299 replies to this topic

[chris106]

I second modafinil - it's the only thing that ever helped me in regards to ADD symptoms without unbearable side effects.

Not a perfect drug to counter ADD, but IMO still way better than Ritalin or Amphetamines!

I would love to try guanfacine, but in europe it seems almost impossible to get hold of. So I guess I'll give clonidine a try first - it's easier to obtain, and depending on how I react to that should give me a pretty good idea wether it's worth chasing after Guanfacine.

[GetOutOfBox]

I second modafinil - it's the only thing that ever helped me in regards to ADD symptoms without unbearable side effects.

Not a perfect drug to counter ADD, but IMO still way better than Ritalin or Amphetamines!

I would love to try guanfacine, but in europe it seems almost impossible to get hold of. So I guess I'll give clonidine a try first - it's easier to obtain, and depending on how I react to that should give me a pretty good idea wether it's worth chasing after Guanfacine.

Definitely don't bother with standard Guanfacine, it's intended for lowering blood pressure. Intuniv is a time-released version much better suited for treating ADHD. Sure, standard Guanfacine would still work in theory, but I suspect dosing would be trickier; therapy using it would probably have a lot more side-effects due to rising and falling concentrations of the drug.

As for Clonidine, it's definitely a similar option (targeting alpha-2-adrenal receptors in the CNS), though it's mechanism of action differs from Guanfacine in a few important ways. First of all, it targets pre-synaptic Alpha-2-Adrenal receptors while Guanfacine targets post-synaptic alpha-2-adrenal receptors. I have a pretty intimate understanding of neuroscience, though my knowledge on the practical difference (in terms of effect) between ligands of pre vs post synaptic terminals is shaky. My understanding is that the pre-synaptic terminal of a neuron is where neurotransmitters are actually released, where they act on the post-synaptic terminal. What the functional difference of targeting one or the other illudes me, so if someone could elaborate upon this that would be very helpful.

Secondly and perhaps much more importantly, Clonidine mostly targets alpha-2-adrenal receptors in the vasomotor center of the brainstem. This results in lower concentrations of norepinephrine in the brainstem and hence lowers sympathetic tone (aka vascular tone; lowers blood pressure). I suspect it may also affect other parts of the brainstem, and hence reduce general motor activity (i.e fidgetiness, utilization behavior, etc), which is why it is applicable to hyperactive forms of ADHD. Now, this doesn't mean it won't have an impact on attention, as the brain is a very interconnected organ. Though based upon this MoA I suspect Clonidine is better suited as a treatment for literal, motor hyperactivity, rather than executive-function related hyperactivity.

Guanfacine, on the other hand, mostly targets alpha-2-adrenal receptors in the prefrontal cortex and specfically the locus coeruleus in the brainstem. I've explained how the PFC relates to ADHD, though the locus coeruleus may play an interesting role in ADHD and comorbid disorders. It's fairly involved in the physiological response to chronic stress or being startled. The primary neurotransmitter involved in neurons in this area is norepinephrine, and many non-stimulant ADHD drugs affect this area through that neurotransmitter. It's very possible dysfunction in this area of the brain could produce an abberant stress response, disrupt normal behavioral acquisition (conditioning responses, etc), produce dysfunctional cognitive arousal, etc.

So anyways, Guanfacine seems to be much more relevant to the cognitive symptoms of hyperactivity, whereas Clonidine seems better suited for motor manifestations. I wouldn't dismiss Clonidine though, there's the potential it may still effect attention and executive function. Since it doesn't carry a risk of addiction or triggering latent neurological disorders (as amphetamines, and to a lesser extent, ritalin do), it's worth a try.

Edited by GetOutOfBox, 10 November 2013 - 01:56 AM.

[chris106]

Again, I'm baffled by your level of knowledge, thanks for all that information.

As soon as I get my next batch of Modafinil, I might be able to do some proper research again myself and actually contribute something valuable to this thread,too

Anyways, for the time being -
so what you're saying is that I should rather try Clonidine and don't bother with regular Guanfacine(aka Tenex), as long as I can't get my hands on actual Intuniv? Would regular Guanfacine be too risky/complicated in regards to dosing and side effects compared to Clonidine?

I'm just asking because I've found ONE single source from which I could MAYBE obtain regular Guanfacine, if I use a mail-forwarding services to by-pass german customs.
However, if you look at their prices for "genuine" Intuniv, it becomes clear that ordering that is out of the question.

I hope you don't mind me posting the link, but maybe it's of interest to other's who read this thread, and live in countries with less restrictions when it comes to importing meds?

http://www.internati...ch/guanfacine/1

Too damn bad neither of these drugs are yet approved in Europe. I actually know a pretty open-minded doc who specializes in ADD and who would be willing to try new things :(

But I guess for now it's back to ordering stuff from overseas at high prices without prescription in dire hope that it arrives weeks later -_-'


Lastly, to at least contribute something - here's a nice (though superficial) comparison between regular Guanfacine (Tenex) and extended release Guanfacine (Intuniv) in treatment of AD(H)D.

http://voices.yahoo....x-12079718.html

Edited by chris106, 10 November 2013 - 09:58 AM.

[GetOutOfBox]

Again, I'm baffled by your level of knowledge, thanks for all that information.

As soon as I get my next batch of Modafinil, I might be able to do some proper research again myself and actually contribute something valuable to this thread,too

Anyways, for the time being -
so what you're saying is that I should rather try Clonidine and don't bother with regular Guanfacine(aka Tenex), as long as I can't get my hands on actual Intuniv? Would regular Guanfacine be too risky/complicated in regards to dosing and side effects compared to Clonidine?

Thanks, for whatever reason neuroscience in relation to psychological disorders is just my thing. Love learning about it :D

Guanfacine is still worth a try, but the main issue is controlling flucuations in drug availability. It's actually a bit of an odd conundrum; ordinary Guanfacine, has a very long half-life, yet it is never prescribed for ADHD. The first time it was, was in the extended release form, which is listed as not particularly longer than the half-life of the ordinary form. The main difference is that the extended release has about half the bioavailability of the standard form, so perhaps it allows for a slower, more even release of the drug into the brain. I suspect when using regular Guanfacine, the sleepy side-effect may be more of an issue than the extended-release. Plus it may drop your blood pressure, which could be dangerous if you already have low to optimal-low blood pressure. Always titrate up from the lowest dose to prevent a sudden drop in blood pressure (Intuniv is almost always started at 1 mg for 1-2 weeks, and then upped to 2 mg if necessary.

I'm just asking because I've found ONE single source from which I could MAYBE obtain regular Guanfacine, if I use a mail-forwarding services to by-pass german customs.
However, if you look at their prices for "genuine" Intuniv, it becomes clear that ordering that is out of the question.

I hope you don't mind me posting the link, but maybe it's of interest to other's who read this thread, and live in countries with less restrictions when it comes to importing meds?

http://www.internati...ch/guanfacine/1

Too damn bad neither of these drugs are yet approved in Europe. I actually know a pretty open-minded doc who specializes in ADD and who would be willing to try new things :(

But I guess for now it's back to ordering stuff from overseas at high prices without prescription in dire hope that it arrives weeks later -_-'


Lastly, to at least contribute something - here's a nice (though superficial) comparison between regular Guanfacine (Tenex) and extended release Guanfacine (Intuniv) in treatment of AD(H)D.

http://voices.yahoo....x-12079718.html

If you know a doc who's open-minded, bring him a printout of Shire's page for Intuniv and perhaps a copy of this study http://www.ncbi.nlm....pubmed/20925474 , and see if you can convince him to prescribe Guanfacine off-label. It can be done, as long as their's justification to use a drug in such a way which outweighs the risks of side-effects (which in Guanfacine's case are minimal, as long as blood pressure is regularly monitored).

Which country are you in? Are you sure Intuniv hasn't been released? It may have been made available recently and the local pharmacy doesn't carry it. I had to go to my pharmacy armed with the Health Canada release papers, DIN numbers, and dosing information, which still wasn't enough for the pharmacist to just pull it up on his computer, he had to call the distributors office and confirm the drug actually existed. I'm sure if I'd just called they'd probably just have said it wasn't available yet.

[Mind_Paralysis]

Ey guys, I just heard about something very interesting...
Phenethylamine.

Apparently, we ADD and ADHD -types, seem to have a SEVERE lack of this amino, and it's connected to a whole bunch of other signal-transmitters. There is also some new research that shows that this actually has a decent effect on ADD -symptoms, when supplemented.

http://en.wikipedia....henylethylamine

It actually seems to be something of a Nootropic as well! Hardly any side-effects, available as a supplement and everything. There seems to be a problem with bio-availability tho'... Monoamine oxidase appears to break down most of it before it reaches the brain. I got this idea tho'...

Are there any compounds that combine Phenetylamine with something that helps bio-availability? Something like Aspartate or Orotate? Would it be possible to create a PEA-salt with those two? Especially PEA-Orotate, might be THE SH*T! :D

Another good idea, might be to start taking some form of MAO-inhibitor, as I hear that the toxicity of these, are based on old research, no longer current, and there are a couple of new compounds there, that should be able to do the jump, and help raise our bodies own internal supplies of PEA.

http://en.wikipedia....idase_inhibitor

Edited by Stinkorninjor, 10 November 2013 - 07:20 PM.

[Mind_Paralysis]

This MAOI -stuff is quite fascinating...

What do you guys think about something like Moclobemide? I can't seem to figure out if it's an MAO-B or MAO-A inhibitor ( as far as I understand it, MAO-B is prefferred, to raise levels of PEA), but there are two new studies showing good results in ADHD, so it might be the right MAOI for us, to be combined with something like ginormous amounts of chocolate, or small amounts of some type of PEA-salt.

http://en.wikipedia....iki/Moclobemide

[GetOutOfBox]

Ey guys, I just heard about something very interesting...
Phenethylamine.

Apparently, we ADD and ADHD -types, seem to have a SEVERE lack of this amino, and it's connected to a whole bunch of other signal-transmitters. There is also some new research that shows that this actually has a decent effect on ADD -symptoms, when supplemented.

http://en.wikipedia....henylethylamine

It actually seems to be something of a Nootropic as well! Hardly any side-effects, available as a supplement and everything. There seems to be a problem with bio-availability tho'... Monoamine oxidase appears to break down most of it before it reaches the brain. I got this idea tho'...

Are there any compounds that combine Phenetylamine with something that helps bio-availability? Something like Aspartate or Orotate? Would it be possible to create a PEA-salt with those two? Especially PEA-Orotate, might be THE SH*T! :D

Another good idea, might be to start taking some form of MAO-inhibitor, as I hear that the toxicity of these, are based on old research, no longer current, and there are a couple of new compounds there, that should be able to do the jump, and help raise our bodies own internal supplies of PEA.

http://en.wikipedia....idase_inhibitor

Phenethylamine levels aren't actually directly lower in ADHD persons, it's excreted more rapidly. I don't think this indicates a dietary issue, more that the body is actively metabolizing it at a faster rate. It may be linked to abnormal Monoamine-oxidase activity in some individuals, which could account for ADD symptoms. However, the bulk of studies point to receptors or transporters themselves being the problem, rather than MAO.

MAO-inhibitors are only risky if they are irreversible, which the most effective ones are. In these cases you have to watch your dietary consumption of things containing amino acids they work upon, such as Tyramine. I would avoid them for this reason, and because using MAO-inhibitors to treat a specific problem like ADD is like trying to put up a painting with a sledgehammer. Inhibiting MAO causes a buildup of all neurotransmitters it normally metabolizes, so it could cause norepinephrine and serotonin to rise beyond normal levels, which would in turn cause their own set of problems.

That being said, I'm not dismissing MAO-inhibitors as a possible treatment course. Some individuals with a MAO polymorphism may greatly benefit from them.

This brings me to an interesting avenue of biological diagnostics; genetic sequencing. I'm thinking about using 23andme's service so I can take the raw data and actually check for various polymorphisms. I know part of their easy access results mentions depression likelyhood, so it's likely COMT and MAO polymorphisms will be part of the data. Genetic testing can greatly assist in narrowing down the selection of medications, without having to try them all (and for a month each to get a reasonable idea of how effective they are).

[Mind_Paralysis]

Ah, yes. Didn't think about the fact that MAOI might cause build-up of signal-substances... The wiki-page needs updating btw, I think it says specifically that the PEA -levels are lower in ADD -people, and not that it excretes/breaks down faster.

What do you think about the results with PEA-supplementation tho'? Combined with something that circumvents MAO. Seems to be some effect there, the results seem a bit inconclusive tho', since there's so little study of PEA-supplementation as an ADD-treatment.

That genetic sequencing-idea sounds like a terrific idea tho!
Do we know what perticular polymorphisms that need to be checked for tho'? There are a couple different ones, if I've got my count right. Like, is COMT several polymorphism all baked into one? And that choline-transporter -issue, is that a COMT -related malfunction?

Edited by Stinkorninjor, 10 November 2013 - 11:25 PM.

[GetOutOfBox]

What do you think about the results with PEA-supplementation tho'? Combined with something that circumvents MAO. Seems to be some effect there, the results seem a bit inconclusive tho', since there's so little study of PEA-supplementation as an ADD-treatment.

Well combining it with a MAO-inhibitor would be very risky, that would be like taking a tyramine supplement with a MAO-inhibitor. I think that rather as you said, a PEA salt would be ideal, perhaps one that would be cleaved apart in the brain. A Lysine-Phenethylamine salt strikes me a strong possibility, lysine has already been used as part of lys-dexamphetamine, as the stimulant Vyvanse. The lysine portion is cleaved in the brain leaving the active amphetamine readily available.

That genetic sequencing-idea sounds like a terrific idea tho!
Do we know what perticular polymorphisms that need to be checked for tho'? There are a couple different ones, if I've got my count right. Like, is COMT several polymorphism all baked into one? And that choline-transporter -issue, is that a COMT -related malfunction?

COMT are actually a group of enzymes that do pretty much the same thing MAO enzymes do, just differently. They degrade dopamine, norepinephrine, and epinephrine. Acetylcholine is broken down by a different enzyme, acetylcholinesterase. A polymorphism in the COMT gene effects how the first three neurotransmitters I listed are metabolized. Depending on the polymorphism, they may be metabolized faster or slower. Same applies to a MAO polymorphism.

The primary polymorphism we should be looking for in ADHD-PI is a DRD4 (Dopamine 4 Double Repeat Gene) polymorphism. Essentially the area releated to the D4 receptor is repeated, which results in less binding efficacy, regardless of receptor densities (think of it like the receptor is a slightly different "shape" than it should be, as such dopamine doesn't stick to it as well).

Another ADHD related polymorphism (and much more common, usually people who respond well to Ritalin suffer from this one), is VNTR-DAT1 (Dopamine Transporter 1 Variable Number Tandem Repeat). Essentially there are an increased number of dopamine transporters, and as such dopamine is "sucked" back up out of the post-synaptic space much more rapidly than it should be.
.

[chris106]

Just a quick side-note about a weird discovery I made today. I may elaborate later, but am really short on time right now.

So a few days ago I started taking Ritalin (SR) again, a product called Medikinet Retard, to be percise. I haven't touched Methylphenidate in a looong time, and only did this because I need to get some important stuff done quickly .I couldn't afford Modafinil right now,, while Medikinet is covered by my insurance.

Anyways, as expected it didn't work all that well.
Little positive effects but noticable side-effects like tension and muscle stiffness, racing/incoherent thoughts and anxiety. I tried adding in a few soothing supplemets here and there, but nothing helped. After just 4 days I had pretty much reached the unbearable amount of tolerance, that I am used to - from the last time using MPH, about 2 years ago.

That was yesterday, and I wanted to quit allready.

However, today I felt a weird urge to try MPH with Inostitol, which I've had lying around forever, but rarely used. That actually originated in my plan to use Glucose/Dextrose in the near future as a carbohydrate energy-source for the TULIP-stack. Inositol was just the closest thing I had.

Long story short, as I will elaborate another time:

I took the highest single dose since I started 4 days ago, 20mg (instant working, since I crushed the little grenules, which i took from the opened capsule, in my mouth) and added the following:

1 full spoon of Inositol (about 5-7g, I guess)
2 Tabs of cheap magnesium oxide (suggested daily dose)
700mg L-Taurine
1,2 mg L-Phenylalanine

And holy shit - I'm experiencing the MPH effects like years ago when I stated taking it. No comparison to the last couple of days, and I took up to 15mg single doses then, so I doubt it's the +5mg of MPH.

I've since repeated this dosing twice today. Effects last up to 3 hours each time, whereas they would allways subside after just 1,5 hours before (I'm a fast metabolizer, I guess). Also after 60mg total mph/day I would usually be really burned ou badly, which I am absolutely not.

Don't know what to make of this yet, and doubt that it is a mid- to long-term solution. I have a few ideas regarding working mechanisms and interactions, but as I said - I am short on time right now. Which is why I decided to take MPH for a few days after a year-long hiatus in the first place.

I just thought I'd share this experience, since I find it remarkable that I could actually re-activate MPH's positive effects from years ago, after having build a strong tollerance to it over a long period of time ( or having fucked up my neurotransmitter balance, whichever caused it to stop working)

As I said - don't quite know what to make of this. I will probably continue this (while carefully monitoring myself,of course) for a few more days, and report back as soon as I find the time!

Edited by chris106, 11 November 2013 - 09:21 PM.

[Adam90]

IMO, Methylphenidate works poorly for long term memory purposes and learning new abstract skills.. it's only semi-useful for not feeling sluggish and/or bored. I wouldn't recommend it for those with mild ADD.
I have taken MPH, modafinil, and dextroamphetamine over the past couple of years (during college) and overall my grades and general cognitive performance was best on modafinil out of those three options. Somehow I just tend to remember things better on modafinil compared to ritalin or dex.. perhaps because it stresses me out the least?

[GetOutOfBox]

So a few days ago I started taking Ritalin (SR) again ...

I took the highest single dose since I started 4 days ago, 20mg (instant working, since I crushed the little grenules, which i took from the opened capsule, in my mouth) and added the following: ...

Dude, the reason why you suddenly felt the effects again is fairly straightforward and in all likelihood has nothing to do with the other supplements you took. You crushed the slow-release beads thus causing it to be metabolized rapidly, and took a larger dose. So all you ended up doing really was effectively taking a much larger dose than you regularly do, and hence mitigating the tolerance you'd built up, but only temporarily.

I really do not recommend defeating the slow-release mechanism in this way. First of all, you're getting slow-release pills for a reason, they stretch out the effective half-life of the drug to prevent highs and lows. This is a good thing. Second of all, it's an unreliable way to convert the medication from slow to rapid release. The amount of increase you get each time will be variable, thus making the effectiveness of the dose fluctuate. Finally, you really should not subscribe to the practice of escalating doses every time the drug becomes ineffective. This isn't a sustainable practice (despite 90% of doctors doing it), as you'll get to the point where you're taking a ridiculously high amount of the drug, and when it wears off, the crash will be much much worse than it would be at a lower dose.

Instead, take a drug holiday for say, 1-2 months to allow receptors to fully upregulate/transports to fully downregulate to normal. Then, start taking the drug again, except this time cycle it regularly (I suggest either 2 days on, 2 days off, 2 days on, etc, etc for maximum efficacy each dose, or if you'd rather have the most time on the drug, 1 week on it, 1 week off).

[chris106]

So a few days ago I started taking Ritalin (SR) again ...

I took the highest single dose since I started 4 days ago, 20mg (instant working, since I crushed the little grenules, which i took from the opened capsule, in my mouth) and added the following: ...

Dude, the reason why you suddenly felt the effects again is fairly straightforward and in all likelihood has nothing to do with the other supplements you took. You crushed the slow-release beads thus causing it to be metabolized rapidly, and took a larger dose. So all you ended up doing really was effectively taking a much larger dose than you regularly do, and hence mitigating the tolerance you'd built up, but only temporarily.

I really do not recommend defeating the slow-release mechanism in this way. First of all, you're getting slow-release pills for a reason, they stretch out the effective half-life of the drug to prevent highs and lows. This is a good thing. Second of all, it's an unreliable way to convert the medication from slow to rapid release. The amount of increase you get each time will be variable, thus making the effectiveness of the dose fluctuate. Finally, you really should not subscribe to the practice of escalating doses every time the drug becomes ineffective. This isn't a sustainable practice (despite 90% of doctors doing it), as you'll get to the point where you're taking a ridiculously high amount of the drug, and when it wears off, the crash will be much much worse than it would be at a lower dose.

Instead, take a drug holiday for say, 1-2 months to allow receptors to fully upregulate/transports to fully downregulate to normal. Then, start taking the drug again, except this time cycle it regularly (I suggest either 2 days on, 2 days off, 2 days on, etc, etc for maximum efficacy each dose, or if you'd rather have the most time on the drug, 1 week on it, 1 week off).

First of all, thanks for your reply. But I think you got me wrong (or rather I should have described clearer) I've been taken it like this the whole 5 days, since I got it.
The only reason I got the slow release form in the first place, is becasue ensurance covers it - unlike regular (instant release) Medikinet.

I have taken single doses of 20mg instant relase before, that was the point In was trying to make.

Anyhow - it all doesn't really matter anyways - because all that whole experiment got me was to waste a huge amount of supplements to delay tollerance for one more day.

Today effects were shitty again with the same combo. Despite that I wouldn't want to take like 7 different supplements at once each time.

Oh, why, MPH still just plain sucks for me. Now patiently waiting for my Adrafinil...

Edited by chris106, 12 November 2013 - 11:30 PM.

[GetOutOfBox]

Received a prescription for Intuniv from my doc finally, starting at 1 mg titrating to 2 mg over a two week period. I'll fill it on Thursday, when the paycheck comes in and post daily updates. Received PRL-8-53 and a fresh batch of Noopept today, going to try the PRL-8-53 tomorrow after I'm well rested. Will post back my results.

[Mind_Paralysis]

Eagerly awaiting your reports, mate! =) Are you prepared for the potential drowsiness tho? Like, do you have some DMAE or Modafinil at hand, should you get all drowsy-like?

[GetOutOfBox]

I doubt the drowsiness will be as potent as a sedative, it'll probably be just that, a slight sleepiness. If it keeps happening, I'll order some armodafinil (pure active isomer of modafinil).

Just took the PRL-8-3, about 5-8 mg (using the Noopept scoop from newstarnootropics). It tastes pretty bitter like Noopept, with a unique sort of decrepit after-taste. Slight tongue numbing (FYI I do have an EpiPen on hand in case of allergic reaction). Will post back in about an hour with my subjective state and results of some digit span tests.

Edited by GetOutOfBox, 13 November 2013 - 02:54 PM.

[GetOutOfBox]

Ok, so just did the first round of testing today using www.cambridgebrainsciences.com .

Digit span was not as amazing as the study, 8 digits was the stopping point. However 8 digits is still fairly impressive for me, as I usually have trouble with phone numbers. So I'd say there's perhaps a slight, though noticable improvement in working memory. Spatial span tests (memorizing the pattern in which squares flash on a static matrix, the size of the pattern increases) were actually not impressive at all strangely, possibly worse than my ordinary self. I had trouble memorizing patterns more than 5, which is very low (the test starts at 4, which I assume was found to be an average starting point). What I felt was impeding my ability to memorize the pattern was I was having trouble focusing and actually paying attention to the pattern. Perhaps this compound exacerbates the attentional-deficit aspect of ADHD-Pi. The paired associates memory test (in which objects are paired with each of a layout of boxes on a static matrix, you have to remember which is paired with which) was a little better, at a score of 7 easily, but couldn't easily get past that. Again, I feel like my attention was the limiting factor, I felt like other stimuli and thoughts were sort of "seeping into" my working memory, overwriting the data I was supposed to hold in my mind. Very much sounds like a prefrontal deficit (the PFC failing to regulate working memory and filtering extraneous stimuli).

I suspect that perhaps my likely defective Prefrontal Cortex is the limiting factor with any memory enhancement, as the deficit interferes with proper memory prioritization. I will be extremely interested to see how nootropics combine with Intuniv therapy.

Anyways, I am going to drink a can of pop, as I regularly drink a small amount of some caffeine source. I could be experiencing minor withdrawal which could be the limiting factor. I will re-test within another hour. I will note that today I did not consume my regular nootropic stack, aside from 10 mg afobazole (as I am going out to socialize later, it seems to help), which is not supposed to effect memory. However, I will try testing again tomorrow without anything to see if perhaps the afobazole is causing or exacerbating memory issues.

I also should note I noticed non-cognitive sensory effects which may or may not be placebo. Definitely getting strong visual effects (strong as in they are likely real and not placebo, not psychadelic strong xD), red objects appear "redder", or perhaps they leap out at me more. All colours seem to have an almost surreal, dreamy, sort of look to them. It's hard to describe, the best comparison I can give is to the "bloom" shading effect in some video games(though not that strong, but very similar). It's actually very beautiful, I find myself enjoying visual observations of the area around my house more than usual. These visual effects lead me to strongly suspect serotonergic mechanisms, I seem to recall similar reports from Tianeptine users. I'm not certain if there's an antidepressant effect, I will report it if I observe it.

Finally, I will say that it's not unusual that I didn't get a lot of cognitive benefit from this substance the first time; the optimal dosing range is fairly wide (ranging from 0.05 mg/kg to 1.2 mg/kg). I'll try doubling the dose tomorrow (normally this would be irresponsible, however several of the studies on this compound tested megadoses and found no negative effects beyond reduction of motor activity at VERY high doses). Also, one study claimed immediate effects, while another claimed benefits only affected long-term memory, with only a tiny improvement in working memory. The study that claimed immediate effects reported digit span results going from 7 to 21 digits, which I am highly skeptical of (there must have been confounding factors, I'd expect to only see such gains using Transcranial Magnetic Stimulation or Transcranial Direct Current Stimulation), so I'm leaning towards the other study which reported the chemical enhanced long-term memory uptake, which is much more reasonable to me.

Edited by GetOutOfBox, 13 November 2013 - 04:44 PM.

[GetOutOfBox]

Ok, I did end up retesting with a small caffeine dose, no improvement in the working memory tests (beyond the small improvement I observed in the previous post). I notice a subjectively improved ability to remember sentences though. I will continue to observe the possible effects this may have on long-term memory acquisition.

The visual phenomenae I described faded within about 4 hours of dosing. I didn't actually notice the effects disappear, but I realized a bit later I was no longer observing a difference in colours. It's fairly subtle and could very well be placebo, though I would expect the placebo effect would be more likely to influence my expectations of memory performance than something unrelated like visual effects. Additionally, a member posted in the PRL-8-53 experiences thread with a similar experience, though at 80 mg dosing (which he admitted was very high, and probably wasteful).

After completing the second test (so about 2.5 hours in), I dosed my regular nootropics stack:

20 mg Noopept sublingually
800 mg Oxiracetam orally
2 grams sarcosine

I did not experience any side-effects, and found the PRL-8-53 fit in nicely. While this does not mean that everyone will react the same, my brain did not melt combining those 3 together, all of which have mild glutaminergic activity. Due to the lack of noticeable potentiation (for me, combining two strong glutaminergic compounds like Sunifiram and Aniracetam produced fogginess and anhedonia, which is consistent with glutaminergic over-activation), I suspect PRL-8-53 is not strongly glutaminergic and hence likely safe to combine with compounds which are. The fact that it was well tolerated by animals even at ultra-high doses (hundreds of mg/kg I believe) suggests it is not glutaminergic, as compounds which are typically produce very observable negative effects and neurotoxicity (excitotoxicity) when megadosed.

[GetOutOfBox]

Mini-update in regards to the Intuniv, just wanted to post this offer from Shire Pharmaceuticals to cut the cost per prescription down from roughly $150 to $15 per 30 day prescription. It expires at the end of this year, which is admittedly soon, but still, worth it. Should help those of you who like myself aren't insured.

[3AlarmLampscooter]

Gah, I'm still looking for a non-prescription source selling Guanfacine to people in the US. Looks so much better than Clonidine for stimulant hypertension.

Really irks me that it isn't a controlled substance, yet no one seems to carry it... while plenty of sites have no problem openly selling schedule IVs like Modafinil.

Anyone got any leads?

[GetOutOfBox]

Nah, it's too new, a lot of online pharmacies don't even have it for prescription holders. Your best bet is presenting your idea to a doc, since it's not an abusable drug I'm sure most would be on board. Just bring a copy of Health Canada's summary basis of review for it, it has a very well written analysis of the drug that should cover all of your docs concerns.

[GetOutOfBox]

Ok, took JUST PRL-8-53 this morning, this time I tried roughly 30 mg orally. This was on an empty stomach, alongside no food aside from a glass of water. I waited 1 hour and then tested myself again, no change in performance in working memory tasks from yesterdays testing. Tomorrow I will test myself without ANY items from my stack (so no PRL-8-53) to see if I'm even improving above baseline. Again, the medical literature points towards improvements being found in long-term encoding of memory, so this isn't indicative of the compound being useless. It's only confirming my suspicion that the bizarrely successful results of the study claiming working memory improvement (it claimed improvements as large as going from the norm of 7 digits to 21 digits; I can't even imagine an ordinary person being able to store and reproduce a number sequence that long after seeing it only once) were likely affected by confounding factors, or flawed in some way.

The visual side effects reproduced themselves, this time with the addition of minor visual noise. I can easily see a scintillating (rapidly changing field of noise) overlaid over certain objects which bring attention to it, especially tight grids (like a screen door) or tightly knit patterns. It can also be seen more easily when I close my eyes. It's subtle so it's not uncomfortable (it doesn't disrupt my vision or distract me). The noise closely resembles the kind present in Hallucinogen Persisting Perception Disorder , I think this further emphasizes the possible serotonergic activity of this compound, as serotonergic hallucinogens are commonly implicated in that syndrome. It should be noted that I have used various psychadelics infrequently (always with a washout period, and never ones with neurotoxic connections) though not for the last 3 weeks. It is possible that PRL-8-53 has mild serotonergic activity which perhaps is interacting with the long-term effect the psychadelics may have had on me (as in, perhaps I already have mild Hallucinogen Persisting Perception Disorder in the form of visual noise, but that it's usually so mild I don't notice it).

Also note again that my ADD may be bottlenecking me in working memory, the PFC is very involved in regulating attention and working memory, so a deficit could be the limiting factor here. So I still suggest that people reading this aquire the compound and try it for themselves.

[GetOutOfBox]

Found another very intriguing study which validates my theory that Intuniv is effective for Inattentive sub-types as well. The study compared both ADHD-Combined and ADHD-Inattentive types and found both responded strongly to "GXR" (Guanfacine Extended Release, same thing as Intuniv, likely an experimental generic for testing purposes) in comparison to placebo. It specifically noted improvements in the inattentive score of both types of patients and made note that based on the evidence suspects Guanfacine does not work through sedation (as some have accused it, due to the somnolence side effect), but through some novel means (likely the cAMP in the PFC MoA I outlined earlier).

I can't wait to get my hands on this compound, it sounds more and more amazing by the day. I will of course subject myself to daily diagnostic testing vis Cambridge Brain Science so as to get a true idea of how my working memory, spatial reasoning, and concentration performance improves, in addition to my own subjective reports.

[Metagene]

It's not. In fact, in ordinary people it would likely have a negative effect as it essentially does the opposite of the CILTEP stack. However, as I outlined in my earlier post, people with the DRD4 polymorphism (stands for Double-Repeat Dopamine 4 I believe), which is linked to ADD specifically, have impaired D4 receptors. D4 receptors have a downstream effect on reducing cAMP in the PFC. Elevated cAMP reduces activity along the neural pathways connecting the PFC to the rest of the brain. Intuniv lowers cAMP as it's method of action. So it seems like the best course of action, as there are no drugs targeting the D4 receptor specifically. Inhibiting DAT or increasing levels of dopamine won't change the fact the receptors do not activate as efficiently as they should, it would take a significant raise in dopamine to compensate, and at that level other receptors would likely be over-activated.

This could be why I never felt a damn thing on CILTEP. I left a note for my GP yesterday to see if he is willing to prescribe Intuniv with a stimulant.

[GetOutOfBox]

Ok, so tested myself completely vanilla today (no nootropics or caffeine). I do actually score lower on the digit span test (numbers are flashed one by one in a specific order, and you have to type them in in the order they originally occurred) it seems, I struggle to get above 6 digits. So it seems that I get an extra 2 digits when on the PRL-8-53. That's a fairly reasonable improvement to get from one chemical I think.

The Intuniv just arrived at the pharmacy, I'm going to grab it before work. Unfortunately, I won't be testing it until Sunday, as I have a date tommorow and can't afford to be falling asleep during it :/ I will post back with my first day results Sunday!

[GetOutOfBox]

Not an update, just a post with some more thoughts I've been having in regards to ADD, cAMP, and the PFC. I've also had an additional idea in regards to augmenting Intuniv treatment, which I'll go over in the second half of this post.

I've been thinking more about the mechanisms I've mentioned lately, specifically the dopamine-4 receptor reducing cAMP levels in the PFC when activated, and how in ADD subjects with a D4 polymorphism, cAMP levels in the PFC are elevated (hence the therapeutic effect of Intuniv). What I've started pondering is how this whole axis works in healthy individuals, and my thoughts are this: the D4 receptor, like most of the dopamine receptors, seems heavily involved in exploratory behavior, learning, and attention regulation. I suspect that the system works in healthy individuals as follows: when a person is not focusing on any specific element of reality or thought process, the D4 receptor is inactivated, and thus cAMP levels are elevated in the PFC. Since the PFC serves as a sort of gating mechanism for attention, when there is lower activity in that part of the brain, the individuals attention is spread out; regulated more loosely. This allows for the individual to be aware of more aspects of their environment (such as in a primeval situation, the human is more aware of sounds or sights indicating a possible threat, while not focussing on any given one. This prevents one stimuli from hogging the subject's attention). The subject's attention will rapidly switch from stimulii to stimulii, better facilitating a global analysis of a situation (rather than a detailed analysis of just one element of said situation). Now, when the subject senses something that grasps their attention (more specifically a "hit" is made in their neural network, a pattern recognised in the vast amount of input data), the D4 receptor is activated, dropping cAMP levels and immediately reconnecting the PFC to the amygdala, hippocampus, and other parts of the brain. Prefrontal cortical activity rises as the subject begins filtering data not connected to the recognized pattern and devotes their attention to just it. The PFC serves to remove extraneous information, allowing the more specialized areas of the brain to get a clearer picture of things.

So we've established ADHD is very likely a case of Prefrontal Cortical Dysfunction in regards to the attentional aspects (with dopamine receptors in the mesolimbic pathway more likely being involved in the motivational aspects). Now why it manifests differently in different people (as in, some become very hyperactive and impulsive, while others only have dysfunctions in attention) is less clear. My best guess is based off my own experience. As a child, I most definetely had ADHD-Combined. I was hyperactive, and frequently very impulsive, often getting in trouble for my actions. However, as I grew, I became more and more restrained; introverted. Now I mostly just have trouble with attention regulation and some minor impulsiveness (pretty much just in money management, not in social interaction, interestingly). What I gather from this is that children may develop coping mechanisms, both psychologically and biologically, to some aspects of ADHD. Perhaps some children's brains develop differently to cope with the prefrontal-cortical dysfunction (similar to how victims of brain damage even as severe as removal of an an entire half of the brain, hemispherectomy, sometimes recover a great deal of function), while others do not. This could be the result of other beneficial polymorphisms (such as increased BDNF/NGF), allowing for other areas of the brain to specialize in order to cope with the extra data.

This could explain the belief that people with ADHD may be more creative than healthy individuals. Our brains have more access to information, and our thoughts are less regulated (and hence the potential for random ideas emerging from the chaos is greater). Treating the disorder may diminish this ability and thus a choice may have to be made to ultimately be more productive or creative. Of course, this is just speculation, but it's based on medical data, not whimsy.

Anyways, on to my idea to augment Intuniv treatment. I've mentioned before that Intuniv might only be one third of the solution, that it opens the pathways to the PFC, but that the PFC might have degenerated due to lack of activity (and hence why some patients do not respond very much to Intuniv). I suspect the other two thirds may be: A) Therapy to condition the brain to utilize regulatory behaviors that were not well learned during childhood development. B) Direct stimulation of the prefrontal cortext through external means, to encourage synaptic branching in the area.

The best available method to accomplish this stimulation is tDCS (Transcranial Direct Stimulation). It uses mild currents through electrodes placed on the temples to increase neuron firing potentials, in essence, increasing activity in the area. I suspect this would be greatly beneficial in encouraging prefrontal development, and could greatly accelerate the process vs therapy alone (the key is that the area MUST be stimulated, either via behavioral conditioning, or direct intervention, in order for regeneration to occur). There are a few tDCS devices floating around on the internet; foc.us is one (but very expensive), tdcs-kit.com is a more basic and cheaper version (manual electrode placement, no computer regulation and hence no tweaking).

Edited by GetOutOfBox, 15 November 2013 - 08:49 PM.

[GetOutOfBox]

Also going to post an interesting anecdote: there's currently a new extended-release mixed-salt amphetamine drug for treating ADHD being investigated by the FDA, known as SPD465 currently. It should produce similar effects as Adderall, though the highs and lows many patients experience with Adderall XR may be fixed in this delivery method.

This study found the drug to have a duration of action of roughly 16 hours, which is pretty remarkable compared to Adderall. Patients responded signifigantly greater to the drug than to placebo.

Some other interesting drugs include Pozanicline (ABT-089), a nicotinic acetylcholine receptor partial agonist. Modafinil may also be of interest due to it's histaminergic properties (may increase prefrontal cortical activity due to elevated histaime in the CNS), I'm definitely going to try it sometime soon, when I can next afford it.

[GetOutOfBox]

Found another possible avenue in which ADHD (or aspects of it, as it's starting to look like there is no one ADHD disorder, instead there is a plethora of genetic polymorphisms each of which can possibly cause one aspect of the disorder). This study in rats found a connection between PKA (Protein Kinase A) dysfunction and ADHD-combined. It also noted that a more specific downstream polymorphism affecting CREB (cAMP Response Element Binding Protein) produced symptoms of inattention but not hyperactivity.

I'm having difficulty understanding how exactly CREB affects cognition (specifically ADHD related cognition), as the wikipedia article on it merely mentions it plays a role in the reward system (without specifying how). Furthermore, I'm unsure if the CREB aspect somehow ties in to the cAMP hypothesis I've been discussing lately, or if it's a different polymorphism. It seems that CREB expression increases with cAMP concentrations, and when CREB is disrupted via an intention genetic knockout, subjects demonstrate impaired long-term memory formation. Another study found that when overexpressed, CREB impaired memory retrieval. So it seems a very precise balance is needed for proper memory function. It's possible that elevated levels of cAMP in the PFC also have a memory retrieval impairing effect, due to overexpression of CREB. Thus Intuniv could also correct memory retrieval aspects of the disease.

When I think about my "reality", I do seem to notice that I often have trouble retrieving memory fast and effectively. However I usually blame this on me having difficult encoding memory in the first place, but perhaps it's a combination of the two. Perhaps PFC dysfunction both impairs working memory due to the lack of the normal "gating" mechanism, and also indirectly impairs memory retrieval as a result of elevated levels of CREB. It's very complicated, and I suspect highly individual.

As I've suspected before, it seems ADHD is actually a group of disorders with similar symptoms, but very distinct causes. Dopamine receptors seem to be at the root of things, but the downstream effects seem to be highly variable.

I know I'm spamming this thread with posts, but I think it's crucial for me to get all of my ideas accessible to fellow ADD/ADHD sufferers, as unfortunately well researched looks into the root causes of the disorder(s) are difficult to come by. I know the frustration of browsing the web for information on the disorders and only coming across your run-of-the-mill ritalin, strattera, and adderall posts. Worst, most doctors know little beyond "there's something wrong with your dopamine receptors" and jump on ritalin without considering novel treatments. There's a lot of research that's been popping up in the last 10 years that really changes what we know about ADD/ADHD, yet most of this info has not made it's way into general practice yet. It could very well be another 10 years before a new round of more specific drugs become mainstream, which is a long time to wait.

Anyways, hope I'm not boring people, and I promise to keep this thread updated with info as I come across it, and to also write detailed posts as soon as I start taking the Intuniv this sunday (which I picked up earlier yesterday).

Edited by GetOutOfBox, 16 November 2013 - 07:33 AM.

[Metagene]

No need to worry GetOutOfBox. It would not be presumptuous to say everyone here appreciates the effort you put into your post. I suffer from ADHD mostly likely as a result of premature birth (33-34 Wks + development delay) so the genetic aspects may not be applicable to me but it's all good.

Edited by Metagene, 16 November 2013 - 03:08 PM.

[Mind_Paralysis]

So we've established ADHD is very likely a case of Prefrontal Cortical Dysfunction in regards to the attentional aspects (with dopamine receptors in the mesolimbic pathway more likely being involved in the motivational aspects).

This is a very painful problem for me, as I'm an artist, and my inability to motivate myself to create, has more or less taken me to a certain glass-ceiling in my carreer. Probably even worse for me personally, than inattentive-ness.

How would you go about upregulating the dopamine receptors? There seems to be dopamine reuptake inhibitor qualities to both Methylphenidate and Amphetamine -compounds, as well as the flooding of dopamine-release, of course.

BUT...! I discovered something very interesting here:

Amineptine - one helluva' Dopamine reuptake inhibitor!
http://en.wikipedia....wiki/Amineptine

It's not the best of drugs tho'... seems the side-effects of a pure Dopamine-reuptake inhibitor like Amineptine, may not be worth it. An interesting side-effect is the increased levels of testosterone tho', I seem to have low levels, since I have always had fairly acne-free skin, but also a curse of an immensely weak physique - I am quite physically underdeveloped, and I always struggle to find the right kind of excercise-regime and diet when trying to gain muscle. ( it may of course be caused by DCD as well, since that is common among us ADD-ers as well)

But do you think the side-effects could be limited with the use of some kind of Amineptine-salt? If one heightens bio-availability of Amineptine, perhaps dose could then be lowered, and therefore the side-effects as well.

B) Direct stimulation of the prefrontal cortext through external means, to encourage synaptic branching in the area.

The best available method to accomplish this stimulation is tDCS (Transcranial Direct Stimulation).

Also going to post an interesting anecdote: there's currently a new extended-release mixed-salt amphetamine drug for treating ADHD being investigated by the FDA, known as SPD465 currently. It should produce similar effects as Adderall, though the highs and lows many patients experience with Adderall XR may be fixed in this delivery method.

This study found the drug to have a duration of action of roughly 16 hours, which is pretty remarkable compared to Adderall. Patients responded signifigantly greater to the drug than to placebo.

Some other interesting drugs include Pozanicline (ABT-089), a nicotinic acetylcholine receptor partial agonist. Modafinil may also be of interest due to it's histaminergic properties (may increase prefrontal cortical activity due to elevated histaime in the CNS), I'm definitely going to try it sometime soon, when I can next afford it.

I just got a neat idea here... maybe the best option right now, side-effects -wise and so on, is a regimen of Intuniv and Modafinil? The Intuniv helps the PFC to get back in the game, and the Modafinil helps to increase PFC -activity, increasing the effectiveness of ones psychiatric treatment! =D

This actually looks more and more like a wonder-combo to me...