19, new here, just started adderall, lots of questions, long..

[mistaben]

Hi, Name is Tony, and this is my first post on here. Sorry if this is not in the correct thread i didn't see one for questions on meds for just yourself. Sorry this is so long, so thankyou those who respond. I have a lot of question and I am feeling very anxious right now, and have included what i thought would be relevant...

First, let me say that i am not that severely adhd (but dad/brother/cousin are and probably a few other family members) but i do have problems concentrating more then about a half hour at any one sitting (ironically, I am a double major and premed). Adderall helps significantly - not a magic bullet or anything - but wears off after about 3-4 hours, about 2 weeks ago I started taking the adderall 10mg bi daily (i will soon be moving up to 20mg 2xdaily adderall XR). I also drink a lot of coffee 6-8 cups a day, but I am down to about 2 - 3 a day because of adderall. Well today I missed my night dose at about 3pmish and had no caffeine and tonight in my late night Calc 2 class I couldn't sit straight - as in a lot more hyper and less focused and bored then usual - by a significant margin. This is a class I really LIKE too. It doesn't feel like caffeine withdrawl because i have no headache and not tired or groggy AT ALL, I feel wired like what people say speed is suppose to be like.

Is that because my neurobiology has already adapted to having adderall or is that caffeine withdrawl or some combo of both?

I hear/read that after about 4-6 weeks this slightly valiumnated/relaxed feeling wears off, but the ability to focus stays, is that other peoples findings? my "high" perse has tapered off pretty much, but i can still focus for longer then normal

I hear that adderall can just start to loose effectiveness after a 1 - 2yrs. Is this true or just heresay?

Anybodys comments on how to keep my focus or what they think about me moving to 20mg of XR?

Thanks guys - Tony.

- Just another stupid teenager.

[robmhill]

the only thing i can add to this, as i have not had the experience of the adderall wearing off and making things worse, is that the general rule is when it makes you dopy sleepy and narcoleptic you are taking too much and reduce the meds.
then you should be at or near the optimum level.

oh and if you have add you are probably not stupid

[jayblaze2]

when you come off adderall it can bring back all the things you never noticed before taking the meds. I feel this all the time. Its just like walking down a dirt path in a park. If you walk down the path everyday nothing will be new to you the trees will look the same, bushes will still have the same look........ (this is your before adderall). Now you take a yr off from walking down the path(you took your meds). You decide to walk down the trail agian and everything seems different but some what familiar the trees are different colors, bushes are taller.......(coming off the meds). Another example is like having a dog. You see the dog everyday as it grows. If you take a picture of the dog and look at it months later you will say, "wow hes gotten so much bigger" and you didnt notice the change.

[MindResearcher]

Hi, there, i have some comments to add. You sounded like me until you said 6-8 cups of coffee. When your taking amphetamines, caffiene is going to interact somewhat with adderall, because of the release of stomach acids. It will lower the potenxy and elimnation. If you must drink it like 2-3 hrs after your dose. But i was drinking 3-4 cups a day, now i dont becaue im trying every way to boost up the tolerance. But after 2 weeks of researching "loosing adderall effects" its seems most everyone looses that initial feeling for 2-4 days. Then if you stop for about 4 days or more, ( took off 7) and i came back and took it and felt like i could stay up for days. So anymore i learned never to just stop a high dose. I now count my meds, and if say i only had 10 left and my appointment was later than that, i would def cut down the dose, from 60-90 down to 60 for about 4-5 days, then down to 20 2x daily or what ever it takes to get me to my appointment. Last month, i ran out 7 days before, because i took more than 2 daily due to the wearing off after 4 hrs, and im up for 16 hrs at least.


I just wonder if my doc would add say an extra 20mg dose, or even a dose of welbutrin. Im sure welbutrin would give me at least a 20 percent increase? I dont think he is going to give me another 30, because he may think im abusing them or something, but he really is a good doc and works with me. My insurance will not pay for adderall xr. If they did, and it lasts 8 hrs, id ask for at least 30mg plus another 20, or at least 30xr, and 10 and 10. to keep the blood levels up. I have to check another med called dexadrine spanuals, which last for 11 hrs. Boy if this is true, and dexadrine causes like almost no anxiety and more mental stimulation.

THen there is always Meth, but thats getting up there and it olny comes in 5mg, but it last probably 12 hrs. easy.

geno

[glammeier5]

I have been on adderall xr now for about 4 months. I started out on 10mg for the first week, than moved up to 20 mg. The next month, I was still on 20 mg, but I noticed it was wearing off sooner, so I started taking two of those when I needed to. The next month I was bumped up to 30mg, but did noticed after a couple of weeks that it was wearing off as well. I would than skip a day and double up on the next day so I could get through it. There was some nights that I was having problems getting to sleep but for the most part it was not bad. The last prescription I was put on was for 30mg, plus an additional 30 scrip of 10 mg to take as needed to get me through the day. This has been going good for me so far. I am not sure if I am getting addicted to the meds, or getting addicted to enjoying the feeling of getting things done, and feeling like you accomplished something in your day.

[Trooper Keith]

Adderall can lose efficacy due to tolerance, but it normally takes much longer than 1-2 years if it is being taken as instructed.

I would say this is likely a caffeine addiction thing. Building a tolerance to Adderall takes a while if you are taking it as prescribed. The caffeine reduction, however, could definitely have an effect. You won't feel caffeine withdrawal symptoms because you have another stimulant there in its place, but you do have less stimulant than normal if you have cut 3-4 cups of coffee, because that is 450-600mg Caffeine you're down...

My suggestion is to tough it out. The human body is extraordinarily adaptive, and will get used to the lower stimulant consumption and adapt.

[janesays]

I have been on Adderall for five years. It hasn't lost it's effectiveness. The only change is that I have had more regular sleep when I take it which may be due to my schedule also my appetite has returned but mostly just because I have regulated that too. If I don't take Adderall on the other hand my whole world gets turned upside down. I feel pretty crappy. The ADD symptoms return only until I crash. Like I am way weird when I stop it for a day and am awake. I kind of feel hung over and kind of goofy like my motor skills are retarded. Then when I fall asleep theres no waking me. Only to eat, then I fall asleep again. When I do wake I am very achy and I can't move around much. I don't like to get out of bed and usually don't wake unless it's necessary. I crash pretty hard.

[Stabile]

Originally Posted by KMiller

Adderall can lose efficacy due to tolerance, but it normally takes much longer than 1-2 years if it is being taken as instructed…

Tolerance to Adderall has never been demonstrated. The definition is specific; what you're describing happens, but the mechanism is different.

Jayblaze2's post hits close to the mark. We recently posted a pretty good description here.

As far as the effect of caffeine is concerned, this is one of the most common psychoactive interactions with our drugs. But it remains largely unrecognized by the medical community.

It doesn't have anything to do with addiction, which also has a strict definition. It also doesn't have anything to do with the classical picture of amphetamines and caffeine as stimulants. The interaction between coffee and stimulant meds is not because you get too 'buzzed'.

Nevertheless, there can be a substantial interaction, and it isn't really a good one. Bryan can't drink coffee at all with Ritalin; Kay and I can get by with a little, but we had to cut way back from the number of cups we were used to drinking.

With Adderall there's a lesser effect, but it's still obvious to us. And our response to the effect has transmuted a bit over time. Now, if we drink two cups of fresh roasted Yirg or Horse on a Sunday morning, we just go off into lala land for an hour or two.

But Ritalin and caffeine is still a bad combo for us. And you can't forget to watch out for the other sources, like colas and chocolate.

--Tom and Kay

[lynx]

Tolerance to amphetamines is a very real phenomenon. It is a result of downregulation of dopamine transporters.

The problem is that tolerance to the reward pathways(mood enhancement) happens long before tolerance to the enhanced vigilance, and people assume that because they don't feel anything that it isn't working; this is a dangerous path to take.

[Stabile]

Originally Posted by lynx

Tolerance to amphetamines is a very real phenomenon. It is a result of downregulation of dopamine transporters.

The problem is that tolerance to the reward pathways(mood enhancement) happens long before tolerance to the enhanced vigilance, and people assume that because they don't feel anything that it isn't working; this is a dangerous path to take.

The formal definition of tolerance does require something similar to what you mention. There are notable behavioral effects, too, which may include increasing the dose, but most commonly, a pattern of maintenance despite the lack of effect. But it must have a physical basis.

Tolerance is closely related to addiction, which also has a formal definition usually involving tolerance, but also requiring a physical mechanism for causing withdrawal symptoms.

Tolerance and addiction have a legitimate classical behavioral interpretation involving first the positive stimulus of the drug effect followed by the trap of behavior designed to avoid the negative stimulus represented by withdrawal.

Such interpretations treat the subject as a kind of 'black box', looking at the entire situation from an impartial external view. The behavioral characterizations fail immediately if you try to apply them to mechanisms inside the box.

You don't mention your source. We’ve looked repeatedly for any studies that show evidence of either tolerance or addiction to common AD/HD drugs, particularly Ritalin and the amphetamine formulations.

The last time we looked, about a year and a half ago, we weren’t able to find any examples in the literature that documented an actual case of either tolerance or addiction.

So forgive us if we remain skeptical about what you posted. It's a nice neat idea, one we've heard elsewhere, but there are several problems with it.

First and foremost is the implication that such changes in brain chemistry are directly associated with the effects you mention.

There is no established formal relationship between concepts like mood enhancement and changes in dopamine transport. If you believe differently, re-read whatever you've seen with a critical eye.

We've never seen any evidence for a relationship reported, but there has been much ballyhooing over the appearance of a correlation.

I say appearance because it's a difficult task to even gather evidence legitimately suggesting a correlation. One problem is that measuring things like mood enhancement and enhanced vigilance is not possible in the same way that we can (for example) measure dopamine levels in a rat's or a monkey's brain.

Thinking of a part of the biochemical mechanism as "the reward pathway" is itself a dangerous path to take. It has a clear anthropomorphic character, and as such is bound to be taken incorrectly by anyone not prepared to be scientifically rigorous.

We doubt the appropriateness of the term, regardless of how narrowly it's defined. Any meaning inherent in behavior arises in a much higher logical level of brain function; for that reason alone it isn't appropriate to characterize neural activity as behavioral.

It's also unnecessary. The well established understanding of how neural networks perform pattern matching and logical modeling is sufficient.

An even more pervasive problem: there's no guarantee that the actual biochemical mechanisms that you mention are taking place in our heads when we take these drugs. It's extremely difficult to routinely monitor such mechanisms, even indirectly. Most of the best data used to support such models comes from extremely limited laboratory experiments, seldom with human subjects.

There's much more to consider, especially when you take a look at the big picture.

For example, you might want to check out work done at the University of Manchester, in England, on sexual behavior in several different species, including humans. I haven’t looked for it in several years, but it should still be out there in one form or another.

This is a fertile branch of research (no pun intended) that has revealed a hitherto unsuspected ability of many species to precisely control body chemistry in extremely sophisticated ways. This fact has not yet penetrated into most other fields of research.

When you've read what they've found in rats, silverback gorillas, and grad students, you should have little doubt that the causal relationships assumed in studies of brain chemistry might in fact be inverted.

Lastly, we have plausible explanations for the various reported effects that are frequently identified as tolerance, and they fit much better into the big picture of having/being AD/HD.

So until something really compelling comes along, we'll stick to our claim. There isn't any demonstrated tolerance to these drugs.

If a person experiences something that seems to be tolerance, we think it's far more productive to figure out the mechanism for the appearance than to assume tolerance actually exists.

And please let us know of any sources that we might have missed, regardless of which side of the debate they seem to support.

--Tom and Kay

[lynx]

Originally Posted by Stabile

The formal definition of tolerance does require something similar to what you mention. There are notable behavioral effects, too, which may include increasing the dose, but most commonly, a pattern of maintenance despite the lack of effect. But it must have a physical basis.

Tolerance is closely related to addiction, which also has a formal definition usually involving tolerance, but also requiring a physical mechanism for causing withdrawal symptoms.

Tolerance and addiction have a legitimate classical behavioral interpretation involving first the positive stimulus of the drug effect followed by the trap of behavior designed to avoid the negative stimulus represented by withdrawal.

Such interpretations treat the subject as a kind of 'black box', looking at the entire situation from an impartial external view. The behavioral characterizations fail immediately if you try to apply them to mechanisms inside the box.

You don't mention your source. We’ve looked repeatedly for any studies that show evidence of either tolerance or addiction to common AD/HD drugs, particularly Ritalin and the amphetamine formulations.

The last time we looked, about a year and a half ago, we weren’t able to find any examples in the literature that documented an actual case of either tolerance or addiction.

So forgive us if we remain skeptical about what you posted. It's a nice neat idea, one we've heard elsewhere, but there are several problems with it.

First and foremost is the implication that such changes in brain chemistry are directly associated with the effects you mention.

There is no established formal relationship between concepts like mood enhancement and changes in dopamine transport. If you believe differently, re-read whatever you've seen with a critical eye.

We've never seen any evidence for a relationship reported, but there has been much ballyhooing over the appearance of a correlation.

I say appearance because it's a difficult task to even gather evidence legitimately suggesting a correlation. One problem is that measuring things like mood enhancement and enhanced vigilance is not possible in the same way that we can (for example) measure dopamine levels in a rat's or a monkey's brain.

Thinking of a part of the biochemical mechanism as "the reward pathway" is itself a dangerous path to take. It has a clear anthropomorphic character, and as such is bound to be taken incorrectly by anyone not prepared to be scientifically rigorous.

We doubt the appropriateness of the term, regardless of how narrowly it's defined. Any meaning inherent in behavior arises in a much higher logical level of brain function; for that reason alone it isn't appropriate to characterize neural activity as behavioral.

It's also unnecessary. The well established understanding of how neural networks perform pattern matching and logical modeling is sufficient.

An even more pervasive problem: there's no guarantee that the actual biochemical mechanisms that you mention are taking place in our heads when we take these drugs. It's extremely difficult to routinely monitor such mechanisms, even indirectly. Most of the best data used to support such models comes from extremely limited laboratory experiments, seldom with human subjects.

There's much more to consider, especially when you take a look at the big picture.

For example, you might want to check out work done at the University of Manchester, in England, on sexual behavior in several different species, including humans. I haven’t looked for it in several years, but it should still be out there in one form or another.

This is a fertile branch of research (no pun intended) that has revealed a hitherto unsuspected ability of many species to precisely control body chemistry in extremely sophisticated ways. This fact has not yet penetrated into most other fields of research.

When you've read what they've found in rats, silverback gorillas, and grad students, you should have little doubt that the causal relationships assumed in studies of brain chemistry might in fact be inverted.

Lastly, we have plausible explanations for the various reported effects that are frequently identified as tolerance, and they fit much better into the big picture of having/being AD/HD.

So until something really compelling comes along, we'll stick to our claim. There isn't any demonstrated tolerance to these drugs.

If a person experiences something that seems to be tolerance, we think it's far more productive to figure out the mechanism for the appearance than to assume tolerance actually exists.

And please let us know of any sources that we might have missed, regardless of which side of the debate they seem to support.

--Tom and Kay

This is a remarkable breakthrough in the understanding of human behavior which completely negates all of the rigorous science conducted in neuropharmacology.

And regarding Manchester U, if you mean the big balled guys cheating and killer sperm stuff, so what.

I will have more later.

[Stabile]

Originally Posted by lynx

This is a remarkable breakthrough in the understanding of human behavior which completely negates all of the rigorous science conducted in neuropharmacology.

And regarding Manchester U, if you mean the big balled guys cheating and killer sperm stuff, so what.

I will have more later.

Thanks, it is a pretty important piece of work. It's been more than thirty years of joint effort. And it does call into question many popular ideas about how drugs affect the brain and the mind. But much of the work in that particular area isn't as rigorous as you might expect, so it isn't really too big a surprise.

The main thrust of our work has been the study of gender related differences in human communication. Chasing that required a rigorous model of how neural structures support things like abstraction, memory and instinct, and ultimately how the logical modeling behavior of neural nets can give rise to the mind and conscious awareness.

We don't claim to know the structures we propose exist in the form we've suggested. But the models are sufficient, in that we can correctly derive from them abstractions such as social behavior.

We’ve identified two different logical organizing principles being used to store and analyze data. We're reasonably certain that the structural details are close to correct, in part because the newer structure closely echoes the underlying hierarchical structure of neural networks themselves.

Our understanding of neural networks is based on extensions to James Albus' CMAC theory. Our focus on differences in how individuals communicate is relatively rare, though; it may be unique.

Nobody else is working across such a broad range, from biochemistry and microbiology to the structure of the mind and consciousness. Noam Chomsky has been outspoken in suggesting that any such effort must fail, which I'm certain has a chilling effect on the research community.

But we don't depend on writing grant proposals that compete directly with Chomsky or anyone else involved in the study of linguistics or theories of mind and consciousness. Much of our work has been privately supported, through its application to general systems analysis and various architectural problems of real time computing theory.

And when we couldn't get anyone to pay us to do it, we put our own time and money into it. We defined the scope and primary goals of our work in 1968. We've had to redefine the scope numerous times up until the early nineties, when we were finally able to derive an acceptable theory of human communication for the first time.

Most of the work over the last ten years has been refinement and dealing with details, like the apparent relationship of the two different logical structures to the appearance of AD/HD.

As far as the work at Manchester University is concerned, I meant to refer to rather remarkable work relating subtle variations in body chemistry to extremely abstract social interactions.

The application of sophisticated on-site chemical analysis of extremely small samples of fresh urine has revolutionized the study of primate behavior. For example, in response to social conditions, male Orangutans can apply a sophisticated control of their hormone balance to achieve the appearance of remaining immature long after they are capable of mating.

Both male and female Silverback Gorillas exhibit sophisticated control of hormone production in response to abstract social stimuli. But the really surprising data came from a nice study of graduate students in long term committed relationships.

Grad students put up with more than gorillas and Orangutans will, and you don't have to follow them around the forest to collect specimens. The subjects in the study were able to exert a completely unexpected degree of control over subtle aspects of their body chemistry, purely in response to abstract qualities of their social experience.

This is an inversion of the classical picture of hormone as mediator and messenger. In some circumstances the message is apparently directed by parts of the brain that are influenced directly by our conscious actions and interactions with others in a social context.

There's been some speculation about what consequences this discovery might have for how we think about any aspect of body chemistry, including the regulation of levels of neurotransmitters in the brain.

It's still too new and different an idea to have found it’s way into much ongoing research, but we’re sure to hear more about it in the next ten years or so.

We don't really have any opinion about the popularly-termed 'killer sperm' and 'large scrotum' ideas. Clearly competition selects, as does competitive advantage. But the higher you look in the hierarchy of species, the more subtle and abstract the qualities on which the competition is based become.

There isn't any real evidence in humans for the various overkill strategies found throughout the animal and insect kingdoms. 'Large scrotums' are likely to play a vanishingly small role in human mating behavior.

But there are behavioral parallels to the 'killer sperm' concept, including the changes in pH balance of secretions mediated by hormone release in response to the expectation of social opportunity, a very abstract trigger indeed.

There are other more overt behaviors that we've identified, which are at an even higher level of abstraction. We'd be happy to share details if you're interested.

We're always glad to hear any ideas about these subjects, and particularly appreciate hearing about any interesting sources that you might come across.

Thanks. –Tom and Kay

[lynx]

Stabile, You obviously didn't get the saracsm in my reply about your insane ramblings being a breakthrough negating neurochemical research.


You know I really had to restrain myself after reading this.
My first instinct was to say that Luddites shouldn’t use psychoactive medications.

My second instinct was to ignore it completely, because it is so incoherent and riddled with sophistry as not to warrant a response. But then I realized that other people might actually believe some of this. Although, it is so disjointed and full of magical thinking thinking that I can't imagine how one would carry on in the modern world relying on such a primitive model.


For example, You said

If a person experiences something that seems to be tolerance, we think it's far more productive to figure out the mechanism for the appearance than to assume tolerance actually exists.

Which in essence means ignore the science and try and invent some completely unfounded interpretation of the feeling.

Such as this

The major effect that Kay and I notice is on a certain low level brain mechanism that we think of as an alarm. An alarm is a low level impulse triggered by something we notice in our perception of ourselves and our environment.

Stimulants act on our conformity alarm, one of our most compelling and far reaching primitive brain mechanisms. They either act directly to suppress the response, or they interfere with our conscious perception of the impulse. On the level of conscious self-awareness, the effect is the same.

ADDers grow up different, with our conformity alarm perpetually triggered at a low level. Stilling it, even just a little bit, gives a giddy sense of relief, that euphoric feeling so common to the first few days or weeks of stimulant use.

The absence of the alarm is our normal state, and eventually the giddy feeling fades. But the effect remains undiminished, in our experience.

What stimulants don't change are the real effects of our differences. We still directly experience the frustration of not being able to perform in the way that we and others expect.

Learning to apply a different standard to our own ways of working allows us to work more naturally, within our different abilities, and produce results at least as good as a normal working in the normal ways.

Stimulants help with that as well, keeping the difference in how we work from setting off our alarms and distracting us. But we still need to make an effort to develop the new methods; it sometimes seems like going back to childhood and starting over.

So the situation is complex, and difficult enough to sort our without the added pressure of making it through school, holding down a job or raising a family.

The effect of the contrast when our alarms are suddenly silenced can initially give us an insight into our selves that helps immensely. But that fades as we grow accustomed to the feeling, and we may replace the conscious effects of the silenced alarms with our awareness of the real effects of our differences.

That may be the biggest contributor to the perception that we develop a tolerance to the drug's effect. Increasing the dose makes a slight change in our perception of the alarms, and that may rekindle memories of how that initial insight made us feel.

And what you appear to be saying there is that Stimulants don’t actually improve Vigilance and Attention, they just turn off our awareness of our impaired functioning?
This is in spite of legions of evidence that Stimulants do enhance vigilance, attention, even learning.



I couldn't any research about grad students at U Manchester, but the stuff about apes is entirely unremarkable.
And you said

As far as the work at Manchester University is concerned, I meant to refer to rather remarkable work relating subtle variations in body chemistry to extremely abstract social interactions.

Below are 6 definitions of "Abstract", none of which apply to social interactions. In fact, social interactions are the MOST CONCRETE things that animals do.Survival of the fittest in social animals like humans depends entirely on social interaction.


1.Considered apart from concrete existence: an abstract concept.
2.Not applied or practical; theoretical. See Synonyms at theoretical.
3.Difficult to understand; abstruse: abstract philosophical problems.
4.Thought of or stated without reference to a specific instance: abstract words like truth and justice.
5.Impersonal, as in attitude or views.
6.Having an intellectual and affective artistic content that depends solely on intrinsic form rather than on narrative content or pictorial representation: abstract painting and sculpture.

I suspect that you use words like "abstract" and "neural networks" just to sound smart, but your ideas are so discursive, tangential and illogical that no amount of flowery language will cover it up. It just reveals the bankrupcy.

Regarding tolerance, the original topic see:



Clin Pharmacol Ther. 1999 Sep;66(3):295-305. Related Articles, Links

Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children.

Swanson J, Gupta S, Guinta D, Flynn D, Agler D, Lerner M, Williams L, Shoulson I, Wigal S.

University of California Irvine, Child Development Center, 92612, USA.



Arch Gen Psychiatry. 2003 Feb;60(2):204-11. Related Articles, Links

Development of a new once-a-day formulation of methylphenidate for the treatment of attention-deficit/hyperactivity disorder: proof-of-concept and proof-of-product studies.

Swanson J, Gupta S, Lam A, Shoulson I, Lerner M, Modi N, Lindemulder E, Wigal S.

University of California, Irvine, Department of Pediatrics, Child Development Center, CA, USA.

BACKGROUND: The duration of action of the immediate-release formulation of methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of methylphenidate had reduced efficacy compared with immediate-release methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. METHODS: Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. RESULTS: The experimental ascending profile matched the effect of the standard regimen of methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-methylphenidate treatment matched the 3 times daily dosing of methylphenidate for onset and duration of efficacy. CONCLUSIONS: These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.




AND THE FOLLOWING TWO STUDIES Pretty MUCH Proves exactly what I said original about tolerance.

Neuropsychopharmacology. 2001 Oct;25(4):548-54. Related Articles, Links

Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance.

Strakowski SM, Sax KW, Rosenberg HL, DelBello MP, Adler CM.

Bipolar and Psychotic Disorders Research Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0559, USA. strakosm@email.uc.edu

Previously, we reported progressively greater behavioral responses to repeated d-amphetamine in human subjects that represented a potential model of behavioral sensitization. To extend this work, 59 healthy volunteers were randomly assigned to one of three protocols: (1) placebo administered on days 1, 3, and 5 (PPP); (2) placebo administered on days 1 and 3, and d-amphetamine (0.25 mg/kg) on day 5 (PPA); and (3) d-amphetamine administered on days 1, 3, and 5 (AAA). Comparisons were made among the three groups to determine whether repeated d-amphetamine produced an increased behavioral response. Subjective ratings of vigor and euphoria exhibited the greatest response following the third dose of the AAA group, as hypothesized. In contrast, drug liking was greatest following a single or first d-amphetamine dose. These effects were greater in women. Progressive changes in subjective responses following repeated d-amphetamine administration may occur in healthy human subjects, although this effect may be greater for women.

Publication Types:
· Clinical Trial
· Randomized Controlled Trial

PMID: 11557168 [PubMed - indexed for MEDLINE]


Psychopharmacology (Berl). 2001 Jun;155(4):397-404. Related Articles, Links

Effects of repeated oral methamphetamine administration in humans.

Comer SD, Hart CL, Ward AS, Haney M, Foltin RW, Fischman MW.

Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA. sdc10@columbia.edu

RATIONALE: Although methamphetamine use has increased over the past several years, few studies have evaluated the effects of repeated methamphetamine administration in humans. OBJECTIVES: Because methamphetamine is often taken in a pattern of repeated use followed by a period of abstinence, the present study sought to evaluate the effects of repeated methamphetamine administration in humans. The hypothesis was that tolerance would develop to methamphetamine's effects. METHODS: Seven normal, healthy volunteers participated in a 15-day residential study. Participants completed subjective-effects questionnaires and psychomotor performance tasks repeatedly throughout the experimental day. Oral methamphetamine (5, 10 mg BID) was administered on days 4-6 and 10-12; placebo was administered on all other study days. RESULTS: Relative to placebo baseline, only two "positive" subjective ratings ("I feel a good drug effect" and "I feel high") were significantly elevated, and only on the 1st day of methamphetamine administration. In contrast, numerous "negative" ratings, including "I feel..." "a bad drug effect," "dizzy," and "flu-like symptoms" were elevated on the 3rd day of methamphetamine administration. Total caloric intake decreased and sleep was disrupted after methamphetamine administration, relative to baseline. CONCLUSIONS: The pattern of methamphetamine's positive subjective effects were altered with chronic administration such that tolerance, or a decreased effect, occurred after repeated administration. In contrast, methamphetamine's negative subjective effects increased over days. These results suggest that in this population of normal volunteers, the abuse liability of oral methamphetamine is relatively low.

Publication Types:
· Clinical Trial

PMID: 11441429 [PubMed - indexed for MEDLINE]


More

Biol Psychiatry. 1998 Dec 1;44(11):1171-7. Related Articles, Links

Progressive behavioral response to repeated d-amphetamine challenge: further evidence for sensitization in humans.

Strakowski SM, Sax KW.

Department of Psychiatry, University of Cincinnati College of Medicine, OH 45267-0559, USA.

[lynx]

BACKGROUND: Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressive behavioral response. Although animal models of sensitization are well established, the phenomenon has been relatively little studied in humans. In a previous study, we reported enhanced responses following a second as compared to a first amphetamine dose in eye-blink rate and ratings of increased motor activity/energy, increased speech, and elevated mood in normal human volunteers. This current study extends those findings in a new sample of normal volunteers. METHODS: Eleven normal human volunteers were administered three single oral doses of d-amphetamine (0.25 mg/kg) at 48-hour intervals, alternating with matched placebo in a randomized, double-blind trial. Hourly behavioral ratings included eye-blink rate, symptoms (elevated mood, increased speech, increased motor activity/energy), and subjective drug effects. RESULTS: Eye-blink rate and increased motor activity/energy ratings progressively increased following each challenge with the third amphetamine dose response significantly greater than all other conditions 4 hours postadministration. Similar, although less pronounced, responses were observed for elevated mood and subjective drug effect. CONCLUSIONS: These results provide further evidence for sensitization of some amphetamine-induced behaviors in human subjects.
PMID: 9836021 []

Biol Psychiatry. 1996 Nov 1;40(9):872-80.




Enhanced response to repeated d-amphetamine challenge: evidence for behavioral sensitization in humans.

Strakowski SM, Sax KW, Setters MJ, Keck PE Jr.

Department of Psychiatry, University of Cincinnati College of Medicine, OH 45267-0559, USA.

Behavioral sensitization is the process whereby intermittent stimulant exposure produces a time-dependent, enduring, and progressively more robust behavioral response. This process serves as an important model of neural plasticity and has also been proposed as a model for a variety of psychiatric syndromes; however, there are no published controlled studies of behavioral sensitization in human subjects. The authors report results from a double-blind, placebo-controlled study of repeated d-amphetamine challenges in a sample of normal human volunteers. Eleven consecutively recruited normal volunteers participated in this 4-day protocol. Each subject received two daily doses of d-amphetamine (0.25 mg/kg) separated by 48 hours that alternated with two daily doses of matched placebo. Symptoms (activity/energy level, mood, rate, and amount of speech) and eye-blink rates were measured hourly for 5 hours following drug administration. All four measures demonstrated significantly enhanced increases following the second amphetamine dose as compared to the first amphetamine dose and both placebo conditions. These findings suggest that behavioral sensitization is measurable in human subjects.






Behav Pharmacol. 1999 May;10(3):271-81.





Subjective and behavioral effects of repeated d-amphetamine in humans.

Wachtel SR, de Wit H.

Department of Psychiatry, University of Chicago, IL 60637, USA. swachtel@yoda.bsd.uchicago.edu

Behavioral sensitization is thought to be an important determinant of drug-taking and drug-seeking behaviors. Although there is abundant research characterizing behavioral sensitization in animals, there is little evidence for this phenomenon in humans. The aim of the present study was to determine if repeated oral d-amphetamine administration enhances self-reported mood and other behavioral indices of d-amphetamine effects in humans. Sixteen healthy volunteers, with no prior stimulant use, received two doses of d-amphetamine (20 mg) and two doses of placebo, in alternating order, on 4 consecutive days, under double-blind conditions. Mood and behavioral effects were measured using standard self-report questionnaires. Heart rate, blood pressure, psychomotor performance, and tapping speed were also monitored. d-Amphetamine elicited prototypical increases on several measures including self-reported drug effects, mood, and physiological responses. However, except for a slight reduction in 'feel drug' scores during the first hour of the second d-amphetamine session, the majority of effects were not altered on the second session. These results indicate that the subjective effects of d-amphetamine display only an apparent mild tolerance after a single exposure 48 h earlier.

Publication Types:




PMID: 10780242

Psychopharmacology (Berl). 2001 Jun;155(4):397-404.





Effects of repeated oral methamphetamine administration in humans.

Comer SD, Hart CL, Ward AS, Haney M, Foltin RW, Fischman MW.

Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA. sdc10@columbia.edu

RATIONALE: Although methamphetamine use has increased over the past several years, few studies have evaluated the effects of repeated methamphetamine administration in humans. OBJECTIVES: Because methamphetamine is often taken in a pattern of repeated use followed by a period of abstinence, the present study sought to evaluate the effects of repeated methamphetamine administration in humans. The hypothesis was that tolerance would develop to methamphetamine's effects. METHODS: Seven normal, healthy volunteers participated in a 15-day residential study. Participants completed subjective-effects questionnaires and psychomotor performance tasks repeatedly throughout the experimental day. Oral methamphetamine (5, 10 mg BID) was administered on days 4-6 and 10-12; placebo was administered on all other study days. RESULTS: Relative to placebo baseline, only two "positive" subjective ratings ("I feel a good drug effect" and "I feel high") were significantly elevated, and only on the 1st day of methamphetamine administration. In contrast, numerous "negative" ratings, including "I feel..." "a bad drug effect," "dizzy," and "flu-like symptoms" were elevated on the 3rd day of methamphetamine administration. Total caloric intake decreased and sleep was disrupted after methamphetamine administration, relative to baseline. CONCLUSIONS: The pattern of methamphetamine's positive subjective effects were altered with chronic administration such that tolerance, or a decreased effect, occurred after repeated administration. In contrast, methamphetamine's negative subjective effects increased over days. These results suggest that in this population of normal volunteers, the abuse liability of oral methamphetamine is relatively low.

Publication Types:

· Clinical Trial


PMID: 11441429

J Neurochem. 2000 May;74(5):2120-6.




The human nucleus accumbens is highly susceptible to G protein down-regulation by methamphetamine and heroin.

McLeman ER, Warsh JJ, Ang L, Li PP, Kalasinsky KS, Ross BM, Tong J, Schmunk G, Adams V, Kish SJ.

Centre for Addiction and Mental Health, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada.

Although the nucleus accumbens is assumed to be a critical brain "pleasure center," its function in humans is unknown. As animal data suggest that a unique feature of this small brain area is its high sensitivity to down-regulation of an inhibitory G protein by drugs of abuse, we compared G protein levels in postmortem nucleus accumbens with those in seven other brain regions of chronic users of cocaine, methamphetamine, and heroin, and of matched controls. Biochemical changes were restricted to the nucleus accumbens in which concentrations of G(alpha)1 and/or G(alpha)2 were reduced by 32-49% in the methamphetamine and heroin users. This selective responsiveness to these abused drugs implies a special role for the human nucleus accumbens in mechanisms of drug reinforcement and suggests that some features of the drug-dependent state (e.g., tolerance) might be related to inhibition of G(alpha)1-linked receptor activity.

PMID: 10800957



---------------------------

Thinking of a part of the biochemical mechanism as "the reward pathway" is itself a dangerous path to take. It has a clear anthropomorphic character, and as such is bound to be taken incorrectly by anyone not prepared to be scientifically rigorous.

To say that "reward pathway" anthropormorphic is another indication of your pseudo-scientific verbiage.



Here is the definition of anthropormorphic:

Attribution of human motivation, characteristics, or behavior to inanimate objects, animals, or natural phenomena.

That in no way characterizes talking about reward pathways in the brain. And your use of the word "scientifically rigorous" is hilarious coming from someone spouting crack-pot theories with no basis in reality. And you talk about funding for your "Research". HA. "Heavens Gate" is about the only organization that would fund you, but they all committed suicide.

There is no established formal relationship between concepts like mood enhancement and changes in dopamine transport. If you believe differently, re-read whatever you've seen with a critical eye.

We've never seen any evidence for a relationship reported, but there has been much ballyhooing over the appearance of a correlation.

I say appearance because it's a difficult task to even gather evidence legitimately suggesting a correlation. One problem is that measuring things like mood enhancement and enhanced vigilance is not possible in the same way that we can (for example) measure dopamine levels in a rat's or a monkey's brain.

All of the below refutes that BS and more....

http://pn.psychiatryonline.org/cgi/c.../full/36/18/18



New imaging techniques have provided early, direct evidence that methylphenidate relieves symptoms of ADHD through modulating dopamine activity in striatal synapses.



This would be beneficial in a patient with ADHD in light of recent studies that indicate that patients with the disorder have a marked increase in dopamine transporters, which are responsible for clearing the synapse of dopamine following signal transduction. This increase in the number of transporters would potentially lead to a nearly immediate increased clearing of dopamine from the nerve endings back into the neuron following its release. Researchers have hypothesized that this would result in a decrease in the intensity of the dopaminergic signal. Blocking of dopamine transport by methylphenidate could lead to stronger dopaminergic signaling, which has been tied to an increase in the "importance" of the stimulus that triggered the signal, causing an individual to pay more attention to the stimulus for a longer period

PMID: 12727693

PMID: 11126397

PMID: 11717374

PMID: 11462792

PMID: 11229977

PMID: 11164755

PMID: 11481152

PMID: 11729018

PMID: 11160455

PMID: 14579420

PMID: 12464459

PMID: 15464140

Am J Psychiatry. 2004 Jul;161(7):1173-80.


Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain.

Volkow ND, Wang GJ, Fowler JS, Telang F, Maynard L, Logan J, Gatley SJ, Pappas N, Wong C, Vaska P, Zhu W, Swanson JM.

Medical and Chemistry Departments, Brookhaven National Laboratory, Upton, NY, USA.

OBJECTIVE: Methylphenidate is the most commonly prescribed drug for attention deficit hyperactivity disorder (ADHD), yet its therapeutic mechanisms are poorly understood. The objective of this study was to assess if methylphenidate, by increasing dopamine (neurotransmitter involved in motivation) in brain, would enhance the saliency of an academic task, making it more interesting. METHOD: Healthy subjects (N=16) underwent positron emission tomography with [(11)C]raclopride (dopamine D(2) receptor radioligand that competes with endogenous dopamine for binding) to assess the effects of oral methylphenidate (20 mg) on extracellular dopamine in the striatum. The authors compared the effects of methylphenidate during an academic task (solving mathematical problems with monetary reinforcement) and a neutral task (passively viewing cards with no remuneration). In parallel, the effects of methylphenidate on the interest that the academic task elicited were also evaluated. RESULTS: Methylphenidate, when coupled with the mathematical task, significantly increased extracellular dopamine, but this did not occur when coupled with the neutral task. The mathematical task did not increase dopamine when coupled with placebo. Subjective reports about interest and motivation in the mathematical task were greater with methylphenidate than with placebo and were associated with dopamine increases. CONCLUSIONS: The significant association between methylphenidate-induced dopamine increases and the interest and motivation for the task confirms the prediction that methylphenidate enhances the saliency of an event by increasing dopamine. The enhanced interest for the task could increase attention and improve performance and could be one of the mechanisms underlying methylphenidate's therapeutic effects. These findings support educational strategies that make schoolwork more interesting as nonpharmacological interventions to treat ADHD.

PMID: 15229048 [PubMed - indexed for MEDLINE]

Neuropsychopharmacology. 2004 Sep;29(9):1715-22.


Methamphetamine activates reward circuitry in drug naïve human subjects.

Vollm BA, de Araujo IE, Cowen PJ, Rolls ET, Kringelbach ML, Smith KA, Jezzard P, Heal RJ, Matthews PM.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK. birgit.vollm@man.ac.uk

Amphetamines are highly addictive drugs that have pronounced effects on emotional and cognitive behavior in humans. These effects are mediated through their potent dopaminergic agonistic properties. Dopamine has also been implicated in the modulation of responses of the 'reward circuit' in animal and human studies. In this study we use functional magnetic resonance imaging (fMRI) to identify the brain circuitry involved in the psychostimulant effect of methamphetamine in psychostimulant-naive human subjects. Seven healthy volunteers were scanned in a 3T MR imaging system. They received single-blind intravenous infusions of methamphetamine (0.15 mg/kg), and rated their experience of 'mind-racing' on a button press throughout the experiment. Data were analyzed with statistical parametric mapping methods. Amphetamine administration activated the medial orbitofrontal cortex, the rostral part of the anterior cingulate cortex, and the ventral striatum. Ratings of 'mind-racing' after methamphetamine infusion correlated with activations in the rostral part of the anterior cingulate cortex and in the ventral striatum. In addition, activations in the medial orbitofrontal cortex were independent of motor and related responses involved in making the ratings. These findings indicate that the first administration of a psychostimulant to human subjects activates classical reward circuitry. Our data also support recent hypotheses suggesting a central role for the orbitofrontal cortex in drug reinforcement and the development of addiction.


PMID: 15138439

PMID: 14736018

Neuron. 2003 Dec 4;40(5):1041-8.

Humor modulates the mesolimbic reward centers.

Mobbs D, Greicius MD, Abdel-Azim E, Menon V, Reiss AL.

Stanford Psychiatry Neuroimaging Laboratory, Stanford University School of Medicine, Stanford, CA 94305, USA.

Humor plays an essential role in many facets of human life including psychological, social, and somatic functioning. Recently, neuroimaging has been applied to this critical human attribute, shedding light on the affective, cognitive, and motor networks involved in humor processing. To date, however, researchers have failed to demonstrate the subcortical correlates of the most fundamental feature of humor-reward. In an effort to elucidate the neurobiological substrate that subserves the reward components of humor, we undertook a high-field (3 Tesla) event-related functional MRI study. Here we demonstrate that humor modulates activity in several cortical regions, and we present new evidence that humor engages a network of subcortical regions including the nucleus accumbens, a key component of the mesolimbic dopaminergic reward system. Further, the degree of humor intensity was positively correlated with BOLD signal intensity in these regions. Together, these findings offer new insight into the neural basis of salutary aspects of humor.

PMID: 14659102 [PubMed - indexed for MEDLINE]

Neuroimage. 2003 Aug;19(4):1709-15.





Feeding-induced dopamine release in dorsal striatum correlates with meal pleasantness ratings in healthy human volunteers.

Small DM, Jones-Gotman M, Dagher A.

McConnell Brain Imaging Center, Montreal Neurological Institute and McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.

Seven healthy subjects underwent two [(11)C]raclopride positron emission tomography (PET) scans, one following a 16-h fast and the other after consumption of a favorite meal (following a 16-h fast) in counterbalanced fashion. Before and after each scan subjects gave ratings of hunger/fullness and desire to eat. In addition, meal pleasantness ratings were collected immediately after consumption of the favorite meal. PET data were analyzed using brain parametric maps to generate regions of statistically significant change, as well as regions of interest manually drawn on each individual's coregistered anatomical image. [(11)C]Raclopride binding potential was compared across the two states (hungry and full). A significant reduction in binding potential was observed in the full compared to the hungry state in the dorsal putamen and caudate nucleus, indicative of dopamine release. There were no changes elsewhere in the striatum. A correlation was observed between the reduction in [(11)C]raclopride binding and meal pleasantness ratings, but not with desire to eat (hunger) or satiety after eating. These results suggest that feeding is associated with dopamine release in the dorsal, but not the ventral striatum, and that the amount of dopamine released correlates with the degree of experienced pleasure.
PMID: 12948725 [PubMed - indexed for MEDLINE]

Synapse. 2004 Nov;54(2):65-71.




The hedonic response to cigarette smoking is proportional to dopamine release in the human striatum as measured by positron emission tomography and [11C]raclopride.

Barrett SP, Boileau I, Okker J, Pihl RO, Dagher A.

McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Canada.

Positron emission tomography and [11C]raclopride were used to assess the dopaminergic response to cigarette smoking in ten smokers. Nicotine-deprived smokers were scanned twice on separate days. In one condition, participants smoked their usual brand of cigarettes while in the scanner and in the other condition they remained nicotine abstinent. On each day, subjects monitored the hedonic properties of their experience as well as their levels of craving. Initial analyses revealed no significant differences between the conditions in [11C]raclopride binding potential (BP) in the caudate, putamen, or ventral striatum. Because previous research suggested that drug-induced dopamine transmission is related to levels of craving and/or hedonic drug effects, the relationship between these variables and [11C]raclopride BP was examined. Craving levels were reduced by smoking but were not systematically related to BP change. However, the hedonic response to smoking was correlated with BP reduction in the caudate (P < 0.001) and posterior putamen (P < 0.05) but not in the ventral striatum. Post hoc analyses revealed that only five of the ten smokers reported mood-elevating effects in response to the smoking procedure. In these subjects, smoking was associated with decreased [11C]raclopride BP in the caudate. On the other hand, among subjects that reported a diminished mood response to smoking there was an increase in BP in the caudate and putamen. These results suggest that pleasurable drug experiences are associated with increased dopamine transmission in the dorsal striatum while unpleasant experiences may be related to decreased dopamine release in this region. Copyright 2004 Wiley-Liss, Inc.

PMID: 15352131

[Stabile]

Stabile, You obviously didn't get the saracsm in my reply about your insane ramblings being a breakthrough negating neurochemical research.

Oh, yeah, we got it. But we're not just kidding around about our work. Because you're not the only audience for these posts, we decided to present a reasonable response about a serious subject, regardless of the sarcasm.

There's nothing insane or particularly rambling about our ideas, and as I said, we do enjoy constructive criticism. That does mean something more of a debate than brash condemnation, though, to most of us here.

Instead of pushing back in a meaningless verbal joust, let us ask you a question about the form of your response instead. Why do you think your reaction to what we wrote has been so intense? We don't mean this to be frivolous.

If you're able to stand off a bit and observe your self in an impartial way, you'll see that the pattern of how we've interacted is probably the only useful information left, at this point.

We don't get one without the other. We have to be, and interact verbally, and that process is intertwined with every fact that we attempt to address.

It's obvious that there's a disconnect between our understanding and presentation of the facts and yours. So, we're left with the disconnect, which is an interesting fact to us in it's own right.

There's nothing solipsistic about it; solipsism is a kind of logical trap caused by an error in understanding the context. What we're directly confronting is usually called the mind – body problem; Noam Chomsky devotes quite a bit of time to it in New Horizons in the Study of Language and Mind [2000]. (We happen to disagree with his assessment, probably no surprise to anyone here.)

It is the same problem that Descartes originally addressed, and it is his incomplete analysis that gives rise to Solipsism. So in a sense everybody is rowing in the same boat, including you; your mention is an open recognition of the relevance of the problem.

That sort of insight is what led us to respond the way we have. We don't believe that the distance between our views is as significant as the recognition of the problems underlying the subject. And usually the difference in opinion can be transcended by shifting context.

Thus the question. What process in your head gives rise to the reaction you're experiencing to our ideas? It isn't a simple question to answer, in the sense of simply saying you disagree, or that you feel strongly that we're wrong.

The answer must address the path to the strong emotion, as compared to other ideas you see as incorrect that don't cause the same visceral response. I should say that your reaction isn't unique, or even unexpected. But that isn't really very useful information at this point.

With respect to the articles you've cited, it's much clearer if you simply provide links with the URLs and a bit of explanation of what is relevant, rather than big chunks of text. Cutting and pasting huge chunks of text runs perilously close to the forum's anti-spam rules.

The text does provide a useful perspective; every article you present cites studies that are (like any scientific endeavor) based on certain assumptions about the context. Our work challenges those assumptions.

There's nothing unscientific about that, and there's no science in the idea that basic principles are unassailable. We do what we do, and do it with dignity.

We're reasonably certain that what we're looking at isn't correctly addressed by the current models of the underlying operating principles of neural based mechanisms. We don't claim to be as certain that our models are correct, only that there are some easily demonstrated features not accounted for.

There are studies of how long it takes for new ideas like ours to penetrate the current mainstream model; in this area, ten to twenty years is considered normal. Probably the most well known recent example is the long path of the medical and pharmacological community to acceptance of the role of Helicobacter pylori in stomach ulcers.

We see no reason to doubt ourselves, and we understand why others might find an unexpected passion in their response. It's just an interesting part of the whole picture, a picture we hope we've managed to present in a way that engages your interest.

I suspect that you use words like "abstract" and "neural networks" just to sound smart, but your ideas are so discursive, tangential and illogical that no amount of flowery language will cover it up. It just reveals the bankrupcy.(sic)

Nope, sorry. We cited the primary source of our understanding of neural networks (we assume you thought to Google 'CMAC'.) Understanding how the mind – body problem necessarily affects any study of the brain is certainly enough to demonstrate that social interactions are indeed purely abstract.

But you don't need to go that deeply into the logic; look up a few sources on the current mainstream thinking about meaning itself. Social interactions are all about meaning, in a way similar to your definition applying to words like truth and justice.

The first definition, considered apart from concrete existence, really hits the nail on the head, though. Our disconnect is in the mistaken idea that you can rely on imprecise ideas like 'concrete existence' if you want to be rigorous about how our brains work. The mind – body problem applies regardless of whether you choose to consider it.

I promised myself I'd keep this to two pages, and it's running over. We would be happy to continue the discussion in a different thread, or feel free to contact us directly. We'll take a look at the articles you cite as time permits, and thanks for that. We won't post our response here, though; if it seems to warrant it, we'll PM you.

Thanks again for the stimulating interchange. –Tom & Kay