Nootropics

Epistemic status: medium

There are a lot of drugs and supplements reputed to improve cognitive function.  I was sick of relying on hearsay and anecdote, so I did my best attempt at a systematic overview of what works and what doesn’t.

BOTTOM LINES

Caffeine, modafinil, amphetamine, methylphenidate, and maybe a discontinued nicotinic-receptor agonist drug called ispronicline, have really big effects on cognitive function in healthy people.

Caffeine and modafinil work significantly better in sleep-deprived than non-sleep-deprived people.

Caffeine, nicotine, and amphetamine, in contrast to methylphenidate and modafinil, do not improve memory performance or accuracy on cognitive tasks in healthy people, but only reaction time.  In other words: caffeine, nicotine, and amphetamine make you more alert but not smarter; methylphenidate and modafinil also seem to improve memory.

Amphetamine and modafinil work better on people with the COMT val/val phenotype (who tend to be less intelligent) and may be ineffective or counterproductive on COMT met/met phenotype people.

All of the above (caffeine, nicotine, modafinil, amphetamine, and methylphenidate) cause some tolerance.

Cerebrolysin, a mixture of neural growth factors, apparently works really well on Alzheimer’s patients, though there’s fewer studies of it than more common Alzheimer’s drugs.  It might extrapolate to people with other kinds of neurodegenerative problems, or to slow the effects of aging.

Cognitive training (memorization practice including spaced repetition) works moderately well on Alzheimer’s patients and schizophrenics.  It’s quite plausible that it’s also good for healthy people.

Healthy people can get small positive effects from nicotine, possibly the herb Bacopa monniera, and from transcranial magnetic stimulation.

Alzheimer’s patients can get small effects from cholinesterase inhibitors (which are standard Alzheimer’s drugs); from a mixture of vitamins, fatty acids, choline, and uridine; from melatonin, the hormone which regulates sleep; and from the amino acid derivative acetyl-l-carnitine. Apart from the cholinesterase inhibitors (which have GI side effects) these are safe for healthy people to take, but it’s not known whether they affect cognitive function in healthy people.

METHODOLOGY

only looked at published studies on cognitive outcomes in humans: tests of memory, reaction time, and the like.  No animal studies. No measurements of neural correlates or biomarkers. To show up in my list, it has to make humans perform better.  I didn’t restrict attention to healthy humans, however; a lot of the studies on cognitive enhancement are performed on subjects with diseases like Alzheimer’s or schizophrenia, so I included some of those, under the suspicion that they might generalize to healthy people.

I ranked nootropics by effect size. That is, Cohen’s d, the difference in mean outcome between treatment and control groups divided by the pooled standard error.

Assume that a trait, like your score on an exam, has a Gaussian distribution. Suppose you have some treatment that increases the mean score in the treatment vs. the control group. Then you can divide by the (pooled) standard deviation of the score to get an estimate of how big a difference the treatment makes, compared to the population variation in the trait. Does it increase your score by one standard deviation? That’s an effect size of one.  Does it increase your score by half a standard deviation? That’s an effect size of 0.5.

This allows us to compare “how big an effect” different interventions have, along one scale, even if they’re acting on different traits. If drug A improves your reaction times by two standard deviations, and drug B improves your memory by half a standard deviation, you can still say that drug A has a larger effect than drug B, even though the effect isn’t on the same thing.

Conventionally, an effect size of 0.2-0.3 is a “small” effect, around 0.5 is a “medium” effect, and anything greater than 0.8 is a “large” effect. Most drugs used in psychiatry have effect sizes around 0.5.  Intuitively, effect sizes of about 0.5 look like “sorta works” to the naked eye. Effect sizes greater than 1 look like “holy shit, that’s an unmistakable effect” to the naked eye.

Anything with a p-value of <0.05 (but not <0.01) I didn’t include in the table of best nootropics, because the vast majority of studies with such high p-values don’t replicate.  I also didn’t include things in the table if they were shown to not work on healthy subjects (even if they did work on ill subjects).  When there was conflict between studies, I erred on the conservative side and chose smaller effect sizes.

 

Drug Effect Size Trait
Modafinil, Caffeine 2-3 Executive function in sleep deprived people
Modafinil, Caffeine 2-3 Wakefulness in sleep deprived people
Ispronicline 2.5 Attention and episodic memory in healthy people
Amphetamine 2.3 Reaction time in healthy people
Cerebrolysin 1.8-2.2 ADAS-cognitive test in Alzheimer’s patients
Methylphenidate 1.4 Memory in healthy non-sleep-deprived people
Modafinil 1.22 Working memory in sleep deprived people
Caffeine 0.7 Reaction time in non-sleep-deprived healthy people
Nicotine 0.7 Attention in schizophrenics
Modafinil 0.56 Attention in non-sleep-deprived healthy people
Melatonin 0.56 ADL’s for Alzheimer’s patients
Cognitive training (including spaced repetition) 0.43-0.47 Various cognitive tests and ADL’s for Alzheimer’s patients and schizophrenic patients
Bacopa monniera 0.32 Learning rate in healthy people
Nicotine 0.3 Reaction times in smokers and nonsmokers
Cholinesterase inhibitors 0.2-0.5 ADAS-cognitive test in Alzheimer’s patients
rTMS 0.2-0.3 Working memory and reaction time in healthy subjects
Souvenaid 0.23 Memory in Alzheimer’s patients
Acetyl-L-carnitine 0.2 Various cognitive tests in Alzheimer’s patients

EFFECTIVE THERAPIES

ALCAR

ALCAR, or acetylcarnitine, is an amino acid derivative used in the metabolism of fatty acids.

A meta-study of 21 studies of Alzheimer’s patients found a median effect size of 0.2, with a total of 499 patients, across various cognitive tests.

Amphetamine

Amphetamine is a dopaminergic stimulant drug.

Amphetamine improved working-memory performance in healthy subjects only if they had low performance at baseline, and worsened it in those who had high performance at baseline.[4]

Improves working memory on healthy val/val COMT subjects, doesn’t, or deteriorates it, on met/met subjects. (“Warriors” benefit, “worriers” do not.)[38]

Improves reaction time on a movement estimation task (effect size: 2.3) but not digit span.[39]

Bacopa monniera

Bacopa monniera is a plant traditionally supposed to improve memory. The active ingredient is bacoside, a triterpenoid saponin.

Randomized study of 46 healthy adults, AVLT learning rate after 12 weeks is better, effect size 0.32, a significant effect at p < 0.01.  State anxiety also lower, p < 0.001. No effect on digit span.[33] No effects on memory.[34]

Caffeine

Caffeine is the most commonly used psychoactive chemical worldwide, and is a stimulant that works by adenosine receptor antagonism.

Cross-sectional study of 9003 adults finds that higher habitual coffee and tea consumption has a significant dose-response relationship (p < 0.001) with performance tests of memory, visuospatial reasoning, and reaction time, suggesting that tolerance to caffeine is incomplete and caffeine does cause higher absolute levels of cognitive performance.[1]

Metastudy found that caffeine had no effect on free recall in most short-term memory studies. It does reliably improve reaction time.  Reduces the risk of sleep-deprivation-related work accidents by about two-fold.  Generally improves cognitive performance more in sleep-deprived than in non-sleep-deprived subjects. Caffeine improves cognitive function in elderly subjects more than in young (20-60) subjects, and regular caffeine consumers have less (half as much) age-related cognitive decline.[20]

Caffeine improves reaction time over placebo with an effect size of 0.7[21]

Cerebrolysin

Cerebrolysin is a mixture of neurotrophic peptides derived from pig brains, including BDNF, GDNF, NGF, and CNTF. It may have a neuroprotective or neurorestorative effect.

Randomized study of 279 Alzheimer patients found scores on the cognitive subscale of the ADAS improved by 4 points on Cere vs. placebo, effect size of 1.86, p = 0.03.  Global clinical outcome significantly better than placebo (p < 0.001).[27]  A randomized trial of 149 Alzheimer patients found an effect size of 2.22, improvement of 3.2 on the ADAS-cog on Cerebrolysin vs. placebo, p < 0.001.[28]  Effect size of 2 on elderly controls on the ADAS-cog.[67]

Cholinesterase inhibitors

This is a class of drugs used for Alzheimer’s disease, including donepezil and galantamine.  A meta-study found they had median effect size 0.28 on the ADAS-Cog for high-dose studies, 0.15 for low dose.[48]  Another meta-study found they had mean effect size 0.1 for ADLs in Alzheimer’s and there’s no difference between cholinesterase inhibitors.

Cognitive Training

For Alzheimer’s disease. Mostly these are memory practice games or drills, many of which are spaced repetition. Across various measurements of outcome (CPT, memory tests, IADLs, etc) median effect size was 0.47.[50] A metastudy of cognitive remediation for schizophrenia found a median effect size of 0.43 across various cognitive tests.[56]

Donepezil

Donepezil is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 1.25 on ADAS-Cog in Alzheimer’s patients (p < 0.001).[51]  Odd that it is so much better than “cholinesterase inhibitors” as a class.  Doesn’t affect progression to Alzheimer’s in mild cognitive impairment.[53] Effect size of 0.6 on the MMSE in Parkinson’s patients, p = 0.0013.[54]  One study showed that donepezil did not have an effect in mild cognitive impairment.[55] Doesn’t work on schizophrenics either. [58]  Did not have an effect on healthy elderly volunteers on cognitive tasks.[66]  I’m going to take the conservative, lower estimates that effect sizes are around 0.2 or 0.5.

Erythropoietin

Erythropoietin is a hormone that increases red blood cell production.

It improves working memory, verbal processing, and Wisconsin Card Sorting scores significantly over placebo in schizophrenic patients.[8]  Significantly improves (p < 0.01) sustained attention and information processing speed in bipolar patients.[72] “EPO acts in an antiapoptotic, anti-inflammatory, antioxidant, neurotrophic, angiogenetic, stem cell–modulatory fashion” so it’s investigated as a neuroprotective for stroke and neurodegenerative diseases, but so far mostly in animals.[42]

Galantamine

Galantamine is an acetylcholinesterase inhibitor used in Alzheimer’s.

Effect size of 8.18 (?!) in Alzheimer’s patients after 6 months; slows cognitive decline.[59] After 3 months, effect size of 2.4 in Alzheimer’s patients, p = 0.002.[63] Galantamine is better than donepezil for Alzheimer’s ADAS-Cog and MMSE.[64] On schizophrenics, effect size of 0.89 in schizophrenic patients on RBANS test, one standard deviation up on the memory subscale, effectively normalizing performance.[60] A much larger randomized study on schizophrenics, however, found no overall effect. [61]  Metastudy on galantamine vs. donezepil for Alzheimers found much weaker effects: 0.48 effect size for donepezil and 0.52 for galantamine.[65]

Ginseng

Panax ginseng is a plant traditionally used as an “adaptogen” to increase alertness and endurance; the active ingredients are triterpinoid saponins called ginenosides.

In a controlled trial of Alzheimer’s, ginseng improves performance on MMSE and ADAS scales after 12 weeks (p = 0.009 and 0.029 respectively) and declined to baseline after discontinuation.[6] Reduces blood glucose acutely (p < 0.001) in 30 healthy volunteers [40] and improves performance at p < 0.05 at “repeated sevens” task. Effect size of 1-2, but since effects were only slightly significant here and were not in other tasks, there’s some reason for skepticism.  This study found that it didn’t improve working memory or reaction time but did improve the “quality of memory” subscore.[41]

Ispronicline

Ispronicline is a nicotinic receptor agonist.  The company that produced it, Targacept, appears to have gone out of business, and the drug was discontinued after it failed to make progress on Alzheimer’s.

It significantly improves measures of attention & episodic memory on healthy male volunteers vs. placebo. Also increases upper alpha peak on EEGs.[44]  2.5 effect size, p < 0.01 for 50 mg AZD vs. placebo for elderly patients on attention, episodic memory, and SDI-cog.[46]   Not statistically significantly effective on Alzheimer’s.[45] 

L-Dopa

This is a precursor to dopamine, used as a treatment for Parkinson’s disease.

Slightly reduces reaction time in healthy subjects, p < 0.05.[74]  Some healthy subjects develop side effects of nausea and excitation under L-Dopa, and these have slower reaction time than placebo; those who don’t have adverse effects have faster reaction times, p = 0.02.[75]

Melatonin

Melatonin is the hormone that regulates sleep cycles, often taken as a sleep aid.

Significant (p = 0.004) improvement in IADL score (activities of daily living, effect size 0.56) on 80 Alzheimer’s patients.[25]

Methylphenidate

Methylphenidate is a stimulant that works by dopamine reuptake inhibition and is used as a treatment for ADD.

Meta-analysis finds a large effect size (1.4) in memory on healthy non-sleep-deprived subjects, but no other improvements on executive function, attention, or mood.  Does not reduce sleepiness after sleep deprivation.[17]

Modafinil

Modafinil is a stimulant that works primarily by histamine agonism.

Significantly improves digit span (by 1-2 digits) and improved pattern recognition (by 8 percentage points), fewer stop errors & lower stop signal reaction time, better spatial planning.[11]

Significant effects (in a meta-study) on working memory, digit span, reaction time, in most studies; no effect on Stroop, spatial planning, verbal fluency; no effect at all on high-IQ population.[14]

Does not cause overconfidence vs. placebo.[15]

Improves performance in a mean 100 IQ group, but not a mean 115 IQ group.[16]

Meta-study founds a moderate improvement on attention (0.56) in healthy non-sleep-deprived individuals. No changes in mood, memory, or motivation.  In sleep-deprived individuals, has a large (2-3) effect size on executive function, a large effect size (1.22) on memory, and a large effect size on wakefulness (2-3).[17]

Comparable alertness and performance effects for 200 or 400 mg modafinil vs. 600 mg caffeine (6 cups of coffee) in sleep-deprived patients.[18]  Caffeine, amphetamine, and modafinil are comparably effective in increasing alertness & reaction time in sleep-deprived patients.[9]

Nicotine

Nicotine is a stimulant and nicotinic acetylcholine receptor agonist.

4-week nicotine skin patch improves performance on continuous performance test vs. placebo in 8-person trials of Alzheimer’s.[3]

In abstinent smokers, nicotine improves performance on all tests; in never-smokers, produces faster reaction times but more errors.

6-month trial on schizophrenics improves performance on the CPT with an effect size of 0.7.[22]

A meta-analysis found that nicotine improved working memory reaction time in both smokers and nonsmokers, effect size 0.34, but did not improve accuracy; also improved reaction time in orienting attention, effect size 0.34, and alerting attention, 0.3

Oxygen

Breathing high-oxygen air increases blood oxygen concentration.

It improves word recall vs. placebo in healthy subjects, but only at a p < 0.05 level.  Reaction time lowered, p < 0.0005.  No effect on working memory.[10]  Effect size on word recall and reaction time in another study on healthy subjects was ~2.5, p < 0.05.[43]

Piracetam

Piracetam has an unknown mechanism of action but is sometimes used as a nootropic.

In a metastudy of piracetam for cognitive impairment (mostly age-related), 63.9% were improved on piracetam vs. 34.1% on placebo. Fixed-effects model OR is 3.35.[29]  Doesn’t work on Alzheimer’s.[69]

PRL-8-53

PRL-8-53 is an experimental compound with some cholinergic properties.

Significant (p < 0.01) improvement in word retention over placebo; 30-45% improvements in # of words retained.[26]

rTMS

Repetitive transcranial magnetic stimulation involves placing a magnetic coil near the head of the subject and produces small electric currents in the brain.

A meta-study found improvements with effect size of 0.2-0.3 in working memory and response times on healthy subjects on n-back tasks.[12]

Semax

Semax is a Russian nootropic that seems to work by stimulate nerve growth factors.

Significant 74% improvement over placebo on memorization exam in power plant operators.[24]  Most of the other evidence about Semax is from Russian rat studies.

Souvenaid

Souvenaid is a cocktail containing essential fatty acids, vitamins, uridine, and choline, used to treat Alzheimer’s.  

A randomized 24-week trial on Alzheimer’s patients found that it improved the memory subscore on the NTB with an effect size of 0.23.[68]

Tandospirone

Tandospirone is a serotonin partial agonist, similar to buspirone, used for anxiety and depression.

In schizophrenic patients, improves performance on Wechsler Memory Scale and Wisconsin Card Sorting, p < 0.001 and 0.0001 respectively, effect sizes of 0.63 and 0.7.[4]  However, tandospirone impaired memory in healthy subjects.[71]

Tianeptine

Tianeptine is an antidepressant that seems to work by enhancing dopamine release, enhancing BDNF, and/or targeting opioid receptors.

In an uncontrolled trial of depressed patients, tianeptine improved working memory and reaction time.[23]  Did not affect memory, attention, or psychomotor performance on young healthy volunteers.

Tolcapone

Tolcapone is a COMT inhibitor used in the treatment of Parkinson’s.

Tolcapone improves memory for val/val COMT healthy subjects, but worsens it for met/met. (“Warriors” benefit, “worriers” don’t.)  Effect size of about 0.8, p < 0.05 on the val/val’s.[73]
INEFFECTIVE THERAPIES

B vitamins

No effect on elderly subjects. [7]

Creatine

Creatine is a compound that occurs naturally in vertebrates and supplies ATP to muscles.

No effect on cognitive function on healthy young adults.[35]  Does have effects on memory in the elderly [36] (d = 1.5, p < 0.001 for backward digit span) and vegetarians [37]

D-Cycloserine

D-cycloserine is an amino acid derivative and antibiotic.

Doesn’t improve cognitive function/digit span in schizophrenics.[57]

DHEA

DHEA is a steroid hormone and precursor to estrogen and testosterone.

No effect on elderly subjects.[5]

Dual N-Back

Dual N-back is a memory practice game.

Metastudy shows that, while performance on the N-back task improves, no crossover improvement on IQ tests occurs.[13]

Gingko Biloba

Fails to find effect on cognitive performance on Stroop test in MS patients.[2]  Also fails to prevent cognitive decline in older adults.[76]g

Oxiracetam

Oxiracetam is in the racetam class of drugs, unknown mechanism of action.

Doesn’t work on Alzheimer’s. [32]

Selegiline

Selegiline is an MAOB inhibitor used in Parkinson’s and depression.

Not effective on cognitive performance in Alzheimer’s.[30]  Doesn’t help in Parkinson’s either.[31]

Tarenflurbil

Tarenflurbil is a discontinued putative Alzheimer’s drug that destroys amyloid plaques.

Doesn’t slow cognitive decline in Alzheimer’s.[49]

NOTES

Unsurprisingly, the classic stimulants do quite well. (Caffeine, nicotine, amphetamine, methylphenidate, modafinil.)  Ispronicline is less well known and its evidence base is much smaller, but since it’s also a nicotinic receptor agonist, it’s possible that it also belongs in this category.

Cerebrolysin is interesting. It’s a legal anti-Alzheimer’s drug in Europe, and one of the few drugs that directly focuses on neural growth factors. These are known (mostly in animal studies) to be protective against brain damage, as from stroke or Parkinson’s.  Deficiency in BDNF is also one of the current hypotheses for what’s going wrong in depression.  “Just give people some growth factors” might be one of these simple obvious-in-retrospect things that could pan out to be widely effective.  In animal studies, growth factor gene therapy often has neuroprotective effects, and Nobel Prize-winning neuroscientist Rita Levi-Montalcini took daily NGF eyedrops.

There’s a common pattern in anything dopaminergic (such as: amphetamines, tolcapone, L-dopa, etc) that they improve cognitive performance in people who have “too little dopamine” (Parkinson’s patients, ADHD patients, val/val COMT genotypes) but are useless or worse in those who have “too much dopamine” (met/met COMT genotypes.)  This seems like a fairly robust finding, across many drugs as well as a lot of fMRI studies about dorsolateral prefrontal cortex activation.  How good dopaminergics are for your mental performance may depend a lot on who you are.

 

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20 thoughts on “Nootropics

  1. I wonder if the finding about modafinil having less effect on high iq populations would generalize. It seems intuitively right that if a brain is already working particularly well, it’s harder to get it to do better by improving some functions at the expense of others – it was probably already relatively well balanced. Alternately high iq could be partly explained by a person’s habits of thinking, which are well tuned for their normal brain function and not optimized for their altered brain function.

    Scott Alexander posted a while back about the permanent effect of psilocybin on personality. In the psychedelics literature are there studies of effects on cognitive performance? I’d be interested to know whether they have a deleterious effect, and also you could imagine that if someone’s openness was too low, pharmacologically increasing it could improve some aspects of cognitive performance.

    • 1. I know that amphetamines work less well on high IQ people as well. It might be a general feature of nootropics, or it might be more specific than that (high IQ people tend to have “more dopamine” in a rough sense, so dopaminergic drugs are less useful for them.)
      2. The psychedelics literature is painfully thin, sorry to say. It is a common hippie truism that LSD microdoses improve cognitive performance, for instance, and this is totally plausible (it’s a stimulant), but good luck finding published evidence.

      • “I know that amphetamines work less well on high IQ people as well. ”
        What about high IQ + low conscientiousness vs. low IQ + low conscientiousness? This almost seems to assume that there is a correlation between IQ and conscientiousness/executive function… But if anything, there isn’t a clear correlation between the two…
        The biggest results I’ve seen from amphetamines were from people in the high IQ + low conscientiousness category (who also often tend to be cognitively uneven).
        Sometimes poor executive functioning can get in the way of high-intelligence people who score lower on IQ tests than how intelligent they seem to be.

      • Or do you mean that amphetamines/modafinil are more likely to exert positive effects on *the* working memory/g-loaded tasks [and not on general conscientiousness/motivation] in lower-IQ/”cognitively compromised” individuals? I’m not sure to what extent intelligence/g affects the positive effects of amphetamines/modafinil on conscientiousness/motivation.

    • Modafinil, like amphetamine, works on Val/Val COMT people much better than Met/Met COMT people. So this might be a dopamine thing.

    • Well, psychedelics do seem to have an effect on creative thought, although the dose can’t be too high, otherwise the ideas won’t be particularly connected to reality. The definitive study in the area (from the 60’s) would be http://www.amsciepub.com/doi/pdf/10.2466/pr0.1966.19.1.211 where a bunch of scientists and engineers who had been working on a problem for weeks or months without finding a satisfactory solution were given 200 mg of mescaline and set free to work on their problems, and the results were quite impressive.

  2. Here are two problems with Cohen’s d, not that there’s anything you can do about them. One problem is that you usually want the denominator to be the standard deviation of the population, but you might have correlated samples. This is a problem with psych studies where a bunch of undergrads from a single school have restricted range, but probably not such a problem with medical studies.

    A variant of this happens in medical studies: if the population is chosen to be impaired, its standard deviation is different than that of the general population (probably larger, unless impairment was defined by a cognitive test). The range from person to person of cognitive decline from sleep-deprivation is probably larger than cognitive abilities in the well-rested. A result of d=2 in the former case is, in some absolute sense, less impressive than d=2 in the latter. And similarly with Alzheimer’s.

    • Looked up phenibut, couldn’t find studies on its nootropic effects good enough to include. This is a problem for a lot of the Russian stuff. I’ve looked into some but not all of them so far.

  3. Given the differing effect sizes reported for eg cholinesterase inhibitors (I saw reports of 0.1, 0.2, 0.5, 1, 2, and 8) and the relatively few studies done on any of this, why is your epistemic status so high? Couldn’t the same process that made people think galantamine had an effect size of 8 be making people think cerebrolysin has an effect size of 2? Or were there big differences between different studies?

    • oh, good point. I am a bit confused by the inconsistency in the Alzheimer’s data and there is just plain less info on cerebrolysin.

    • Possibly. Maybe “intelligence” is an overly judgmental term; my point is that IQ tests are heavily driven by working memory and attention, and as I recall COMT genotype correlates with performance on IQ tests. It’s certainly true that a person can be insightful and make intellectual contributions without having lots of working memory.

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  5. Sarah,
    I really like your analytical style with this post. Two things jumped out at me about Cerebrolysin:
    – Much of the evidence for Cerebrolysin is published in Russian and Eastern European journals that don’t have the same academic rigor as US journals.
    – Cerebrolysin is derived from homogenized porcine brain. Prion diseases are zoonotic and so Cerebrolysin may carry the risk of infecting oneself with misfolded prion proteins. This risk is compounded by the fact that Cerebrolysin is administered intramuscularly or intravenously.

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