What is the “Mechanism of Action?”

CBD is a safe, non-intoxicating, and non-addictive cannabis compound with significant therapeutic attributes, but CBD-drug interactions may be problematic in some cases. CBD and other plant cannabinoids can potentially interact with many pharmaceuticals by inhibiting the activity of the liver’s enzyme system responsible for metabolizing 90% of drugs and other foreign substances (the Cytochrome P-450 System). This leads to higher levels of the drug in your system at one time, which can cause unwanted side effects and even overdose. Thus, if you are taking a drug affected by CBD, you may need a dosage adjustment in order to take both drugs safely. With CBD poised to become widely available in pharmaceutical, nutraceutical, and herbal preparations, medical scientists are taking a closer look at CBD-drug interactions.

When CBD or any other foreign compound enters the body, they are metabolized. This process is generally very complicated. Metabolizing something properly can involve multiple molecular pathways and various enzymes that enable the body to get rid of the compound (often done by adding chemical group(s) to the original compound). Or, metabolism can entail breaking down a compound into a more basic molecule that the body then uses.

Products of a drug’s metabolism are called its metabolites. These metabolites can have very different properties than the initial drug. Ethanol, for example, owes some of its effects, including much of the hangover, to its two-step metabolism. The buildup of acetaldehyde in the liver (ethanol is first converted to acetaldehyde) is a major reason for ethanol’s liver toxicity and the nausea and vomiting caused by excessive consumption.

What is the Cytochrome P-450 System?

The Cytochrome P-450 enzyme system is a system within the liver that is responsible for metabolizing 90 percent of the drugs and foreign substances we consume. This system contains more than 50 enzymes that process and eliminate toxins.  It is also essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A2. Of the more than 50 CYP450 enzymes, the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize 90 percent of drugs with the two most significant enzymes being CYP3A4 and CYP2D6. These enzymes are predominantly expressed in the liver, but also occur in the small intestine (reducing drug bioavailability), lungs, placenta, and kidneys.

Cytochrome P-450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the Cytochrome P-450 enzymes. Knowledge of drugs metabolized by Cytochrome P-450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of drug interactions as well as adverse drug reactions.

In addition, genetic variability (polymorphisms) in these enzymes may influence a patient's response to commonly prescribed drug classes.

Further, certain drugs affect “processing times” within the Cytochrome P450 system, thus making other drugs metabolize faster or slower than they would by themselves. Similarly, if the system is unhealthy because of liver problems or other pre-existing conditions, drugs may not metabolize as they should. This may lead to elevated and potentially toxic blood levels.

Metabolizing Tetrahydrocannabinol (THC)

THC metabolites contribute significantly to the effects of Cannabis. Eleven-hydroxy-THC (11-OH-THC), for example, is a THC metabolite that activates the CB1 cannabinoid receptor in the brain and induces a high that may be greater than that of THC itself. This means that the body’s metabolism of THC can make it more potent.

Different routes of cannabinoid administration have different effects. Inhaled THC enters capillaries in the lungs, passes into general circulation through the pulmonary arteries, and quickly crosses the blood-brain barrier. When ingested orally, however, THC is absorbed in the small intestine and then carried to the liver, where it is metabolized by subclasses of Cytochrome P450, specifically the CYP2C and CYP3A enzymes. These liver enzymes also metabolize CBD, converting it into 7-OH-CBD and 6-OH-CBD. But there has been relatively little research into the properties of these CBD metabolites.

Metabolizing Cannabidiol (CBD)

The way CBD interacts with Cytochrome P-450 is pivotal; they deactivate each other. Preclinical research shows that CBD is metabolized by Cytochrome P450 enzymes while functioning as a “competitive inhibitor” of the same liver enzymes. By occupying the site of enzymatic activity, CBD displaces its chemical competitors and prevents Cytochrome P-450 from metabolizing other compounds.

The extent to which CBD behaves as a competitive inhibitor of Cytochrome P450 depends on how tightly CBD binds to the active site of the metabolic enzyme before and after oxidation. This can change greatly, depending on how—and how much—CBD is administered, the unique attributes of the individual taking this medication, and whether isolated CBD or a whole plant remedy is used.

If the dosage of CBD is low enough, it will have no noticeable effect on CYP activity, but CBD may still exert other effects. There is no clearly established cut-off dose, below which CBD does not interact with other drugs.

How do CBD-generated changes in Cytochrome P-450 activity impact the metabolic breakdown of THC? Animal studies indicate that CBD pretreatment modifies brain levels of THC. That’s because CBD, functioning as a competitive inhibitor of Cytochrome P450, slows down the conversion of THC into its more potent metabolite, 11-OH-THC. Consequently, THC remains active for a longer duration, but the peak of the extended buzz is blunted somewhat under the influence of CBD.

Grapefruit and Ganja

Lester Bornheim, a research pharmacologist at the University of California in San Francisco, was among the first scientists to study the metabolism of CBD. In 1987, he was awarded a NIDA grant to investigate the effects of Phyto-cannabinoids on Cytochrome P-450 enzymes. THC and Cannabinol (CBN) also inhibit CYP activity, but CBD, of all the plant cannabinoids studied, is the strongest Cytochrome P-450 deactivator.

In 1999, Bornheim addressed the annual gathering of the International Cannabinoid Research Society (ICRS) and drew attention to the possibility that CBD could interfere with the metabolism of many medications. A year earlier, a team of Canadian scientists identified certain compounds in grapefruit that inhibit the expression of some Cytochrome P-450 enzymes—which is why physicians often warn patients not to eat grapefruit before taking their medications. CBD, it turns out, is a more potent inhibitor of Cytochrome P450 enzymes than the grapefruit compound Bergapten (the strongest of several grapefruit components that inhibit CYPs).

What does this mean in practical terms for a medical marijuana patient on a CBD-rich treatment regimen who takes a prescription blood-thinner like Warfarin, for example? CBD reduces the enzymatic degradation of Warfarin, thereby increasing its duration of action and effect. A person taking a CBD-rich product should pay close attention to changes in blood levels of Warfarin, and adjust dosage accordingly as instructed by their doctor and pharmacist.

CYPs In Cancer and Epilepsy

In cancer treatment, the precise dosing of chemotherapy is considered to be extremely important. Doctors often struggle to find the maximum dose that will not be catastrophically toxic. Many chemotherapy agents are oxidized by CYPs before their inactivation or excretion. This means that for patients using CBD, the same dose of chemotherapy may produce higher blood concentrations. If CBD inhibits the Cytochrome-mediated metabolism of the chemotherapy and dosage adjustments aren’t made, the chemotherapy agent could accumulate within the body to highly toxic levels.

However, there have been few reported adverse cannabinoid-drug interactions among the many cancer patients who use cannabis to cope with the wrenching side effects of chemotherapy. It is possible that whole plant cannabis, with its rich compensatory synergies, interacts differently than the isolated CBD that is administered in most research settings. As well, the cytoprotective effects of the cannabinoids may mitigate some of the chemotherapeutic toxicity.

Some epileptic patients have encountered issues with how CBD interacts with their anti-seizure medication. A small clinical study at Massachusetts General Hospital involving children with refractory epilepsy found that CBD elevated the plasma levels and increased the long-term blood concentrations of an anticonvulsant. A majority of these children needed to have their dose reduced due to side effects. Given that both the anti-seizure drug and CBD are metabolized by Cytochrome P450 enzymes, a drug-drug interaction is not surprising.

Dr. Bonni Goldstein has observed cases in which small doses of high-CBD/low-THC cannabis oil concentrate seemed to aggravate seizure disorders rather than quell them. How could this happen, given CBD’s renown anti-epileptic properties?

A 1992 review by Lester Bornheim and his colleagues indicated that CBD inhibits some Cytochrome P-450 enzymes at smaller doses than what is required for CBD to exert an anti-epileptic effect. This means that a certain dose of CBD could alter the processing of an anti-epileptic drug taken by the patient, but this amount of CBD might not be enough to provide any anti-epileptic relief itself. The advice some physicians offer in this situation may seem counterintuitive: Increase the dose of CBD—perhaps even add a little more THC (or THCA, the raw, unheated, non-psychoactive version of THC)—and this may be more effective for seizure control.

Drugs That Interact with Cannabidiol

Any drug metabolized by Cytochrome P-450 enzymes could potentially interact with Cannabidiol. According to the Indiana University Department of Medicine, drugs known to use the Cytochrome P-450 system include:

    •    Steroids
    •    HMG CoA reductase inhibitors (Statins)
    •    Calcium Channel Blockers
    •    Antihistamines
    •    Prokinetics
    •    HIV Antivirals
    •    Immune Modulators
    •    Benzodiazepines
    •    Anti-Arrhythmics
    •    Antibiotics
    •    Anesthetics
    •    Anti-Psychotics
    •    Anti-Depressants
    •    Anti-Epileptics
    •    Beta Blockers
    •    Proton Pump Inhibitors (PPIs)
    •    NSAIDs
    •    Angiotensin II Blockers
    •    Oral Hypoglycemic Agents
    •    Sulfonylureas

Keep in mind that this list does not necessarily contain every medication that could be affected by Cannabidiol. Likewise, not every medication in each of the categories listed will cause an interaction. For this reason, you should consult with a Pharmacist or Physician prior to taking any combination of drugs at the same time. Alternative medications or dosage adjustments of current medications may be required. If you are worried that your P-450 enzyme system may not be functioning properly, physicians can test the system to ensure that the medications you take are metabolizing as expected.