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Absorption describes the rate and extent to which a substance, such as cannabis molecule THC, enters the bloodstream. Having a drug in your mouth may seem like it is in your body, but it needs to enter the blood first before it is considered absorbed. There are various ways for THC to enter the bloodstream, and each way has its own benefits and challenges. These ways, called administration methods, can be intravenous (drug injection directly into the vein) or extravascular (outside of the bloodstream), for example, administration via the mouth (oral), the mouth tissue (oromucosal), the skin (transdermal), the anus (rectal), inhalation via the lungs (intrapulmonary), etc. Understanding how much of a substance is absorbed into the body is important to understanding its effectiveness and safety.1 In general, THC is almost instantly absorbed after inhalation, within minutes. In contrast, after oral ingestion, it can take up to an hour or more before a large amount of the THC is absorbed from the gastrointestinal tract.2, 3, 4, 5 Figure 1: If a drug is given by any other route than intravenously (directly into the bloodstream), it is considered extravascular and must therefore undergo absorption into the bloodstream. In Figure 1, the bloodstream is called the “systemic circulation” and is depicted in the center of the image. The various routes of administration depicted are oral, or via the mouth, after which the absorption takes place in the gastrointestinal tract; rectal, or via the anus; (intra)ocular which is via the (inside) of the eye; inhalation, which can be done via smoking, vaporizing, or nebulizing; subcutaneous or transdermal, which is under or through the skin; and intramuscular, which is for example done with inoculations. During these administration modes, it is possible that some of the medicine gets lost or otherwise not administered efficiently, and that not all of the drug reaches the systemic circulation. THC absorption

Illustration caption and image taken with permission from TRC Pharmacology Database.

Absorption of a compound such as THC depends on many factors such as the formulation, mode of administration, dose, concomitant use with food or other substances, and individual physiological characteristics.6, 7, 8, 9 Within the scope of administration, there are two important factors to understand when considering patient treatments: Bioavailability (click here to read more) and Inter-/Intravariability. Inter-individual variability is the difference in drug effects between different individuals. The same dose of the same medicine might work for you, but can be toxic to another patient. This also applies to the effectiveness, safety, and tolerance of the drugs. Factors that contribute to this variability are age, gender, weight, disease, and many others. Intra-individual variability is the discrepancy in effects within the same person when taking the same dose of the same medicine: you might think that the same medicine always has the same effect in the same person, but this is not the case. The effect can be influenced by factors such as whether the drug is taken with or without food, the time of the day, or how a person is feeling around the time of dosing. It is important for patients to understand the reasons behind different dosing of drugs between individuals.

1. Inhalation (lungs) absorption

With inhalation, product is absorbed via the lungs. Smoking Smoking is the most prevalent form of cannabis administration and gives very fast effects due to a rapid delivery of THC from the lungs to the central nervous system without the so-called first-pass metabolism (read more about it on Metabolism page.10, 11 The bioavailability of THC after smoking cannabis is estimated to be between 2% and 56%, of which the upper range is relatively high.12, 13, 14, 15 This variability of the bioavailability can be due to factors that include the inter- and intra- individual variability of smoking dynamic, such as inhalation volume, amount, duration, and spacing of puffs. Vaporizing With vaporization, the volatile cannabinoids enter the system through lung absorption of the vapor. The bioavailability of vaping is relatively high and generally does not differ compared to smoking.16 Watch a brief summary video on cannabis inhalation vs. cannabis ingestion made in collaboration with Enlighten on YouTube or on the screens page.

2. Oral absorption

With oral administration, the drug is swallowed through the mouth, goes down the digestive system and gets absorbed in the small intestine. Via the intestine, the drug makes its way to the liver and enters the central blood (systemic) circulation. In theory, small amounts of product could be absorbed in the oral cavity, but there is too little scientific information on this topic to draw any conclusion about how often this happens and how much might get absorbed. After oral absorption, it can take an hour or even a few hours until the medication effects are felt. Due to the longer distance that a drug needs to travel in the body, he absorption of cannabis through oral administration happens at a later time than through inhalation. Oral THC: The bioavailability of THC through oral route is approximately 10-20%, which means that 10-20% of the ingested amount eventually reaches the bloodstream.17 However, this number can be altered by absorption enhancers that can do a variety of tricks to increase the absorption of THC and other compounds to the bloodstream. Through first-pass metabolisms, THC will be transformed into active 11-OH-THC and then into inactive THC-COOH metabolites in the liver. This transformation reduces the oral bioavailability of THC from 10-20% to 4-12%.9 The effects of THC, such as the “high” feeling, are generally stronger when taking cannabis orally compared to inhaling (smoking or vaporizing) the same dose. This is caused by forming a greater amount of active 11-OH-THC metabolite, which is believed to cause stronger effects than THC.18, 19 Due to slower absorption, which results in a delayed and stronger “high” effect, users tend to overdose when taking cannabis orally.20 In other words, if they don’t feel any effect within the first hour, they may take more cannabis thinking that the dose wasn’t high enough, which can lead to undesirably strong effects once they start manifesting.

3. Oromucosal and Sublingual absorption

Sublingual administration means that medication is placed under (sub, in Latin) the tongue (lingua). The absorption under the tongue happens via the abundance of blood vessels there, and a relatively thin skin. Oromucosal (or-, os, which means mouth, and mucosa, which is the skin layer that produces mucous) is an administration method that works via the mucosal skin in your mouth, including the inside of your cheeks and your gums. Although these two routes of absorption happen after putting the medicine in the mouth, they are generally not the same as the oral administration due to the different locations of absorption: sublingual and oromucosal absorption happen directly via the oral cavity, whereas oral absorption only happens later in the digestive system. This generally has different consequences for the effect onset time, the effect strength, and the effect duration. After sublingual and oromucosal absorption, the drug goes directly into the central blood (systemic) circulation, while oral absorption goes through the digestive system first. Sublingual and oromucosal routes generally have a fast absorption, within seconds or minutes. For example, nitroglycerin, the medicine for a heart attack, that is administered sublingually, takes about 6-7 minutes to reach the blood.21 The rest of the unabsorbed drug is swallowed and metabolized in the liver, just like with other oral administrations.22 Oromucosal and sublingual THC: Unlike nitroglycerin, there is no evidence from scientific studies that oromucosal or sublingual THC are absorbed faster or better than oral THC in humans. In a study done on rabbits, when administered sublingually, the THC bioavailability was higher than the bioavailability of THC taken orally.23 However, in studies done on human participants, oral administration appeared to have similar bioavailability and effects as sublingual and oromucosal intake.24, 25 More studies are needed to better understand the pharmacology of sublingual THC administration.

4. Skin

For a refresher about the difference between transdermal and topical administration, click here. Transdermal absorption By penetrating through the skin, a medicine enters the central blood flow.26 This way of administration has some benefits over the oral route, since drug does not have to go through first-pass metabolisms, which lower the bioavailability of THC, decreasing its effect.27 Transdermal and cannabis: THC is a very lipophilic substance (i.e. likes fat, but does not like water). Compounds that easily penetrate skin layers, are ideally moderately lipophilic, so less lipophilic than THC. Therefore, bioavailability of cannabinoids such as delta8-THC, CBD, and CBN for transdermal absorption is expected to be low when no absorption enhancer is applied.28 There are some methods to improve absorption through the skin layers, including temperature changes, applying voltage pulses, or ultrasound. Another method is to dissolve compounds in a solution of penetration enhancers. These will increase penetration and thereby absorption by interacting with the skin’s lipids. They can be incorporated in products such as dermal patches to increase the absorption rate of THC and other cannabinoids.29 There are still not enough studies regarding the exact effect of absorption enhancers on THC absorption, which need to be studied in clinical trials. Topical absorption Topical drug administration is used for local action, whereby the drug does not penetrate deep, thereby not reaching the systemic circulation. Consequently, the topical route does not imply bioavailability of cannabis compounds. Some studies have shown that increasing skin moisture can improve the permeability of THC. Vehicle compounds, such as propylene glycol, can transfer moisture into the skin to enhance absorption. Moreover, oleic acid, an unsaturated fatty acid that is found in hemp oil, can also increase the permeability. However, these vehicles and compounds can only insignificantly increase the skin absorption of THC.29 Figure 2: Representation of the skin cross-section showing the different levels of medicine penetration. Transdermal products penetrate epidermis and dermis and enter the blood circulation, while topical products generally do not reach layers below the epidermis. THC topical transdermal skin Watch a brief summary video on Topical vs. Transdermal made in collaboration with Enlighten on YouTube or on the screens page.References:
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