15 High-Yield Nootropics For 2016
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
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
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.
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.
Mechanism: Antioxidant; neuroprotectant
Why I like it: Colorful foods are often conjugated (have alternating double bonds). This property also confers powerful free radical scavenging effects
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
Mechanism: Enhanced high-affinity choline uptake (HACU)
Effects: Anti-amnesia; psychostimulant-like effects (mixed reports)
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
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
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)
15 High-Yield Nootropics for 2016
What Are the Best Nootropics?
Would you like to cut to the chase and identify the best nootropics? Such knowledge would save time and avoid fruitless experimentation.
If you're drawn to the idea of cognitive enhancement, you're not alone. On some level, everyone hopes to realize their latent potential and perform at their peak. Whether that happens depends in part on how well your brain is working 1.
Nootropics and supplements are just one aspect of a brain optimization strategy, but they're an important one.
There's an element of self-experimentation that goes into figuring out which nootropics work best. But self-experimentation can only take you so far. One limitation is that cognitive enhancement and the self-perception of enhancement often do not align. Adderall might make you feel smarter, but how do you know it's not just increasing your confidence?
Not everyone responds the same way to a nootropic, drug, or supplement. Despite this intrasubject variability, we can make some generalizations about what works. Over the years, I've gleaned a sense of what leads to tangible cognitive gains.
When most people begin their nootropics journey, they tend to ignore the fundamentals.
They are drawn to the cutting edge stuff and are less interested in basic nutrition.
Before delving into nootropics, cover the following bases:
- Vitamin D – a potent neurosteroid
- Probiotic – the number of papers published on the brain-gut axis is staggering
- Dietary iodine – iodine deficiency is the leading cause of intellectual disability worldwide. Even if you're not frankly deficient, you don't want to suboptimal either. I recommend seaweed.
Read my related post: 5 Supplements Everyone Should Take
The Best Nootropics According To Reddit
The 2016 survey posted on Reddit attracted a whopping 850 participants. The participants ranked nootropics on a scale from 0 to 10, agreeing not to rate nootropics that they had not personally tested.
Anecdotal self-report isn't particularly useful for evaluating the efficacy of nootropics. But it does reveal trends in consumer sentiment. Note that the highest rated nootropics in the 2016 study (Adderall, Phenibut, Modafinil, Tianeptine, LSD micro, Semax, and Caffeine) are all obviously psychoactive.
This reveals a bias for nootropics that you can acutely "feel" vs nootropics that exert beneficial effects which only manifest after weeks of daily consumption. It's important to distinguish between mood elevation and cognitive enhancement. Also, it's not necessarily true that you'll be able to feel improvements in your brain function – but that doesn't mean that you won't accrue serious benefits over the long haul.
Remember that the criterion a substance must satisfy in order to be a nootropic are:
- Benign at nootropic dosages
- Improve at least one cognitive domain (attention, arousal, mood, memory, creativity, etc)
There are always trade-offs with nootropics. Amphetamine has the potential for harm but enhances attention in ADHD and some non-ADHD subjects. The trade-off here is that enhanced attention may interfere with cognitive flexibility and creativity. But a subset of individuals will experience cognitive improvement across the board from amphetamine, despite not having ADHD.
Best Nootropics – Key Resources
Caveats and Intrasubject Variability
One caveat is that you might not respond to the nootropics that work well for me, or vice-versa. There are so many factors at play. Differences in 1) individual neurophysiology, 2) the pattern of polymorphisms you inherited from your parents, 3) the DNA alterations you've accrued up until this moment (~100 mutations) and 4) any underlying psychiatric conditions will all potentially affect how you respond to a particular nootropic.
Given this high degree of heterogeneity, only certain generalizations can be made about effective vs ineffective nootropics. But that doesn't necessarily mean the entire project of is fruitless. I'm going to to tell you about the 15 nootropics that have consistently outperformed for me, while also imparting some tools you can use to follow suit.
Here's an example about what I mean in terms of individual neurophysiology. The follow cases are simplistic, but still illustrate the point I'm conveying:
If you have undiagnosed ADHD, you'll probably find dopaminergic or noradrenergic nootropics most effective. Things like l-tyrosine, modafinil, l-deprenyl. You'll usually have positive results from correcting something that is off-kilter in terms of your neurophysiology with certain nootropics.
You're a 60 year-old man with a 20 pack-year history of smoking, you're pre-hypertensive (untreated), and possibly in the early stages of vascular dementia. You might benefit from some nootropic vasodilators, like niacin or cacao. Obviously, you'll benefit most from seeing a neurologist and getting expert care, but sometimes physicians are reluctant to address health concerns before they are unmistakable, and nootropics may be your only option initially.
Generalizations About How to Approach Nootropics
This reddit post succinctly summarizes some key lessons about using nootropics responsibly and productively. (An example of unproductive nootropic use would be trialing so many compounds simultaneously that you can't draw any conclusion about what's helpful or harmful). Here's what the Redditor norepinephrinex has to say:
- Like any community, the nootropics scene periodically undergoes trends, fads and changing consensuses.
- Anecdotally, I've found the best nootropics tend to be Russian.
- My responses to various substances have evolved over time.
- The often-discussed U-shaped response curve applies to nearly everything.
- Simple stacks are often best; distilling a stack down to its most effective components is underrated.
- At some point, you have to really ask yourself about personal risk tolerances.
- Figure out your lowest-hanging fruit and target that first.
- Know thyself – otherwise, it's easy to get caught up on others' glowing reports.
- Take breaks from time to time.
- Some of the best nootropics are often not things you can find in a pill.
Best Nootropic Foods (The Brain Food Pyramid)
Most people associate nootropics with white, crystalline powders developed in clandestine labs in cold war era Russia. It's true, the Russians have brought us some of the best nootropics. On the other hand, many Russian nootropics don't have much evidence supporting their use, besides anecdotal reports.
But let's not forget about non-synthetic nootropics, nootropics that naturally occur in nature. For example, nootropic foods tend to be underestimated and overlooked. They're dismissed because they don't provide instant gratification – it may take months until you realize benefits – and also because foods seem too mundane to actually provide substantial cognitive benefits.
It is well-documented that certain foods have robust nootropic effects. For example, there is better evidence supporting the neuroprotective and cognitive enhancing effects of cacao flavonoids, blueberries and curcumin, than for an obscure racetam that remains untested in humans.
Let's consider cacao, for example. Here's my rough summary of the biomedical literature from PubMed.gov about the beneficial effects of cacao on brain function.
- 1) Improve cerebral blood flow and brain perfusion (Fisher ND, Sorond FA, Hollenberg NK. Cocoa flavanols and brain perfusion. J Cardiovasc Pharmacol. 2006;47 Suppl 2:S210-4).
- 2) Encourage angiogenesis (formation of new blood vessels), inhibit neuronal apoptosis (programmed cell death), and enhance neurogenesis in animal models (Nehlig A. The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. Br J Clin Pharmacol. 2013;75(3):716-27).
- 3) Penetrate the blood brain barrier and directly interact with signal transduction cascades important in the hippocampus,
- 4) Modestly improve measures of cognitive function in older adults (Sokolov AN, Pavlova MA, Klosterhalfen S, Enck P. Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior. Neurosci Biobehav Rev. 2013;37(10 Pt 2):2445-53).
- 5) Improve insulin resistance4)Desideri G, Kwik-uribe C, Grassi D, et al. Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment (the Cocoa, Cognition, and Aging (CoCoA) study. Hypertension. 2012;60(3):794-801).
- 6) Reverse Alzheimer's-like pathology (Williams RJ, Spencer JP. Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med. 2012;52(1):35-45).
Some of these studies are conducted in rodents, and can't be neatly translated to humans.There's also publication bias, and probably some undisclosed commercial interests (the chocolate lobby?!). But the results of these studies are at least _suggestive _of cacao's cognitive benefits.
Brain Health, Diabetes, and Heart Disease
What you're eating is just as important as what you're not eating.
Try to limit foods that have a deleterious effect on brain health.
Put simply, most foods that exacerbate cardiovascular disease or diabetes are also bad for the brain. The brain needs to be well-perfused to perform optimally, and so you need a vasculature (blood vessels) that functions well. Too much sugar is pro-diabetic and impairs insulin resistance and has a number of negative downstream consequences for the brain
I've written previously about this issue here. Many of these points are common sense, but I'll summarize them anyway. Here's the take-home message from the article:
- Limit Sodium. Prepare foods with little or no salt. Also consider using potassium salt. Sodium chloride tends to raise blood pressure, whereas potassium lowers blood pressure.
- Limit beverages (except water). Most fruit juices (e.g., orange juice) contain as much sugar as soft drinks like coca cola and are often nutrient-poor compared to whole fruits and vegetables. In addition, appetite satiation after consuming liquid calories is blunted, soda and juice drinkers tend to consume more calories overall.
- Limit alcohol. If you drink alcohol, drink moderately. Moderate alcohol use is defined as 1 unit of alcohol per day in women, and 2 drinks in men.
- Choose fat-free or low-fat dairy products.
- Prepare your own food. Restaurant food is invariably less healthy.
- Avoid pre-packaged and processed foods. The worst offenders are deli meat (high sodium), candy, chips.
- Exercise portion control. Exploit thermodynamics: try consuming fewer calories than you expend.
- Eat fish twice a week.
- Avoid partially hydrogenated vegetable oils* and trans fat*.
- Fiber-rich foods. Fiber can help control blood sugar levels and decrease the risk of heart disease. Fiber-rich foods include vegetables, fruits, nuts, legumes (beans, peas, lentils), whole wheat flour and wheat bran.
Cornerstones of the Best Nootropic Stack
Once nutrition and regular exercise are covered, what can be done to reach your intellectual potential?
There are a few nutraceuticals and essential dietary minerals/vitamins that are the foundation to the best nootropic stack. These basics are usually compounds that you won't feel acutely but improve the neurotrophic environment in your brain. I'm talking about a expanded version of the Mr. Happy Stack:
- Choline (as CDP-choline or Alpha GPC)
- Bacopa monierra
- Magnesium (the counter-ion probably isn't important)
- Vitamin D
- DHA/EPA (dietary sources are preferred)
- B vitamins (lower homocysteine, improve O2 saturation, etc.)
- B1 – prevent alcohol-induced brain damage (Wernicke-Korsakoff Encephalopathy)
B6– avoid supplementation; excessive B6 inhibits its own absorption, and so paradoxically B6 supplementation may result in deficiency
- B9 – folic acid is converted to 5-methylfolate – dubbed the "trimonoamine modulator" that is needed for the endogenous biosynthesis of the three major neurotransmitters (serotonin, dopamine, norepinephrine)
- B12 – required for the normal function of the CNS; a 3 year supply is stored in the liver because the consequences of deficiency are so dire
Needless to say, acute supplementation with the above will not result in immediate nootropic effects; these are just elements that support an efficient neurochemical milieu.
Nootropics and Risk Tolerance
It can also be helpful to determine your risk tolerance at the outset when customizing a nootropic stack. Some people will be comfortable trialing research chemicals (RC) that remain formally untested in humans; others are comfortable taking drugs that have good safety records but are not approved for use in healthy subjects (e.g., modafinil). If you have a very low risk tolerance, you may only be interested in dietary supplements that are endogenously (naturally) present in your body, like vitamin D, B12, or magnesium.