In 2015, Lexaria commissioned an independent, third-party laboratory to test our DehydraTECH technology under carefully monitored in vitro conditions. Specifically, we wanted to gain scientific evidence of two hypothesis. As it turned out, we learned that and more.
First, does our technological process yield an improvement in intestinal absorption? The answer was YES. Second, does our lipid formulation yield an improvement in intestinal absorption? The answer was also YES. In addition, we also learned that our DehyrdaTECH-enabled infused tea was absorbed at higher levels in the presence of “gastric juices” than in a more sterile environment without any “gastric juices”, suggesting though certainly not proving that our DehydraTECH technology may be effective in an actual gastrointestinal system rather than just in a simplified in vitro simulation.
Below, we explore why bioavailability is such an important consideration, and how it affects more than one might at first imagine. There are a number of important considerations to contemplate before making changes to one’s diet or consumption habits, but one vital fact outweighs all the others: the vast majority of many substances that are orally consumed without technology such as ours ends up being excreted as waste by the body without meaningful absorption and bioavailability.
Lexaria Bioscience Corp. has since 2015 conducted a number of studies in vitro, in vivo, and in human clinical environments and has done so chiefly with nicotine or with cannabinoids as the active pharmaceutical ingredient (“API”) under study. Over time we became interested in other molecules such as human hormones, antiviral drugs, and more. There are certain similarities between these fat soluble, molecules that have led Lexaria down its investigatory pathways.
A key part of the 2015 in vitro study evaluated how APIs are ingested and absorbed, assessing different delivery mechanisms, recent technological advances in bioabsorption, and how those advances offer users an alternative to smoking. In undertaking this study, it was important to understand what bioavailability is and how it differs from absorption. They are related and similar, but different. Absorption is just one component of bioavailability. To truly understand bioavailability, we have to speak briefly about how the human body digests food. The object of digestion is to transform large food particles into smaller molecules, which can more easily be absorbed into one’s water-soluble blood plasma. That is how humans get nutrients and energy.
Very little digestion actually occurs in the stomach, which is designed, in part, to kill pathogens and foreign substances that should not be ingested. In fact, roughly 95% of all digestion and absorption happens in the small intestine. Digestive enzymes intermingle with food during the roughly 2-hour journey to arrive at the small intestine, breaking down the food and preparing it for absorption. Unfortunately, hydrochloric acid in the stomach is also quite capable of destroying many nutritious, fragile molecules before they can ever be absorbed.
There are dozens of different potential active pharmaceutical ingredient (“API”) molecules under consideration for DehydraTECH processing. Many APIs do not tolerate acidic environments. Studies have shown poor recoveries, or even 0% recoveries in acidic environments (Source: Detection and Quantification Of 17 Synthetic Cannabinoids And One Metabolite (JWH-018- COOH) In Blood And Urine, J Sobhani Sefy).
The mouth and throat are a roughly neutral environment, with a pH of roughly 6.8. Stomach pH can be anywhere in the 1.0 – 3.0 range, which is highly acidic. In contrast, the small intestine has a highly alkaline environment conducive to molecular absorption, with a pH of about 8.5. Normal water is neutral or slightly alkaline and has a pH of 6.2 – 7.0. For scale, a pH of 8.0 is ten times more alkaline than a pH of 7.0; and a pH of 3.0 is 10,000 times more acidic than a pH of 7.0.
For these and other reasons, digestion, absorption, and bioavailability of many APIs in their unprocessed form is very low. The molecules often do not survive their passage through the stomach undamaged and are not free to be absorbed in the alkaline environment of the small intestine.
Finally, the liver has a major role to play in that it regulates what molecules are allowed to reach the general circulation after ingestion, absorption through the small intestine, and finally passage through the liver’s filtration and processing systems. It often “wraps up” what it identifies as dangerous molecules in water-soluble chemicals that are identified for ejection through urine.
Bioavailability from both vaping and sublingual drops will generally be in the 14% – 40% range which is quite high but also associated with certain negative health impacts. Edible ingestion of API’s often drops to the 5%-6% range which is quite low, but with far fewer negative health impacts. Absorption of nicotine through smoking (burning is an oxidizing process) is relatively high because the molecules are not required to pass through the hostile stomach environment, and instead are absorbed into the bloodstream through the lungs – known as pulmonary absorption. Although smoking is a relatively efficient and quick acting process, it is also a well-known health hazard. Of the one billion people around the world who smoke, over six million people currently die each year from diseases caused directly by smoking. More on that below.
This is a good place to summarize what we know so far:
The goals of higher bioavailability of nicotine are thus threefold: to mollify objections to its smoking from non-smokers, to reduce unhealthy hazards of smoking, and to more efficiently and effectively deliver a higher proportion of useful molecules comprised from lower overall dosages that place less of a load on the liver. The challenges associated with efficient delivery of nicotine and the reduced harm to be experienced both by consumers and society through overcoming those challenges are now well understood.
Lexaria has focused on discovering new technologies that can more efficiently deliver molecular APIs to the bloodstream where they can have their desired effect. To this end, our lab and human experiments have greatly expanded our understanding of the most efficient ways to deliver APIs through ingestion.
In order to succeed in delivering a higher percentage of ingested cannabinoids into the human bloodstream, we needed to figure out how to protect the API molecule on its journey through the gastrointestinal system and into the bloodstream.
It is well known that ingesting fats (the terms “fats” and “lipids” can often, though not always, be used synonymously), while simultaneously ingesting other focused-upon substances can often lead to higher absorption levels of those key substances. “The US FDA recommended high-fat meals for food-effect studies because such fatty meals (800–1000 cal, 50%–65% fat, 25%–30% carbohydrates and 15%–20% proteins) affect GI physiology and maximize drug transfer into the systemic circulation.” (Food and Drug Administration, Guidance for industry: food-effect bioavailability and fed bioequivalence studies, food and drug administration).
The reasons for this increased absorption have, in part, been previously discussed. Fats are emulsified by gallbladder secretions, breaking them down into more easily absorbed particles in the small intestine. And some types of fats take a different path into the human bloodstream than most other nutrients – they bypass the hepatic portal vein that otherwise goes straight from the intestine to the liver for filtering before nutrients are generally allowed to reach the majority of the body. Instead, the body re-assembles certain fats and shuttles them to the lymphatic circulatory systems where they enter the general bloodstream without passage through the liver. Many so called long chain fatty acid compounds, therefore bypass the portal vein “freeway” to the liver, whereas smaller fatty acids that are more water soluble do indeed go to the liver first.
As well, in order to prepare the API for higher bioavailability, the API molecules can be manipulated in certain ways to connect them at a molecular level with various foods. Lexaria’s DehydraTECH technology “shuttles” the API molecules “within” other food molecules, even unrelated to lipids. Then lipids, such the long chain fatty acids found in sunflower oil, can be added due to their well-known beneficial properties within the human GI system.
In the summer of 2015, the US laboratory we commissioned performed some of the first tests ever known to be conducted on long chain fatty acid processed with certain APIs that measured absorption into human intestinal cells. The results were astonishing. Utilizing a mixture of API, black tea and select lipids, processed using our patented dehydration synthesis technological method, the final result showed intestinal tissue API permeability 325% higher than API similarly processed with black tea and water but lacking our lipid incorporation. And when that same mixture of API, black tea and select lipids, processed with our DehydraTECH™ method was compared to the absorption of API suspended in water alone without any benefits of lipid incorporation and our processing techniques, the absorption levels into the human intestinal cells rose to a 499% improvement via our methodology.
This early scientific research adds to our cumulative understanding that APIs can indeed be ingested with bioabsorption levels that approach or perhaps even surpass those achieved from smoking. However much remained to be learned. For example, we did not know what ratio of API might be delivered to the liver for filtration via the portal vein as compared to delivery straight to the lymphatic and circulatory systems for higher bioavailability. And, additional laboratory testing with different individual lipids will have to be undertaken to determine which might perform best.
During 2018 Lexaria performed two separate animal studies that evaluated DehydraTECH and its ability to improve the deliver of nicotine into both blood plasma and brain tissue in rats. The studies were an overwhelming success that included certain results that were so significant, they have led to additional new patent filings by Lexaria Bioscience Corp.
In the study reported in Spring 2018, a small rat population of 12 animals was used. Blood was analysed at eight time-intervals. Highlights from that study include:
At the dosing level of 10mg/Kg of nicotine polacrilix, the control formulation required nearly 3 hours to reach similar levels of blood absorption that the Lexaria formulation reached in only 15 minutes. The more rapid delivery and higher overall delivery level of the DehydraTECH-enabled formulation strongly evidenced the efficacy of DehydraTECH technology. Because the animal population was small, it was desirable to attempt to replicate the study results in a larger population.
In the second study reported in Summer of 2018, a rat population of 40 animals was used. Blood was analysed at nine time periods. Highlights from this study included:
The results were notable for several reasons. First, the population of test animals was considered large enough to generate statistically significant results. Second, the results corroborated those of the smaller initial study: even though the specific data generated differed, the data trend was similar. Third, much finer-grained and earlier blood data collection points illustrated for the first time ever, the ability to deliver nicotine to the blood in as little as 2 or 4 minutes.
The fact that DehydraTECH is able to deliver nicotine to the blood in only minutes; and an average of 70% over the critical first 15 minutes, is a good indication of the ability of this powerful technology to actually meet the rapid delivery needs of consumers.
In this second-generation study, confirmatory data was also generated regarding the ability of DehydraTECH technology to influence blood-brain-barrier penetration.
The FDA has repeatedly made mention of its desire to down-regulate the amount of nicotine available in cigarettes and, more recently, in vape devices. Lexaria’s technology utilized in a food, beverage, or capsule, could conceivably deliver lower levels of nicotine that still satisfy the cravings of the consumer, but do so at more acceptable overall dosing levels.
In 2019, Altria Ventures Inc invested sufficient funds into Lexaria Nicotine Corp to support an extensive R&D program designed to evaluate one of Lexaria’s same 2018 nicotine formulations that was used in the animal studies referenced above. The Altria-funded program successfully concluded in 2020 and Lexaria was pleased to report summary conclusions.
The 2019 research and development program was initiated to evaluate reduced health risks relative to combusted tobacco of a preliminary DehydraTECHTM oral nicotine formulation that Lexaria had previously announced findings with in 2018. The following main findings were determined about the early-stage DehydraTECHTM formulation:
The 2019/20 nicotine research delivered a wealth of valuable data to Lexaria and has served to expand our knowledge of how DehydraTECH interacts with and improves delivery characteristics of oral, non-combusted nicotine. This indirectly supported Lexaria’s ongoing internal formulation experimentation with the result that, as of the Fall of 2020, we are currently investigating more advanced oral nicotine formulations that we believe offer even greater superiority to earlier attempts.
The benefits are obvious: a person requiring 10mg of a substance in order to achieve a desired outcome would have to consume 200mg of that substance if the bioavailability is only 5%. But raise the bioavailability rate to 30%, and the necessary consumption level drops to just 33mg. This is a massive reduction in intake with a lower risk of over-dosage and leads to a potentially lighter workload on the liver accompanied by certain reductions in waste and consumer cost.
Until recently, smoking was the most effective way to ingest nicotine, provided one was willing to overlook the unhealthy side effects and the social stigma. This creates a deadly paradox: “nicotine is pleasurable, but smoking is killing me”.
Smoking is an increasingly unacceptable activity in large segments of society. The toll from disease caused by smoking is unarguable. There is a large segment of society which reasonably argues that the act of smoking impacts non-smokers. The moment a smoker impacts a non-smoker, either through odor or second-hand smoke, smoking is no longer a personal decision, even though it may deliver a pleasurable user experience.
Now, because our understanding of bioavailability has increased, and with the new and exciting advances in technology, it is possible to deliver comparable bioavailability to that of smoking, but without the negative side effects. It is actually possible that one day, using disruptive, absorption enhancing technologies like DehydraTECH, oral products will reasonably be able to replace smoking as the most effective delivery mechanism for nicotine, while also providing a powerful new way to deliver a host of other beneficial molecules more efficiently and effectively like pain relievers, vitamins, supplements and more.
Following earlier work, a series of independent, well designed, well controlled human focus studies were undertaken corroborating Lexaria’s in vitro performance findings. A study in healthy volunteers (n=6) suggested as much as a 5-10X increase in CBD absorption, which was assessed indirectly through measurement of the increase in salivary nitric oxide as a directly proportional surrogate biomarker, with onset of action in as little as 15-30 minutes. In all cases, the maximum increased level of salivary nitric oxide remained evident at the 60-minute end period of this particular test. Further testing is required to determine the full duration of elevated nitric oxide levels.
Thereafter, a blinded human focus study was conducted to evaluate the performance of chocolates formulated with psychotropic cannabinoids using Lexaria’s DehydraTECH™ technology. This study compared the performance of the chocolates powered by Lexaria’s technology to concentration matched chocolates formulated using a commercial dextrin absorption enhancer. The subjects (n=12) that participated in this study indicated a clear preference on taste and overall effectiveness with the chocolates formulated using Lexaria’s technology, and onset of effectiveness was again observed very quickly, in as little as 15-20 minutes.
Lexaria’s DehydraTECH™ -Powered TurboCBD™ vs. Control
The degree and speed of CBD absorption into blood plasma was tested in a randomized, placebo-controlled, double-blind clinical study in 12 healthy human volunteers comparing a 90 mg CBD dose of a Lexaria-developed capsule formulation (i.e., TurboCBD™) powered by its patented DehydraTECH™ absorption and palatability enhancing technology to a concentration-matched control formulation without DehydraTECH™ incorporation.
Key study highlights were as follows:
Results from this study were compared to the findings from a Mount Sinai study* previously conducted with orally administered CBD furnished by market leader GW Pharmaceuticals LLC (maker of FDA-approved Epidiolex), suggesting that Lexaria’s DehydraTECH™ delivered over 900% more CBD to the blood in the first 30 min than the GW formulation on a concentration-adjusted basis.
Key bioavailability data highlights from the study comparing the 90 mg dose of Lexaria’s TurboCBD™ to a 90 mg dose of a positive control formulation without Lexaria’s DehydraTECH™ technology were as follows:
These results corroborate and confirm earlier in vitro and in vivo studies that have evaluated Lexaria’s DehydraTECHTM technology and have consistently measured higher levels of drug delivery much more quickly than positive controls with matching CBD concentrations. Although this study evaluated absorption only of CBD and its metabolites, Lexaria believes nearly identical bioavailability enhancement results would be achieved if other cannabinoids had instead been studied
These study findings were of particular interest relative to a Mount Sinai study previously completed that tested orally administered CBD supplied by market leader GW Pharmaceuticals PLC at much higher doses of 400 mg and 800 mg [*J. Addict. Med. 2015 May-Jun; 9(3): 204-210]. CBD delivered in the Mount Sinai study achieved peak blood levels of 181 ng/mL and 221ng/mL respectively at their 400 mg and 800 mg doses tested, respectively. These values equate to blood levels of 40.77 ng/mL and 24.87 ng/mL, respectively, when adjusted for concentration to match Lexaria’s 90 mg dosage findings described above.
As such, the Mount Sinai results, although potentially influenced by concomitant opioid administration within that study, were substantially lower than the 56.0 ng/mL peak blood level achieved with Lexaria’s TurboCBD™ capsules, and it is further interesting to note that the peak blood levels in the Mount Sinai study required three hours to achieve whereas the Lexaria formulation met and eclipsed these levels when adjusted for dose concentration within only the first 60 minutes of the Lexaria study as noted above. It is also particularly interesting to note the rapidity by which Lexaria’s TurboCBDTM capsules at the 90 mg dose achieved concentration-adjusted blood levels that outperformed those from the Mount Sinai study: at the 30-minute time interval, we estimate the TurboCBDTM concentration-adjusted CBD blood level to have been over 900% higher than the levels achieved in the Mount Sinai study.
Lexaria was also pleased that, as expected, blood levels of THC, 11-OH-THC, and THCCOOH were non-detectable, highlighting the absence of THC and the extraordinary CBD purity within the TurboCBDTM capsules.
Few companies around the world have advanced to the state of achieving successful appropriately controlled (i.e., randomized, placebo-controlled and double-blinded) human clinical trial results utilizing cannabinoids. Increasing regulatory scrutiny of CBD by agencies such as the US Food and Drug Administration could result in the necessity of clinical evidence in the future to enable commerce in products containing CBD.