Effects of the P450 Enzymes

Do you remember learning about metabolism in high school biology? Just in case you’ve forgotten, I’ve listed here the basic definitions of the word “metabolism” according to Dictionary.com:

  1. the sum of the physical and chemical processes in an organism by which its material substance is produced, maintained, and destroyed, and by which energy is made available
  2. any basic process of organic functioning or operating

When any foreign compound, including prescription or over-the-counter medication, is introduced into the human body, it is metabolized. Metabolism is a sum of processes, and as such, it is generally very complicated. Multiple molecular pathways and a variety of enzymes work together to break down foreign compounds, which are then either used by the body in the more basic molecular form or eliminated. When the body metabolizes medications, the products are called metabolites, and metabolites are often significantly different from the initial drug. Among the variety of enzymes that metabolize pharmaceuticals in the human body is the cytochrome P450, a family of liver enzymes. This key enzyme group metabolizes most of the drugs we consume by oxidizing them, which generally means incorporating an oxygen atom into the drug’s molecular structure. Oxidation will usually make a compound more water soluble and therefore easier for the kidneys to filter out.

CBD and other plant cannabinoids can potentially alter how human bodies metabolize a wide range of compounds by inhibiting the function of cytochrome P450 enzymes.  At sufficient dosages, CBD will temporarily deactivate the P450 enzymes by occupying the site of enzymatic activity. CBD displaces chemical competitors and prevents the cytochrome P450 enzymes from metabolizing other compounds. The extent to which CBD acts as a competitive inhibitor depends on how tightly it binds to the active site of the metabolic enzyme before and after oxidation.  Several variables affect the process, including how -- and how much -- CBD is administered, the unique attributes of the individual taking the medication, and whether the individual is using isolated CBD or a whole-plant remedy. People take CBD orally for anxiety, bipolar disorder, dystonia, seizures, multiple sclerosis, Parkinson's disease, and schizophrenia (among others). CBD can be inhaled to help people quit smoking.

Different methods for introducing cannabinoids into the body create different effects. For example, inhaled THC enters capillaries in the lungs, passes into general circulation through the pulmonary arteries, and quickly crosses the blood-brain barrier. However, when ingested orally, THC is absorbed in the small intestine and then carried to the liver, where it is metabolized by subclasses of cytochrome P450 enzymes. CBD appears to reduce pain and anxiety. Additionally, CBD seems to have antipsychotic effects. Although it remains unclear exactly how these effects occur, CBD appears to prevent the breakdown of a chemical in the brain that affects pain, mood, and mental function. Most studies suggest there is a bidirectional modulatory relationship between the human body’s natural opioid system and its endocannabinoid system. Understanding exactly how they interact remains elusive, but the pain-relieving properties of cannabis are well-established.  In fact, many medical professionals have suggested that cannabis could play a role in easing the overuse of opioids. CBD could represent an effective alternative for managing chronic pain. 

Drugs that cause CYP450 drug interactions are referred to as either inhibitors or inducers. An inducer can increase the rate of another drug's metabolism by as much as two- to threefold over a period of a week. When an inducer is prescribed with another medication, the dosage of the other medication may need to be adjusted since the rate of metabolism is increased and the effect of the medication is reduced. This can lead to the medication not working. Conversely, if a medication is taken with an agent that inhibits its metabolism, the drug level can rise and possibly result in harmful side effects. Cytochrome P450 enzymes are crucial for metabolizing most medications. Sometimes cytochrome P450 enzymes are either inhibited or induced by specific medications, resulting in significant interactions that can cause unexpected side effects. Sometimes the drugs just don’t work as usual. Genetic variability in these enzymes can influence how a patient responds to medications. Knowledge about the drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of negative drug reactions and interactions.

In cancer treatment, the exact dosage of chemotherapy is extremely important; doctors strive to find the maximum dose of medication that will not become tragically toxic. Many chemotherapy agents are oxidized by P450 enzymes before they run their course and are eliminated. For patients using CBD, the same dose of chemotherapy may produce higher blood concentrations. If CBD inhibits the cytochrome-mediated metabolism of the chemotherapy but dosage adjustments aren’t made, the chemotherapy agent might accumulate to highly toxic levels. However, few adverse interactions have ever been reported by the numerous cancer patients who use CBD to help cope with the side effects of chemotherapy. This might be due to the fact that whole plant cannabis interacts differently than the isolated CBD generally administered in most research settings.

Some epileptic patients have had issues with the way CBD interacts with their anti-seizure medication. A small clinical study at Massachusetts General Hospital, published in May 2015, involved children with refractory epilepsy.  The study found that CBD both elevated the plasma levels and increased the long-term blood concentrations of an anticonvulsant, and an active metabolite of the medication. Most of the children who participated in the study needed to have their dosage of the medication reduced because of side effects. Considering that that the medication and CBD are both metabolized by cytochrome P450 enzymes, a drug-drug interaction is not surprising. The study concluded that “CBD is a safe and effective treatment of refractory epilepsy in patients receiving [clobazam].” Additionally, a 1992 review determined that CBD inhibits some cytochrome P450 enzymes at smaller doses than that required for CBD to exert an anti-epileptic effect. This means that a certain dose of CBD could alter the way the body processes anti-epileptic medications, but this amount of CBD is probably not enough to provide any anti-epileptic relief itself.