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The Unique Synergies Of Caffeine

The Unique Synergies Of Caffeine

Posted by Nootropics Depot on 16th Mar 2023

Learn about what caffeine is, where it comes from, and how it works in combination with other plants and compounds!

Where Does Caffeine Come From?

Caffeine is a very fascinating compound, which plays an enormous role in human civilization. In fact, it is thought that caffeine is the most widely consumed psychoactive substance on the planet! From a quick espresso, to hours long tea ceremonies, almost every culture on earth integrates caffeinated plants into their daily lives. What’s especially interesting to note, is that these caffeinated plants seem quite different from each other. However, they actually have quite a lot in common!

Caffeine biosynthetic pathways developed in various species of flowering plants, most surprisingly in fact, various citrus species! Thus it is no surprise that the majority of caffeine-containing plants are in fact flowering plants. Coffee flowers are probably the last thing you think of when drinking a roasty cup of coffee, but the coffee tree does in fact display some beautiful flowers!

These flowering plants attract pollinators through scents and the nectar contained in the flowers. Recent research in fact found that when the scent of a citrus flower is combined with a very small amount of caffeine in the nectar, bees are more likely to remember the flower and return to it. Research has even indicated that small doses of caffeine actually have a cognition and productivity enhancing effect on bees! However, in higher concentrations, caffeine is a deterrent for bees, and other insects. Calibrated at just the right level though, and beneficial pollinators like bees can come back to get their fix of caffeinated nectar over and over, while pests are kept at bay by the deterrent effects of caffeine.

Where Does Caffeine Come From?

Caffeine is a very fascinating compound, which plays an enormous role in human civilization. In fact, it is thought that caffeine is the most widely consumed psychoactive substance on the planet! From a quick espresso, to hours long tea ceremonies, almost every culture on earth integrates caffeinated plants into their daily lives. What’s especially interesting to note, is that these caffeinated plants seem quite different from each other. However, they actually have quite a lot in common!

Caffeine biosynthetic pathways developed in various species of flowering plants, most surprisingly in fact, various citrus species! Thus it is no surprise that the majority of caffeine-containing plants are in fact flowering plants. Coffee flowers are probably the last thing you think of when drinking a roasty cup of coffee, but the coffee tree does in fact display some beautiful flowers!

These flowering plants attract pollinators through scents and the nectar contained in the flowers. Recent research in fact found that when the scent of a citrus flower is combined with a very small amount of caffeine in the nectar, bees are more likely to remember the flower and return to it. Research has even indicated that small doses of caffeine actually have a cognition and productivity enhancing effect on bees! However, in higher concentrations, caffeine is a deterrent for bees, and other insects. Calibrated at just the right level though, and beneficial pollinators like bees can come back to get their fix of caffeinated nectar over and over, while pests are kept at bay by the deterrent effects of caffeine.

What is Ashwagandha?

Ashwagandha is a herb that belongs to the night shade family of plants. The nightshade family of plants is a very interesting one and includes a lot of vegetables that make up large parts of many diets. Notable nightshade members are potatoes, tomatoes, chili peppers, goji berries and even tobacco! Another name for the nightshade family is Solanaceae. This is where Ashwagandha gets its Latin name from; Withania somnifera. Ashwagandha is a short perennial shrub, with a large root system that develops small deep orange fruits. The fruits resemble a small cherry and the leaves look frosty due to the many tiny hairs that are on them. This one of the reasons why Ashwagandha is also referred to as ‘winter cherry’. Traditionally, the Ashwagandha root is used, however new research has found high concentrations of key components in the leaves too. Various manufacturers have taken notice of this. One of the most notable being Natreon who produce a specialized extract of Ashwagandha called Sensoril. Sensoril is made from the leaves of Ashwagandha, giving it a unique chemical composition, which produces noticeable calming effects.

Clearly, caffeine serves a very important role for these flowering plants, and thus it is no surprise that caffeine is found in numerous different species of plants. However, humans aren’t buzzing around slurping down caffeinated nectar, so how did humans first come into contact with this energizing compound?

Figure 1. A flowering coffee tree


How Did Humans Discover Caffeine?

This is where things get tricky, and there are lots of different theories as to how humans first came into contact with caffeine. One common theory is that once humans discovered fire, and were able to heat up water, they started making water infusions of various leaves. This makes quite a lot of sense, a cup of tea is wonderful, but chewing on tea leaves is not a very pleasant experience. Additionally, caffeine is highly water soluble in the context of hot water. Caffeine is found in the leaves of lots of different plant species, which are found throughout the world. For example, Camelia sinensis (Asia), Ilex paraguariensis (South America), Ilex vomitoria (North America) and Coffea arabica (Middle East & Africa) leaves all contain caffeine and all seem to have a long established history of the leaves being used to brew infusions with.

More than likely however, the first uses of caffeine containing plants likely were spiritual/ceremonial. These beverages would have acquired tastes, and would not be nutritious while demanding quite a bit of effort to make. However, caffeine, especially in ancient times would have had mind blowing effects on the consumers of these mystical leaf infusions. This would especially be the case for leaves that are especially rich in caffeine, such as the Ilex species. In fact, Ilex vomitoria and Ilex cassine have historically been used ceremonially by various different Native American tribes, in a ceremonial beverage referred to as “black drink”.

Other caffeine containing plants certainly seem to have been utilized ceremonially too. Theobroma cacao for example comes to mind, having been a highly important botanical for the ancient Mayans. Tea and even coffee have traditionally also been used ritualistically. One thing that all of these caffeine containing plants however seem to have in common, is that more often than not, they are made into beverages using hot water to extract bioactive molecules, of which caffeine is one of the primary bioactives! Thus, there likely is something to the theory that our first encounters with caffeine were facilitated via the discovery of hot water!

Figure 2. The highly complex process of roasting coffee

Fire also, of course, led to the discovery of coffee which gets its characteristic flavors and properties, from fermentation, drying and most importantly, roasting processes. Coffee is much more complex and advanced than other caffeine preparations due to this, which in contrast mostly consists of picking leaves, drying them and infusing them in hot water. However, as civilization progressed, so did technological advancements in caffeinated products.

We oftentimes don’t take a moment to think about just how complex coffee is, but from growing, processing, drying, shipping, roasting and brewing coffee, there is a lot of complexity involved.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

High quality coffee needs to be grown at high altitudes, where it can be very difficult to pick the coffee, which for the highest quality coffee is solely done by hand. The coffee cherries then need to be sorted by density, and the seed needs to be liberated from the coffee cherry. The seeds are then fermented, and sometimes even washed, in order to remove the mucilage around the seeds. The seeds are then dried in the open air until their moisture content hits the perfect level.

Figure 3. Drying of honey processed coffee beans

Then the seeds have a coating of parchment on them, which needs to be removed. Now we have green coffee beans, which are shipped around the world to roasters. Roasters then take the processed coffee beans, and meticulously roast them, in a process where the coffee bean itself starts to function as a bioreactor that generates bioactive compounds. They then end up in the hands of homebrewers or professional baristas who need to precisely grind the beans to within exacting particle size standards. Then, grind sizes need to be dialed in, in order to make the perfect cup of coffee. Humans have certainly spent A LOT of time, money and effort into making that morning cup of coffee many of us drink.

Figure 4. Depiction of the worlds favorite stimulant being served in a delicious beverage form

Our obsession with coffee is vast, and has been the case for a long time. Thus, it is unsurprising that caffeine was first isolated from coffee beans, and in fact, this is where caffeine gets its name from. The actual isolation of caffeine is quite a fascinating story too, and resulted from the unlikely liaison of a poet and a chemist! Around the time when caffeine was isolated from coffee beans, coffee was a highly prized commodity, and not commonly drunk by the average person.

Thus, it was quite incredible that one of the most famous poets at the time, Johann Wolfgang von Goethe had quite the affinity for both coffee and science. After seeing a demonstration from a young chemist called Friedlieb Ferdinand Runge, where Runge dilated the pupils of a cat with atropine he had isolated, Goethe was so impressed that he handed Runge a bag of coffee beans. Goethe’s intention with this transaction would be for Runge to isolate the, at the time, unknown compound from it, which gave coffee its unique properties. After tinkering with it for a few months, Runge was successfully able to isolate caffeine, which he at the time called “Kaffebase”

Figure 5. The chemical structure of caffeine


Synergies Of Caffeine Within Caffeine Containing Plants

When Runge isolated caffeine from coffee beans, he only discovered part of why coffee is stimulating. Over the years, we have discovered that coffee contains a plethora of psychoactive compounds. For example, it contains other methylxanthines which are related to caffeine and have similar effects, such as theophylline and paraxanthine, albeit in very small quantities. More interestingly though, coffee beans contain beta-carbolines which block monoamine oxidase (MAO) enzymes, which can enhance the stimulant properties of caffeine. Coffee beans also contain the unique compound trigonelline, which appears to have significant mood promoting effects.

If we look at other caffeine-containing beverages, we also quickly discover that caffeine is oftentimes found in the presence of lots of different bioactive compounds. Take green tea for example, which contains caffeine in addition to small amounts of L-theanine, and catechins like EGCG and epicatechin. Yerba mate oftentimes contains a broad spectrum of methylxanthines in high concentrations such as theophylline and theobromine, in addition to of course caffeine itself. Yerba mate also contains a wide array of polyphenols and flavonoids, like rutin and quercetin, which can also modify the effects of caffeine. Theobroma cacao is also a very interesting example, it contains high amounts of theobromine in addition to caffeine, while also containing endocannabinoid compounds such as anandamide.

It’s quite clear then, that caffeine is never naturally consumed in total isolation, as it is always contained within plants that contain a wide array of other bioactive compounds which modulate the activity of caffeine. It was only until Runge isolated caffeine from coffee beans, that we really started to focus on caffeine in total isolation. This became especially prominent once pure caffeine was easily obtainable through total synthesis, which was first performed in 1895 by Hermann Emil Fischer. It of course took a long time before pure synthetic caffeine was commercialized, but once it was, it started to pop up everywhere! Synthetic caffeine is very cheap and abundant, so it’s easy to make pure caffeine products. However, subjectively, pure caffeine in total isolation feels quite lackluster when it is compared to traditional caffeine sources, such as coffee, yerba mate, or tea. Thus, it is no surprise that most commercial energy drinks (which usually utilize synthetic caffeine or pure isolated caffeine) often contain a plethora of other bioactive compounds such as taurine and B-vitamins.

Subjectively speaking I (Emiel, Nootropics Depots product specialist) have noticed huge differences in effects between pure isolated caffeine, and my favorite caffeine delivery systems, coffee and yerba mate. In fact, I’ve even noticed stark differences in effects between different cultivars of coffee, and even coffees from different origins. For example, coffee beans from Ethiopia tend to feel smoothly stimulating with a prominent mood brightening effect. On the flipside, coffee beans from Columbia tend to have a much zippier and focusing effect for me. I recently brought this up on a reddit thread, and discovered others had experienced these differences too. I’ve even noticed that the type of coffee extraction makes a big difference too. For example, a shot of espresso often feels more “full bodied”, stronger, motivating and mood boosting to me, whereas a simple filter coffee can oftentimes feel more cleanly stimulating and focusing. This is somewhat independent of caffeine content, because contrary to popular belief, espresso actually contains less caffeine than filter coffee! This was recently brilliantly demonstrated in this great video by James Hoffman:

This clearly demonstrates that caffeine appears to be highly modifiable by other compounds. For example, the high pressure of an espresso extraction may be extracting other non-caffeine bioactive compounds from ground coffee beans, such as the beta-carbolines, more efficiently than percolation. There is still a lot we have yet to discover on this front, but one thing is clear, caffeine makes a fantastic base compound for designing nootropic stacks around. So let’s jump outside of the plants caffeine is contained in, and let’s look at some novel caffeine based combinations we can make utilizing pure isolated caffeine!

Synergies Of Caffeine With Other Plants & Compounds

There are going to be a few distinct goals when making caffeine stacks, the two most prominent goals here will be to make the caffeine feel more potent, and/or to smooth out the effects. For example, the majority of energy drinks that are on the market often aim to achieve both goals. Let’s take a look at the formula for one of the most popular energy drinks, red bull:

●       Caffeine (80 mg)

●       Taurine (unknown amount)

●       Vitamin B3

●       Vitamin B5

●       Vitamin B6

●       Vitamin B12

This is a pretty simple formula, which includes a very modest dose of caffeine which is being smoothed out by the relaxing effects of taurine. The energizing effects are then slightly enhanced by the selection of B-vitamins, but overall, red bull will be a fairly smooth ride due to the low caffeine dose and addition of taurine. Our take on a similar type of beverage would be the following formulation:

Caffeine + NALT Solution

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Taurine Capsules

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Super B12 Solution

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Take the above components and mix it with sparkling water to create a sugar-free energy drink. The addition of NALT to caffeine in our solution ramps up the stimulating and mood boosting properties of caffeine without making the effects too edgy. The caffeine dose is very reasonable so it will provide a smooth energizing effect. These energizing effects are then smoothed out (but not dampened) by taurine, which has a mild relaxing effect on the body but not too much on the mind. In various research and development efforts we have conducted over the years, we find that taurine can shave off just the right amount of edginess from caffeine, without blunting the effects too much. The blood flow enhancing effects of taurine also stack very nicely with the effects of caffeine, especially in the case of physical activities.  Last but not least, a dose of our super B12 solution to give a more natural sense of energy. A lot of energy drinks will utilize this same basic type of formula. It oftentimes is just a simple three-component stack designed to produce a very distinct and recognizable effect, by using
the following building blocks:

1- Stimulant

Caffeine

2- Smoothing Agent

Taurine

3- Energizing B Vitamins

B6, B12, etc.

However, even though this basic formula is simple, the effects oftentimes are perceived as being much more full bodied and impactful when compared to just pure caffeine without any adjuncts. This demonstrates just how well caffeine takes to the addition of adjuncts, even if they are very simple.

Another very popular example of a simple caffeine stack that is aimed more at the singular goal of smoothing out the effects of caffeine finds its roots in green tea. Many green tea drinkers remark that the effects of green tea are smooth and gentle. This is oftentimes attributed to the presence of the amino acid L-theanine which can be found in small amounts in green tea. While this is certainly the case, the smooth effects of a cup of green tea however, are more than likely largely due to the very modest amount of caffeine it provides. Regardless of this, the fact is that caffeine and L-theanine do make a fantastic pair, and there is a lot of research on this combination. One of the most unique effects that L-theanine can have in conjunction with caffeine, is allowing individuals to enter a “flow state”, which is a state of calm stimulation. L-theanine certainly has more calming effects than taurine, so the classic stack of one part caffeine to two parts L-theanine can dampen the stimulation of caffeine too much for the average seasoned caffeine user. However, for individuals who are very sensitive to caffeine, the classic 100 mg caffeine to 200 mg L-theanine stack is perfect. Providing just the right amount of energy and focus, without becoming jittery and distracting. For more seasoned caffeine users though, we have found that flipping the ratio to 200 mg caffeine balanced with 100 mg of L-theanine to be the ideal combination. This helps deepen the focus of caffeine and allows you to channel it to where it is needed most.

Caffeine/L-theanine Capsules
100mg/200mg

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Caffeine/L-theanine Capsules
200mg/100mg

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Over the years, we also sought to perfect the caffeine + L-theanine stack in order to make it fit the bill more for those who like to sip on coffee throughout the day. A few things needed to be addressed here. In North America, coffee is oftentimes drunk fairly slowly over a long period of time. Thus, a capsule of caffeine + L-theanine is not going to mimic this prolonged sense of smooth stimulation that slowly drinking a cup of coffee can. Thus, we looked towards a very novel time release caffeine combination from ZÜMXR. We played around with a lot of different formulas and in the end decided on an upfront dose of instant release caffeine, stacked together with a delayed, and extended release caffeine formulation. The delayed release caffeine formulation releases all of its content after 2 hours to smoothly kick things into higher gear after your body has had some time to acclimatize to the initial dose of instant release caffeine. Then we added an extended release formulation of caffeine which slowly feeds more caffeine into your system over the course of about 8 hours. This keeps the effects feeling robust for a long time, while also mitigating the caffeine crash. However, we still felt the caffeine section could use some improvement, and frankly the effects didn’t kick in fast enough with the instant release caffeine. When you take a sip from a cup of coffee, you seemingly already start to feel perked up just by smelling the coffee. To mimic these quick effects, we added in a dose of dynamine methyliberine. This unique caffeine derivative kicks in extremely rapidly, and has the benefit of sensitizing us to the effects of caffeine. Now all of a sudden, we had a caffeine section that closely mimicked the effects of slowly sipping on a cup of coffee throughout the day! Adding in a dose of L-theanine really gelled the stack together, and made it ultra-smooth. We ended up calling this stack DynaMAX.

DynaMAX Capsules

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DynaMAX Capsules

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So far, we have been focusing on smoothing out the effects of caffeine, and keeping caffeine doses modest, but let's switch gears now! We thought DynaMAX was powerful, however, around the time we released it a lot of energy drinks started popping up that had 400+ mg of caffeine per serving. We also realized that the largest size coffee from places like starbucks could also contain caffeine in excess of the 300-400 mg mark. Thus, we designed DynaMAX +, our strongest caffeine focused stack to date. We upped the level of dynamine to give it a very punchy and quick start, while also helping to enhance the effects of caffeine. We then upped our caffeine dose to 270 mg, while dropping our L-theanine dose to just 100 mg. In most beta-testers, this resulted in a little bit of physical jitteriness but the mental effects were perfect. We then added in 100 mg of taurine, which helped smooth out the physical jitteriness without dampening the mental effects.

One thing we learned with DynaMAX+, is that enhancing the stimulating effects of caffeine, rather than continuing to increase the dose of caffeine, oftentimes is the best strategy. So let’s take a step back and look at coffee again. One of the reasons coffee oftentimes feels quite a bit more stimulating than other caffeine sources, is because it contains beta-carbolines. These beta-carbolines inhibit the monoamine oxidase enzymes (MAO). This is important because caffeine induces a release of monoamines like dopamine and norepinephrine. Thus, by blocking the enzymes which break down these monoamine neurotransmitters with beta-carbolines, we can potentiate the effects of caffeine. Within coffee this MAO inhibiting effect is fairly mild, but it still has a significant impact on the stimulant effects of caffeine. So, what happens if we lean into MAO inhibition a little further? To test this out, we combined Vignatex with a 100 mg dose of caffeine. Vignatex contains vitexin and isovitexin which act as MAO-B inhibitors. When combining a dose of caffeine with Vignatex, the effects are very coffee like but turned up to 11! Definitely practice caution around this combination, but if you really want to mimic the effects of a large cup of coffee but in a more convenient form factor, give the following stack a try:

Caffeine/NALT Capsules

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Vignatex Capsules

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Let’s take a look at another caffeine containing beverage, the original formula of which was quite controversial and no longer exists. You may have already guessed it, but it is coca-cola! Currently, this is quite a boring soda with some synthetic caffeine in it. However, back in the day, this was a fascinating botanical drink! The caffeine in the original coca-cola was derived from kola nuts which in my experience have a unique mood boosting effect. The kola-nut derived caffeine is then combined with a notorious plant which contains a dopamine reuptake inhibitor. Unfortunately, this plant must remain unnamed. This makes for a very unique effects profile! Similar to how the beta-carbolines in coffee help enhance the effects of caffeine, a dopamine reuptake inhibitor can too. Dopamine reuptake inhibitors function by blocking the reuptake of dopamine once it has been released from a neuron. This means that dopamine can stick around much longer, and thus increase overall dopaminergic tone. This comes in handy in the context of caffeine, since caffeine helps release dopamine. Thus, the combination of caffeine and a dopamine reuptake inhibitor produces a more full bodied, motivating and mood enhancing effect. To re-construct this old school coca-cola type effects profile we can look towards the following stack:

Caffeine/NALT Capsules

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Sabroxy Capsules

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As we discussed in our recent sabroxy podcast, sabroxy contains a unique flavone called Oroxylin A. Oroxylin A acts as a dopamine reuptake inhibitor and in our experience produces a very smooth stimulating effect when combined with caffeine. Not only is the dopamine reuptake inhibitor effect at play here though, oroxylin A also activates adenosine A2A receptors, which is one of the few adenosine receptors that caffeine blocks in order to produce its stimulant effects. However, blockade of adenosine A2A appears to produce some jittery effects, so filtering it out to some degree with sabroxy helps smooth out the effects of caffeine, while enhancing the dopaminergic effects of caffeine. Overall, this results in a very uplifting and motivating effects profile!

We’ll stop this blog here, because we could keep going on and on about various different combinations we can make with caffeine, and we don’t want this to turn into an E-Book! However, we hope this blog has provided you with some insight that will help you develop many different caffeine stacks. As has become abundantly clear throughout this blog, caffeine stacks well with just about anything and can thus be a very flexible part of many different nootropic stacks!

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*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

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