Does Ritalin specifically target the prefrontal cortex?

I've long been impressed by the unexpected safety of Ritalin (methylphenidate). It's rare for a medication to both alter brain function and have low toxicity, yet many years of use have given us little bad news.

Now FP reports on a study that suggests why Ritalin is both safe and effective for ADHD. It might not the drug we thought it was ...

FuturePundit: Research On Ritalin Mechanism Of Action

... In a paper publishing online this week in Biological Psychiatry, University of Wisconsin-Madison psychology researchers David Devilbiss and Craig Berridge report that Ritalin fine-tunes the functioning of neurons in the prefrontal cortex (PFC) - a brain region involved in attention, decision-making and impulse control - while having few effects outside it.

... Mounting behavioral and neurochemical evidence suggests that clinically relevant doses of Ritalin primarily target the PFC, without affecting brain centers linked to over-arousal and addiction. In other words, Ritalin at low doses doesn't appear to act like a stimulant at all.

Ritalin at lower doses appears to cause the prefrontal cortex (PFC) to be more sensitive to signals coming in from the hippocampus.

When they listened to individual PFC neurons, the scientists found that while cognition-enhancing doses of Ritalin had little effect on spontaneous activity, the neurons' sensitivity to signals coming from the hippocampus increased dramatically. Under higher, stimulatory doses, on the other hand, PFC neurons stopped responding to incoming information. "This suggests that the therapeutic effects of Ritalin likely stem from this fine-tuning of PFC sensitivity," says Berridge. "You're improving the ability of these neurons to respond to behaviorally relevant signals, and that translates into better cognition, attention and working memory." Higher doses associated with drug abuse and cognitive impairment, in contrast, impair functioning of the PFC...

I wonder if this will change thoughts about optimal dosing of Ritalin. I would very much like to see animal models studied to look for tolerance of Ritalin's alleged PFC effects.

The unreasonable non-toxicity of Ritalin

Some drugs, like acetominophen (tylenol), are considered "safe" when they are fundamentally quite toxic.

Others, like Ritalin, are properly regarded with great suspicion. How can such a powerful medication be safe for decades of use in a developing brain?

Surprisingly, the literature is reassuring. I can now add some informal updates courtesy of a family member who does NIH funded research in this domain. The research community has long expected ritalin to have some deleterious effect on neuronal proliferation, but recently concluded studies, and those still in progress, will likely show (again) surprisingly negative results. Probably Ritalin has some effect on brain development, but the effect size is small.

Hard to believe really, but it does affirm my prejudice in favor of this well aged medication. Given Ritalin's safety record, it would take a lot to make me shift to another medication of the same or similar class.

Scientific American goes nuclear on Ritalin

Edmund Higgins, a clinical associate professor [1], has written a blistering attack on Ritalin, and gotten it published in Scientific American – a magazine that’s presumably sharing the industry’s revenue problems.

Dr. Higgins compares Ritalin (methylphenidate) to methamphetamine. This is the rhetorical equivalent of comparing a human to Hitler; it’s chemically correct but it’s the mark of a crank. It’s a Godwin’s Law violation.

On the other hand, as someone who’s child has been on Ritalin and other ADHD meds for years, I’ve long had the same sort of concerns. Ritalin has an astounding safety record, but we’re messing with the neurochemistry of a rapidly evolving brain over a period of years and decades. I personally wouldn’t use this, or any other, long-term psychiatric medication medication in my child unless all other options had been exhausted and the disability and risks of non-treatment were severe. I’ve previously made the comparison to treating cancer. Nobody should expose a child to life threatening chemicals with severe long term effects– unless the alternative is worse.

Another point in Higgins favor is his interest in animal models. Given the immense difficulty of studying psychiatric medications in children, animal models are pretty much all we’ve got. So let’s see what he says about the animal models, stripping out some inflammatory rhetoric and considering only studies of meds used to treat ADHD. Note that much of this research is more recent that a 2006 review of mine that was pretty reassuring, but that means it won’t have been validated by other researchers …

Do ADHD Drugs Take a Toll on the Brain?: Scientific American

Edmund S. Higgins is clinical associate professor of family medicine and psychiatry at the Medical University of South Carolina and co-author, with Mark S. George, of The Neuroscience of Clinical Psychiatry (Lippincott Williams & Wilkins, 2007) and Brain Stimulation Therapies for Clinicians (American Psychiatric Publishing, 2009).

… In an experiment published in 2003 psychiatrist Eric Nestler of the University of Texas Southwestern Medical Center and his colleagues injected juvenile rats twice a day with a low dose of methylphenidate similar to that prescribed for children with ADHD. When the rats became adults, the scientists observed the rodents’ responses to various emotional stimuli. The rodents that had received methylphenidate were significantly less responsive to natural rewards such as sugar, sex, and fun, novel environments than were untreated rats, suggesting that the drug-exposed animals find such stimuli less pleasurable. In addition, the stimulants apparently made the rats more sensitive to stressful situations such as being forced to swim inside a large tube. Similarly, in the same year psychiatrist William Carlezon of Harvard Medical School and his colleagues reported that methylphenidate-treated preadolescent rats displayed a muted response to a cocaine reward as adults as well as unusual apathy in a forced-swim test, a sign of depression.

In 2008 psychopharmacologist Leandro F. Vendruscolo and his co-workers at Federal University of Santa Catarina in Brazil echoed these results using spontaneously hypertensive rats, which—like children with ADHD—sometimes show attention deficits, hyperactivity and motor impulsiveness. The researchers injected these young rats with methylphenidate for 16 days at doses approximating those used to treat ADHD in young people. Four weeks later, when the rats were young adults, those that had been exposed to methylphenidate were unusually anxious: they avoided traversing the central area of an open, novel space more so than did rats not exposed to methylphenidate. Adverse effects of this stimulant, the authors speculate, could contribute to the high rates of anxiety disorders among ADHD patients…

… In February 2009 neuroscientists Yong Kim and Paul Greengard … injected … mice with either methylphenidate or cocaine daily for two weeks. Both treatments increased the density of tiny extensions called spines at the ends of neurons bearing dopamine receptors in the rodent nucleus accumbens. Compared with cocaine, methylphenidate had a somewhat more localized influence; it also had more power over longer spines and less effect on shorter ones…

Furthermore, the scientists found that methylphenidate boosted the amount of a protein called ΔFosB, which turns genes on and off, even more than cocaine did…

So when I strip out everything else, the bulk of Higgins’ article is coming from 3 animal studies in 2003, 2008, and 2009. All of the studies involved injecting methylphenidate, which is not how it’s used in humans. Injecting Ritalin is a mark of abuse with pretty different pharmacology from oral use.

The most interesting of these articles is Nestler et al in 2003 [2], an article with a rather strange title (emphases mine – incidentally, Nesler is the last listed author, so why did Higgins credit the study to him?) …

Methylphenidate treatment during pre- and periadolescence alters behavioral responses to emotional stimuli at adulthood.

Bolaños CA, Barrot M, Berton O, Wallace-Black D, Nestler EJ.
Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Biol Psychiatry. 2003 Dec 15;54(12):1317-29.

BACKGROUND: Methylphenidate (MPH) is a psychomotor stimulant medication widely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Given the extent of prescribed use of MPH, and because MPH interacts with the same brain pathways activated by drugs of abuse, most research has focused on assessing MPH's potential to alter an individual's risk for adult drug addiction. Data examining other potential long-term behavioral consequences of early MPH administration are lacking, however. METHODS: We investigated the long-term behavioral consequences of chronic administration of MPH (2.0 mg/kg) during pre- and periadolescent development in adult rats by assessing their behavioral reactivity to a variety of emotional stimuli.
RESULTS: The MPH-treated animals were significantly less responsive to natural rewards such as sucrose, novelty-induced activity, and sex compared with vehicle-treated control animals. In contrast, MPH-treated animals were significantly more sensitive to stressful situations, showed increased anxiety-like behaviors, and had enhanced plasma levels of corticosterone.
CONCLUSIONS: Chronic exposure to MPH during development leads to decreased sensitivity to rewarding stimuli and results in enhanced responsivity to aversive situations. These results highlight the need for further research to improve understanding of the effects of stimulants on the developing nervous system and the potential enduring effects resulting from early-life drug exposure.

Why did I say that was a “strange title”? Because an article on rats in a journal called Biol Pyschiatry would normally contain the word rats in the title.

If we simply scaled the dose to humans, but the way, this would be 80 mg (twice daily?!) by injection – which would be a whopping abuse dose in humans. The article has gotten very little attention in the past six years, being cited only four times of which two appear to be reviews.

A related articles query produced a very large number of similar rat studies, including one that, surprisingly, found no effects (surprisingly, because these look like “fishing expedition” studies, when you include publication bias they almost always show some effect.) These are boom times for rat studies of methylphenidate, probably reflecting new NIH funding.

On review I’m left with several only mildly related conclusions …

1. I’m happy the animal studies are being done. I’d like to see fewer fishing expeditions, and more replication of results. For example, repeat the Bolanos study with a larger group, maybe a different clonal line, and see if the same results appear. These need to be registered studies, so we don’t get messed up by publication bias (which is a huge problem in the low cost animal studies domain). I would really like to see more studies of tolerance effects in rats.
2. Higgins may turn out to be correct (lots of people are suspicious that stimulants can be used so long, including me) but I think he’s got a crank agenda. His article is more inflammatory than the evidence supports. A more sober article would have been welcome.
3. You shouldn’t put children on psychoactive medications without a very good reason. Of course that was always true.
4. Don’t assume any other medications are in any way safer – Ritalin has been studied far more than, say, Stratera.
5. Scientific American is running out of money. We’ll know they’ve hit rock bottom when they do an article on the scientific evidence for Creationism. They should have known better than to publish this article in its current form.

[1] I have a similar sort of title today, and have had similar roles in the past. In the hierarchy of academia, this title carries less glory than research assistant.

[2] Parenthetically, why does PubMed make it so very hard to find the link to a citation? It’s like they’re trying to hide things.

The safety and efficacy of Ritalin

Another article reiterating the peculiar longterm efficacy and safety of Ritalin (methylphenidate). The side-effect data is based on chart review, so it's particularly meaningful (22%). The primary value of the study is to show that ritalin works as well in the real world as in clinical trials.

J Dev Behav Pediatr. 2006 Feb;27(1):1-10.
Long-term stimulant medication treatment of attention-deficit/hyperactivity disorder: results from a population-based study

* Barbaresi WJ, et al

Department of Pediatric and Adolescent Medicine, Division of Developmental and Behavioral Pediatrics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. barbaresi.william@mayo.edu

The purpose of this study was to offer detailed information about stimulant medication treatment provided throughout childhood to 379 children with research-identified attention-deficit hyperactivity disorder (ADHD) in the 1976-1982 Rochester, MN, birth cohort. Subjects were retrospectively followed from birth until a mean of 17.2 years of age. The complete medical record of each subject was reviewed. The history and results of each episode of stimulant treatment were compared by gender, DSM-IV subtype of ADHD, and type of stimulant medication. Overall, 77.8% of subjects were treated with stimulants. Boys were 1.8 times more likely than girls to be treated. The median age at initiation (9.8 years), median duration of treatment (33.8 months), and likelihood of developing at least one side effect (22.3%) were not significantly different by gender. Overall, 73.1% of episodes of stimulant treatment were associated with a favorable response. The likelihood of a favorable response was comparable for boys and girls. Treatment was initiated earlier for children with either ADHD combined type or ADHD hyperactive-impulsive type than for children with ADHD predominantly inattentive type and duration of treatment was longer for ADHD combined type. There was no association between DSM-IV subtype and likelihood of a favorable response or of side effects. Dextroamphetamine and methylphenidate were equally likely to be associated with a favorable response, but dextroamphetamine was more likely to be associated with side effects. These results demonstrate that the effectiveness of stimulant medication treatment of ADHD provided throughout childhood is comparable to the efficacy of stimulant treatment demonstrated in clinical trials.

There's something interesting about a medication that's this safe and effective. We don't see that very often in medicine, even physiologic substances like thyroid hormone have more side-effects.

Guanfacine (Tenex) and working memory

#1 takes both Ritalin and Guanfacine (Tenex and other trade names) - longterm. So I track research on both meds.

Ritalin is as well understood as any brain med. As best we can tell it's unreasonably safe and effective for ADHD, despite a trashy article in a pop science magazine.

Guanfacine, a second line med for ADHD also used (off label) for "explosive" kids, is much less studied than Ritalin. The proposed mechanisms of action are interesting, it seems to increase certain kinds of neuronal connections and to perhaps facilitate learning capabilities.

On the one hand, this is encouraging. Working memory deficits are a significant component of most developmental disorders of the brain. On the other, it's disturbing. When clinicians hear "increased cellular activity" in brains we think "cancer" and "seizure".

Fortunately, so far, there's no sign of that (though we're in early days). There is, however, continued research on Guanfacine's effect on working memory and task performance in primates. Studies have recently moved to using elderly primates, but results are mixed. As best I can tell from the abstract, this was a negative result (A typical child dose of Guanfacine would be .04 mg/kg) ...

Effects of the alpha-2 adrenoceptor agonist g... [Eur J Neurosci. 2011] - PubMed - NCBI

Alpha-2 adrenergic receptors are potential targets for ameliorating cognitive deficits associated with aging as well as certain pathologies such as attention deficit disorder, schizophrenia and Parkinson's disease. Although the alpha-2 agonist guanfacine has been reported to improve working memory in aged primates, it has been difficult to assess the extent to which these improvements may be related to drug effects on attention and/or memory processes involved in task performance. The present study investigated effects of guanfacine on specific attention and memory tasks in aged monkeys.

Four Rhesus monkeys (18-21 years old) performed a sustained attention (continuous performance) task and spatial working memory task (self-ordered spatial search) that has minimal demands on attention. Effects of a low (0.0015 mg/kg) and high (0.5 mg/kg) dose of gunafacine were examined. Low-dose guanfacine improved performance on the attention task [i.e. decreased omission errors by 50.8 ± 4.3% (P = 0.001) without an effect on commission errors] but failed to improve performance on the spatial working memory task. The high dose of guanfacine had no effects on either task. Guanfacine may have a preferential effect on some aspects of attention in normal aged monkeys and in doing so may also improve performance on other tasks, including some working memory tasks that have relatively high attention demands.

The doses are interesting here -- much lower than a human therapeutic dose and much higher. They were also looking at a one time dose effect. This reads like a mini-pub as a research team gears up for the real research. It's a modest investigation, and they basically didn't find anything. (Give the cost and ethics of primate experimentation one assumes there's much more to come.)

So the results are pretty meaningless. What's interesting is that the research is gearing up.

We should learn a lot more about the risks and benefits of Guanfacine over the next five years. For now I'm comfortable with our son's use of this medication.

Guanfacine (Tenex) for ADHD - more good news

These results are gratifying, but not surprising ...

Guanfacine Extended Release in Children and Adoles...[J Am Acad Child Adolesc Psychiatry. 2008] - PubMed Result

.... Guanfacine extended-release was effective in reducing symptoms of ADHD. Adverse events were mild to moderate, did not interfere with improvements in attention, and rarely led to discontinuation....

Guanfacine is a curious and perhaps powerful drug, so we need to treat it with cautious appreciation. The value comes because it's complementary to methylphenidate (Ritalin); it works by different mechanisms and the two seem to mesh well. Although Ritalin is exceedingly safe, it has some street value and can be problematic with adolescents. Ritalin can also exacerbate OCD symptoms and tics; Guanfacine doesn't seem to.

Even more interestingly, many believe Guanfacine can reduce "explosive" type behaviors.

Overall, good news.

Tolerance and Ritalin in ADHD: We know nothing

You'd think that after 30 years we might know something about how much of a problem tolerance is in the treatment of ADHD with methylphenidate (Ritalin), a stimulant medication. You'd think we'd have done to research to find out what happens when children take this medication for years.

You'd think. You'd be wrong.

One retrospective study done in 1989 on 108 boys with good responses, a highly selected group, seemed to show ongoing benefit without tolerance. It would have been interesting to see how well these children would have done with no medication at all. That's it.

On the other hand, the Google search on Ritalin and Tolerance had 190,000 hits today. Heck, some bored medical student could do a qualitative review of the Googleplex and compare it to the indexed literature. It could be exhibit A in the indictment of biomedicine. This is a topic of interest that is not being addressed by our research.

It boggles the mind. This is a scandal and a crime. All physicians and researchers ought to hang their heads in shame. Why aren't we screaming about this lack of work? (I mean, other than my screaming?)

I know the studies are terribly expensive and very hard to do. I suspect there's no tenure at the end of the tunnel. There's probably no NIH funding and no pharma money. I think I understand why we haven't done to the work. It's still a scandal. The way we do biomedicine is broken.

Ritalin and Adderall shortages -- the DEA and the other side of outrage

Beyond outrage, there is a point where we can only laugh and cry...

F.D.A. Is Finding Attention Drugs in Short Supply - NYTimes.com

... While the Food and Drug Administration monitors the safety and supply of the drugs, which are sold both as generics and under brand names like Ritalin and Adderall, the Drug Enforcement Administration sets manufacturing quotas that are designed to control supplies and thwart abuse. Every year, the D.E.A. accepts applications from manufacturers to make the drugs, analyzes how much was sold the previous year and then allots portions of the expected demand to various companies.

How each manufacturer divides its quota among its own A.D.H.D. medicines — preparing some as high-priced brands and others as cheaper generics — is left up to the company.

Now, multiple manufacturers have announced that their medicines are in short supply. The F.D.A. has included these pills on its official shortages list, as has the American Society of Health-System Pharmacists, which tracks the problem for hospitals. And the American Academy of Child and Adolescent Psychiatry has told the more than 8,000 doctors in its membership that shortages seem to be “widespread across a number of states” and are “devastating” for children.

Officials at the Food and Drug Administration say the shortages are a result of overly strict quotas set by the Drug Enforcement Administration, which, for its part, questions whether there really are shortages or whether manufacturers are simply choosing to make more of the expensive pills than the generics, creating supply and demand imbalances...

Let us set aside the trivial matter. Drug company CEOs would sell their mother's liver to "meet expectations". I'm sure they're exploiting every legal and even semi-legal angle they can find in an age where patents are expiring and the drug pipeline is dry.

That's not the problem though. Just think for a minute about how this is supposed to work. The DEA wants to stop the recreational use of stimulant drugs. They do this by restricting the supply. So recreational use will stop because one of two things happen. Maybe the drug companies, who get paid either way, will start assassinating stimulant dealers. Alternatively, parents of kids with ADHD will put on capes and masks and start beating up college kids prepping for exams.

Yeah, think about that. How else are these DEA restrictions supposed to work?

Now if you're a relatively young person you may be thinking senior leadership at the DEA couldn't really be this stupid. Trust me, powerful people are often stupid. It's almost a prerequisite.

It's time to contact Senators and Representatives. Again. Here's what I'm sending Al Franken and Amy Klobuchar..

Dear Senator

I read in the New York Times that DEA quotas on stimulant drug production are leading to shortages of critically important medications for the treatment of ADD and related disorders.

I understand that the DEA has set these quotes to motivate parents of children with ADHD to prevent the recreational use of stimulant medications. I assume we're supposed to don costumes and start pummeling stimulant dealers to reduce diversion.

Please ask the head of the DEA to explain to you and all of us how their production quotes are supposed to work. In detail. Repeatedly. Until they get a clue.

Thanks very much...

Guanfacine for ADHD in children with autism -- and a recent literature report

Guanfacine in Children with Autism and/or Intellec...[J Dev Behav Pediatr. 2008] is basically reassuring. Guanfacine substantially improves ADHD behaviors in children with autism and similar cognitive disorders. It doesn't have other behavior score benefits. Side-effects were as expected.

I have a standing PubMed search on Guanfacine because it's a long used medication that was recently found to be an "alpha 2A adrenoceptor". That's making it the subject of extensive research, such as:

• changes in neuronal connectivity
• extended release works well in children and adolescents
• strengthening working memory networks (?)
• better prefrontal cortical regulation of behavior in aging animals (?)
  

Guanfacine (Tenex) is not FDA approved for use in ADHD, but the recent crop of articles expect approval shortly. It has been widely used for several years. Our son has taken it for about 2 years.

The challenge is that this medication will be taken for a very long time by very large numbers of children, often in combination with Ritalin. There are sure to be surprises, both good and bad. We don't know it nearly as well as we do Ritalin.

Provigil and ADHD

This is old news (2006) but recent enthusiasm for using Provigil (modafinil) as a productivity enhancement for scientists brought it to mind:

Use of Drug to Treat ADHD in Children Opposed - washingtonpost.com

... A Food and Drug Administration advisory committee voted 12 to 1 against recommending modafinil as safe for children with ADHD. Earlier, the psychopharmacologic drugs panel unanimously agreed that modafinil works as a treatment for ADHD...

... The committee recommended that Cephalon Inc. undertake a 3,000-patient trial to determine the risk modafinil may pose for Stevens-Johnson syndrome...

... one out of 900 children involved in earlier studies of the drug developed the disease. He and Cephalon spokeswoman Jenifer Antonacci said the agency and the company will discuss the committee's recommendation ...

Please note that the enthusiasm for Provigil use by healthy people is occurring at the same time as a series of studies showing accelerated aging associated with lack of sleep.

A new drug for ADHD would be interesting, but it's hard to beat the incredible safety record of Ritalin. Provigil would have to have some really unique or complementary effect to be worth serious consideration.

Rethinking neuropsychiatric diagnoses

I started bemoaning the classification (aka ontology, nosology) of neuropsychiatric disorders about 8 years ago. I'm not the only one. One of the things I liked about Greene's Explosive Child book is that he is clearly unimpressed with the DSM IV nosology.

We're due for another DSM edition, but I doubt that will be any better.

The good news is that in the last 8 years it's become clear to every researcher that all of the common neurospychiatric conditions, from "ADHD" to "ODD" to "Autism" to "Aspergers" to "Bipolar disorder" to "Schizophrenia" are very rough categorizations of thousands of different "phenotypes" (where a phenotype is the end-result of the interaction between genes and environment) that are themselves dynamic over the lifetime of the brain. (Even after adolescence, we see major changes in schizophrenic symptoms between 20 and 50.)

Over the last 3 years we've seen that many different combinations of diverse gene variants, combinations, "malfunctions" and prenatal genetic express modification can produce superficially similar clinical presentations that we squeeze into the garbage bins of "mental retardation", schizophrenia, and "autism spectrum disorder". Most surprisingly, many brains with extraordinary genetic disorders appear normal.

This classification problem isn't simply an annoyance for researchers and industrial ontologists. It has important legal, educational, financial and, yes, clinical implications. The legal, educational and financial implications are large but outside the scope of this post. Suffice to say there is a reason that the diagnosis of "autism" has exploded while the diagnosis of "mental retardation/DCD" has shrunk (clinically speaking both diagnoses are about equally useless).

The clinical implications are what matter to most of us. Autism is a fine diagnosis for getting hugely beneficial school and family services, but if it leads to pure therapeutic choices or misguided interventions then it's harmful. If we lump too many conditions into one bucket, we risk choosing the wrong interventions because they don't match the bucket.

I'm hopeful that over the next decade we'll see a revolution in thinking about neuropsychiatric disorders, and the evolution and diversity of mind. We'll become more empirical about what works and what doesn't, and recognize that the brain at 8, 14, 17, 20, 30 and 40 may be very different. We'll always need classifications, but they may be more akin to "Ritalin responsive" than to "ADHD".

Progress has been slow, but it's coming.

When ADHD is not a disorder: the adaptive advantages of spontaneity

We have often thought our son would have done well laboring on a farm, or scouting ahead of a tribe spying for enemies, predators, and prey. Alas, his superior visual processing and restless activity are ill-suited to today's world. In our world his ADHD and other traits mean he is profoundly disabled.

Paul Steinberg writes about how a set of traits that are adaptive in on setting, can be maladaptive in another...

Attention Surplus? Re-examining a Disorder - New York Times:
March 7, 2006
By PAUL STEINBERG, M.D.

... Every generation likes to believe that it is witnessing the most dramatic epoch in history. In the case of the current Western world, that belief may indeed be accurate, particularly in light of the striking changes of the last 30 years.

As the business writer and consultant Peter Drucker pointed out, most people in the United States, Japan and parts of Europe are "knowledge workers." We live in an information age, in a knowledge-based economy.

For those of us who have "attention-surplus disorder" — a term coined by Dr. Ned Hallowell, a psychiatrist in Boston who has A.D.H.D. — this knowledge-based economy has been a godsend. We thrive.

But attention disorder cases, up to 5 to 15 percent of the population, are at a distinct disadvantage. What once conferred certain advantages in a hunter-gatherer era, in an agrarian age or even in an industrial age is now a potentially horrific character flaw, making people feel stupid or lazy and irresponsible, when in fact neither description is apt.

The term attention-deficit disorder turns out to be a misnomer. Most people who have it actually have remarkably good attention spans as long as they are doing activities that they enjoy or find stimulating. As Martha B. Denckla of the Kennedy Krieger Institute in Baltimore has noted, we should probably be calling the condition something like "intention-inhibition disorder," because it is a condition in which one's best intentions — say, reading 50 pages in a dense textbook or writing a 10-page paper in a timely fashion — go awry.

Essentially, A.D.H.D. is a problem dealing with the menial work of daily life, the tedium involved in many school situations and 9-to-5 jobs.

Another hallmark, impulsivity, or its more positive variant, spontaneity, appears to be a vestige from lower animals forced to survive in the wild. Wild animals cannot survive without an extraordinary ability to react. If predators lurk, they need to act quickly...

... For those with attention disorder who wish to be full participants in a knowledge-based world, medications equalize their opportunities. The drugs should and can be used only as needed in the context of dealing with the tedium of school or the drab paperwork of some jobs.

Cardiologists, biostatisticians and consumer advocates may clamor, appropriately or inappropriately, to reduce the use of the medications. But unless we go back to the caveman world, some people will find the drugs increasingly necessary to succeed as knowledge workers in a drastically transformed modern world.

Paul Steinberg is a psychiatrist and writer in Washington.

Paul's primary agenda is to justify the use of Ritalin despite its new 'black box warning'. Even so, it's nice to see some attention given to how a set of traits can become a disorder -- depending on the context.

As to that black-box warning, it should focus minds prior to prescribing stimulant meds of all classes. That's not bad, even though I rather suspect we'll find caffeine has similar problems. In our case, however, we didn't blink an eye. When you're receiving incoming fire, sometimes you drive without a seat belt.