A rationalist's guide to psychoactive drugs (2011)
A rationalist's guide to psychoactive drugs
This is a first draft.  Over the next few days I'll add citations and that sort of thing, but I'm posting it as-is in order to solicit feedback.  Also, I wasn't able to find any specific policy regarding mention of illicit substances, so I'm going to assume this is okay, but if not please let me know.
Disclaimer: This is a work of postmodern fiction about two irredeemable junkies named Alice and Bob and their cat Fido.  The views contained herein are not medical or legal advice, they are not my views, and they are not the views of LessWrong.com or any of its members.  In fact they are not views at all: they are transnarrative flows in alterity-space, or that's what my lit prof tells me.  I do not condone any illegal activity whatsoever, except jaywalking.
Introduction
Today, says Alice, I'm going to talk to you about drugs.  I'll be covering several nutritional supplements, some stimulants and nootropics, and - as some of you have probably guessed - I'll also be talking briefly about recreational drugs, particularly psychedelics.  Now, I don't have any sense of what the popular perception is of drugs around here, but I presume that at least some of you will be a little put off at the suggestion of recreational drug use.  If that is how you feel, please bear with me.  To partake or not partake of prohibited substances is a choice that must be made individually, and for many the payoffs may not be worth the risks; but I hope to convince you that, at least for some people, responsible drug use is a very reasonable and beneficial activity.
Well, hold on, says Bob - who takes a permissive but detached view of these things - hold on, now.  It may be true (as cursory research will show) that drug use is far less dangerous than it's made out to be, and it may be true that some people get a lot of enjoyment out of them.  But if you value knowledge and reason over hedonic pleasure, it seems better to cut them out entirely.  After all, it's your brain on the line if anything goes wrong!
As a matter of fact, says Alice, drugs are good for more than just hedonism.  First of all, they give you a handle on your own neurochemistry.  It's unlikely that your brain is optimally tuned for the things you want to accomplish, so if you can tweak it the right way, you might be able to improve your functioning.  In extreme cases, you might have chronic imbalances leading to depression, mania, etc., in which case you'll probably want to talk to a doctor about medication; but the ability to use drugs to change yourself goes well beyond this.  For example, judicious use of MDMA can help you retrain your social reflexes and become more outgoing and sociable.  Having this handle also allows you to begin to experimentally correlate your subjective experience with the physical processes to which they correspond, and by carefully observing more unusual states of consciousness, you broaden your understanding of the mind and how it operates.  Lastly, psychedelics can sometimes help you understand things differently or more deeply.  I've often found my mathematical ability improved by moderate doses of LSD, for example.  So, even for someone concerned primarily with rationality and the accumulation and application of knowledge, drugs are at least worth considering.
And what of the risks? says Bob.
I was getting to that, says Alice.  There will always be a risk/benefit tradeoff, but the risks can be minimized through careful and responsible use:

Thoroughly research every new drug before trying it.  Unfortunately, in the case of prohibited substances, very little good clinical research has been done (this has started to change in recent years, but there are still vast swaths of uncharted territory).  Nevertheless, there's good information to be had.  For drugs used recreationally, I usually start at Erowid.org, which provides an overall summary of the effects of a wide variety of drugs; academic citations and sometimes full articles, if there are any; "trip reports" (anecdotal evidence is better than nothing, especially if there's a lot of it); and other useful information.  For nootropics and "smart drugs", I usually just start with a Google search and/or Wikipedia.
Pay particular attention to addictive potential, toxicity and contraindications.  Drugs with high addictive potential require extra caution, and should perhaps be avoided by people with akrasia problems.  Also be mindful of any history of addiction you may have in your family.  Regarding contraindications: beside drug interactions, a lot of this is just common sense.  If you are prone to anxiety, you should probably avoid amphetamines.  As far as toxicity goes, a good number to look at is the therapeutic index, which is the ratio of the LD50 (the dose, per kilogram of body weight, at which 50% of experimental test subjects (usually rodents) die) to the effective dose (per kilogram of body weight).  However, keep in mind also that frequent or heavy drug use can tax the liver, and that otherwise safe chemicals may build up to toxic levels over time.
If you decide to take a drug known to be addictive, take it in moderate quantities over brief periods of time, well-separated from each other.  This is not a hard and fast rule: under a doctor's supervision, for example, you may choose to take prescribed medication every day.  You should recognize, however, that this comes at a cost: antidepressants can be used to pull your life together and overcome depression, but it's going to be nasty coming off them.  Finally, as a rule of thumb, oral ingestion is significantly less addictive than smoking, insufflation or injection, since this gives a gradual and delayed onset of the reward stimulus.  For the same reason, you can further reduce your chances of becoming addicted by taking prodrugs wherever possible (e.g. Vyvanse instead of Dexedrine).
Always take a low dose first, in case you react badly, and do so around other people who know what you are taking.
To the greatest extent possible, maintain an open and honest relationship with your doctor, who is in a position to help you minimize the health risks associated with your drug-taking.
If you decide to seek out prohibited substances, it's important to have a good source of high-quality product.  Street drugs may be cut with cheap substitutes or contaminated with solvents used in extraction/synthesis, or they may simply not be what they are claimed to be.  Go to people you trust who already do drugs on a regular basis, and ask them for help finding a reputable dealer.

With that out of the way, continues Alice, let's start simple: what is a drug?  For our purposes, we'll say a drug is any substance consumed for reasons other than its nutritive value or the sensory experience of consumption.  We'll specifically be focusing on psychoactive drugs, which are consumed for their effects on the mind.  Note that just about anything you eat or drink is potentially a psychoactive drug, and you may not have to turn to outlandish synthetic compounds to alter your neurochemistry.  For example: after three years of vegetarianism, I gradually began to develop chronic anxiety, with occasional panic attacks.  It plateaued at a (barely) manageable level, so I never ended up seeking medical help; it took two years before I thought to try eating meat again.  When I finally did, the anxiety immediately vanished and has not returned.  So, for me, meat is a psychoactive drug.  In fact, let's talk about nutritional supplements first.
Supplements and Neurotransmitters
The first group of drugs we're going to be looking at are neurotransmitters, and their chemical precursors, which can be found at health food stores.  First, there are 5-HTP and tryptophan, which are serotonin precursors.  There is some evidence that these can help treat depression, improve quality of sleep, and improve your mood, but since you need to take it for a few days before you start to notice the effect, it might be hard to tell if this is actually doing anything for you.Next, consider phenylalanine, an amino acid which serves as a precursor to dopamine, norepinephrine and adrenaline.  Phenylalanine is first metabolized into tyrosine, which is also available as a dietary supplement.  Research seems to suggest that these are mainly effective only for people under conditions of physical, emotional or mental stress, and don't do much for the general population.  I've found that, in fact, L-phenylalanine has a noticeable uplifting effect on my mood within a short time of taking it; but maybe this just says something about how much stress I'm under.Lastly, there's GABA, a neurotransmitter which has an inhibitory effect on the dopamine system and certain other neurotransmitters.  In short, this will calm you down right quick, which makes it useful for dealing with intense and uncontrollable emotions - anxiety, grief, rage, etc.  I find that, for this purpose, theanine is even better: it promotes GABA production and alpha brainwave activity, and also seems to increase dopamine levels.  Its calming effect is very similar to that of GABA, but I find it much less likely to leave me feeling tired and out of it: if anything, it seems to have a mildly stimulating effect.  As an added bonus, theanine appears to boost the immune system.  Theanine synergizes well with caffeine, which we'll cover shortly.All of the above - 5-HTP, tryptophan, phenylalanine, tyrosine, theanine and GABA - are not only useful for regulating your mood, but also for learning what your neurochemistry feels like from the inside.  I found it edifying to take fairly large doses of 5-HTP (or phenylalanine, etc.) every day for a couple weeks, stop for a few weeks, go back on for a couple weeks, stop, etc. - all the while noting changes in my mood and perception.  In that respect, melatonin tablets can be added to this list: they're not really going to make you a more effective rationalist, but they will teach you what melatonin does to your cognition.  Melatonin will also be useful if you're taking stimulants, which might otherwise interfere with your sleep patterns.
It is also worth mentioning that vitamin deficiencies (or excesses) can have a significant impact on mood and cognitive functioning.  I recommend taking multivitamins; this need not be a daily regimen if you have a healthy diet, just kind of take them when you remember to.  Women should look for multivitamins with iron, and men should look for those without.
Stimulants
Next, let's talk about stimulants, starting with caffeine - by far the most popular, although by no means the most effective.  Caffeine works by blocking the activity of adenosine, an inhibitory neurotransmitter that plays a role in sleep and drowsiness.  As a result, neural activity goes up, accompanied by a kick to the sympathetic nervous system and an increase in blood sugar levels.  Taken on a fairly regular daily schedule, caffeine seems to improve my attention, motivation and energy level.  In the long term, there appear to be health benefits from drinking coffee in this way: in addition to its stimulating effects, it appears to help prevent heart disease, Alzheimer's disease and Parkinson's disease, among others.  For all-nighters, though, caffeine is an inferior choice: although it suffices to keep you up and running, it doesn't seem to do much to mitigate the cognitive effects of sleep deprivation.  Also, as increasing amounts are consumed, a variety of unpleasant side-effects begin to appear, including tremors, heart palpitations, anxiety, diarrhea, and dehydration.  It should also be noted that caffeine builds tolerance, and the withdrawal is rather unpleasant.  Despite this, it seems to make sense to take coffee every day in moderation, unless you are especially sensitive to its negative effects.
Caffeine can also be had in tea (green tea, in particular, also contains theanine, as we discussed), in chocolate, preferably dark (chocolate also contains a number of other psychoactive alkaloids, including phenylalanine and theobromine), in caffeine pills and in energy drinks.  It is perhaps worth mentioning that I find that the energy drinks and energy shots containing other medicinal ingredients (phenylalanine, taurine, B vitamins, etc.) really do seem to be slightly better, minimizing the unpleasant side effects and smoothing out the crash.  Still, I try to avoid these because of the sugar and/or artificial sweetener content.  It is unclear exactly what effect each of these other medicinal ingredients has individually, if any at all, so you should also be warned that you are probably buying some nonsense along with your actually mind-altering compounds.
Next are amphetamines, which act on the serotonin, norepinephrine and especially dopamine systems, causing increased focus, improved cognitive ability, and elevated energy levels.  They also mitigate some of the effects of sleep deprivation, although your cognitive performance will still suffer.  While amphetamines can greatly improve your productivity if used correctly, they can also easily do the opposite, because it's just as easy to hyperfocus on video games as it is to hyperfocus on neural network algorithms.  Body tics and bad habits can also get strongly reinforced, since your reward systems are getting pummelled by dopamine.  Basically, if you're doing amphetamines, keep your akrasia-fighting systems on high alert (fortunately this, too, will be aided by the amphetamines).  Another downside to amphetamines is that they're quite addictive; take them either in fixed quantities on a regular schedule (if you have a prescription) or else in occasional bursts of no more than a few days, and in moderate quantities.
Beside addiction, a lot of the danger from amphetamines comes from failing to eat and sleep, if you're taking them for more than a day or two.  Amphetamines are strong appetite suppressants, and of course they keep you awake, so you'll need to force yourself to eat three square meals a day and get to sleep at a reasonable hour.  Sleep is especially important because the longer you stay up, the more amphetamines you have to take to stay awake; if your dose gets high enough, and if you're badly enough sleep deprived, you put yourself at risk of amphetamine psychosis, which is about as much fun as it sounds like.
There are a number of prescription amphetamines on the market, and these are generally to be preferred to street speed, due to their purity and lack of adulterants.  It's not terribly hard to get diagnosed with ADD/ADHD, so this can be above-the-board.  Dexedrine is pure dextroamphetamine, while Adderall is a mix of dextroamphetamine and racemic salts (which contain a 50%/50% split between dextro- and levoamphetamine).  The difference between the two stereoisomers is complicated, and your best bet is to experiment to see which works best for you, but a rule of thumb is that Adderall has more "kick" at lower doses, while Dexedrine is stronger at higher doses.  Methamphetamine, you may be surprised to learn, is also prescribed for ADHD, although much more rarely.  Meth is stronger, longer-lasting, and significantly more addictive, than amphetamine.  It is also more neurotoxic.  I would recommend exercising extreme caution around this one, or else avoiding it entirely, unless you actually have severe ADHD and this is the only thing that works for you.  Lastly, there is a prodrug for dextroamphetamine that just came on the market, called Vyvanse (lisdexamphetamine).  This has a much slower onset, since it has to be metabolized into dextroamphetamine, and therefore has significantly less addiction potential.
Ritalin works similarly to amphetamines; apparently it tends to produce less euphoria.  Ephedrine is chemically similar to amphetamines, but works primarily by increasing the activity of noradrenaline; it has the advantage of being legally available without a prescription.  I mention these only in passing because I don't have much experience with them; if you want to contribute some information about them, please comment!
I also want to briefly mention MDPV (methylenedioxypyrovalerone), an experimental stimulant still legally available in the U.S. and in Canada (sold online as a research chemical or, sometimes, as "envigorating bath salts").  This one acts as a dopamine and norepinephrine reuptake inhibitor, producing a state reminiscent of that caused by amphetamines.  It has a quick onset and short lifetime (3-5 hours), which makes it well-suited to accomplishing quick chores.  However, there are a number of nasty side effects reported, and it seems to have some addictive potential.  Looking at the evidence, it appears that most of the people reporting this sort of thing were insufflating larger doses; so taken orally and in moderation, this one can still be reasonably safe.  But there's very little out there that's peer-reviewed, so take a look at some trip reports and proceed with caution.
All of this probably makes it sound like stimulants are, at best, not far off from a zero-sum game: they may benefit cognitive performance, but they come with side effects and addictive potential and a nasty crash when you come off them.  Well, good news: we'll be considering Modafinil next, which some are calling the perfect stimulant.  Modafinil is sold by prescription only, but its prodrug, Adrafinil, can be purchased online.  I've taken the latter on a number of occasions, and have been quite impressed with the results.  Adrafinil promotes a state of wakefulness and energy, but without the "edge" that comes with amphetamine use.  Even under conditions of sleep deprivation it has a significant positive effect on cognitive functioning, memory retention, focus and motivation.  It has no significant crash, produces no tolerance, and seems to have very little addictive potential.  You can even sleep on Adrafinil, if you wish; this is a significant advantage over all of the other stimulants we've discussed, since if you take dexedrine at 9PM and finish your work at 1AM, you're still effectively committed to staying up all night.  Adrafinil also seems to have a positive effect on mood; lastly, there are signs it can be used both to prevent and to treat some of the effects of aging on energy level and cognitive ability.
Modafinil and Adrafinil are not perfectly safe, though.  They put a fairly heavy load on the liver and kidneys if taken daily, and should therefore be taken only occasionally, unless as part of medically-supervised treatment.  There are also occasional side effects to watch out for, most notably skin infections.
Nootropics
Nootropics are still a very new and experimental class of drugs.  Many purported nootropics give negative or inconclusive results in clinical tests, and many of them have not been tested at all, or very little: more specifically, most of the research has focused around using nootropics to treat neural disorders and injuries, or to mitigate the effects of aging, with very little focus on young and healthy individuals.  This does not mean, however, that they do nothing beneficial; it only means that you'll have to do some careful experimentation to determine how they effect you, if at all.  For our purposes, I'll only be covering some of the more popular and (most importantly) well-studied nootropic drugs.
We'll start with piracetam.  The research on piracetam shows positive effects in the prevention and treatment of aphasia, dementia, epilepsy and hypoxic injury, but says almost nothing about its effect on healthy individuals.  The general consensus among those who take it daily is that it seems to do something, though it's hard to put a finger on.  One friend of mine suggests that it seems to subtly improve the general flow of cognition, making memories and good ideas more available.  One significant effect that piracetam seems to have is general potentiation of other drugs, especially stimulants and psychedelics, so if you incorporate piracetam into your daily regimen, you should be extra-careful about trying new drugs.
Another "smart drug" is DHEA, an endogenous chemical with a variety of functions, including inhibition of cortisol.  The research shows that it has anti-depressant effects, and seems to improve cognitive functioning under stressful conditions.  It also seems to improve episodic memory in young men, but has no such effect in elderly people.  You'll note I said "young men", not "young people": the effects of DHEA appear to be asymmetric with respect to gender.  In particular, higher levels of endogenous DHEA are correlated with longer lifespan in men, but there is no such correlation in women.
On the life extention angle, another nootropic worth considering is Selegiline, which appears to be available for purchase online, although technically it's not supposed to be sold to anyone without a prescription (possession, on the other hand, is legal).  Selegiline is an MAO-B inhibitor, commonly used to treat Parkinson's, depression and dementia.  Even for someone without these conditions, Selegiline produces cognitive benefits similar to those of Adrafinil, and there are reports that long-term use might tend to increase your lifespan.  Looking at the evidence, I am inclined to take such claims seriously.  Since it targets MAO-B specifically, Selegiline is less dangerous than nonspecific MAOIs.  However, at higher doses, Selegiline to lose its specificity and inhibit MAO-A also.  Women on oral contraception should be especially careful, as birth control pills appear to increase Selegiline's bioavailability, so that MAO-A inhibition may kick in at lower doses.  At any rate, use caution with this one, and take lower-than-usual doses of other substances, including foods containing tyrosine and other potentially dangerous monoamines (e.g. chocolate, cheese, wine).
Some other less common nootropics with effects similar to those of the above include Vinpocetine and Hydergine, which function as neuroprotectives and might also improve cognitive functioning.  I haven't tried these, and available research is slim, so I can't say much.  Beyond the nootropics we've discussed, the field begins to look a little grim.  For example, the jury seems to be out on ginkgo biloba: some clinical trials failed to demonstrate any measurable effect on memory or cognition, and others appeared to show short-term benefits.  It gets worse, though, than merely ambiguous research.  For example, DMAE, once marketed as a life-extension agent, may actually shorten your lifespan.  Other nootropics have turned out to be severely toxic, such as Fipexide, which appears to cause liver failure with prolonged use.  At any rate, your best bet is probably to stick with established and well-studied drugs; there are whole communities out there perfectly willing to put themselves on the line testing new contenders, and I feel it's best to leave that up to them.
Psychedelics and "recreational" drugs
Now, says Alice, for psychedelics.  We should begin with some general remarks.  First of all, these are contraindicated for anyone with a family history or predisposition to psychotic disorders.  More generally, set and setting (mental state and external circumstances, respectively) are extremely important to having a positive experience.  Psychedelics have been described as "nonspecific amplifiers of experience", which means that if you're having a bad day, acid will probably make it worse.  Ideally, your first trip should be in a place where you feel safe and inspired, with a few people you trust and who are experienced and knowledgeable about the drug you're taking.  You'll probably want to have art books, sketchbooks, good music and someplace comfy to lie or sit.
Your provisos and warnings are all well and good, says Bob, but what do psychedelics actually do?
It's... hard to describe, says Alice, in the same way that the colour red is hard to describe, but I'll give it a shot; just keep in mind this is an incomplete description.  First there are the visual effects.  These aren't hallucinations, in the sense that you'll recognize them as being effects of the drug.  With your eyes open, you'll tend to see colours intensified and altered, and your brain will be having a field day reinterpreting interesting textures (cf. pareidolia and form constants); with your eyes closed, you'll see animated geometric patterns, tessellations, visions, and all kinds of surprisingly interesting stuff.  Depictions in popular culture of psychedelic experiences are notoriously bad, but this movie does a reasonably good job.  In addition to visual alterations (which can teach you a lot about the functioning of your visual cortex) you might also experience changes in auditory and tactile sensation, as well as synaesthetic crossover between senses.
Even more interesting than the sensory changes are the cognitive effects.  It turns out that your sense of a coherent self can be overridden, and you may experience a blurring of the boundary between you and everything else.  You may have strange, spontaneous ideas or insights; to some extent this is because the peculiarity of the experience forces you to reexamine tacit assumptions hidden deep in your reality model; these assumptions do not always turn out to be wrong, but it's good to be aware of them and to understand them more deeply.  You may also become unusually aware of pathologies in your lifestyle and relationships, and with practice you may be better able to articulate those pathologies, than you are normally.  Ideas that come to you while high must be carefully examined and tested while sober, of course, but my experience has been that many of them turn out to be genuinely good ideas, and some have even led to significant improvements in my functional relationship to the world.
LSD, in particular, seems well-suited to understanding technical fields, including math and physics.  Unlike mushrooms, acid does not significantly impair my ability to read and understand mathematical texts, and the heightened ability to flex my visual cortex allows me to see difficult and abstract constructions quite vividly, as well as to understand on an intuitive level how they work.  Mushrooms, conversely, are more likely to present me (somewhat forcefully) with ideas I might never have otherwise considered.  These two are the most popular psychedelics, and the two experiences bear a definite family resemblance.  LSD is calmer, and easier to control and direct, but it lasts up to twice as long as mushrooms - twelve hours is common.  Mushrooms tend to be more emotionally intense: usually this means euphoria and lots of giggling, but occasionally you might be overcome by grief or anger, especially if you're already feeling that way before you dose.
I'm not going to say much about cannabis, because while the experience is certainly interesting, it's probably not going to help most of you think better (there are some, mind you, who actually function better with THC in their systems; Carl Sagan, for example, was a notorious pothead).  One reason you might want to take cannabis anyway is that it can serve as a gentle introduction to psychedelia - but be warned that some people, even those who generally enjoy psychedelics, have consistently bad reactions to THC.  Proceed with caution.  Another reason to take cannabis is for life extension purposes; there's good evidence that THC helps prevent certain kinds of cancer.  If you're taking it for health reasons, though, you probably want to use a vapourizer or eat it instead of smoking it.  Also note that, at least for some particularly susceptible people, cannabis can be addictive.  Again, if you have reason to believe you're prone to substance abuse, you might want to give this one a skip.
Another controlled substance to consider is MDMA.  MDMA has a variety of neurochemical effects: it inhibits dopamine and norepinephrine reuptake, actually reverses the serotonin reuptake pump, and also seems to increase levels of oxytocin, the "trust hormone".  So, you feel a sense of love, joy, wellbeing, safety, etc.  You'll also get many of the same stimulant effects as methamphetamine, albeit milder.  I mention MDMA because in my experience, if you already have a decent idea of how social interactions are supposed to work but still have trouble getting over your anxiety, this can help you teach yourself to be more socially confident, if taken in the appropriate environment (hint: do this around other people on MDMA).  The surge of oxytocin makes you temporarily fearless about approaching strangers, and also cushions the blow if things go badly, while the increased dopamine activity strongly reinforces behaviours leading to successful interactions.  This learned confidence persists into the sober state.  MDMA is also useful for confronting emotionally difficult issues - indeed, it was used for psychotherapy before it became popular recreationally and was banned - but I'll leave that to you to research on your own.
Some warnings about MDMA.  First of all, most "Ecstasy" contains adulterants (commonly caffeine and methamphetamine and sometimes PCP, among others), and sometimes contains no MDMA at all.  As a general rule, avoid pressed pills; pure MDMA most commonly comes in crystal form.  If you don't have a reliable source, you might want to skip MDMA entirely.  Also note that MDMA commonly causes hangovers, although these can be mitigated by taking 5-HTP.
Lastly, although all the drugs I've mentioned in this section are controlled, you might actually be able to experience very similar altered states legally.  Alex and Ann Shulgin, the research chemist and psychotherapist (respectively) who first popularized MDMA, also came up with literally hundreds of other psychoactive compounds, many of which are still legal outside America and can be purchased online from so-called "research chemical" companies (the U.S. has the Analogues Act, which automatically makes illegal any chemical broadly similar to any other illegal chemical, but Canada, among other countries, has not shared this dismal fate).  For example, instead of MDMA, you might consider AMT, a tryptamine with similar and in some ways better effects.  Another research chemical, 4-ACO-DMT, is actually metabolized into psilocin, as is psilocybin, and so the trip is almost identical to that of mushrooms.  The downside to all this is that research chemicals are generally sold only in larger quantities, so if you don't want to drop a couple hundred dollars on something you may not enjoy, this may not be your best bet.  There's also the fact that these are not as well-understood as more popular psychedelics, which makes them riskier, although these risks can be minimized by using caution and moderation.
Conclusion
As we've seen, says Alice with a smirk, you too can alter your neurochemistry for fun and profit - but this must be done responsibly.  Although I've tried to give a sense of the dangers alongside the benefits, this post is really only meant to serve as a broad introduction.  If you're thinking of actually trying any of the drugs I've mentioned, it's important that you do some in-depth research, and a proper cost-benefit analysis.  But with a little practice, you too can expand your mind.