299 replies to this topic

[GetOutOfBox]

2 questions: 1.) What do you think of PRL-8-53? I read that it should be very good for writing exams

First off, the hype for PRL-8-53 is completely unfounded. It's largely based off of two small studies from the 80's I believe, one of which seems really shady (makes extremely grandiose claims, it claimed that subjects digit recall went from 7 digits to 21 digits. I really don't buy that a chemical could consistently do that, such an enhancement would likely require structural improvements, or electrical stimulation. That's just my guess, but my experience is both pharmaceuticals and nutraceuticals generally provide modest results at best, so in this case maybe an increase of 2-4 digits would make sense). Also, for a drug apparently so succesful, it was never followed up on. If it was as good as rumored, the pharma companies would have lept on it. It definitely would have gotten more attention from the medical community than it did.

Finally, my personal experience is that it seems to have serotonergic effects; I noticed slightly increased visual saturation of colours, and maybe a mild mood improvement. I did not notice improved performance, nor did digit span tests reveal any real improvement (I consistently scored about the same). Now, one study seems to indicate the gains are more for long term memory formation, which is harder to rule out. It could be a possibility. But I did not notice any dramatic acute effects.

2.) Since Piracetam is usually the #1 option to start and has been most tested from all racetams, how come you never mentioned it (or at least I cant remember reading it in your thread)? Didnt it work for you or do you find that Oxi just works better?

I skipped Piracetam mainly because the bulk of actual clinical evidence seems to suggest that it at best seems to be moderately beneficial for those with cognitive decline secondary to aging or trauma, and may subtly enhance cognition in healthy individuals (very subtly). It's probably one of the safest nootropics, but also the weakest. It's also inconvienient to dose due to the large doses required. There are a lot of better alternatives that are likely more beneficial for healthy individuals, such as Oxi, Prami, etc. Modafinil isn't a nootropic, and should be used with caution, but for those who are regularly sleep deprived, it will probably have the most "wow" factor of them all. It's considered to be a much cleaner stimulating effect than caffeine's. Plus addiction is not as much of an issue with modafinil as it is with caffeine, as it works primarily on the histaminergic system, which is less vulnerable to up and down regulation than adenosine receptors (which downregulate relatively quickly, usually within a week of daily use).

[GetOutOfBox]

A little interesting note for cannabis use and people with ADHD; cannabis may be a potent alpha-2 adrenal receptor agonist, just like Intuniv. Thus theoretically it may restore prefrontal function in those with ADHD. This restored prefrontal function would likely have acutely anxiolytic effects very similar to those experienced with Intuniv. I don't think cannabis is a good treatment for ADHD, as the fogginess it causes during use counteracts the positive nootropic effects it may have. However it may lay more credence to the theory that people with ADHD are unconsciously self-medicating with cannabis, explaining it's high use amongst ADHD patients, rather than it previously being thought to be a potential cause of ADHD.

It's probably compensated against by the potent NMDA antagonist effect of cannabis, which produces the characteristic fogginess, though it is my experience glutaminergic supplements like Sunifiram do not have a large effect on the dulling aspect of cannabis, so there may be other factors at play. An interesting note though: the heavy NMDA antagonism may be the key to Cannabis' lack of addictive qualities (and possibly explain why it's now thought to not cause mental illnesses). NMDA antagonists have been found to reduce downregulation induced by opioids and stimulants. It's possible this not only prevents addiction to the dopaminergic effect of cannabinoids, but prevents chronic disruptive dopaminergic neuralcircuitry changes (hence why it is now thought that cannabis can only trigger acute psychosis, but rarely, if ever chronic psychosis).

Edited by GetOutOfBox, 26 December 2013 - 08:29 AM.

[Mind_Paralysis]

GetOutofBox: Sounds to me like Cannabis is the superior RECREATIONAL drug for us ADD-people then! =) Since fogginess isn't a problem when one is going out partying, rather feelings of goodness and social courage is what is required.

I was just thinking about the recreational thing btw, would you recommend PEA as a potential recreational drug use, for ADD-people? I'm thinking something mild, with few side-effects and perhaps even positive effects on ADD, for taking when going out.

Many of us are on Methylphenidate, and me and a few friends have been warned that in the long run the combination of alcohol and methylphenidate ends up dulling the Methylphenidate quicker, and the high euphoria one gets from the combo is quite habit-forming.

So what would you suggest as a replacement for alcohol? PEA or a bit of Pot? Or perhaps something else entirely?

A friend of mine potentially has commorbidity with Bipolar disease as well, so something that works with that commorbid to ADHD would be lovely.

[GetOutOfBox]

GetOutofBox: Sounds to me like Cannabis is the superior RECREATIONAL drug for us ADD-people then! =) Since fogginess isn't a problem when one is going out partying, rather feelings of goodness and social courage is what is required.

I was just thinking about the recreational thing btw, would you recommend PEA as a potential recreational drug use, for ADD-people? I'm thinking something mild, with few side-effects and perhaps even positive effects on ADD, for taking when going out.

Many of us are on Methylphenidate, and me and a few friends have been warned that in the long run the combination of alcohol and methylphenidate ends up dulling the Methylphenidate quicker, and the high euphoria one gets from the combo is quite habit-forming.

So what would you suggest as a replacement for alcohol? PEA or a bit of Pot? Or perhaps something else entirely?

A friend of mine potentially has commorbidity with Bipolar disease as well, so something that works with that commorbid to ADHD would be lovely.

Cannabis isn't really an effective treatment for the cognitive effects, and it can be an erratic treatment for the emotional effects. In theory (and I have observed this in practice) it would help with the emotional dysregulation in people with this subtype of ADHD effecting cAMP levels. It's why a lot of people with ADHD find it's effective at calming them down, and also why Ritalin (albeit in a much more indirect way) calms people with ADHD down. However, cannabis has a plethora of other psychoactive effects which can counteract this and cause anxiety, emotional fluctuations, etc. So it's something you'd have to figure out for yourself. I'd certainly expect low doses to be more effective than higher doses, as the NMDA antagonism would be less pronounced.

PEA really isn't that useful. MAO enzymes pretty much prevent any from reaching the brain, unless you megadose, which would be costly, and isn't guaranteed to do anything anyways. A lot of supplement companies like to ignore this and market it as a psychoactive substance, but at most sane doses it is barely if not at all psychoactive. It gets destroyed in your intestines (and sublingual doesn't do much difference, plus you can imagine the difficulty of cramming your mouth full of the stuff for 10 minutes straight to get one dose in xD).

I don't think alcohol would increase the rate of tolerance to other substances, but it's not something that I would advise consuming regularly. It's actually worse than a lot of illegal substances, it causes more harm socially and biologically than LSD (and most run of the mill psychadelics), cannabis, ketamine, etc. It's up there with MDMA and Methamphetamines in regards to the potential neurotoxic and neurodegenerative effects it has. We're talking regular heavy consumption of course. If you're talking about getting hammered every now and then to celebrate a birthday or something, you're probably not at a huge risk (I personally still avoid heavy intoxication). But if you're talking binge drinking every weekend then there's potential hippocampal degeneration, global brain atrophy, increased inflammation, etc. Most of the neurodegenerative effects seem to come from it's NMDA antagonism and GABA agonism. The two combine for potent inhibition of neuronal firing, and of course long term reduced neuroexcitation results in degeneration of affected circuit pathways. The brain does it on purpose as it perceives them as unused.

A replacement for alcohol is tricky. Do you mean something recreational, or a legitmate long-term strategy to fix chronic anxiety? Recreational is tougher, as most substances that produce alcohol like effects come with it's side-effects. If you just need to be dumbed down for whatever reason, I suspect ketamine would do the job, and with less risk in the long run than alcohol (though less studies as well, it's a tricky thing to balance, in theory it's better, but it's not guaranteed in practice). The only major ketamine risk I'm aware of is bladder damage, but it still beats how alcohol trashes the liver, heart and most major organ systems.

For a healthy approach to anxiety, there a few very benign substances which can have very beneficial effects. Bacopa is a good one to try, though effects can take a month to see. It also has very beneficial memory effects. Afobazole is another approach to try (I'd say after trying Bacopa), and again it takes about a month to see the benefits. Both benefit the brain by inducing long term changes in receptor densities and brain structure, and hence don't occur at a great magnitude immediately.

As for Bipolar, I'm currently investigating a possible novel augmentitive treatment in the form of Agmatine (an arginine derivative). Bipolar's neuropathology is unclear, but excessive calcium channel activity has been suspected in a few studies, and in theory makes sense (excessive calcium channel activity would cause erratic function of neurons, which in turn could translate to alternating bursts of neurotransmitters causing mania and reduced quantities released causing depression). Agmatine is a calcium channel inhibitor (amongst very many other interesting properties), and holds a possibility of being effective when combined with a mood stabilizer. It's something worth looking into for your friend.

*Of course there's the legal disclaimer that my views in regards to substances considered illegal by various countries including the US are my own and in no way represent those of longecity or it's other associates.

[Mind_Paralysis]

Thanks for the run-down, GetOutofBox. =)
The reason some say Alcohol makes you tolerant towards Methylphenidate, is because apparently there's some evidence to suggest it combines with alcohol in the body to form Ethylphenidate, and then your brain gets used to the fact that the high must come from Ethylphenidate instead of Methylphenidate. Ethylphenidate appears to induce more euphoria, and have more of a crashing effect when it runs out of your body.

I should probably note that I myself is actually more or less a straight-edge type of guy, I usually don't drink at all, even at big celebrations, and I'm very picky with the nutrient-values in my food. I eat a lot of raspberries and almonds for the magnesium, for instance.

So, I was mostly asking for my friends, who have this problem that needs solving, and I'm the type of guy that jumps at problems and want to solve them immediately.

I must say tho', this ketamine doesn't seem like a very nice drug, the reported k-hole-effect seems positively scary, even! o.o

Btw, interesting idea about Agmatine - do you figure it could actually work better than a nootropic stack? I'm especially interested in the problem with the calcium-levels - some Bipolar, and other type of disorder-suffererers, such as ourselves, report improved symptoms on mega-doses of Magnesium, I believe.

Like, for instance, IMHO, this stack is what I always presumed would be ideal for Bipolar:

1400 mg Omega-3 oil
4x pill of Magnesium-Citrate
15 mg ( two tabs, I believe) Lithium-Orotate
DLPA ( to help with potential brain-fog, unsure of the dosing)

BUT, in theory... if Bipolar has to do with Calcium-channels, then perhaps Mega-doses of Magnesium and a bit of Li-O is all that's needed? I do believe one of the reason why us westerners have so much more depression than other cultures is suspected to be because of Magnesium-deficient food, and a highly Calcium-rich dairy-based diet, yes?

So, using the superior bio-availability of Li-O in small doses, one gets a more stable mood, and with mega-doses of Magnesium-Citrate, one takes care of excess calcium! =) Done! Square! Sealed!

If this actually works... then in effect curing Bipolar-disease with such a simple noot-stack of supplements, is almost bafflingly simple, in comparison to curing ADD, now innit? 0_o

[GetOutOfBox]

Thanks for the run-down, GetOutofBox. =)
The reason some say Alcohol makes you tolerant towards Methylphenidate, is because apparently there's some evidence to suggest it combines with alcohol in the body to form Ethylphenidate, and then your brain gets used to the fact that the high must come from Ethylphenidate instead of Methylphenidate. Ethylphenidate appears to induce more euphoria, and have more of a crashing effect when it runs out of your body.

Interesting, this is the first time hearing about this specific stimulant. I think it's unclear whether the methyl group can be cleaved from methylphenidate and replaced with an ethyl donor in the body though. Chemical reactions such as that often require more than two compounds being in each others presence, or being metabolized together. It's certainly possible though. However, it seems ethylphenidate has a lower binding affinity to dopamine transporters and effects dopamine uptake to a lower degree than d-methylphenidate, and much lower than dl-methylphenidate. I think the issue is that it's effects are more variable, and hence can make users use larger doses to compensate, sometime resulting in excessive dopaminergic activity.

I would note that alcohol could reduce the rate of addiction to a substance, as it is a moderately potent NMDA antagonist, drugs of which reduce downregulation. However, it may compensate for that effect by potentiating stimulants, as ethanol also produces fairly large releases of dopamine in various areas in the brain.

I should probably note that I myself is actually more or less a straight-edge type of guy, I usually don't drink at all, even at big celebrations, and I'm very picky with the nutrient-values in my food. I eat a lot of raspberries and almonds for the magnesium, for instance.

So, I was mostly asking for my friends, who have this problem that needs solving, and I'm the type of guy that jumps at problems and want to solve them immediately.

Yeah, there's nothing wrong with some drinks, it's when the brain is regularly being exposed to large amounts of ethanol you start seeing problems.

I must say tho', this ketamine doesn't seem like a very nice drug, the reported k-hole-effect seems positively scary, even! o.o

Yeah, it's very different than alcohol. But it's pretty much the one similar recreational substance that also is less unhealthy in the long term. Taken in small doses it produces effects similar to alcohol intoxication, but also very different in some respects. It has the benefit of being much simpler in it's actions, whereas ethanol has several MoAs, all of which are potentially negative in the long term.

Btw, interesting idea about Agmatine - do you figure it could actually work better than a nootropic stack? I'm especially interested in the problem with the calcium-levels - some Bipolar, and other type of disorder-suffererers, such as ourselves, report improved symptoms on mega-doses of Magnesium, I believe.

I would add it into a stack. It's pretty benign in that it's not very psychoactive on it's own, so it's unlikely to produce negative side-effects. The anti-calcium channel effect is moderate, so it may help shift things back to normal for those with erratic activity, but shouldn't negatively effect those with normal activity. Interestingly, it also potentiates several substances, especially cannabis. It's been found to potentiate cannabis' activity at CB1 receptors.

Magnesium is always good to add to a stack (I wouldn't "mega-dose" though, simply taking enough to fulfill the RDA should be sufficient for most people. Mega dosing can produce some positive effects in specific cases, but has the tendency to produce diarrhea), as a large portion of people eating modern western diets are slightly to moderately deficient (along with several other nutrients too). The body is fairly good at handling minor deficiencies of most nutrients (especially the fat soluble B-vitamin group), but mineral deficiencies are more difficult to compensate for as they are not stored in signifigant levels in the body. Your body gets most of the magnesium/potassium/sodium/calcium it uses from daily food intake. The minor magnesium deficiency many American's (and you can probably extrapolate that to those with similar diets, such as Canadians) suffer from is unlikely to be clinical for most, but could produce neuromuscular signs such as cramps, and neurological signs such as minor bouts of unexplained anxiety, irritability, depression, fatigue etc. Not everyone manifests symptoms of sub-clinical deficiencies, but many do.

Like, for instance, IMHO, this stack is what I always presumed would be ideal for Bipolar:

1400 mg Omega-3 oil
4x pill of Magnesium-Citrate
15 mg ( two tabs, I believe) Lithium-Orotate
DLPA ( to help with potential brain-fog, unsure of the dosing)

I would make that 2 grams of Fish oil (specifically Fish oil, as non fish sources tend to have very poor bioavailabilty, as they contain ALA, which must be converted to DHA and EPA. The conversion process is very inefficient). Make sure the fish oil is microfiltered, as it can contain mercury levels which can accumulate over long term usage.

I don't know how much 4x pills of Magnesium Citrate is, so I'd advise 400 mg. If the person has a relatively good diet that should be enough. If diarrhea is encountered, split it into two 200 mg doses.

The lithium is tricky. That is a fairly low dose which is good, but I would still get a thyroid/liver/kidney workup every 6 months for the first year of using it to be safe, as at clinical doses lithium fairly often (1-10%) causes hypothyroidism, and can cause renal/hepatic issues (to a less common degree, but still possible). Ordinarily doctors will do said workups when prescribing lithium due to those side-effects. Also, although lithium orotate looks very interesting, there is a very large lack of human studies, so little is known about it's pharmokinetics in humans. The studies indicating the elemental lithium availability from it were done in rats only. I would probably microdose lithium carbonate instead, as you can be more sure that you're actually microdosing it due to it being much better researched.

The DLPA may help for a bit, but I suspect that just like L-Tyrosine supplementation, the rate limited enzymes involved in metabolizing it will eventually adjust to elevated levels, resulting in lower uptake in the brain. A study in those with ADHD found positive effects on mood that were abolished in all participants by 3 months of usage (note that doesn't mean the effects will last 3 months, it means that by 3 months all participants stopped experiencing positive effects. The specific data isn't available, but I suspect the majority of participants experienced effects for only 1-2 months, that's usually the time required for complete upregulation/downregulation to occur). If the resulting depression is severe, I would probably add a low dose of an SSRI on to the stack, but SSRIs can be voletile in those with bipolar (not as risky as tricylic antidepressants, but can still induce mania occasionally).

BUT, in theory... if Bipolar has to do with Calcium-channels, then perhaps Mega-doses of Magnesium and a bit of Li-O is all that's needed? I do believe one of the reason why us westerners have so much more depression than other cultures is suspected to be because of Magnesium-deficient food, and a highly Calcium-rich dairy-based diet, yes?

So, using the superior bio-availability of Li-O in small doses, one gets a more stable mood, and with mega-doses of Magnesium-Citrate, one takes care of excess calcium! =) Done! Square! Sealed!

The problem is not that those with bipolar have too much calcium in their bodies, it's that calcium channels in neurons are remaining open longer than they should. Mineral channels (potassium channels, sodium channels, magnesium channels, etc) are part of how neurons neurochemically signal each other, different levels of electrolytes alter the voltage potentials of the neurons. Reducing global calcium levels in the body will do more harm than good, as calcium is very important to several biological processes. The goal is to simply inhibit excess calcium channel activity. Lithium seems to have calcium-channel inhibiting properties, but it also has a lot of other MoAs which have the potential to produce greater side-effects. More selective agents are currently being investigated, but it'll be a while before they enter mainstream use.

If this actually works... then in effect curing Bipolar-disease with such a simple noot-stack of supplements, is almost bafflingly simple, in comparison to curing ADD, now innit? 0_o

Unfortunately, it's probably not as simple as that. The neurological deficits involved in bipolar are still not entirely clear; the calcium-channel hypothesis is just one facet of possible dysfunctions involved. Also, it's not as simple as just inhibiting excessive activity, or increasing deficient activity, as doing so will inevitably interrupt other neurological functions, producing side-effects. The attainable end result right now is not a cure, but a band-aid. You can squash the mood fluctuations, but often at the cost of general emotive experience in general. Flat affect (blunted emotions) is a common side-effect of mood stabilisers at therapeutic levels. Cognitive effects are also common, such as memory impairment.

Now, nootropics have the potential to have positive augmentive effects (perhaps reducing memory impairment, etc), so I'm not saying they're useless. But don't expect a total cure.

[Mind_Paralysis]

Cheers for the replies, as always GetOutofBox. =)

Btw, before we dig deeper into the problems of Bipolar, I want to ask you a bit about Modafinil - do you know if it's possible taking it similar to Methylphenidate, aka when needed? Like, I have an exam coming up, so I take it while studying, and while doing the test, but otherwise I go easy on it, with very low doses? Or does it work in the way that it needs to build up into the body for a while, so there isn't a direct effect?


About Lithium Orotate tho', as you probably know, there's a lot more research into Magnesium Orotate, showing that it has a superior bio-availability to just about every other magnesium -chelate or salt.
Neogenic on these very forums definitely swear by it, and his reference to Pubmed is definitely legit, there's tons of research on it.

http://www.longecity...718#entry201718

There's also a lot of research showing that orotate itself, has a lot of nice bio-protective properties, it's just plum good for ya'. Taking these things into context, and combined with the multiple personal experiences online, I'd say there's a lot pointing towards orotate really being 8x or so better at providing minerals for your body.

Hence, the reason why end-users are reporting efficiency of LI-O at such low levels of supplementation, 15mg is a far cry from the 350mg or so, that I believe is the starting therapeutic doses of Lithium Carbonate. The toxicity and side-effects does in general come from the incredibly high dosing LI-Carbonate, hence the reason why it starts wrecking havoc in your body, before it actually starts improving your mood. ( the bio-availability for LI-C is pretty laughable, imho. Citrate is a bit better, but far from as potent as orotate)

Just taking into consideration the positive research around Mag-O, I'm actually a bit STUNNED that LI-O has never gotten the fair chance of research that other chelators have. Why the H*LL are the companies and researchers not doing more with this?? This could be really good stuff!

Yeah, sorry about the rant there, but stuff like this keeps coming up whenever I research any type of medical science, seems like scientists can often be a bit TOO sceptical, instead of actually trying out new and unexpected hypotheses, there's a tendency to only exhaust tried and true theories, before something new is actually considered.

[GetOutOfBox]

Cheers for the replies, as always GetOutofBox. =)

No prob, if I can help someone directly, that's great, and it's even better that other people might come upon this thread even if I ever stop maintaining it, and find it a good resource.

Btw, before we dig deeper into the problems of Bipolar, I want to ask you a bit about Modafinil - do you know if it's possible taking it similar to Methylphenidate, aka when needed? Like, I have an exam coming up, so I take it while studying, and while doing the test, but otherwise I go easy on it, with very low doses? Or does it work in the way that it needs to build up into the body for a while, so there isn't a direct effect?

As far as I'm aware, it is immidiately active. User experiences seem to confirm this, and in theory it makes sense. No one is entirely sure how exactly modafinil brings about it's effects, as its a drug with a surprising amount of different pharmocological properties. It seems to be a mild DAT inhibitor, perhaps indirectly. It also seems to be pro-histaminergic, this may be the principal action causing it's wakefulness related effects (note that antihistamines such as benedryl cause sleepiness as they are histamine antagonists in the central nervous system, aside from their effect on immunologic histamine receptors). It seems to differ from caffeine signifigantly in this sense. I suspect caffeine very indirectly affects histamine receptors through it's adenosine antagonism, but it seems that caffeine works more through increasing dopaminergic and glutaminergic activity (through it's adenosine antagonism). Histamine receptors seem to be very involved in the actual behavior of falling asleep and subjectively feeling sleepy, whereas adenosine seems to have a more biological role in that it reduces overall brain activity (possibly to allow CNS receptors to re-sensitize, and to allow various repairs to be made that would not be conducive under the ordinary metabolic stress of a fully active brain). Increasing histamine activity or reducing adenosine activity both seem to result in sleep being inhibited, but some benefit may be had from combining the two (though dosing would have to be careful to avoid being overstimulated by the stacking dopaminergic effects).

I am however wary of caffeine's adenosine antagonist effect. There's a good reason adenosine makes one sleepy, it's essentially signaling your brain requires a period of low-activity (sleep, or more specifically the deeper non-rem sleep), and specifically supresses brain activity. This of course sucks when you want to feel awake, but at the same time constantly overriding this process could result in serious long term issues. It's even thought that sleep deprivation is a signifigant factor in possibly causing and definitely progressing degenerative brain diseases such as Alzheimer's and Parkinsons.

So my point is, sleep is very important. Not a new message, I know xD. But avoid getting into the habit of using wakefulness enhancers as a replacement for greater sleep, there is likely consequences down the road (note that the drugs themselves are not implicated in the diseases I mentioned, rather, regular lack of sufficient sleep is).

Also on, another interesting anecdote; drugs that take a while to manifest effects such as SSRIs (and to a lesser degree DAT inhibitors like Ritalin) do not require the time because they need to accumulate in the body, but because their desired effects are not the result of their immidiate pharmocological actions, but rather the brain's response to their pharmocological actions. The mechanisms are multiple and complicated, but it's thought that they induce neurological changes (including downregulation of the serotonin receptor 5-HT2A which is implicated in depressive and suicidal behavior when overactive, as well as normalizing serotonin signaling by acting as a sort of chemical "signal compressor", and possibly increasing the release of BDNF and NGF, similar to Noopept, but more indirectly) over a period of time. Generally for physical changes to take place in the brain, a few weeks to a month is required. Food for thought!

About Lithium Orotate tho', as you probably know, there's a lot more research into Magnesium Orotate, showing that it has a superior bio-availability to just about every other magnesium -chelate or salt.
Neogenic on these very forums definitely swear by it, and his reference to Pubmed is definitely legit, there's tons of research on it.

http://www.longecity...718#entry201718

There's also a lot of research showing that orotate itself, has a lot of nice bio-protective properties, it's just plum good for ya'. Taking these things into context, and combined with the multiple personal experiences online, I'd say there's a lot pointing towards orotate really being 8x or so better at providing minerals for your body.

Hence, the reason why end-users are reporting efficiency of LI-O at such low levels of supplementation, 15mg is a far cry from the 350mg or so, that I believe is the starting therapeutic doses of Lithium Carbonate. The toxicity and side-effects does in general come from the incredibly high dosing LI-Carbonate, hence the reason why it starts wrecking havoc in your body, before it actually starts improving your mood. ( the bio-availability for LI-C is pretty laughable, imho. Citrate is a bit better, but far from as potent as orotate)

Just taking into consideration the positive research around Mag-O, I'm actually a bit STUNNED that LI-O has never gotten the fair chance of research that other chelators have. Why the H*LL are the companies and researchers not doing more with this?? This could be really good stuff!

My concern isn't that Lithium Orotate might be harmful vs Lithium Carbonate, it's that it's bioavailability in humans really isn't known. Comparing it to Magnesium Orotate isn't really an effective way of gauging it's availability, as they are completely different chemicals. Just because they both share orotic acid doesn't mean they'll both behave the same in the body. Now, you can extrapolate, but again, you're going out on a limb. It's just a guess. Current medical practicioners prescribe Lithium Carbonate due to the thorough research providing a good guide for dosing. Now, at that low dose it's unlikely it will be harmful, so I'm not super concerned. But just keep in mind that you have no way of knowing for sure how much you're getting, or whether the human body metabolizes it at a variable rate based on secondary factors such as food contents (hence a possibility of highs and lows in absorbed lithium). But again, it should be ok. There is a lot of positive user experiences available, I would just keep an eye open for weird effects.

Yeah, sorry about the rant there, but stuff like this keeps coming up whenever I research any type of medical science, seems like scientists can often be a bit TOO sceptical, instead of actually trying out new and unexpected hypotheses, there's a tendency to only exhaust tried and true theories, before something new is actually considered.

It's the responsibility of medical practitioners to ere on the side of caution. They are bound by the philosophical and moral principle first discussed in the hippocratic oath; a responsibility to assure to the best possible that no harm is inflicted on the patient during the course of medical treatment. That may not be the most efficient principle, but in the end it's the most effective. Trying radical treatments may help the odd patient more than the usual treatment, but the tried and true ones help the most patients while producing the least negative effects. It's sort of a "for the greater good" kind of idea.

Now, that doesn't mean it's immoral for one to voluntarily decide to try radical treatments on oneself, the system is more in place to prevent chaos of blame every time a patient dies under the care of a medical practitioner (if the doctor can prove he tried the way least likely to kill the patient, he can prove his innocence of malpractice, whereas if he tried a radical unstudied treatment, the waters are much murkier whether who's to blame if the patient dies).

As for research, it takes a while, because sometimes drugs can seem very exciting and perfect, and then it turns out 10, 20, 30 years down the line you see they caused severe issues in the current or next generation. Thalidomide is a good example of this tragic possibility. So the scientific community very slowly progresses from basic animal testing to human. Drugs can be very volatile, producing different effects in different animals, despite said animals sharing very similar nervous systems. They can even behave different in chimpanzees, who are our closest living relatives.

Edited by GetOutOfBox, 30 December 2013 - 03:02 AM.

[Nootmeup]

I've learned more from this thread then I would reading literally 1000 different forums. Most of the statements GetOutOfTheBox makes are completely valid and with good reason and support. That's why I love this thread I can relate to you so much. More so on the ADD side and not so much the anxiety side.
Im happy you quit coffee as did I a few days ago. Someone the smartest people I ever met did not drink coffee and also I have been doing a lot of reading on it that says it damages your memory.
It is my understanding that coffee in fact tricks the mind into thinking it is more focused or smarter, but I think it stimulates the fight or flight response too much. I feel a lot more clear headed now at work without the coffee. Now I see others jacked up on it trying to be or sound more intelligent but they just come off as jittery and nervous not being able to focus. I believe it helps focus a bit for people with ADD because most stimulants will. But there are far better substitutes
Ie oxiracetam, DMAE, d3, mag tyrosine and l theanine.
I'm thinking of trying noopept GOTB but idk it just seems there's not enought succes stories that come with it and more..// I got brain fog lolol I see you take 20 mg sublingual should I give it a shot? I'm scared of the side effects/ ohhh and let me know what you think about the coffee subject

[Nootmeup]

I've learned more from this thread then I would reading literally 1000 different forums. Most of the statements GetOutOfTheBox makes are completely valid and with good reason and support. That's why I love this thread I can relate to you so much. More so on the ADD side and not so much the anxiety side.
Im happy you quit coffee as did I a few days ago. Someone the smartest people I ever met did not drink coffee and also I have been doing a lot of reading on it that says it damages your memory.
It is my understanding that coffee in fact tricks the mind into thinking it is more focused or smarter, but I think it stimulates the fight or flight response too much. I feel a lot more clear headed now at work without the coffee. Now I see others jacked up on it trying to be or sound more intelligent but they just come off as jittery and nervous not being able to focus. I believe it helps focus a bit for people with ADD because most stimulants will. But there are far better substitutes
Ie oxiracetam, DMAE, d3, mag tyrosine and l theanine.
I'm thinking of trying noopept GOTB but idk it just seems there's not enought succes stories that come with it and more..// I got brain fog lolol I see you take 20 mg sublingual should I give it a shot? I'm scared of the side effects/ ohhh and let me know what you think about the coffee subject

Sorry about the double posting I like the whole candy reward system that's cool too. You pretty much so think outside of the box.
Hey GOTB have you ever tried to cut carbohydrates from your diet for ADD purposes?
I notice I get a huge clarity in mind when I do. Just a suggestion it's hard to do but I definilty notice a difference

[sigma88]

GetOutOfBox, amazing thread. One of the best and most informative threads I have
read on here. Been following this for a while,

What's the progress with Intuniv? Could you please update on your status,
your input is very appreciated by all here.

Thanks

[GetOutOfBox]

So far the positives have remained the same, I'm noticing very much increased emotional regulation, and complete reduction in obsessive thought patterns (for me, this manifested as constantly ruminating over a past relationship), and reduced sensation of "burnout" from stress (mild dissociation, lethargy, etc). It seems to have positively affected my working memory, but not in a miraculous way, more just a mild nudge. It has had no noticable effect on motivation or hedonic response (deriving pleasure from activities), which is unsurprising due to the lack of dopaminergic action. I'll do some cognitive tests tommorow when I'm feeling more refreshed to see if the numbers are any better this time around.

Overall I'd say it's worth it just for the positive effect on my emotional health. The only barriers I've encountered is that 2 and 3 mg doses are not available from any suppliers in Canada, the pharmacies I talked to were only able to order 1 or 4 mg. This is a major financial issue, as it means I have to order 60 1 mg pills for one month dosing at 2mg daily, vs ordering 30 2 mg pills. The 2 mg pills are only about $30 more for a months supply than the 1 mg pills, but since I'm ordering double the amount of 1 mg pills I end up paying much much more (about $100) more than I would have to if I could get 2 mg pills. It stems from the fact that the medications cost starts high, but doesn't increase much as you jump up the dosage amounts (because they know they wouldn't be able to keep patients paying if they scaled the costs). It's like how movie theaters charge you like $5 to buy a small pop, but only $6.50 for the largest size. They're already making such a profit from even the small, they don't need to scale the cost up to something like $10-$15 for the large.

[FosteredWill]

This has been a good thread to follow. Thanks! Read it through over a couple days between my classes.

[stablemind]

This is a very good thread. I wish OP started this 3 years ago.

[GetOutOfBox]

An update on my current stack:

I've added several items to my current daily stack (assume oral dosing unless otherwise stated):

Ashwagandha Extract (2.5%) - 2000 mg once prior to sleep
Bacopa Extract (20%) - 1000 mg once in the morning
Rhodiola Rosea (3%, 3%) - 200 mg once in the morning (sometimes a booster in the evening if I had poor sleep)
Uridine-5-Monophosphate - 300 mg sublingually in the morning and again before sleep

The ashwagandha I take due to it's potentiation of GABA receptors, which would theoretically enhance sleep quality without the risk of addiction of GABA agonists/releasers (also excessive GABA activity can disrupt sleep architecture). I also take it for it's effect on serotonin; it repartitions the subsets of the 5-HT receptors (upregulating some, downregulating others). This balancing effect is a desirous quality for me, as I infrequently use psychadelics and would like to prevent dysfunction in the serotonergic circuit. It also has a plethora of other benefits.

The Bacopa I take for it's anxiolytic effect, as well as the positive effects on memory that build over time (it's one of the few nootropics in which clinical studies find a statistically significant effect on performance in healthy subjects, not just elderly/brain damaged subjects). It's also got great neuroprotective effects, which although aren't as relative to a young person (who avoids potently pro-oxidative substances such as MDMA/amphetamines) such as myself, are nice.

The Rhodiola Rosea I take for it's potent anti-stress properties. It seems to not only alleviate chronic stress, it seems to increase one's resistance to stressors via the novel mechanism of Neuropeptide Y. It's also got a bunch of nice neurological effects which are bonuses.

The Uridine I'm taking for it's modulatory effects on dopamine. I stopped using it before due to there only being one source of UMP (superiornutraceuticals) which was expensive. Other vendors have since started stocking it, at more affordable prices. I think I'll cycle it on and off (for reasons of cost). Uridine is great for encouraging general brain health, as it helps to stabilize cell membranes. It would be especially useful for older people where cell-membrane fluidity is a common problem due to the oxidative stress of the decades.


Also, I'm pursueing a novel approach to ADHD; hormonal. I have found a couple of studies and a case report linking DHEA and Pregnelone levels inversely to greater ADHD-like issues (low levels of the hormones produce hyperactivity in particular, as well as anxiety and inattentiveness). One VERY interesting anecdote I discovered is that methylphenidate produced an increase in serum DHEA levels in patients over time, suggesting that correcting deficient DHEA levels could be part of it's mechanism of action. This interests me greatly, as one thing I've always failed to understand is why many studies seem to suggest chronic administration of ritalin produces escalating improvements in symptoms, whereas one would expect it's efficacy to drop due to upregulation of Dopamine Transporters (which ALWAYS happens). Many people seem to find that Ritalin continues to work even after supplementing for years, which seems to suggest that perhaps it's dopaminergic action is not nessesarily it's primary MoA (since in theory the brain should adjust to the reuptake inhibition within 1-3 months). This in turn suggests that perhaps in some people, DHEA is the primary cause of the disorder, whereas in those who eventually find Ritalin becomes ineffective, Dopamine is the primary cause. It's hard to tell whether the low DHEA levels observed are signs of dysfunction, or cause the dysfunction. The case report seems to suggest that correcting DHEA levels is therapeutic (though placebo is a distinct possibility). I've always strongly believed that like depression, ADHD is likely an umbrella condition for several different pathologies, perhaps more so (there are so many different systems that dysfunction of which can produce hyperactivity, inattentiveness, impulsivity, etc as a symptom. There's already about 3 different dysfunctional dopamine genes identified, let alone dysfunctional PKC genes, dysfunctional glutamate receptors, etc). This is all speculation of course, but it's speculation based on my observation of clinical data.

So I've ordered DHEA (70 mg dosing), 7-Keto DHEA (100 mg dosing), Pregnelone (100 mg dosing). I am also going to order a DHEA blood test kit from ZRTLabs (who seem to be credible vendors, especially since they only sell tests and not supplements. Vendors who sell supplements have motivation to report back false issues, in order to get you to buy supplements). I'll take this test before supplementing to get an idea of whether I have low DHEA levels like the studies suggest. I'll then proceed to supplement for a month, then retake the test to assure I'm not getting excessive hormones. The latter is very important, as increasing serum DHEA beyond the optimal range will produce signs of hypergonadism (elevated testosterone/estrogen), so it could cause problems with metabolism, feminization/masculinization, etc. You have to be careful when messing with hormones.

Here are the relevant studies:

http://www.lef.org/m...b2006_ch_01.htm
http://www.ncbi.nlm....pubmed/23021477
http://www.ncbi.nlm....pubmed/18937300
http://www.ncbi.nlm....pubmed/20822373
http://www.ncbi.nlm....pubmed/14586159

[GetOutOfBox]

Interesting anecdote possibly supporting my having low innate pregnenolone levels (and perhaps other people with AD(H)D as well). Pregnenolone prevents THC from activating the CB1 receptor, and thus lessens the "high" produced by cannabis. I occasionally use cannabis (not daily, and when I do smoke, I usually smoke once, later in the day before bed. Do note that I've had the issues described in this thread long before I first smoked cannabis, additionally FYI I did not smoke when I was a child/teenager), and have noticed that in comparison to others, I require a ridiculously small amount of cannabis to get high. I only require around 30 mg to feel high (roughly a pinch of weed), whereas others smoke between 100-500 milligrams in a single sitting. Many joints contain at least a gram of weed. This seems to suggest that I have lower levels of pregnenolone than most, and hence require less THC to fully activate my CB1 receptors, since there's less pregnenolone blockading them.

http://www.ncbi.nlm....pubmed/24385629

[Mind_Paralysis]

How's the blood-test coming along? Have you had time to order it?

Also, have the plant-extracts helped any? Like, do you feel more balanced on bakopa and Rosea?

Edited by Stinkorninjor, 24 January 2014 - 08:37 AM.

[GetOutOfBox]

I've ordered one, it might take a week to arrive.

Yeah, I've found the bacopa has really augmented the intuniv's anxiolytic action, just a general stabilized feeling. The rhodiola also seems to make me feel more clear when I fatigued, but unlike caffeine doesn't force wakefulness.

[GetOutOfBox]

Another unrelated update:

Tried 20 mg Ritalin Instant-Release alongside my usual stack (and Intuniv 2 mg) today. I have to say it's an amazing combo! I feel like the Ritalin covers the motivation side of things, work feels satisfying and I don't feel the need to do more instant-pleasure oriented things. The Intuniv seems to help more with the actual performance side of things, I concentrate better and am less distractible. Unlike some people, I don't find Ritalin helpful for socializing, rather I find it makes me slightly overstimulated at effective doses, making me slightly nervous in social situations. Essentially, at the dose I find effective for cognition, I find it has slightly uncomfortable peripheral effects. It doesn't actually make me feel more anxious emotion-wise, but I feel the "fight or flight" response (body tension: chest tightness, heart racing, skin flushing, etc) more acutely. I also seem to get minor racing-thoughts at the effective dose, but not to an uncomfortable level.

So I think I'm going to restart the Ritalin, but with one crucial difference: I won't be taking it regularly. Doctors frequently say that Ritalin doesn't build tolerance, or claim that it's perfectly fine to keep increasing the dose until it gets to ridiculous levels (a patient should never be allowed to escalate from 20 mg dosages to 80 mg). This is usually because the majority of the patient studies conducted follow a time-frame of 4-6 weeks, which is generally too short to fully observe the effect of tolerance. Since Ritalin does cause a net increase in dopamine concentrations (through the gentler mechanism of preventing reabsorption, vs Adderall forcing transporters to reverse and spew out greater concentrations at once), transporters and receptors will adjust to compensate for it's actions.

So to prevent this, I plan to take Ritalin no more than 2 days in a row, with at least one day seperating two day blocks. Since I don't find I require it's effects for everyday life, I'll reserve it's use for periods in which I intend to do a lot of academic work, which I usually find difficult.

It's hard to tell whether the ritalin's effectiveness is being augmented by my stack, so here's a list of possibly relevant items which could effect it's outcome:

-Uridine (essentially amplifies dopamine signals; doesn't increase resting levels of dopamine, but increases the amount released when a receptor is activated)
-Bacopa (anti-dopaminergic effects, in some parts of the brain. Seems to specifically decrease dopaminergic activity in the motor-oriented areas, while it seems to have no effect in the reward circuitry. So it possibly decreases the fidgity side-effects of Ritalin)
-Rhodiola Rosea (possibly very mildly inhibits monoamine oxidase and COMT enzymes, but this is very tenuous and probably not clinically relevant)
-Intuniv (Ritalin also effects norepinephrine reuptake to a more limited degree, norepinephrine is the natural ligand for the alpha-2-adrenal receptor which Intuniv targets. So Ritalin might increase some of the effects relevant to Intuniv)

EDIT:

Also, I noticed my sense of smell seems to be enhanced while on the Ritalin. It's a reasonable side-effect, Parkinson's Disease patients often undergo a progressive loss of sense of smell (and sometimes taste as well). Since Parkinson's Disease seems to only be characterized by dopaminergic neuron loss, it can be assumed that dopamine neurons in the olfactory bulb are crucial to olfaction. Thus ritalin may amplify their activity thus causing an increased perception of smell (it should be noted that the actual accuracy of smell is likely not affected, rather just the subjective experience of it. It's like amplifying music; you can increase the strength of the signal, but you can't add detail that's not there)

Edited by GetOutOfBox, 27 January 2014 - 10:59 PM.

[Mind_Paralysis]

I would say your moderate use of stimulants when needed, in combination with Intuniv is definitely the way to go. I really feel Intuniv and low-dose stimulants is what would help me with my own problems.

I have a few questions which I don't think anybody has ever asked tho...

Bacopa - You say it inhibits dopaminergic activity in the areas related to motor-functions - would this mean that Bacopa-extract might actually be somewhat detrimental to someone who also suffers from DCD, like me? I'm hesitant to add it to my stack, knowing I have coordination-problems.

Sulbutiamine - You're not taking this, but I gotta' ask about it, since it haven't been covered in this thread yet. It seems to inhibit Dopamine, HEAVILY, some people even report depressive qualities on it, while others actually report anti-depressive qualities to it. The reason I'm interested in it tho', is because it seems to increase cholinergic activity, and it promotes wakefulness and energy. In theory, it could help me with coordination-problems, but I don't want to increase coordination with the side-effect of worsening all of my other problems.

[MangekyōPeter]

So what is the general consensus on when Intuniv might be available for Europeans?

And Stinkornijor,

for me personally, Sulbutiamine causes a headache and a feeling of pressure, can't do anything active after having takin it as my head feels like a rock, a definite "dirty" feeling which is why I don't take Sulbutiamine anymore.

[GetOutOfBox]

I would say your moderate use of stimulants when needed, in combination with Intuniv is definitely the way to go. I really feel Intuniv and low-dose stimulants is what would help me with my own problems.

I have a few questions which I don't think anybody has ever asked tho...

Bacopa - You say it inhibits dopaminergic activity in the areas related to motor-functions - would this mean that Bacopa-extract might actually be somewhat detrimental to someone who also suffers from DCD, like me? I'm hesitant to add it to my stack, knowing I have coordination-problems.

Sulbutiamine - You're not taking this, but I gotta' ask about it, since it haven't been covered in this thread yet. It seems to inhibit Dopamine, HEAVILY, some people even report depressive qualities on it, while others actually report anti-depressive qualities to it. The reason I'm interested in it tho', is because it seems to increase cholinergic activity, and it promotes wakefulness and energy. In theory, it could help me with coordination-problems, but I don't want to increase coordination with the side-effect of worsening all of my other problems.

Bacopa may not be the best for you in that case. It's hard to tell, since there's not a lot of data specifically examining that effect. The study seems to imply that it affects initiation of movement and not movement itself, reducing excessive motor activity induced by stimulants. It doesn't cause any long term changes in that department so it's worth trying. If you feel your DCD is worsened by it, the effect will only last 7-10 hours at most.

As for Sulbutiamine, I have actually covered it earlier in the thread. I personally advise against it; mostly for economic reasons. There are no studies examining it's use in healthy individuals as a nootropic, and very few even supporting it's use as a treatment for various disorders. The few studies that do support it seem to report a fairly mild effect. When it comes down to it, it's just two Vitamin B6 molecules bound together, and is likely cleaved apart in the brain into plain old Vitamin B6. It likely just acts as a more bioavailable B6 vitamin, and thus more easily corrects a deficiency, or helps to raise levels specifically in the brain. Most of the hype associated with it is just user experiences without placebo control, and interestingly most users who report positive results note that it seems to magically build tolerance after a day or two, which is pretty consistent with the placebo effect induced by the initial excitement wearing off.

It's worth a try for your DCD, but I would definitely try placebo controlling it to see if it's worth the money.

So what is the general consensus on when Intuniv might be available for Europeans?

No idea. There doesn't seem to be any indication from Shire that they plan to market it in Europe soon, but I'm sure it'll happen in the next few years. Keep in mind that the drug must be approved in each European country, so when Shire decides to bring it to Europe some countries might get it earlier than others.

Even though it's not approved in Europe, I believe physicians can still prescribe it to you "off-label" (anything would be considered off-label if it's not approved in your country). You can use that prescription to buy from an online pharmacy. The difficult part will be convincing a doctor to prescribe a drug that's not approved in your country. They are allowed to, but most are uncomfortable with doing so, especially for non-life threatening conditions. Furthermore you will not be able to get your insurance provider to cover a drug not approved in your country, so you'll have to pay out of pocket. Intuniv typically runs at $130 for 30 1 mg tablets. It might cost more from an online pharmacy.

[Mind_Paralysis]

Cheers for keeping the thread alive and answering questions GetOutofBox. =)

I think you mentioned Memantine back on page 2 or 3? Well, I got out and started checking this compound out a bit, and found a very good thread about it, on Addforums.

http://www.addforums...ead.php?t=80317

Two fellows who are both med-students have both evaluated their trials on the compound there, and the way they describe it, and the other people that jumped on the band-wagon, there's definitley evidence of, if not regulation of the D4-receptor, clear improvements of ADD-symptoms.
The effects seem similar to Guanfacine in many ways, except that there appears to be some mild effects on motivation as well! =D
The main draw-back is the dosing, it's incredibly fidgety, one slip-up, and you're back to zero.
It's essentially similar to a Parkinsons medication - which makes sense, because you mentioned how those meds are the only ones you could find with an affinity for D4-receptors.

The main guys trying it both seems to fit a profile similar to you, me, and several others in this thread.

Maybe you could have a look, and tell us what you think? It's damn long tho', so I get it if it's going to take some time, to evaluate what they're saying.


Some references:

Findling R et al. A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type.

Breier A et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse 1998;29:142-7.

Turic D et al. Follow-up of genetic linkage findings on chromosome 16p13: Evidence of association of N-methyl-D-aspartate glutamate receptor 2A gene polymorphism with ADHD. Mol Psychiatry
2004;9:169–73.

Findling R et. al. A pilot evaluation of the safety, tolerability, pharmacokinetics, and effectiveness of
memantine in pediatric patients with attention-deficit/hyperactivity disorder combined type. J Child Adolesc Psychopharmacol. 2007 Feb;17(1):19-33.

Differential Efficacy of Memantine for Obsessive-Compulsive Disorder
vs. Generalized Anxiety Disorder: An Open-Label Trial. Jamie D. Feusner, Lauren Kerwin, Sanjaya Saxena, Alexander Bystritsky

An Open-label, Flexible-Dose Study of Memantine in Major Depressive Disorder James M. Ferguson, MD,* and Richard N. Shingleton, PhD†
DOI: 10.1097/WNF.0B013E3180314AE7

Edited by Stinkorninjor, 29 January 2014 - 02:53 PM.

[GetOutOfBox]

It's no problem. The main reason for memantines partial efficacy for ADHD is Dopamine D2 receptor agonism. Combine that with the fact that NMDA antagonism (the primary action of memantine) reduces the development of tolerance and you have a dopaminergic agent that will maintain peak efficacy for longer than others.

So that's all very nice, but I'm highly adverse towards using memantine for anything other than it's purpose (treating dementia). NMDA antagonism will inhibit cognitive performance to some degree. The nice thing about memantine is that it's voltage dependent in it's NMDA antagonizing properties and thus reduces NMDA signaling much less aggressively. However the reduction is still enough to negatively affect normal processes. Memantine also antagonizes nicotinic-acetylcholine receptors, which are involved in memory. Overall it doesn't seem worth the cognitive detriment it creates. Also, keep in mind that people merely saying that it subjectively doesn't negatively affect their cognition is not evidence that it actually doesn't. Mild cognitive impairment is usually not a perceivable state (you don't always "feel" impaired). Memory performance tests such as those from cambridgebrainsciences.com are required to actually measure memory performance.

[Mind_Paralysis]

Did not consider the cognitive impairment, hmm, interesting. I might just have to register to ADDforums and suggest to the people taking it, and those about to take Memantine, to do a cambridgesciences.com test, before and after! =)

I still feel memantine or Amendatine show promise tho', and if the cognitive impairment turns out to be limited, I definitely feel they might be worth looking into.

The reason I'm so interested in Memantine at the moment, is because I'm currently on a stim, or rather, I WAS on a stim - Concerta.
But I have quit it because quite frankly, it was f***ing me up. Itchiness, heightened heart-rate, mood-swings, mouth-dryness, and perhaps even some limited depressive qualities as well.

The main problem is of course that I was merely on 18mg's, and that's far too low a dose, for probably something like 90% of all ADD-sufferers. I am hesitant to even start titrating the dose ( I've talked to my psychiatrist, but she consults with a Dr, who's very busy), since the side-effects are god-awful.
The side-effects of Memantine, seem quite a lot better, in comparison - considering it stimulates you.

[GetOutOfBox]

So I'm going to not only get my DHEA-S levels tested by ZRT Lab, but I'm going to get a thyroid panel (Free T3, Free T4, TSH and Thyroid Peroxidase Antibodies) and testosterone checked with them as well. They do those tests via blood-spot testing (the patient uses a lancet to remove blood from their body onto provided sterile sample paper, the blood dries fairly rapidly in open air. The samples are then mailed back to the lab. My understanding is that various hormones are more stable when desicated than when in a liquid solution, and thus do not require refrigeration. I'm still going to slip an ice-pack into the return envelope to hopefully keep things cool longer).

If abnormal levels are revealed by the tests, I will use the results as leverage to get my doctor to do blood test for his own confirmation. I have had a yearly blood test done, but it only includes TSH, which is well known to be an unreliable indicator of thyroid function (abnormal TSH is indicative of thyroid issues, but does not always occur with them. Additionally, there is no consensus in the medical community of what levels are normal. Some labs use smaller ranges, some higher).

The blood-spot tests provided by ZRT labs are not in themselves useful as diagnostic tools, at least in my opinion. The provided samples are too small (quite a lot of extrapolation, to take the hormone levels in a couple of drops of blood and measure them against the whole body's levels), and I suspect that although hormones may degrade more slowly when dried, I suspect the degradation can still be signifigant when exposed to fluctuating temperatures for 3-4 days. In my opinion, these tests are useful simply to determine whether more thorough testing should be done.

A note in regards to the testosterone test; it turns out that low testosterone function can produce many of the cognitive problems I've had (fogginess, easily fatigued, memory and concentration issues), and additionally explains some quirks of my body (fat accumulation around my thighs, despite a healthy BMI and my young age, relatively low masculine hair growth). I do not however, have the hallmarks of hypotestosteronism (more commonly referred to as hypogonadism), which are low libido, sexual dysfunction, and genital abnormalities. To be candid, my libido is fairly normal for my age (which is to say, relatively high), I've never had erectile dysfunction, and I have normal penis and scrotum dimensions and pubic hair growth. I think it would be highly unusual for low testosterone levels, particularly during my youth (since these problems have stretched back years, prior to puberty) to not cause any sexual side effects of any kind. However, the test only costs $35 so I think it's worth throwing in just to be sure.

[GetOutOfBox]

IMPORTANT UPDATE:

I just discovered a huge potential link to my own and possibly many cases of ADHD. I'm not sure of the scale of this connection, but it's pretty mind blowing: Asthma, and more specifically, the treatment of it.

Briefly on asthma, it's a fairly common condition of chronic (with acute flare-ups) inflammation of tissue in the bronchial tubes leading to the lungs. It's pathophysiology is fairly similar to that of allergies, involving dysfunctional immune system action. One prominent theory as to why it's becoming more and more common, is the hygiene hypothesis in which excessive cleansliness in modern western life prevents the immune system from being properly calibrated, and thus potentially causes immune related conditions such as Lupus, allergies, and asthma. It is typically treated with beta-2 adrenal receptor agonists (i.e Salbutamol) and/or corticosteroids to suppress the inappropriate immune action. Corticosteroids are the class of treatment relevant to my theory.

Endogenous (naturally occuring in the body) corticosteroids are mostly known for their action upon the immune system, however they are actually important components of the central nervous system as well. Specifically glucocorticoid receptors are quite numerous in a few regions of the brain: the hippocampus (associated strongly with memory, predominantly abstract memory), amygdala (very involved in arousal and specifically regulating rapid mood changes such as the fear response), and frontal lobes (associated with executive function; directing attention, modulating working memory, processing the subjective sensory experiences, introspection). These receptors seem to be fairly important to the proper functioning of those areas, though they seem to have a more general purpose (possibly modulating many different types of neurons, such as dopaminergic, serotonergic, etc). Note the interesting coincidence, that the 2 main areas of the brain in which dysfunction is implicated in ADHD (the hippocampus and frontal lobes, specifically the prefrontal cortex) have a high density of glucocorticoid receptors. The amygdala is also implicated in some of ADHDs symptomalogy. Here's the relevant quote:

Glucocorticoids act on the hippocampus, amygdala, and frontal lobes. Along with adrenaline, these enhance the formation of flashbulb memories of events associated with strong emotions, both positive and negative.^[4] This has been confirmed in studies, whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect was more important in men). The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation. In multiple animal studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction of the neurons in this area of the brain, which has been connected to memory performance.^[5][6][7]
Glucocorticoids have also been shown to have a significant impact on vigilance (attention deficit disorder) and cognition (memory).

Now, the interesting connection here is that exogenous (introduced into the body externally) corticosteroids have been observed to interact with CNS steroid receptors, and not only that, but have been observed to cause symptomatic dysfunction with regular use. "Steroid dementia syndrome" is a documented occurence in which disruptions in attention, memory, and self-regulation occur with prolonged corticosteroid usage. Here are the symptoms of "Steroid Dementia Syndrome":

The symptoms include deficits in

• verbal and non-verbal memory
• working memory
• attention
• sustained concentration
• executive function
• psychomotor speed
• academic or occupational performance.

Sound familiar?

The interesting thing, is that although the medical community is aware of the syndrome (at least in the research side of things), for some reason it is not documented as an actual condition on the prescription side of things (corticosteroids do not have warnings of this condition), and every doctor I've ever talked to always claims that the corticosteroids given for sinus inflammation or asthma have no serious side-effects (some doctors will note that the possibility of a slightly increased chance of getting colds and flues, but they generally think of corticosteroids as harmless). So externally provided corticosteroids could potentially interact with steroid receptors in the brain, and cause dysfunction of those systems.

Not only are there receptors in the brain affected by corticosteroids, but the HPA (Hypothalamic-Pituitary-Adrenal) Axis is affected by corticosteroid medication, potentially downregulating it's natural steroid output in response to elevated exogenous levels. In adults, it seems this downregulation will reverse itself with cessation of the external steroids, however, an interesting phenomenon observed in many young animals (humans included) is "calibration" of the HPA axis. It's still mostly speculation by researchers, but it seems that young animals at one point experience a "calibration" of their HPA axis which is affected by the current levels (it's not an instantaneous thing of course, my best guess is that it's a period lasting days to weeks in which the HPA axis locks in a normative value):

Several mechanisms have been proposed to explain these findings in rat models of early-life stress exposure. There may be a critical period during development during which the level of stress hormones in the bloodstream contribute to the permanent calibration of the HPA Axis. One experiment has shown that, even in the absence of any environmental stressors, early-life exposure to moderate levels of corticosterone was associated with stress resilience in adult rats, whereas exposure to high doses was associated with stress vulnerability. ^[20]

So it's very possible that administration of corticosteroids in young children with asthma can cause changes in the HPA axis that can last through adulthood. These changes in the HPA axis can cause downstream dysregulation in the areas of the brain with high densities of glucocorticoid receptors. Interestingly, these areas of the brain are also the ones observed to be dysfunction in ADHD. The reason why not all children who are treated with corticosteroids develop ADHD later in life is possibly due to varying times in which the period of HPA calibration occurs, so some children might receive the treatment after they've already entered that period, and thus are not permanently affected by the medication.

This theory not only explains the symptoms of ADHD, but also explains why it's suddenly becoming more common. Corticosteroids entered common use for asthma around the 1950s, becoming more and more commonly used for other conditions between then and the 70s. If my theory is correct, the first generation of people affected by this syndrome would begin manifesting ADHD symptoms around the 60s and 70s. This is about the time when ADHD began drawing attention from the medical community, and popping up more.

Finally, for the "Pièce de résistance" of this theory, ADHD occurence has been strongly linked with asthma:

Comorbidity of asthma with ADHD.

Fasmer OB, Riise T, Eagan TM, Lund A, Dilsaver SC, Hundal O, Oedegaard KJ.

Author information


Abstract


OBJECTIVE:

To assess how frequently drugs used to treat asthma and ADHD are prescribed to the same patients.
METHOD:

The authors used data from the Norwegian Prescription Database for 2006, including the total Norwegian population (n = 4,640,219).
RESULTS:

Anti-asthma drugs were prescribed to 350,894 persons (7.56 % of the population), anti-ADHD drugs to 18,481 persons (0.40 %), and both to 1,730 persons. There was a 65% increased overall risk (OR = 1.65) of being prescribed one of the drugs given a prescription of the other. Women had a markedly higher risk than men. When data for each age group (10 years interval) and each gender were analyzed separately, the strongest associations were found for women between 20 and 49 years of age and men between 30 and 49 years of age.
CONCLUSION:

These prescription patterns suggested a marked comorbidity between asthma and ADHD.

Also, Asthma and Comorbidities.


Returning to me, I had severe asthma as a child and was given a cocktail of corticosteroid medications for at least a year during a period between 4-6 years of age.

Now, just to finish things off I would emphasize that I'm not claiming that ALL cases of ADHD are associated with asthma, nor do I think this theory covers all cases of ADHD. As I've mentioned several times before, I believe (based on the evidence) that ADHD is actually quite a few different conditions. Some are associated specifically with dopamine receptor dysfunction, some seem to be related to the HPA axis, some seem to be related to thyroid issues. I suspect that people who respond extremely well to Ritalin and/or Adderall (the ones who seem to return completely to "normal" when treated with them) have the specific dopamine related disorder (possibly a problem with the dopamine transporter, or the D4 receptor gene being dysfunctional), whereas the ones who find only moderate to mild response to Ritalin/Adderall may have a more systemic issue (possibly a problem with the HPA or thyroid). It's very unlikely that a dysfunctional HPA axis (and especially a dysfunctional thyroid system) would cause only cognitive issues, there would likely be systemic problems as well (although potentially mild if the dysfunction is not extreme).

[Metagene]

Finally starting my first day on Intuniv. I'll fire up double trouble in a few weeks to see if I can elevate my score above a measly 6%.

Edited by Metagene, 06 February 2014 - 07:55 PM.

[Mind_Paralysis]

Very interesting, GetoutofBox. I have asthma as well, and have been treated with cortico-steroids.

A friend of mine was not tho', he had the hyper-active version, but have more or less been able to rise above it in adulthood. And he only developed asthma as an adult, as a result of occupational injury.

My treatment with corticosteroids began pretty late as well, probably around when I was 7 or 8, so quite a few years after you. It's definitely worth looking into tho', because you and me have such similar cognitive issues and profiles. ( for instance, I often obsess about a former love as well, and have other similar anxiety-related problems)

EDIT:

It appears as if a Swedish study, actually showed that it may not be the youngest kids, but the kids around 8-9 years of age, that are at risk for attracting ADHD when maturing, from potential side-effects of cortico-steroids.

http://onlinelibrary...2648.x/abstract

This might actually make me a more likely candidate than yourself, GetoutofBox! o.o


EDIT2: On a related note - Second-hand-Smoking have long been implicated as a potential trigger for Asthma in children - but a 2011 study also showed that children of smokers had a higher rate of ADHD and related disorders as well.

http://pediatrics.aa.../2/263.full.pdf

What do you think, Box? Could SHS be behind Asthma, and then the treatment in itself be behind the ADHD, or is it a chicken-egg thing? I'm a bit intrigued by the idea that Nicotine seems to affect the same part of the brain that is implicated with ADHD, so I feel there might be several connections here.

Perhaps a combo of sensitivity during the formative years with HPA axis, as well as the nicotine-affinity in the brain, and then you add in the immune-system response as well? I do believe there's a growing theory, that many neurological and mental diseases have a immunological connection as well.

What I can say for myself is this, my parents definitely subjected me to SHS. My mother stopped smoking during her pregnancy, but she and my step-father began subjecting me to SHS when I was around 5 years old, so it definitely overlaps with my development of asthma, and then the subsequent ADD-problems during my tween and teen-years.

Edited by Stinkorninjor, 07 February 2014 - 04:34 PM.

[GetOutOfBox]

Back to the corticosteroid link I discussed earlier, I should outlay where one goes forward if the link is the cause of ADHD symptoms. There are several ways which might in theory correct the dysfunction. It seems SSRIs indirectly affect corticosteroid secretion. Whether or not they can cause persisting changes in the HPA axis is not known however, and the side-effects may not justify continuous treatment. Still an avenue worth investigating. I suspect Semax might be greatly of use, as it mimics the actions of a corticosteroid, and seems to have beneficial effects on mood and attention. I have used it and did indeed found it made me much clearer, but unfortunately it is unavailable in the west and is incredibly expensive to aquire online. Awakebrain.com sells it, however it costs $49.99 for a 0.1% solution with enough for only 6 days of use at their suggested dosing schedule (though I would not assume their recommendations are correct, as there is no authoritative source providing a definitive dosing recommendation).

Very interesting, GetoutofBox. I have asthma as well, and have been treated with cortico-steroids.

A friend of mine was not tho', he had the hyper-active version, but have more or less been able to rise above it in adulthood. And he only developed asthma as an adult, as a result of occupational injury.

My treatment with corticosteroids began pretty late as well, probably around when I was 7 or 8, so quite a few years after you. It's definitely worth looking into tho', because you and me have such similar cognitive issues and profiles. ( for instance, I often obsess about a former love as well, and have other similar anxiety-related problems)

EDIT:

It appears as if a Swedish study, actually showed that it may not be the youngest kids, but the kids around 8-9 years of age, that are at risk for attracting ADHD when maturing, from potential side-effects of cortico-steroids.

http://onlinelibrary...2648.x/abstract

This might actually make me a more likely candidate than yourself, GetoutofBox! o.o


EDIT2: On a related note - Second-hand-Smoking have long been implicated as a potential trigger for Asthma in children - but a 2011 study also showed that children of smokers had a higher rate of ADHD and related disorders as well.

http://pediatrics.aa.../2/263.full.pdf

What do you think, Box? Could SHS be behind Asthma, and then the treatment in itself be behind the ADHD, or is it a chicken-egg thing? I'm a bit intrigued by the idea that Nicotine seems to affect the same part of the brain that is implicated with ADHD, so I feel there might be several connections here.

Perhaps a combo of sensitivity during the formative years with HPA axis, as well as the nicotine-affinity in the brain, and then you add in the immune-system response as well? I do believe there's a growing theory, that many neurological and mental diseases have a immunological connection as well.

What I can say for myself is this, my parents definitely subjected me to SHS. My mother stopped smoking during her pregnancy, but she and my step-father began subjecting me to SHS when I was around 5 years old, so it definitely overlaps with my development of asthma, and then the subsequent ADD-problems during my tween and teen-years.

I should point out that you cannot develop asthma from an injury. It's the result of a systemic immunological dysfunction which is likely caused by a combination of genetics and environmental facts (hygiene hypothesis, chronic air pollution exposure, etc).

I wouldn't say secondhand smoke is behind the majority of asthma cases. Smoke tends to aggravate asthma (in healthy people, smoke causes an inflammation response, but it's controlled, whereas asthma patients can experience severe bronchial inflammation in response to it), but it seems less likely that it could actually cause it. The prevalent theory is that asthma is the result of our overly clean western life during childhood (the hygiene hypothesis), which prevents the immune system from properly calibrating itself and can result in autoimmune disorders and/or dysfunctional immune response (sensitivity, depressed function, elevated function, etc). This theory is sound in reasoning, and seems to have been evidenced in practice, as autoimmune disorders, allergies, and many other dysfunctional immune problems (such as asthma) are far less common in developing countries with lower qualities of living, while it has been on the rise in countries whose quality of living has been increasing over the last hundred years.

I do suspect that if the mother smokes or is regularly exposed to second-hand smoke during pregnancy, the chance of ADHD-like issues in the child are more likely. The fetal brain is likely highly reactive to external stimulation of it's various circuitry, and thus affecting neurotransmitter levels with something like nicotine could cause permanent changes. However that's just speculation. It's also likely second hand smoke can adversely affect a child's developing brain. It depends on how much psychoactive particles are present in secondhand smoke, my guess is that they're definitely much less than that inhaled by the smoker (I have friends who smoke, and even when I've been with one smoking in the car, I noticed no subjective effects characteristic of tobacco (no changes in attention or mood). The concern is more how second hand smoke affects the lungs, as it can cause a buildup of carbon particulates on the surface of the lungs (and deeper carbon infiltrations over time), however one shouldn't rule out neurological effects related to circulating psychoactive particles too quickly. Unfortunately there are virtually no direct studies of the impact of tobacco smoke on the developing brain, as it is unethical and unlawful to administer a known harmful compound to subjects for the purposes of research, children or not. The only way to investigate such things is to investigate subjects who take the substance at their own accord, which opens up the observations to contamination from confounding factors brought about by the lack of control of the subjects.