Are THC and CBD actually safe for everyone?
These cannabinoids can cause drug interactions similar to grapefruit
I had been interested in taking CBD for a while, after hearing all the buzz about its anxiety-killing and insomnia-alleviating effects. Every Google search about CBD I made was inundated with article after article detailing its benefits, safety, and efficacy.
Eventually I said, “screw it” and purchased a bottle of 60 15mg pills, from a brand that was recommended to me by a friend.
Before I take any new substance, I like to quickly investigate any potential drug interactions through an online search. The only drug I currently take consistently is Flonase, a steroid nasal spray that combats stuffiness from seasonal allergies. Flonase doesn’t interact with too many other drugs, since it’s a topical medicine for the nasal passages and most of it doesn’t get absorbed into the bloodstream.
I knew I could’ve, and should’ve, just asked my doctor rather than going rogue on Google Scholar. But at the time it seemed like a rather trivial thing to bother her with, since I assumed it was going to be safe.
Also, if any of you read my content regularly, you know I love doing research.
Leaning back into my living room couch, CBD pill bottle open on the coffee table in front of me, I commenced my routine iPhone scroll-through of drug interaction websites and a couple scholarly articles. I thought it would be over quickly, but what I found led me down a rabbit hole, and made me hesitate to take the CBD. It concerned me, as well, that what I found is not common knowledge despite CBD’s increasing popularity.
It’s often assumed that everyone can take CBD, but it turns out the popular cannabinoid is not quite as universally safe as many people think. Until recently, I was one of those people — the only potential negative consequences of CBD I had heard about were increased drowsiness and some anecdotal reports of nightmares.
Preliminary research has shown many potential benefits of CBD. I am in no way trying to argue that its popularity is not justified, or that the risks outweigh the benefits. However, recent studies have also found it has the potential to interact with quite a few drugs, many of them vital for a person’s health. Individuals with certain medical conditions, and those who take some types of medications may need to avoid CBD or use it with caution.
CBD can change how medications are metabolized
Have you ever heard of a “grapefruit warning” when it comes to drugs?
Some prescription drugs have labeling that advises a patient to avoid eating grapefruit or drinking grapefruit juice while taking that medication. More than 85 drugs have this warning, and they are a diverse bunch. This group includes some medications that treat high blood pressure, high cholesterol (so-called statin drugs), and arrhythmias, as well as ones that prevent organ transplant rejection.
The reason that this bitter citrus fruit interacts with so many drugs is due to compounds called furanocoumarins. Found in abundance in grapefruits, when these chemicals enter the human body they can inhibit the production of a rather important liver enzyme known as CYP3A4.
CYP3A4 is responsible for metabolizing a wide variety of drugs. When this enzyme’s production is stunted, and a drug that is metabolized by it is then consumed, this can ultimately lead to increased blood levels of the drug and a higher potential for adverse side effects. The body’s reduced ability to break down a drug can even lead to a person overdosing after taking what would ordinarily be a perfectly safe dose.
The risks of adverse effects from enzyme inhibition are particularly pronounced in drugs that have a “narrow therapeutic index” meaning there isn’t much of a difference between the dose required for a medication to be effective, and an overdose.
CBD affects CYP3A4 in a similarly inhibitory way to grapefruit. But as Joshua Brown, PharmD, Ph.D., assistant professor in the Dept. of Pharmaceutical Outcomes and Policy of the University of Florida College of Pharmacy, explained to me in an email, CBD can affect other vital liver enzymes as well.
Brown is the co-author of a 2019 study on potential adverse interactions CBD can have with other drugs and medical conditions. He is also a researcher with the Consortium for Medical Marijuana Clinical Outcomes Research.
CYP3A4 belongs to a family of enzymes known as Cytochrome P450 (CYP450). There are approximately 57 functional enzymes in this group, but only about a dozen of them (CYP3A4 included) are responsible for processing an estimated 70–80% of all medications. CYP3A4 is involved in metabolizing about 60% of all medications, whether alone or alongside other enzymes.
CBD inhibits the production of several other enzymes within this family besides CYP3A4, making the prospects for drug interactions with CBD more widespread than interactions with grapefruit. Though despite the wide range of drugs that may be affected, not all drugs processed by these enzymes are known to lead to dangerous interactions when combined with CBD. Some medications have more dire interactions with CBD than others, and are labeled “high-risk”.
One prominent example of a “high-risk” drug with CBD is Warfarin, a blood thinner. Warfarin also has a grapefruit warning. Many other drugs that are high-risk with CBD also come with grapefruit warnings, such as the aforementioned statin and blood pressure drugs, but not all. One example of this discrepancy is the thyroid medication Levothyroxine; while grapefruit only seems to have a minor effect on its bioavailability, combining it with CBD can be dangerous.
Additionally, Brown explained that the inhibition of these enzymes is not the only way that CBD can change how a drug is metabolized in the body.
“While most of these interactions increase the amount of the other medications, which can increase side effects or adverse drug events (e.g., increased bleeding risk with Warfarin), some drug interactions are a little more nuanced,” he said.
In some cases a drug may be activated by an enzyme rather than simply broken down by it. If there is a lack of an activating enzyme in this scenario, then the drug will be less effective, increasing the risk of a person suffering from the condition or symptom that the drug is meant to treat.
CBD, is also, according to Brown, “highly protein bound”. THC shares this quality with CBD as well. Brown explained that being highly protein bound means “they can displace other medications that are bound to proteins in the body and increase their concentrations and side effects.”
We’ve mainly been exploring how CBD affects other drugs, but Brown also added that CBD is not immune to being the “victim” of drug-drug interactions. CBD levels in the body can be modulated by some select enzyme inhibitors, as it is itself processed by the CYP3A4 enzyme.
Maybe CBD itself should come with a grapefruit warning.
Other ways CBD and THC can interact with medications
To a lesser extent, THC also plays a role in inhibiting enzymes in the CYP450 family. Brown’s 2020 study on THC’s role in drug-drug interactions found that though THC alone is not often responsible for drug interactions as compared to CBD, when THC and CBD are combined they can bolster the effects of one another.
“Considering many products contain both THC and CBD, and because they overlap in the enzymes they interact with, they should be used with caution more so when they are combined,” Brown said.
Moreover, when consumed alongside THC products, CYP3A4 inhibitors (such as grapefruit) can increase THC levels in the blood. This can be a concern due to the neuropsychiatric side effects commonly associated with THC, such as paranoia.
Drug interactions with CBD and THC are not limited to altered enzymatic activity. There’s also the matter of what happens when you take multiple drugs that produce the same effects, or take a medication that mirrors symptoms you experience on a regular basis.
These effects are known as pharmacodynamic interactions. They are particularly important to consider in medically complex patients, i.e., those with chronic conditions or older adults, since they may regularly experience symptoms which could compound with CBD or THC’s effects (either from their condition or from medications they take).
“For example, both CBD and THC are associated with sedating effects. If you pair these with benzodiazepines, sleep medications, opioids, or alcohol, sedation will be much worse. This too is a drug interaction and could lead to adverse outcomes like impaired driving, disruption of daily activities, or even falls and fractures,” Brown explained.
As detailed in Brown’s 2020 THC study, THC can have significant psychoactive effects. It may cause adverse reactions in some people, such as anxiety, even in those without an underlying condition. Unpleasant or even dangerous psychiatric symptoms as well as cognitive impairment, sedation, and loss of balance can occur in people with certain medical conditions.
THC should also be used with caution in people with heart conditions, as it can increase heart rate and alter heart rhythm.
Overall, THC can be fun and may have therapeutic benefits, especially as a way to ease nausea, but potential interactions and adverse side effects should be taken into account.
Do you need to avoid CBD and THC if you’re on medication?
Even if a drug you’re taking doesn’t have a grapefruit warning, you may be wondering whether consuming cannabinoids can lead to increased side effects.
A general rule of thumb that has proliferated in recent years is: if your drug has a grapefruit warning, avoid CBD as well. While this metric may help predict whether a medication may be affected by CBD, it’s not foolproof. Grapefruit only acts on enzyme CYP3A4, while CBD affects several other enzymes in the Cytochrome P450 family on top of CYP3A4. So this rule may not catch every potential drug interaction.
However, Brown said that, though caution should be exercised, you may not need to avoid CBD or THC-containing products even if you’re on a medication that’s metabolized with CYP450 enzymes. Though CBD and THC do have the potential to affect a wide variety of drugs, in some cases a low dose can offer therapeutic benefits without inhibiting liver enzymes enough to cause negative effects.
“In typical medical or recreational products, the dose of CBD may not be high enough to cause a significant interaction for most medications, unless they are “high-risk””, Brown said.
The inhibitory effects increase with dose, so the old adage, “start low and go slow” definitely applies here. Starting with 5mg of CBD can be a good way to test for side effects. But don’t do it alone like I tried to; if you want to try CBD but think it may lead to adverse effects with your medication, talk to your doctor.
Also, Brown says, it’s important to be open with your doctor about any CBD/THC usage in general, especially if you’re being prescribed a new medication.
We don’t yet have conclusive information on how CBD affects every drug. Brown said the best studies we have on CBD drug interactions comes from studies on Epidiolex, the only FDA-approved CBD product which is used to treat rare forms of epilepsy. Future studies on Epidiolex, as well as more studies on CBD in general due to legalization, will help provide more information on drug-drug interactions.
If you take a medication that is considered high risk, CBD/THC still may not be entirely out of the question, but additional monitoring by a medical professional will likely be necessary to make sure your med is still giving the desired effect without blood levels rising or falling outside of the therapeutic range.
As the research catches up with demand for and curiosity surrounding CBD products, we will better understand which medications cause the most medically significant interactions with CBD. My hope is that in the near future, we will start seeing CBD warnings on certain medications to increase awareness and prevent safety hazards.
Edit: Brown is the lead author of a newer article, published in August of 2021 in the Journal of Clinical Pharmacology, that explores in detail the pharmacological implications of THC and CBD in recreational and therapeutic contexts, and the potential for drug interactions associated with these chemicals. It is an excellent source if you’d like a comprehensive overview of the current research on THC and CBD.
