In this article, we examine how metabolism affects cannabinoid pharmacology. To take a deeper look at cannabinoid pharmacology, we examine the role of metabolism and its effect on inhaled versus ingested cannabinoids. When comparing the effects of inhaled and ingested cannabinoids it is critical to examine the differences between the stomach and the lungs in human anatomy.
The lungs contain a very large amount of blood vessels that very quickly absorb cannabinoids, and this blood is directly pumped into the heart and then up to the brain, where many cannabinoid receptors are present. This direct route allows the cannabinoids, such as THC, to arrive unmetabolized by the liver. In the next post, we will examine the main metabolic reaction in the liver to convert THC to 11-OH-THC.
Metabolism is the process by which a living organism converts one compound into another. 11-OH-THC, the primary human THC metabolite, does have psychoactive effects very similar to THC, with some minor distinctions that are still being explored by researchers. 11-OH-THC is theorized to explain certain phenomenon, like somnolence (sleepiness). Before we delve into the effects of 11-OH-THC versus those of THC, let's review where 11-OH-THC comes from in the human body.
OH-THC is produced in the human body by an enzyme called Cytochrome P450 Oxidase 2C9 or CYP2C9. In this case CYP2C9 is targeting THC and adding an OH to it, increasing its water solubility and the ease with which it can be excreted by the body through urine. Although CYP2C9 is present in small amounts in the brain, it is present in vastly larger amounts in the liver. CYP2C9 is responsible for metabolizing serotonin and over 100 pharmaceutical drugs, such as warfarin.
In contrast to the direct path taken through the lungs, cannabinoids entering the stomach start a longer journey to the brain. Ingested cannabinoids begin their path to the brain in the stomach, which has no ability to absorb cannabinoids into the bloodstream directly. After a digestion period, cannabinoids pass into the small intestines, a region called the duodenum where the stomach contents are mixed with bile which allows water insoluble substances such as fats, oils, and cannabinoids, to first dissolve. After dissolving, they are absorbed into the blood by the intestines, but this blood is not heading into general circulation. Instead this blood is pumped to the liver, which attempts to detoxify its contents before releasing them to general blood circulation. It is here that cannabinoids are metabolized into new compounds.
Many studies have examined the liver's ability to transform THC into 11-OH-THC, a psychoactive cannabinoid distinct from THC proper. Once the newly minted 11-OH-THC cannabinoids leave the liver, they pass through general circulation to the brain. This long route of administration also explains why edibles take such a long time, often over an hour, to begin to take effect. It may also explain why edibles produce more somnolent symptoms (sleepy or drowsy state of mind).
An open flame or red hot nail will freely convert THCA to THC, as will an oven of baking temperature (over approximately 177 C, 350 F) with 30-70% efficiency. Studies have shown that although outside the body it is common to decarboxylate THCA to THC, in vivo this is not possible. These studies have shown that once THCA is introduced to the body, it is metabolized and excreted by the body as a metabolite of THCA, and does not convert into THC.
Here we can see the blue carboxylic acid (COOH) group attached to both THCA and its metabolite. THCA can be decarboxylated with relatively gentle heat outside the body, but once THCA enters body fluid it follows a different metabolic pathway than THC, leading to no psychoactive effects.
A firm grasp of the science behind cannabinoids and their interactions in the body can help a medical patient, a prescribing doctor, or an industry professional to better understand the effects that different routes of administration will have on health, function, and experience.
Although 11-OH-THC does posses psychoactivity, the next metabolite down the chain COOH-THC does not. When the body converts all of the available THC and 11-OH-THC into COOH-THC, the effects of the “high” end. COOH-THC is often used for drug testing kits, as it builds up in the body very easily and can take up to one month to completely clear. One study claims that urban sewage and groundwater have levels as high as 10 part per trillion (ppt) of COOH-THC due to excretion after human consumption.
Cannabinoids are also degraded in the human body by metabolic processes. The blood plasma levels of THC and other cannabinoids begin to drop when the liver enzymes responsible for oxidizing the 11-Carbon-Methyl group create two cannabinoid subspecies, the 11-Hydroxy and 11-nor-9-Carboxy derivatives. These derivatives are more water soluble and more easily excreted by the body, especially the nephrons in the kidneys. A metabolic process that often occurs concurrently with the action of liver enzymes is that of conjugating THC with the sugar glucuronic acid (an oxidized derivative of glucose). A cannabinoid or its metabolite may be glucuronidated at any stage of oxidation shown in the diagram. Vertical arrows show addition of glucose, and horizontal arrows show oxidation steps.
To help illustrate the changes in water solubility that these metabolic changes confer onto the THC molecule, we have developed a simulated electrostatic potential map (ESP) for the surface charge on the cannabinoid molecule. An ESP map helps to show the distribution of positive and negative charges on the surface of the molecule, which help give a sense of a molecules water solubility. Compounds that have perfectly balanced charges on their surface have a very non-polar ESP charge distribution, which makes them hydrophobic or highly water insoluble (white in this image). The more the ESP map reveals areas of dense positive and negative charge (blue and red, respectively), the more easily a molecule will be able to interact with and therefore dissolve among water molecules. As the image shows, the unmetabolized THC molecule is largely neutral (white) on its ESP surface map, but after being thoroughly metabolized is mostly a combination of positive and negative regions in its ESP surface mapping. Calculations were made with Avogadro 1.0 software including the estimated dipole moments shown under each compounds name.
The metabolic pathway of THC to 11-OH-THC to COOH-THC represents the majority of human metabolism of THC, but there are minor metabolites and variants in the metabolic pathways. The next most relevant metabolite is the 8-OH-THC metabolites, an isomer of 11-OH-THC. CYP3A4 metabolizes THC at the 8 carbon instead of the 11 (done by CYP2C9), creating 8-OH-THC.
Enzymes have been observed oxidizing THC at a variety of carbon locations, creating polyhydroxylated THC derivatives, like the one used in the example of solubility and ESP maps in the previous post. Many of these minor variants have been seen in larger amounts in studies on non-human animals as models to understand metabolism of THC and other cannabinoids. In the diagram known molecules and enzymes are labeled, but many enzymes are still being discovered and must be labeled as unkown. Also note that the metabolic pathways often have overlapping and redundant routes to the same metabolite, making a web of chemical reactions rather than a linear scheme with a singular, definite path.
Now that we are familiar with the general pattern of THC/metabolite concentrations in blood after inhalation, we can examine empirical evidence from a published study, conducted by Huestis et al in 20095, from which this image is taken.
Here we can see three functions representing the concentrations of THC and its metabolites over time. We can also see vertical arrows indicated when the test subject inhaled cannabinoids. As inhalations occur, the blood levels steadily climb of all cannabinoids. When the subject stops inhaling the THC levels begin to decline rapidly, but the metabolites continue to grow as the THC is metabolized to the other compounds. In the time interval displayed, THC is the dominant cannabinoid in the blood after inhalation of cannabinoids. The somnolence seen at the end of an inhaled cannabinoid experience may correspond with the time it takes the liver to metabolize the THC into 11-OH-THC, and when compared with edibles, the beginning of an inhaled cannabinoid experience is often called “energetic”.
The next scenario to examine is the oral ingestion of cannabinoids and how the resulting blood serum levels of THC, 11-OH-THC, and COOH-THC over time are different.
In this graph showing oral ingestion of THC edibles, we see functions representing the blood concentration levels of THC and its metabolites over time. We can see the absorption in the beginning of the experiment, with 11-OH-THC being at very slightly higher levels than THC in the blood. Between hours 5 and 15, we can see THC levels falling off while 11-OH-THC continues to grow as it accumulates from THC metabolism. Eventually, from 15-25 hours, the levels of 11-OH-THC fall to zero as it becomes COOH-THC is the dominant cannabinoid in the blood, but also begins to decrease.
Notice that the scale covered in this experiment is between 0-2 parts per billion (ppb) in the blood. The previous experiment done on inhalation, though over a much shorter time interval (minutes), displayed concentrations ranging from 0-150 ppb, with the concentration of THC being the only one to go above about 30 ppb. This difference in scale could be interpreted as supporting evidence of the theory that 11-OH-THC has increased potency over THC, and this is a causal factor behind the lowered doses of THC when orally ingested achieving a similar effect to higher doses of inhaled THC. Though these assumptions look promising, further studies are needed to validate their conclusions.
When compared to the inhalation pharmacokinetics from the previous post, we also see that the first-pass metabolism (a term for passing contents from the stomach through the liver before blood circulation) causes the amounts of THC and 11-OH-THC to begin approximately equal, instead of THC dominated as in inhalation. This combined with 11-OH-THC’s more somnolent (sleepy or drowsy) pharmacological profile may explain the more sedative effects of edibles compared to inhalation.
Thank you for following us on the metabolism and physiology article exploring cannabinoid routes of administration! Stay tuned for more series focusing on key issues in cannabinoid science.
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CITATION
Huestis MA (June 2009) “Human Cannabinoid Pharmacokinetics”. Chem Biodivers. 2007 August ; 4(8): 1770–1804. doi:10.1002/cbdv.200790152.
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