Meds CBD and Drug Interactions

[momofthegoons]

They aren't clear whether this is about ingesting CBD as an edible or if it also includes smoking/vaping.... ​

A list of drugs that can interact with cannabis can be found here in our research section.

​

What CBD And Grapefruit Have In Common When It Comes To Drug Interactions: Risks You Should Know​

Interest in cannabidiol (CBD) is exploding. Now that major retailers are carrying CBD products, plus an enormous selection online, curiosity is only going up. But we also need some healthy skepticism and caution to balance out the exuberance. CBD research is still in the early stages, and marketing is predictably outpacing facts. Concerns about safety, among other topics, are getting lost in the hype.

Apart from a short list of possible side-effects, bigger concerns revolve around how CBD interacts with other drugs. Here’s a brief breakdown of possible risks if you're thinking of trying it out.

What CBD and grapefruit have in common

You’re probably familiar with “grapefruit warnings” that appear on a variety of medications, or maybe your doctor or pharmacist has told you to avoid grapefruit or grapefruit juice when taking a particular med.

The reason for the warning is that grapefruit contains compounds called furanocoumarins that bind with and effectively neutralize enzymes in the gut (specifically a type called CYP450 enzymes), which help break down and eliminate drugs from the body. When these enzymes can’t do their job, too much of the drug enters the liver and flows unprocessed into the bloodstream. That elevates risk of having dangerously high levels of the drug in your system.

CBD is similar to grapefruit in that it also binds with those enzymes, but research suggests that it’s possibly even more potent because it binds in multiple parts of the gut and liver (grapefruit mainly affects enzymes within the small intestine). Once an enzyme has been inhibited, the effect isn't immediately reversed. It can take days for enzyme function to return to baseline and start the process again.

In particular, research has found that CBD is a "potent inhibitor" of two enzymes (CYP3A4 and CYP2D6) that affect many common drugs, including antihistamines, benzodiazepines, certain antidepressants and statins.


What’s the risk?

The enzymes that both grapefruit and CBD inhibit are thought to break down a significant percentage of prescription and over-the-counter medications, so the potential for problems could be high.

A low dose of a med could become a high dose if it’s not properly broken down and eliminated. A high dose of a med could become a dangerously high dose, or even an overdose. Drugs with a narrow “therapeutic window” (they must stay within a certain blood-concentration range) are especially susceptible.

One of the big problems with CBD at the moment is we don’t really know yet which drugs are affected the most, and it’s difficult to identify exact levels of risk because the research has a lot of catching up to do after decades of science-blocking illegality. But since the compound appears to exert similar effects as grapefruit, caution is needed.

What’s the best path forward?

At a minimum, the evidence at this point suggests that grapefruit warnings on medications should also apply to CBD. And it’s important to check with your doctor before taking CBD, especially if you’re taking other medications.

The market for CBD products is predicted to pass $22 billion over the next four years, and that's coming with the expected hurricane of fact-obscuring hype. With so much fanfare, it’s easy to ignore the fact that CBD is a potent compound that's far from exhaustively understood. Research is uncovering upsides of taking it for a variety of conditions, and we’ll likely see more to come, but it’s also on us to recognize that this is an unfolding story and proceed with caution.

 

[momofthegoons]

CBD-DRUG INTERACTIONS: ROLE OF CYTOCHROME P450​

With CBD becoming widely available, scientists are taking a closer look at CBD-drug interactions.


Cannabidiol 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 cytochrome P450, a family of liver enzymes. This key enzyme group metabolizes most of the drugs we consume, including more than 60 percent of marketed meds.

At sufficient dosages, CBD will temporarily deactivate cytochrome P450 enzymes, thereby altering how we metabolize a wide range of compounds, including tetrahydrocannabinol (THC), which causes the high that cannabis is famous for.

METABOLIZING THC​

When THC or any other foreign compound enters the body, it is 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 something 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—while ethanol is converted first to acetaldehyde and then to acetic acid—is a major reason for ethanol’s liver toxicity and the nausea and vomiting caused by excessive consumption.

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

Cytochrome P450 enzymes contribute to the metabolism of drugs 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. Both steps in the metabolism of ethanol, mentioned above, and the conversion of THC into 11-OH-THC involve oxidation (though ethanol is not oxidized specifically by cytochrome P450).

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 (abbreviated CYP), 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 CBD​

The way CBD interacts with cytochrome P450 is pivotal; in essence, 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 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 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 cannabidiol 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. A 2013 report on a clinical trial using GWPharmaceutical’s Sativex, a whole plant CBD-rich sublingual spray, found no interactions with CYP enzymes when approximately 40mg of CBDwere administered. A subsequent clinical trial, however, found that 25mg of orally administered CBD significantly blocked the metabolism of an anti-epileptic drug.

How do CBD-generated changes in cytochrome P450 activity impact the metabolic breakdown of THC? Animal studies indicate that CBDpretreatment increases 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 cannabidiol.

Other factors figure prominently in CBD’s ability to lessen or neutralize the THC high.

GRAPEFRUIT & 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 phytocannabinoids on cytochrome P450 enzymes. THC and cannabinol (CBN) also inhibit CYP activity, but CBD, of all the plant cannabinoids studied, is the strongest cytochrome P450deactivator.

“It’s a very unusual enzyme. Almost all other enzymes are designed to fit a single substrate and carry out a single chemical process resulting in a single product,” Bornheim noted, whereas numerous drugs are substrates for cytochrome P450, which seems to function like a generic breakdown mechanism for a wide range of exogenous and endogenous substances.

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 P450 enzymes—which is why physicians often warn patients not to eat grapefruit before taking their meds. 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.

CANCER & EPILEPSY​

In cancer treatment, the precise dosing of chemotherapy is 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.

By and large, 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 clobazam, an anticonvulsant, and norclobazam, an active metabolite of this medication. A majority of these children needed to have their dose of clobazam reduced due to side effects. Given that both clobazam and CBD are metabolized by cytochrome P450 enzymes, a drug-drug interaction is not surprising. Published in May 2015, the study concluded that “CBD is a safe and effective treatment of refractory epilepsy in patients receiving [clobazam].” But the report also emphasized the importance of monitoring blood levels for clobazam and norclobazam in patients using both CBD and clobazam.

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 P450 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.

ENIGMATIC ENZYMES​

But why would preventing the breakdown of an anti-epileptic drug reduce its effect? There are a number of possible answers, depending on the drug in question. The active component of the drug (the chemical that exerts an anti-epileptic effect) may be a breakdown product of the actual drug taken. So, by slowing the metabolism of the original drug, CBD would make that drug less active.

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

To complicate matters even further, a presentation by Dr. Kazuhito Watanabe at the 2015 International Cannabinoid Research Society meeting in Nova Scotia disclosed preliminary evidence that cannabidiol may “induce”—meaning amplify the activity of—some cytochrome P450 enzymes. (Induction of a protein involves increasing the transcription of its corresponding mRNA, which leads to greater synthesis of the protein.) This suggests that CBD can either increase or decrease the breakdown of other drugs. Again, it depends on the drug in question and the dosages used.

Any pharmaceutical, nutraceutical or green rush scheme to exploit the therapeutic potential of CBD must reckon with the fact that cannabidiol can both inactivate and enhance various cytochrome P450 enzymes in the liver—and this can potentially impact a wide range of medications. Drug interactions are especially important to consider when using life-saving or sense-saving drugs, drugs with narrow therapeutic windows, or medications with major adverse side effects. In particular, those who utilize high doses of CBD concentrates and isolates should keep this in mind when mixing remedies.

Adrian Devitt-Lee is a senior at Tufts University, studying mathematics and chemistry.

Learn More:

AED Potential Interactions with CBD

---

SOURCES​

1. Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug interactions. 1998. Br J Clin Pharmacol. 2004.
2. Bland TM, Haining RL, Tracy TS, Callery PS. CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoin. Biochem Pharmacol. 2005.
3. Bornheim LM, Everhart ET, Li J, Correia MA. Characterization of cannabidiol-mediated cytochrome P450 inactivation. Biochem Pharmacol. 1993.
4. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015.
5. Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. 2011.
6. Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, et al. Cannabidiol potentiates Delta(9)-tetrahydrocannabinol (THC) behavioural effects and alters THCpharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology. 2011.
7. Stott C, White L, Wright S, Wibraham D, Guy G. A phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the phamacokinetics of THC/CBD oromucosal spray in healthy volunteers. SpringerPlus. 2013.
8. Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007.
9. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. 2011.
10. Yamaori S, Kinugasa Y, Takeda S, Yamamoto I, Watanabe K. Cannabidiol induces expression of human cytochrome P450 1A1 that is possibly mediated through aryl hydrocarbon receptor signaling in HepG2 cells. Life Sci. 2015.
11. Yamaori S, Kushihara M, Yamamoto I, Watanabe K. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem Pharmacol. 2010.
12. Yamaori S, Okamoto Y, Yamamoto I, Watanabe K. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos. 2011.
13. Yamaori S, Okushima Y, Masuda K, Kushihara M, Katsu T, Narimatsu S, et al. Structural requirements for potent direct inhibition of human cytochrome P450 1A1by cannabidiol: role of pentylresorcinol moiety. Biol Pharm Bull. 2013.

 

[arb]

Clinically
Brain
Dead

 

[nadjetblock]

Thank you for warning us and sharing the risks of consuming CBD and medicines. Nowadays, more and more people consume CBD, but I don't know people who mix medicines with CBD. In most cases, people use CBD instead of drugs. I could say it is a very good choice. For a while, I also replaced the medicines with CBD. This is how I treated my sleep problems and other health problems.