The entourage effect; it has been discussed here before, but can you leverage this phenomenon to enhance your experience of cannabis?
Well, the answer is not so cut and dry. The observable phenomenon known as the “entourage effect” should be a focus for future research into cannabis and its biological consequences in the human body. However, as it stands today, the entourage effect is still a hypothesis not a theory.
Granted, the reasoning behind the entourage effect may be persuasive, but it is not, as of yet, a substantiated theory.
What is the Entourage Effect?
The entourage effect is a hypothesis that seeks to explain why the therapeutic effects of cannabis seem to be greater when the plant is ingested holistically rather than when ingested as an isolate or extract.
This is to say that when dry or fresh cannabis is used, either smoked or vaped, its therapeutic potential in the human body appears to be greater than singular cannabinoid extracts such as THC, CBD, or CBG.
The proposed explanation for the observable phenomenon is that when the plant is ingested holistically, the effects of cannabinoids are modulated by the presence of the terpenoid compounds also in the plant.
When cannabinoids are isolated and ingested in the form of extracts or isolates, the concentration of terpenoids is reduced or removed, thereby lowering the therapeutic potential of the extract compared to the ingestion of the unadulterated plant.
The exact mechanism through which terpenoids modulate the metabolization of cannabinoids in the human body is not fully understood. So, while it is certainly a persuasive explanation, the entourage effect hypothesis is not settled science.
However, this does not mean that we cannot speculate as to how this phenomenon, should it prove to be true, can be leveraged to enhance our experience of cannabis.
TokeSmart: The Natural Way to a Better High
One company that is seeking to leverage the entourage effect to enhance a user’s experience of cannabis is TokeSmart.
TokeSmart is a supplement company that boasts a “natural supplement specifically formulated to reduce tolerance in medical marijuana users.”
The Marijuana Facts reached out to TokeSmart through twitter, as we were intrigued by the ideation behind the product, and because the company seems to be marketing the product with the aim of making the ingestion of cannabis more economical.
We offered to post a review of TokeSmart, and their representatives agreed. Our motivations for the review are strictly to be informative. We feel that reviewing products, like TokeSmart, is a great way to engage consumers who are actively searching for marijuana online, and hopefully, educate them about cannabis along their path to purchase.
The Marijuana Facts does not endorse TokeSmart, nor do we recommend using the product. That being said, we have conducted a thorough review of their product and hope you will take the time to read it.
What is TokeSmart?
As stated previously, we found the ideation behind TokeSmart intriguing. After conferring with company representatives, we came to understand that TokeSmart is an ingestible capsule comprised primarily of dried thyme and lemongrass.
On the bottle, this is referred to as the TokeSmart Formula. Other ingredients include rice flour, silicon dioxide, magnesium stearate and vegetable cellulose – which according to company representatives are “flowing agents” used by the manufacturer to get the dry material into the ingestible capsules and are only present in trace amounts.
There are 60 capsules in the bottle we were given, and each capsule contains a combined total of 1 gram of thyme and lemongrass.
The recommended dosing is 2 capsules to be taken 15 minutes before using cannabis.
How Does TokeSmart Work?
This question is more complex than it appears to be. As discussed, the entourage effect is a hypothesis seeking to explain the observable phenomenon that the therapeutic effects of marijuana appear to be greater when the plant is ingested holistically.
The connection between TokeSmart and cannabis hinges on this hypothesis. Thyme and lemongrass share a common terpene with cannabis called myrcene. The ideation behind the TokeSmart product is that by pre-dosing with thyme and lemongrass, the concentration of the terpene myrcene in your body will be higher, thereby potentiating the therapeutic effect of your cannabis.
This rationale is suspect, insofar as the entourage effect is not, as of yet, settled science. This means that in order for TokeSmart to do what it claims to do, in the way it says it does, the entourage effect would need to be a substantiated theory.
Seeing as the entourage effect is only a hypothesis, then using it as a basis to explain how TokeSmart works would also be a hypothesis. This is not to say that the product doesn’t work, rather that the explanation for how it works is a conditional statement. In other words, it is only true if it is derived from a true premise – in this case the premise is the entourage effect.
That being said, The Marijuana Facts reached out to the TokeSmart representatives and asked for clarification on this point. We postulated four ways that TokeSmart could work to enhance a user’s experience of marijuana, they were as follows:
- Increasing the bioavailability of ingested cannabinoids, and consequently the efficiency of the dose.
- Increasing the affinity endocannabinoid receptors have for cannabinoids.
- Decreasing a user’s metabolic resistance to cannabinoids.
- Up-regulating endocannabinoid receptors – the number of binding sites for cannabinoids.
For your edification, the following is a brief overview of each mechanism of action we proposed.
The bioavailability of a drug is the amount of the drug available for absorption after it has been ingested. This is relevant insofar as the first-pass effect (drugs enzymatically metabolized in the liver) decreases the bioavailability of a drug to be absorbed by receptors.
Intravenous drugs have 100% bioavailability because systemic circulation can be achieved directly. Other routes of administration, such as drops, pills, etc., pass through the liver which results in lower concentrations of the drug in the bloodstream for receptors to absorb.
In the context of Tokesmart, increased bioavailability would only have been relevant for cannabis or extracts ingested through means other than smoking or vaping.
Moreover, the TokeSmart Formula would have needed to inhibit the enzymes responsible for the breakdown of cannabinoids, or by acting as a protectant to cannabinoids as they pass through the digestive tract and liver, thereby increasing the amount available for absorption.
This explanation was also not compelling due to the fact that cannabis, more specifically THC, increases in potency in its metabolite form, 11-Hydroxy-THC. It is one of the few compounds that increases in potency when enzymatically broken-down in the liver.
The affinity of a receptor can be described, generally, as the attractive forces between two like structures, and the tendency of those structures to form bonds. This binding rate is critical for the absorption, and efficacy, of certain drugs.
In the context of TokeSmart, it isn’t clear how the terpene Myrcene would increase affinity endocannabinoid receptors have for cannabinoids.
The term metabolic resistance, when used in the context of drug efficacy, can be described as a user’s tolerance of a drug. When a drug is ingested, it affects a number of physiological processes, and our bodies work hard to maintain homeostasis.
In order to maintain homeostasis, our liver enzymatically breaks down a drug before it reaches systemic circulation. This is an attempt to mitigate the degree to which a drug affects physiological processes.
Over time our ability to enzymatically break down a drug improves, which increases our metabolic resistance to that drug. This is why some drugs require larger doses the longer you take them – to compensate for increased tolerance.
In the context of TokeSmart, metabolic resistance could have been applicable in two ways. The first of which is that when ingested through means other than smoking or vaping, it could inhibit our liver’s ability to enzymatically break down cannabis or extracts thereby increasing the amount that reaches systemic circulation. The second of which is that it could prevent the down-regulation of endocannabinoid receptors brought on by their repeated, and long-term exposure to cannabis or extracts.
You may be wondering, isn’t decreasing metabolic resistance in the liver, and increasing the bioavailability of cannabinoids ingested through means other than smoking or vaping, the same thing? The answer is no, but the result is the same.
It depends what the TokeSmart Formula acts upon – the extract or isolate, or liver enzymes. Whether it inhibits the enzyme responsible for breaking down cannabis or preserves the integrity of the isolate or extract through the liver, has the same consequence – higher concentration in systemic circulation.
As stated previously, the enzymatic break-down of cannabis, particularly THC, actually produces a more potent metabolite called 11-Hydroxy- THC. For this reason, a decreased metabolic resistance in the liver would not be a compelling explanation for how TokeSmart works.
In contrast, the possibility that the TokeSmart Formula, particularly the terpene Myrcene, could prevent the down-regulation of endocannabinoid receptors brought on by their repeated, and long-term exposure to cannabis or extracts, is a more compelling explanation, albeit an unlikely one. To determine whether the TokeSmart Formula works via this mechanism entails extensive in vitro and in vivo studies, and chemical assays in a lab.
Up-Regulation of Receptors
The term up-regulation refers to increasing the number of receptors on a cell for a particular molecule. This can be achieved with an external stimulus like a drug. A cell can have a number of sites for a molecule to bind to, and increasing the relevant cellular component elevates the cell’s sensitivity to a molecule or drug.
In the context of TokeSmart, an up-regulation of binding sites would mean that Myrcene temporarily elevates the sensitivity endocannabinoid receptors have for cannabinoids. Similar to what was said previously regarding the down-regulation of receptors, to determine whether the TokeSmart Formula works via this mechanism entails extensive in vitro and in vivo studies, and chemical assays in a lab.
The basic idea behind up-regulation and down-regulation is that cells receive signals (from hormones or neurotransmitters), and depending on the strength of the signal, can either increase or decrease the number of binding sites on the cell. This can positively or negatively impact a cell’s sensitivity to a molecule such as a cannabinoid. In order for TokeSmart to work via this mechanism, it would need to modulate how these signals are sent.
We cannot say definitively whether TokeSmart works via this mechanism, but we are skeptical to the idea that dried thyme and lemongrass could elicit such effects.
It is important however, to discuss the association between affinity and up-regulation. The term affinity, as stated previously, refers to the attraction between two like structures – in this case ingested phytogenic cannabinoids and endocannabinoid receptors. There are two features of affinity worth mentioning, they are the tendency of molecules and receptors to bind to one another, as well as the strength of the chemical bond itself.
When we use the term up-regulation, it refers to an increase in the number of binding sites on a cell. This of course increases the tendency that molecules will bind with receptors, but this is not the same as saying that the affinity a receptor has for a molecule has increased. In order for this to happen, the molecule (cannabinoid) would need to be modified directly in order to approximate the receptor site more closely. This is reflected in the type of chemical bond that is formed.
The likelihood that TokeSmart, more specifically its active ingredient Myrcene, acts upon the cannabinoid directly is unlikely. We could not find evidence that would support the claim that the terpene Myrcene could alter the molecular structure of a phytogenic cannabinoid.
According to the TokeSmart representatives, the formula somewhat increases endocannabinoid receptor affinity for cannabinoids as well as somewhat decreases a user’s metabolic resistance to cannabinoids. These two effects exacerbate one another to provide a user with an enhanced experience of cannabis. However, they were quick to point out that they are not certain how exactly their formula achieves these results. Further research is required to make definitive statements.
It is our position that whether TokeSmart increases endocannabinoid receptor affinity for cannabinoids or decreases a user’s metabolic resistance to cannabinoids, or both, cannot be understood at this time. The state of research just isn’t at a point where it is possible to address these questions.
Although, it is our opinion that the mechanism of action by which TokeSmart enhances a user’s experience of cannabis is more likely due to an increase in the permeability of cell membranes – particularly the permeability of the endothelial cells in the capillaries that form the blood brain barrier.
The endothelial cells only allow small molecules, fat-soluble molecules, and some gasses, to pass into the brain. It has been suggested that myrcene increases the permeability of these cells thereby shuttling more cannabinoids to the brain tissue. This coupled with the fact that myrcene, in and of itself, elicits strong analgesic effects in high doses, could account for the enhanced experience of cannabis when pre-dosing with TokeSmart.
However, there is a lack of hard data on the effect myrcene has on the permeability of endothelial cells in the capillaries forming the blood brain barrier. So, no matter how compelling we feel our hypothesis is, it should not be taken as fact.
Regardless of which explanation for how TokeSmart works seems most plausible to you, a fair test of its efficacy is to try it yourself.
Our Experience Using TokeSmart
Did it work?
Answering this question proved difficult, in that it was hard to distinguish any perceivable difference in our use, or experience, of cannabis with or without TokeSmart.
In order to communicate whether TokeSmart enhanced our experience of cannabis, we needed a baseline or control group to compare against. Moreover, we would have needed to control the mode of ingestion, the size and titration of the dose over a fixed period of time, as well as have a sample group sizeable enough to draw accurate conclusions about the product.
The other issue was maintaining objectivity insofar as our evaluation of the product is subjective, experiential, and anecdotal – and our evaluations were made while “high” on cannabis. Consequently, it was rather difficult for us to retroactively determine whether TokeSmart had any perceivable effect.
We also struggled with trying to evaluate our experience of the product because we couldn’t agree on the parameters that would characterize someone as a habitual or regular user – a metric that we felt would be significant for testing efficacy.
Given these challenges, we could not make a determination as to whether TokeSmart had a perceivable effect on our experience of cannabis. It is important to recognize that this is neither an affirmation or refutation of whether the product works.
We are aware that this does not qualify as a product endorsement or testimonial, but it was never intended to be.
Our intention was not to galvanize you to try this product, rather to provide you with enough information to decide for yourself.
As for why we chose to try the product, even though we had reservations about the credibility our evaluations would hold, is that we felt we had a responsibility to give the fairest assessment possible – even if our assessment was not substantive.
Thanks for Reading!