What role do enzymes play in CBD?

CBD and enzymes

Cannabidiol is a safe, non-intoxicating, and non-addictive cannabis compound with significant therapeutic properties, but interactions between CBD and drugs can be problematic in some cases. 

CBD and other plant cannabinoids can potentially interact with many drugs by inhibiting the activity of cytochrome P450, a family of liver enzymes. This important group of enzymes metabolizes most of the drugs we consume, including more than 60 percent of the drugs marketed. 

When dosed in sufficient quantities, CBD temporarily deactivates cytochrome P450 enzymes, thereby changing the way we metabolize a wide variety of compounds, including tetrahydrocannabinol (THC), which causes the high cannabis is known for. 

Metabolize THC 

When THC or some other foreign compound gets into the body, it is metabolized. This process is generally very complicated. Proper metabolism can involve multiple molecular pathways and various enzymes that allow the body to get rid of the compound (often this happens by adding something to the original compound). Metabolism can also mean breaking down a compound into a simpler molecule that the body then uses. 

The products of the metabolism of a drug are called metabolites. These metabolites can have very different properties than the original 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 and then to acetic acid - is a major cause of ethanol's liver toxicity and the nausea and vomiting caused by excessive consumption. 

The THC metabolites contribute significantly to the effects of cannabis use. Elf-Hydroxy-THC (11-OH-THC), for example, is a THC metabolite that activates the CB1 cannabinoid receptor in the brain and induces a stronger high than THC itself. This means that the body's own metabolism of THC can increase its effects. 

Cytochrome P450 enzymes contribute to the metabolism of drugs by oxidizing them, which generally means they build an oxygen atom into the drug's molecular structure. Oxidation usually makes a compound more soluble in water and can therefore be more easily filtered out by the kidneys. Both of the steps in the metabolism of ethanol and the conversion of THC to 11-OH-THC mentioned above involve oxidation (although ethanol is not specifically oxidized by cytochrome P450). 

Different routes of administration of cannabinoids have different effects. Inhaled THC reaches the capillaries of the lungs, is conducted into the general circulation via the pulmonary arteries and quickly crosses the blood-brain barrier. When taken orally, however, THC is absorbed in the small intestine and then transported to the liver, where it is metabolized by subclasses of the cytochrome P450 (abbreviated to CYP), particularly the CYP2C and CYP3A enzymes. 

These liver enzymes also metabolize CBD, converting it to 7-OH-CBD and 6-OH-CBD. However, the properties of these CBD metabolites are still relatively little explored. 

Metabolism of CBD 

The way CBD interacts with cytochrome P450 is critically important; essentially they disable each other. Preclinical research shows that CBD is metabolized by cytochrome P450 enzymes and at the same time acts as a “competitive inhibitor” for the same liver enzymes. By occupying the site of enzymatic activity, CBD displaces its chemical competitors and prevents cytochrome P450 from metabolizing other compounds. 

The extent to which cannabidiol 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 vary greatly depending on how - and in what amount - CBD is administered, the particular characteristics of the person taking this drug, and whether isolated CBD or a whole herbal remedy is used. 

When the dosage of cannabidiol is low enough, it has no noticeable effects on CYP activity, but CBD can still have other effects. There is no clearly defined limit dose below which CBD will not interact with other drugs. In a 2013 report on a clinical study with Sativex from GW Pharmaceutical, a CBD-rich sublingual spray made from the whole plant, no interactions with CYP enzymes were found when approximately 40 mg of CBD was administered. However, in a later clinical study it was found that 25 mg of orally administered CBD significantly blocked the metabolism of an anti-epileptic drug. 

How do CBD-related changes in cytochrome P450 activity affect the metabolic breakdown of THC? Animal studies suggest that CBD pretreatment increases levels of THC in the brain. That's because, as a competitive inhibitor of cytochrome P450, CBD slows the conversion of THC into its more potent metabolite, 11-OH-THC. As a result, THC stays active longer, but the peak of the prolonged high is somewhat weakened under the influence of cannabidiol. 

Other factors play an important role in CBD's ability to mitigate or neutralize the THC high. 

Grapefruit and marijuana 

Lester Bornheim, a research pharmacologist at the University of California at San Francisco, was one of the first scientists to study the metabolism of CBD. In 1987 he was awarded a NIDA grant to study the effects of phytocannabinoids on cytochrome P450 enzymes. THC and cannabinol (CBN) also inhibit CYP activity, but of all the plant cannabinoids studied, CBD is the most powerful cytochrome P450 deactivator. 

“It's a very unusual enzyme. Almost all other enzymes are designed for a single substrate and carry out a single chemical process that leads to a single product, ”noted Bornheim, while numerous drugs are substrates for cytochrome P450, which acts as a general breakdown mechanism for a wide range of exogenous and endogenous substances seems to work. 

In 1999, Bornheim spoke at the International Cannabinoid Research Society (ICRS) annual meeting, pointing out the possibility that CBD could affect the metabolism of many drugs. A year earlier, a team of Canadian scientists had identified certain compounds in grapefruit that inhibit the expression of some cytochrome P450 enzymes - which is why doctors often warn their patients not to eat grapefruit before taking their medication. As it turns out, CBD is a stronger inhibitor of cytochrome P450 enzymes than the grapefruit compound bergapten (the most potent of several grapefruit constituents that inhibit CYPs). 

What does this mean in practice for a medical marijuana patient who is receiving high-CBD treatment and using a prescription blood thinner such as B. taking warfarin? CBD reduces the enzymatic breakdown of warfarin and thereby extends its duration and effect. A person taking a product containing CBD should pay close attention to changes in blood levels of warfarin and adjust the dosage accordingly as directed by their doctor. 

Cancer and epilepsy 

In the treatment of cancer, the exact dosage of chemotherapy is extremely important; doctors often struggle to find the maximum dose that is not catastrophically toxic. Many chemotherapy drugs are oxidized by CYPs before they are inactivated or excreted. This means that the same dose of chemotherapy can result in higher blood concentrations in patients taking CBD. If CBD inhibits the cytochrome-mediated metabolism of chemotherapy and no dose adjustment is made, the chemotherapeutic agent could accumulate in the body in highly toxic concentrations. 

However, by and large, there have been few reports of adverse drug-drug interactions among the many cancer patients who use cannabis to cope with the severe side effects of chemotherapy. It is possible that whole plant cannabis, with its abundant compensatory synergies, works differently than the isolated CBD that is administered in most research facilities. In addition, the cytoprotective effects of cannabinoids could mitigate some of the chemotherapeutic toxicity. 

Some epilepsy sufferers have had problems with how CBD interacts with their anti-seizure medications. A small clinical study at Massachusetts General Hospital, which was attended by children with refractory epilepsy, found that CBD increased plasma levels and long-term blood concentrations of clobazam, an anticonvulsant, and norclobazam, an active metabolite of this drug. The majority of these children had to reduce their dose of clobazam due to side effects. Since both clobazam and CBD are metabolized by cytochrome P450 enzymes, drug interaction is not surprising. The in Study published May 2015 concluded that "CBD is a safe and effective treatment for refractory epilepsy in patients receiving [clobazam]." But the report also emphasized the importance of monitoring blood levels of clobazam and norclobazam in patients taking both CBD and clobazam. 

Dr. Bonni Goldstein has observed cases of small doses of Cannabis oil concentrates those with high CBD and low THC levels appeared to make the seizure disorders worse rather than alleviate them. Given the well-known anti-epileptic properties of CBD, how did this happen? 

A 1992 study by Lester Bornheim and his colleagues showed that CBD inhibits some cytochrome P450 enzymes in lower doses than is necessary for the anti-epileptic effects of CBD. This means that a given dose of CBD could change the processing of an anti-epileptic drug taken by the patient, but that this amount of CBD may not be enough to produce an anti-epileptic effect on its own. The advice some doctors give in this situation may seem counter-intuitive: increase the dose of CBD - maybe even add a little more THC (or THCA, the raw, unheated, non-psychoactive version of THC) - and it can Make seizure control more effective. 

Enigmatic enzymes 

But why should preventing an anti-epileptic from breaking down should reduce its effectiveness? There are a number of possible answers depending on the drug. The active ingredient of the drug (the chemical that has an anti-epileptic effect) may be a breakdown product of the drug taken. So, by slowing down the metabolism of the original drug, CBD would make that drug less active. 

Other explanations are possible. For example, if the activity of certain CYPs is slowed down, the drug could be broken down through another metabolic pathway, the products of which could then interfere with the drug's effectiveness. Or perhaps the inhibition of CYPs is not the predominant way that CBD interacts with certain anti-epileptic drugs. 

To make matters even more complicated, a talk by Dr. Kazuhito Watanabe presented preliminary evidence at the 2015 International Cannabinoid Research Society meeting in Nova Scotia that cannabidiol can “induce”, ie increase, the activity of some cytochrome P450 enzymes. (When a protein is induced, the transcription of the corresponding mRNA is increased, which leads to an increased synthesis of the protein). This suggests that CBD can either increase or decrease the breakdown of other drugs. Again, it depends on the drug and the dosage used. 

Any pharmaceutical, nutraceutical, or green plan to harness the therapeutic potential of CBD must take into account the fact that cannabidiol is different Cytochrome P450- Can both inactivate and enhance enzymes in the liver - and this can potentially affect a wide range of drugs. Drug interactions are particularly important when taking life-saving or meaningful drugs, drugs with narrow therapeutic windows, or drugs with severe side effects. Especially those who use high doses of CBD concentrates and isolates should keep this in mind when mixing drugs. 

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