyhexa is used alongside the results could be remarkable

 

[Lunast]

I have been awaiting and order of Vorinostat for nearly a month, which may or may not ever arrive. My fear is that it has been confiscated by customs. Hell is with me. Can anyone PM me a reliable source for the compound?

[musicman4534]

I'm very interested too If you canb keep me uptodate, I think if Dyhexa is used alongside the results could be remarkable

 

David,

 

Do you have some dihexa coming in/have you tried it yet?

 

Have you tried lostfalco's intranasal insulin regime? It's super cheap and has been the most effective thing so far in getting rid of my brain fog, which in turn has helped me a lot with my anxiety simply by allowing me to have a deeper grasp on situations and my life in general. The first day I tried it I was able to plan out my actions, my day, my social interactions like I hadn't been able to for years.

 

 

I have been awaiting and order of Vorinostat for nearly a month, which may or may not ever arrive. My fear is that it has been confiscated by customs. Hell is with me. Can anyone PM me a reliable source for the compound?

 

Lunast,

 

Where'd you buy from?

 

I haven't used them before, but you may try LC Labs here:

 

http://www.lclabs.co...8477-vorinostat

 

They have fairly good prices for who they are, but I haven't used them or heard any reviews. For the group buy I'm looking at some bulk chemical suppliers that are going to quote at around 50 a gram, which, at 150mg per dose for our uses, would be great. This would mean we could all get a gram or more for a pretty good price and have more chances to use the compound.

 

 

-Evan

[David Middlemiss]

Hi Evan,

 

natasjlp is close to aquiring an order of Dihexa which is said to be verified at 98%+ in purity

 

Its going on around this thread: http://www.longecity...e-2#entry788365

 

I'm up for purchasing some to try but not tried personally as yet

 

I'm not sure who is involved in the group buy etc

 

Thanks for the heads up on lostfalco's insulin thread,

 

I'm not too interested in insulin as such at this moment although will research a little further to see if application could be beneficial,

[David Middlemiss]

P,s

 

Evan,

 

What is your experience like with the the insulin and does it build dependency in your case?

 

Thanks again

David

[musicman4534]

David,

 

Intranasal insulin has been wonderful. The first time I did it was monumental. It had the most noticeable effects on the first day, and I could use my brain in ways I hadn't since I was 18. After it wore off the effects remained (I only dose every three days for now). I felt like I could actually plan out what I was going to do next while doing the tast at hand, as well as see the bigger picture. I could do these things before, but compared to now it was like I couldn't do them at all. I had bad brain fog, and now that I've taken intranasal insulin I can see just how much brain fog I had. The mental effects remain after each dose, but there are some effects that only occur during administration. These include being hungry, and having a lot more stamina, physical and mental. If you take a look at lostfalco's articles on his website, or look through his thread, you'll find there's been some very promising research done on it so far, and quite a number of glowing anecdotes from here at longecity as well as reddit.

 

Not to turn this into an intranasal insulin thread, but there has been some pretty impressive research done on it so far. For example, the enzyme that degrades insulin is the exact same enzyme that degrades amyloid beta plaques. Also, insulin resistance lessens the amount of insulin transported to the brain (lower insulin in brain consequently deteriorates cognitive function), but intranasal insulin lessens insulin resistance, therefore increasing the amount of natural insulin produced in the pancreas that is transported to the brain. This means that intranasal insulin creates a positive feedback loop creating permanent improvements to the entire insulin system. The studies, if you glance at them on lostfalco's website, are very promising, and if you're a medical buff you would enjoy looking deeply into the studies and looking into the link between insulin resistance and alzheimer's.

 

It's had an effect on me no other nootropic has, like it has spot-cleaned my brain.  Some specific effects, for me, include confidence, but not a steroid-type confidence, just a natural confidence that comes out of being on top of things. Knowing how to act in situations better. Being able to read faster. Being able to plan my day to me more efficient. Being calmer, having less chatter going on in my mind, and what feels like having control over my thoughts, so I can use them better.

 

Highly recommended.

 

-Evan

[David Middlemiss]

Sounds pretty amazing, i'm very interested in this, I'll have to research the technique,find a supply and weigh up the pro''s etc from other articles,
Very very interesting indeed,

[David Middlemiss]

I must say Evan,

Thanks very much for that,

Thats a great explanation.

 

Just wondering the legality of intranasal Insulin here in the UK,

Also what affect Vorinostat first and foremost would have used to undo traumatic experiences,

I,m thinking briefly diary as many major traumatic instances as possible, with a dose of Vorinostat, focus on each one until fear is dissolved/extinguished, working through as many as possible,

 

Then Trialling a supply of Dihexa with possible intro of Intranasal Insulin ii

 

I'm also thinking what affect would ii have on type 2 diabetes, I know there are major issues with the pancreas in this case,

Is there any way of kick starting production with ii, or in conjunction with other things,

 

David

[Lunast]

Can anyone verify as to whether or not it is legally safe to order Vorinostat from LC labs? When I go to complete my order there is a box that requires me to enter the name of the laboratory that the substance is for. And I do not work at a laboratory. Help me out here. I've been trying to get a hold of this stuff for awhile.

[musicman4534]

It's legally safe. If it was me, I would just put my name a second time for the lab, signifying you're a sole proprietor of sorts.

 

Edit: You could also email them telling them that you're an independent researcher and see what they say, but that would just give them more of a chance to think about it. Complete the order, give them their money, and there's a very low likelihood of them wanting to give your money back and not selling to you.

 

Every time I buy syringes I tick the box that says they're for my dog... That company must be amazed at the amount of people injecting things into their dog haha

Edited by musicman4534, 21 September 2016 - 07:02 PM.

[Lunast]

Brick walls all over the place in my crusade to find a gram of Vorinostat. The places I have tried online will only sell to qualified labs and such. Please. If anyone can help me out here, it might just save my life.

[Lunast]

I'm beginning to seriously wonder if Vorinostat is a myth in its proported effects (due to the unpopularity and lack of available sources) or if it is actually some major whirlwind of permanent benefit to those who have tried it. It seems any persons with anectdotal success have given up the ghost in this forum. I wonder if they have gotten significantly better and are spending more time living their lives than inhabiting forums. Anyway, I'm still here and still bitching. And still hoping for Vorinostat.

[musicman4534]

If you look back in the thread, you'll see an anecdote from StevesPetRat about vorinostat, poker and an ex-girlfriend. He reached out to me a week ago telling me to let him know personally through his email when the group buy is going down because he's not active on longevity anymore. So, that's one of the old members in at least.

 

There are also studies on vorinostat's and other HDAC inhibitors' strong effects in regards to fear extinction and neuroplasticity.

 

Evan

[Flex]

Brick walls all over the place in my crusade to find a gram of Vorinostat. The places I have tried online will only sell to qualified labs and such. Please. If anyone can help me out here, it might just save my life.

 

I guess I can´t help You finding Vorinostat but maybe I can help You with Your problem or at least I can try.

[StabMe]

I was wondering, since HDACis so dramatically increase neuroplasticity, is it safe to conclude that they will also increase effectiveness of such modalities as neurofeedback?

 

There are some patterns in NFB that are easily trainable and do no require a lot of sessions for the changes in EEG and behavior to take place, but there are some that are b$#ch to change.

 

Of course, this is pure theory. But... being in theory, i am willing to try to those hard to train patterns under Vorinostat maybe.

 

Thoughts?

[tolerant]

Below is a collection of quotes from this thread with my comments in italics which show that there seem to be two divergent views: (1) that you need successful extinction therapy for HDACi to work (I've omitted the studies referred to in this thread that show that without successful extinction training, the fear memory may actually strengthen!), and (2) that attempting to be calm while taking HDACi may actually ruin the fear extinction process. Very confusing and somewhat risky.

 

 

Celebes: "In short, taking a HDAC-inhibitor (like CL-994) creates a window where it's possible to eradicate fear conditioning. My impression is this would only really be useful in a therapeutic setting."

 

Tree: "Depends on what you call therapeutic setting. Keep in mind the mice didn't need any therapy for it to work. Just recalling memories (for instance by confronting yourself with the anxiety inducing situations) while the window is open is clearly sufficient. GAD sufferers usually have a few things which causes more anxiety than the rest so those are points of confrontation. But if anxiety has gotten to the point were it remains continuous then I'm not sure any confrontation is even required. The anxiety/stress switch is forceably and permanently set to high through epigenetic means. Enter Cl-994 which is an epigenetic resetter."

 

 

Question: Why would an epigenetic resetter selectively resest the anxiety switch? What if it resets the "calmness" or some other useful switch as well? Does the same apply to vorinostat? The mice didn't need any therapy for it to work? They did receive extinction training whereby the foot shock was unpaired with the tone so the fear memory could be extinguished! 

 

...

 

Tree: In regard to the earlier question whether aversive memory wiping is the same as removing consistent anxiety/stress states, I recommend this popular science article. It explains the basics of epigenetic storage very well. Negative memories that are stored in the brain AND persistent anxiety are both the results from epigenetic switches being set. The process can be simplified by saying that methylation can be considered an off switch, and acetyl an on switch. While stress/fear causes genes to shut off due to methylation (including genes necessary to normalize stress responces) a compound like Cl-994 is very indiscriminate and hyper-acetylates proteins and genes. This causes them to become active again and effectively resets your entire epi-genome (to one degree or another, depending on dosage and accessibility in the body).

 

Same question: if it's so indiscriminate, will it hyper-acelate other genes, resulting in detrimental effects? Does the above information also apply to vorinostat?

 

...

 

Celebes: "TrkB and NMDA agonism are both fear extinctive in themselves (along with CB1, Mu, GABAB, 5-HT1A and H2). HDAC inhibition's upregulation of both (in the absence of therapy) is the most likely explanation for its effects. A big part of the phenotype of trauma or anxiety is just the direct consequence of diminished BDNF and NMDA activity (along with CB1, Mu, GABAB, 5-HT1A and H2). You would expect anything that corrected any of that to take a big chunk out of fear conditioning, which demonstrably it does. I think the 'window' was a misconception, an artifact of the design. What we're really doing here is disinhibiting the biological basis of 'resilience', As with anything involving changing the brain, that takes time.

And another thing: How many situations is exposure therapy actually useful in? Sure it works for phobias but those are pretty much defined by being irrational. How does it work with rational fear? Combat veterans: attack people who can't fight back? Assault victims: be the one doing the beating? Child abuse: become dependent on people who are nice to you? Bullying? Infidelity? Failure? Loss? Now all of those things are actually practiced by the people in those groups. But in an hour or two? What's more, the fear extinction studies exposed the rats to a single stressful event. How many people here have had exactly one stressful experience?"

 

If the first paragraph is correct, that is very encouraging. The second paragraph is what I was thinking: how do we replicate extinction learning in humans?

 

...

 

StevesPetRat: "Very interesting experiences, tree. I wonder if an HDACi could help with more general emotional / behavioral plasticity."

 

This is what I'm wondering also.

 

...

 

StevesPetRat: "But it sounds like one has to face the fear and then become unafraid during the treatment which if I could do I wouldn't really need the help..."

 

Exactly.

Edited by tolerant, 12 November 2016 - 03:48 AM.