Nuvigil (armodafinil)

Why I like it: It’s a more potent, purified form of modafinil, and the effects are very robust

Type: Wakefulness-promoting agent

Mechanism: Histamine/orexin release; catecholamine reuptakine inhibition; glutamate; orexin/hypocretin

Effects: Anti-fatigue; enhanced vigilence, arousal, motivation (Nuvigil vs Provigil).


Why I like it: Really the only substance that reliably improves working memory in healthy individuals. But depending on who you ask, nicotine can be harsh on the cardiovascular system, and tolerance to its effects develops quickly.

Type: CNS stimulant

Mechanism: Nicotinic acetylcholine receptor agonist

Effects: Enhanced working memory; psychostimulant-like effects

Coffee (Caffeine)

Why I like it: The world’s most popular drug may help prevent Parkinson’s. Coffee >> caffeine, because coffee delivers a potent blend of polyphenols which thwart oxidative stress.

Type: CNS stimulant

Mechanism: Adenosine receptor antagonist, phosphodiesterase inhibitor

Effects: Anti-fatigue, increased attention


Why I like it: Safe, reliable, and synergistic with caffeine. Very safe in overdose.

Type: Amino acid analogue

Mechanism: Glutamate receptor antagonist/agonist depending on subtype; increases serotonin, dopamine GABA, BDNF, NGF

Effects: Reduced mental and physical stress; increased mood and attention; synergistic with caffeine

Magnesium (counterion irrelevant)

Why I like it: Protects against excitotoxicity and is an essential dietary mineral

Type: Essential mineral

Mechanism: Endogeneous NMDA receptor antagonist

Effects: Neuroprotection; anxiolysis; decreased mental “noise”; increased clarity


Why I like it: It replenishes acetylcholine stores, is safe for daily consumption, and is a uridine prodrug. Uridine is a nootropic in its own right.

Type: Choline is an essential nutrient

Mechanism: Choline precursor

Effects: CDP-choline restores the mylin sheath around axons and improves learning and memory

Rhodiola rosea

Why I like it: Provides some much-needed stress relief. Chronic, severe stress is neurotoxic.

Type: Scandinavian herb

Mechanism: Neuropeptide Y, MAO, COMT, neurogenesis

Effects: Mitigates deleterious effects of chronic stress, abolishes memory impairing effects of scopolamine (rodents)


Why I like it: Improves cognitive function in older adults; offsets the negative impact of caffeine on cerebral blood flow.

Type: Food

Mechanism: Antioxidant; anti-inflammatory; neuroprotectant; cerebral vasodilator

Effects: Enhanced cerebral blood flow and functional brain connectivity; anti-dementia


Why I like it: Curcumin has limited bioavailability, but if it can get into the brain, there’s hundreds of papers supporting beneficial effects.

Type: Food

Mechanism: Antioxidant; neuroprotectant

Effects: Anti-dementia


Why I like it: Colorful foods are often conjugated (have alternating double bonds). This property also confers powerful free radical scavenging effects

Type: Food/Antioxidant

Mechanism: neuroprotectant

Effects: Anti-dementia (long-term consumption); improved memory


Why I like it: PhenylP is the racetam that feels like it’s a psychostimulant

Type: Racetam/CNS stimulant

Mechanism: Poorly characterized

Effects: Psychostimulant-like effects; enhanced memory and verbal fluency; increased clarity


Why I like it: Like nicotine, one of the few substances that improves memory

Type: Racetam

Mechanism: Enhanced high-affinity choline uptake (HACU)

Effects: Anti-amnesia; psychostimulant-like effects (mixed reports)

NSI-189 phosphate

Why I like it: The jury is still out on whether it works in humans, but who wouldn’t want to boost hippocampal volume?

Type: Nicotinamide derivative, pharmaceutical under development for depression.

Mechanism: Enhanced neurogenesis (neuronal targets are a trade secret)

Effects: Increased resilience to stress; antidepressant effect

Tianeptine sodium

Why I like it: Clean, fast-acting mood elevation that doesn’t impair cognitive performance

Type: Prescription antidepressant in Europe, nutraceutical elsewhere

Mechanism: mu-opioid agonist, glutamate receptor modulator

Effects: Reverse stress-induced synaptic remodeling

Methylene Blue

Why I like it: Promising drug for Alzheimer’s, and doesn’t perturb any neurotransmitter systems, which makes it cleaner than AChEI like Donepzil.

Type: Chemical dye; pharmaceutical under development for Alzheimer’s disease

Mechanism: Enhanced ATP synthesis; artificial electron donor/acceptor; MAO inhibitor

Effects: Mitochondrial enhancement; anti-dementia; general increase in cognitive performance (this post is about the nootropic effects of methylene blue)


What are the best nootropics?

Nootropics are drugs, dietary supplements, or herbal extracts that are purported to enhance cognitive function or protect the brain from neurodegenerative disease.

There are two groups of people that tend to be interested in nootropics. Group one: twenty-somethings who want to push their cognitive ability to supraphysiologic levels. Adults worried about the specter of cognitive decline.

Wouldn’t it be nice if you could cut to the chase and identify the best nootropics?

Nootropics vary in their effectiveness. Some have subtle effects. Others, like the wakefulness enhancer modafinil, have acute effects that are unmistakable.

It’s important to distinguish between nootropics that you can “feel” vs the efficacy of a given nootropic.

Some drugs can have pronounced subjective effects, but aren’t nootropic. On the other hand, nootropics might be highly effective yet you might not necessarily feel anything at all after ingestion. The point is: don’t assume you’ll be able to feel cognitive enhancement immediately.

Certain nootropics – like bacopa or noopept- boost neurotrophic factors like brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF). The subjective effects of bacopa are very subtle. That’s because it takes a number of weeks of daily dosing to realize benefits.

This makes intuitive sense. Boosting BDNF or NGF for a few hours won’t do much. But chronically elevating these neuropeptides could affect synaptic plasticity, neurogenesis, and serve as a pro-survival signal for nascent neurons.

Let’s mention one last caveat before we cut to the chase and discuss the best nootropics. Subjective experiences influence our assessments of nootropic efficacy. This means that what works for me might no necessarily work for you.

Best Nootropics Poll

In your opinion, which class of supplements have benefited your cognitive performance the most?

  • Stimulants (like amphetamine (Adderall) or methylphenidate (Ritalin))
  • Nootropic foods (like cacao, blueberries, or tumeric)
  • Amino acids (like l-tyrosine or glycine)
  • Vitamins or common dietary supplements (like vitamin E, or vitamin B12)
  • Herbal extacts (like bacopa monnieri or lion’s mane mushroom)
  • Cholinergics (like CDP-choline, galantamine, nicotine, or coluracetam)
  • Racetams (like piracetam)

Best Nootropics (Survey)


Interestingly, the top nootropics were all modafinil-analogues:

  • Armodafinil
  • Modafinil
  • Adrafinil

These three drugs all share the same mechanism. Armodafinil is the R enantiomer of modafinil. Provigil (modafinil) is comprised of both R and S stereoisomers. Adrafinil is a prodrug for modafinil. This means that it’s converted to modafinil in vivo (in the body).

Besides modafinil, the top rates nootropics were caffeine, coluracetam, and phenylpiracetam. This also squares with my experience with nootropics.

Survey respondents poorly rated DMAE, Ginseng and Gingko Biloba. Gingko in particular has fallen out of favor in recent years. Despite this, the supplement review website Examine rates gingko biloba as having relatively strong evidence for nootropic effects.

The Five Most Robust Nootropics (Opinion)

Nootropic Notes Effects
Modafinil Prescription drug Increases wakefulness, motivation, cognitive tempo, and decreases fatigue
Nicotine OTC smoking cessation product Enhanced working memory; facilitates learning and memory
Phenylpiracetam Racetam Mild psychostimulatory effect; enhanced motivation and verbal fluency
Noopept Dipeptide (nutraceutical) Increased mental clarity; increased neurotrophic factors
CDP-choline Choline and uridine prodrug Increased acetylcholine; anti-amnesic effect

Best Racetams

Let’s delve into more detail and consider the best nootropics by classification.

The best raceatms are:

  • Piracetam
  • Phenylpiracetam
  • Coluracetam
  • Pramiracetam

Piracetam is the archetypal racetam that started this whole series of compounds. Phenylpiracetam is like piracetam, but with the addition of a phenyl group (benzene ring separated by a methylene group). Phenylpiracetam has psychostimulatory effects, and is much more potent than piracetam. Two downsides are there tolerance to phenylpiracetam develops quickly and it is very expensive.

Coluracetam is a high-affinity uptake (HACU) enhancer. The net effect is increased efficiency of cholinergic neurons.

Best amino acids and amino acid analogues

Amino acids are some of the best selling dietary supplements in the US and elsewhere.

If you eat a balanced diet, your probably already getting the majority of the amino acids you need to be healthy. (This is especially true if you eat a complete protein, like beans plus rice. A complete protein means that you’re getting all the essential dietary amino acids in a single serving.)

But there are certain situations when supplementing with dietary amino acids can help keep you lucid and intelligent. You might want to consider taking any of the following amino acids for nootropic purposes:

  • L-theanine – a classic nootropic that is commonly paired with caffeine
  • L-tyrosine – precursor to L-DOPA which is converted into the neurotransmitter dopamine
  • Branched-chain amino acids (BCAA) – these help replenish the neurotransmitter glutamate.
  • Preclinical studies suggest that BCAA supplementation can help with concussion recovery
  • Glycine – may improve sleep quality, but more research is needed
  • D-Serine – binds the glycine site of NMDA-type glutamate receptors. This may help facilitate long-term potentiation (LTP). D-serine is particularly useful for individuals with schizophrenia or schizoaffective disorders

Best stimulants

Modafinil and nicotine are not psychostimulants in the classical sense. Drugs like Adderall (comprised of mixed amphetamine salts) are considered classic psychostimulants.

Even so, modafinil and nicotine are subjectively stimulating and so they’re included here. The best stimulants (or stimulant-like nootropics) are:

  • Modafinil (Provigil)
  • Armodafinil (Nuvigil)
  • Nicotine
  • Caffeine
  • Phenylpiracetam
  • Selegiline