Drug metabolism refers to the entire process of how drugs are transformed and converted from one chemical form to another from the moment they enter our bodies until they are excreted.
Sometimes people talk about this metabolism process as “breaking down” chemicals in your body, but in most cases metabolism actually does the opposite — adding in more molecules to the chemical structure. As it turns out, often the larger the chemical becomes, the easier it is to eliminate it from your system.
So how does drug metabolism work? In general, drug metabolism primarily takes place in the liver, due to the presence of a large amount of different enzymes. But it doesn’t take place exclusively in the liver, and metabolization of drugs can take place in every biological tissue present in the human body. Still, these other sites are involved to a more limited extent in this process when compared to the liver.
The drug metabolism itself takes place in two different phases:
In phase 1, enzymes initiate a chemical reaction that adds an oxygen molecule to the drug. While this phase might also produce compounds that are easier to eliminate from the body, most of the chemicals aren’t ready for elimination yet.
In phase 2, these modified chemical compounds undergo another round of chemical reactions where another larger molecule is linked to the drug. Catalyzed by another class of enzymes, called transferase enzymes or UTG’s, this transformation causes the chemicals to become water soluble — and thus able to be eliminated from the body in urine.
Activating Cannabis in the Body
The two primary cannabinoids in marijuana, THC and CBD, actually begin life in an acid form. In raw cannabis flowers, like those used for smoking, vaping or making edibles, there isn’t much THC or CBD. Instead we find THC-A and CBD-A — their acidic precursors.
While these precursors sometimes have active medicinal effects, they tend to be markedly different from their well-known neutral forms. THC-A, for example, shares THC’s anti inflammatory effects but produces no psychoactive high.
THC becomes active when THC-A is transformed through a process called decarboxylation. Decarboxylation usually occurs with heat, so it happens naturally when you burn or heat cannabis to smoke or vaporize it. The same is true for CBD-A and the other minor cannabinoids.
How Cannabis Metabolism Begins
Once cannabinoids — the active chemicals in cannabis like THC and CBD — have been consumed absorbed into our bloodstream, and deposited into tissues throughout the body, they can begin to cause their desired effects. But how does this happen?
At this point, you’ve activated and consumed the important cannabinoids and they should be circulating through your bloodstream. So how does our body react next? First, your heart will send blood to your liver, and the cannabinoids contained in your blood will be metabolized by your liver cells.
While the liver is the primary location that metabolic transformations take place (due to the high level of enzymes), cannabinoid metabolism can also take place in other tissues. For example, it’s been shown experimentally that THC can be metabolized in the brain.
Liver cell contain most of the drug-metabolizing enzymes that you need for the transformation process. The new molecule produced by this process is known as a metabolite.
While there are many different ways cannabinoid metabolism can happen, much like other drugs, it commonly takes place in the following two phases:
Phase 1 metabolization is all about hydroxylation and oxidation. In this phase, particular enzymes hydroxylate part of the cannabinoid, adding an oxygen and hydrogen molecule to its structure.
With THC this leads to the creation of 11-OH-THC, a very pharmacologically active metabolite, known for its sedative and psychoactive effects.
Interestingly, we see lower levels of 11-OH-THC in blood plasma when someone has smoked cannabis than we do when cannabis is eaten. This is primarily because THC passess through the digestive system when eaten, so more of it is processed by the liver and converted to 11-OH-THC before making its way into the bloodstream.
When 11-OH-THC is oxidized by the same family of enzymes, it produces THC-COOH, an inactive metabolite which is one of the main end products of cannabis use. Usually by 30-45 minutes after smoking, THC-COOH concentrations have gradually increased and are found in higher levels than THC concentrations. This indicates that the THC is being metabolized into these derivatives — which are no longer able to bind to cannabinoid receptors and so are without medicinal effects. THC-COOH is what drug tests generally look for to detect the presence of cannabis in urine.
Other cannabinoids, such as CBD, go through similar processes, undergoing metabolization into a variety of metabolites. Although notably, a large portion of any CBD dose passes through the system unchanged and is excreted in feces.
Interestingly, the enzymes responsible for phase 1 metabolization can vary from person to person due to genetic factors. So some people metabolize THC and CBD differently from others. Some experience the psychotropic effects longer than others, or are more likely to fail a drug test due to a higher accumulation of cannabinoids in their system.
In phase 2, the process is all about preparing the drug to exit the body. In this step UGT enzymes are able to connect a glucuronide molecule to THC-COOH. This turns the chemical into a THC-COOH-glucuronide molecule, which is easy to excrete from the body in substances like urine and fecal matter. Once transformed to this metabolite, the drug is ready to be eliminated from the body.
In the last stage of this process, the metabolites of THC are eliminated from the body when the person urinates or has a bowel movement.
Within an average of five days, 80-90% of THC and (mostly) its metabolites will have been excreted — more than 65% via feces and 20% via the urine. But this isn’t the end of the story. Some of the THC (and its metabolites) will remain bound up in tissue, and will be released more slowly. This is why THC’s metabolites can be detected weeks after use for some cannabis users.
As we can see, cannabis’ active components take a long journey from absorption to elimination — transforming from one chemical to another as they go. What starts out as THC when we first absorb it, will likely end up as a totally different chemical by the time it exits your body. Still, this incredible process enables cannabis to enter our system, provide its impressive array of effects, and then exit our system without building up — making medical cannabis use possible.