When To Take Supplements | A Look At Stomach Contents and Bioavailability

When we talk about absorption of supplements, we are talking about ‘pharmacokinetics’. The word pharmacokinetics refers to the study of how bioactive compounds move through the body. On the flip side, we have pharmacodynamics, which is the study of how bioactive compounds act on the body. To achieve the best possible pharmacodynamic profile, we first need to optimize the pharmacokinetics of a bioactive compound. Within pharmacokinetics we are looking at five core principles:

1. Liberation: How a supplement enters the body and releases its contents. Think for example of a capsule, it enters the body through the mouth and starts dissolving in the stomach. However, we can also modify this step by putting an enteric coating on a tablet, which delays absorption until the supplement reaches the intestines. Take for example our enteric coated Gotu Kola tablets which are designed to release in the intestines instead of in the stomach. Alternatively, we can also completely forego the stomach and intestines and design a supplement to release its content under the tongue (sublingually). We have utilized this method for a few of our solutions that are specifically designed for sublingual use.

2. Absorption: This step describes how a supplement absorbs into our bloodstream. For example, a capsule that releases its contents in the stomach, now has the opportunity to absorb through mucosal membranes in our stomach. However, there is also a chance that the supplement does not absorb in the stomach and instead can only absorb in the intestines. When this is the case, we run the risk of the supplement getting damaged in our stomach acid. If this is the case, then we can consider an enteric coating so that the supplement can pass through the stomach unscathed. We also run the risk of the supplement interacting with food in our stomach. This effect is called the ‘food matrix effect’ and we will discuss this in more depth later. If, instead, the supplement is liberated under our tongue, we can absorb the bioactive compounds into our bloodstream directly through the sublingual membrane under our tongue.

3. Distribution: This step describes what happens to a supplement when it has entered our blood stream. Take for example Curcumin, after we have absorbed it through our stomach and intestines, it needs to exert its beneficial effects in our muscles, joints and brain. How it gets there is determined by a host of different factors, such as passive diffusion through cell membranes or active transport through the use of transporters. In the case of plain Curcumin, it has a very hard time getting absorbed but we can find solutions to this issue. Once we do reach adequate absorption levels, it now becomes quite a challenge to get Curcumin to where it is needed most. For example, regular Curcumin has a very hard time reaching the brain. However, we can modify this by for example microencapsulating the Curcumin, as is the case with our Longvida product. The technology behind Longvida addresses both key absorption issues, but perhaps more importantly, helps get the Curcumin to where it is needed most!

4. Metabolism: As soon as a bioactive compound has successfully been absorbed, it starts to become metabolized by our bodies. One of the main ways our bodies metabolizes bioactive compounds is by attaching glucuronic acid to them. This process is called glucuronidation, and it often makes the target bioactive compound more water soluble. This increase in solubility helps our bodies break down compounds in addition to extracting them more easily from our bodies. Glucuronidation also often makes the target bioactive compound too large to attach itself to its target receptors. This causes an overall loss in effects. When supplements are particularly sensitive to glucuronidation, we can modify this process by combining the supplement with Piperine. For example, when plain Curcumin is absorbed, it is also quite rapidly glucuronidated. By combining Piperine with Curcumin, we can both enhance its absorption and slow down it’s metabolism. This allows us to experience a greater efficacy from our Curcumin supplement.

5. Excretion: Once a supplement has been absorbed, it also eventually needs to leave the body again. Our bodies employ a variety of methods to do this, and a lot of them depend on the previous step, metabolism. However, some bioactive compounds like Ginsenosides, can be prematurely excreted before they can exert any beneficial effects on our bodies. In the case of Ginsenosides, this excretion is primarily performed by p-glycoprotein (P-gp), which pumps Ginsenosides out of the cells where they exert their benefits. We can slow this process down by regulating the function of P-gp. In the case of Ginseng, we can achieve this by combining Ginseng with Schisandra, which is a P-gp regulator. We utilized this technique in our PanaMAX optimized ginseng formulation.

For most of the steps discussed above, we have taken it upon ourselves to optimize the pharmacokinetics of our supplements for you. Whether it is unique liberation methods like with enteric coated gotu kola, optimized absorption methods like with cyclodextrin ALA, optimized distribution methods like with Longvida, optimized metabolism methods like with Curcumin + Piperine or optimized excretion methods like with PanaMAX, we have got you covered! This also means you have very little to worry about in terms of supplementation efficacy. This is why we often suggest to just take your supplements whenever is most convenient for you. However, there are some exceptions to the rule and those occur during the absorption stage.

When we take a supplement on an empty stomach, we can often see an increase in absorption speed. Without anything in your stomach, a supplement can quickly liberate and dissolve into our stomach fluid. From there it can absorb through the mucosal membranes in the stomach, or it can travel to the intestines quite rapidly. This is for example why you may feel the effects of caffeine faster on an empty stomach. The speed of onset can convey the feeling of a stronger effect, so this can be a preferable way to take supplements that have an acute effect. In fact, some supplements may actually experience an overall increase in magnitude of effects when they are taken on an empty stomach. To understand this better we have to look at two important factors:

● tmax: This is the amount of time it takes for a bioactive compound to reach its maximum serum concentration, which is referred to as Cmax. For example, if you take caffeine on an empty stomach, the time to tmax will be much faster than when taken on a full stomach or alongside a meal.

● Cmax: This is the highest concentration a given bioactive compound is able to reach and is generally studied in specific body areas. For example (these examples are not based on real data), after taking caffeine on an empty stomach it reaches Cmax at 1 hour, however, when taken on a full stomach, caffeine reaches Cmax at 2 hours.

This is where things do get a little bit complicated, but also quite interesting! The longer it takes for caffeine to reach tmax, the more opportunity there is for metabolism to occur. This means that in certain scenarios, a longer tmax time correlates with a lower Cmax value. However, in this scenario overall bioavailability is oftentimes not affected at all.

In this graph, we actually see a very nice representation of tmax and Cmax too! Before we dive into this graph, let’s describe some of the other abbreviation being used:

● Minimum Effective Concentration (MEC): This refers to the amount of a bioactive compound that needs to be in our serum, for us to experience any effects.

● Maximum Tolerated Concentration (MTC): This refers to the maximum amount of a bioactive molecule that can exist in serum before we start to experience diminishing returns. For example, if we have too much caffeine in our serum, we may start to experience jitters.

● Area Under the Curve (AUC): This refers to the total amount of a bioactive compound that becomes absorbed and is generally considered to be synonymous with ‘bioavailability’.

When we take caffeine on an empty stomach, the peak (Cmax) may be much higher. However, we may then also see a much steeper decline in serum concentration. On the flip side, if tmax is longer, then the peak (Cmax) may be lower. At the same time however, due to caffeine reaching Cmax at a slower rate, and reaching an overall lower Cmax, the clearance rate may also be slowed down. This means that the overall Area Under the Curve (AUC) remains the same. Long story short, this means that whether you take caffeine on an empty stomach or on a full stomach the overall bioavailability may be the same. The factors that will differ are the onset time (how fast do we reach MEC), the overall intensity of effects (how high does Cmax get) and the overall duration of effects (how long before we fall under MEC again). These are all important considerations when determining how and when to take a supplement. However, this often just comes down to personal preference which is why we do not often give recommendations on when to take a supplement.

One factor that may influence this personal preference is wanting to reach a certain Cmax while making sure we stay underneath MTC. If we take 100 mg of caffeine on an empty stomach, we may shoot up to Cmax at a very fast rate. Perhaps so fast, that we briefly reach slightly above MTC. This may cause some undesirable effects such as a brief period of jitteriness and perhaps some GI upset. There are two ways we can modify this. We could take a smaller dose of caffeine, let's say 75 mg on an empty stomach, but that may not reach adequate effects levels for us. So another option would be to take 100 mg of caffeine alongside a meal. This will increase tmax, and slightly decrease Cmax, however the overall AUC may stay the same. In this scenario, we may be able to circumvent GI upset and jitteriness, leading to an overall smoother and more desirable experience. In general, individuals seem to prefer taking supplements that have acute effects alongside a small snack as it may help smooth things out a little bit. This is especially true, if you are taking a few different supplements all at once.

So, with this all in mind, let’s put together a little checklist:

In general, you will get the most of your supplements when you take them on an empty stomach. They will take effect faster and they will oftentimes reach higher serum concentrations. However, the overall bioavailability is generally not affected by taking it on a full or empty stomach. For example, a supplement that lacks significant acute effects and is taken on a daily basis, would be best suited to being taken alongside a meal. Our Immune Defense formulation is a supplement that does not have significant acute effects, and thus would be perfectly suited to be taken alongside a meal. On the flipside, you may want to consider taking our Sleep Support formula on an empty stomach as there is a clear advantage to having Sleep Support take effect faster and having it reach a higher serum concentration. By achieving a lower tmax and higher Cmax in this scenario, sleep support may be more effective at helping you fall asleep. That being said, if you take sleep support solely for the purposes of improving overall sleep quality, then it may actually be ever so slightly more advantageous to take it alongside a small snack.

Overall, it becomes quite clear that there are oftentimes no hard rules when it comes to taking supplements. We would suggest trying supplements out on both an empty and full stomach to see what you like best. Remember, we are not benefiting or hurting overall bioavailability much by taking supplements on an empty or full stomach, so it oftentimes really just comes down to personal preference.

As with almost anything in life, there are exceptions to the rule. Sometimes, supplements do indeed clearly benefit from being taken on an empty or full stomach. Oftentimes in this scenario supplements will experience a decrease in overall bioavailability when taken alongside food. This doesn’t happen very often, but when it does happen, it can be quite significant. Take for example elemental Magnesium. In its elemental form it has two open binding sites. When Magnesium is supplemented alongside a meal with leafy greens that are rich in phytates, you may see a significant reduction in Magnesium uptake. This is because phytates, such as phytic acid, are very good at binding to dietary minerals such as Magnesium. Once bound, the Magnesium can no longer be absorbed and thus we may see a significant reduction in Magnesium uptake. In this scenario, it would be in our best interest to take Magnesium on an empty stomach. However, an average dose of the most common Magnesium supplement; Magnesium Oxide, may cause some degree of GI upset when taken on an empty stomach.

Luckily, there are some fairly easy ways around the food matrix effect, even if you take a supplement alongside a meal. For example, you can occupy the two binding sites on the Magnesium molecule with absorption enhancers. This achieves two things, absorption is promoted and we can protect Magnesium from binding to phytates from food. This concept has resulted in the creation of Magnesium formulations such as our Magnesium Glycinate. Magnesium Glycinate has both of its binding sites occupied with Glycine. Glycine buffers intestinal pH, allowing for better absorption, but it also prevents Magnesium from binding to Phytic acid in the intestines. This means that Magnesium Glycinate can be taken alongside a meal as it is less susceptible to the food matrix effect.

Other supplements that may be susceptible to the food matrix effect are supplements such as Green Tea EGCG. We are working on a solution to this issue, but for the time being it would be best to take EGCG on an empty stomach. This again falls in line with our earlier recommendation, if you can handle it, try and take your supplements on an empty stomach as this may prevent food matrix effects.

There are very few instances in which taking a supplement alongside food will promote bioavailability, but the odd case does exist. For example, taking Creatine Monohydrate alongside a carbohydrate containing meal, may allow it to absorb better. Another example that exists is fish oil, where taking it alongside a fat containing meal may slightly promote bioavailability.

Overall, it appears that most supplements do not benefit much from being taken alongside food. However, as we mentioned earlier, taking a supplement alongside food can slow down absorption and peak serum concentrations whilst not affecting bioavailability much. This can prove beneficial if we find that we experience smoother benefits when a supplement absorbs slightly slower. In this scenario, we would recommend taking your supplements alongside food. Again, this will be quite dependent on personal preference and will require a little bit of personal experimentation.