Cognance | Bacopa Reimagined | The Journey Of Humble Bacopa To Mighty Cognance

The Story Of Bacopa Monnieri

Origin and Spread

The story of cognance starts with an inconspicuous creeping amphibious herb, called Bacopa monnieri. This plant can grow both terrestrially and aquatically, and appears to be native to marshy areas of India. From its origin point, it quickly spread throughout the world, now being present in almost every continent on earth. The most important country for the story of Bacopa monnieri, is India however. In India, Bacopa monnieri became a highly revered herb. The Indian Materia Medica extensively wrote about it. Additionally, Indian Ayurveda considered it a crucial herb.

Ayurvedic Reverence

In Indian Ayurveda, Bacopa monnieri is known as a Rasayana herb with Sattvic qualities. Rasayana refers to the rejuvenating nature of Bacopa monnieri. Sattvic refers to its wisdom and enlightenment effects. People have used Bacopa monnieri as a natural nootropic for centuries. There’s a strong emphasis on memory improvement. Ayurvedic practitioners held this knowledge. As the story of Bacopa monnieri progresses, curiosity about its effects grew.

Chemical Discoveries

In 1963, a major discovery was made by Chatterji et al. They found that Bacopa monnieri contained two distinct saponin compounds, bacoside A and bacoside B. Years later, researchers discovered that these compounds tend to stick together due to their saponin nature. This made them difficult to separate in an HPLC column. After developing new methods, researchers found that bacoside A was actually a mixture. This mixture included bacoside A3, bacopaside II, bacopaside X, and bacopasaponin C. To this day, we still don’t know what bacoside B is or if it even exists.

Standardization Efforts

After 1963, it finally became possible to analyze Bacopa monnieri to some degree. In the 1970s, the Central Drug Research Institute (CDRI) of India set out to create a high-quality standardized Bacopa monnieri extract. The CDRI recognized the need for a consistent extract with known bioactive quantities for high-quality research on Bacopa monnieri. The extract, known as CDRI-08, remains available commercially today under the names Synapsa or Keenmind, which is remarkable. CDRI-08 led to a lot of fascinating research, finally confirming scientifically, what Ayurvedic practitioners had been saying for centuries now. It became abundantly clear that Bacopa monnieri does in fact enhance cognitive function, mood and memory!

Testing Challenges:

If we advance a little bit more in the story of Bacopa monnieri, we start running into testing difficulties. As mentioned earlier, the saponin nature of bacosides causes them to stick together, complicating their separation in the HPLC column. Researchers could acid hydrolyze the bacosides to ebelin lactone and then quantify it using UV-spectrophotometry. Working backwards with some math allowed determining the amount of bacoside present. At the time, no one considered the contribution of ebelin lactone to Bacopa monnieri’s effects, so it was briefly forgotten.

Bacogenin Insights:

The CDRI seemed aware of ebelin lactone and other bacogenins, the hydrolyzed derivatives of bacosides. In fact, ebelin lactone is bacogenin A4! However, researchers conducted sparse research on the bacogenins, and they seemingly made no solid attempts to concentrate them. Then one day, we were diving deep into Bacopa monnieri research, and we came across a fascinating study from 2015. The study concluded that bacosides probably didn’t absorb in the gut or cross the blood-brain barrier.

Deglycosylation Discovery:

The fact that bacosides cannot absorb properly nor cross the BBB obviously poses some major problems. The compounds responsible for the benefits of Bacopa monnieri must absorb and be able to cross the blood-brain barrier. So, was everyone looking at the wrong compounds all along, or is there something else going on? Well, according to the 2015 study, the bacosides quite rapidly hydrolyze to their aglycone counterparts, jujubogenin and pseudojujubogenin. Jujubogenin and pseudojuju

Bacopa Reimagined

Pursuing Ebelin Lactone:

Obtaining ebelin lactone became a priority, driving us to explore various avenues to access this remarkable compound. Well, this proved to be quite challenging. Exploring synthetic sources was our initial approach, consistent with our strategy for obtaining “nature identical compounds” like salidroside and tyrosol. No synthetic ebelin lactone was available, and custom synthesis was financially unfeasible due to prohibitive pricing. Back to the drawing board it was!

Inspired by Natural Metabolism:

The realization struck that the human body naturally produces ebelin lactone, likely contributing to Bacopa monnieri’s cognitive effects. During the initial research period, Panax ginseng GS15-4 gained popularity for a unique extraction method by its makers. They mimicked the metabolism of the ginsenosides contained within Panax ginseng, via fermentation and yielded the more potent ginsenoside metabolites. Contemplating GS15-4’s mimicry of natural processes, we wondered why we couldn’t replicate it ourselves.

Developing the Process:

Analyzing the bacoside metabolism, we devised a two-step process to emulate the natural breakdown. First, we hydrolyze the bacosides into their aglycone counterparts, jujubogenin and pseudojujubogenin. Then we apply a secondary acid hydrolysis step on the jujubogenin and pseudojujubogenin in order to yield ebelin lactone and the other bacognenins. A great idea, but easier said than done! Eventually we started working together with an Australian company that shared many of our values and had the capabilities to help us develop this two stage hydrolysis process. After many months, they made an initial pilot batch, packaged it up, and sent it to us.

Refining the Extract:

Once the pilot batch arrived, we immediately dosed 50 mg of the extract, and experienced effects that were somewhat similar to our Bacopa monnieir 24% bacosides extract, however the effects kicked in much quicker and there was an extra little sparkle there. Then we upped the dose to 100 mg and the effects got pretty interesting, however it was still similar to regular Bacopa monnieri and this is not exactly what we were after. After some analytical testing, we discovered that the second acid hydrolysis step wasn’t complete, which meant that we now had a mix of jujubogenin, pseudojujubogenin and ebelin lactone. They started a new batch with a much more complete secondary acid hydrolysis stage, and we waited patiently.

Success and Patenting:

A few months later, the second completely acid hydrolyzed extract was in our hands! Upon trying it, lots of beta-testers were not able to identify it as Bacopa monnieri. The sometimes overpowering calming effects of Bacopa monnieri vanished, and those of us with microdosing experience felt stark similarities. We were on to something now! After extensive analytical testing we found that we had now achieved our goal, a fully acid hydrolyzed Bacopa monnieri extract, with effects that drastically set it apart from traditional Bacopa monnieri extracts. We instantly experienced heightened focus, energy, and a greater sense of presence in the moment – precisely our goal!

Patenting and Release:

Now came the hard part, patenting the extraction and processing method that yielded this ebelin lactone rich Bacopa monnieri extract. It already took almost two years to get to the final beta-test sample, and we knew the patent could take almost as long too. We hunkered down, sat down with a bunch of lawyers, all chipped in and in Novemeber 2022, we were finally able to submit the patent and release the extract, which we called Cognance! This was the story of Cognance, truly Bacopa reimagined!

The Science Behind Cognance

Now that we’ve covered the story of cognance it is time to move onto the most exciting aspect of this novel extract, the effects and the science behind them! Strap in, because this is going to get very nerdy!

As we mentioned briefly in the story of cognance, the principle compounds within Bacopa monnieri, the bacosides, are not very bioavailable. Part of this is due to their sheer size! Take a look at the structure of bacoside A3 for example:

The Challenge of Molecular Size:

Visually, it’s huge! Molecularly, it is also quite heavy, clocking in at 929.10 g/mol. Big molecules tend to not absorb well which was made abundantly clear by Christopher A. Lipinski, a famous medicinal chemist. He stated that for a molecule to be absorbed, its molecular weight should be under 500 g/mol.

The Solution: Deglycosylation:

This means that bacoside A3, is almost two times over Lipinski’s limit! This is where things get interesting though, because we can “shave” some weight off. On the left hand side of the molecule, there are three similar looking chemical structures. These are sugar groups, and are not particularly important to the effects of bacoside A3. Removing these sugar groups significantly reduces the molecular weight of the compound. This process is referred to as deglycosylation (removal of sugar groups) which then yields an aglycone (a compound with sugar groups removed). This means that we can refer to bacoside A3 as a glycoside (a compound with a sugar group), and when we remove the sugar groups we end up with the following compound:

Aglycones: Unlocking Bioavailability:

This compound is called jujubogenin and can be considered to be an aglycone of bacoside A3. Now when re-evaluate the molecular weight of jujubogenin we find that 456.4 g/mol of sugar groups have been removed, which now means that jujubogenin clocks in at 472.7 g/mol, which is well below Lipinski’s limit of 500 g/mol! Indeed, we also see that the bioavailability now goes up considerably. Jujubogenin in contrast to bacoside A3, now shows good gastrointestinal absorption and blood brain barrier (BBB) penetration. This indicates that jujubogenin most certainly is very bioactive.

Metabolism and Effects:

Interestingly enough, the bacosides deglycosylate in the human gut after human consumption, to jujubogenin as we just discussed, but also pseudojujubogenin. After oral consumption of a Bacopa monnieri extract, a significant delay in effects occurs as the bacosides are converted to their active metabolites. We also had a sneaking suspicion that jujubogenin and pseudojujubogenin were responsible for the lethargy inducing effects of Bacopa monnieri. Part of this theory was based on research on jujubogenin indicating that it interacts with the GABA-A receptor. More specifically, two distinct subunits of the GABA-A receptor, alpha1 and alpha 5. Activation of both GABA subunit alpha 1 and alpha 5, can induce very strong relaxing effects. More interestingly we even discovered that jujubogenin could upregulate these GABA subunits over time, which corroborates with anecdotal reports that Bacopa monnieri can become progressively more lethargy inducing over time!

Testing the Theory:

We got an opportunity to put this theory to the test with our first pilot batch of cognance. A very complete deglycosylation reaction was carried out via hydrolysis for this batch. This yielded high concentrations of jujubogenin and pseudojujubogenin. However, the second acid hydrolysis step to turn jujubogenin into ebelin lactone (which normally also happens in the human gut) had not been very efficient in this first pilot batch and thus we had a more jujubogenin and pseudojujubogenin leaning extract. When we tried this extract out, we experienced very rapid and fairly strong relaxing effects which meshed well with the research we had read. After this experience, we knew we were on to something, and that if we were able to turn jujubogenin and pseujujubogenin into their bacogenin counterparts efficiently, then we could very well bypass the lethargy inducing effects!

This meant we had to better dial in the acid hydrolysis step. After some tweaking we finally got it to work! Our lab director drew up a fantastic graphic to show all of you chemistry nerds exactly what happened during this stage:

Once we got this second pilot batch in our hands, everything changed. The new focus-enhancing, creative energy replaced the lethargy-inducing effects that were previously present. This is mostly due to ebelin lactone, so let’s discuss in detail exactly what it is doing!

Ebelin Lactone: A 5-HT2A Positive Allosteric Modulator

Unique Pharmacodynamic Profile of Ebelin Lactone

Ebelin lactone is a very unique compound, with a pharmacodynamic profile that is not often found elsewhere. The most unique effect is that it acts as a positive allosteric modulator of the serotonin 5-HT2A receptor. What this means is that ebelin lactone binds to the allosteric site of the 5-HT2A receptor, which is distinctly different from the orthosteric binding site, which is where most serotonin 5-HT2A agonists or antagonists bind. When a compound binds to the orthosteric binding site of 5-HT2A receptors, it can either directly activate or deactivate the receptor. In contrast, when a compound binds to the allosteric binding site of the 5-HT2A receptor, it can either make the receptor more or less sensitive.

With a positive allosteric modulator, like ebelin lactone, the sensitivity of the 5-HT2A receptor is increased. This means that it will require lower concentrations of ligands to activate the 5-HT2A receptor. The most relevant ligand in this scenario is the main endogenous ligand of the 5-HT2A receptor, serotonin. This is because serotonin will always be present, thus, enhancing the sensitivity of the 5-HT2A receptor with ebelin lactone will produce more serotonin induced activation of the 5-HT2A receptor.

Advantages of Positive Allosteric Modulators

There are numerous benefits to utilizing a positive allosteric modulator over a direct agonist. The first of which is that allosteric binding sites from receptor to receptor are often very different, while the orthosteric binding sites of receptors often have lots of similarities from receptor to receptor. This means that allosteric ligands oftentimes are much more receptor selective. The second advantage of a positive allosteric modulator, is that the effects can be less pronounced but more sustainable. In addition to this, there seems to be a ceiling to how much positive allosteric modulation can occur. In the case of the 5-HT2A receptor for daily functional use, this is very beneficial.

Role of Increased 5-HT2A Activity

So, what does increased 5-HT2A activity provide? The 5-HT2A receptor is one of the most abundant serotonin receptors in the neocortex, especially in layer V of the cerebral cortex. These parts of the brain are absolutely crucial to cognitive function and sensory processing. Within these brain regions, 5-HT2A receptors have an excitatory effect, mostly through their effect on glutamate and dopamine release. With this in mind, it is clear to see why modulation of 5-HT2A receptors has become such a sought after concept.

When we directly activate 5-HT2A receptors to a high degree, we see very extreme effects, especially on sensory processing and cognitive flexibility. While this can certainly be useful in certain situations, such high intensity of 5-HT2A receptor activation is undesirable for functional daily use. Due to this, alternatives were sought out, and the concept of microdosing was discovered, which basically takes high level 5-HT2A activation and minimizes the activation to the bare minimum. When this is done, the sensory processing and cognitive flexibility enhancement becomes incredibly useful!

Ebelin Lactone: Mimicking Microdose 5-HT2A Effects

This is where ebelin lactone is very unique, since it produces this exact low level increase in 5-HT2A activity, thereby closely mimicking microdose 5-HT2A effects. Thus, after dosing ebelin lactone via cognance, we can expect an uptick in sensory processing, coupled with increases in cognitive flexibility. This can help enhance focus, and divergent thinking, a concept many of us know as “creativity”. Furthermore, after periods of more extensive dosing, the increased sensitivity of 5-HT2A receptors may also result in memory enhancing activity.

Ebelin Lactone: A Muscarinic Acetylcholine M1 Positive Allosteric Modulator

Effects on Muscarinic Acetylcholine M1 Receptor

Another very interesting aspect of ebelin lactone are its effects on the muscarinic acetylcholine M1 receptor. This receptor, similar to the 5-HT2A receptor, is absolutely crucial to cognitive function and memory. In fact, in many studies on cognitive function, a muscarinic M1 antagonist is often employed to simulate cognitive deficiencies. This muscarinic M1 antagonist is called scopolamine, and the study design is called a “scopolamine challenge”. When the muscarinic M1 receptor is blocked, major reductions in cognitive function and memory consolidation are observed. This is useful in study designs, because you can then try to overcome these reductions in cognitive function and memory consolidation with your target compound or plant extract. Ebelin lactone achieves the exact opposite effect however, and instead makes the muscarinic M1 receptor more sensitive rather than blocking it, once again acting as a positive allosteric modulator there.

Selectivity Challenges and Allosteric Modulation

One big issue with compounds that act on the muscarinic M1 receptor however, is that they are not very selective. This is problematic because the other muscarinic acetylcholine receptors can produce some very undesirable effects when activated, such as excessive sweating and salivation. It’s very hard to find selective muscarinic M1 agonists because the orthosteric binding sites between the different muscarinic acetylcholine receptors are all very similar. However, similar to the serotonin receptors, the allosteric sites on the muscarinic acetylcholine receptors are all fairly distinct from each other. Since ebelin lactone is acting as a positive allosteric modulator of the M1 receptor, this means that it can be fairly selective. Thus, providing powerful cognition enhancing effects without many if any downsides!

Distribution and Role in Brain Function

Similar to the 5-HT2A receptor, the muscarinic M1 receptor is also abundantly distributed throughout the neocortex, and also has an excitatory role here. While 5-HT2A has a more direct effect on sensory processing in these brain regions, muscarinic M1 has a more direct effect on memory consolidation. This means that when combined, the effects of positive allosteric modulation of both muscarinic M1 and serotonin 5-HT2A receptors, produces a very unique and comprehensive nootropic effect! We get the benefits of more cognitive flexibility and enhanced sensory processing, via 5-HT2A, while achieving higher levels of memory consolidation via muscarinic M1 receptors. Together this leads to a unique acute focus enhancing effect, and in the long run, this pharmacodynamic profile leads to enhanced cognitive performance and memory consolidation!

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