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Valproic acid allegedly restores the plasticity of the brain to a juvenile state.

plasticity valproic acid

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#1 Absent

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Posted 05 January 2014 - 05:00 AM


I found this on reddit a few hours ago.

Valproic Acid, also known as Depakote.
http://en.wikipedia....i/Valproic_acid

http://www.reddit.co...alprioc_acid_a/
http://www.reddit.co...criticalperiod/
http://www.reddit.co...earning_skills/

Edit: I believe the first article has a mistype. It put Valprioc Acid, where as Valproic Acid is mentioned in the latter article.

The article, created today:

http://www.npr.org/2...a-pill-for-that

Hensch is studying a drug which might allow adults to learn perfect pitch by recreating this critical period in brain development. Hensch says the drug, valprioc acid, allows the brain to absorb new information as easily as it did before age 7.

"It's a mood-stabilizing drug, but we found that it also restores the plasticity of the brain to a juvenile state," Hensch tells NPR's Linda Wertheimer.

And...

Hensch gave the drug to a group of healthy young men who had no musical training as children. They were asked to perform tasks online to train their ears, and at the end of a two-week period, tested on their ability to discriminate tone, to see if the training had more effect than it normally would at their age.

In other words, he gave people a pill and then taught them to have perfect pitch. The findings are significant: "It's quite remarkable since there are no known reports of adults acquiring absolute pitch," he says.


Is is just me or is he insinuating that he gave these healthy young men a substance that under the influence of they were able to train their brains to recognize perfect pitch in a matter of 2 weeks...?

If this is true then such a substance is working on the underlying subconscious learning. Things like language, tone recognition, automatic skills, etc.

Supposedly this substance has a lot of side effects... I am indeed somewhat skeptical of the article as it is commonly perscribed and many redditors have said on it they have not experienced anything remarkable. Though perhaps intentional effort to learn something has some sort of effect as well.

Edited by Siro, 05 January 2014 - 05:25 AM.


#2 joelcairo

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Posted 05 January 2014 - 06:56 AM

I have taken VA for maybe a year because it's a very interesting HDAC inhibitor and appears to slow the progression of cancer (of which I am in a high risk group).

HDAC inhibitors are also postulated to have some rejuvenating effects on normal cells, but this is the first I have heard about enhancing learning or attaining perfect pitch.

That list of side effects sounds like BS. I haven't read the full list of conceivable side effects, but the only one that has ever been presented to me as a likely possibility is sleepiness, which is reversible by scaling back the dosage. Personally I haven't even experienced that one.

Edited by joelcairo, 05 January 2014 - 07:07 AM.


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#3 ta5

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Posted 05 January 2014 - 07:22 AM

I would be concerned about insulin resistance with valproic acid.

#4 smithx

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Posted 05 January 2014 - 09:38 AM

It does this by unwinding the DNA from the histones.

I'm not sure such a generalized effect is a good thing, in most cases.

#5 nightlight

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Posted 05 January 2014 - 12:52 PM

The full paper is in the December 3, 2013 issue of the journal "Frontiers in Systems Neuroscience."

As always, when I find such "youth elixir" research makes it into general news story, I check the effects of the ancient medicinal plant, tobacco, on the same biochemical levers and invariably find that it pushes the same levers in the 'good' direction i.e. the same way as the new miracle drug. So, I checked Google scholar and the ancient indian medicine didn't disappoint this time either -- as it happens, it was discovered just year earlier that nicotine is also HDAC inhibitor, just like Valporate used in the experiments above.

It's yet another example illustrating the motivation behind the Big Pharma's war on tobacco. Pharma has invested billions into creating and propping "grass roots" antismoking groups, on inciting antismoking hysteria via its junk "science", on promoting Nazi style denormalization and hate of smokers, on buying politicians and bureaucrats to push through the antismoker laws and regulations,... All that while quietly doing real research on numerous medicinal effects of tobacco smoke in order to replicate them with synthetic, patentable substitutes.

Of course, as always in the present pharma fueled antismoking hysteria, this effect is given as negative spin as they possibly could, focusing on the possibility that this rejuvenating mechanism could enhance the addictiveness of drugs such as cocaine. Or addictiveness to music, math, computer programming or science. Of course, these other possible effects of the rejuvenated brain plasticity were not of (overt) interest to the researchers.
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#6 nupi

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Posted 05 January 2014 - 02:13 PM

It's yet another example illustrating the motivation behind the Big Pharma's war on tobacco. Pharma has invested billions into creating and propping "grass roots" antismoking groups, on inciting antismoking hysteria via its junk "science", on promoting Nazi style denormalization and hate of smokers, on buying politicians and bureaucrats to push through the antismoker laws and regulations,... All that while quietly doing real research on numerous medicinal effects of tobacco smoke in order to replicate them with synthetic, patentable substitutes.


Because it is absolutely unprofitable to big pharma to treat lung cancer. Riiiiight.
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#7 nightlight

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Posted 05 January 2014 - 03:35 PM

It's yet another example illustrating the motivation behind the Big Pharma's war on tobacco. Pharma has invested billions into creating and propping "grass roots" antismoking groups, on inciting antismoking hysteria via its junk "science", on promoting Nazi style denormalization and hate of smokers, on buying politicians and bureaucrats to push through the antismoker laws and regulations,... All that while quietly doing real research on numerous medicinal effects of tobacco smoke in order to replicate them with synthetic, patentable substitutes.


Because it is absolutely unprofitable to big pharma to treat lung cancer. Riiiiight.


It's sad to see how easily people are duped by the antismoking fear mongers. The link I provided points to the highlights of an earlier thread "Smoking is good for you" in this forum, discussing that topic at great length. As you will find out if you care to check at the links, in animal experiments and few randomized trials, tobacco smoke is protective against cancers, including lung cancer. The antismoking "science" is still entirely resting on statistical associations on non-randomized samples, six decades since the "scientific" antismoking started in the west.

Such associations merely indicate that tobacco smoke and lung cancer are in the same web of causes and effects, but cannot uncover the nature the links. The therapeutic or protective substances are statistically associated with diseases they treat or protect against, just as the causes of diseases are. One needs hard science, such as randomized trials and animal experiments to disentangle such opaque webs of causes and effects implied by the statistical observations on non-randomized samples.

Note also that your point is weak even if one were to grant you for the sake of discussion, that the inhalation of tobacco smoke causes lung cancer. Namely, as the post at the link above indicates, it is a lot more profitable for the sickness industry to have a life-long customer with chronic inflammatory or autoimmune diseases linger on for decades on expensive drugs and treatments, than have someone die within months of lung cancer diagnosis. After all, we all will eventually arrive to some kind of terminal condition, cancer, cardiovascular disease, Alzheimer's,... and receive their final treatments. So that part is pretty much a sure buck in their pockets. It is the time they can stretch you before that, alive but sick, that makes a big difference. In comparison, dying prematurely of a fast killing disease like lung cancer (which is often detected very late), is the loss for the sickness industry.

As that example given earlier illustrates, tobacco smoking is statistically associated (on non-randomized samples) with higher rate of rheumatoid arthritis (RA) and doctors routinely urge (even force) RA patients to quit smoking, since smoking is a strong "risk factor" for RA. Yet, in the animal experiment cited, tobacco smoke (and to a lesser degree pure nicotine which was also tested on one group) showed potent anti-inflammatory effects which delayed onset of RA and reduced subsequent damages to the cartilage once the disease began. What that means is that the observed statistical associations on non-randomized samples are result of self-medication -- the people with RA (at any stage) are instinctively treating themselves with tobacco smoke, which among others upregulates internal corticosteroids, suppressing inflammation and providing perceptible relief. Of course, the pharma would rather scare you away from the inexpensive and effective ancient medicinal plant, and make you pay for their patented, synthetic corticosteroids (with long lists of damaging side effects, hence more downstream treatments of those damages, too). The pharma profits come here not only from making smokers with RA quit, who are a minority of population, but scaring everyone else away from ever trying it, monopolizing thus the entire chronic inflammatory and autoimmune market for its own drugs.

Hence, the large long term investments into antismoking by the pharmaceutical industry, from producing and peddling antismoking junk science to inciting Nazi style denormalization and hate of smokers, is enormously profitable business strategy for the pharma (just as their similar investments in suppressing other natural or traditional medicines are, through buying politicians, FDA, CDC, NIH,... and other government attack dogs to muscle away the competition).
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#8 Volcanic

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Posted 05 January 2014 - 05:25 PM

You can't do randomized human interventional studies on smoking. Non-smokers wouldn't agree to start for the sake of science, nor would many researchers ask them to. Furthermore, you can't realistically blind the studies.

Meanwhile, animal studies are likely to ignore some of the harmful effects:
  • Heat: You can't duplicate this without getting the animals to actually smoke cigarettes. Simply filling a box with smoke won't do - if the smoke is as hot as cigarette smoke, it will burn the animals. I think heat is a major source of damage for smokers.
  • Smoke: An animal study might use non-tobacco smoke as a control in order to isolate the effects of tobacco. This may be worthwhile for science, but positive results don't mean that smoking tobacco is better than smoking nothing.
I'm open-minded to the possibility that tobacco may have beneficial effects. But even if it does, you shouldn't smoke it any more than you should smoke astragalus to lengthen your telomeres. Nor should you use flame-cured tobacco products, since the process produces some of the same harmful chemicals (tobacco-specific nitrosamines, at least). If you really think tobacco is good for you, try Swedish snus. Or put it in a pill, or make a tea, etc... but it still seems risky.

Edited by Volcanic, 05 January 2014 - 05:25 PM.


#9 Volcanic

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Posted 05 January 2014 - 05:35 PM

Per the NPR article, Hensch urged caution with VA:

If we've shaped our identities through development, through a critical period, and have matched our brain to the environment in which we were raised, acquiring language, culture, identity, then if we were to erase that by reopening the critical period, we run quite a risk as well.


The way I read this, using VA could alter deeply ingrained areas of your personality. Maybe using it for short periods to learn specific skills wouldn't do that, though.

Perhaps it also raises the possibility of using it in conjunction with (for example) CBT to treat common psychiatric disorders? Increased plasticity would likely help therapy.

#10 Hebbeh

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Posted 05 January 2014 - 05:42 PM

It's a well known fact that oral tobacco use can and does lead to oral cancers. I've seen results of that effect and it is very ugly. Doesn't appear very life enhancing. From an anecdotal perspective, look around and you will see that most if not all of the tobacco users you have known died relatively young while all the people that you know that have achieved advanced age haven't used tobacco. Of course there are always the rare outlier that survives due to exceptional genetics regardless but they are rare and not the normal. Tobacco use would certainly appear to be contrary to reaching 80's, 90,s or 100's in the real world.
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#11 Volcanic

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Posted 05 January 2014 - 05:58 PM

It's a well known fact that oral tobacco use can and does lead to oral cancers. I've seen results of that effect and it is very ugly. Doesn't appear very life enhancing. From an anecdotal perspective, look around and you will see that most if not all of the tobacco users you have known died relatively young while all the people that you know that have achieved advanced age haven't used tobacco. Of course there are always the rare outlier that survives due to exceptional genetics regardless but they are rare and not the normal. Tobacco use would certainly appear to be contrary to reaching 80's, 90,s or 100's in the real world.


I didn't mean to imply otherwise. But snus is better than other forms of oral tobacco (see, e.g., WebMD). And even snus is processed. I'm just not sure that the data on tobacco products support the idea that the raw leaf is harmful.

Edited by Volcanic, 05 January 2014 - 05:59 PM.


#12 nightlight

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Posted 05 January 2014 - 06:52 PM

You can't do randomized human interventional studies on smoking. Non-smokers wouldn't agree to start for the sake of science, nor would many researchers ask them to. Furthermore, you can't realistically blind the studies.


The randomized studies on humans were done by randomly splitting a group of smokers into a quit group and controls. The quit group is urged and helped quit (and most of them do quit at least for the duration of the study), while the controls are left alone to smoke as before, then the subjects are followed from several years to more than a decade. Only a handful of such randomized intervention trials were done, since whenever they showed anything at all, the quit group did worse, including getting more lung cancers or heart attacks. So, they just gave up on randomized trials in favor of what "works", the pliable non-randomized studies. See this survey article on the few that were done (also a longer excerpt from a book chapter).

Meanwhile, animal studies are likely to ignore some of the harmful effects:

  • Heat: You can't duplicate this without getting the animals to actually smoke cigarettes. Simply filling a box with smoke won't do - if the smoke is as hot as cigarette smoke, it will burn the animals. I think heat is a major source of damage for smokers.
  • Smoke: An animal study might use non-tobacco smoke as a control in order to isolate the effects of tobacco. This may be worthwhile for science, but positive results don't mean that smoking tobacco is better than smoking nothing.


Not at all, as you will see if you follow the links to the highlights of that thread mentioned earlier. The experimenters did their absolute best to maximize the harm to smoking animals (they were hired to find it and prove it), including insertion of narrow high pressure nozzles pushing the hot smoke into animal noses or bronchi and burning holes right through the exposed tissues (German experiments). Another way was to use radioactive tracers added to the smoke, allegedly to measure smoke exposure, while irradiating animals to such levels they had to be handled as hazardous radioactive waste after the experiments. Yet another approach is to condense given daily quantities of smoke into few hours of super-concentrated exposure, driven right up the edge of asphyxiation. At the same time, the control would get hepa filtered pure air. And still, the smoking animals did better, living longer, while remaining thinner and sharper (in cognitive tests). The methods of hard science simply don't work for antismoking "science", going always the "wrong" way, which is why six decades later all they can parrot is the same junk science they started with in 1950.

I'm open-minded to the possibility that tobacco may have beneficial effects. But even if it does, you shouldn't smoke it any more than you should smoke astragalus to lengthen your telomeres. Nor should you use flame-cured tobacco products, since the process produces some of the same harmful chemicals (tobacco-specific nitrosamines, at least). If you really think tobacco is good for you, try Swedish snus. Or put it in a pill, or make a tea, etc... but it still seems risky.


Well, until I see experiments showing any benefit of such variants, I will stick with the ancient technique honed over eight thousand years on more than billion life-long test subjects, and which has even managed to demonstrate benefits in experiments optimized to show exactly the opposite.
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#13 Darryl

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Posted 05 January 2014 - 07:34 PM

As a regular snus user, I'm aware of only one beneficial effect, nicotine reduces the incidence of Parkinson's disease by about 60%, and smokeless tobacco works just as well.

Podhraski, Valerie, et al. "Tobacco, coffee, and Parkinson's disease."BMJ 2003; 326: 561-562
O'Reilly, Eilis J., et al. "Smokeless tobacco use and the risk of Parkinson's disease mortality." Movement disorders 20.10 (2005): 1383-1384.

That said, I'm well aware that snus, while reducing risks from tobacco, still increases the risk of pancreatic cancer and perhaps elevates stroke risk. I consider my moderate (4-5 portions / d) use low-cost, relatively low-side effect self medication for anxiety.

Luo, Juhua, et al. "Oral use of Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study." The Lancet 369.9578 (2007): 2015-2020.
Hansson, J., et al. "Use of snus and risk for cardiovascular disease: results from the Swedish Twin Registry." Journal of internal medicine 265.6 (2009): 717-724.

Back to valproic acid - like other anti-epileptics, its effect on learning has been extensively studied. In animals, it appears as effective as piracetam, but in human children with epilepsy, it impairs learning, though much less than other anti-epileptics.

Interestingly, valproic acid and other compounds known to lower Inositol-(1,4,5)-triphosphate (carbemazepol, lithium) known to increase animal learning also increase autophagy. I'd love to see whether safer CNS acting autophagy inducers (like rilmenidine, which has negligible side effects) also have effects on learning. To my knowledge, it hasn't been studied.

Edited by Darryl, 05 January 2014 - 07:36 PM.


#14 Absent

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Posted 05 January 2014 - 10:37 PM

Am I on the wrong thread here or something? Why is everybody talking about smoking? Anyone who is even slightly applying that smoking is a longevity enhancer is an idiot. I know several people who have been diagnosed with lung cancer and some who have even died of it, whom were all smokers, and no people who weren't smokers with lung cancer. No doubt Nicotine has some nootropic effects but really this debate on if smoking tobacco is healthy or not is ridiculous. Please stay on topic.
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#15 PWAIN

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Posted 06 January 2014 - 12:52 AM

Can someone create a smoking/tobacco thread and move this stuff there, This has nothing to do with VA which is the only reason I want to read this thread.

#16 nightlight

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Posted 06 January 2014 - 03:34 AM

Can someone create a smoking/tobacco thread and move this stuff there, This has nothing to do with VA which is the only reason I want to read this thread.


It certainly is relevant for HDAC inhibition, which is the mechanism of action in the observed effects in the thread starter. Hence, it is of interest to bring up alternative sources of substances used, especially if they are available in inexpensive medicinal plants with thousands of years of traditional medicinal use behind and without the nasty side effects of the experimental drug. Unfortunately, any time the ancient medicine tobacco is brought up regarding some beneficial biochemical mechanism being discussed, a group of antismoking hysterics here can't resist diverting the thread into tangential topics.
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#17 PWAIN

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Posted 06 January 2014 - 03:39 AM

Can someone create a smoking/tobacco thread and move this stuff there, This has nothing to do with VA which is the only reason I want to read this thread.


It certainly is relevant for HDAC inhibition, which is the mechanism of action in the observed effects in the thread starter. Hence, it is of interest to bring up alternative sources of substances used, especially if they are available in inexpensive medicinal plants with thousands of years of traditional medicinal use behind and without the nasty side effects of the experimental drug. Unfortunately, any time the ancient medicine tobacco is brought up regarding some beneficial biochemical mechanism being discussed, a group of antismoking hysterics here can't resist diverting the thread into tangential topics.


The debate whether tobacco products are harmful or not is however not relevant and just fills an otherwise interesting thread. The correct process would probably be to say something like lets carry this on in another thread and provide a link for anyone that is interested.

#18 joelcairo

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Posted 06 January 2014 - 06:43 PM

Re the initial study, I just looked at the full paper and it isn't too stunning. They only have data for 17 people who completed the entire test, counting the placebo group. And it doesn't appear that there's a pattern of guesses getting closer to the correct pitch, just that there is a spike of correct answers on the exact right pitch. Maybe that's a sign that the training is working, or maybe it's a statistical glitch due to the small number or people in the study.

#19 Sartac

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Posted 06 January 2014 - 10:20 PM

Think I'd sooner smoke a pack than consume VA, just based on cursory reading of Depakote warnings on WebMD.
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#20 gavino

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Posted 09 January 2014 - 04:07 AM

Can we just forget the whole smoking stuff and keep this to valrpoic acid?

I'm been interested in valproic acid for sometime for above reasons. The main issue is the dose. Yes, it and all the other anti-epilectic drugs used to treat mania do have gnarly side effects, but only when used at psychiatric doses. IIRC, valproic acid doses range from 500-1000mg for bipolar treatment. I've thought about using 30mg/day just because it would likely be harmless, but without any studies at low-doses I don't think it's worth the risk.

#21 nickthird

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Posted 09 January 2014 - 07:38 PM

They only have data for 17 people who completed the entire test, counting the placebo group.

There has not been a single study with the improvement shown here under the test conditions (short time to learn, 6 sounds simultaneously, practically no musical training, sound relative height not taught) using any method, drug or otherwise. Even with N=4 this would be impressive. (You have to take into consideration that they did a crossover and gave the VPA group placebo and vice verse).

And it doesn't appear that there's a pattern of guesses getting closer to the correct pitch, just that there is a spike of correct answers on the exact right pitch.

That's right! this is exactly what you would expect when training a person in absolute pitch. Training simultaneously in relative pitch would get them to guess close to the real pitch. Remember they have no idea what sound is higher than what (they can't tell if it is between two sounds, and they weren't even taught the order or height), only what the names of given sounds are. To me D sounds alot like G but not like C (or C#), and I have relative pitch training. The height and the similarity of the sounds are completely separated.

or maybe it's a statistical glitch due to the small number or people in the study

As for absolute pitch studies, the extremely low success rate (we are talking about improvement in people with professional musical skills, and teaching ONE tone for a period of MONTHS) allows for the small sample. There could not be a statistical glitch as the people who completed the first arm went over again, this time taking placebo, and they failed to surpass chance. This means both that the learning was not long term, and that they had no superior innate absolute pitch ability compared with the initial placebo group.

However, this study suffers from a serious problem: in the second arm both groups did not surpass chance. This is very strange.

A memory conflict between the pitch classes and proper names used in the first treatment arm could have interfered with those used in the second.


This explanation is not satisfactory. Memory of what? they failed to associate the sound with a name, why would the placebo -> VPA group get WORSE?
Posted Image


It is clear based on this data that a longer study period seems to be making the judgement worse (possibly a U shaped curve as function of time - for short term pitch learning) as all groups got worse with time. It's possible that if you tested the placebo group on day 2 of their study they might score as high as the VPA group. It's possible that the VPA could be actually impairing learning and thus giving the effect of day 2 to the VPA group. This would explain why no group scored above chance in the second arm (the group that was placebo at first learned something even with VPA, and so scored lower). In this case you would also expect the group that learned better (no VPA impairment) closer to the test to score lower (that is the placebo in the second arm), but this effect is not seen here. However, given the uncertainty of the results in both groups, the difference between the scores in the second arm is not statistically significant (they scored the same given the error of the score). Notice that the the uncertainty (length of the line) is highest in the VPA group in the second arm. This is a most curious result that should not be taken lightly, and one that I cannot provide an adequate hypothesis for.

Can anyone find any information regarding the performance of pitch judgement as function of time for short term learning (few days to weeks)?
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#22 joelcairo

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Posted 09 January 2014 - 09:06 PM

Yes, your discussion of that chart is one of the reasons why I suspect statistical factors at play. That seems to be the simplest explanation, although certain elements of the way the test was administered could have contributed to it.

For example, on one hand you'd think that increased training would tend to improve the accuracy of the subjects across the board rather than cause it to go down; OTOH perhaps boredom was setting in.

#23 protoject

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Posted 21 January 2014 - 08:43 PM

I was considering low dose valproate, not for the same reasons of restoring plasticity of the brain, and I apologize if I'm off topic but , with all the depakote warnings, would the same apply to such a tiny dose like 30 mg? just wondering if there are evil changes in the body if using such minute doses

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#24 pi-

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Posted 07 August 2014 - 03:58 PM

@NickThird, I agree entirely. This is a problem.

 

While results from the first treatment arm look spectacular, this is undone to a large extent by the second arm.

 

I would say these results warrant a further experiment that is more thorough.

 

One thing is for sure, when you take VPA you know you're on it. My experience is headache, feeling fuzzy, stomach feeling unsettled. So unless they are providing a placebo that mimics these sensations, certainly the purpose of placebo in the second arm is made redundant.

 

I am putting myself through a similar experiment to this. I will post the results up when I have them.

 

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