Nootropics: Mood, energy, and focus

Nootropics: Mood, energy, and focus


11 minute read

Introduction

This document should act as a beginners guide to nootropics with some historical context built into the science.

Why Build a Nootropic Stack?

Our stacks began as a passion project. TheCryptoDog and Dr. Chris collaborated and the goal was to identify natural (existing in and extracted from nature), semi-synthetic (existing in nature but manufactured through synthetic pathways), and synthetic (existing and manufactured only through synthetic pathways) ingredients that could support the heavy workload associated with the program. Not only that, but identifying compounds that could potentially enhance the ability to maintain attention over extended periods of time could have potentially profound importance in the everyday life of individuals all over the world where lapses in attention are a common occurrence. That’s where nootropics come in. 

What are Nootropics?

It depends on who you ask. “Nootropic” is the term used to describe “smart drugs”, although most are not considered drugs and do not require a prescription. Of course, regulations vary from country to country. 

There are two generally accepted definitions. The original definition, established by Dr. Corneliu E. Giurgea, Romanian psychologist and chemist considered to be the founding father of nootropics, and the common definition.

Dr. Giurgea was the first to attempt a descriptive criteria for what qualifies as a nootropic, which includes:

  1. Enhancement of memory and learning
  2. Improved cognition under stress
  3. Protection of brain cells (e.g. the compound has neuroprotective properties)
  4. Facilitation of cell-to-cell communication
  5. Backed by human research demonstrating brain bioactivity
  6. Absence of usual pharmacological effects (to include side effects) of psychotropic drugs

Using the original definition, it is hard to imagine a compound that provides benefit and lacks pharmacological effects of psychotropics as it is difficult to separate the impact on behavior, mood, perception, and thoughts related to productivity from the compound itself. 

The common definition is any compound that boosts productivity, memory formation, and a host of other cognitive functions. 

What is a Nootropic Stack?

A “stack” is the term for the combination of two or more nootropics. Most times (but not always), the goal is synergy. For example, the combination of caffeine and L-theanine is the most basic and common example. Theanine acts as an anxiolytic to balance out the jittery effects of caffeine, and they are generally dosed in a 2:1 ratio. 

There are various categories that nootropic ingredients can fall into, and some are open for debate:

  • Cholinergics
  • Stimulants
  • Racetams
  • Adaptogens
  • Miscellaneous

In general, cholinergics upregulate acetylcholine (ACh), stimulants increase activity in the sympathetic nervous system (SNS), racetams work in a number of ways to include acting on the parasympathetic nervous system (PNS), and adaptogens work to support the body’s response to environmental and non-specific stress. The categories are listed in table 1 based on their mechanism of action. 

Table 1: Nootropic Ingredients by Category

Category*

Ingredient Examples

Cholinergics*

Huperzine A, Alpha GPC, Citicoline

Stimulants*

Caffeine, Theobromine, Theacrine (new era), Methylliberine (new era), Armofinil†, Modafinil†, Methylphenidate†, Amphetamine†

Racetams*‡

Piracetam, Oxiracetam, Phenylpiracetam, Aniracetam

Adaptogens*

Ginseng, Rhodiola, Schisandra 

Miscellaneous*

Bacopa, Theanine, Lion’s Mane, ISRIB‡

*Not an all-inclusive list, †Prescription only in the US, ‡Not considered prescription drugs or dietary supplements in the US and cannot be labeled as such

Cholinergics

“Cholinergics” are any compound that acts on cholinergic synapses, which are ubiquitous throughout the central nervous system (CNS). Their high density in various parts of the brain to include the limbic system (e.g. the hypothalamus involved in homeostasis, the amygdala involved in mood and emotion, and the hippocampus involved in memory consolidation), suggest that cholinergic transmission is critical for memory, learning, attention, and other higher brain functions. Research suggests additional roles for cholinergic systems in overall brain homeostasis and plasticity. With that in mind, the brain’s cholinergic system occupies a central role in ongoing research related to cognition.

Stimulants

The word “stimulant” usually refers to agents stimulating the CNS with an effect on alertness, locomotion, and mood, or generally targeting the SNS. This can elicit the well known fight-or-flight reaction to increase blood flow to skeletal muscles, and mobilize energy. Stimulants can include compounds that increase alertness and reduce fatigue, such as coffee. Others such as amphetamines can affect mood and modify mental alertness. The majority of stimulants act on the monoaminergic systems and are listed in table 2.3  New era stimulants, such as theacrine and methylliberine, stimulate without impacting heart rate or blood pressure, a novel characteristic.

Table 2: Stimulant Ingredients by Category

Category*

Neurotransmitter

Sympathomimetic†

Norepinephrine (NE), Epinephrine (Epi)

Dopaminergic‡

Dopamine (DA)

Serotonergic‡

Serotonin (5-HT)

*Not an all-inclusive list, †Sympathomimetic is a term used to describe agents that mimic sympathetic/adrenergic responses, ‡Less commonly used phrases dopaminomimetic and serotoninomimetic could be used to describe actions on the DA and 5-HT systems 

Ingredient Categories

Racetams

While a number of racetams are commercially available, they are considered “research only” products and cannot be sold as dietary supplements, or included in pre-mixed stacks in the US market. 

Racetams share a common structural feature, a pyrrolidinone ring. Nootropics developed from pyrrolidinone derivatives have common features such as enhancing the learning process, diminishing impaired cognition, as well as neuroprotective properties - fitting the classic definition perfectly as piracetam was discovered by the father of nootropics. Studies support the role of piracetam in enhancing memory and learning, as well as acting synergistically with choline. This makes sense as the administration of piracetam impacts the ACh receptor binding in various brain regions.4 Alternatively, racetams may act on the AMPA receptor, which glutamate binds to. Glutamate is often referred to as the “gas pedal” or the principal excitatory neurotransmitter in the CNS.5 Despite having a low affinity for glutamate receptors, piracetam initiates a number of effects: activation of AMPA receptors, increasing the density of AMPA receptors in the synaptic membrane of the cortex, and the release of glutamate itself. In short, research suggests the neuroenhancing effects of piracetam are via stimulation of ACh and glutamatergic systems.4

Adaptogens

During World War II, the idea that a pill could improve mental and physical performance in healthy people was devised and various stimulants were given to pilots and members of submarine crews, prior to the formal definition of nootropics. Adaptogens were initially defined by Nikolay Lazarev as substances that enhance the “state of nonspecific resistance” in stress based on Hans Selye’s theory of stress and general adaptation syndrome. Studies on animals and humans support that adaptogens exhibit neuroprotective, anti-fatigue, anxiolytic, and CNS stimulating properties. In essence, they combine elements from several of the categories of nootropics. In addition, a number of clinical trials have demonstrated that adaptogens exert an anti-fatigue effect that increases mental work capacity against the background of stress and fatigue, particularly in tolerance to mental exhaustion and enhanced attention.6

A few recognizable herbs classified as adaptogens are ginseng, Rhodiola, and Schisandra, all of which are detailed below. 

The Panax genus (ginseng) of herbs contains several species such as Korean ginseng (Panax ginseng) and American ginseng (Panax quinquefolius) that are relatively well-known. Ginsenosides such as Rb1, Rd, Re, Rg1, Rg2, Rg3, Rh1, Rh2, Rh3, PF11, and NTR1, and gintonin and compound K, are the active components within the ginseng plant responsible for its qualities.7 However, other plants are sometimes referred to as ginseng, such as Siberian “ginseng” (Eleutherococcus senticosus), however, eleutherosides are the active compounds in this plant. In both animal and cellular models, ginsenosides are responsible for activity against oxidative stress and exert their effects by modulating cholinergic, glutaminergic, and other molecular signaling pathways that are vital for cognitive activity.7

Rhodiola rosea has been observed to increase the levels of NE in the cerebral, prefrontal, and frontal cortex regions of the brain while also upregulating DA and ACh in the limbic system pathways.4 With that underlying mechanism in mind, Rhodiola can improve attention when fatigued after single and repeated administration and has been observed to do so when experiencing physical, emotional, and mental exhaustion.6,8 

Schisandra chinensis has been reported to be effective in relation to reduced physical and mental performance in open label studies, showing improvement after 2–10 weeks of use. In particular, an increase in general well-being and work capacity, as well as a decrease in sleepiness and exhaustion has been observed.6

Miscellaneous

There are a number of ingredients that do not fit neatly into other categories. The following details a few select ingredients of interest. 

Bacopa monnieri has been studied preclinically and clinically with some statistically significant findings relating to retention of new information. The effects were attributed to antioxidant action in the hippocampus region of the CNS.9 Bacopa monnieri is also known for anxiolytic effects.4

Hericium erinaceus, commonly referred to as Lion’s Mane, is a fungus with a long history of use. It contains bioactive metabolites that can be classified into high molecular weight compounds, typically as polysaccharides, and low molecular weight compounds, typically polyketides and terpenoids. These compounds are thought to have neuroprotective properties and to promote nerve growth factor gene expression.10 In behavior testing on mice, supplementation with Lion’s Mane induced a statistically significant improvement in short-term memory and visual recognition. In a double-blind placebo-controlled clinical trial in humans with mild cognitive impairment, supplementation with Lion’s Mane for 16 weeks was associated with improvement in cognitive function compared to controls.11

Integrated stress response inhibitor (ISRIB) is an experimental drug that inhibits a key step in the integrated stress response (ISR) associated with cognitive deficits. Animals with more inhibition of this key step show enhanced long-term memory storage, and those with less inhibition have trouble forming long-term memories.12 Research is still underway on this ingredient. 

Conclusion

Optimistically, everyone made it this far and learned something, despite the length of the material. There is more to come and Dr. Chris is always available on twitter or via email at chris@betterbrandhealth.com for any follow up questions, concerns. or requests for new material. 

References

  1. Giurgea C. Vers une pharmacologie de l'activité intégrative du cerveau. Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology. Actual Pharmacol (Paris). 1972;25:115-56. French. PMID: 4541214.
  2. Hampel, Harald, et al. “The Cholinergic System in the Pathophysiology and Treatment of Alzheimer’s Disease.” Brain, vol. 141, no. 7, 2018, pp. 1917–1933., doi:10.1093/brain/awy132.
  3. McGrath, J C, and D A Cowan. “Drugs in Sport.” British Journal of Pharmacology, vol. 154, no. 3, 2008, pp. 493–495., doi:10.1038/bjp.2008.171.
  4. Suliman, Noor Azuin, et al. “Establishing Natural Nootropics: Recent Molecular Enhancement Influenced by Natural Nootropic.” Evidence-Based Complementary and Alternative Medicine, vol. 2016, 2016, pp. 1–12., doi:10.1155/2016/4391375.
  5. Meldrum, Brian S. “Glutamate as a Neurotransmitter in the Brain: Review of Physiology and Pathology.” The Journal of Nutrition, vol. 130, no. 4, 2000, doi:10.1093/jn/130.4.1007s.
  6. Panossian, Alexander, and Georg Wikman. “Effects of Adaptogens on the Central Nervous System and the Molecular Mechanisms Associated with Their Stress—Protective Activity.” Pharmaceuticals, vol. 3, no. 1, 2010, pp. 188–224., doi:10.3390/ph3010188.
  7. Jakaria, Md., et al. “Active Ginseng Components in Cognitive Impairment: Therapeutic Potential and Prospects for Delivery and Clinical Study.” Oncotarget, vol. 9, no. 71, 2018, pp. 33601–33620., doi:10.18632/oncotarget.26035.
  8. Panossian, A., et al. “Rosenroot (Rhodiola Rosea): Traditional Use, Chemical Composition, Pharmacology and Clinical Efficacy.” Phytomedicine, vol. 17, no. 7, 2010, pp. 481–493., doi:10.1016/j.phymed.2010.02.002.
  9. Roodenrys, S. “Chronic Effects of Brahmi (Bacopa Monnieri) on Human Memory.” Neuropsychopharmacology, vol. 27, no. 2, 2002, pp. 279–281., doi:10.1016/s0893-133x(01)00419-5.
  10. Spelman, Kevin, et al. “Neurological Activity of Lion’s Mane (Hericium Erinaceus).” Journal of Restorative Medicine, vol. 6, no. 1, 2017, pp. 19–26., doi:10.14200/jrm.2017.6.0108.
  11. Mori, Koichiro, et al. “Improving Effects of the Mushroom Yamabushitake (Hericium Erinaceus) on Mild Cognitive Impairment: a Double-Blind Placebo-Controlled Clinical Trial.” Phytotherapy Research, vol. 23, no. 3, 2009, pp. 367–372., doi:10.1002/ptr.2634.
  12. Chou, Austin, et al. “Inhibition of the Integrated Stress Response Reverses Cognitive Deficits after Traumatic Brain Injury.” Proceedings of the National Academy of Sciences, vol. 114, no. 31, 2017, doi:10.1073/pnas.1707661114.

« Back to Blog