How Does the Body Metabolize Cannabinoids?

We love smoking some weed — it's fun — but what exactly happens in your body when you do so, and how does your body process it?

Have you ever wondered why some people love cannabis while some detest it? Some users can't stay away from it, whereas others can go on for years without touching a joint ever again. 

The metabolism process of cannabis is quite intricate, unlike other drugs, because cannabis has over 18 classes of chemicals consisting of over 421 ingredients. And the majority of them require metabolism in your body to be processed. 

Scientists are still trying to figure out how the body metabolizes all these ingredients, but they have uncovered some interesting insights. 

In this article, learn what they are and how your body metabolizes cannabinoids after you smoke one doobie.

About Cannabinoids

But what exactly are cannabinoids?

You've probably heard of the endocannabinoid system if you've been in the cannabis space for a while. Named after cannabis — the herb responsible for its discovery — the endocannabinoid system (ECS) is a physiologic system that regulates bodily functions, including emotion, sleep cycle, inflammation, temperature, control, and libido. 

And cannabis contains cannabinoids, too, known as exogenous cannabinoids. These cannabinoids interact with our endocannabinoid system, causing various effects, like getting high. 

When you consume cannabis, its cannabinoids latch onto your body's cannabinoid receptors (CB1 and CB2), leading to the high. 

However, the process is not so simple. First, your body needs to metabolize the cannabinoids to eliminate them from the body. Otherwise, you'd be perpetually high with a single joint.

Cannabinoids Activation

Before we get into metabolism, we must understand cannabinoids in their pre-active and active forms. When cannabis buds are harvested, the cannabinoids are primarily in a pre-active acid form. For example, THC is in THC-A form, where the A stands for acid. 

These cannabinoid acids have some dynamic effects, but they are not psychoactive. So, for example, THC-A has some of the anti-inflammatory effects of THC, but it will not get you high. 

To activate the cannabinoids, the compounds must undergo a decarboxylation process before consuming them. You can do this by heating the compounds to a specific temperature. Otherwise, you won't get high even if you eat the buds. For example, you heat the buds in the oven before making cookies, right? Or, you light up a joint, which is nothing but heating teh buds. That's your decarboxylation process right there. 

But, why is it necessary? Well, it's because your body's metabolism does not activate the cannabinoids. It only tries to process it and excrete it out of your system. You can understand metabolism by knowing the pre-active and active forms of cannabinoids.

Metabolism of Cannabinoids

Every drug you consume, whether it is caffeine or cannabis, is metabolized in your body before it is excreted in the form of feces or urine. 

When you consume cannabis, it enters your system in two ways, depending on how you consume it. If you smoke cannabis, it gets absorbed via the lungs, and if you eat an edible, it gets absorbed in the small intestine. 

The cannabinoids get absorbed into the bloodstream from the lungs or small intestine, then get distributed to the rest of your body, where they get you high or provide medicinal benefits.

During this metabolism process, the drug (read: cannabinoids) is modified and made less active to make it easier for your body. However, unlike what many think, metabolism does not break down the cannabinoids; instead, it adds more molecules like oxygen and sugars to the cannabinoids.

The unique thing about cannabis is that its metabolism process is more complex than other drugs, which are done by enzymes in your GI tract and liver. 

Metabolic enzymes are a type of enzyme responsible for regulating your body's metabolic pathways. These enzymes convert the cannabinoids into conjugates, making them easier for the kidneys and bile to filter and excrete out of the body. 

Below is what the metabolism of cannabinoids looks like.

Phase I: Oxidation of Cannabinoids via CYP 450

There are over 300,000 CYP proteins in life on earth, and everything from a tiny virus to plants and humans use these proteins and enzymes for compound metabolism. According to studies, these proteins take care of about 75% of the overall metabolism. They also metabolize hormones like testosterone, estrogen, and glucocorticoids.

And they are responsible for metabolizing cannabinoids, too. 

When cannabinoids enter your body, your body quickly starts metabolizing them, beginning with phase I with the help of CYP 450. This stage includes oxidation, hydrolysis, reduction, and cyclization of the cannabinoids.

This is the first step of metabolism, where oxygen is added to the cannabinoids. This process relies heavily on special enzymes like the cytochrome P450 monooxidase system (CYP 450).

The phase I metabolism of cannabinoids produces inactive and active metabolites, like 11-OH-THC (active) and THC-COOH (inactive). The 11-OH-THC is formed first, where it gets oxidized and turned into THC-COOH.

An interesting occurrence with 11-OH-THC is that lower levels of it are found in the blood plasma of someone who has smoked cannabis than someone who has eaten weed brownies. This shows that more THC is processed by the liver. 

Phase II Metabolism: The Conjugation of Metabolites

In the next phase, the metabolites are paired with other functional groups of metabolites, like sulfate, glucuronic acid, glycine, and glutathione. 

During cannabinoid metabolism, glucuronic acid acts as the primary metabolite. So, during phase II, both CBD and THC are converted into CBD-COOH-Glucuronic Acid and THC-COOH-Glucuronic Acid.

phase II metabolism's function is to completely deactivate the cannabinoids, thereby increasing their renal clearance and water solubility, which helps your body get rid of them quickly via urine and feces.

Metabolism of CBD

Let's get into the two main cannabinoids in cannabis, CBD and THC, beginning with CBD.

Scientists have discovered over 30 unique CBD metabolites, where the primary ones are 7-COOH-CBD and 7-Hydroxy-CBD (7-OH-CBD). Both the primary metabolites are at par with CBD when it comes to potency. 

During phase I metabolism, CBD is metabolized using CYP3A4, CYP2C19, and CYP2D6. This gives rise to metabolites like 7-COOH-CBD, 6β-OH-CBD, 1-OH-CBD, 5-OH-CBD, 6α-OH-CBD, and 4-OH-CBD.

Then, in phase II, these metabolites are converted into glucuronide conjugates in the liver. UDP-glucuronosyltransferases UGT2B7 and UGT1A9 accomplish this process. And finally, they are eliminated from the body via feces and urine.

CBD's Detectability in the Body

Coming to the important question — will you fail your drug tests? Fortunately, CBD is metabolized by the body quickly. So, if you are an infrequent user, your body can eliminate all the CBD within a couple of days. And if you smoke daily going over 10 mg every day for about two weeks), your body will take around five days to eliminate CBD.

Metabolism of THC

Coming to THC, your body begins metabolizing THC instantly — in some users, this occurs in your lungs itself when you smoke. 

During THC's phase I metabolism, oxidation and hydroxylation are carried out in the liver with the help of CYP2C9, CYP3A4, and CYP2C19 isoenzymes.

Phase I leads to the production of over 100 THC metabolites, where the primary ones are 9/11-Carboxy-Tetrahydrocannabinol (THC-COOH) and 11-Hydroxy-Tetrahydrocannabinol (11-OH-THC). Here, the latter is the active metabolite that is responsible for the high; it peaks around 13 minutes after you smoke up. 

The other metabolite, THC-COOH, is inactive and does not get you high, and it is formed due to the 11-OH-THC's oxidation. This metabolite peaks around 80 minutes after you smoke up.

In the phase II metabolism of THC, both the metabolites are further converted into glucuronide conjugates like THC-COOH-glucuronide and 8α-OH-THC in the liver. Here, glucuronic acid combines with the metabolites to make them water-soluble so that they can be excreted out of urine via kidneys.

Delta 8 THC Metabolism

The body similarly metabolizes Delta 8 THC like Delta 9 THC. In phase I, it is converted to THC-COOH and 7-OH-THC conjugated in phase II and eliminated through urine and feces. 

Other THC isomers, like Delta 10 THC, THCP, HHC, etc., also probably go through the same route, but more studies are required to confirm the same.

THC's Detectability in the Body

When it comes to THC's half-life in your body, it is around 1 to 3 days if you smoke up occasionally and approximately two weeks if you smoke up regularly. According to studies, THC-COOH, a primary metabolite, remains in your blood for around 74.3 hours.

THC Excretion

Research suggests that over 65% of THC is eliminated from your body via feces and around 20% via urine. But that's not 100%? You're right. Most of the THC is converted to glucuronide conjugates like THC-COOH and 7-OH-THC during the metabolism process, but some of it is directly eliminated from the body.

Metabolism of Other Cannabinoids (THCV, CBG, and THC-O)

What about other cannabinoids present in cannabis, like THCV or CBG? There aren't enough studies to determine how the human body metabolizes these cannabinoids. Only little is known. Let's take a look at the data available so far.

THCV Metabolism

There haven't been any substantial studies that examine the metabolism of THCV; however, being THC's homolog, scientists believe that it perhaps goes through the metabolic pathways taken by THC as well. 

And some studies even suggest that THCV's metabolites are excreted via urine in the form of THCV-COOH and other conjugates. These studies found that THCV stays detectable in the urine for up to 14 days after smoking even one joint.

CBG Metabolism

Similarly, not a lot is known about the metabolism of cannabigerol (CBG). The most significant studies date back to the early 1990s.

However, according to the limited research we have so far, scientists think that CBG travels through the same metabolism routes as CBD and THC. It most likely undergoes oxidation in phase I followed by phase II, where it turns into glucuronic conjugate, eventually being eliminated via feces and urine.

THC-O Metabolism

THC-O is a prodrug of THC. So, your body first converts THC-O into THC through similar metabolic pathways used to metabolize other cannabinoids. This is a unique case where the compound is made stronger during the metabolism process instead of being neutralized.

Here, the THC-O compound is esterified through acetate groups and converted to THCA or THC. The acetate group allows your body to absorb the cannabinoid more efficiently. Then, it is converted into Delta 8 THC, Delta 9 THC, or Delta 10 THC. 

It follows the same metabolism pathways as regular THC to be eliminated from the body subsequently. However, due to the additional step where it is converted to THC, the compound takes over an hour to peak and stays active for about 25% longer than regular THC.

Duration of Cannabinoid Metabolism

How fast your body metabolizes and excretes cannabinoids depends on how you consume them. Let's look at the two most common forms of consumption: smoking and eating.

Metabolism After Smoking Cannabis

Smoking is the most common form of consuming cannabis around the world. So, once you smoke cannabis, the THC and CBD, along with other cannabinoids, are absorbed by the lungs within seconds, reaching high concentrations within ten minutes.

Most of the THC peaks around 15 minutes after smoking as it gets converted into a psychotic compound, while the rest turn inactive and are excreted after 81 minutes. 

After five days, around 65% of the THC is eliminated from the body via feces, and another 20% is expelled via urine. There will still be some residual THC in your blood plasma for a couple of weeks and inactive THC for under a month.

On the other hand, CBD reaches its peak within three minutes after smoking, where a fraction of it is turned into inactive CBD, and the rest is metabolized into conjugates. The rest is eliminated via the urine.

However, things get tricky when THC and CBD are consumed simultaneously. CBD latches onto Cytochrome P450, making it less effective in metabolizing THC. So, more CBD can enhance the effects of THC in your body and keep it in your body for longer. Terpenes like pinene, myrcene, and limonene can also inhibit P450, causing similar results.

Metabolism After Eating Edibles

If you've ever eaten an edible, you know how potent it can be. It's because the digestion of cannabis is comparatively slower than smoked cannabis. 

When eaten, the cannabinoids first go through the stomach, reaching the small intestine, where they get absorbed and transferred to the liver. So, it usually takes a couple of hours for consumed cannabinoids to peak and reach the maximum concentration in the blood. 

Factors that Affect the Cannabinoid Metabolism

Cannabinoids are complex compounds, and many factors affect how it is metabolized in the body. And understanding how these factors play a role is quite complicated and under-researched.

However, according to studies, here are some of the significant factors that affect metabolism:

• Age: The older you get, the slower your body metabolizes cannabinoids.
• Genetics: Genes affect how your body produces the CYP450 enzymes, so it alters how your body metabolizes these cannabinoids. 
• Underlying illness: Some diseases, especially those in the liver and kidney, slow down your body's metabolic pathways, leading to longer metabolism times.
• Other medications: If other drugs you consume use the same metabolic pathways, your body will metabolize cannabinoids a lot slower than usual.

Interactions Between Cannabinoids and Other Medications

While cannabis itself is safe to consume in moderate quantities, there may be interactions with other drugs, making it more harmful for your body. And unlike many claims on the internet, studies have proved that cannabinoids in cannabis do interact with various medications and other drugs.

Cannabinoids interact with other medications that require the same metabolic pathways or enzymes. If that happens, cannabinoids are forced to wait in the queue, so it slows down the metabolism process significantly, leading to two possible outcomes:

1. Side effects may increase due to slowed metabolism.
2. The effect of cannabinoids is wholly negated due to slow metabolism.

On the other hand, cannabinoids can get ahead in the queue and stop other drugs from being metabolized. When this happens, harmful compounds may stay in your body longer than intended, causing adverse side effects.

For example, Warfarin is an anticoagulant that tends to interact with CBD. Thus, the interaction between CBD and Warfarin leads to a higher concentration of the drug in your body, leading to bleeding. 

So, it's better to know how cannabinoids will react with other medications to consume those medications safely without experiencing side effects. Below are some examples of how cannabinoids react with other prescription medications.

Interaction of Cannabinoids with Prescription Medications

While the risk of non-psychotropic cannabinoids like CBD, CBC, and CBG, reacting with prescription medications is low, some cannabinoids can still lead to harmful effects. This is especially the case when metabolic competition between these cannabinoids and medications occurs.

High-Risk Interactions

Here, the risk of interaction between cannabinoids and prescription medications is higher, leading to severe side effects. In addition, these are commonly used medications, and the risks often have a short therapeutic window. Consuming these medications with cannabinoids regularly can lead to serum levels rising in your body, which can lead to toxicity. 

Here are some of the common drugs that are high-risk when taken with cannabinoids:

Moderate Risk Interactions

Drugs that use CYP3A4 and CYP2D6 usually have a mild risk of interacting with cannabinoids in your body. These prescription medications don't really interact, but we recommend caution when consuming these anyway. 

Here are some of the common drugs that are moderate-risk when taken with cannabinoids:

Let Your Doctor or Pharmacist Know

The list mentioned above does not encompass everything you need to know about cannabis interaction with other medications. It's hard to pinpoint whether a specific strain of cannabis will interact with your medicine — it depends on several factors — however, the table can guide you to make better decisions.

We also recommend discussing with your doctor or pharmacist before consuming your prescription medicine with cannabis, even if you are consuming cannabis for its medicinal benefits. A healthcare professional can help you make an informed decision and make it safer to consume the medicines.

Summary: How Does the Body Metabolize Cannabinoids?

Cannabinoids mostly follow the same metabolic pathways in your body. And in some cases, the metabolism begins as early as the smoke enters your lungs or small intestines. And the rest of the metabolism occurs in the following couple of hours when the cannabinoids enter the liver.

CYP450 enzymes start metabolizing cannabis during the metabolism process by adding various compounds to them, making them water-soluble and easy to eliminate via feces or urine.

THC gets converted to another metabolite, 7-OH-THC, which gives you the high, followed by being converted into THC-COOH and other inactive conjugated metabolites.

On the other hand, CBD follows the same metabolic pathway to turn into 7-OH-CBD, followed by COOH-CBD and other conjugates.

These conjugates are then filtered and excreted from the body via the bile and kidneys.

It is essential to know how cannabinoids metabolize in your body and potentially interact with other drugs, so you can be wary while consuming them and spot any negative interactions as soon as they appear.