What is First-Pass Metabolism?
First-pass metabolism, often called the first-pass effect, is a key concept that explains why taking cannabis orally can lead to different effects compared to smoking, vaping, or using transdermal products. In short, when a substance is consumed through the mouth, it travels to the digestive system and passes through the liver before reaching the rest of the body. This process can alter both the concentration and the nature of the compounds that eventually enter the systemic circulation.
What Is Metabolism?
Metabolism is the body’s process of breaking down almost any material that enters it. This includes the food we eat, environmental chemicals, and various medications. Most metabolic processes occur in the liver, where specific enzymes transform fat-soluble (lipophilic) compounds into water-soluble (hydrophilic) molecules. This transformation facilitates the excretion of these substances through urine or feces.
When cannabis compounds (like THC or CBD) first enter the body, they are called parent compounds. After enzymes in the liver act upon them, they are turned into metabolites. These metabolites may be less active, equally active, or in some cases, more potent or toxic than the original compound.
How Does Cannabis Metabolism Work?
When cannabis is taken orally (e.g., edibles, oils, or capsules), it passes through the stomach and then into the intestine. From there, it enters the bloodstream through the portal vein, which carries it directly to the liver. Enzymes in the liver modify cannabis compounds during this first pass, typically making them more water-soluble so they can be more easily excreted.
For cannabidiol (CBD) and other cannabinoids, a group of enzymes called Cytochrome P450 (CYP) plays a major role. The activity of these enzymes can also be influenced by other substances (such as medications or certain foods), which helps explain why some people experience different reactions or intensities when combining cannabis with other drugs or supplements.
The Significance of the First-Pass Effect in Cannabis
When cannabis is administered via inhalation, it enters the bloodstream through the lungs and bypasses the liver’s initial metabolic step. With oral or oromucosal (under the tongue or in the cheek) administration, however, the first-pass effect ensures that liver enzymes transform a portion of the compounds before they reach the central bloodstream. This change affects both the concentration of the parent compound (such as THC or CBD) and the types of metabolites circulating in the body.
Because of the first-pass effect:
– Oral doses of cannabis may have delayed onset but can lead to longer-lasting effects.
– Certain metabolites, like 11-OH-THC, can be more potent than the original THC, resulting in a stronger or different kind of high than inhalation might produce.
– The ratio of parent compounds to their metabolites in the bloodstream greatly differs from that of other administration routes.
After the First-Pass Metabolism
Oral cannabis products often require higher initial doses to account for the loss of active compounds (or transformation into different metabolites) during first-pass metabolism. Depending on the specific compound, first-pass metabolism can either reduce or enhance its pharmacological activity:
Reduced Activity
Many cannabinoids become less active when metabolized. In practical terms, this means you may need a larger oral dose compared to inhalation to achieve similar results. While the breakdown of harmful substances is beneficial for detoxification, it can also reduce the desired potency of beneficial cannabinoids.
Enhanced or Altered Activity
Some metabolites formed during first-pass metabolism can be as active—or even more active—than the original compound. For THC, the formation of 11-OH-THC often leads to potent psychoactive effects that differ from those experienced with smoked or vaporized cannabis. In some cases, metabolites may also carry different side effects or toxicity levels.
Factors Influencing the First-Pass Metabolism
Route of Administration: Oral or oromucosal products undergo first-pass metabolism. In contrast, inhalation or transdermal applications bypass the liver at first, altering how much of the parent compound remains unchanged.
Genetic Variations: Individual genetic differences can lead to variations in liver enzyme activity, meaning some people produce more or fewer metabolites than others.
Environmental Factors: Diet, concurrent medications, and supplements can all affect how efficiently the liver’s enzymes metabolize cannabinoids. A high-fat meal, for instance, might enhance the absorption of lipophilic compounds and modify their metabolic pathways.
The First-Pass Effect and CBD
CBD also undergoes extensive first-pass metabolism when taken orally or through mucosal routes. Research suggests that humans produce several metabolites of CBD (including 7-COOH-CBD, 7-OH-CBD, 6⍺-OH-CBD, and 6β-OH-CBD), but their exact roles in producing CBD’s therapeutic effects are not yet fully understood. It remains to be seen whether these metabolites have their own health benefits or if they influence the overall profile of CBD’s activity. Future studies will help clarify whether these byproducts are beneficial, neutral, or perhaps even detrimental.
Why Knowing About the First-Pass Effect Matters
Understanding the first-pass effect is crucial for anyone interested in the therapeutic and recreational use of cannabis:
Dose Adjustments: Oral cannabis often requires a higher dose compared to smoking or vaping to achieve the same level of effects.
Timing of Effects: Edibles may take longer to produce noticeable results, but they can also provide a longer duration of action due to the metabolic processes in play.
Safety Considerations: Certain metabolites may increase the compound’s psychoactive strength or toxicity profile, underscoring the importance of responsible consumption and proper dosing.
Drug Interactions: People taking other medications should be mindful of possible interactions that could heighten or diminish the effects of cannabis.
Conclusion
The cannabis first-pass effect is a vital component of how cannabinoids are absorbed, distributed, and ultimately experienced in the body. Whether you’re using cannabis therapeutically or recreationally, understanding this phenomenon can help you make informed decisions about dosage, administration methods, and potential interactions. As research advances, scientists will likely uncover even more about how metabolism shapes the ways in which cannabis exerts its wide-ranging effects.