Natural Nootropic Solutions vs. Sublinguals: What's the Difference?

Natural Nootropic Solutions vs. Sublinguals: What's the Difference?

Posted by Natrium Health on 15th May 2018

What is Sublingual Administration?

Sublingual administration is a dosing method by which the active substance is administered under the tongue. The mucous membrane under the tongue is highly vascularized and can readily absorb various compounds, such as vitamins, amino acids and phytochemicals. The compounds diffuse through the mucous membrane and enter into venous blood through the internal jugular vein, the subclavian vein, and finally the brachiocephalic vein which feeds directly into the superior vena cava. The compound of interest is now in systemic circulation, meaning it has bypassed the harsh environment of the stomach and first-pass metabolism in the liver. The main advantage of sublingual administration is that tmax and Cmax increases significantly. This reflects as a significant increase in bioavailability and speed of onset.

If a compound is administered successfully through the sublingual route it can take effect much quicker and more of the compound will reach the areas of interest, such as the brain. This means that the sublingual route can offer better and more noticeable effects.

The Basics of Sublingual Administration

That all sounds great, so why don’t we administer everything sublingually? There are a few major limitations when it comes to sublingual administration and a lot of it has the do with the chemical properties of a compound. As a basic rule of thumb, all of these factors must be met in order for it to be optimally sublingually bioavailable:

• Molecular weight that is under 500 daltons • A partition coefficient (LogP) value that is under 5

• If the compound is basic and ionizable, its acid dissociation constant (pKa) must be below the pH of the sublingual area (5.6-7.6, mean = 6.4)

• If the compound is acidic and ionizable, its pKa must be above the pH of the sublingual area

• A sufficiently low dosage

• Tolerable taste profile

• Non-caustic to delicate oral mucosal tissue


Natrium Health Graduated Dropper

Each of Natrium Health's sublinguals and solutions include a graduated dropper with clearly defined mL markings to allow for easy and convenient dosing. 

The first major consideration has to do with solubility in saliva and in the lipid bilayer of the sublingual area. This is measured by the partition coefficient (LogP), which measures how water soluble a compound is (hydrophilic) versus how water insoluble a compound is (hydrophobic). The more hydrophobic a compound is, the harder it will be for it to dissolve in saliva, which makes it really hard for it to pass through sublingual tissue. However, hydrophobicity will allow it to better partition in and out of the lipid bilayer in sublingual tissue. Due to this we want to ensure that a compound is slightly hydrophobic but hydrophilic enough to dissolve in saliva. In general, we are looking for LogP values under 5 but above 1 for best results in sublingual administration. Higher LogP values indicates more hydrophobicity whereas lower LogP values indicate high hydrophilicity. However, as long as a compound has a LogP value under 5, it can be sublingually viable. Below is a list of LogP values for the compounds that are in our sublingual solutions:

• Hydroxocobalamin (in super B12): 2.56

Methylcobalamin (in super B12): 2.08

Tyrosol (in Salidrosol): 0.85

Salidroside (in Salidrosol): -1.16

• L-Theanine (in L-Theanine): -0.49

As can be seen from the list above, all of the compounds in our sublingual solutions meet the requirement of having a LogP value below 5. This means that all compounds will have adequate sublingual bioavailability based on this requirement. In particular, hydroxocobalamin and methylcobalamin have LogP values that fall right in between 1 and 5 meaning that based on LogP values they are optimized for sublingual use.


A compound can only be used sublingually if it is soluble in water/saliva. It is optimized for sublingual use if the compound is also fat soluble as it will be able to pass through the membrane under the tongue and into our blood better.

To measure this, we can use a partition coefficient (LogP) value which tells us how water soluble and lipid soluble a compound is. Any LogP value over 5 indicates that it is not soluble enough in water, and thus, cannot dissolve in saliva. This means that a compound with a LogP value over 5 will not be suitable for sublingual use.

The second major consideration for sublingual administration is whether or not a compound can become ionized. If a compound can become ionized then this could be problematic as the ionized form of a compound has a much harder time absorbing sublingually. Below is a list that indicates ionization ability for the compounds that are in our sublingual solutions:

• Hydroxocobalamin (in super B12): Can ionize

Methylcobalamin in (super B12): Can ionize

Tyrosol (in Salidrosol): Cannot ionize

• Salidroside (in Salidrosol): Cannot ionize

• L-Theanine(in L-Theanine): Can ionize

Solubility - Log P

Solubility and Log P

From this list, we can see that tyrosol and salidroside are exempt from this rule, however the rest of the compounds need to adhere to this rule.

Ionization is dependent on a compounds acid dissociation constant (pKa) and the mouths pH (5.6-7.6, mean = 6.4) which is why we need to study the pKa of sublingually administered compounds. As a general rule of thumb, an acidic compound can be sublingually absorbed if its pKa is above 2, and for a basic compound, if its pKa is below 10. If a compound falls out of this range, then it will be fully ionized which for most compounds greatly hinders sublingual absorption.

The reason for this, is that ionization decreases the lipid solubility of a compound. This difference in lipid solubility is ultimately due to the charge of the compound, unionized compounds have a neutral charge which allows for the best lipid solubility. Acidic compounds are negatively charged when ionized and basic compounds are positively charged when ionized, which both decreases their permeability through the sublingual membrane.

For a weak acid, the closer it is to an acidic pH, the less ionized it will be, which increases lipid solubility, allowing it to pass through the sublingual membrane readily. As the pH starts to become more basic, more of the weak acid will become ionized, which hinders its absorption through the sublingual membrane. For a weak base it is the opposite, the more basic the pH the less ionized the compound will be, the more acidic the pH the more ionized the compound will be. Due to this, we want to ensure that we are in the pKa range of 2 or above for acidic compounds and a pKa of 10 or below for basic compounds. This is to ensure optimal absorption through the sublingual membrane.

Now this is where things get complicated, as a compound can have multiple ionizable sites, meaning it can have multiple pKa’s. For L-Theanine for example, it has four separate ionizable sites, two of which are acidic and two of which are basic:


• Basic: pKa = 6.68 (65.6% ionized at pH 6.4)

• Basic: pKa= 9.54 (99.9% ionized at pH 6.4)

• Acidic: pKa = 2.15 (100% ionized at pH 6.4)

• Acidic: pKa = 4.58 (98.5% ionized at pH 6.4)

Overall, at a pH of 6.4, L-Theanine would be 91% ionized, meaning it will be very soluble in saliva but not very lipophilic meaning it is not optimized for passing through the sublingual membrane efficiently. That being said, it will still pass through the sublingual membrane, it is just not optimized for it.

For the Super B12 solution, Hydroxocobalamin which makes up half of the formulation, is optimized for sublingual use, with a pKa of 7.65. Being a weakly acidic compound, this means that at pH of 6.4, only 5.3% of the compound is ionized, leaving the rest unionized. This leads to excellent sublingual bioavailability. Methylcobalamin on the other hand has a pKa of 2.72 and thus falls within our range but, at a pH of 6.4, would be 100% ionized and thus would not be optimized for passing through the sublingual membrane. Luckily, its LogP value is 2.08 meaning that it has relatively good lipophilicity to begin with. Thus, despite not having an optimal pKa value, it should still be bioavailable via the sublingual route.


For a compound to be absorbed quickly and efficiently through the sublingual membrane, the right conditions need to be met in regards to the pH of the mouth. The pH of the mouth which on average is 6.4, dictates how readily a compound becomes ionized. The degree to which a compound ionizes at a pH of 6.4 depends on its pKa value.

Highly ionized compounds have a hard time being absorbed, whereas un-ionized compounds readily absorb. This is due to the fact that ionization influences the solubility of the compound, the less ionized the compound is the more readily it will pass through the sublingual membrane and the more ionized the compound is, the harder of a time it will have passing through the sublingual membrane.

Why is our Caffeine + N-Acetyl L-Tyrosine solution not a sublingual solution?

Even though the Caffeine + N-Acetyl L-Tyrosine solution meets all of the requirements for being efficiently absorbed through the sublingual membrane, there are some practical limitations that prevent it from being used sublingually. The first consideration, is that Caffeine is very bitter and thus, administering it sublingually is not pleasant. This, however, can be solved by flavouring it. The main issue, is with the N-Acetyl LTyrosine, which is very acidic. First and foremost, this produces a very sour and vinegar like taste. Secondly, the sheer acidity can degrade tooth enamel upon prolonged contact with teeth and can damage the sensitive sublingual membrane. This unfortunately render this solution unusable for sublingual use.

That being said, both Caffeine and N-Acetyl L-Tyrosine both adhere to Lipinski’s rule of five, a set of five rules established by Christopher A. Lipinski that determine whether or not a compound is orally bioavailable. The five rules are:

• Five or less hydrogen bond donors

• Ten or less hydrogen bond acceptors

• A molecular weight that is under 500 daltons

• A LogP value under five

When all five rules are met, the compound has optimal oral bioavailability. Both Caffeine and N-Acetyl LTyrosine meet all five requirements meaning they are both highly bioavailable. In addition to this, the complexing of Caffeine with N-Acetyl L-Tyrosine, significantly speeds up absorption and leads to a much faster onset of action compared to most other Caffeine sources. Based on the already fast onset time, and the drawbacks of using this solution sublingually, there is no reason why this solution should be used sublingually.

How should a sublingual solution supplement be used?

The best way to use the sublingual solutions, is to measure out a dosage with the graduated dropper (0.5 mL is one dosage), lift up the tongue, and squirt the solution under the tongue. To contain the solution, lower your tongue again, over the solution. Let the solution sit for about five minutes, or until effects can start to be felt. Before swallowing, swish the solution around your mouth, making sure it comes into contact with the inside of your cheeks, as compounds can absorb through there too. Then swallow the solution and if you do not mind the taste, try not to drink anything for a few minutes as there will still be solution coating the inside of your mouth that will be actively absorbing.

How should a oral solution supplement be used?

The Caffeine + N-Acetyl L-Tyrosine solution can be used in two different ways. The easiest one is to squirt the solution into your mouth and follow it up with a big gulp of water. Some people find the taste of the solution to be a little too overwhelming via this method. The other method for using this solution, is to simply squirt the solution into a beverage of your choice. The dilution cuts out most of the more prominent flavors.

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