Thank you panacea for the link, and thank you Eric, for the work put into the development of all this info I get to translate.
Medium
By Eric Giesterfer - I've done volunteer background research for Project CBD. The Endocannabinoid System is a scientific fact. It is the reason why cannabis works as a medicine.
Mar 25, 2017
The Bioavailability of Medical Marijuana
Updated 3/25/2018
Bioavailability is an extremely important concept in pharmacology. The Merriam-Webster dictionary defines it as: the degree and rate at which a substance (as a drug) is absorbed into a living system or is made available at the site of physiological activity. In order for a medicine to work, it has to reach its intended destination. This article incorporates the latest scientific findings on the bioavailability of the various ways of consuming medical cannabis (marijuana). In addition, it also takes into consideration anecdotal evidence from patients throughout the medical cannabis community.
Before starting, a fact needs to be pointed out which can greatly increase bioavailability but is rarely mentioned anywhere — the food you eat. As this study points out —
Fatty Acid Binding Proteins are intracellular carriers of THC and CBD. If you are taking any form of medical cannabis, it is important that your body have healthy levels of these fats in order to maximize bioavailability. This is the same concept that applies to fat soluble vitamins like vitamin A, D, E, and K.
However, not all fats are the same. The two most famous are saturated fats and unsaturated fats. Saturated fats are low-density lipoproteins (LDL) also known as “bad” cholesterol, and unsaturated fats are high-density lipoproteins (HDL) also known as “good” cholesterol. The function of LDL is to
deliver cholesterol to cells throughout your body, whereas HDL takes cholesterol
away from your heart and other organs and delivers it back to your liver.
This is an important distinction because when you consume medical cannabis you are trying to
deliver THC and CBD to cells throughout your body. When I contacted Dr Dale Deutsch, one of the authors of the above study, about the HDL vs LDL difference, he responded:” …Look at this
paper and it actually says that THC is in all the lipoproteins but LDL carriers the most…”. The study he pointed out, “
The use of zonal ultracentrifugation in the investigation of the binding of delta9-tetrahydrocannabinol by plasma lipoproteins.”, states that THC has a clear affinity for the LDL fraction of human plasma (although the study also showed that THC binds to HDL carriers, but not as much as LDL carriers).
So don’t let the “good” and “bad” tags mislead you, after all, CBD has been tagged as “good” and THC has been tagged as “bad” but the medical cannabis community knows better. Therefore, if you want the medical cannabis to be delivered to its intended destination, it’s important that your body have
healthy levels of saturated fats flowing through it so the THC and CBD can hitch a ride on them. Healthy foods high in LDL are: all organic dairy foods with 2% or more fat, eggs, non-factory farmed beef, lamb, pork & chicken, fish, shellfish, cocoa butter, palm oil and coconut oil.
This aspect of bioavailability has been partially verified in studies done by GW Pharmaceuticals. They found that “
when Sativex is co-administered with food the mean Cmax and AUC for THC were 1.6- and 2.8-fold higher compared with fasting conditions. Corresponding parameters for CBD increased 3.3- and 5.1-fold.”
Cmax is the “maximum concentration of a drug achieved after dosing”.
AUC stands for “area under the curve” and it represents the “total drug exposure over time”.
While doing research for this article, I ran into some interesting facts:
1) THC seems to be more bioavailable than CBD — This clinical study used cannabis based medicinal extracts and concluded that “
the bioavailability of THC appears to be greater than CBD”. This other clinical study found that after administering a cannabis based medicinal extract of 10mg each of THC and CBD via the sublingual, buccal, oropharyngeal and oral methods, “
concentrations of THC were higher than the corresponding levels of CBD at most time points.”
2) Transdermally, CBD is more permeable than THC — From a transdermal perspective (passing through the skin), this study found that
CBD was 10 times more permeable than THC.
3) Coconut oil is the preferred oil — If you surf the internet, coconut oil seems to have the most positive reviews in the medical cannabis community, whether it’s used to make edibles or mixed with cannabis extracts. The other advantage of coconut oil is its stable chemical structure which gives it a much longer shelf life than other oils.
4)
Nanoemulsion has the potential to greatly increases the bioavailability of cannabis based edibles, sprays and creams— Nanoemulsions have been
successfully used for many years in the food, cosmetic, pharmaceutical and chemical industries. Because cannabis is lipophilic (hydrophobic), from a cannabis perspective, the most relevant definition of a nanoemulsion is that it’s a
fine oil/water dispersion stabilized by an interfacial film of surfactant molecule having droplet size range 20–600 nm. Nanoemulsion offers
the following advantages to potentially increasing the bioavailability of cannabis edibles, sprays and creams:
- It may be used as substitute for liposomes and vesicles.
- It is non-toxic and non-irritant in nature.
- It has improved physical stability.
- The nano sized droplets, having greater surface area, provide greater absorption.
- It can be formulated in variety of formulations such as foams, creams, liquids, and sprays.
- It provides better uptake of oil-soluble supplements in cell culture technology.
- It helps to solubilize lipophilic drugs.
Unfortunately, there has been very little testing done on the bioavailability of THC and CBD through the various administration modes. This is not surprising since very few pharmaceutical companies have tried to develop cannabis based medicines. In addition, due to cannabis being a Schedule 1 drug, researchers have been severely limited in their ability to study THC and CBD in the United States. Moreover, when they have done research in the US, they have been limited to using synthetic versions of these compounds like Marinol and Nabilone. Lastly, it is important to note that tests using animals don’t necessarily translate to the same results occurring in humans.
Oral — Even though anecdotal evidence does show positive medicinal results from swallowing THC and CBD, the bioavailability of swallowing THC & CBD has been proven to be low —
ranging from 4% to 20% with most results in the lower range. This is attributed to what is known as “
first-pass metabolism”. In addition, in all studies,
oral intake of THC always showed lower peak plasma levels than other intake forms. Moreover,
there were great differences in bioavailability among individuals. Lastly, when THC is metabolized by the digestive system, it is converted to 11-OH-THC which is estimated to be 4 to 5 times more psychoactive than THC. This is why some people have reported getting incredibly/uncomfortably high from marijuana edibles. The only advantage found from oral consumption is the fact that the pharmacodynamic effects last from 5–8 hours which means an individual does not have to medicate as often.
Oral Nanoemulsions — No independent studies were found on the bioavailability of cannabis using nanoemulsions. However, a study conducted by Phytotech Therapeutics Ltd using a self-emulsifying oral drug delivery system (SEDDS),
yielded 1.6-fold higher plasma Cmax than the equivalent dose of the oromucosal spray (Sativex), for both THC and CBD. Their relative bioavailability was also higher (131% and 116% for CBD and THC, respectively). Values of Tmax were significantly shorter for both CBD and THC (median of 1.3 h for PTL401 vs. 3.5 h for the spray).
NOTE — Curcumin has a well known low bioavailability.
A study using nanoemulsions to increase its bioavailability resulted in a 9 fold increase when tested on rats.
NOTE — According to
Industrial Sonomechanics, since cannabis oil nanoemulsions already “
comprise nano-sized oil droplets and already include all the necessary carrier oils, they are to a large extent able to directly penetrate through the mouth, throat, esophagus and stomach lining into the bloodstream. This results in a very quick (10–15 min) onset of therapeutic action…The rest of the nanoemulsion arrives in the small intestine, where it is digested and absorbed in a way similar to common edibles, but much faster and more completely. Since the nanoemulsion already comprises droplets similar in size to the mixed micelles to be formed in the small intestine, its digestive absorption does not require large oil globules to be broken down into nano-particles. The most inefficient step occurring during the digestive absorption of edibles and gel capsules is thereby circumvented. The results of replacing traditional edibles and gel capsules with nanoemulsion-infused beverages, therefore, include superior bioavailability, faster onset of action and straightforward dosing with fewer pharmacokinetic variations.”
Rectal — Anecdotal evidence shows positive results using rectal suppositories. In addition, the rectal approach, when placed correctly (which means avoiding the superior rectal vein), prevents first pass metabolism. Unfortunately, there are very few scientific studies on the bioavailability of rectal administration.
One conducted on monkeys showed a bioavailability of 13.5%.
Another
study conducted with two patients deduced that the bioavailability was approximately twice that of oral ingestion but did not provide bioavailability percentages. In addition, the studies that were conducted showed that “
bioavailability strongly differed depending on suppository formulations”, with THC-hemisuccinate having the best results. However, the average person does not have access to
hemisuccinates. Lastly, a clean rectum is required before applying the suppository.
NOTE — These two articles (
link 1,
link 2) claim bioavailability of 50% to 70% via rectal administration but they provide no scientific proof.
Sublingual — Anecdotal evidence shows positive results using the sublingual (under the tongue) route. However, since there is a salivary gland underneath the tongue, this method may result in some reflex swallowing, decreasing bioavailability and increasing the psychoactivity of THC. Although there are plenty of studies on other drugs via this route, there are virtually no scientific studies on the bioavailability of THC and CBD via this route. Bioavailability was found to be just a bit higher than oral bioavailability. Lastly, sublingual application is the second fastest way to introduce THC and CBD into the body behind smoking/vaporizing.
Buccal/Oromucosal — Anecdotal evidence shows positive results using the buccal/oromucosal (inside the cheek or on the gums) route. It has a few advantages over sublingual administration. It avoids reflex swallowing, it avoids the salivary gland beneath the tongue, and the substance stays in place when placed between the gum and the cheek. In addition, according to GW Pharmaceuticals:”The area under the absorption curve (AUC) is similar for sublingual and buccal formulations, for cannabinoids. After buccal administration there is a substantial reduction in the amount of the primary (11-hydroxy-) metabolite of the cannabinoids. This confirms that a greater proportion of cannabinoid/active is absorbed transmucosally than from the sublingual area.” It must be noted that these studies mixed the THC and CBD extracts with
excipients like ethanol, propylene glycol and peppermint oil.
Smoking/Vaporizing — Anecdotal evidence shows positive results using smoked or vaporized cannabis. In addition, this form of administration avoids first pass metabolism. Although it has been established that vaporizing is healthier than smoking, from a bioavailability standpoint, they are virtually identical. The bioavailability of smoking/vaping was greater for experienced users than novices which is why bioavailability has been shown to
range from 2% to 56% in different studies, with most results in the higher range. In addition,
with the exception of intravenous application, smoked/vaporized consumption showed a higher peak plasma than any other form of consumption. It is also the fastest way to introduce THC and CBD into the body. But the pharmacodynamic effects last less than 3 hours which means an individual has to consume it more often to maintain a constantly medicated state. However, smoking/vaping is extremely inefficient and the proof is in the exhale. All the smoke/vapor that comes out after exhaling, is cannabis that was not absorbed by the lungs and is basically thrown away.
Transdermal — This form of delivery is relatively new with mixed anecdotal evidence (more positive for CBD patches, less positive for THC patches). The biggest challenge to transdermal delivery is the fact that “
cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion”.
Only three studies were found and all of them were in vitro or on animals —
link 1,
link 2,
link 3. No studies have been done on humans. There are some companies that have developed transdermal patches for THC and CBD, and there are a few patents relating to this method of delivery. But just because a patent exists, it does not mean it works.
However, to quote analytical chemist Noel Palmer who is a member of the International Cannabinoid Research Society: “
The common theory is that if you disrupt the stratum corneum with ‘permeation enhancers’ and/or ‘carriers’ — then you can promote diffusion of API (Active Pharrmaceutical Ingredient) into the bloodstream, even if it’s lipophilic. This has been proven time and time again with other drugs, which is where the precedent came from. THC isn’t that different. Permeation enhancers can be liposomes, fatty acids, terpenes, etc.” The potential positives of transdermal delivery are the facts that it avoids first pass metabolism, and offers the possibility of providing a dosed amount over a longer time period.
NOTE — According to Industrial Sonomechanics, “
Transdermal delivery of cannabinoids can be significantly enhanced with a novel formulation type called "nano-emulgel", which is produced by entrapping an aqueous nanoemulsion of cannabis oil in a semi-solid colloidal network (hydrogel) Nano-emulgels enhance skin permeability of oils, leading to faster, more complete absorption of cannabinoids into the bloodstream than has been possible with traditional creams, ointments or patches. They are also non-greasy, more spreadable and stable, have better active substance loading capacity, and can be easily washed off the skin whenever desired.”
Lotions/Balms — Medicinal cannabis works by interacting with CB1 and CB2 receptors. These CB receptors are present throughout the body, including muscles, skin, bones, peripheral nerves and synovial tissue. So, even though it has not been proven that THC and CBD are able to enter the bloodstream via the skin without the use of permeation enhances/carriers, anecdotal evidence suggests that they are able to interact with CB receptors in these areas. No studies were found on cannabis infused lotions/balms.
.
.
