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ADME. This acronym is one of the most important things to remember if you are studying drug delivery and pharmacokinetics.

It stands for Absorption, Distribution, Metabolism, and Excretion; it is used to analyze how a given compound behaves in an organism. As we study for our preliminary exams (pray for us), we have been going over the ins and outs of ADME and how it relates to our own drug delivery projects. So, ADME has been on our minds pretty much constantly. We decided to write a post following the ADME of a drug that many people might be familiar with--Tetrahydrocannabinol (THC). This chemical is responsible for most of marijuana’s psychological effects and acts much like the cannabinoid chemicals made naturally by the body. Cannabinoid receptors are concentrated in certain areas of the brain associated with thinking, memory, and perception so THC molecules compete with endogenous molecules to bind to these receptors and activate them.

We want to note that the use of recreational marijuana is legal in Washington state, where we reside. However, even if it is not legal in your area, learning about the ADME process of a particular drug and how it affects a patient’s body is informative! What better way to get an intro to ADME than through a controversial drug like THC?


Absorption of a drug describes things like how it gets in, where it goes, and how it gets from the site of administration to systemic circulation. There are quite a few routes of absorption when it comes to THC, from oral to sublingual to pulmonary to topical to rectal. Let’s take a closer look at the most common types, pulmonary (AKA smoking and vaping) and oral ingestion (AKA edibles).

Pulmonary administration of a drug can provide a quick and direct route to the bloodstream. The lungs contain millions of alveoli which are the site of gas exchange. Here, THC is rapidly absorbed into the bloodstream and can then make its way to the blood brain barrier (BBB). THC has a high octanol-water partition coefficient, meaning it is lipophilic and can be absorbed into fatty tissue as well as cross lipid bilayers of cells. It is not so lipophilic that it can’t partition out of cells, however. This lipophilicity means it can cross the BBB and access the central nervous system (CNS). Not all of the THC can make it across, for a number of reasons. For one, THC binds to other proteins in the blood, meaning not all THC is free to cross the BBB. There are also special proteins in the BBB that recognize THC (among other drugs) and prevent the drug from reaching the brain. These proteins are another line of defense to protect your CNS!

Oral administration is exactly what it sounds like; a drug is taken orally and absorbed in the gastrointestinal (GI) tract. Aforementioned, THC is lipophilic, so it is easily absorbed by the intestines as it moves through one's system. There is a glaring issue when it comes to the oral route of administration: the first pass effect. Before a drug can reach systemic circulation from the GI tract, it enters the hepatic portal system. From there, it is taken to the liver, where a significant amount of metabolism occurs. This can degrade and reduce the amount of active drug that is bioavailable. The first pass effect is not always a hindrance, however. In the case of THC, it is metabolized into 11-hydroxy-THC-- the main psychoactive metabolite of THC. 11-hydroxy-THC crosses the BBB more readily than THC [5]. If you’ve ever heard that edibles are highly potent, this is part of the reason.

Each route of administration has pros and cons, and must be weighed for each therapy. When it comes to cannabis, the pulmonary route provides speed and direct access to the bloodstream, while avoiding the first pass effect (this may be a desirable trait for people who do not want to blast off into space for an unknown amount of time). However, there is evidence that chronic smoking of marijuana can harm the lungs and lead to persistent cough, shortness of breath, and bronchitis [6]. As for the oral route, there is no smoking necessary and the effects can be both prolonged and heightened, but absorption can vary according to differences within the GI tract on an individual basis, and so dosing can be difficult.


As mentioned earlier THC is rapidly distributed throughout the body due to its highly lipophilic composition. About 90% of THC in the blood is distributed in the plasma, and 10% is in red blood cells [2]. Many drug carriers take advantage of this phenomenon and are coated in a lipophilic shell to increase cell uptake. THC is initially taken up by tissues that are highly vascularized, such as the heart, brain, and the lungs. The fast uptake of drug into the lungs is why smoking THC is an effective form of administration to maximize drug in the bloodstream. After inhalation, the peak concentration of drug in the blood is about 6-10 minutes after onset of smoking [2]. However, the total amount of drug that is distributed throughout the body is highly variable between users. This is due to various reasons including fat index, lung capacity, and smoke volume.

Perhaps the most obvious effects of THC on the body is through behavioral changes. Studies of distribution of THC into the brain is especially important to evaluate the impact of dosage to behavior. One study in rats showed that a single intramuscular administration of radio-labeled THC reached maximum levels of distribution to the brain after 2-4 hours [1]. However, less than 1% of administered drug reached the brain via intramuscular administration after that timeframe. This may be due to the difficulty of crossing the blood-brain barrier (a highly selective barrier of tightly bound endothelial cells that prevent non-specific solutes from crossing into the brain). However if THC is metabolized into 11-hydroxy-THC (through eating edibles), it crosses the BBB more readily.

With prolonged drug exposure for long-term users, THC concentrates in fat tissues, where it is stored until elimination.


Metabolism just means: how is the drug broken down? The body has a host of ways to break down molecules. There are different phases to metabolism, with the main being Phase I and Phase II. During Phase I, drugs can undergo different reactions including redox reactions, hydrolysis, and acetylation. Phase II is primarily conjugation reactions, or covalent attachment of endogenous molecules. In Phase I, THC undergoes some hydroxylation, oxidation, and degradation. In Phase II, it is conjugated with glucuronic acid in a reaction called glucuronidation. This increases the water solubility of the drug, meaning it won’t partition into cells as easily and can be excreted [7]. Remember the first pass effect? This is a form of metabolism. The liver is the workhorse of metabolism, where Cytochrome P450 enzymes can break down endogenous and exogenous chemicals.

Image taken from

Here, THC is broken down to 11-OH-THC, which is then broken down into THC-COOH. THC-COOH is inactive, so it won’t be getting anyone high [1]. Extrahepatic metabolism (metabolism outside of the liver), occurs in organs such as the brain, intestines, and lungs. There is evidence that extrahepatic metabolism contributes to the metabolism of THC, however it is not as potent as hepatic metabolism [1].


Within 5 days, a total of 80-90% of THC is excreted, mainly through renal (about 20%) and biliary excretion (about 65%) [3]. Cannabinoids have a strong binding affinity to proteins such as metabolites and form complexes with these metabolites, so that is why the predominant excretion route is through feces (biliary excretion). Due to this elimination timeline, the window of detection for THC in plasma samples is 2-7 days after smoking 16mg of THC. In the body, THC molecules conjugated with glucuronic acid are eliminated through urine (renal excretion). Many studies sample the drug concentration of plasma over 24-72 hour intervals to monitor its half-life. The elimination half-life of a drug is defined as the time it takes for the concentration of a drug in plasma to be reduced to 50% of its initial plasma concentration. These studies report that the half life of THC in plasma is about 4.1 days in chronic cannabis users [4]. You might have heard about urine sampling to test for THC use. Detection of cannabinoids in the urine is indicative of cannabis exposure, but due to the long excretion half-life of THC in the body, it is difficult to predict the exact time of drug use especially if the patient is a long-term user. For example, if a urine test comes up as ‘positive’ for THC, does this mean that the patient has administered THC recently or is this residual THC from several days ago? To date, there has been no reliable method for determining the timing of drug use through urine alone especially because there are many pharmacological factors (drug dose, type of administration, rates of metabolism and excretion) as well as analytical factors (assay sensitivity, specificity, accuracy) between patients and assays. However, studies on using physiological factors such as hair (for cumulative drug use), sweat, and saliva are being investigated as potential methods of monitoring cannabis use in patients.

Common routes of elimination for drugs: the renal and biliary system

Once a majority of THC is eliminated from plasma, the rate of elimination slows down as the THC from the tissue fat is slowly released. This secondary phase of slower elimination is also a factor in the long half-life of THC. The high lipophilicity of THC results in higher reabsorption and low renal excretion of unmodified drug. We highly doubt that users think about how THC exits the body, but if there’s anything we've learned from our classes and from research on the ADME process, it’s that the body readily has many modes of elimination for drugs. However, these routes of elimination rely on many physiological variables and are highly affected by drug composition. For example the reabsorption of weak electrolytes depends on the pH of the urine and pKa of the drug. Due to this dependency, your diet can influence the absorption of electrolytes because it alters your urine pH. Eating a plant based diet actually increases your urine pH, which would influence how the rate at which the drug is eliminated from your system and how much of it is reabsorbed back into the body. Your everyday actions such as changing your diet can really impact the way your body metabolizes and eliminates substances!


[1] Huestis, Marilyn A. "Human cannabinoid pharmacokinetics." Chemistry & biodiversity 4.8 (2007): 1770. doi: 10.1002/cbdv.200790152

[2] Musshoff, F et al. "Review of Biologic Matrices (Urine, Blood, Hair) as Indicators of Recent or Ongoing Cannabis Use". Therapeutic Drug Monitoring: Vol. 28,2 (2006):155-163 doi: 10.1097/01.ftd.0000197091.07807.22

[3] Wall, M E et al. “Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women.” Clinical pharmacology and therapeutics vol. 34,3 (1983): 352-63. doi:10.1038/clpt.1983.179

[4] Johansson, E et al. “Prolonged apparent half-life of delta 1-tetrahydrocannabinol in plasma of chronic marijuana users.” The Journal of pharmacy and pharmacology vol. 40,5 (1988): 374-5. doi:10.1111/j.2042-7158.1988.tb05272.x

[5] Calapai, F et al. “Cannabinoids, Blood–Brain Barrier, and Brain Disposition”. Pharmaceutics. 12,3 (2020): 265.

[6] Rubeiro, L et al. “Marijuana and the lung: hysteria or cause for concern?”. Breathe (Sheff). Vol 14,3 (2018): 196–205. doi: 10.1183/20734735.020418

[7] Sharma, P et al. “Chemistry, Metabolism, and Toxicology of Cannabis: Clinical Implications”. Iran J Psychiatry. 7,4(2012): 149–156.

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