Analyzation of Cannabindiol’s Side Effect Profile and The Deactivation of Cytochrome P450 Enzymes
We are sure you have been getting barraged with questions about hemp oil within the last year or two, and interest in hemp products is only growing. With its increasing popularity comes big claims.
The first big claim is that it helps with a long list of medical conditions: inflammation, anxiety, epilepsy, and even cancer. We’re not going to touch too much on this claim -- there are more than enough studies, articles, and anecdotal evidence that shows hemp oil has real potential for helping with many different medical conditions. For literature on hemp’s role in the body and its medical properties, we recommend Innovet Pet.
Instead, we are looking at the second big claim made about hemp oil. That hemp oil has a low side effect profile, and that it’s much lower than many current pharmaceuticals currently on the market -- medication that hemp oil is claimed to replace. Most importantly, we are going to discuss at length about hemp interaction with cytochrome P450 enzymes.
When it comes to mild side effects, current research shows that hemp oil has a very minor side effect profile which includes:
*When hemp is absorbed through the bloodstream, it produces a quick drop in blood pressure. Normally this produces no side effects -- except for a potential wave of dizziness. However, because blood pressure makes a rapid return to normal, this may in turn potentially harm blood pressure sensitive conditions such as glaucoma.
Hemp has an affinity for attaching to enzymes -- its attachment to FAAH enzymes inhibits them from breaking down endocannabinoids, and this proliferation of endocannabinoids (notability anandamide) to attach to CB2 receptors appears to produce the majority of hemp oil’s medical properties. In regards to hemp’s medical properties, hemp will directly bind to TRPV1 and 5-HT1A (hydroxytryptamine) serotonin receptors, activate PPAR receptors, and deactivate GPR55 receptors.
However, hemp draws a stalemate with cytochrome P450 enzymes and when it attaches to them, both hemp and CYP enzymes inhibit each other.
As you know, CYP enzymes are responsible for metabolizing hepatic drugs or over 60% of current pharmaceuticals on the market. In theory, if hemp inhibits CYP enzymes from metabolizing hepatic drugs, we should see higher concentrations of said drug increase when monitoring blood levels because hemp may directly affect the duration and rate of metabolization. Furthermore, we should see side effects then occur from the increasing drug concentration.
This coincidentally has and hasn’t been seen in studies, and even the rare studies that have shown that hemp raised drug concentration levels don’t necessarily recommend against hemp oil. Let’s us explain.
Unfortunately, there are not enough studies that have looked at hemp’s deactivation of CYP enzymes. Above we mentioned that current research shows that hemp has a low side effect profile, and that most studies conclude that hemp oil is relatively low risk -- these studies more often than not conclude that hemp needs to be further looked at because of early great results. Let’s look at these studies in greater detail.
In 2017, Kerstin Iffland and Franjo Grotenhermen extended the comprehensive survey performed by Bergamaschi in 2011 on hemp’s side effects and reinforced Beramaschi’s results concluding :
In general, the often described favorable safety profile of hemp in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, hemp has a better side effect profile.
In 2013, a clinical trial concluded there would likely be no impact between hemp and drugs metabolized by CYP enzymes after they tested Nabiximol (trade name Sativex) dosed approximately at 40mg . Sativex is a specific extract of cannabis and was approved for use in the U.K. in 2010 -- however, it contains tetrahydrocannabinol (THC) potentially altering metabolization of hemp.
One study at Massachusetts General Hospital did see that hemp increased the long-term concentration of both clobazam and norclobasam in children who needed their seizure medication lowered to avoid the side effects . So now we have proof that hemp can raise drug levels, but not so fast.
9 out of the 13 children looked at, saw their seizures decrease by over 50% even though the concentration of clobazam increased, and even after reducing the clobazam to combat the increase in levels, frequency of seizures continued to decrease across the board.
A small study for sure, however, even when this study found that hemp directly contributed to increasing the concentration of clobazam, the study concluded with “Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, hemp is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.”
In a 1993 review, Lester Bornheim saw proof that hemp inhibits CYP enzymes before the required dose for its anti-epileptic effects could be met . This is troublesome because this potentially means that hemp oil could increase seizures if the dose is too low and this has been observed in both studies and in anecdotal reports.
The solution by some physicians is to actually increase hemp’s dosage to the required levels for anti-epileptic effects even though lower doses increased seizures. This seems counterintuitive, but our Massachusetts General Hospital study backs up why increasing dosage may work, as does this next study.
Published in 2017, hemp’s interaction with Warfarin, a popular anticoagulant, was looked at . The goal of this study was to keep the patient’s International Normalized Ratio (INR) between 2 and 3. When hemp was first administered at a low dose it raised his INR up to 7, however when hemps dosage increased and passed 15mg (starting average dose for humans), while also simultaneously lowering his Warfarin dose, the patient's INR levels returned to normal. The patient was able to reduce his Warfarin dosage by 30% with no bleeding (most common side effect).
So why are there conflicting findings on hemp oil interactions with hepatic drugs? Well, besides the lack of large studies looking directly at the issue, there may be several reasons why we don’t always see an interaction, and if we are nervous about raising drug concentrations, then there are steps we can take to prevent this issue.
Dosage is a bit catch-22 with hemp. In theory and most studies appear to back this, smaller doses of hemp will deactivate less CYP450 enzymes. However, we know from some of our other studies that a low dose may not always be appropriate, even if that means increasing CYP450 enzymes deactivation and temporary increasing drug concentration levels.
Basing our findings on the research available, notable deactivation of CYP450 enzymes will not occur with low and average doses of hemp. In fact, the only common medical condition that would require a higher than normal dose is insomnia, which is not much of a concern for pets.
However, because we have studies that show hemp increased the rate of seizures and raised INR levels when administered at low doses, caution is advised and we wholeheartedly recommend blood tests to monitor drug concentration levels -- especially with long-term use of hemp.
Putting space in between the metabolization of hemp and the metabolization of pharmaceuticals is most likely the best method we currently have. This idea is not foreign, as doctors time and time again have warned against eating grapefruit before taking drugs metabolized in the liver. Hemp’s deactivation is notably stronger, however, and a larger interval will be required.
If we take into account the metabolization rate of both hemp oil and the hepatic drug we can create a window for proper dosage. Care should be taken with elderly patients as the CYP450 system can disease by over 30% with age, and this can create a rather long half-life for some drugs.
Now, this is a tricky subject because metabolization rates vary depending on the medication and a specific window will need to be created depending on a number of factors, such as the medication, the age of the patient, the dosage of all medication involved, etc.
We feel it incredibly important that research on hemp and its interaction with individual meditations needs to start right away. It is commonly recommended by many to simply put 1 to 2 hours between hemp and other drugs without taking into account the drug’s specific metabolization rate. This catch-all can lead to dangerous consequences.
Fortunately, this research can start in your clinic and with careful monitoring and a close relationship between veterinarian and patient, hemp can safely be administered to a patient as an additional treatment, and may even lower the dosage of other medications that have higher side effect profiles.
One of the reasons we want to see hemp accepted in the medical community by health professionals is because we don’t want pet owners attempting to find the right dose without medical guidance and if hemp is shunned we fear that this will be the case.
Potentially little contact with CYP enzymes is made when hemp is inhaled. When studying the metabolization of THC when its administered through inhalation, we see that THC enters the capillaries in the lungs and can be found in the blood within seconds reaching max concentration levels within 3-10 minutes, all the while bypassing the liver . When administered orally THC will slowly metabolize in the liver, deactivating CYP enzymes. These differentiating routes of metabolization appear to be the same for all cannabinoids including hemp.
This again will need to be more closely looked at, but people in the medical marijuana community have been mixing marijuana with other drugs metabolized in the liver for decades, and this concern has never gain attraction or really be seen to be an issue.
Now, of course, this application method is much easier for humans than pets, unfortunately. However, if hemp continues to provide substantial evidence that it can effectively offer wide-sweeping treatment while remaining relatively safe, is safe to say administering hemp through inhalation will become a thing for pets -- that is if future evidence shows hemp administered orally causes worrisome drug interaction.
At Innovet Pet, we pride ourselves on our relationship with veterinarians and look forward to continuing the ones we have and building many more.
With the World Health Organization 2017 statement that “To date, there is no evidence of recreational use of hemp or any public health related problems associated with the use of pure hemp.” and the information that we provided here, we hope you will consider the use of hemp in your clinic .