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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 17, 2008

Getting Smarter Already?

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Posted by Derek

There have been several articles in Nature recently about performance-enhancing drugs. But these aren’t steroids or blood-cell therapies: they’re performance enhancers for scientists and engineers. Chief among them are Ritalin (methylphenidate), Provigil (modafinil), and various beta-blockers, to enhance concentration and wakefulness. The whole topic came to the fore last December, in an article suggestively titled "Professor's Little Helper". Here are the results of their informal readership poll. It's not a huge trend, at least not yet. The fraction of their self-selected sample who had never taken any such compound was in the solid 70% range, and you'd expect people with some experience to be disproportionately represented in such a poll. But usage is out there, nonetheless.

The first question to ask in these situations is, do such drugs work? As you’d guess, there’s no controlled data set to work with. There is, under current regulations, absolutely no way that any company with such a compound would run a trial for cognition enhancement in otherwise healthy people. The FDA has made it clear over the years that they are in the business of regulating drugs that help sick people, not ones for people who have no disease at all. In fact, I don’t think that the current regulatory framework even accommodates the idea of making people “better than well”, and if someone proposed such a study, it’s a solid bet that the FDA would turn it down.

So, in the absence of anything rigorous, we have a flood of anecdotal data, which is what the Nature pieces are full of. Take that along with the many reports of students using these drugs, and you have something significant going on, which has been coming on for a while now. Back when I used to work on Alzheimer’s, we used to speculate about what would happen if we ever did come across something that usefully enhanced human memory. I was sure that a large off-label market would develop among college students. I have to admit, I never considered their professors.

But do they work? Well, I’m willing to stipulate that they do, but I’m not sure to what extent. One confounding variable, which will be very hard to address outside of a controlled trial, is the placebo effect. I have to think that there’s a strong one in this area, that if you think you’ve taken something that helps your concentration and memory, that those functions will measurably improve. How much this counts for is impossible to say – but again, I’m willing to stipulate that there are pharmacological effects above and beyond placebo. In other words, I believe that a controlled trial of healthy individuals would, in fact, show improvement in cognition while taking such compounds. How much, and in what particular tasks, and for how long, and across what subgroups of people, and across what particular dosing regimens, and in what proportion to objectionable side effects, I have no idea. But I think that there’s something there.

And there will be more. I feel sure that other compounds will be developed that affect normal cognition in what are (at least under some circumstances) are beneficial ways. They will not, however, be approved for that purpose. That’s a long, long way off. They’ll be approved for Alzheimer’s, or sleep disorders, or some category of attention deficit disorder, which is how we have the compounds we have now.

This situation is similar to various possible anti-aging therapies. There, too, I think that compounds will come eventually that should be able to show benefits, according to what we understand about aging in other species. But they won’t be approved for that. They’ll be approved for diabetes, most likely, considering the strong links between insulin action and lifespan, or possibly for other slow-developing degenerative disorders. But if aging itself is a slowly developing degenerative disorder, what then?

I’ve been meaning to write something about this story for a while, but one of the problems has been that I’m still quite divided about what I think about it. (Normally my opinions come to me more quickly, for better or worse). Some background: people who’ve known me personally for a while generally know that I’m personally very much opposed to chemically altering the way that I think or feel. I never drank in high school, for example, which I can tell you made me stick out a bit in late-1970s Arkansas. Nor did I in college or afterwards; I still don’t drink now. And that personal prohibition goes even more for other recreational drugs, as you’d imagine.

My reason for that has long been that I enjoy my brain the way it is, and have seen no reason to mess up its function for fun. But the advent of cognition enhancing drugs is a scalpel to dissect that line of thought. What if the ingested chemicals add to some of the parts of my brain that I value the most? That “mess up its function” clause has been taken out and flipped upside down. And what if it’s for work, and not for recreation? Is that more allowable, because it’s somehow less frivolous? (All right then, what if I were to enjoy having a better memory, which I likely would?) That gets to a less creditable reason for my objection to alcohol and other such drugs – perhaps I’m not just objecting to them on practical grounds. Perhaps I’m objecting because I don’t want other people to have a good time, at least not like that.

Food for, well, thought. I’m still working this one out, I have to say. The issue of caffeine will come up as I do – I don’t drink tea or coffee, actually, having never wanted to end up in the position of having to drink either to function. But I don’t object to caffeinated soft drinks, although I don’t generally seek them out. But I have, when I’ve needed to stay awake – so how high a horse can I get on, anyway? Caffeine is a good proving ground for positions on the newer compounds.

Comments are, as always, welcome. I suspect that this is one of those issues that everyone has an opinion on. . .

Comments (27) + TrackBacks (0) | Category: General Scientific News


1. azmanam on April 17, 2008 8:22 AM writes...

"The FDA has made it clear over the years that they are in the business of regulating drugs that help sick people, not ones for people who have no disease at all."

What about birth control?

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2. Lethe on April 17, 2008 8:24 AM writes...

The whole issue makes me uncomfortable in a visceral sense; it sits on the milder end of the continuum whose stronger end includes genetic improvement of unborn children.

In a practical sense, I don't see as there's any way to avoid the coming of such changes. Just as steroids and the like have proven irresistible to atheletes, "smart drugs" will prove irresistible to intellectuals. If they become accepted (and perhaps more importantly, legal), then it's likely I'll use them along with everyone else.

It seems possible to advance an argument for a moral obligation to use these sorts of drugs rather than rejecting them. If, as scientists, we see ourselves (rigthly or not) as advancing the state of humanity through increased knowledge, would it not be morally questionable to refuse to take otherwise harmless drugs that would let us do our jobs better? (Note that I'm not advocating this argument personally; I'm just considering whether it has merit.)

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3. Roadnottaken on April 17, 2008 9:19 AM writes...

The question of 'legitimate' use becomes clouded by prescriptions of Ritalin to children with hyperactivity disorders. The definition of what a "sick person" is changes with the times and cultures. Perhaps we define "sickness" as that which can be treated with medication. In the future when we have really good cognition-enhancing drugs perhaps stupidity will be seen as a 'disorder' much the way hyperactivity is now.

Also, it is relatively easy to define moral guidelines for yourself regarding use of psychoactive drugs but what about your children? Something like 5% of kids today are on Ritalin. As use of these substances becomes widespread, you're effectively putting your kids at a disadvantage by not jumping on the pharmaceutical bandwagon.

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4. emjeff on April 17, 2008 10:42 AM writes...

That definition of "sick people" has gone out the window with the approval of Viagra. While I am not saying that ED is not a problem, I will go on record as stating that someone with ED is not "sick" in the classic sense.

Cognitive enhancement drugs are nothing new. Derek mentioned caffiene, which is a biggie. In the mid-80s, there was alot of press around beta-blockers and their use in kids taking the SAT. There were some pretty convincing (but small studies) on that.

This brings up a problem similar to what is going on in athletics right now. Do we test high school seniors prior to tking the SAT? Do we invalidate the results of a test if a kid is positive for a cognitive enhancer? It's a brave new world...

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5. Merkwurdigliebe on April 17, 2008 10:46 AM writes...

"What about birth control?"

A controversial example, to be sure. But if you have been involved in the birth of a child post 1990, then you know that the medical community treats pregnancy as if it were a disease.

But on the topic at hand: as with all biologically active compounds, there are almost always multiple effects. Some good. Some bad. From a scientific point of view, you would want to remove as many of the other effects (and certainly most if not all of the bad ones) before you would try touting the compound as an "enhancer" (I'm not sure what else to call the opposite of a "cure").

Then there are long-term effects to consider.

As for the ethical considerations: from a personal standpoint, it's no one else's business what you do with your body, however most countries and communities do not provide that much personal freedom. I'm sure any enhancing drugs that are discovered will become either highly regulated, or more likely, banned altogether thus relegating any who wish to partake to sources of questionable quality.

Until then we always have caffeine. Do you ingest caffeine, Derek?

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6. hibob on April 17, 2008 10:59 AM writes...

"What about birth control?"
Whatever the medical community thinks about pregnancy, I think the FDA has made it pretty clear over the past few years that its leaders would prefer not to approve new methods or drugs for birth control, and often go against the recommendations of their own advisory boards in order to avoid doing so.

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7. John Novak on April 17, 2008 11:43 AM writes...

Well, finasteride is FDA approved specifically to combat male pattern baldness, so in that light, I guess baldness is a disease or a sickness. Admittedly, there are other uses, and those came first, but still.

On the deeper issue, I have a very similar opinion to chemically-altered thinking as Derek describes, with similar social effects-- I was the one in high school and college (and largely even today) who just doesn't drink. However....

...Within certain (admittedly hazy) limits, I do defend the rights of people to think as they choose to think, which means I am generally supportive of their rights to achieve those thoughts with chemical assistance.

And I am absolutely enchanted by the idea of wakefulness drugs like Modafinil. It is one of the ironies of my life and career that:

1) The military promoted wakefulness research for fighter pilots,
2) I design equipment for fighter jets,
3) The results of the former are schedule IV drugs, and,
4) Even though we don't do random drug sweeps here, I value my promise to my employer highly enough that I have not indulged illicitly, or even pestered my doctor friends for a prescription.

When I think of what I could accomplish if my need for sleep were slashed by 75%, I mean hell, I could keep my job and go back to school and get my doctorate...!

I am thinking that sooner or later, either the FDA is going to need to change, or there will need to be a parallel organization devoted to non-therapeutic drugs.

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8. Eli on April 17, 2008 12:05 PM writes...

Derek, did you get a concurrent PhD in philosophy of which I was unaware?

Since you actually are an organic chemist, maybe I could interest you in some tetrahydrocannabinol for some mind expansion on this subject. If we are advocating compounds closely related to methamphetamine to enhance our alertness, I say what the hey.

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9. Kyle Finchsigmate on April 17, 2008 12:08 PM writes...

Current polling suggests usage would be at least 15% higher if they had the drugs.

At least that's the current polling on my self-selected survey here.

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10. Pete on April 17, 2008 1:15 PM writes...

In addition to the approval issue, there is a payment issue as well. Whereas health insurance will pay (at least partially) for on-label medicinal uses, I doubt they'll pay for off-label enhancement uses.

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11. anon on April 17, 2008 1:15 PM writes...

Having used both ritalin and modafinil to enhance my preparation for exams, I can attest to the effectiveness of the latter. Whilst most literature seems to focus on its 'stay awake for 72 hours with only 8 sleep' properties, I have used it for memory enhancement, coupled with a healthy diet, exercise and adequate sleep. It seems particulary effective when used to memorise structures and patterns- particularly useful for learning the organic chemistry of biosynthetic pathways. Ritalin on the other hand, is more useful when VERY occasionally used for boosting motivation to work for long periods. It doesnt however seem to have any positive effect on memory or recall time and it would be quite 'moreish' for someone with little self control...

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12. rosko on April 17, 2008 1:20 PM writes...

I have actually ONLY used Ritalin for recreational purposes, not to study. As someone who finds stimulants interesting from an enjoyment point of view, I would somehow find it a waste to use such drugs for as mundane a purpose as getting some homework done. The same goes somewhat for caffeine--I don't drink that much coffee, but only because I find that it loses its "buzz" quite quickly with regular intake. I'd rather be able to appreciate the stimulation when I really want it, not just use it as something I rely on to get up every day. Of course, no matter what I do I think about science a lot, even when I'm having fun, and so it may end up contributing to human knowledge after all.

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13. Mark M on April 17, 2008 1:23 PM writes...

I use OTC memory enhancers daily for my line work which requires me to speak fluently across many fields of biology and chemistry. With lots of little kids running around at home and the inherent lack of sleep they cause, I need all the help I can get!

But I have always been a proponent of Ach mechanisms vs those involving catecholamines.

Hence, I take DMAE--readily absorbed across the BBB and a substrate for enzymes that methylate it to choline.

Of course, getting a good night's sleep, exercising and eating well are the best cognition and mood enhancers.

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14. processchemist on April 17, 2008 2:28 PM writes...

There's a whole market about enhancers, and it's all about nutraceuticals. Natural extracts: ginseng, guarana, soybeans (lecitine). Note that some drugs of a forgotten family (ergotamines), such nicergoline and cabergoline (still used as geriatric drugs) are found in quite a lot of nutraceutical formulations. The same for some aminoacids derivatives (phosphoserine, phosphocreatinine).

In my university days, 200 mg of ginseng standardized extract were working fine for the "heavy" examination sessions (when you were alone at the hands of the commission for about 2 hours)

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15. processchemist on April 17, 2008 3:26 PM writes...

Apart from ergoline derivatives, there are also the two of the vinca family, vincamine and vinpocetine

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16. psi*psi on April 17, 2008 4:56 PM writes...

"What about birth control?"
Ovarian cysts? Endometriosis?!

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17. qetzal on April 17, 2008 10:14 PM writes...

The first question to ask in these situations is, do such drugs work? As you’d guess, there’s no controlled data set to work with.blockquote>

I wonder why not? I agree no sane pharma is going to target an unapproved drug for this, but I don't see any major barrier to an academic group running a double blind trial on one of the existing drugs (Ritalin, Provigil). Psych depts run studies of memory and concentration all the time, so reasonable methods exist to detect real short-term effects.

In fact, I'd be rather surprised if someone somewhere isn't running such as study already. In fact....

Yep. I checked Pubmed. There are a number of randomized, double blind studies on effects modafinil or methylphenidate on cognitive function in healthy, non-sleep-deprived adults. A quick skim suggests evidence observable benefits are pretty limited.

P.S. Derek - there's something wrong with your spam blocker. Every time I've tried to post recently, it blocks me. Says I've posted too many comments, but all I've done is previewed. Same with the above. I'm waiting a while to try to repost.

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18. RTW on April 17, 2008 10:57 PM writes...

Lethe - Your comment "smart drugs" will prove irresistible to intellectuals. Reminds me of the human computer Mentats of Frank Herberts DUNE. These people where addicted to a Sapho which "amplified speculation and extrapolation"

As Derek has indicated substances of this type could legitimately be thought to be useful in dementia and Alzheimers. Back 27 years or so ago as an undergraduate - I was following the research of a fellow named Alexander T Shulgin. He was studying the pharmacophore for the amphetamine/mescaline chemotype. I did a report on this area for a senior seminar course in chemistry. He found what he believed to be a cognition activator, which he assigned to Bristol Myers in 1978. See US patent 4,105,695.

In many of his J.Med.Chem. papers he very carefully characterized behavior and psychological effects on human volunteers, who had prior experence with psychotropics and amphetamine useage, and made a pretty good case for some of these compounds. Perhaps these are the precusrors to drugs such as Ritalin which could fall into a very similar chemotype.

I think it quite likely that these types of drugs might be more and more abused by this sector of society as time goes on, thinking it safe and perhaps able to give them an edge in their work.

Think of what many artists use to do to get greater insight and expand their minds. Heroin, LSD etc.... Of course this killed a lot of very talented people, and more than likely had nothing or very little to do with their talent, and more to do with just breaking down social inhibitions.

Just my two cents..

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19. Hedonist scientist on April 18, 2008 5:57 AM writes...

"I still don’t drink now; I don’t drink tea or coffee"; and: "having to drink to function"....

Holy cow, Derek! You sound like a rare member of the human race. Isn't your asceticism the explanation as to why your opinion on today's topic does not come more quickly....-;)

(WHM, Amsterdam)

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20. Gaudisso on April 18, 2008 7:16 AM writes...

It's a hazy line to draw between improving someone's quality of like and enhancing or altering their reality. I occasionally prescribe SSRI's for social awkwardness, topical testosterone in older women with decreased libido and topiramate for weight loss. The net benefit of these interventions has been healthier and happier patients so I have no qualms about exploiting my pharmaceutical armamentarium in this way. I've also tried Namenda (memantine) for improvement of mild cognitive deficits in healthy due to its competitive inhibition of NMDA receptors. Empirically I see some early benefits, but it's difficult to separate out the placebo effect in these cases.

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21. Justin on April 19, 2008 7:59 PM writes...

great stuff, good to see you got around to writing it

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22. Brooks Moses on April 19, 2008 11:57 PM writes...

Hedonist Scientist @19: While it might be rare, I'm the same way with not drinking alcohol or coffee or tea. (I also don't do caffeinated soda -- or non-caffeinated, for that matter.) I don't hold any sort of moral superiority for it; a lot of it is just inertia -- and the fact that the times when I might actually benefit from some caffeine are decidedly not the times to learn how it actually affects me.

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23. Retread on April 20, 2008 5:55 PM writes...

Has no one been in a Whole Foods store with its upscale and highly educated clientele (at least around here) and gone into the aisle where the memory enhancing, and intelligence enhancing nostrums are. The claims are incredile (but apparently believable to the masses thronging the store). They wouldn't be stocking the stuff if it wasn't selling. No double blind studies for them. Like a fundamentalist church it's all testimony (which is fine for religion, but not for us scientists).

It takes a lot of education to believe something this dumb.

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24. Anonymous on April 21, 2008 3:17 PM writes...

"There's a whole market about enhancers, and it's all about nutraceuticals...such nicergoline and cabergoline"

Isn't that a bit of a stretch--semisynthetic (or totally synthetic, I don't really know) ergolines as "nutraceuticals"?

and RTW is correct about how many great minds have used psychoactive drugs. I bet there are several reasons for this. First, these drugs do put you in a different state of mind, and may help you think in a mode that's a little different than what you're used to. Secondly, I think such people have less of a problem ignoring society's general disapproval of those substances. Also, many such people may not feel satisfied trying to pursue the life goals that society seems to set for them, and look for another source of entertainment.

--says Rosko the day after 4/20

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25. processchemist on April 22, 2008 4:53 AM writes...

>Isn't that a bit of a stretch--semisynthetic (or >totally synthetic, I don't really know) ergolines >as "nutraceuticals"?

It's amazing what can you find digging the "nutraceuticals" field (last I heard about is N-acetylcysteine, as antioxidant).

Ergolines (all semisynthetic) are not exactly "safe substances" (see pergolide), the market is not so big, but still about 100 Kg (rough estimate) of the whole family find their way to the consumers worldwide, as API or nutraceutical ingredient.

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26. Jen on April 22, 2008 11:44 PM writes...

I taught college level organic chemistry at a small public college in Massachusetts a couple of years back.

Most of my students were open about their use of Ritalin as a "study aid". They were less forthcoming as to their source of the drug though one student hinted it was fairly easy these days to go to a doctor, give him/her a laundry list of symptoms typical of ADD/ADHD and come away with a prescription.

One student even describe the huge amounts of money she had been offered for her monthly prescription. Truly frightening.

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27. rtyecript on August 25, 2011 10:47 AM writes...

I really liked the article, and the very cool blog

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