May 31, 2006
Ritalin Boosts Norepinephrine Against ADHD

Insights into how Ritalin boosts ability to focus attention:

BETHESDA, MD. (May 30, 2006) Methylphenidate (Ritalin) elevates norepinephrine levels in the brains of rats to help focus attention while suppressing nerve signal transmissions in the sensory pathways to make it easier to block out extraneous stimuli, a Philadelphia research team has found.

Their report in the Journal of Neurophysiology helps explain how a stimulant aids people with attention deficit and hyperactivity disorders to improve their focus without increasing their motor activity. Methylphenidate, prescribed under the brand name Ritalin, has been used for more than 20 years, mostly in children, to treat attention deficit hyperactivity disorder (ADHD) and attention deficit disorder (ADD). The drug can also help people who don't suffer either disorder to attend better to a cognitive task.

Despite its wide use, little is known about how the drug, a chemical cousin of amphetamines, produces its therapeutic effects. Researchers want to unlock the mystery of why the drug has the paradoxical effect of decreasing hyperactive behavior and increasing the ability to focus, even though it is a stimulant, said Barry Waterhouse, the study's senior author.

"We're developing a series of behavioral and electrophysiological assays for examining the actions of drugs like methylphenidate," Waterhouse said. "If we can show exactly how methylphenidate works, we may be able to produce even more effective drugs and provide a better understanding of the physiology underlying ADHD."

The study, using rats, is the first to document the increase in norepinephrine and suppression of the neuronal response in this sensory pathway of the brain. "Methylphenidate enhances noradrenergic transmission and suppresses mid- and long-latency sensory responses in the primary somatosensory cortex of awake rats," by Philadelphia-based researchers Candice Drouin, University of Pennsylvania; Michelle Page, Thomas Jefferson University; and Barry Waterhouse, Drexel University College of Medicine appears online in the Journal of Neurophysiology, published by The American Physiological Society.

Can Ritalin boost the mental performance of the average person? It is increasingly popular with college students. Should brain workers be taking it in order to boost their productivity?

The development of better drugs to increase the ability to focus will eventually result in strong market pressures for their use. Workers who do not take such drugs will find it increasingly difficult compete with those who embrace cognition-enhancing drugs.

Modafinil can not compete with amphetamines for treating ADHD.

"The larger effect sizes we calculated for stimulant ADHD medications, compared to nonstimulants or the novel stimulant modafinil, leads us to conclude that amphetamine and methylphenidate based stimulant medications are more effective in treating symptoms of ADHD," said Stephen V. Faraone, Ph.D., lead researcher and director of child and adolescent psychiatry at SUNY Upstate Medical University. "Our results should help physicians who have had to rely on qualitative comparisons among published trials, along with their own clinical experience, to draw conclusions about an ADHD medication's relative efficacy because of largely absent direct head-to-head drug comparisons."

The researchers compared study outcomes using effect sizes, a commonly used, standard statistical measure to determine the magnitude of a particular effect resulting from an intervention, such as a drug used on a population, irrespective of the population size. Effect sizes are generally categorized as small (0.2), medium (0.5) and large (0.8). Standardized mean averages, or effect sizes, for dependent measures in each study were computed by taking the mean of the active drug group minus the mean of the placebo group and dividing the result by the pooled standard deviation of the groups.

After adjusting for the influence of individual study design features, the researchers calculated effect size based on Total ADHD scores. Long-acting and short-acting stimulant medications showed the largest effect size among all medications (E = 0.83 and E = 0.9 respectively), followed by nonstimulant or modafinil based stimulants medications (E = 0.62). Statistically significant differences in effect size occurred in comparisons between nonstimulant/modafinil based stimulant medications and long-acting (p = 0.004) as well as short-acting stimulants (p = 0.002).

For the analysis, Faraone and his colleagues used data from 29 double-blind, placebo-controlled treatment studies of 4,465 children with ADHD, with an average age 10 years, published during or after 1980. Designs for all of the studies were randomized, double-blind with placebo controls that lasted for two or more weeks in populations diagnosed with ADHD as defined using criteria from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition or Fourth Edition (DSM).

My guess: ADHD is a product of natural selection. Tendency to totally focus on a single subject was probably maladaptive for much of human history.

Share |      Randall Parker, 2006 May 31 09:41 PM  Brain Enhancement

Agnostic said at May 31, 2006 11:12 PM:

Re: ADHD being the product of natural selection -- you've been scooped:

Hans Eysenck's idea was that the brain difference b/w introverts & extroverts was that the former had a higher base level of cortical arousal, while the latter had a lower level. This lower level leads them to seek out exciting situations and social engagement in order to boost arousal to a happy optimum, while introverts don't need to engage others since their levels are already pretty high. That's borne out by some good experimental work, too, but probably isn't the complete story. So, that resolves the paradox: higher levels of arousal make you more sensitive to most stimuli, so you don't want to be disturbed (like those who use cocaine), while lower levels leave you longing for stimulation, so you become more social (like when you get drunk).

Now, a stimulant drug is an artificial way to boost arousal -- so, for these extroverted people who can't sit still and focus like us good introverts, Ritalin will obviate the need to socialize & goof off just to reach the happy optimum. Introverts have to be careful of stimulants, since the same dosage as given to an extrovert will push us farther over the happy optimum -- and we'll become too on-edge. That's good for some things, but not always for focusing.

Of course, this is exactly what caffeine does, so I don't see why we aren't just giving these hyperactive kids a triple espresso before they go to school. It's damn cheaper, no need for prescription, and humans have been ingesting it for longer than Ritalin, so the potential side effects will be less -- esp since the long-term side-effects of Ritalin are unknown, as it's only been in use for 20 years. They may be identical to those of caffeine, but here I'd bet people would be more risk-averse.

Rob said at June 1, 2006 5:16 AM:

That's really interesting. I'm super-introverted, but I'm pretty sure I have ADD, and I drink tons of caffiene.

Lono said at June 1, 2006 10:32 AM:

I am an extrovert and my wife is an introvert - we both drink excess caffine - and we both have significant ADD.

So, caffine doesn't help and personality in my personal experience is not directly linked to one's ADD, although it may be a learned, indirect behavior.

(and I also didn't drink caffine excessively until well after I was diagnosed with ADD)

However, my experience with Ritalin was particularly odd.

When I took the normal dosage - I did indeed experience a large increase in concentration - almost to the point of distraction - but shortly thereafter I experienced intense fear and inability to sleep for up to ten hours.

Fear is not something I normally experience, as I am one of those individuals prediposed to huge risk taking - so it was a particularly unpalatable experience for me.

I took it again on two seperate occasions and I had the exact same symptoms each time.

I would be very curious if any readers here have experienced this "fear effect", or have any idea what neuro-chemical process may have caused this effect.

(if this effect could be recreated on non ADD people it could be a potent psycohological tool)

Also I wanted to note that part of the Evolution of ADD and ADHD may be due to the fact that such a condition also allows for Hyper Focusing in small bursts which researchers have speculated would have been excellent for hunting, and thus perpetuated in the gene pool.

It certainly does have some real drawbacks in this sedentary information age we now live in however.

Randall Parker said at June 1, 2006 4:22 PM:


Is being introverted different than being shy? Shyness seems pretty specific to human dealings rather than to stimuli in general. Shyness seems driven more by fear than by a feeling of being highly stimulated already.

Agnostic said at June 1, 2006 9:24 PM:

Randall -- introversion / extroversion just refers to how naturally outgoing you are, more or less. If you prefer being alone, i.e. are introverted, that doesn't mean you're shy or not -- you just prefer being alone, don't feel the need to go out of your way to engage people, chat them up, etc.

That's just one part of it, though. It turns out that introverts are more sensitive to all sorts of stimuli -- if you squirt lemon juice in their mouths, they salivate more than extroverts. They react more strongly to electric shocks (sweat, heart rate, etc.). And they find it more difficult to perform cognitive tasks when there's background / distracting noise. These things obviously have nothing to do w/ personality, so when you do personality tests, only the social engagement stuff is asked about, but it probably reflects an underlying brain difference (at least cortical arousal) that has broader effects.

Rob said at June 2, 2006 7:30 AM:

Has anyone here tried provigil for off-label use? I must admit I find it intriguing for the IQ boost

crush41 said at June 2, 2006 8:50 AM:

Wow. Great explanation Agnostic. Thanks for that!

Doug said at June 4, 2006 3:20 AM:

Given the seeming importance of increasing norepinephrine release in order to boost attention, it seems attention should be paid to vitamin D3 sufficiency in people with an attention deficit. One of the metabolites of vitamin D3 regulates the rate-limiting step in the production of tyrosine, a precursor of norepinephrine. The proximate source of my information is John Cannell's website, The Vitamin D Council.

John Faughnan said at June 4, 2006 7:19 PM:

Caffeine was studies as an ADHD drug in the 1970s I think, and used earlier. There really wasn't much good research when I last looked five years ago. Looks like not much has changed: (search for caffeine ADHD).

So we just don't know. I'd love to see some more studies. Problem is Ritalin works pretty well for a lot of kids, so it's hard to justify putting them on caffeine instead for a clinical trial. Also there's no money in caffeine, so funding would have to come from the feds. Ritalin is off patent, so there's not a lot of cost incentive to do the studies. The research would cost a bundle ... said at June 11, 2007 1:17 PM:

Okay, so I just started taking ritalin and over a week took about 1500 mg. The thing is when I take it the right way, it really really helps, but I cant control myself. Now I'm out and craving it bad and want more and I dont know what to do.

Ritalin Side Effects said at December 8, 2008 12:32 PM:

My name is Lance Burnet and i would like to show you my personal experience with Ritalin.

I am 56 years old. I have taken Ritalin for 30 years. I have been diagnosed with a mild form of narcolepsy. I use 4 (10 MG ) pills per day. The drug ahs worked wonders and eliminated the drowsiness and sleep attacks. My concern now is the length of time I have been on it. When taking a "drug holiday" it seems like my symptoms are worse.

I have experienced some of these side effects-
rebound effect when dosage wears off.

I hope this information will be useful to others,
Lance Burnet

Tom said at March 29, 2009 6:42 PM:

It is the norepinephrine that causes the fear in some people. It is connected to the "fight or flight" response. Probably stimulates it in some way. I was on Wellbutrin and it was not long, a few weeks, before I had panic attacks. Well there goes the Wellbutrin "flush". What my brain needs is to raise serotonin levels, which prozac does a great job of eliminating the negative symptoms of depression for me. The positive fellings of motivation ect... are not being addressed at this point. What I need is a drug that will just target the dopamine levels not norepinephrine. And if medical science can't help me I will go to an alternative way. Tyrosine, methionine, B6, Folic Acid and any other precursors to dopamine. It will be tricky because I have to find just the right amount that will raise dopamine without raising norepinephrine too much. Perhaps there are some herbs that can bring those levels(norepinephrine) down?

Adam A said at June 7, 2010 1:25 AM:

Tom, there is a drug called Clonidine (Catapress) that I am prescribed along with dexamphetamine (and ritalin when I was on it) that inhibits the release of norepinephrine. It doesn't affect DA levels.

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