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Why (and How) Nootropics Bypass the Blood-Brain-Barrier

There are many obstacles for any substance that tries to affect the way our brains work, but one of the biggest ones is the Blood-Brain Barrier, or BBB.

This is the separation between the blood that supplies the brain with oxygen and nutrients, and the extracellular fluid that the brain sits in.

Any substances that we take, such as drugs, nootropic supplements or even food, have to make the transition from blood into this fluid if they want to have any sort of effect on the brain.

Evolution of the BBB

It makes sense that our brains have a system in place to prevent just any old thing entering them, and the BBB does a pretty good job of this.

It has a thick basement membrane and a lining of cells that dictate what gets in and what gets out.

These are called epithelial cells, and are a special kind of thin layer that lines all surfaces in the human body.

In the case of the blood brain barrier, this layer is what lets things in and out and allows the exchange of materials across the barrier.

How do nootropics get through?

Since nootropics are focused on interacting with the brain, they have to find some sort of way of getting across the BBB.

If they can’t get into the fluid surrounding the brain, they can’t give us the increased focus, attention span and information retention skills that we know and love them for.

One of the most common ways of sneaking across the blood brain barrier is the use of a carrier, as is the case with tyrosine and other amino acids.

Tyrosine is one of the 22 key amino acids that are used for building proteins around the body.

In addition to this, however, it also raises the levels of certain neurotransmitters in the brain, namely dopamine and norepinephrine.

These are famous for being “feel good” chemicals that can help boost mood and elevate concentration, making tyrosine a popular nootropic.

However, tyrosine is completely incapable of passing the BBB. This way, no matter how much of it you were to take, you’d feel almost no effects.

So how does it get into the fluid surrounding the brain?

Molecular structures allow for membrane permeability

Membranes are set to be permeable (i.e. allow the passage of) certain types of molecules, and the BBB is no different.

If tyrosine has a chemical compound known as an acetyl group tacked onto it, it is able to sneak through the BBB and can be absorbed by the brain on the other end, producing all of those positive effects that we expect from it.

The addition of acetyl groups is an extremely common way that drug manufacturers can manipulate the structure of their substance to allow it to pass through the BBB.

Nootropic fans out there are likely familiar with GABA, or gamma-aminobutyric acid. GABA compounds interact with (not surprisingly) GABA receptors in the brain which interfere with anxiety and stress, resulting in an anxiolytic and relaxing effect.

GABA is used in this way to treat people suffering from chronic stress, insomnia, sleep apnea and other sleep related problems.

The good night’s sleep that results can lead to improved mood, concentration and general wellbeing.

However, GABA alone does not produce particularly strong effects because it can’t cross the BBB.

‘Prodrugs’ are the solution

The way we work around this problem is by creating a prodrug. A prodrug is a substance that in and of itself isn’t biologically active, but will produce biologically active products when it is broken down by the body.

In the case of GABA, we can fuse it with niacin to form nicotinonyl-GABA, which you likely know by its trade name: Picamilon.

1. Picamilon

Picamilon is an extremely popular nootropic, and all it is is a vessel for GABA.

Picamilon will cross the BBB into the extracellular fluid around the brain, and then it is broken down into its original constituents: niacin and GABA.

Then, the GABA has reached the brain and can provide all of those relaxing and anti-anxiety affects that it is sold for.

2. Phenibut

If you’re familiar with nootropics, then you’ve probably heard of Phenibut. Otherwise, it’s probably just another funny-sounding chemical substance.

Structurally, Phenibut is very similar to the neurotransmitter GABA, which inhibits excessive activity in the brain. Both Picamilon and Phenibut are unique on a molecular level, allowing them to bypass the blood-brain barrier. 

Phenibut’s phenyl side ring is a small change from GABA, but it has a big impact. The phenyl ring helps Phenibut cross the BBB and get metabolized to GABA inside the brain.

The point I’m trying to make is that Phenibut’s mechanism of action is quite simple: it is a modified form of GABA that crosses the blood-brain barrier. 

The modification is chemically straightforward and easy, allowing it to be manufactured cheaply and reliably, and its legality allows all sorts of people to try it and use it for their anxiety.

Important to note: Phenibut is not technically a true nootropic; although it has many nootropic effects, they are indirect consequences of lower anxiety, as noted by this Phenibut user on Longecity:

I think it is only considered nootropic from a marketing perspective… It provides functional but powerful anxiolysis, as opposed to pure sedation. I am unaware of any short or long-term cognitive gains. I blame Russian publications for phenibut’s dissemination as a nootropic. Perhaps they operate on a slightly different definition, because it has very noticeable and dangerous side-effects which violate both Giurgea’s and Skondia’s nootropic criteria.

As this individual points out, Phenibut can have some very serious negative side effects.

Nootropics, by definition, have little to no side effects. Other phenibut users have similar feelings about keeping Phenibut out of the realm of nootropics, no matter the dose:

In therapeutic doses (~500mg) [phenibut] reduces my sleep latency and also helps me wake up and remain alert the following day… Higher doses (~1500mg) were used in a recreational manner and have no benefit as a nootropic. [Phenibut] is less effective for severe anxiety but could potentially be a viable candidate for milder forms of anxiety though I would imagine this drug to be useful when used infrequently: daily dosing is out of the question.

Classification aside, Phenibut has very practical use, owing to its chemical structure and ability to cross the Blood Brain Barrier.

Conclusion

All in all, the BBB poses a major problem for drug and supplement manufacturers around the world.

However, through using sophistication chemical techniques like those above, we can engineer solutions to what would otherwise be a giant stop sign for any substance that would affect the brain.

Without these mechanisms, nootropics wouldn’t exist in the way we know them today.

Without them, we wouldn’t have their stress reducing and focus boosting effects to help us go the extra mile in work, studying for exams or anything else that we might happen to use them for.


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10 Ways to Increase Dopamine Levels In The Brain | Collective-Evolution - January 20, 2016

[…] “Tyrosine is one of the 22 key amino acids that are used for building proteins around the body. In addition to this, however, it also raises the levels of certain neurotransmitters in the brain, namely dopamine and norepinephrine. These are famous for being ‘feel good’ chemicals that can help boost mood and elevate concentration, making tyrosine a popular nootropic. However, tyrosine is completely incapable of passing the BBB. This way, no matter how much of it you were to take, you’d feel almost no effects.” (source) […]

Reply
10 Ways You Can Increase Dopamine Levels In The Brain Without Medication - Take control of your health! - January 20, 2016

[…] “Tyrosine is one of the 22 key amino acids that are used for building proteins around the body. In addition to this, however, it also raises the levels of certain neurotransmitters in the brain, namely dopamine and norepinephrine. These are famous for being ‘feel good’ chemicals that can help boost mood and elevate concentration, making tyrosine a popular nootropic. However, tyrosine is completely incapable of passing the BBB. This way, no matter how much of it you were to take, you’d feel almost no effects.” (source) […]

Reply
10 Ways You Can Increase Dopamine Levels In The Brain Without Medication - Take control of your health! - January 20, 2016

[…] “Tyrosine is one of the 22 key amino acids that are used for building proteins around the body. In addition to this, however, it also raises the levels of certain neurotransmitters in the brain, namely dopamine and norepinephrine. These are famous for being ‘feel good’ chemicals that can help boost mood and elevate concentration, making tyrosine a popular nootropic. However, tyrosine is completely incapable of passing the BBB. This way, no matter how much of it you were to take, you’d feel almost no effects.” (source) […]

Reply