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The Brain User's Guide to Pills [Apr. 30th, 2007|11:35 pm]
Arvind Narayanan
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The Brain User's Guide to Pills: an overview of Cognitive Enhancing Substances

My post on caffeine elicited much interest, especially about other ways to enhance mental performance, creatine in particular. Prepare to read the mother of all brain posts, the alpha and the omega of cognitive enhancing substances (a.k.a nootropics or "smart drugs.") What I've found greatly surprised me: while there are an enormous number of substances with the potential for preventing the degradation of memory and intelligence, many of which are regularly used to slow or reverse mental aging in the elderly and also to treat a variety of mental and developmental disorders, there is little or no research on using these drugs on healthy individuals.

Lack of demand. At the same time, there is surprisingly little interest or awareness among the general public in the use of nootropics. Surely, even if people are not interested in cognitive enhancement for its own sake, it should be clear that by being smarter we also give ourselves the chance to become more successful professionally, and become more wealthy or whatever our definition of success is. After all, the majority of us in modern times live by our brains -- doctors, journalists, programmers, you name it. So before I proceed further, I'm going to take a guess about the answers to these twin questions of absence of research and lack of demand. The impatient can skip to the table at the bottom.

The first question is easier to answer. We live in a welfare state (or something pretty close to one); the government is more interested in providing a safety net to unfortunate individuals than helping fortunate ones excel. Clearly then, the emphasis of publicly funded research is on using nootropic drugs to treat pathological conditions than to enhance cognition in healthy individuals. Further, because of medicare and medicaid,  and the nature of health insurance in general, it is much more lucrative for pharma to target people with ailments. While I might disagree with all forms of government welfare, it is the reality of the world we live in, and I will move on instead of complaining about it.

What about the lack of public awareness or interest? Why the obsession with caffeine but ignorance of other safer, possibly more potent substances? This appears to be due to a complex of related reasons. One is that people have trouble believing that cognition can be enhanced (and probably view coffee as a cure for sleepiness rather than what it really is.) A related, second reason is ethical opposition perhaps stemming from the argument that wealthier people will have more access to smart drugs if they become available. Finally, there's a psychological aversion to consuming pills when you're apparently healthy.

In praise of poppin' pills.
While the idea that the human form is perfect may have biblical roots, some form of it appears to be held by most people, sometimes subconsciously. We believe that our "normal" condition is healthy, and that we don't need to fix ourselves up unless we deviate from it. I disagree: if we can augment our physical and cognitive abilities without serious side-effects, I can't see why we shouldn't do so, and further, our "normal" condition must be viewed as diseased. As for ethics, as far as I'm concerned, ethics can bite my chemical ass. Consider this article about smart drugs that asks "What would happen if people got smarter? Is this a good thing or a bad thing?" and then goes on to ask a number of similarly inane questions. It is very hard for me to fathom that people could not want to be the smartest, healthiest or most successful person that they have the potential to be.

Wading through the crap. The abundance of research on geriatric subjects means that there's an enormous number of compounds to look at. The lack of research on healthy volunteers has led to a large number of quacks on the Internet. Even with pagerank, the ratio of genuine to fake articles is around 1:5. Fortunately, some simple and well-known rules of thumb increase the signal/noise ratio considerably: for instance, you can generally trust articles on PubMed, and anything that contains 'natural' or 'herbal' in the title is a scam :) The process still took way longer than expected, but I felt it was worth the trouble. Many compounds fell by the wayside, either because of side effects, not enough studies, or because the efficacy is proven only in the aging population. In particular, DMAE, Vasopressin, ALCAR, hydergine, pyrinitol, ginkgo biloba, B. monnieri and vinpocetine are all potentially interesting but I can't recommend any of them based on the current evidence. This list includes a number of compounds frequently used and sold as smart drugs.

Disclaimer: obviously, I have no medical qualifications whatsoever and none of this is medical advice. With that out of the way, let's get to the meat.

Vitamins. Possibly the dumbest thing you can do to yourself is not to take a daily multivitamin supplement. One are more vitamins are essential for every single known mechanism of cognitive enhancement. The role of vitamins is more to keep things chugging along smoothly than to bestow super-normal cognitive abilities, but the fact that there are so many different vitamins, and that our diets differ so much from the "natural" diet of our ancestors means that without vitamin supplements, you are very likely to fall short on one or more essential nutrients, with an inevitable effect mental performance. Of course, vitamins are also essential for all kinds of disease prevention, but I'm not going to talk about that here.

Omega-3 Fatty acids. Another essential supplement group. Here are the facts, in short: a balanced omega-3/omega-6 dietary ratio is essential for good health, including mental health; however, omega-3/omega-6 ratios dramatically skewed in the Western diet. Omega-3's are essential for correcting cognitive deficiencies; when given to pregnant women, it improves mental health of fetus; it prevents learning disorders in children; deficiency of omega-3 is implicated in a variety of mood disorders; it also improves general health in a variety of ways. So again the role is one of disease/disorder prevention than cognitive enhancement per se, but the risk of deficiency is high and swallowing your daily two omega-3 capsules is so easy there's no reason not to be doing it.

Green tea. The cognitive benefits appear to be mainly due to theanine, which increases seratonin and dopamine levels, but possibly also due to tea's antioxidant properties. Again, studies on young healthy volunteers are lacking, and most of the evidence is circumstantial. There appear to be a number of noncognitive benefits however, and therefore tea goes on the recommended list. Note that tea has caffeine in it; check the label. Also note that there are a number of overblown health claims around green tea, as with anything else that is herbal, Eastern or ancient.

Caffeine. Caffeine hits you like a hammer -- it has a very broad spectrum of action, and comes with a list of side effects that would put viagra to shame, not the least of which is stained teeth. Ugh! But it works, and that's been established without question by a barrage of scientific studies. Since I said a lot about it last time, I won't say much more, except to suggest getting caffeine pills instead of drinking the corrosive liquid.

Creatine. Only one scientific study exists. But that study is conclusive -- vegetarians benefit substantially on intelligence and memory tasks from creatine supplementation. What about meat eaters, who get more creatine in their diet than vegetarians? If you read the paper, there is a good bit of evidence that it benefits everyone. As well, the mechanism of action appears to be well understood compared to other substances (improving brain oxygen supply via ATP stabilization). Note, however, that you lose the benefits once you stop taking creatine. Creatine is safe in the short term if taken properly, and while there is no particular evidence that it could be harmful in the long term, there haven't been any large studies on it, so use it at your own risk.

Piracetam. Remarkably safe, reasonably side-effect free. Multiple modes of action have been hypothesized, primarily through replenishment of the neurotransmitter acetylcholine. According to wikipedia, "it has become popular as a cognitive enhancement drug among students, who often buy it in bulk as a powder and then consume it with orange juice to mask the strong, bitter taste." This post on imminst.org by someone attempting to determine the effect on healthy individuals is illustrative of the frustrations of trying to find information on the use of nootropics for normal people, but the balance of evidence appears to point in piracetam's favor.

Modafinil. Easily the most intriguing item on this list.  Modafinil has been in the news a lot -- it's claim to fame is that it lets you go 40 hours without sleep and without loss of productivity, and the US army is interested in it for obvious reasons. Adrafinil was the precursor drug developed in the 70s, and it works by metabolizing into modafinil; the latter when taken directly has a quicker action and fewer side effects. Adrafinil and modafinil are ampakines, which fall into the broad category of stimulants along with amphetamines (which Erdos famously used), ritalin and caffeine. While the earlier drugs offer varying tradeoffs between efficacy and side-effects, ampakines promise to deliver the goods without the nuisance.

While there is no doubt about the wakefulness promoting properties, claims have also been made about cognitive enhancement, and there is much anecdotal evidence to support increased vigilance and alertness. It's also been claimed that effects persist after usage is stopped. Double-blind studies are as usual harder to come by, and I can't tell for sure how effective they are. It's also been claimed that the effects persist after you stop taking them. Unsurprisingly, modafinil is classified as a drug, although off-label use (prescription for a purpose other than approved by the FDA, which is not illegal) in healthy individuals is apparently widespread. Further, adrafinil is classified as a dietary supplement, and so should be even easier to obtain. This seems really, really worth checking out further.

Safety/side effects/side benefits Notes
Obviously good for you
All-round Proven Same as above
Green tea
Seratonin/dopamine enhancement
Plausible Antioxidant/several other benefits
Caffeine Concentration/stamina
Proven Several mild but unpleasant side effects
Recommended (short term)
Piracetam All-round/Acetylcholine replenishment Probable
Remarkably safe, few side effects
Creatine Oxygen supply Probable
Aids muscle building; Long term safety unknown
Suggested, especially for vegetarians
Modafinil Anti-sleep, Stamina/focus, long term effects
Drastic action, effects not sufficiently well understood
More research needed
Classified as drug; hard to obtain

Cocktails. Obviously, there is even less research on using nootropics in combination. I wouldn't worry about the first three, and caffeine is used by a large percentage of the world's population, so the potential for surprise is small. While piracetam is very safe, it tends to interact, typically synergistically, with other drugs including caffeine, and therefore the dosage may have to be modulated. As for how creatine and modafinil interact with each other and with caffeine and piracetam, I have no idea.

Exercise appears to improve cognition in two different ways -- increasing brain oxygen supply and increasing dopamine and serotonin levels (which are important mood and reward chemicals.) Only aerobic exercise has this property, and not, say, weight training. Even mild exercise such as walking is significantly better than no exercise at all. Therefore I would recommend high-intensity interval training as often as you can manage and walking every day.

Personal note. Of course I'm putting my money where my mouth is :) My plan, as a result of this post, is to continue taking vitamins, omega-3s and creatine daily, start taking green tea regularly instead of sporadically, cut down caffeine to a less-than-daily frequency, buy piracetam and start using it daily, and try to obtain modafinil and experiment with it. Let's see how it goes. I haven't been doing any cardio recently, and it looks like I'll need to start up again. Finally, thanks to everyone who asked me questions last time and prompted me to research and write this.

[User Picture]From: normalcyispasse
2007-05-06 02:02 pm (UTC)
Thanks again for a well-conceived post -- however, I disagree that multi-vitamins are truly a miracle. I've read a fair bit of literature that indicates that the hyperconcentration of vitamins and minerals in typical vitamin pills simply leads to, well, expensive urine.
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[User Picture]From: arvindn
2007-05-08 04:26 am (UTC)
All I'm claiming is that one pill a day helps avoid deficiency disorders. I'm definitely not suggesting overdosing! I did find a number of references supporting this weaker claim, but I'm too lazy to dig them up again.
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From: (Anonymous)
2007-05-20 05:04 pm (UTC)
Even one multivitamin a day results in funky-colored, odoriffic urine for me. I weigh very little, so the recommended dosage is way too much for me.
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[User Picture]From: arvindn
2007-05-21 12:56 pm (UTC)
Drink more water.
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