I.

Taking nootropics is an inherently questionable decision. The risk isn’t zero, and the benefits are usually subtle at best. But even within this context, special caution is warranted for branded combination nootropics.

I wanted to make up a caricatured fake name for these sorts of things, so I could make fun of them without pointing at any company in particular. But all of the caricatured fake names I can think of turn out to be real products. MegaMind? Real. SuperBrain? Real. UltraBrain? Real. Mr. Power Brain? Real, for some reason.

Even the ones that don’t make sense are real. NeuroBrain? Real, even though one hopes that brains are always at least a little neuro. NeuroMind? Real, with its own Indiegogo campaign. The only thing I haven’t been able to find is a nootropic called BrainMind, but it’s only a matter of time.

These usually combine ten or twenty different chemicals with potential nootropic properties, then make outrageous claims about the results. For example, Neuroxium says on its ridiculous webpage that:

Neuroxium is a revolutionary brain supplement formulated to give you ultimate brain power. Known in Scientific Terms as a “NOOTROPIC” or “GENIUS PILL” Neuroxium improves mental functions such as cognition, memory, intelligence, motivation, attention, concentration and therefore happiness and success.

Your first warning sign should have been when they said “genius pill” was a scientific term (or as they call it, Scientific Term). If you needed more warning signs, this is word-for-word the same claim made by several other nootropics like Synagen IQ, Nootrox, and Cerebral X. So either they can’t even be bothered not to plagiarize their ads, or they change their name about once a week to stay ahead of the law.

I was eventually able to find a list of the ingredients in this stuff:

DMAE (dimethylethanolamine bitartrate), GABA (?-Amino-butyric acid), Caffeine anhydrous, Bacopa monnieri leaf extract, NALT (N-acetyl-L-tyrosine), Centrophenoxine HCl, Alpha-GPC (a-glycerophosphocholine, Agmatine sulfate, Gingko biloba leaf extract, Pine (Pinus pinaster) bark extract, Phosphatidylserine, Aniracetam, CDC Choline (Citicoline), Sarcosine (N-methylglycine), Vincamine [Lesser Periwinkle (Vinca minor) aerial extract], L-Theanine (?-glutamylethylamide), NADH (nicotinamide adenine dinucleotide), TAU (triacetyluridine), Noopept, Adrafinil, Tianeptine, Piperine [Black Pepper (Piper nigrum) fruit extract 445mg.

And the weird thing is, a lot of these are decent choices. Everyone knows caffeine is a good stimulant. Adrafinil is the over-the-counter version of modafinil, an FDA-approved medication for sleep disorders; many of my patients have been very happy with it. Bacopa monnieri has been found to improve memory in so many studies I can’t even keep track of all of them. Noopept is an approved medication in Russia. Tianeptine is an approved medication in France. All of these are chemicals with at least some evidence base behind them, which are potentially good for certain people.

But taking Neuroxium/Synagen/CerebralX is exactly as bad an idea as you would expect from the advertising copy.

For one thing, they don’t list the doses of any of these things – but they have to be getting them terribly wrong. A standard dose of adrafinil is 600 mg. A standard dose of bacopa is 300 mg. A standard dose of Alpha-GPC choline is about 600 mg. So combining standard doses of just these three ingredients means you need a 1.5 g pill. This is probably too big to swallow. The only pills I know of that get that big are those gigantic fish oil pills made of pure fish oil that everybody hates because they’re uncomfortably big. But this is just what you’d need to have three of the 22 ingredients listed in CerebralX at full doses. The pill is already unswallowably large, and you’ve only gotten a seventh of the way through the ingredient list.

I conclude that they’re just putting miniscule, irrelevant doses into this so they can say they’ve got exciting-sounding chemicals.

For another thing, all of these substances have unique profiles which have to be respected on their own terms. For example, lots of studies say bacopa improves memory – but only after you’ve taken it consistently for several months. If you just go “WOOO, CEREBRALX!” and swallow a bunch of pills and hope that you’ll do better on your test tomorrow, all you’re going to get are the short-term effects of bacopa – which include lethargy and amotivation.

Most sources discussing Noopept recommend starting very low – maybe as low as 5 mg – and then gradually increasing to a standard dose of 10 – 40 mg depending on how it works for you. Some people will apparently need higher doses, and some find it works best for them as high as 100 mg. Needless to say, none of this is possible if you’re taking CerebralX. You’ll take whatever dose is in the product – which they don’t tell you, and which is probably so low as to be meaningless – and stay at the same level for however long you’re taking the entire monstrosity.

Tianeptine has a short half-life and is typically dosed three times a day, unlike most of the other things on the list which are dosed once per day. CerebralX says you should take their whole abomination once a day, which means you’re getting the wrong dosing schedule of tianeptine.

Piperine is a chemical usually used to inhibit normal drug-metabolizing enzymes and enhance the effect of other substances. This is very occasionally a good idea, when you know exactly what drug you’re trying to enhance and you’re not taking anything else concurrently. But I can’t figure out which drug they’re trying to enhance the activity of here, or even whether they’re trying to enhance the activity of anything at all, or if they just heard that piperine could enhance things and thought “Okay, it’s in”. And if I were giving someone a concoction of twenty-one different random psychoactive drugs, which I was dosing wrong and giving at the wrong schedule, the last thing I would want to do is inhibit the body’s normal drug metabolism. The entire reason God gave people drug-metabolizing enzymes is because He knew, in His wisdom, that some of them were going to be idiots who would take a concoction of twenty-one different random psychoactive drugs because a website said it was, in Scientific Terms, a “GENIUS PILL”. Turning them off is a terrible idea and the only saving grace is that the dose of everything in this monstrosity is probably too small for it to do anything anyway.

Taking any of the ingredients in CerebralX on its own is a potentially risky affair. But if you study up on it and make sure to take it correctly, then maybe it’s a calculated risk. Taking everything in CerebralX together isn’t taking a calculated risk as part of a potentially interesting hobby. It’s just being an idiot.

II.

But that’s too easy. I have a larger point here, which is that these sorts of branded combos are bad ideas even if they’re by smart, well-intentioned people who are doing everything right.

Tru-Brain is undeniably in a class above CerebralX. It has a team including neuroscience PhDs. It seems to be a real company that can keep the same name for more than a week. Instead of promising a GENIUS PILL, it makes comparatively modest claims to be able to “perform at your peak” and “stay sharp all day long”.

Correspondingly, its special nootropics combo makes a lot more pharmacological sense. For one thing, it’s a packet rather than a single pill – a concession to the impossibility of combining correct doses of many substances into a single capsule. For another, it limits itself to mostly things that some sane person could conceivably in some universe want to dose on the schedule they recommend. And it’s only got seven ingredients, none of which counteract any of the others or turn off important metabolic systems that God created to protect you from your own stupidity. This is probably about as well-designed a branded nootropics combo as it’s possible to make.

But I would still caution people away from it. Why?

Last year, I surveyed people’s reactions to various nootropics. I got 870 responses total, slightly fewer for each individual substance. Here are the response curves for two of the substances in TruBrain – piracetam and theanine:

These are on a 1-10 scale, where I directed responders to:

Please rate your subjective experience on a scale of 0 to 10. 0 means a substance was totally useless, or had so many side effects you couldn’t continue taking it. 1 – 4 means for subtle effects, maybe placebo but still useful. 5 – 9 means strong effects, definitely not placebo. 10 means life-changing.

Some substances known to be pretty inert averaged scores of around 4. Piracetam and theanine averaged around 5, so maybe a little better than that. But the most dramatic finding was the range. Almost 20% of people rated theanine a two or lower; almost 20% rated it a nine or higher. More than a third placed it in the “probably placebo” range, but 5% found its effects “life-changing”.

The effect of nootropics seems to vary widely among different people. This shouldn’t be surprising: so do the effects of real drugs. Gueorguieva and Mallinckrodt do an unusually thorough job modeling differences in response to the antidepressant duloxetine, and find a clear dichotomy between responders and nonresponders. This matches psychiatric lore – some medications work on some people, other medications work on others. I particularly remember one depressed patient who had no response at all to any SSRI, but whose depression shut off almost like a lightswitch once we tried bupropion. Other people fail bupropion treatment but do well on SSRIs. Probably this has something to do with underlying differences in their condition or metabolism that we just don’t know how to identify at this point (sample simplified toy model: what we call “depression” is actually two diseases with identical symptoms, one of which responds to SSRIs and one of which responds to bupropion).

I think this is why there are no multidrug combo packs. Your psychiatrist never treats your depression with a pill called “MegaMood”, boasting combination doses of Prozac, Wellbutrin, Remeron, and Desyrel. For one thing, either you’re giving an insufficient dose of each drug, or you’re giving full doses of four different drugs – neither is well-tested or advisable. For another, you’re getting four times the side effect risk. For a third thing, if one of the four drugs gives you a side effect, you’ve got to throw out the whole combo. For a fourth, if the combo happens to work, you don’t know whether it’s only one of the four drugs working and the others are just giving you side effects and making you worse. And if it sort of works, you don’t know which of the four drugs to increase, or else you just have to increase all four at once and hope for the best.

All these considerations are even stronger with nootropics. There shouldn’t be universally effective nootropics, for the same reason there’s no chemical you can pour on your computer to double its processing speed: evolution put a lot of work into making your brain as good as possible, and it would be silly if some random molecule could make it much better. Sure, there are exceptions – I think stimulants get a pass because evolution never expected people to have to pay attention to stimuli as boring as the modern world provides us with all the time – but in general the law holds. If you find a drug does significantly help you, it’s probably because your brain is broken in some particular idiosyncratic way (cf. mutational load), the same way you can double a computer’s processing speed with duct tape if one of the parts was broken.

If everyone’s brain is broken in a different way, then not only will no drug be universally effective, but drugs with positive effects for some people are likely to have negative effects for others. If (to oversimplify) your particular brain problem is not having enough serotonin, a serotonin agonist might help you. But by the same token, if you have too much serotonin, a serotonin agonist will make your life worse. Even if you have normal serotonin, maybe the serotonin agonist will push you out of the normal range and screw things up.

Most effective psychiatric drugs hurt some people. I mean, a lot of them hurt the people they’re supposed to be used for – even the psychotic people hate antipsychotics – but once you’ve brushed those aside, there are a lot of others that help a lot of people, but make other people feel worse. There are hordes of people who feel tired on stimulants, or sleepy on caffeine, or suicidal on antidepressants, or any other crazy thing. You rarely hear about these, because usually if someone’s taking a drug and it makes them feel worse, they stop. But psychiatrists hear about it all the time. “That antidepressant you gave me just made me feel awful!” Oh, well, try a different one. “That’s it? Try a different one? Aren’t you embarassed that your so-called antidepressant made me more depressed?” You’re pretty new to this ‘psychopharmacology’ thing, aren’t you?

Thus the tactic used by every good psychiatrist: try a patient on a drug that you think might work, make them report back to you on whether it does. If so, keep it; if not, switch.

If you take a seven-drug combo pack, you lose this opportunity for experiment. Suppose that two of the drugs make you feel +1 unit better, two others have no effect, and three of the drugs make you feel -0.5 units worse, so in the end you feel +0.5 units better. Maybe that seems good to you so you keep taking it. Now you’re taking five more drugs than you need to, including three making you actively worse, and you’re missing the chance to be a full +2 units better by just taking the drugs that are helping and not hurting.

You’re also missing the opportunity to play with the doses or the schedules of things. Maybe if you doubled the dose of one of the drugs making you +1 better, you could be +2 better, but if you double the dose of the other, you start getting side effects and the drug only breaks even. If you experiment, you can figure this out and take twice the dose of the first and the starting dose of the second, for +3 better. Taking them all as part of a combo ruins this: if you try taking twice the dose of the combo, nothing happens.

(And a special word of warning: if some stimulant product combines caffeine with something else, and you feel an effect, your first theory should be that the effect is 100% caffeine – unless the “something else” is amphetamine. There are like a million products which bill themselves as “organic energy cocktails” by combining caffeine with some rare herb from Burma. People drink these and say “Oh, this high feels so much more intense than just drinking caffeine”. Yeah, that’s because it’s much more caffeine. Seriously. Check the doses on those things. I will grudgingly make an exception for some chemicals that are supposed to decrease caffeine jitters, like theanine, which might have a real effect. But the stimulation is from caffeine. Go get an espresso instead.)

III.

But don’t drugs interact? Instead of viewing these seven drugs as seven different variables, shouldn’t we view them as coming together in a seven-color beautiful rainbow of happiness, or whatever?

Once again, I can only appeal to psychiatry, which is still unsure whether there are any useful interactions between its various super-well-studied drugs which it’s been using for decades and prescribing to millions of people. Take the CO-MED study, which combined the popular SSRI escitalopram with the popular NDRI bupropion. Since depression seems to involve abnormalities in the three major catecholamine systems, and escitalopram hits one of these and bupropion hits the other two, this seems like exactly the sort of synergistic interaction we should expect to work. It doesn’t. CO-MED found that the two antidepressants together didn’t treat depression any better than either one alone, let alone produce some synergy that made them more than the sum of their parts. They did, however, have about twice as many side effects.

Other smaller studies say the opposite, so I’m not saying never try escitalopram and bupropion together. I’m saying we don’t know. These are intensely-studied drugs, the whole power of the existing system has been focused on the question of whether they synergize or antisynergize or what, and we’re still not sure.

Also from psychiatry: we know a lot less about the mechanisms of action of drugs than we like to think. Ketamine has been intensively studied for depression for a decade or so, and we only just learned last year that it probably worked on a different receptor than we thought. SSRIs might be the most carefully studied drug class of all time, and we still don’t really know exactly what’s up with them – it can’t just be serotonin; they increase serotonin within a day of ingestion, but take a month to work.

So when people point to these incredibly weird substances that have barely been studied at all, where we have only the faintest clue how they work, and then say from their armchair “And therefore, drug A will enhance the effects of drug B and C” – this is more than a little arrogant. Is it all made up? I can’t say “all” with surety. But it might be.

The best-known and most-discussed interaction in nootropics is piracetam-choline. Piracetam increases levels of acetylcholine, which is formed from choline, so it makes sense that these two substances would go well together. Most sites on piracetam urge you to take them together. TruBrain, which predictably is on top of this kind of stuff, combines them together in its combo pack.

But there’s never been a human study showing that this helps. Examine.com, another group which is usually on top of stuff, summarizes (emphasis carried over from original):

[Choline] may augment the relatively poor memory enhancing effects of Piracetam in otherwise healthy animals, but administration of choline alongside Piracetam is not a prerequisite to its efficacy and has not been tested in humans

I surveyed a bunch of choline users, using a little gimmick. Some of the forms of choline sold these days don’t cross the blood-brain barrier and shouldn’t have an effect, so they provide a sort of placebo control for more active forms of choline. In my survey, people who took piracetam with inactive forms of choline didn’t report any worse an experience than those who took the real thing.

This is the most famous and best-discussed interaction in the entire field of nootropics, and it’s on super-shaky ground. So trust me, the CerebralX people don’t have good evidence about the interactions of all twenty-one of their ridiculous substances.

I have to admit, I’m not confident in this part. Maybe psychiatry is wrong. Sometimes I wonder what would happen if we just throw five different antidepressants with five different mechanisms of action at somebody at once. Realistically, maybe this would involve some supplements: l-methylfolate, SAMe, tryptophan, turmeric, and a traditional SSRI. One day I want to try this on someone I know well enough to let me test things on them, but not so well I don’t mind losing a friend when it all blows up in my face. Until then, keep in mind that anyone who says they bet a certain combination of things will produce a synergistic interaction is engaging in the wildest sort of speculation.

IV.

One more piece of evidence. The 2016 nootropics survey asked people to rate their experiences with 35 different individual substances, plus a branded combo pack (“AlphaBrain”) of pretty good reputation. The AlphaBrain performed worse than any of the individual substances, including substances that were part of AlphaBrain!

This is of course a very weak result – it wasn’t blinded, and maybe the survey responders have the same anti-branded-combo prejudice I do. But it at least suggests knowledgeable people in the nootropics community are really uncomfortable with this stuff.

90% of the people making branded combo nootropics are lying scum. A few, like TruBrain, seem like probably decent people trying to get it right – but are you confident you can tell them apart? And if you do manage to beat the odds and get something that’s not a complete pharmacological mess, aren’t you still just going to end up with an overpriced bundle of black boxes that won’t provide you with useful information, and which, empirically, everyone hates?

If you’re interested in nootropics, consider trying one substance at a time, very carefully, using something like examine.com to learn how to take it and what the possible side effects are. If you can, do what people like Gwern do and try it blind, mixing real pills with placebo pills over the space of a few weeks, so you can make sure it’s a real effect. If you find something that does have a real effect on you, treat that knowledge as a hard-won victory. Then, if you want to go from there, tentatively add a second chemical and test that one in the same way. Do this, and you have some small sliver of a chance of doing more good than harm, at least in the short term.

But if you’re going to order a combination of twenty different things at homeopathic doses from somebody who thinks “GENIUS PILL” is a Scientific Term – well, I hope it works, because you need it.