Questions can be about anything; not just science, biology, and supplements, but random topics as well if you wish. I’ll answer any question asked be…

Read more

Questions can be about anything; not just science, biology, and supplements, but random topics as well if you wish. I’ll answer any question asked before the next month’s Q&A post at the end of August.

Rules:

• 1 question per person per Q&A, although 1-2 follow up questions are allowed

• “Thoughts on xyz…” is not a question

• Do not ask for medical advice

• The better the question you ask, the better my answer will be

Disclaimer: None of the answers provided below should be taken as medical advice. Any and all content on this Substack is for educational purposes only. BowTiedNeuron is not a licensed medical professional. Always consult your doctor before making any major health decisions.

Questions can be about anything; not just science, biology, and supplements, but random topics as well if you wish. I’ll answer any question asked before the next month’s Q&A post.

Rules:

• 1 question per person per Q&A, although 1-2 follow up questions are allowed

• “Thoughts on xyz…” is not a question

• Do not ask for medical advice

• Ask good questions. The better the question, the better my answer will be

Disclaimer: None of the answers provided below should be taken as medical advice. Any and all content on this Substack is for educational purposes only. BowTiedNeuron is not a licensed medical professional. Always consult your doctor before making any major health decisions.

Before that though, I want to dive into Semax as a molecule—as I normally do with nootropic reviews—to explain what it is, what it does, and the different forms available for those who may be curious.

If you're not curious and are only here for my review, go for it. You’ll find it close to the end of this post.

What is Semax?

Simply put, Semax is a synthetic peptide—a short chain of amino acids strung together. More specifically, it is a small fragment of adrenocorticotropic hormone (ACTH), a naturally occurring hormone in the human body that is cleaved from pro-opiomelanocortin (POMC) and is involved in regulation of cortisol.

For my fellow chemistry enjoyers the amino acid sequence is Met-Glu-His-Phe-Pro-Gly-Pro.

Semax was developed in Russia, and is still used there medically. Its primary uses are to treat stroke and other cognitive disorders due to its neuroprotective and neurotrophic effects, which can be useful in the recovery from brain damage by minimizing damage and promoting neuroplasticity. However, Semax is most well known in the West as a nootropic, or cognitive enhancer, that can improve memory, attention, learning, and general mental performance. 

Despite lacking FDA approval, Semax is available online in the United States and other countries as a compound designated “For Research Purposes Only”. (I’ll share my preferred vendor with my subjective experience at the end of the article)

What does Semax do?

While its exact mechanism of action is unknown, Semax has profound neuroprotective and neurotrophic effects. In animals, Semax has been shown to significantly increase levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the frontal cortex and hippocampus shortly after administration [1, 2, 3].

Both BDNF and NGF are powerful modulators of neuroplasticity and promote the growth and survival of neurons. This likely explains why Semax has been shown to improve learning in animals [2, 4], counteract the behavioral effects of chronic stress [5], and aid in the recovery from stroke. The effect on stress is particularly interesting, since chronic stress is known to cause drastic decreases in BDNF. Additionally, Semax has been shown to have nootropic properties in healthy humans, improving attention and short-term memory [6].

Interestingly, Semax has also been shown to prevent the deficits in learning and memory caused by heavy metals in animals [7]. This effect is likely influenced not only by Semax’s positive impact on growth factors, but also its ability to act as an antioxidant, protecting against oxidative stress [7].This adds another layer to Semax’s neuroprotective and restorative potential, which has been shown in animal models of ischemic stroke [8] and in humans [9].

One of Semax’s most unique properties though, is its relationship with dopamine neurotransmission. Administration of Semax alone has no impact on dopamine release in rodents, but when paired with a dopaminergic substance—in the case of this study, amphetamine—dopamine release in the striatum is significantly increased compared to animals that received only amphetamine (Figure 1). Locomotor activity (movement) was also significantly increased by Semax + amphetamine when compared to the group receiving only amphetamine [10]. This indicates that Semax has the ability to potentiate the effects of dopaminergic compounds and further enhance dopamine release in the striatum, leading to increased motivation and drive.

Based on these various effects in vivo, Semax can be labeled as a potent neuroprotective and nootropic compound that can enhance cognition in healthy users, while also possessing the potential to aid in the recovery from neurological damage and promote neuroplasticity. Its impact on neurotrophic factors and monoamine neurotransmission also indicate that Semax may be effective as an antidepressant, given their implications in the pathology of depression, and in combatting the detrimental effects of chronic stress on cognition.

Different forms of Semax

Semax is available in four main chemical forms:

• Semax

• N-Acetyl (NA) Semax

• NA Semax Amidate

• Adamax

All of these contain the original seven amino acid sequence that make up Semax, but the latter three have slight modifications to improve their stability and pharmacokinetic profile. In the NA molecules, an acetyl group is attached to their N-terminus to improve bioavailability and potency. The amide group added to NA Semax Amidate is thought to enhance this further, creating an even more potent molecule. Finally, Adamax is a unique form of Semax with an Adamantane group attached, which may improve stability and bioavailability even further than the NA versions.

Due to their differing structures and potencies, all four versions of Semax have been reported to exert different effect profiles, and the three modified versions are seen to be more potent than basic Semax.

Administration of Semax

As a peptide, Semax does not have great oral bioavailability, so it is commonly administered intranasally (via spray or dropper) or injected subcutaneously. Intranasal administration seems to be as effective as injection, so it's the common recommendation for use in humans due to its ease.

Semax’s half life is only a few minutes when administered intranasal, but it quickly enters the brain and its effects can last for 24 (or more) hours on just a single dose.

My Personal Experience

Over the past 6 months, I’ve been experimenting with the acute use of intranasal NA Semax. By that, I mean that I used it intermittently as opposed to running it every day for a longer amount of time. 

For me, Semax produces a very smooth nootropic feel that kicks in within minutes and lasts all day, potentially lingering into the next day. My mind feels very sharp when I’m on it, and cognitive tasks are less mentally taxing than usual. The feeling it provides me consists of a subtle mental clarity, generally enhanced cognition, improved short-term memory, and increased visual acuity. It’s a similar feeling to that of other compounds that act via neurotrophic factors, but is less outright stimulatory than 4-DMA-7,8-DHF and much more profound than lion’s mane, which gives it a unique feel along with other benefits such as:

Less brain fog after intense exercise - This is an issue that has plagued me for a while, especially on weekends when I choose to lift in the morning. Normally, I’m out of commission mentally for several hours after a workout, but using Semax before (and sometimes after) my workout cuts that mental recovery time significantly. It also improves the quality of my lifts by improving my concentration and mind-muscle connection.

Potentiation of dopaminergics - This is similar to the effect described above where Semax potentiates the dopamine release induced by amphetamine, and it actually translates to my use (even if I take the dopaminergic several hours after Semax). When I’m using Semax, the effects of dopaminergic compounds (mainly caffeine and sabroxy in my case) are greatly enhanced—so much so that I’d express caution when pairing the two because it can easily lead to overstimulation. I’m able to use half the dose of sabroxy I normally do, and it still feels like a huge dose. As a result, this combo has been my go-to for productivity and focus.

Increased libido - Considering my libido is already normal/high, this can be annoying at times, but is welcome at others. This usually takes a few hours to kick in, but can definitely last 24+ hours in my experience. It’s not an overwhelming uptick, but it’s definitely noticeable.

Improved reaction time - This is something that has stuck around even when I’m not using Semax or other neurotrophic nootropics, but is a new phenomena in my life. This is most notable to me when I drop things or knock them off a table. In the past few months, I’ve begun catching things at an alarming rate, which I never did before. Whether or not I can contribute this to Semax entirely is unknown, but it didn’t start until after I started using it.

After realizing that it had potent acute effects for me, I determined that this was how I wanted to use Semax for the time being, as opposed to running a cycle of it (which is still likely better for some use cases, just not necessary for my current goal of acute cognitive enhancement). Although I do still plan to run a cycle in the future.

Concerning dose, I’ve stuck to 300-600mcg per day, either all in the morning or split up between morning and noon, and have had great success with that. I’ve tried 900+mcg several times, but I noticed no more benefit than the lower doses.

I’ve been trialing NA Selank as well, but I only feel like I derive a benefit from it when used in conjunction with Semax as the two are highly synergistic. If I was dealing with anxiety or other mood issues its effects may have been more apparent, but I’m not, so Selank alone hasn’t done much for me. Using the two together though seems to improve the effects I see when using just Semax, especially reducing brain fog after exercise. 

In all, Semax is definitely not a magic bullet for productivity or focus, but it’s definitely been a great tool for me in improving those when I want/need it most. In an acute context, the most useful effects i’ve noticed are the improved mental recovery after a hard workout and the potentiation of dopaminergic compounds, but the uptick in mental clarity and cognition are certainly great as well.

Where to Source Semax (For Research Purposes)

Limitless Life Nootropics has become my preferred source for research peptides.

After experimenting with a few of their products over the past few months, I’ve recently become affiliated with them which means code “neuron” gets you 15% off anything on their site. Their peptides are made in the USA, third-party tested, and they ship quickly, so I trust them as a source.

If you’re interested in researching Semax or its derivatives, you can use the links below and use code “neuron” for a discount.

Semax spray- Link

N-Acetyl Semax spray - Link

N-Acetyl Semax Amidate spray - Link

Adamax spray (currently on sale, code doesn't work) - Link

Conclusion

That’s all for now. If you have any questions or want to recommend a compound for me to do a write up on similar to this one, feel free to comment or DM me on Twitter.

Thanks for reading,

-BowTiedNeuron

Disclaimer

This article is for education purposes only. BowTiedNeuron is not a doctor, and the contents of this article is not medical advice. Always consult your doctor before starting any new supplements, peptides, or health protocols.

Starting this month, May 2025, I’m going to be doing monthly Q&A’s here on Substack as an extra perk for paid subscribers (check out my full catalog of free and exclusive posts if you’re new around here).

To participate, simply leave a comment below with your question and I’ll do my best to answer. Questions can be about anything; not just science, biology, and supplements, but random topics as well if you wish. I’ll answer any question asked before the next month’s Q&A post.

Rules:

• 1 question per person per Q&A, although 1-2 follow up questions are allowed

• “Thoughts on xyz…” is not a question

• Do not ask for medical advice

• Ask good questions. The better the question, the better my answer will be

That’s it. If you’re a paid sub, drop your questions in the comments. Also, if you have an article topic request, feel free to leave them in your comment as well and I’ll take it into consideration.

Disclaimer: None of the answers provided below should be taken as medical advice. Any and all content on this Substack is for educational purposes only. BowTiedNeuron is not a licensed medical professional. Always consult your doctor before making any major health decisions.

Balance between GABA and glutamate is required to have a healthy, well functioning brain. The relationship between these two molecules—the primary inhibitory and excitatory neurotransmitters—influences the function of every single neural circuit in the brain. It’s not a coincidence that an imbalance of the two is a feature in many neuropsychiatric disorders (epilepsy, depression, OCD, Alzheimer’s, Autism, Schizophrenia, etc).

However, an imbalance doesn't always result in a psychiatric condition. Even a relatively minor GABA/glutamate (E/I) imbalance can cause general cognitive impairment. Some of these symptoms may include:

• Anxiety

• Inability to focus

• Social deficits

• Brain fog

• Irritability

• Sensory hypersensitivity

• Insomnia

• Racing and intrusive thoughts

In this context, these symptoms can be chalked up to one of two things; too much glutamate signaling or not enough GABA signaling (or a combination of both). Unfortunately, a state like this often involves a feedback loop in which excess glutamate can damage neurons, negatively impacting GABA signaling and increasing glutamate signaling further, worsening the imbalance. Therefore, to truly fix an imbalance you need to address the root cause and fix the problem at the source to stop the feedback loop.

While that seems relatively simple, there’s one glaring issue; the root cause could be one of several factors, many of which overlap with and contribute to one another. As a result, what it takes to fix an imbalance is going to be highly individual and, as we’ll get into shortly, your current state of health.

I want to preface the rest of this article by saying that this is not a “How to guide” and will not provide step by step instructions on how to fix an imbalance because 1) I am not your doctor, and 2) there is no one size fits all protocol for something like this. This will take some effort on your part as an individual. You need to take a realistic look at the factors in your life that may be driving an imbalance, and do what you can to correct it.

I do not have all of the answers here (if I did this article would be hundreds of pages long), but I will do my best to explain the most common root causes and a loose framework for how you can start working to fix them through the implementation of supplements and lifestyle changes.

With that out of the way, let’s get into it.

The more research I did for this article, the more I realized that E/I balance is a marker of good health. Many of the factors that have a negative influence on E/I balance are rooted in the pillars of physical health; circadian rhythm, light, diet, sleep, exercise, and mental health—meaning that for many, an imbalance is a symptom of other bodily dysfunction (unless of genetic or developmental trauma origin). 

Note: For the sake of brevity, I’m going to avoid diving into the weeds for each root cause and potentially beneficial intervention/supplement. I think it would hurt the reading experience and impair the accessibility of the information below to have it presented as a wall of text. If there is any specific topic you'd like to see a more in depth dive on, let me know in the comments. 

I've identified what I believe to be the main factors that may contribute to an E/I imbalance and subsequent cognitive dysfunction. They are as follows:

• Diet

  • Dietary requirement of metabolic cofactors (B vitamins, magnesium, etc.)

  • Obesity and metabolic syndrome (insulin resistance, high blood pressure, etc.) increase oxidative stress and induce neuroinflammation

  • Gut health

    • Gut-brain-axis

    • Gut inflammation = neuroinflammation

• Circadian Rhythm

  • Importance of sleep

    • E/I balance shifted toward excitation with sleep loss

    • Glymphatic clearance is enhanced during sleep (clearance of glutamate and waste)

    • Sleep loss induces neuroinflammation

  • Cell specific circadian rhythms for interneurons and other cell types influencing their activity

  • Circadian rhythm influences EVERYTHING

• Chronic Stress

  • Chronically elevated cortisol increases glutamate and downregulates GABA via HPA

  • Induces neuroinflammation and increases BBB permeability

  • Reduces BDNF

  • Induces atrophy of dendrites in cortex and hippocampus

• Metabolism and Mitochondrial Health

  • GABA-Glutamate-Glutamine cycle is dependent on mitochondrial metabolism

  • Glutamate uptake and recycling is metabolically expensive

  • ATP production important for all cells to function properly (especially PV interneurons, key regulators of E/I balance)

  • Excess reactive oxygen species and nitric oxide induce inflammation, increase BBB permeability, and impair mitochondrial ATP production

• Inflammation

  • Peripheral inflammation can induce neuroinflammation

    • E.g. gut, exposure to irritants, etc.

    • Influx of inflammatory cytokines and potential breakdown of BBB, which allows dietary free glutamate and other potentially harmful molecules into the brain

  • Reduces BDNF

  • Increases glutamate release

  • Microglia activation

  • Positive feedback loop of more inflammation

  • Glymphatic clearance dysfunction induced by neuroinflammation

  • Increased oxidative stress

• Non-Native Electromagnetic Frequencies (nnEMF)

  • Increases calcium influx (mitochondrial damage and increases ROS)

  • Increases permeability of BBB

  • Increases glutamate release

  • Impairs synaptic plasticity

• 5-AR and DHT derived neurosteroids

  • DHT derived steroid molecules are highly GABAergic

• Childhood Trauma and Genetic Factors

  • Traumatic stressors in childhood and genetic factors can alter the developmental trajectory of the brain and E/I balance

• Feedback loop of excess glutamate → mitochondrial damage and oxidative stress → more glutamate release

Okay, that’s a lot to take in… Now let's look at how to potentially combat these issues.

Read more

Because of its overwhelming predominance as the brain’s primary messenger molecule, glutamate needs something to keep its activity in check and prevent excessive signaling. That something is GABA. See, GABA and glutamate are direct opposites in the way they function. Glutamate is the primary excitatory molecule in the brain and it drives other neurons to fire as a way of transmitting information. On the other hand, GABA is the primary inhibitory molecule, and it stops neurons from firing as a way of controlling neuronal activity. Both are transmitting information via receptors located on other neurons, but one induces more neuronal activity while the other inhibits it. As a result, a balance between these two molecules is necessary to ensure that the glutamate signaling does not occur in excess.

This relationship shapes the way the brain and its neural circuits function, and any disruptions in this balance can impair cognitive function, which is why we see GABA/Glutamate balance as a common feature in neuropsychiatric disorders [Examples: Autism and Schizophrenia, Alzheimer’s, ADHD, Depression, OCD].

GABA/Glutamate balance is commonly referred to as Excitatory/Inhibitory (E/I) balance in the scientific literature, referring to the excitatory and inhibitory nature of glutamate and GABA, respectively. For the sake of brevity, I will refer to it as E/I balance for the remainder of this article.

The concept of E/I balance throughout the entire brain is very complex, because it involves many brain regions with different types of neurons. For that reason, let’s focus in on the cerebral cortex, a structure that is heavily reliant on E/I balance to function properly. The cortex is the outermost, “lumpy” layer of the brain and is responsible for the more complex cognitive functions, such as thinking, planning, focusing, and socialization. It is made up entirely of glutamatergic and GABAergic neurons, which are organized into six layers. 

About 75% of all cortical neurons are glutamatergic pyramidal neurons (release glutamate), and the other 25% are GABAergic interneurons (release GABA) [source]. As a result, all higher order cognitive processes (as mentioned above) revolve around these two neurotransmitters.

Other neurotransmitter systems provide input to cortical neurons via long-range projections, so they do have an impact on GABA and glutamate neurotransmission. However, all cells located in the cortex only release either glutamate or GABA.

Pyramidal neurons receive input from a wide variety of neurons, both long-range and local, and release glutamate on to other neurons as a means of transferring information. All the while, the small population of interneurons release GABA onto local pyramidal neurons to inhibit their activity and effectively control their output.

You can think of E/I balance in terms of a signal to noise ratio. In such analogy, signal refers to meaningful input or things in your environment worth paying attention to, and noise refers to input that is not meaningful. With too much neuronal activity, the noise in a circuit increases and it becomes more difficult for your brain, and the neural circuits within it, to respond to meaningful inputs.

For example, with too little GABA transmission in relation to glutamate, pyramidal neuron activity increases. As a result, neural circuits can become “noisy” due to excess firing, which makes complex computations much harder. This directly interferes with the functions that the cortex is responsible for and has been shown time and time again in animal studies– although many focus on social behavior or disease-specific deficits [Example: Social deficits and information processing].

The opposite type of imbalance can be true as well, where GABA activity outweighs that of glutamate and you may become tired, unable to focus, and less likely to form memories. This is actually the state we want to be in when trying to fall asleep, which is why many useful sleep supplements work by elevating GABA activity or inhibiting glutamate.

The Importance of Interneurons for Maintaining E/I Balance

The importance of interneuron function cannot be overstated when it comes to a well-functioning cortex (and brain). The study of interneurons and their specific subtypes has been an important topic in neuroscience research since it has become apparent that they play a necessary role in regulating neuronal activity and, therefore, complex cognitive processes.

In the cortex, E/I balance is essentially reliant on this small population of neurons, since they’re the main source of GABA. Any disruption in their function–even minor–can impair cortical function to a significant extent and may even be the root of certain symptoms in neuropsychiatric disorders [source].

This is especially true of the parvalbumin (PV) interneuron, an interneuron subtype of specific interest to researchers because they can fire incredibly fast, attach directly to the cell bodies of pyramidal neurons, and inhibit a large number of pyramidal cells with large axonal arbors. Not only are these interneurons firing incredibly fast, releasing tons of GABA on to nearby pyramidal cells, their area of effect is super close to the axon, which makes them more impactful at inhibiting action potentials compared to other subtypes that focus on inhibiting the dendrites. This offers them an immense amount of control over pyramidal cell activity, which prevents unnecessary spiking, decreases pyramidal cell firing, and, as a result, contributes significantly to E/I balance.

Furthermore, these interneurons tend to work in ensembles, or small networks of cells that fire simultaneously. Since each individual PV interneuron can effectively inhibit a large number of pyramidal neurons, a single ensemble can coordinate the activity of an entire cortical microcircuit.

The fast-spiking phenotype of PV neurons is a double-edged sword though. While they can inhibit pyramidal cells extremely well and push extremely precise spike timing on them, their ability to spike fast leaves them vulnerable to any metabolic deficits [source]. These cells have monstrous energy requirements to frequently recover from action potentials, continually package and release GABA, and filter glutamatergic input from other neurons, which means that any disruption in their mitochondrial function or energy production can interfere with local inhibition, leading to an E/I imbalance.

Metabolic deficits can interfere with E/I balance in other ways as well since GABA and glutamate synthesis, neurotransmitter release, recovery from action potentials, and many other factors are all dependent on metabolism and ATP production. This is something I will write about in much greater detail in the near future.

Potential Symptoms of an E/I Imbalance

Just because E/I imbalance is a common feature in neuropsychiatric conditions, obviously doesn't mean that E/I imbalance = neuropsychiatric condition. However, the sentiment that an E/I imbalance can lead to some type of cognitive impairment is undeniably true.

Some potential symptoms of a relatively minor E/I imbalance include:

• Anxiety

• Inability to focus

• Social deficits

• Brain fog

• Irritability

• Sensory hypersensitivity

• Insomnia

• Racing thoughts

• Intrusive thoughts

I say “relatively minor” here because extreme imbalances are often accompanied by seizures and neuronal death as a result of excitotoxicity (calcium overload due to excess glutamate).

One of the easiest ways to test if you have an minor E/I imbalance is to take a small to moderate dose of L-Theanine (a glutamate antagonist). If it rids you of these symptoms and improves cognition, then you're likely dealing with an imbalance.

A decent proof of this concept is the synergy behind caffeine and L-Theanine. As a stimulant, caffeine increases neuronal activity which shifts the E/I balance towards E (increasing glutamate). Theanine counteracts this by antagonizing glutamate receptors, which helps restore balance and smooths out the caffeine stimulation to produce a calm focus that this stack is famous for.

Long-term E/I imbalances are detrimental to brain health as well. Excess glutamate signaling–as a result of reduced GABA or otherwise–can overactivate the NMDA glutamate receptor, which is involved in learning and synaptic plasticity. Overactivation of this receptor leads to excessive calcium entering neurons, which has a negative effect on mitochondrial health and can damage neurons through production of reactive oxygen species. If bad enough, this cascade can even lead to cell death (aka excitotoxicity), but it doesnt need to go that far to be detrimental.

Even further, calcium overload can contribute to a feedback loop of excess glutamate.

Excess calcium → Negative impact on mitochondrial health → Less energy production → Impaired interneuron function or hyperexcitability of pyramidal cells → Increased glutamate release → Even more calcium influx and more glutamate release

Supplements to Combat an E/I Imbalance

There are three supplements that stand out among the rest to rest to fight an E/I imbalance, including:

• Magnesium

• L-Theanine

• Taurine

Homage Grimhood (@grimhood on X). Grim is a friend of mine, and has been posting about these three supplements for their effects on GABA and glutamate for years.

These supplements are easy recommendations because they are cheap, effective, and safe for daily use. All three have either an inhibitory effect on glutamate, are pro-GABA, or a combination of both.

Here’s a quick rundown on why they're so effective…

Magnesium

First off, most people don't consume enough magnesium [source], so it's a great thing to supplement for most people.

Most notably, magnesium is an NMDA receptor channel blocker. This directly protects your neurons from excessive calcium influx and allows these receptors to function as intended. NMDA receptor blockade is a key function of magnesium in the brain, and is the main reason people experience an anti-anxiety effect when they start supplementing with it. I’ve written more about this interaction in this article for those who are interested.

Furthermore, magnesium is an essential cofactor for thousands of reactions in the brain and body. So many that I’m not even going to attempt to list all of its functions, but here's a great figure illustrating many of them;

Of note for its positive impact on E/I imbalance, we have:

• Inhibits NMDA receptor

• GABAA receptor agonist

• Essential for ATP synthesis and utilization

• Decreases glutamate release

• Inhibits calcium channels

• Inhibits oxidative stress and inflammation

• Cofactor for carbohydrate metabolism enzymes 

In short, take your magnesium. It’s anti-glutamate and pro-GABA, making it the most effective supplement for fighting an E/I imbalance.

Use multiple forms if possible, take at several points throughout the day, consume 5-10mg/lb of bodyweight in elemental magnesium, and increase your intake when using stimulants or are under excessive stress.

L-Theanine

Theanine is an amino acid that occurs naturally in green tea. It primarily functions as a glutamate antagonist, binding to glutamate receptors and reducing glutamate’s binding to them. This directly reduces glutamate activity and offers an insane synergy with magnesium to indirectly reduce NMDA receptor activity by inhibiting AMPA receptors.

It is safe, well tolerated, and can be dosed daily and multiple times throughout the day with no risk of tolerance [source]. It is another no brainer supplement for those looking to combat an E/I imbalance.

If you want to use L-Theanine as a sleep supplement, I highly recommend pairing it with magnesium to counteract a potential paradoxical excitatory effect that can occur in some individuals. 

Taurine

Taurine is another naturally occurring amino acid, but it acts as a GABA receptor agonist among other beneficial mechanisms. 

Of those other mechanisms, taurine notably helps maintain low levels of calcium in cells and plays an important role in energy metabolism, which further contributes to its neuroprotective and E/I balance promoting effects.

Conclusion

By now, it should be clear that maintaining E/I balance is crucial to having both a cortex and brain that are operating to the best of their ability. An imbalance may very well be at the root of some cognitive dysfunction, including symptoms mentioned above, because the brain relies on GABA and glutamate as their main neurotransmitters.

Stay tuned for an upcoming post on how to fix a potential imbalance. It’s too complicated to cover in a post like this because the root cause could be many different things, although the three supplements discussed above can be of great help for many and may even be enough to maintain a balance for some (especially magnesium due to its effects on the NMDA receptor and energy metabolism).

That’s all for now. Thanks for reading and feel free to leave any questions you have below,

-BowTiedNeuron

Disclaimer

This article is for education purposes only. BowTiedNeuron is not a doctor, and the contents of this article is not medical advice. Always consult your doctor before starting any new supplements.

But why?

My guess is that it is due to its mainstream popularity as the “reward molecule”. Dopamine (DA) has essentially become a buzzword as it relates to all the things in today's society that can be associated with an addiction of sorts (social media, smart phones, processed foods, etc), but this is just a small part of the puzzle when it comes to DA’s function in the brain. What you may not know is that DA is a molecule involved in focus, motivation/drive, working memory, and movement in addition to its role in behavioral learning. This means the dopaminergic system is an excellent target for nootropics if your goal is to enhance your cognition and the likelihood of taking action on certain tasks. However, it’s not as simple as just “increase dopamine”. DA is a molecule that is part of several distinct pathways that use different tactics to regulate DA levels… it’s kind of complicated.

Complicated is good in this context though, as it means there are several ways to leverage DA to our advantage, and that is exactly what I will teach you. Throughout the remainder of this article, we will cover the various mechanisms that can be used to manipulate dopamine, the different results you can expect from each of them, and examples of compounds for each mechanism. That comes, of course, after we dive into the neuroscience behind the neurotransmitter so that we understand these potential manipulations.

But without further adieu, let’s dive into the inner workings of everyone’s favorite neurotransmitter, Dopamine.

Overview of the Dopaminergic System

The biggest misconceptions about DA arise from people not knowing that it's part of three different pathways in the brain. That in and of itself tells us that DA does not have just one function, but an assortment of functions that depend on where it is released.

Almost all DA neurons originate from two small nuclei in the midbrain. In fact, there are only 500,000 total dopaminergic neurons in the whole brain out of a total of ~100 billion neurons. Despite that relatively small number of total cells, DA is able to exert immense behavioral effects via its three main pathways.

Mesocortical pathway: VTA → Cortex

Mesolimbic pathway: VTA → Nucleus Accumbens

Nigrostriatal pathway: SNc → Striatum

DA’s influence on focus, working memory, impulse control, and attentional processing comes from its actions in the cortex. This is known as the mesocortical pathway which originates in the ventral tegmental area (VTA) and projects to the cortex.

The name of all these pathways are derived from the location of the dopamine neurons + where they project to. In this example, “meso” means middle because the VTA is located in the midbrain and “cortical” refers to the cortex.

DA’s influence on motivation, drive, and movement comes from its action in the striatum via the nigrostriatal pathway which originates in the substantia nigra pars compacta (SNc). This is the pathway that’s disrupted in Parkinson’s disease, a disorder that results from the death of DA neurons in the SNc and causes issues with movement.

Finally, DA’s influence on behavioral learning, addiction, and motivation (again) comes from its actions in the nucleus accumbens (NAc). This is known as the mesolimbic pathway (“limbic” referring to the limbic system), and is commonly referred to as the “primary reward synapse” due to its role in learning as it relates to rewards/punishments.

Through its action in these pathways, DA stands as a neurotransmitter that when manipulated has the unique potential to both enhance cognition and increase motivation. However, before we get into tools we can use to leverage dopamine for cognitive enhancement, I want to briefly go over the process of dopaminergic neurotransmission. This includes its synthesis, release, clearance from the synapse and action on receptors. In the end, we will have a greater understanding of how dopaminergic nootropics actually work, as well as learn a lot about how the brain actually functions which has its own perks.

Dopamine Synthesis

DA belongs to a group of molecules known as the catecholamines which also includes norepinephrine and epinephrine. These three neurotransmitters are all part of the same synthesis pathways that begin with the amino acids phenylalanine and tyrosine, eventually leading to the synthesis of DA then subsequently norepinephrine and epinephrine in that order.

More TH activity → More DA produced

Less TH activity → Less DA produced

The activity of TH is regulated by both the amount of DA in the cell and activity dependent protein kinases that inhibit or speed up the enzyme's activity to keep a steady supply of DA for the neuron. While these processes are tightly regulated, there are potential compounds out there that directly increase levels of TH or its activity… more on that later though.

Once it has been synthesized, DA is packaged into vesicles via the vesicular monoamine transporter 2 (VMAT2) transporter protein where it will await its release in an action dependent manner.

(For more information on the packaging and release process of neurotransmitters, I recommend checking out the three part Neuroscience Crash Course series I put out here on Substack. Link to part 1 here.)

Dopamine After Release

After its release, DA binds to receptors on the postsynaptic neuron. Therefore, the effect that DA has is dependent on the receptor it binds to, which can be one of two main categories: D1-type and D2-type receptors. D1 receptors increase cyclic AMP (cAMP) in the cell which is going to promote synaptic plasticity and increase the likelihood a neuron fires, while D2 receptors do the opposite and may even inhibit dopamine release by acting as inhibitory autoreceptors on the presynaptic neuron.

DA’s effects on postsynaptic receptors is (like all other neurotransmitters) dictated by the concentration of DA located near the receptor, a factor that is primarily influenced by extracellular dopamine clearance. Simply put, the action of DA is enhanced when extracellular levels are increased. A phenomenon that may occur is extracellular clearance mechanisms are inhibited.

What are said clearance mechanisms?

Well, that depends on where in the brain we’re talking about.

In the striatum, the dopamine transporter (DAT) is the primary method of clearance. DAT is a reuptake transporter protein that sucks excess dopamine from the synapse back into the presynaptic terminal. This serves two purposes: clearing dopamine from the synapse to terminate the signal, and recycling dopamine for future release. However, in the cortex DAT isn’t prevalent, so the norepinephrine transporter (NET) is the primary clearance system there. Then you need to consider enzymes that break down DA inside neurons like catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), and where they primarily reside. This is going to heavily impact the effect of certain dopaminergic nootropics that act via these mechanisms, since a compound that inhibits DAT is going to elevate DA in a different brain region than one that inhibits COMT or NET resulting in different behavioral effects.

Nootropics that Target Dopamine

With an understanding of the dopaminergic system fresh in our minds, let’s look at ways in which we can manipulate it in order to elevate levels of DA in and outside of our neurons to enhance cognition and motivation, of which there are three main categories:

Read more

Acetylcholine (ACh) is an incredibly unique molecule in the body with a wide range of functions. In the brain, it supports the various cognitive functions mentioned above and influences REM sleep, but ACh is also responsible for making our muscles contract and controlling the function of our autonomic nervous system (fight or flight/rest and digest). While those last two functions are interesting on their own, I want to focus on ACh’s actions in the brain here because supplements and herbs that manipulate cholinergic neurotransmission are incredibly useful tools and should be a part of even the simplest supplement stacks aimed at improving cognitive function.

But what exactly makes ACh such a great target for cognitive enhancement?

It primarily has to do with where it is released in the brain. Cholinergic neurons (those that produce and release ACh) reside in the basal forebrain and brainstem and project to various regions of the brain, primarily the hippocampus and cortex. These target regions implicate ACh in learning/memory, focus, arousal, and cognitive performance.

The hippocampus is the brain’s memory center (discussed more in depth in my how to improve memory article linked here), and it’s densely packed with ACh receptors and receives a ton of cholinergic input. While the cortex, especially the prefrontal cortex, is involved in higher level thinking, reasoning, and arousal. As a result, increasing ACh neurotransmission in the brain is going to enhance cognition greatly in several ways, which is what makes ACh is such a useful nootropic target.

Before we can dive into tools that leverage ACh for cognitive enhancement, we first need to know a little bit of background on how ACh functions as a neurotransmitter. This way, we will understand how these compounds work and synergise with each other to enhance our memory and cognition.

Acetylcholine Synthesis

Interestingly, ACh is the only major neurotransmitter that is not derived from an amino acid. Instead, it is synthesized from the precursors choline and acetyl-CoA.

Acetyl-CoA is generated in the mitochondria as a product of glycolysis. From there, it is transported into the cytoplasm of the synaptic terminal to be combined with choline by the enzyme choline acetyltransferase to make ACh.

The choline necessary for this synthesis is obtained by either uptake from the extracellular space or the internal breakdown of phosphatidylcholine, a molecule that is abundant in cell membranes. While choline can be produced endogenously in the liver, the body can't produce enough to meet needs, so we must get at least some choline through diet to support healthy ACh levels. Adequate intake levels of choline are 550mg/day for adult males and 425mg/day for adult females (500mg+ if pregnant or breastfeeding) as determined by the Food and Nutrition Board of the Institute of Medicine [source]. Choline is found in many different foods, but is highly prevalent in egg yolks and meat, so just a few eggs and/or a good amount of meat per day is enough to hit that.

This is just the established “adequate intake”, yet most people still aren’t hitting these numbers. Going above that threshold is going to be beneficial for not just acetylcholine levels, but for providing phosphatidylcholine to support the cell membranes of our neurons and all other cells throughout the body.

Acetylcholine after release

Like all other neurotransmitters, once synthesized, ACh is packaged into vesicles and subsequently released in an action potential dependent manner. 

(For more information on this process, I recommend checking out the three part Neuroscience Crash Course series I put out here on Substack. Link to part 1 here)

After its release, ACh binds to receptors on the postsynaptic neuron as a way of transmitting its message, typically increasing the likelihood of the postsynaptic neuron firing (not always true because there are inhibitory metabotropic ACh receptors). However, immediately after ACh molecules are released into the synaptic cleft, the enzyme acetylcholinesterase (AChE) begins breaking them down into choline and acetate. This serves as a way of terminating the signal the presynaptic neuron is sending and allows the choline to be reuptaken and recycled into more ACh. This is doubly important since there is no ACh reuptake transporter like there is with most other neurotransmitters to help with this recycling process, just a choline transporter.

Fun fact, AChE is one of the fastest enzymes in the body, breaking down 5,000 molecules of ACh per second.

Because of the importance AChE plays in terminating cholinergic signals, inhibiting this enzyme is a common mechanism among nootropics and drugs prescribed to treat the cognitive decline and memory deficits associated with dementia (e.g. Donepezil and Galantamine).

Nootropics and Supplements that Target Acetylcholine

Now that we have a fundamental understanding of the cholinergic system, it should be clear that there are three primary ways to manipulate it to reap the cognitive enhancing benefits;

1. Increase synthesis and release

2. Inhibit breakdown in the synapse

3. Directly activate receptors

Let’s go through each of these individually, with examples, and discuss potential synergies.

Increase Synthesis and Release

In order to increase ACh synthesis and release we are going to want choline sources. Yes, choline can be obtained through dietary sources (and I do recommend getting more than the adequate intake from food sources), but choline containing supplements are going to be superior for quick hitting cognitive enhancement.

There are several choline containing supplements out there, but the top two in my eyes are;

• CDP-Choline

• Alpha-GPC

CDP-Choline (aka Citicoline or Cognizin) is a unique nootropic compound that provides both choline and cytidine, the latter of which can be converted into uridine. While choline supports ACh activity as a precursor, uridine has a dual neuroprotective and cognitive enhancing effect by increasing the synthesis of neuronal membranes (choline can contribute to this as well through conversion to phosphatidylcholine). Together, these two molecules support memory and overall cognitive function by promoting ACh activity directly and increase the potential for neuroplasticity.

Alpha-GPC works similarly to CDP-Choline, except instead of supplying cytidine alongside choline it’s focused on providing as much choline per gram as possible. Each Alpha-GPC molecule contains a much larger percent of choline than CDP-Choline per weight (40% vs 18%), which means you’d need a much smaller dose of Alpha-GPC to get the same amount of choline.

Both of these compounds provide bioavailable choline which readily crosses the blood-brain-barrier. This contributes to increased cholinergic transmission and neuroprotection by supplying choline and their accompanying molecules that aid in cell membrane synthesis. The primary difference between the two is that CDP-Choline trades total choline per gram of supplement in exchange for packing two nootropic compounds in one (choline and cytidine). In my opinion, this makes Alpha-GPC better for acute cognitive enhancement, while CDP-Choline is the superior everyday choline supplement.

Inhibit Breakdown in the Synapse

While ACh precursors are a great way to support cholinergic neurotransmission and even push it a bit, inhibiting AChE is where we really start to see a marked increase in cholinergic activity (unless you were previously choline deficient). By inhibiting the breakdown of ACh after its release, this mechanism indirectly increases the activity of ACh on postsynaptic receptors by leaving a higher concentration of ACh in the synapse for longer.

There are many herbs and other compounds out there that inhibit AChE, but some of the most well known and popular over the counter ones are;

• Huperzine A

• Bacopa Monnieri

• Ginkgo Biloba

While Huperzine–the most potent–provides the most bang for your buck AChE inhibition wise, the others have a host of other cognitive enhancing mechanisms alongside a more mild AChE inhibiting effect. Which you should choose will depend on what your goal is.

Chasing pure cholinergic activity? Go for Huperzine A

Want a more well rounded experience? Try the others

Directly Activate Receptors

There is one infamous nootropic out there that is well known to directly activate a subtype of ACh receptors, and that’s nicotine. Nicotinic acetylcholine receptors actually got their name because of nicotine’s binding affinity for them.

Nicotine is going to be the most potent cholinergic nootropic that’s readily available over the counter. It binds to and activates nicotinic ACh receptors, which directly increases cholinergic activity without the need to alter ACh levels at all.

The obvious caveat with nicotine use is that it’s incredibly addictive and is easily abused if proper precautions are not taken. If you’re using nicotine enough to become addicted, it has likely lost most of its potency as a nootropic and will require larger and larger doses to be effective which pushes you further into physical dependency.

No one wants that…

The best way to avoid addiction and tolerance with nicotine is to limit its use to a set number of days per week. For me, it’s three days a week at a maximum and always less than 3mg per day. Maybe I could get away with four, but the risk outweighs the reward by a long shot when I have other nootropics in my arsenal for those other days if needed/wanted.

This isn’t an endorsement of nicotine use, and I definitely recommend avoiding it if you don't have the self control or desire to limit your use.

Potential Synergies

The obvious synergy of the above mechanisms is going to be stacking an ACh precursor with an AChE inhibitor. The combination of increased ACh synthesis/release and inhibiting its breakdown in the synapse is a match made in heaven. With a pairing like this you’re able to use a lower dose of each compound for a more efficacious and prolonged effect since their combination results in a 1+1=3 effect.

A common stack I’ll run is Alpha-GPC + Huperzine A. I was previously underwhelmed by Alpha-GPC, and while it definitely provided me with some notable cholinergic activity it was nothing to write home about. However, once I paired it with Huperzine I realized its full potential. I was able to use less than half of the dose for each of these nootropics to achieve a more potent, fluid cholinergic state that lasts longer, and at this point it's rare that I use one without the other. The same thing will apply to any choline source and any other AChE inhibitor.

Conclusion

Acetylcholine is an incredibly underappreciated neurotransmitter and has tons of potential as a target for improving memory and general cognition. Your ability to manipulate it relies simply on knowing what mechanisms to target (precursor, AChE, receptors) and what compounds have said mechanisms. The example compounds listed above should be all you really ever need to take advantage of ACh in its entirety (even without nicotine), but knowing the mechanisms is beneficial if you’re trying to understand the potential benefits of an herb/supplement you're looking into.

This article is the first in a two part series looking at how to manipulate various neurotransmitter systems to benefit you cognitively in a nootropic context. Next, we’re looking at everyone’s favorite, dopamine, which gets a little more complex but with more potential benefits. After that, we’ll tie it all together with a “How to build your own nootropic stack” post, so stay tuned for those coming soon.

That’s all for now. Thanks for reading,

-BowTiedNeuron

Disclaimers

This article is for education purposes only and is not medical advice. Always consult your doctor before starting any new supplements.

This article contains affiliate links that will reward me with a commission if you choose to use them, however it comes at no cost to you and helps support my content.

It’s been incredibly effective at helping me fall and stay asleep, as well as combatting anxiety when I need it most. As a result, it will be a staple in my supplement rotation moving forward (exactly how I plan to use it is detailed later in this post).

What makes Magnolia Bark so effective are its two primary active compounds, magnolol and honokiol. These molecules act as GABAA receptor positive modulators, the same mechanism of action as benzodiazepines like Xanax.

Unlike Xanax though, the actives in magnolia bark also act on extrasynaptic GABAA receptors. This allows them to enhance constant GABA signaling that heavily influences overall neuronal excitability, as opposed to just the fast inhibitory transmission that occurs in synapses. The obvious tradeoff here is potency. Xanax, or any other benzodiazepine, is going to be much more potent than magnolol and honokiol.

The active components of Magnolia Bark have other potential mechanisms as well. There’s evidence they inhibit glutamate receptors, which would further contribute to their anxiolytic and pro-sleep effects. They have also been studied for anti-inflammatory, anti-oxidant, and even anti-cancer activity, but the potent GABAergic activity is the primary use case for a supplement like this.

The extract I used contained a minimum of 80% magnolol and honokiol, up from the roughly 10% that occur naturally in magnolia bark. This allows it to pack a greater punch per milligram, and provide a large amount of inhibition in just a small tablet.

My Subjective Experience

I used Magnolia Bark exclusively as a sleep supplement. However, I made sure to take it much earlier than I normally would (>2 hours before bed) on occasion, so that I could test its effectiveness as an inhibitory agent without being influenced by my normal drowsiness closer to bed.

Over the course of my testing, I tried just 3 doses; 200mg, 400mg, and 600mg, as I didn’t feel the need to go any higher than that.

200mg provided me with a light sense of inhibition. Not enough to make me want to lie down and fall asleep, but enough to help slow my mind down enough to facilitate an easy transition to sleep. This was about on par with the effect I get from an average dose of L-theanine and magnesium.

400mg has a much more pronounced effect. It was enough to easily rid me of any anxiety and actively made it much easier to fall asleep. I've used this to my advantage while traveling to fix my sleep schedule, helping me fall asleep earlier than I had nights prior, and to really crush anxiety that was making it tough for me to fall asleep. This dose was my sweet spot overall.

600mg quickly became my “nuclear option” for nights I was having issues falling asleep. Every time I’ve taken this dose I’ve passed out within the hour. My most notable experience with it was a night I pulled a muscle in my low back lifting and I couldn't even lie down without being in pain/discomfort. I took 600mg and it eased my discomfort so much that I fell asleep rather quickly and slept through the whole night. That was the night I really gained an appreciation for this supplement.

Magnolia Bark had notable inhibitory effects about 25-30 minutes after taking it, although I can’t say how long it lasted because I fell asleep within 2 hours of taking it every time. I never had the need to utilize it for anxiety during the day because I’m not an anxious person, but my mind tends to race occasionally before bed so I used it primarily as a “sleep supplement”. It never actively sedated me, but was incredibly effective at helping me turn my brain off and fall asleep when I needed it most.

Given its mechanism as a GABA agonist, these results are about what I expected going into this experiment.

My Protocol Moving Forward

My experience with Magnolia Bark has been nothing but positive so far and it served as a short-term fix for any difficulties falling asleep or insomnia I’ve experienced. As a result, it is something I will always try to have on hand moving forward, and I’ll deploy it as wanted/needed under the following general guidelines;

• When my mind is racing excessively before bed or other issues falling asleep (400mg)

• For nights when I’m having serious issues falling asleep (600mg)

I want to note that I never used Magnolia Bark extract more than two times per week. This is a pretty potent GABA agonist and using it more often could result in the downregulation of your endogenous GABA system. This is something I’m extremely cautious of and is not worth the risk in my opinion. Despite that, in my experience it can be used one to two times per week safely with no drawbacks.

Magnolia Bark also has an excellent synergy with another GABAergic supplement I really enjoy, Lemon Balm, which increases levels of GABA in the brain. Combined with enhanced GABAA receptor activity they have a potent inhibitory effect, so I’ll use a lower dose of Magnolia Bark (200-400mg) when combined with Lemon Balm on occasion as well.

Please note that these are the doses I found to work for me after several months of testing. If you choose to use Magnolia Bark for yourself, I recommend you start with the lowest possible dose and titrate up slowly as needed. Biology and neurobiology are not one size fits all, find what works for you.

Conclusion

When I originally started experimenting with Magnolia Bark, my goal was to experience what high GABA activity felt like as a sort of learning experience. I already had so much knowledge about how GABA worked in the brain, but no real experience enhancing its activity so selectively. That experiment turned out to be a great success. The ability it has to silence my mind before bed is unlike any supplement I’ve used before–which isn’t exactly shocking given this was the first potent GABAergic supplement I’ve used.

Over the course of my experimentation with Magnolia Bark extract I not only learned a lot, but found a new tool I’ll keep in my sleep supplement rotation (just never more than two times per week).

Supplementary Information

Brand Used: Nootropics Depot

Form: Tablets

Method of Administration: Orally

Height & Weight for dosage comparison: 6’2, 195lbs

Within this article I will offer not only a comprehensive understanding of the science behind sleep, but also provide nine simple behaviors that are the key to unlocking high quality sleep.

Article Table of Contents:

• What is sleep?

• Physiology of Sleep

• Regulation of Sleep/Wake Cycles

• Sleep Architecture

• Sleep Hygiene

• Conclusion

But enough with the introduction, let’s get into it.

What is Sleep?

Unlike what you may think, sleep is not a passive state. The brain doesn’t just “turn off” for eight hours every night so we can recharge for the day ahead. Instead, it’s an active, incredibly complex state of reduced consciousness. Even though mental activity is technically reduced and we are less responsive to our environment when asleep, there are distinct patterns of brain activity taking place. It’s even unlike a coma or being under anesthesia since it's an easily reversible state.

While it is an active process, sleep is still a time of restoration. It is a time of anabolism (the creation of new larger molecules). Not just in a muscle building context, but also general repair and maintenance of the body.

High quality sleep positively impacts every bodily system (cardiovascular, immune, central nervous system, etc), which provides tons of health benefits including effects on mood and cognitive performance. Because of that, impaired sleep (decreased quality or quantity) has countless detrimental impacts - so many that I could never list them all, but here are just a few;

• impaired memory formation

• compromised immune system

• insulin resistance (diabetes risk)

• reduced testosterone production

• impaired growth hormone secretion

• high blood pressure

• increased risk for depression

• reduced energy levels

Before we move to discussing the behaviors that enhance sleep, I'll explain the biological systems that drive our need/want for sleep, as well as what determines sleep quality. This will hopefully leave you with a scientific knowledge base that provides some context to the behaviors that can improve and support your sleep habits (it’s also incredibly fascinating).

Read more

To me, it’s a good sleep supplement helps calm your mind before bed, facilitates an easy transition to sleep, and enhances the quality of your sleep. In this article I’ll explain not only the neuroscience behind why certain supplements are good for sleep, but also provide a list of supplements that are so effective that you won’t need to look for more after reading.

The Neuroscience of Sleep Supplements

The majority of effective sleep supplements work by either decreasing glutamate activity or increasing GABA activity. Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters in the brain, respectively, working to either increase or decrease the likelihood of a neuron firing. Normally, these two balance each other out, allowing our neural circuitry to function as intended. However, before bed we want to tip the scales in favor of GABA activity relative to glutamate, which can help us calm our mind and transition to sleep smoothly by decreasing brain activity.

GABA

In the brain, GABA primarily works to inhibit neuronal firing via the GABAA receptor, a chloride channel that opens when GABA binds to it. Once GABA is bound, the channel associated with the receptor opens and chloride ions (Cl-) are able to enter the neuron with a large driving force. The result is a lowering of the neuron’s membrane potential (the cell becomes more negative internally) which reduces its likelihood to fire an action potential.

Increasing GABA activity is important because this neurotransmitter plays a large part in inducing sleep by inhibiting neurons that would otherwise promote a sense of wakefulness. GABAergic neurons in the ventrolateral preoptic nucleus (VLPO) project to brain areas that release orexin, histamine, and norepinephrine - which are some of the primary neurotransmitters that promote wakefulness. The inhibition of these areas underly the VLPO’s role as a key sleep promoting brain region.

An uptick in GABAergic activity will also reduce neuronal activity across the entire brain, which can help to calm a racing or active mind. There’s a reason a large number of prescription sleeping pills (i.e. Ambien, Xanax) act by enhancing GABA signaling. As you’ll read shortly, several effective sleep supplements do as well – just not as potently.

In those ways, increasing GABA activity via supplements is a great way to help reduce latency to sleep.

For those curious, Ambien and Xanax are GABAA positive allosteric modulators, meaning they bind to the GABAA receptor at a site separate from GABA (like the benzodiazepine site shown in the image of the GABAA receptor) and enhance the effect of these receptors. The result is more chloride influx into neurons, which facilitates more inhibition and less neuronal firing overall.

Glutamate

Reducing glutamate activity is also highly effective at helping us fall asleep, although it's not the most prevalent supplement mechanism. It doesn't have the double edged upside of supporting inhibition of areas that promote wakefulness, however it will effectively decrease neuronal activity across the entire brain. Since most people are generally glutamate dominant, supplements that do so can be extremely effective at promoting sleep by reducing anxiety and calming the mind.

The mechanisms discussed above are incredibly effective for supplements taken before bed as sleep aids. However, their ability to calm the mind and slow brain activity also makes many of them useful for combating anxiety and stress as well. As a result, many of the supplements I’ll mention shortly will also work to reduce anxiety. Just look for the ones that directly increase GABA signaling or decrease glutamate signaling (almost all of them).

Sleep Supplements

1. Magnesium

If you've been following me for a bit on twitter/X, you know how much I love magnesium. It's an essential mineral in the body that’s involved in thousands of processes and reactions, yet most people are deficient in it. While the list of magnesium supplementation benefits is incredibly long, I want to focus on how it impacts sleep.

Magnesium not only promotes GABA activity, but blocks the NMDA glutamate receptor at rest. This NMDA antagonism is its primary pro-sleep mechanism of action as it directly decreases glutamate activity. I’ve written previously about the interaction between magnesium and the NMDA receptor in more depth, and you can find that here. 

It’s best to opt for an inhibitory form of magnesium before bed, since they can provide a secondary benefit for sleep based on the molecule the magnesium ion is bound to. These forms are primarily glycinate, chloride, and acetyl-taurate (which is the most potent of the bunch and is best used intermittently). Some like the threonate form, but personally I think it's overrated as a sleep supplement and is too expensive for what it is. The glycinate and chloride forms are much better daily drivers and are far more cost effective.

2. L-Theanine

Theanine is an amino acid found naturally in green tea. It’s very similar in structure to glutamate and as such its mechanism of action relates to it. Theanine inhibits the uptake of glutamine (the precursor to glutamate) into neurons and antagonizes AMPA glutamate receptors, overall reducing glutamate activity. The AMPA antagonism of theanine makes it extremely synergistic with magnesium, since sufficient AMPA activation is needed to remove the magnesium block from the NMDA receptor.

Some people find that theanine can have a paradoxical effect and lead to a racing mind when taken before bed, but this is typically remedied by pairing it with magnesium. For that reason, I only ever take theanine paired with magnesium before bed, and it's my favorite sleep supplement pairing of all time.

3. Glycine

Glycine is the most simple amino acid possible, with a side chain of a single hydrogen. In the brainstem and spinal cord it functions as an inhibitory neurotransmitter, while also playing a role as an NMDA receptor co-agonist throughout the entire brain. As an inhibitory molecule, it works extremely similar to GABA, except it acts on glycine receptors which are mostly localized in the brainstem and spinal cord.

Glycine has been shown to decrease sleep latency, improve sleep quality, and even facilitate a drop in body temperature (something that’s very beneficial for sleep).

Side note: As a powder, it is very sweet in taste. This makes it a great 0 calorie sweetener to add to bedtime teas or other beverages.

4. Taurine

Taurine is an amino acid found naturally in foods like meat. It has a wide range of benefits in the body, but as a sleep aid it acts primarily as a GABA and glycine receptor agonist. Activation of these receptors gives taurine a direct inhibitory effect in the brain. As such, it is a great sleep supplement.

5. Magnolia Bark

The bark of the Magnolia Officinalis tree has well documented anti-anxiety and sleep promoting effects. It contains two primary active compounds, honokiol and magnolol, which are potent GABAA receptor positive allosteric modulators. These molecules bind to GABAA receptors and enhance the action of GABA without directly activating them. This mechanism is extremely similar to that of Ambien or Xanax, just much less potent.

Magnolia bark can be used in its full form (steeped in tea for example), or as an herbal extract supplement (look for a high % of honokiol and magnolol).

6. Apigenin

Apigenin is a flavone found in chamomile that plays a large role in what makes chamomile tea so great for sleep and anxiety. It, like the active constituents in magnolia bark, acts as a positive allosteric modulator of the GABAA receptor.

Apigenin can be bought and consumed as a dietary supplement, or obtained through chamomile tea.

7. Lemon Balm

Lemon balm (aka Melissa Officinalis) is another herb well known for its calming effects. It’s most prominent GABAergic mechanism of action is the inhibition of GABA transaminase, the enzyme that breaks down and inactivates GABA. Inhibiting this enzyme leaves more GABA in the brain, enhancing GABA activity generally.

Similar to magnolia bark, lemon balm can be taken as an herbal extract or the whole herb (as part of tea for example).

Other Supplements

Obviously, this isn't a comprehensive list of effective/useful sleep supplements. However, the list above offers a great variety of those that can be taken nightly (Magnesium, theanine, taurine, glycine) and those that are extremely effective for when you're exceedingly anxious and need an extra bit of help calming your mind and falling asleep (magnolia bark extract, lemon balm extract, apigenin). Between these 7 supplements listed above you really shouldn’t need to go out in search of more, unless that is you enjoy experimenting with different supplements like I do.

If there’s enough interest, I can put out another post covering more obscure sleep supplements. If interested, let me know by commenting on this post.

Dosing and Usage Frequency

When it comes to the dosing of supplements, I don't like to give out specific recommendations because everyone is different. What works for me or anyone else might not work for you, and vice versa. My recommendation is always to start with the lowest dosage of any given supplement, increasing in small steps until you find a dosage that produces a desired effect. If you want to find what works best for you, it takes a bit of experimentation.

Regarding usage frequency, every supplement listed above is safe to be used nightly (magnesium can and should be taken daily) except for the herbs in an extract form. Any use of potent GABAergic supplements (i.e. lemon balm extract and magnolia bark extract) should be limited to 1-2 times per week maximum to avoid any tolerance build up as a result of GABA downregulation.

Conclusion

Sleep supplements shouldn’t be seen as a replacement for optimizing your circadian rhythm or other otherwise good sleep hygiene. Once good sleep habits are established, you should be able to get quality sleep without sleep supplements.

Despite that, supplements can be extremely useful for fixing a broken sleep schedule by helping you fall asleep, enhancing sleep quality when good habits are present, or even act as a crutch on occasion when you’re extra anxious/stressed. They are tools, and should be used as such.

That’s all for now. Thanks for reading,

-BowTiedNeuron

Disclaimer

This article is for educational purposes only and is not medical advice. Always consult your doctor before starting any new supplements.

This was originally planned as a brief follow up, but has since turned into a full fledged 3000+ word post. So, hopefully by the end you’ll be left with not only a list of 12 memory and cognition enhancing supplements/nootropics, but also an understanding of how exactly they work to support memory.

That last part is something I’d like to emphasize, “understanding”. Instead of just having a list of supplements that do x, y, or z, try to acknowledge the biology behind a mechanism of action. Then, you not only understand why some compounds have a certain effect, but can extrapolate further to think “what other compounds would synergize with this” or theorize the effect of a supplement you’re researching based on its mechanism and so on.

However, I know that not everyone wants to think about these topics that deeply and just wants a list of supplements. If that’s you, feel free to skip to the end and check out the list. Otherwise, I think you’ll find it interesting to understand the biological basis for memory, as well as learning about some over the counter supplements that can be used to enhance it.

With that out of the way, let’s get into it…

What is memory?

Memory is the ability to retain information and recall it at a later time, a phenomenon largely reliant upon physical changes in the brain. 

Read more

It contains 5 active ingredients, targeting the 2 primary neurotransmitters involved in focus and cognitive performance, dopamine and acetylcholine.

This formulation contains 3 of my all time favorite supplements, 1 of the most popular generally, alongside one that I’ve never even heard of, so I was really eager to try this out.

Ingredients

For the sake of brevity, I’ve decided to list a short description of each ingredient here. For those interested, you can find a full list of their mechanisms at the end of this post.

enXtra (300mg): A proprietary extract of Thai ginger that is proven in human studies to increase mental alertness

Sabroxy (500mg): A proprietary extract and nootropic derived from the bark of the Oroxylum Indicum tree that contains a minimum of 10% Oroxylin A, its premier active component

Polygala Tenuifolia (100mg): An herb that has been used medicinally in China for thousands of years and has nootropic properties

Ginko Biloba (80mg): One of the most used herbal supplements for brain health and cognitive function

L-Theanine (100mg): An amino acid found in tea well known for its calming effect. It’s commonly used to help ‘smooth’ out stimulants

Note: 1 serving is 2 capsules of powder

Collectively, this product contains several active ingredients that should increase focus, alertness, and learning/memory potential with a specific aim of increasing the activity of dopamine and acetylcholine in the brain.

My Subjective Experience

I have spent the last 2 months using this supplement regularly. My goal was to gain an understanding of how it affects me, and use it in a variety of scenarios at several doses to see if it lives up to the laundry list of beneficial mechanisms it seems to boast.

So… Does it perform as well as it should on paper?

In my experience, yes 

In almost every way that I have tried it, Notable performs well and gives me a solid cognitive boost and slight to moderate stimulation to pair with it.

My primary use case for this supplement was to take it right before I wanted to be at my peak mental performance (a general nootropic context). I found its effects noticeable after ~15-30 minutes, lasting a good 4-5 hours. Importantly, it did not interfere with my sleep when taken as late as 6pm and going to bed by 10pm.

You can take Notable both orally and sublingually (dissolved under tongue), so I naturally had to try both at various doses. I’ll briefly describe my experiences with it before I cover how/if I will use it in the future.

Oral

This is the primary way in which I used Notable. It’s quick, easy, and I can take it in the lab without being that guy pouring exotic powders under his tongue.

I tried dosing 1-3 pills (.5-1.5 servings) and even splitting one full serving throughout the day (taking one pill in the morning and another after lunch).

My results were in line with about what you’d expect from a supplement like this:

One pill: Noticable smooth stimulation

Two pills: Obvious dopaminergic spike and meaningful drive

Three pills: The same as two pills, just enhanced further

When doses are split (usually one at 9am, one at 2pm), I get a nice boost after each dose. The dopaminergic drive is still there, just not to the level of a full dose taken at once. This is beneficial on days where I needed a small boost all day as opposed to a more pronounced stimulation for a shorter time. As I’ll touch on shortly, this became one of my favorite ways to utilize Notable.

I never felt the need to try two servings at once, 1.5 servings taken orally has been more than enough for me when I really want/need.

Sublingual

In theory (and my experience), this is the best way to take this supplement as it enhances absorption of the actives and increases its potency. However, there’s a lot of powder in each capsule and a full serving requires two.

Despite that, just one capsule taken sublingually is fantastic. Two taken sublingual (while it's a ton of powder) is even better.

You get much more potency than the same doses when taken orally. It can just be a pain to do so, and is not nearly as convenient as popping two pills.

I personally wasn't a fan of taking a full serving sublingual, although I tried on several occasions.

With Caffeine

A short note on my experience using Notable with caffeine.

It pairs exceptionally well with caffeine, and in my experience helps dial in and direct the energy that caffeine provides toward a task. As little as a cup of black tea is enough to enhance its efficacy even further, taking a half dose to the next level.

My Protocol Moving Forward

Notable has become my go to for times when I want/need a true cognitive boost (I might have even taken 1.5 servings before sitting down to write this). It provides me with a really smooth stimulation while simultaneously boosting focus, mood, and motivation a fair bit. I feel I perform mentally well on it, and will continue to use it in the future. My specific use cases and doses are outlined here:

• For an all day focus/productivity boost (0.5 servings in the morning, 0.5 servings in early afternoon)

• For short bouts of focus and work (1 full serving, 0.5 servings w/ caffeine, 0.5 servings sublingual)

• For shorter intense bouts of focus and work (1.5 servings taken orally)

These are the doses I found to work best for me. If you choose to try Notable, I recommend you start with the lowest dose and taper up as wanted/needed.

To avoid tolerance/dopamine downregulation I limited my use of Notable to 3-4x a week maximum

Conclusion

Throughout my testing with it, Notable has been an extremely effective nootropic and leads to a profound dopaminergic spike that you can really feel within 30 minutes. Its utility and overall efficacy has made it something that I am constantly reaching for when I find myself needing a mental boost.

This doesn't make it perfect though. My primary critique is that one serving only contains 100mg of L-Theanine. Personally, I would've liked to see this doubled to 200mg as a way to help smooth out the stimulation that this supplement provides (this is more of an issue at higher doses)

A nootropic being too effective isn't the worst complaint to have though.

Overall, Notable is an excellent nootropic supplement and I prefer it heavily over a simple dose of just Sabroxy, my former favorite nootropic of all time. While Sabroxy alone gives me an increase in raw motivation, Notable seems to provide me with a directed and focused motivation. For that reason, it has been my go to nootropic lately.

If you’re interested in trying Notable, you can get it linked here. Use code “neuron” at checkout for a discount.

Ingredient Mechanisms of Action

enXtra:

• Dopamine Reuptake inhibition

• Acetylcholinesterase inhibition

• Adenosine Receptor antagonism

• Increase BDNF via dopamine and acetylcholine

Sabroxy Mechanism of Action:

• Dopamine reuptake inhibition

• Increase BDNF via dopamine

Polygala Tenuifolia:

• Dopamine, Serotonin, and Norepinephrine reuptake inhibition

• Monoamine Oxidase inhibition

• Acetylcholinesterase inhibition

• NMDA Receptor antagonism

• Increase BDNF via monoamines

Ginko Biloba:

• Acetylcholinesterase inhibition

• Norepinephrine reuptake inhibitor

• Increases dopamine in the prefrontal cortex (Norepinephrine transporter reuptakes DA in the PFC)

• Increase BDNF via acetylcholine and dopamine

L-Theanine:

• AMPA antagonism

  ---

Supplementary Info

Product name: Notable Focus

Route of Administration: Both oral and sublingual

Height and Weight for dosage comparisons: 6’2, 190lbs

Plasticity is much higher during childhood and declines with age, giving our early experiences as young children a large influence over how our brains develop. However, neuroplasticity is still prevalent through adulthood, which is why we can continue to learn things and change our brain even later into life.

In the adult brain, neuroplasticity occurs mostly as synaptic plasticity and synaptogenesis, two ways in which the brain physically changes as related to learning and memory. Understanding each of these processes in depth will allow us to leverage various protocols and supplements to boost plasticity as a way to enhance learning, memory, and overall brain function. 

Read more

The axon terminals are the sight of neurotransmitter release. They are small hubs located at the end of axons where neurotransmitters are both synthesized and stored while they await release.

When the action potential reaches the terminal, the positive charge it brings opens voltage-gated calcium channels. These are similar to the voltage-gated sodium and potassium channels involved in the propagation of the action potential, except they're only permeable to calcium ions (Ca2+). 

Calcium ions are very highly concentrated outside of neurons while there is almost none inside most of the time. As a result, when these voltage-gated channels open calcium floods into the terminal. This is significant because calcium ions are required for neurotransmitter release to happen.

How do calcium ions trigger neurotransmitter release?

Once neurotransmitters are synthesized they are packaged into vesicles, small bubbles composed of a plasma membrane similar to the neuron itself. They act as storage vessels for neurotransmitters, and bind with the membrane itself to release its contents out of the neuron.

Read more

Knowing about the membrane potential and action potential makes the rest of neuroscience accessible. Things really start to make sense on a cellular level, and you gain a deeper understanding of how neurons actually function and communicate with one another.

Let’s get into it.

Membrane Potential

If you remember from part one (link here if you missed it), neurons rely on internal electrical impulses in order to communicate with one another. These impulses are created by the movement of ions in and out of the neuron. 

Neurons, like all other cells, have a cell membrane composed of lipids separating its insides from the outside. This membrane doesn't allow any ions through it, so their movement in or out of the cell is entirely dependent on proteins that function as channels and transporters located within it.

Ions are just charged molecules that have an extra or missing electron, which means they have a positive (+) or negative (-) charge. The main ions at play in neurons are sodium (Na+), potassium (K+), and chloride (Cl-); however, there are also a large amount of negatively charged proteins (A-) inside neurons that contribute to the highly negative resting state of the neuron which we’ll talk about shortly.

These molecules are located in different concentrations across the cell membrane and generate the membrane potential, or difference in charge between the inside and outside of the cell. 

The inside of neurons are more negative than the outside at rest. On average it’s about 70 millivolts (mV) more negative, which makes the resting membrane potential -70mV. The ions and proteins mentioned above (Na+, K+, Cl-, A-) and their relative concentrations inside or outside the cell contribute to this resting potential.

But why are neurons negatively charged at rest?

Read more

We’ll start here with an introduction to the basic cell types of the nervous system to lay a foundation of knowledge, then dive into how exactly neurons work and the different regions of the brain.

With that out of the way, let’s begin by asking a simple question…

What is a neuron?

Neurons are the simplest unit and building blocks of our nervous system. They're cells that have a unique structure specialized for receiving, conducting, and transmitting electrochemical signals. With almost 100 billion neurons in our bodies, they are much more than just the cells that make up our brain.

They control our muscles, take in sensory information from our environment and relay it to the brain so that we can perceive it, and innervate our various organ systems. Neurons are how the brain communicates with the body and vice versa.

Let’s take a look at the anatomy of a neuron, so we can understand how exactly how they work.

Neurons have four main parts that allow them the unique ability to communicate with each other:

• Dendrites

• Soma

• Axon

• Axon Terminals

Like all human cells, neurons contain a nucleus and other organelles needed to maintain life which are stored in the soma (aka cell body). What makes neurons unique though, are the branch-like protrusions coming off of the soma. These are referred to as the dendrites and the axon. Dendrites receive input from other neurons, while the axon carries new messages away from the cell body and delivers it to other neurons.

It is important to keep in mind that neurons typically have many dendrites (most neurons make thousands of synapses), but only one axon. This means they can receive signals from tons of different neurons from all over the brain, though can only pass that signal forward to one specific area.

This path of communication only flows in one direction; in through the dendrites, collects in the soma, passes through the axon, and onto the next neuron. You can think of this internal flow like electricity traveling through a wire, since the internal communication in a neuron is electrical.

How Neurons Communicate

Neurotransmission, or how neurons communicate, involves two mechanisms:

• Chemical transmission

• Electrical impulses

Chemical transmission is the means by which neurons are able to communicate with each other, while electrical impulses (described above) are how the message is communicated internally.

In response to an electrical impulse one neuron releases small molecules (neurotransmitters), from its axon terminals into the space located between the two, or synapse. These neurotransmitters bind to receptors on the dendrite of the receiving neuron and contribute to the electrical impulse that travels within the neuron, through the body, down the axon, to the terminals.

Different Types of Neurons

Now you know what the “stereotypical” neuron looks like. However, there is so much diversity in their shape and size depending on their function in the body; it can be narrowed down to three main classes that serve different functions within the nervous system.

Sensory Neurons:

These guys do what you’d expect based on the name. They sense things from their environment and send that information to the brain where you are then able to perceive it. They have highly specialized nerve endings that are sensitive to a particular type of stimulus and convert that into electrical impulses.

The image below shows a few examples located in skin. Different nerve endings allow them to sense different inputs, whether it be pressure, stretch, or raw sensation and pain. This class also includes neurons that sense taste, vision, smell, temperature, sound, and even our heads position in space.

In this type of neuron the nerve endings take place of the dendrites, as they’re receiving information externally and not from other neurons.

Interneurons:

These are the primary neurons in the central nervous system. They serve as relay units, and function in the way I described as the “stereotypical neuron” earlier, receiving input from other neurons, and passing that message on to the next.

Their exact function depends on where they’re located in the brain or nervous system generally.

Motor Neurons:

Motor neurons are unique as they elicit a direct effect upon their activation. Instead of sending their signals to other neurons, they activate muscles causing them to contract. Whenever you decide to move, your brain outputs a signal that travels via neurons through the spinal cord and to the effector muscle required to complete that movement.

However, they can also be stimulated by reflexes that bypass the brain entirely. I’ll give you a real life application. Whenever your doctor hits your knee and your leg reflexively kicks out, that signal from your knee bypasses the brain entirely via the spinal cord, causing your quad to contract and hamstring to relax (shown below).

Glia

Glia is a blanket term for the different types of cells that support the function of neurons. They are the unsung heroes of the nervous system. Without them our nervous system would cease to function entirely. In fact, there are more glia than neurons in the brain (there are trillions of glia), and there are five main types: 

• Astrocytes 

• Microglia 

• Ependymal cells 

• Oligodendrocytes 

• Schwann cells 

Let's go over the function of each.

Astrocytes are the most abundant type of glia, and they have a wide range of function in the brain. This includes, regulating the blood-brain barrier (BBB), providing structural support for neurons, synthesizing neurotransmitters, reuptake of extracellular neurotransmitters, forming scar tissue after injury in the central nervous system (CNS), and more.

Note - The CNS includes the brain and spinal cord, while the peripheral nervous system (PNS) includes all other neurons not present in the brain or spinal cord.

These cells serve as the primary support cells for neurons, as well as have the important job of maintaining the BBB, the first line of defense for what gets to enter the brain. Astrocyte's end feet wrap around blood vessels to help maintain their tight junctions (shown below). The integrity of these junctions limit what can and can't enter the brain, keeping out toxins, pathogens, and other harmful substances.

Microglia are the immune cells of the brain. They react to pathogens and damage. When a threat is detected, they rapidly change shape (or activate) and move to the area of need.

These cells will 'eat' dead cells, debris or pathogens via phagocytosis to clean house in the brain. 

Ependymal cells form the lining of ventricles, a series of connected cavities filled with cerebrospinal fluid (CSF) in the brain and spinal cord. The main function of these glia is to produce and secrete CSF into ventricles, as well as assisting in its circulation using the cilia present on their exterior.

The last 2 have very similar functions as they both myelinate the axons of neurons, but they operate in slightly different ways (and locations). 

Oligodendrocytes myelinate neurons in the CNS. They can myelinate many parts of several different axons, which is their biggest difference from the next type. They also contribute to maintenance and repair of axons in the CNS.

Schwann cells myelinate one part of a single axon in the peripheral nervous system (PNS), so it takes multiple Schwann cells to cover one whole axon. They also maintain and regenerate the axons in the PNS is damage occurs.

Myelin is the white fatty substance that surrounds the axons of most neurons, allowing the action potential to travel faster. This is why the axon tracts are known as 'white matter' in brain tissue.

Note - Not all neurons have myelinated axons, in particular some sensory neurons in the PNS don't, but all motor neurons do since we want that message traveling as fast as possible.

Proper neuronal function requires neurons and glia to work together. They all exist in the same micro-ecosystem that is our nervous system, and neurons can't function to the best of their ability (or at all) without glia there to support and protect them.

Conclusion

With that, we have an introduction to the primary cell types that make up the human nervous system, neurons and glia. This content barely scratches the surface of neuroscience, but it’s important to have a know these things before we dive deeper into neuronal function and other topics.

A brief recap:

• Neurons are the primary cells that make up the nervous system

  • They communicate with each other using a combination of electrical and chemical signals

• There are three main types of neurons

  • Sensory Neurons

  • Interneurons

  • Motor Neurons

• There are 5 main types of glia that work to support neurons

Looking Forward

With this base of knowledge we can now begin to dig into the specifics of how neurons work. The next installments will cover:

• Membrane Potential and the Action Potential

• Neurotransmitters and Synaptic Transmission

• Different brain regions and their function

After that, you should have a much greater understanding of the nervous system and how exactly neurons work.

Moving forward, all “Neuroscience Crash Course” articles will be for paid subscribers only. A subscription is only $5 a month ($50 for the year) and I believe it is more than reasonable for the amount of content you’ll get in return.

Along with the continuation of this series, I have other articles planned aimed at helping you optimize neurotransmitters and brain health/function using diet, lifestyle, and obviously supplements/nootropics.

There is still free content coming as well, so make sure to subscribe to not miss any new articles. Reminder that if you sign up as a free or paid sub you’ll get my “Intro to Neurotransmitters” eBook sent to you immediately, which includes an in depth intro to all the main neurotransmitters in the brain.

That’s all for now. Thank you for reading.

Link to Neuroscience Crash Course #2

On the surface it seems like a miracle herb, but I wanted to see if Rhodiola could be used as a nootropic. By that I mean taking it only a few times a week and observing any short-term enhancements I may notice throughout the day, as opposed to taking it every day like many people and most studies do.

To be frank, it was a great success.

Mechanism

Before we get into my experience with Rhodiola, I want to briefly discuss its mechanisms.

They aren’t fully fleshed out, but this is partly because this species of plant has well over 100 compounds in it. Some of its most notable mechanisms may include:

• MAO inhibition (increase in monoamines)

• Influence HPA axis (anti-stress)

• Increasing activity of endorphins (anti-stress)

• Scavenging of reactive oxygen species (anti-stress)

MAO inhibition sticks out to me the most (the brain is kinda my thing). Monoamine Oxidase is the enzyme responsible for breaking down monoamines in the brain (dopamine, serotonin, norepinephrine). 

Its inhibition leads to an increase of activity from those molecules since they aren't being broken down. This is likely a large contributor to the antidepressant and cognitive enhancing effects of Rhodiola.

I could go on for a while, it really does so much, but in short Rhodiola works to help the body fight stress (physical and mental) and fatigue generally.

Rhodiola has 2 primary active components; Salisrosides and Rosavins. These are the two main “forms” you’ll see being sold.

This review was done with a high Salidrosides (3%) extract as they tend to be more stimulating, while its counterpart high in Rosavins is more relaxing. This choice was nothing more than a personal preference as to what I wanted to get out of Rhodiola. If you plan to try rhodiola and want a more calming experience, look into an extract high in Rosavins.

My Subjective Experience

Since I started using Rhodiola there have been 2 kinds of days for me:

1. Those that I have super high energy all day

2. And those that don’t take Rhodiola

That’s somewhat hyperbolic, but when I take Rhodiola my energy is sky high all day. Even after stressful, mentally taxing mornings doing surgeries (on mice) or other things that would normally wipe me out for a bit I still have extremely high levels of energy going into the late afternoon.

Over the course of my experimentation with this herb, I haven't experienced a single true “afternoon crash”. Most I’ve felt when taking it is a slight energy dip. Not a crash, but a slight decrease for about an hour after lunch. Even then I maintain mental clarity and focus.

The crash I normally have isn't entirely detrimental. It usually hinders my mental performance for about an hour after lunch, but it's been great to be able to rid myself of it at will.

That’s really only a side benefit to taking Rhodiola though. The real upside is the mental clarity and energy it provides over the course of a whole day.

Looking back through my notes during this experimental phase that’s what stuck out to me the most. A lot of “I’ve never had so much energy while driving home” and “energy is still high into late afternoon”.

When I refer to the “energy” when taking Rhodiola it's not just a mental feeling, it's a physical manifestation. There's a stark contrast to the “mental energy” that other nootropics provide by boosting acetylcholine or dopamine, and the sheer lack of fatigue I feel when taking Rhodiola. The best way I can describe it is by calling it a whole body energy.

That's where Rhodiola truly shines in a nootropic context. The ability to shrug off stressor after stressor and still have immense amounts of energy to take on the rest of the day. It’s unlike any other nootropic or supplement I’ve ever tried.

On that same note, I did not observe an immediate effect when taking Rhodiola. It took about 4-5 hours for me to notice any effects when taken. This may be skewed because I had a cup of coffee everyday I took it though.

Well, not everyday. Once I tried to go cold turkey on caffeine using this as a way to counterbalance withdrawal induced fatigue. Didnt work one bit. Was tired all day and had a headache at points. Horrible failure of a test.

However, Rhodiola is highly synergistic in my experience. High energy in the morning fueled by caffeine, crash mitigated and energy extended by Rhodiola.

My Protocol Moving Forward

Based on my overwhelmingly positive experience with Rhodiola, it's going to become a permanent addition to my supplement stack as a nootropic moving forward. I’ll outline my general use cases moving forward below:

• When I know I have an excessively busy day ahead of me (500mg)

• If I need/want high energy all day (500mg)

My specific use cases here are limited due to the nature of its effects, but Rhodiola will be an extremely effective tool for me moving forward.

I’d like to note that this isn't the usual use case for Rhodiola. Based on both the literature and anecdotal reports it seems to be best used as a long-term supplement taken everyday to help the body deal better with stress and fatigue long-term.

My goal with this experimental phase was to test it in a ‘nootropic context’, meaning to observe its short-term effects on me throughout the day. 

In this context it was a great success for me. It’s not the average ‘nootropic’, but it works extremely well for me and I’ll continue to use it like this moving forward. 

However, I do plan to test it as a supplement in the near future, taking it every morning for ~4 weeks and seeing how it works. That’ll require its own “Supplement Review” in the future.

Conclusion

To sum it up, my experience with Rhodiola Rosea was fantastic. If I’m being honest I didn’t expect much from it at all when I ordered it. The first time I used it I was so shocked by the results I labeled it as a one off experience. There was no way it could be that great. Right?

I was wrong, it is that great. It’s 10 times better than I anticipated. The overall lack of mental and physical fatigue I feel is unmatched, and I’m still shocked by the amount of energy I have on my drives home at the end of the day when I take it.

Supplementary Info

Brand used: Nootropics Depot (affiliate link)

Extract: 3% Salisroside

Form: Pills

Height & Weight for dosage comparison: 6’2, 190lbs

If you decide to pick some up for yourself, or anything else from Nootropics Depot, consider using my affiliate link above. It comes at no cost to you and it’s an awesome company that I get basically all my nootropics from.

Thanks for reading! More content coming soon.

This study, “The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA_A receptors” (link) aimed to further investigate the mechanisms of these compounds and see if their action is sub-unit specific. Here I’ll focus on the former, honing in on the researcher’s single cell voltage-clamp recordings that were used to measure GABAergic activity.

What is voltage-clamp recording?

Voltage-clamp is an electrophysiology technique commonly used in neuroscience research. It involves inserting a small glass electrode through the membrane and into a neuron, granting the electrode access to the inside of the neuron. This process is highly detailed in the methods of this paper under the section “Hippocampal slice recording”, but I’ll sum it up here in an attempt to make it more understandable.

Researchers can remove the brain from a rodent (rat here) and keep it alive in a cold artificial cerebrospinal fluid (aCSF) solution. aCSF contains everything needed to keep neurons alive; a mixture of electrolytes (Na+, K+, Ca2+, Cl-, MG2+) and glucose. It’s essentially just salty sugar water. The brain is then cut into 300 micrometer thin slices, and stored in room temperature aCSF that is being bubbled with oxygen. The goal here is to keep neurons alive so they can be recorded from.

When it’s time to record, brain slices are taken and placed into warm, oxygenated aCSF in an electrophysiology rig. This rig contains everything needed to perform these recording experiments including a well to hold the brain slice, various pipette and electrode holders, recording equipment hooked up to computers, etc.

In short, brain slices are collected, and the tissue can be kept alive to run experiments on.

Slices are taken one at a time, and the researchers can ‘patch’ into individual neurons with small glass electrodes. This process involves pressing the pipette against the cell membrane and ejecting a bit of pressure outwards to break through, leaving them with a recording electrode located inside the neuron. 

This electrode has its own internal solution that will enter the neuron upon patching. This internal solution contains substances that block different ion channels (Cs, cesium, blocks K+ leak channels and QX-314 blocks voltage-gated Na+ channels) and enters the neuron. Blocking these ion channels removes any sources of ion flow that aren’t neurotransmitter receptors and inhibits action potentials. For this experiment, NMDA and AMPA glutamate receptors are also blocked by 2 drugs in the extracellular solution. 

This setup makes the pathed neuron an ideal environment to record GABA currents because it has no way to change its internal voltage other than GABA-gated ion channels (GABAA receptors), or the electrode inside that allows the researchers to control and measure current in and out of it.

This is where the term “voltage-clamp” comes in. This electrode is hooked up to a series of amplifiers and a computer which allows the researchers to ‘clamp’ the voltage of the neuron at a desired voltage for the experiment. The voltage changes based on what they are recording and the established concentrations of ions (specifically chloride). The specifics of this aren't as important as knowing what is being recorded.

What's being recorded is the current that's being injected into the neuron by the electrode. Clamping the neuron at a specific voltage requires a computer to read changes in internal voltage (caused by ion flow in or out) and correct for that by injecting current.

For example, when GABAA receptors open, Cl- enters the neuron making it more negative. The electrode reads this change and injects an equal positive current back into the neuron to negate this negative change. The current injected into the neuron is the read out they get, since it is equal to the current caused by the opening of the receptors. That’s how this data is collected, and the neuron remains at the desired internal voltage.

Two different types of recordings were done for this paper; one measuring inhibitory postsynaptic currents (IPSCs) in response to a GABA neuron firing an action potential and releasing a ton of GABA onto one synapse, and the other which records miniature IPSCs (mIPSCs) which are the result of spontaneous, random vesicle releases not caused by an action potential. The former gives us a better understanding of the active compounds' effects on GABAA, so I’ll cover that here and touch on the latter at the end.

Measuring GABAA mediated IPSCs

For this experiment, the neuron to be recorded was set up as described above. To get IPSCs though, a GABA neuron needs to be stimulated to fire an action potential to release GABA onto the neuron they are recording. To do so, they inserted an electrode into a GABAergic neuron, which they could then inject current into and cause it to fire an action potential on demand, releasing GABA. So, the researchers have one electrode to stimulate GABA release, and another to record changes in voltage (where the data comes from). This was done without the active components of Magnolia bark, then with them added to the bath. The results are shown in the figure below. 

On the left, we have the average trace of current in response to these evoked IPSCs, control in grey and magnolol added in black. This is the trace of current that enters the neuron in response to GABA binding to GABAA receptors. The graphs to its right are showing the same things we can see in the trace, just quantified.

What does this figure tell us?

1. The amplitude of the IPSC is unchanged with the addition of magnolol and honokiol.This is shown most clearly in the far right graph. Amplitude of the trace is shown as a percentage of the control trace. Both substances show no change in the peak amplitude. These results indicate that neither magnolol or honokiol allow a greater flow of ions through at peak. The initial response is the same with or without these compounds

2. The decay time of the IPSC is greatly increased by the presence of these 2 substances. This is clear from both the trace and the first graph. This indicates that the GABAA receptors are open for longer when activated by GABA in the presence of magnolol and honokiol, or they're closing is delayed on average, dragging out the decay of current. With just GABA (control) the channels open instantly and close very fast (sharp decline in the trace), but in the presence of these 2 compounds the tail is elongated, indicating that the channels aren't closing as fast.

From these results, you can conclude that the action of these compounds at the synapse is to slow the deactivation rate of GABAA receptors without increasing their peak response. (Without increasing peak response is important to keep in mind, as that is not the case extra-synaptically)

How do they know these currents were only mediated by GABAA receptors?

They added bicuculline, a GABAA antagonist, to the bath after the experiment and found that these currents were completely blocked. If all current recorded is stopped by simply adding a GABAA antagonist, you can assume that all of the recorded current is coming from GABAA receptors.

mIPSC Recordings

When recording miniature IPSCs, TTX is added to the bath containing the brain slice. TTX is a toxin that blocks voltage-gated sodium channels of all neurons in the slice, effectively inhibiting any action potentials from taking place. This allows you to record signals only from random vesicular releases, just a spontaneous single vesicle full of neurotransmitters being released not in response to an action potential. This provides insight into the presynaptic inner workings, since if frequency of release is increased, something must be causing that to occur.

This is what we see in Figure 1c:

The findings show a massive increase in mIPSC frequency, but no change in their amplitude. This is significant because it shows these compounds may have the ability to increase GABA release from the presynaptic neuron. There’s no way to derive a possible mechanism from these results, but an average increase of 400% is staggering and worth noting.

Figure 1B provides some interesting data as well, showing us that magnolol and honokiol can potentiate current coming from extrasynaptic GABAA receptors (which have a different subunit makeup and function). This was recorded in a similar fashion to the data from 1C, but I want to cover this in a separate post because we can dive into the importance of subunit composition and tonic vs phasic current. Phasic being activity at the synapse mostly driven by action potentials, and tonic being current that is always there caused by neurotransmitter ‘spillover’ from synapses.

Conclusion

Based on the findings of this paper and those prior, the two main psychoactive compounds in magnolia bark extract potentiate the action of GABA by enhancing activity of the GABAA receptor. That is what makes this supplement a potent anxiolytic. This action seems to be different depending on the subunit composition of the receptor, but we’ll explore that in an upcoming post as it would be way too much to cover here.

Thank you for reading!

Source:

Alexeev M, Grosenbaugh DK, Mott DD, Fisher JL. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. Neuropharmacology. 2012 Jun;62(8):2507-14. doi: 10.1016/j.neuropharm.2012.03.002. Epub 2012 Mar 12. PMID: 22445602; PMCID: PMC3652012.