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The Pharmacokinetics of Cannabis

Cannabis contains more than a hundred known cannabinoids, each stimulating a subtly different effect within the human body. But, what happens when a cannabinoid enters the body? Where does it go, what does it do, and how quickly does it dissipate?


The pharmacokinetics of cannabis is complicated by several mitigating factors, like the route of administration, formulation, and the individual patient. 


As cannabis enters the world of modern medicine, it’s increasingly critical to understand how bioavailability, metabolism, elimination, and more play out. Knowing how each cannabinoid travels through the body and what elements influence its effects will lead to safer, more effective medicinal applications.


A Journey Starting in the Endocannabinoid System


The primary target for most cannabinoids is the endocannabinoid system, a body-wide network of receptors and chemical transmissions. Cannabinoids like THC, CBD, and presumably others, interact with the two primary receptors (CB1 and CB2) to produce different effects.


One of the most recognized cannabinoid relationships is THC, which binds to the CB1 receptor but is a known partial agonist for both CB1 and CB2. Interestingly, CBD may inhibit the THC interaction with CB1 and seems to have little affinity for either of the primary receptors. 


There are some indications that CBD could bind to other non-cannabinoid receptors, like 5HT1A and TRPV1 receptors, as well as work with fatty acid amide hydrolase (FAAH).


The effects of each cannabinoid are dependent on what endocannabinoid receptor it interacts with. For example, most CB1 receptors are concentrated in the central nervous system, peripheral nervous system, and some organs. Therefore, THC provides the greatest effects to those areas. Most CB2 receptors exist in the immune tissues, which means the effects would be most pronounced for the immune system.


Bioavailability and Route of Administration


Bioavailability, which is the measure of how much of a substance enters into circulation within the body, is a tough one for cannabis. No matter the route of administration, cannabis and individual cannabinoids have comparatively low rates of absorption. 


One reason why the human body so poorly absorbs cannabis-derived formulations is that cannabinoids are extremely hydrophobic. With roughly 60 percent of the human body made up of water, this is a challenging mix. But, it’s not all bad news. The route of administration plays a big role in determining the final rate of absorption. 


Inhaled cannabis, including smoked, vaped, and inhaler-style products, is fast-acting but short-lived. According to the literature, the bioavailability for inhaled THC ranges between 10 to 35 percent. Much of the variation boils down to differences between duration of inhale, depth of inhaling, and other intraparticipant differences.


Interestingly, different cannabinoids seem to exhibit different inhaled bioavailability, even if the route of administration remains the same. For example, while THC’s absorption rate may be as low as 10 percent, CBD’s is reportedly as high as 31 percent.


With oral routes of delivery, the bioavailability plummets to as low as six percent. Absorption of THC from an edible, drink, or capsule faces the disadvantage of hepatic first-pass metabolism. As a result, most of the value is lost through the digestive tract and liver. 


Finally, transdermal patches are growing in popularity for their clinical potential, but as one review explained, “Transdermal administration of cannabinoids avoids first‐pass metabolism but their extremely hydrophobic nature limits diffusion across the aqueous layer of the skin.” Without permeation enhancement, like the technology developed for the RYAH Smart Patch, absorption rate remains low.


The Role of Metabolism


A key aspect of a cannabinoid’s pharmacokinetic effects is in relation to metabolism. Metabolization usually occurs in the liver, but other organs within the body can also metabolize these compounds.


For example, the primary routes for metabolizing THC are cytochrome P450 (CYP 450), including isozymes CYP2C9, CYP2C19, and CYP3A4. Although these isozymes are concentrated in the liver, they also exist in the small intestine and the brain. CYP 450 transforms THC into 11‐hydroxy‐THC (11‐OH‐THC), which is thought to be several times more psychoactive than the original cannabinoid.


The process through which the human body metabolizes CBD is much less understood, although it seems to follow similar pathways as its intoxicating cousin. Hepatic isozymes (specifically CYP2C19, CYP3A4, CYP1A1, CYP1A2, CYP2C9, and CYP2D6) are responsible for metabolizing CBD, transforming it into a compound known as 7‐OH‐CBD.

 

Many of the hepatic enzymes responsible for processing cannabinoids are the same enzymes that metabolize common pharmaceuticals. According to a 2007 report in the American Family Physician, although the CYP “class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6.”


Meaning, there is a significant potential for drug-drug interactions between a patient’s pharmaceutical prescriptions and medicinal cannabis. However pertinent this issue is for patients and their physicians, there is almost no research explicitly testing the possible interactions.


The Half-life of a Cannabinoids


An additional layer in the complex world of cannabinoids is the half-life, meaning how long it takes for these compounds to break down.


Cannabis’ most notorious cannabinoid, THC, has a relatively lengthy half-life and it seems to build up over time depending on frequency of use. As per a 2012 review, for people who rarely consume THC, the half-life is on average 1.3 days. However, for chronic consumers, it could be up to 13 days. 


What about other, less-psychoactive cannabinoids? According to “A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans,” there is a high degree of variability in the half-life of CBD, depending on the route of administration. 


For example, the half-life following an aerosolized or nebulized dose of CBD was between 1.1 to 2.4 hours. For oromucosal spray, the half-life was between 1.44 to 10.686 hours. And finally, for chronic oral administration, it may be as long as two to five days.


Pharmacokinetics of Cannabis: An Ongoing Area of Study


There are a lot of complicated considerations within the study of the pharmacokinetics of cannabis. With so many variables influencing absorption, metabolism, and elimination, even clinicians find it difficult to summarize hard and fast rules. 


As cannabis becomes more socially accepted and finds its place within modern medical practices, it’s paramount to continue this scientific undertaking. The more we uncover how cannabis works in the human body, the better we can make it in terms of predictable results, improved bioavailability, and consistency between doses.

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