The Guide to Drug Conflicts and the List of Medications accompanying the guide found on this site have not been examined by the Ministry of Health / HKR, and/or received a dedicated approval from these bodies.
Project CBD, a non-profit educational institution based in the United States, has published an in-depth review of cannabinoids and drug collisions aimed at health experts, customers, consumers, and policymakers.
The 33 pages that we have translated and edited for you, led by Dr. Yaakov Waxman, can be originally downloaded in English on the organization’s website or in a link here under the article Cannabinoid-drug interactions
Drug collisions are tested with extreme caution in modern medicine. More than half of adult residents in the United States take prescription drugs on a regular basis and at least 75% of Americans use more than one drug without a doctor’s prescription. In short, many people take several medications together and they can affect each other’s metabolism.
The use of the cannabis plant becomes common from year to year and a large number of cannabis consumers simultaneously consume “regular” pharmacological drugs. In light of the consent and acceptance of cannabis as an option for pain relief, consumers and medical professionals are advised to know and get to know how key ingredients in the plant such as CBD and THC may conflict with other pharmacological drugs.
Relevant information about drug and cannabinoid collisions is difficult to obtain due to the prohibitions and restrictions that apply to the cannabis plant (marijuana) in clinical studies and medical surveys.
Therefore, this brief may not only help medical professionals and consumers predict and avoid the problematic consequences and consequences of such collisions, but also take advantage of situations in which cannabis and pharmacological drugs may work synergistically and positively together.
How do I know if a prescription drug you are taking conflicts with CBD?
Full list of the drugs that should not be taken with which grapefruit (and therefore CBD)
Complicated topic:
Drug collisions are complicated, although they rarely require discontinuation of medication.
At the same time, they can have a significant impact on the overall patient’s care and quality of life.
The summary includes a discussion of several drugs that are metabolized by cytochrome P450 enzymes, a large family of nonspecific enzymes that are involved in the breakdown of 60% – 80% of all drugs recognized today. CBD (and also THC and other plant ingredients) may inhibit or increase the action of unique cytochrome P450 enzymes, thereby reducing or prolonging the activity of the drug taken at the same time.
By suppressing or expediting specific cytochrome P450 enzymes, CBD and THC can alter and affect the metabolism of a wide range of substances. Much of this depends on one “layer” or “substrate” involved in the collision. Some drugs known as “prodrugs” do not become functional until they are metabolized into the active ingredient. If CBD or THC inhibits the disintegration of the drug, parts of the drug will not be metabolized and will remain inactive – on the other hand, inhibiting the metabolism of a regular drug will result in the accumulation of high levels of the active substance in the blood.
A large number of variables make accurate predictions of such conflicts extremely difficult, even for experienced doctors and pharmacists. It is easier to assess whether there will be a collision between a drug and the CBD than to predict the exact impact of the collision.
CBD Paradox
So far, based on observations relating to the wide spread of the use of cannabis infloopers or CBD oils “pool spectrum”, there do not appear to have been many problems in this area of drug collisions. The clinical use of Sativex and Marinel amounted to a small number of drug collisions. If there have been problems with collisions between drugs and cannabinoids in the past, these were cases of the use of preparations containing CBD and cannabinoids in general.
Although THC is an intoxicating molecule and CBD is not, the fact that some people use high doses from products containing pure CBD makes the use of high CBD doses more risky than THC in the metabolism of other drugs. Consider the numbers: 10mg of THC in a cannabis product is a respectable serving for the average patient or the user for pleasure.
10mg of THC combined with 10mg of CBD in Sativex spray causes pain relief in clinical studies.
These are medium doses compared to the amount of pure CBD given to children suffering from epilepsy in clinical studies – up to 50mg/kg – and up to 2,600mg/day – are not considered uncommon in consumers who purchase CBD products independently (from unregulated sources).
THC has a built-in “guardrail” – if you consume too much you will know that you have reached your border and will stop. With CBD there is no such guardrail and there is no sense of dysphoric feedback (discomfort – the opposite of euphoric) that signals that you have consumed enough THC. Cannabidiol is substantially safe, but when extracted from the cannabis plant and concentrated in its pure form (isolate), a high dose is required for therapeutic efficacy, unlike full extractions (full spectrum, whole plant extracts), which have a wider treatment window and are also effective at a lower dose than treating the molecule in its pure form.
The sequence and form of taking
the cannabinoids (smoking, vaping, eating, oil, sticker, skin ointment, etc.) also has a big effect on whether or not there will be a drug collision. Collisions are much more common in cases where both are taken orally (internally) and processed in the liver before they are distributed to the whole body. Cannabinoids are more absorbed/absorbed when taken on a full stomach. Swallowing cannabinoids will have higher concentrations in the liver than evaposion cannabinoids, for example, so CBD products will have greater potential for drug collisions.
The order of operations and the continuum of the CBD’s taking as well as the way it is taken has an effect on how another drug will be affected by it in metabolism. The conclusions of one study indicate that CBD has a stronger inhibitory effect specifically on cytochrome P450 enzymes when given 20 minutes before the second drug.
CBD also interacts with THC (Tetrahydrocannabinol).
When taking CBD and THC together, humans may find that the effect of THC moderates but lengthens somewhat.
It is known that 11-OH-THC, which is the primary product of THC metabolism, is stronger in its psychoactive action compared to THC and is associated with a higher affinity for CB1 receptors which “mediate” the into frothing psychoactive sensation.
l-COOH-THC Another secondary metabolic product of THC, it has anti-inflammatory effects and does not cause a feeling of intoxication, but binds to fats in the body and remains in it for an extended period of time.
Some humans are unable to tolerate even a minimal amount of THC. Due to this sensitivity, and because of a wide range of reactions to cannabis products rich in THC it can be assumed that this effect also consists of hereditary characteristics.
Polymorphism or a variant of genes that specifically encode cytochrome P450 enzymes change individually from person to person and affect metabolism differently so that THC breaks down slowly and remains active for longer in people whose liver enzymes are inactive and as a result will experience hypersensitivity to the psychoactive effects of THC.
This is the approximate reason why some people find that cannabis products rich in THC are unpleasant for them, while millions worldwide smoke THC to relax. This genetic variant exists in 20% of the European population and Western countries in general, that is, 1 in 5 of the white human population has natural resistance to THC. Less than 10% of the African population has this genetic variant and among the Asian population less than 5%.
In general a third of the population is attracted to THC, a third shy away from it and a third in an intermediate state.
Positive synergy: Important findings that emerge from the CBD project’s summary:
- THC against lung cancer.
When cannabis or tobacco is used by way of burning and smoking, cytochrome P450 enzymes in the lungs convert smoke inhaled into powerful carcinogens, including polycyclic aromatic hydrocarbons (PAHs) with a high level of toxicity. THC may protect against the development of lung cancer by inhibiting those metabolic enzymes that hydrocarbons trigger. As a result of the delay of CYP1A and CYP1B health enzymes, by CBD, THC and CBN, the risk of causing cancer in smoking cannabis and/or tobacco decreases. - Cannabinoids – opioid drugs – collisions
- The simultaneous use of opioid drugs for pain relief and cannabis may result in reducing the dose of the opioid drug and still maintaining the absence of a feeling of pain. Reducing the dose of opioid drugs will reduce the number of deaths per year from overdoses. This is a good example of a positive interaction between CBD in particular and cannabinoids in general and prescription drugs.
- CBD, THC and chemotherapy.
Limited preclinical research has indicated that taking CBD and/or THC in combination with top-notch chemotherapy drugs may strengthen the latest drug, thereby reducing the dose required of it (chemotherapy drugs are drugs of very high toxicity to the body) to treat cancer. If this research is translated into broad human experience and other clinical studies, this is important news for patients.
It is already important to note that if CBD inhibits the metabolism of chemotherapy drugs, and also causes chemotherapy to be more tolerated by the body, and increase its effectiveness, it should be taken into account, lower and administer the dose of chemotherapy drugs in a supervised manner. - Cannabinoids and blood thinners.
Both CBD and THC inhibit the metabolism of warfarin (also known as warfarin), a prescription blood thinner widely used among the population. A mistake in the dose of warfarin causes tens of thousands of cases of attending the ICU each year due to constant bleeding. In the manual you can find a case study of varperin suitability for the consumer who also uses pure CBD.
Study limits: The information presented in the guide is designed to help doctors and patients understand whether and when drug collisions with cannabis or cannabinoids may occur. The guide does not intend to raise fears about drug collisions and add to years of ignorance and anti-marijuana hysteria.
How dangerous is the meeting between cannabis and drugs?
Like the danger of taking an excessive dose of any other drug the patient takes.
Problems may arise when a patient combines an extremely high dose of pure CBD with another prescription drug that has a very narrow window between medical efficacy and dangerous toxicity.
GW Pharmaceuticals has conducted clinical trials for the drug Epidiolex, a compound of pure CBD (99%) that could potentially have collisions with Clobazam, an anti-epileptic drug, which required adjustments in the dose of the clobazem. The FDA recently approved Epidiolex as a drug for children with seizure and seizure disorders and classed Epidiolex as SCHEDULE 5 in September 2018.
Drug collisions are an important consideration in modern medicine, although they are rarely dangerous to the point of completely disqualifying the use of the drug, and can have serious consequences for patient care and quality of life.
There are 3 main ways in which a drug can conflict with another drug:
- Collisions of metabolism. One drug may affect the metabolism of the other drug and thus prolong or reduce its activity, potency and side effects.
- Absorption and distribution of the drug in the body. One drug can influence and change the way a second drug is absorbed and distributed in the body.
- Convergence routes. Two drugs may work through similar or identical biological pathways or transitions, which may lead to antagonistic or synergistic effects. In order to predict and prevent collisions between drugs that operate in the same pathways, it is necessary to study the mechanism of action of each drug individually.
Some of the collisions between drugs can be understood by looking at the components of one compound of the two.
For example, if we know how CBD, a non-intoxicating substance from the cannabis plant, inhibits enzymes responsible for drug metabolism, then we can predict several collisions. For another example, if we recognize how THC, the psychoactive molecule of the cannabis plant is absorbed and regulated in the digestive tract, we can observe whether THC will affect another drug or not.
Such information may help doctors decide whether special caution is required when it is recommended to use cannabinoid treatment.
CytochromeP450
One of the largest families of pharmaceutical joint enzymes is cytochrome P450 (cyp, used to sip) This family of proteins are nonspecific enzymes, meaning they are able to metabolize many chemicals. Cytochrome P450 enzymes usually cause chemicals to become more water-soluble and involve a metabolism of 60% to 80% of existing drugs. Once a toxin becomes soluble in water it is easily eliminated in urine and feces.
While CYPs are more pronounced in the liver, (the main organ involved in metabolism), other tissues also contain significant concentrations of these enzymes. (See Note #1) CyP1 enzymes, for example, are found in health.
Oral (internal) medications are absorbed through the intestines, in which various CYPs enzymes are also expressed.
If cannabinoids like CBD or THC inhibit the action of CYP enzymes then the metabolism of the other drug will be delayed and its effect will increase. If cannabinoid affects the acceleration of CYP enzymes, while causing an increase in enzyme production, the result may shorten the duration of the second drug (which competes for the same enzymes) and weaken its effect.
Modulatory Effects
There are several ways to characterize CYP enzymes. Preclinical studies have found that CBD is capable of affecting CYPs enzymes through the following mechanisms of action:1. Competitive inhibition – a chemical can bind to CYP enzymes without activating them, thus preventing the other drug from being linked to the active site of the enzyme, where the metabolic response usually occurs.
2. Allosteric modulation control – a chemical can alter the way and efficacy of a second molecule and adapt it to enzymes, whether in improving or reducing the relationship between the second drug and the enzyme.
3. Heteroactivation – Certain CYP enzymes like CYP3A4 are inactive in normal pharmacological metabolism but a second chemical may alter their structure so that they can now participate in the metabolism and decomposition of the second drug.
4. Enzyme disintegration – Some drugs cause essential components of CYP enzymes to disengage and make the enzyme inactive.
5. A change in gene expression – Altered gene expression – a compound can affect the expression of genes that encode CYP enzymes, thereby increasing or lowering the overall amount of the enzyme in cells.
These modular effects depend on the second drug taken in parallel with cannabinoids when they come into contact together.
It could be tricky. This may cause a competitive delay in one cannabinoid-based drug and may promote metabolism in another form of collision.
For example, CBD increases the metabolism of an anti-epileptic drug (S-mephenytoin) through its effect on the CYP3A4 enzyme, but it also appears to inhibit the metabolism of cyclosporin through the effect on the same enzyme.
There is another possible complication: Some drugs, called prodrugs, do not become active until they are metabolized in the body that make them active. If CBD or THC slows the breakdown of a drug in the front, it will remain sedentary – while inhibiting the metabolism of a regular drug will result in higher levels of the active substance in the bloodstream.
When used for an extended period of time, many CYP enzyme inhibitors will cause hereditary induction that can sometimes help balance the effect of drug collision. Thus, doctors may find that the effect of cannabinoids on other drugs changes or stabilizes and moderates after one to two weeks.
All these variables make accurate prediction a collision between drugs difficult and complicated even for specialist doctors.
It is much easier to predict the possible prevalence of such a collision than to predict the exact effect.
Case study: Warfarin
And for a lot of complex details, collisions between drugs can be very simple to manage.
As indicated in a test case involving CBD and Warfarin (warfarin) is a blood thinner as a prescription drug for a wider population. (See Note #2)Estimate that over 60,000 visits to emergency and intensive care rooms per year in the United States alone are caused by warfarin which is very challenging to find its correct dose (incorrect dose leads to constant internal bleeding)
The test case published in February 2018 describes a patient who took 7.5 mg warfarin per day regularly. The patient began using pure CBD tinator (Epidiolex) at a dose that increased to 15 mg/kg per day for a month.
CBD delayed the metabolism of the blood thinner, causing the concentration of warfarin in the blood to increase (it did not break down and excess was created from it) and it was decided to lower the dose of warfarin by 20% of the original dose. (See Note 3)
But over the next nine months, CBD increased to 35 mg/kg (1800 mg OF CBD) so the verperin dose also had to change several times for adjustment until it stabilized to 71% of the original dose. Although warfarin is a drug with exceptional risks and possible complications – especially bleeding – none of these effects have been observed in this test case. Which was conducted by researchers at the University of Alabama at Birmingham, England. This case demonstrates what approach medical professionals can use when they manage possible collisions between Warfarin and the CBD.
Another example was published during a clinical trial study with Epidiolex, which was approved for use by the FDA for the treatment of epilepsy and Drwa syndrome. One draw down of a single-molecule formula such as epidiolex is the high doses required, up to 50 mg/kg per day. (For an adult weighing about 60 kg this dose is equal to 3000 mg of CBD per day) For comparison, the initial dose of THC use is between 1 mg and 5 mg. Epidiolex’s target range in this trial was initially 5 to 25 but the dose increased to 50 mg/kg per day in subsequent studies. (SeeNote4)
Klobzam is one of the many anti-epileptic drugs on the market. When active, its metabolite, Ndesmethylclobazam (nCLB), is active against seizures. Therapeutic doses of Epidiolex increased nCLB levels, so the dose of clobasm was needed for some of the children tested.
Many medications are safe but those with dangerous side effects or a narrow “healing window” (when there is not much difference between the effective effect of the drug’s dosage and its toxic dose) should be supervised by the attending physician for drug collisions when they arise. After the dose of any drug stabilizes it is usually possible to continue consuming without fear, followed by a doctor.
How to use this information?
Not everyone should learn about the subtleties of interactions between drugs to get a general idea of whether cannabis or a specific phytocannoid may affect specific drug activity. The information provided in this brief may help doctors and patients to be alert to potential drug conflicts that are common in the population.
For a more accurate assessment of whether a particular cannabinoid will conflict with a drug, it is necessary to check whether both are metasized by the same CYP enzymes. In the United States, the main ways in which a drug undergoes metabolism are examined in in-depth research before each drug is approved. Pharmaceutical companies must give access and evaluate a collision between drugs and any new drug. Typically, the pharmaceutical company will include information using which CYP enzymes (if any) the drug breaks down. When this information is clear and known, the patient or doctor can examine how cannabinoids regulate the same group of CYP enzymes. This information can prepare and assist physicians to approve a drug in parallel with the use of cannabinoids and adjust the dose accordingly.
Important talking points
Are interacting with CYPs in a variety of ways. The main part of studies on the interaction of cannabinoids with CYPs is pre-clinical. Their results are starting points and not clear proof that interactions will indeed happen. And while pre clinical information provides an indication of which drugs may come to collision with CBD and other cannabinoids, it is difficult to anticipate the effect of the interactions.
Also, the doses used in these studies can hardly be “translated” into the human experience.
Of all the information in the pre-clinical studies on cyp’Ki inhibition (pronounced ‘K-I’) is one of the most important values. The KI of CBD inhibition for the CYP enzyme group shows the potency intensity of the CBD. The smaller the Ki value, the greater the delay (the stronger the stop). (See note5) Although the Ki suggests the extent to which CBD regulates CYP enzymes, it is impossible to determine an exact dose at which cannabidiol may be a problem due to enzyme inhibition. It depends on how CBD is given, the efficacy of the second drug, the patient’s liver condition, genetics and other factors.
The Ki value of inhibiting some CYPs enzymes by three phytoconnabinoids – CBD, THC, and CBN are shown in the table attached to the summary.
An assessment of cannabinoid activity in relation to CYPs enzymes approximately in the order of intensity is included in the summary in the following chapters.
The Ki values can be used to determine the relative importance of different CYPs enzymes, but should not and should not compare them to the effects of non-“intermediary” (regulated) cannabinoids by the liver, such as the effect of THC on CB1 receptors (which causes the feeling of intoxication). (See Note6)
Also, it is important to consider the dosage of cannabinoids that are used in discussing the intensity of the delay of CYP enzymes.
THC is given orally at a dose of 1 to 10 mg in average patients, while doses of CBD range in a wide arc from 5 to 500 mg, while a dose of 2000 mg is also common in public for certain situations.
Therefore, even in situations where THC is stronger than CBD, the fact that individual consumers tend to use high doses of CBD makes it a more dangerous player in liver metabolism and in cases of drug collisions. As mentioned above, the way cannabinoids are taken (ingestion, smoking, etc.) also has a major role and a major impact whether or not such collisions happen.
SPECIFICATIONS: The CYP1 Family(CYP1A1, 1A2, 1B1)
1A2 1A1, CYPs and 1B1 enzymes are found primarily in the liver and lungs.
The health of these enzymes make the products of burning tobacco, cannabis and other smoking substances stronger carcinogens, including polycyclic aromatic hydrocarbons (PAHs). These hydrocarbons are found in both tobacco smoke and cannabis smoke. These PAHs hydrocarbons also stimulate activity of the CYP1 enzyme, which increases their cancerous potential.
THC inhibits the cyp1 enzyme family in moderate concentrations which usually occur during cannabis vaping or pure extract (DAB) of THC. While smoking cannabis, the inhibitory effect of THC on CYP1 may contrast with the inductive effects of PAHs. In other words, smoking and THC may alleviate each other’s effect on CYP1 enzymes. This can contribute to the anti-cancer properties of cannabis especially in relation to lung cancer.
Cannabinol (CBN), which is formed when THC gets old (influenced by light, oxygen), is a very potent inhibitor of enzymes 1A1, 1A2 and 1B1. That is why it is important to deepen and investigate the effect of CBN on cancer and lungs.
Cannabidiol (CBD) is also a potent inhibitor of enzyme 1A1, but not as potent as CBN.
Although the CBD is less powerful than the CBN, it seems to be running faster.
In one study, CBD was found to inhibit a stronger inhibitor of the CYP1 enzyme family when given 20 minutes before the second drug while the taking time did not affect the inhibition intensity of THC and CBN. (See Note7)In addition, high concentrations of CBD or THC increased the gene transcription of CYP1A, thereby increasing the production of these enzymes the following day.
In the liver, CYP1 enzymes metabolize compounds such as caffeine, melatonin and a number of different medications.
Whether CBD is consumed inhaled or eating, reactions between drugs with CYP1 enzymes are less likely if they take CBD after the other drug. Edible products made from cannabis may also slow down drug metabolism, which in the case of THC may intensify and prolong the effect of caffeine, for example. (See Note8)
The CYP2B Family (2B1, 2B6, 2B10, 2B13) 2B enzyme family is responsible for the metabolism of a variety of chemicals, including pesticides, acid and valproate, methadone, ketamine and anesthetics.
CBD can significantly regulate the activity of 2B enzymes, especially the 2B6, 2B10 and 2B13. CBD inhibits the CYP2B6 enzyme at low to moderate intensity. At very high doses, CBD is also stimulating (inducer) of enzymes 2B10 and 2B13 increases the production of these enzymes between 10-60 fold in various studies.
One of the metabolic products of CBD generated from cyp enzymes in the liver, 6α-OH-CBD, stimulates the action of the CYP2B10 enzyme, probably by the nuclear receptor PPARα . (See Note9)
The induction of these enzymes occurs in one-time taking and high doses of CBD, contrary to the usual pattern of induction of CYP enzymes, which occurs in response to long-term use of the drug, at low doses. Drugs that are metabolized by CYP2B enzymes, particularly increased metabolism by enzymes 2B10 and 2B13, may reach a high level quickly when taken together with high doses of CBD. Drug collisions may also occur with 2B6 enzymes, such as some opioid drugs or pesticides allowed for use in cannabis cultivation in some countries in the United States and Israel.
In clinical studies of “Epidiolex” for pediatric epilepsy: some children used both CBD and valproate. The changes in the treatment of holphroic acid metabolism seem insignificant, although the information suggests that CBD may further worsen the dysfunctional liver function already caused by holphroic acid. This is not a reason to immediately call for all patients using CBD-rich cannabis products or CBD extractions, but caution should certainly be exercised and continue to strive for accurate and reliable research on the subject.
Studies on THC and CBN suggest that they have some effect on the CYP2B enzyme, but in a fifth the potency of CBD.
THC is usually consumed at much lower doses than CBD.
In CBN, the product of the breakdown of THC, it is barely used intentionally. Thus, THC and CBN do not affect drug interactions that depend on CYP2B. Limited pre-clinical studies have also suggested that aromatic terpenes in the cannabis plant include:
- β-caryophyllene {Bcp}
- α-pinene
- β-myrcene, and limonene, can also precipitate or inhibit the CYP2B1 enzyme, while CBD does not appear to regulate the action of this enzyme.
It is not at all clear how clinically important this issue is, since terpenes are in more concentrations than cannabinoids, and the profile of terpenes varies widely from plant to plant.
The CYP2C Family (CYP2C9, 2C19) Regarding cannabinoids, two significant CYPs enzymes in the family2C are: 2C9 and 2C19.
These two enzymes metabolise many anti-epileptic drugs, phytocannabinoids like CBD and THC, some endocannabinoids (cannabinoids produced in the body) as well as non-steroidal anti-inflammatory drugs (NSAIDs) = warfarin, diazepam and other drugs.
2C9 and 2C19 are highly polymorphic enzymes. Common genetic variants of 2C9 have 30% of the activity of a normal enzyme. Anzeim 2C19 has both active and inactive genetic variants.
Individuals with low-functioning CYP2C enzymes will typically experience significantly more drug collisions and lower doses because the underlying activity of these enzymes is already close to their maximum possible activity.
THC, CBD and CBN all inhibit CYPs 2C9 and 2C19 enzymes at moderate or low intensity.
While CBD and CBN appear to inhibit 2C enzymes competitively, THC inhibits them in a mixed way, (partly competitive, partly as an alostrial interaction). This suggests that THC in low concentrations (around 0.01 – 0.1 μM) is a catalyst (inducer) of 2C9 enzymes. This dose is similar to the dose in which THC activates the CB1 receptors and causes an intosizing sensation (HIGH). In the brain, THC metabolites can also affect 2C9 enzymes. In other words – if there is enough THC that will cause a feeling of intoesuation, then the activity of CYP2C9 enzymes also decreases.
At relatively low doses of THC, these enzymes become more active, thereby increasing the disposal of metabolic drugs by CYP2C. But the inhibitory effect of THC in relation to CYP2C enzymes may become dominant in moderate to high doses of THC or when it is used in combination with CBD and CBN.
There is probably an intermediate range in which the positive and negative effects balance each other, leading to the neutralization of mutual influence.
This could explain why pure CBD (isolate) as in the drug Epidiolex has caused significant reactions with anti-epileptic drugs, when extractions containing a full spectrum of cannabinoids (whole-plant extracts) usually did not cause these side effects.
CBD is a stronger inhibitor of CYP2C19 than CYP2C9. This is interesting, given that the 2C19 enzyme is involved in the metabolism of CBD, while enzyme 2C9 is involved in the metabolism of THC.
According to various studies, CBD affects and speeds up the 2C enzyme family but, surprisingly, this does not cause an increase in 2C enzyme activity. Perhaps because of the increase of CYP2C enzymes by CBD is met by the competitive delay of the CBD on these precisely these enzymes. Further research is needed on how chronic CBD use affects the cyp2C enzyme family in order to gain a better understanding of their interactions and relevance to drug collisions.
In one way or another, there is clear potential for collisions between specific drugs and cannabinoids because of their effect on CYP2C9 and CYP2C19 enzymes. The unique hereditary variance for each individual, as well as the dose and rate of cannabinoids will play an important and significant role in situations of collisions between drugs and phytoconnabinoids. And again it should be erratic that pure CBD causes stronger reactions with anti-epileptic drugs than pool spectrum extractions.
TheCYP3A Family (CYP3A4, 3A5)CyP3A family enzyme family may be the most important of any group of CYP enzymes.
CyP3A4 enzyme speeds up the metabolism of about 30% of all existing drugs. This enzyme is most common in the intestines and liver, so orally administered drugs actually undergo metabolism by 3A4 twice before they circulate throughout the body. (“firstpass metabolism”) The strong drug interactions of grapefruits result from the double delay of 3A4 enzymes in the intestine and liver.
CYP3A4 enzymes are the most important enzymes involved in CBD and THC metabolism (along with CYPs 2C9 and 2C19). CBD regulates the enzymes CYP3A4 and 3A5. From preclinical research, it seems that a low and moderate dose of CBD can inhibit both of these enzymes. This information is based on studies examining how CBD inhibits the metabolism of diltiazem, a prescription drug for hypertension. But it is most likely that the effect and potency of CBD will vary relative to another second drug.
THC and CBN at an average dose do not interact with metabolic drugs by
3A enzymes. Although THC and CBN are weak inhibitors of enzymes 3A4/5, CBD activates 3A4 in relation to certain drugs (mephenytoin and indinavir) and inhibits 3A4 in relation to other drugs (cyclosporin, diltiazem). CBD can also stimulate the production of the 3A enzyme, which balances the effects of the delay of CBD as found in a 1980 study. (See Note #10)
One of the few clinical studies on CBD and drug interactions has been carried out with clobazam, an anti-epileptic pre-drug (prodrug) which is metabolized by CYP3A4 for the active compound N-desmethylclobazam. CBD appears to increase the production of the active compound both by increasing 3A4 activity and delaying the CYP2C19 enzyme, which breaks down N- desmethylclobazam.
While interactions between CBD and drugs metabolized by 3A4 are possible, some variables make it difficult for us to know the exact effect of the collision. It is important to remember that collisions are more common when both drugs are given orally together.
CyP2D6: Enzyme CYP2D6 metabolized opioids, antipsychotics and antidepressants (both tricyclic antidepressants and SSRIs). Given that CBD has shown promising abilities as an anti-anxiety, antipsychotic and as a pain suppressor/soothing, there is a chance that it will be taken together with drugs that are metabolized by 2D.CYP2D6 enzymes also activating the pre-drug (prodrug) tamoxifen, which is intended to treat breast cancer.
Since CBD inhibits the ID-1 gene, which can reduce the development of metastases of breast cancer, it is worth further investigating possible collisions.
Cannabidiol may inhibit the CYP2D6 enzyme in moderate to high doses similar to the 2C enzyme family. There is not yet much research based on collisions between cannabinoids and 2D6 enzymes. CBD is also likely to interact with certain drugs by regulating neural courier systems on which these drugs operate. For example, CBD increases the activity of Serotonin receptors, which are targets of many antidepressants.
CYP2J2Enszyme CYP2J2 has minimal liver activity, but is expressed in areas of the heart, brain and pancreas.
It breaks down some antihistamines (medications for soothing allergies), but it also has a role in regulating endocannabinoids. THC, CBD and CBN are all inhibitors of the CYP2J2 enzyme at a moderate or high intensity.
CYP2J2 is able to metabolize arachidonic acid (AA), which is the main decomposition product of endocannabinoids as well as some of the endocannabinoids themselves. 2J2 metabolites (arachyonic acid breakdown products) may regulate cannabinoid receptors in the heart and brain.
However, CYP2J2 enzymes are a low-sized player in drug metabolism, so it is unlikely to be relevant to most collisions between drugs and cannabinoids.
Full list of the drugs that should not be taken with which grapefruit (and therefore CBD)
Chapter 3: More Considerations: Less Effective or More Dangerous?
What actually happens when you add high doses of cannabinoids to a person who uses certain medications? First, cannabinoids interact with some CYPs enzymes, as described in the previous chapter. The interaction will usually start between 10 minutes and two hours, depending on whether the cannabinoids were consumed by smoking, swallowing or absorbed under the tongue.
The immediate interaction usually reduces drug metabolism through inhibiting CYPs enzymes but in some cases (2B10/13, 2C9, 3A4) the interaction may increase the metabolism of other drugs.
Moreover, metabolism may be an integral stage in activating the drug if the drugs are a pre-drug(prodrug).
Some medications (such as those metabolized by CYP1A enzymes) are more susceptible to cannabinoids when cannabinoids are taken first, before the drug. For one to several weeks, some of the delayed CYP may manifest themselves too much in an attempt to restore humostasis and normal baseline activity.
Some CYPs enzymes (1A, 2C9, 2C19, 3A4, 3A5) will likely restore some of their activity after the initial delay, but this may not be enough to compensate for the delay in general due to the long-term provision of cannabinoids.
At the same time, 3 other variables begin to manifest:
- The body may develop tolerance for the delay of . CYPs It can happen when very high doses of cannabinoids are consumed on a regular basis, although the effect of low-dose cannabinoids is unknown.
- Chronic inflammation and stress negatively affect liver function. Inflammation initially causes a decrease in cyps enzyme activity in the liver, phytocannabinoids, including CBD, lower stress and inflammation and therefore return the activity of these enzymes to the normal level. (amplification) (See Note Number 11)
- CBD, monitors the expression of at least 1200 genes, and therefore may alter the manifestation of certain CYPs.
Ways to use:
The way cannabis is consumed adds an additional “layer” to the complexity of drug collisions.
Cannabinoids can be smoked, laded, eaten, applied to the skin, absorbed under the tongue and more. From a reductionist point of view, the way cannabis is consumed affects the maximum amount of cannabinoids in the liver and how quickly they get there. Some models of cannabinoid use try to describe these amounts in the bloodstream but there is no model that can accurately predict concentrations in the liver. (Much easier to take blood and test than a respectful biopsy) An explanation of Cmax can be found in the link following about the uses of the model in the following link.
Smoking and vaping
inhaled cannabinoids pass through the lungs (where some CYPs enzymes are present) into the bloodstream, directly towards the brain and heart. They will then pass slowly through the liver.
Changes in the metabolism of a drug – if they occur at all – will usually begin a few minutes after evaporation and inhalation. Inhibition of the CYP1 enzyme will most likely occur. A few hours after smoking, the risk of a collision between drugs will be much lower. Evaporation of cannabis may have a different effect than smoking cannabis. Compared to smoking, vaping cannabis rash (bud) is usually characterized by slightly higher doses and slower absorption. So far, no study has compared evaporation of cannabis ounce extraction with evaporation or smoking of land inflorescence.
Ingestion:
Swallowing cannabinoids are mainly absorbed through the intestines (where the CYP3A enzyme is found) and are absorbed through the walls of the small intestine into the bloodstream and transferred to the liver for processing. Cannabinoids are best absorbed if taken on a full stomach, but absorption is slow in this case. The time it takes cannabinoids to be absorbed into liver metabolism and from there be absorbed into the bloodstream can range from 2-4 hours.
Taking cannabinoids in ingesting has three important differences compared to smoking/evaporation:– Swallowing cannabinoids will have a higher peak concentration in the liver than inhaled and evaporation cannabinoids, so engulfed cannabinoids may have stronger inter-pharmacological interactions.
– Swallowing cannabinoids will have a greater impact on drugs that are metabolized by CYP3A, because they interact with the same enzyme in both the intestine and the liver.
– After liver processing, swallowing cannabinoids will be mostly converted into their metabolites and then the effects of cannabinoids ingestion will depend on less studied metabolites like -11-OH-THC and -7-COOH-CBD, which are the main metabolites of THC and CBD, respectively. Some of these metabolites interact with CYPs enzymes.
Taking under the tongue and the oral mucosa:
Taking medicine under the tongue on the mucous membranes of the mouth and palate is the intermediate way between evaporation and swallowing. If taken correctly, medications taken under the tongue are absorbed through membranes in the mouth (under the tongue and along the cheeks) without swallowing. This taking comes in forms of solutions, mouth sprays and oil. When cannabinoids are taken under the tongue, they are not immediately processed by the liver – such as those taken by swallowing – but also do not reach directly to the brain and heart — such as inhaled cannabinoids.
They’re absorbed into the bloodstream. Many drugs for taking under their tongue have their maximum time for the onset of the effect takes about 15 minutes, but in the case of cannabis products studies suggest that the start time of effect can be up to two hours, similar to swallowing. It is not clear whether this difference is due to patients ingesting the oil or spray instead of letting it be absorbed into oral mucosa or simply the absorption time of cannabinoids is longer orally than most other drugs.
Local use on the skin: Although cannabinoids in a local spread may be absorbed through the skin to the joints, they do not enter the bloodstream, so there is no fear of drug collisions.
Taking cannabinoids through the skin is slightly different from a normal local application. A patch or sticker on the skin will slowly release a few cannabinoids into the bloodstream, usually at a low and permanent level.
Like sublingual and inhaled/evaporation cannabinoids, the concentration of cannabinoids in the liver should roughly be equivalent to their concentration in the blood. Tmax and Cmax will depend on accurate formula.
More clinical examples:
A small number of clinical studies have accurately assessed the risks of collisions between cannabinoids and opioid drugs, anti-epileptic drugs and antiretroviral therapies. Although cannabinoids had little effect on drug metabolism in most of these studies, the results were clinically significant compared to some anti-epileptic drugs.
* When individuals taking 50-60mg of morphine or oxycodone also steamed cannabis rich in THC no changes in total exposure to opioids were observed, a slight decrease in the maximum concentration of morphine consumed was observed, and a lower rating of pain intensity.
* HIV patients take Indinavir or Nelpinavir and also smoke cannabis rich in THC or ingest 2.5mg of pure CBD. THC ingestion does not affect the concentration of anti-HIV drugs, but smoking cannabis lowers the maximum concentration of Indinavir.
* Individuals taking 400mg to 800mg of pure CBD ingestion, an hour before being injected with 1 μg/kg fentanyl. CBD was not associated with any measure of opioid toxicity. However, this study did not perform a direct examination of the concentration of fentanyl in the blood.
Several collisions have been diagnosed between the form of pure CBD (“Epidiolex”) and antiepileptic drugs, as described in the previous chapter. These collisions may have occurred due to a very high dose of CBD in many of the drug’s preliminary tests.
These collisions happen because of the encounter with 3 main CYP enzyme groups:CYP3A4 – in the intestines CYP3A4 – in the liverCYP2C19, CYP2C9 – in the liver.
In 2015, researchers from Massachusetts General Hospital described a significant collision with clobazam, which is benzodiazepine. Benzodiazepine benzodiazepine are psychoactive drugs with soothing, hypnotic, anti-anxiety, anti-epileptic, and muscle relaxant effects. Long-term use of benzodiazepines can be problematic due to the development of tolerance, physical dependence and sometimes mental dependence.
CYP3A4 is responsible for the metabolism of active metabolite clobasema, N-desmethylclobazam (nCLB) and then CYP2C19 breaks down the nCLB metabolite. Cannabidiol increases nCLB concentrations by 500%, probably by activating CYP3A4 and increasing its activity while simultaneously inhibiting CYP2C19. But the authors concluded that “CBD is safe and effective in treating epilepsy for patients who already use calobasem” although “monitoring and monitoring of clobasm and nCLB levels by a doctor is necessary.”
Another study on the interaction between epidiolex and anti-epileptic drugs was recently published. CBD has caused significant statistical changes in the concentration of some antiepileptic drugs: clobazam), rufinamide, topiramate, zunisamide and slicarbazepine. Clobazem was the only drug whose concentration moved outside the “healing window” (the stage at which the medical benefit is lower than the risk of side effects and toxicity). Especially nCLB levels that increased by about 100% so the dose of the clobaceam had to decrease.
Patients taking CBD with valproate acid have abnormal liver function, as written in the chapter on CYP2B enzymes.
In adults, CBD collision with medications will manifest slightly differently than in children.
Interactions between cannabinoids and cannabinoids: There are many ways in which different cannabinoids (such as THC and CBD) can interact with each other.
These interactions contribute to the “entourage effect”, in which the effects of various cannabinoids, flavonoid terpenes and other plant components integrate synergistically, thus often alleviating side effects while improving therapeutic actions. Some preclinical and clinical studies have confirmed the assumption that compared to fully-extracted cannabinoids (full spectrum) of the plant, a lower dose is required in order to achieve an effective and positive effect and have a wider range of medicinal properties, as a treatment for more medical conditions and almost no significant side effects. (See Note Number12)
What’s causing the “entourage effect”? In order to gain a full understanding, one must compare the mechanisms of action in which cannabinoids move and behave in the body and then learn how cannabinoids can regulate each other’s activity. But the metabolic interactions between CBD and THC can be demonstrated relatively simply: THC is metabolized mainly by two groups of CYP enzymes: CYP2C9 makes THC a much more psychoactive chemical compound 11-OH-THC, and then the CYP3A4 enzyme breaks down this metabolite into 11-COOH-THC, which is a secondary metabolite without psychoactive effects, which binds to fatty tissues in the body for weeks and has anti-inflammatory properties.
CBD is also metabolized primarily by two groups of CYP enzymes: CYP2C19 transforms CBD into a 7-OH-CBD metabolite and the CYP3A4 enzyme continues the metabolism and turns this metabolism into 7-COOH-CBD. (See Note Number13)
CBD metabolites have not yet been fully and comprehensively characterized. When taking CBD and THC together, people can sometimes feel that the effects of THC moderate, on the one hand, but last for a longer time, on the other. The delay of CBD and cyp3A4 enzymes is probably responsible for prolonging the effects of THC, while the delay of CYP2C9 enzymes is associated with numbing the THC’s “high” sensation. (See Note Number14)
Full list of the drugs that should not be taken with which grapefruit (and therefore CBD)
The chemistry of inhibiting enzymes: In japan, a large preclinical work conducted in Japan by Satoshi Yamaori and Kazuhito Watanabe at Hokuriku University, shed light on the chemical properties of cannabidiol that allow it to inhibit various CYPs enzymes.
This is very useful information for groups trying to design new drugs based on phytocannabinoids, and may also help predict whether other untested cannabinoids may inhibit CYP enzymes and cause drug collisions.
The fenthyl-resurceinol part of the molecule is one of the main properties that cause CBD to inhibit many CYP enzymes. Other cannabinoids with changes in this structure have different strengths and can be predicted in the delay of CYP enzymes.
Specifically, if one of the hydroxyl groups (the UH attached to carbon carbon) is different, CBD intensity as a inhibitor of some CYP enzymes decreases by approximately 20%.
THC, which does not have free hydroxyl in its molecule, is a less potent inhibitor of these CYPs enzymes compared to CBD. Both CBD hydroxyles are required for the strong delay of CYPs 1A1, 2B6, 2D6, 3A4 3A5 but not of 2C9, 2C19, 2J2
Moreover, if the five-carbon side chain (typical of CBD) is replaced by a group with three carbons (making it a chemical: cannabidiverin, CBDV), the efficacy of this three-carbon compound (‘varin’) delays most CYP enzymes by about 20 percent compared to CBD.
Consider the cannabinoid tetrahydrocannabivarin
THCVTHCV, which increases insulin sensitivity in type II diabetics, and can be useful as an anti-smoking helper to reduce cravings for nicotine.
Based on the discussion above, THCV will most likely be at least 5 times stronger than CBD as a CYP inhibitor, except perhaps in CYPs 2C9, 2C19 and 2J2. Overall, THCV seems to cause fewer metabolic interactions, unless the dose of THCV is given to be very large.
Conclusions: The information presented in this manual is intended to help doctors and patients understand if and when drug collisions with cannabis are likely to occur. This information is not intended to raise fears of interactions with drugs or to add injustice to a crime of decades of cannabis hysteria, but to be as faithful as possible to recent science and research.
How dangerous is a collision between drugs and cannabinoids?
Like the danger of taking the wrong dose of the second drug the patient is taking. This is a complicated issue, but it is not necessary to meticulously get around all the details of drug collisions in order to provide basic guidance for cannabis patients.
So far, based on observations regarding widespread use of raw cannabis inflated and full spectrum cannabis oil, there appears to be no further serious problems due to drug-cannabinoid interactions. Clinical use of Sativex (CBD 1:1: THC) and marinol (pure synthetic THC pill) has resulted in few, if any, reports of side effects specifically attributed to drug interactions. As difficult as negative interactions were, these were involved in particularly high doses of pure CBD products.
Moreover, pure CBD (insulated), unlike the extracts of a whole plant (pool spectrum), usually require higher doses to be effective. Doctors and patients should be concerned that the current regulatory regime and legal law in most of the world prefers pure CBD products to whole plant extractions.
Sometimes a blood test may be needed to see how the concentration of the drug varies – and if a change in dose is required – when a consumer starts taking CBD.
This can be the case with chemotherapy, for example because oncologists often use the non-lethal maximum dose to kill cancer cells. If CBD inhibits the metabolism of a chemotherapy substance, this can cause dangerous levels of a highly toxic drug. Therefore, it is possible to lower the dose of the chemotherapy drug when also taking CBD.
Preclinical studies indicate that administering CBD and / or THC in combination with first-line chemotherapy drugs may strengthen the latter, thereby reducing the dose of chemotherapy necessary to treat cancer. If it does translate into a human experience, it would be a huge advantage. Similarly, completing a regimen to treat opioid pain with cannabis may result in lower doses of opioids required for pain relief. Lower doses of opioids will reduce the number of overdose deaths.
We need to learn much more about drug interactions with cannabinoids to prevent negative reactions and harness possible positive synergy. However, this uncertainty is not an excuse for medicine to continue to reject cannabinoid treatments – many drugs sold in millions to the general public are not fully understood.
Hopefully, as cannabis treatments continue to gain consent among physicians and patients, sufficient resources will be available for clinical studies including drug interactions with CBD, THC and other herbal cannabinoids.
The addition of cannabinoids to opioid-based pain medications may result in the need for lower doses of opioids required for adequate pain management.
See, for example, the label of Cesamet, a drug derivative of THC, approved for the treatment of intolerable nausea and vomiting from chemotherapy. “Accurate information regarding the metabolites that may accumulate is not available. The relative activity of metabolites and the parent drug has not been determined.” The mechanism of action of common drugs like Thylanol and SSRI antidepressants is not well established.
How do I know if a prescription drug you are taking conflicts with CBD?
Our use is given a warning that accompanies the taking of certain medications – not to eat or drink grapefruit for the entire duration of use of the drug.
* The doctor who registers the drug should warn the consumer before using the drug that a collision between the drug and grapefruit may have bad results. Pharmaceutical companies are also obliged to warn consumers about not using grapefruit and the warning can be searched in a newsletter to the customer or on the drug’s website.
Why grapefruit?
Grapefruit contains plant chemicals called Furanocoumarinsthat inhibit one of the enzymes responsible for the breakdown of drugs in the body (the enzyme CYP3A4 is found in the liver and in the walls of the small intestine). The result of inhibiting the enzyme is a significant increase in the level of drugs in the blood and a worsening of their side effects. It should be noted that this effect of inhibiting enzymes from pharmaceutical joints is probably also responsible for plant chemicals called flavonoids that are also found in grapefruits.
Medications that should not be taken with grapefruit: (and therefore also avoid taking CBD)
- Are there many medicines that are affected by grapefruit juice?
- There are currently more than 85 drugs affected by grapefruit juice.
- These include, among others: drugs to treat high levels of cholesterol: statin family drugs, and especially Symbastamine and Osteurstatin
- Immunosuppressive drugs such as Cyclosporin and Crolimus
- Drugs to treat arrhythmias such as Amiodrone and Rhondron
- Anti-allergy drugs like Astemizole and Terfenadine.
- New cancer treatment drugs mainly from the family of the enzyme inhibitors Tyrosine kinase as Immathinib.
A complete list of drugs that may conflict with CBD can be found on the following page: Full list of the drugs that should not be taken with which grapefruit (and therefore CBD)
The Guide to Drug Conflicts and the List of Medications accompanying the guide found on this site have not been examined by the Ministry of Health / HKR, and/or received a dedicated approval from these bodies.
Guide footnotes:
- CYP enzymes do not simply exist in the liver; They reside in certain subcellular organberries in the liver cells called endoplasmic reticulum. A recent study suggests that protein 1 (Fatty acid binding protein-1) that requires fatty acids (FABP1) to bind and transfer cannabinoids to CYP enzymes within the cell in ER. FABPs are also required to transfer endocannabinoids into intracellular organelles so that they can act on nuclear receptors or decay.
- An interaction between warfarin and cannabidiol, a case report– warfarin concentrations are described by the international normalization ratio, INR, which should be between 2-3. That’s the number doctors use to adjust the dosage.
- For an adult weighing 60kg, this dose is equal to 3000mg of CBD. (For comparison, an initial initial dose of THC is between 1 and 5mg.) Epidiolex’s target range in this trial was initially between 5 and 25 mg of CBD kg/mg, but the maximum dose was increased to 50 mg/kg per day in subsequent studies.
- Intuitively, the Ki values are the concentration of CBD required for a delay of 50% of enzyme activity, compared to the concentration of the second drug. It varies with different primary origins.
- It is difficult to relate to the different intensities of the effect of a compound – it is impossible to simply compare THC inhibition of CYPs enzymes to its psychoactive effect because the first occurs in the liver and the second occurs in the brain. So relative strengths must come respectively and calculate how cannabinoids separate into different parts of the body, which also depends on the form of taking (smoking, vaping, swallowing, etc.), but has not yet been studied enough for each form of taking separately. Differences in affinity with transport molecules (FABPs – carrier proteins) that bring cannabinoids to CYP may also affect the measured potency of the enzyme and subterest.
- In the article mentioned, using CBD 20 minutes before the second drug made CBD 2-3 times more potent. One possible explanation is that compounds created from CBD decomposition are stronger in cyp1 delay than the CBD itself.
- CBD is less likely to intensify the effects of caffeine because it may act against or neutralize some of the effects of caffeine on adenosine receptors. Caffeine is stimulating because it blocks adenosine receptors. At high doses CBD inhibits the reuptake of adenosine molecules and prolongs its operation in adenosine receptors. This could be the partial cause of the soothing effect of CBD at high doses.
- No CBD mechanism of action has been proposed on CYP3A enzymes in the study (induction). Sometimes the body tries to compensate for the action of inhibitors by over-expressing the inhibited enzymes. Another study noted that the nuclear receptor PPARα increases the synthesis of some CYPs enzymes, including 3A4, 2B10 and 1A1. CBD indirectly activates the PPARα nuclear receptor by increasing the duration of operation of endocannabinoids in the body.
- This point can help explain why some individuals are very sensitive to THC. THC is metabolized and breaks down into 11-OH-THC mainly by the CYP2C9 enzyme, however, CYP3A4 does so as well. But 11-OH-THC has a stronger intoxicating effect than THC either because it binds to CB1 receptors with a higher affinity than THC or because it accumulates more in the brain. CYP3A4 breaks down 11-OH-THC further into a non-intoxicating compound (11-COOH-THC). That you stay in the body in the fat tissues for an extended period of time.
- If the CYP2C9 enzyme is inactive because of a genetic mutation, then CYP3A4 will participate in the effort to make THC the psychoactively stronger compound 11-OH-THC and less free to break it down into non-psychoactive ingredients (11-COOH-THC).
- These variables can balance some of the inhibitory effects of cannabinoids in relation to CYPs enzymes, but may also lead to over-compensation of CYP enzyme activity. In order to understand enough details to make accurate predictions, more clinical studies should be carried out examining collisions between cannabinoids and medicines.
- Although there is a lot of research that suggests this, the results are mixed and inconclusive. For example, CBD was found to increase appetite stimulation caused by THC in one study, and as an increase in appetite suppression from THC in another study.
- The location 7 of the CBD is the same as the location 11 of THC. The different numbers are part of the method of numbering carbons and their position in the rings of the different molecules in chemistry.
- Additional effects of CBD are expressed for example, CBD can increase levels of adenosine in the atmosphere which may prevent memory problems due to the use of isolated THC. There is also preclinical evidence suggesting that CBD is a negative Alostri inhibitor that regulates CB1 receptors in high doses, meaning it may reduce the effect of THC in CB1 receptors.
APPENDIX A: GLOSSARY
Allosteric modulation
A type of protein-chemical interaction. An allosteric modulator changes the shape of the protein, which alters how well another chemical would fit.
Anandamide
The first known endocannabinoid. Discovered by Devane et. al. in 1992.
Cannabidiol (CBD)
A major non-intoxicating plant cannabinoid with significant anti-epileptic and anti-inflammatory properties.
7-carboxy-cannabidiol (7-COOH-CBD)
A major metabolite of CBD which bears some chemical resemblance to the antiepileptic drug valproate.
6alpha-hydroxy-cannabidiol (6α-OH-CBD)
A minor metabolite of CBD formed when CBD is oxidized by CYPs 3A4, 3A5, 2D6, and 2C19.
Cannabidivarin (CBDV)
A minor plant cannabinoid that has been studied for the treatment of epilepsy and autism-spectrum disorders.
Cannabinol (CBN)
An ostensibly non-psychoactive cannabinoid that is formed when THC degrades in sunlight or heat.
Competitive inhibition
A type of protein-chemical interaction wherein the chemical sits in the active site of the protein, preventing other chemicals from entering.
Cytochrome P450 (CYP)
An important family of enzymes that is involved in metabolizing many pharmaceuticals and endogenous compounds.
Epidiolex
A pharmaceutical formulation of nearly pure CBD that is applied as a sublingual spray.
Induction
A process whereby the activity of an enzyme is increased. Genetic induction refers to changes in gene expression that increase the cell’s production of the enzyme
Ki
A measure of the strength of protein-ligand binding. In this piece, the Ki indicates the potency with which cannabinoids inhibit CYPs, normalized to the experimental conditions of the study.
Marinol
A pharmaceutical formulation of nearly pure THC. Approved by the FDA for treating cancer- and AIDS-related health problems.
Polycyclic aromatic hydrocarbons (PAHs) A class of compounds produced in smoke, whether from cannabis, tobacco, or wood fires.
Prodrug
A drug whose metabolites are the primary active compounds.
Sativex
A pharmaceutical cannabis extract with a 1:1 ratio of CBD to THC. Approved in many countries outside of the United States
Terpenes
Volatile hydrocarbon compounds produced by plants. They are responsible for the smells associated with many plants.
Tetrahydrocannabinol (THC)
The major intoxicating plant cannabinoid. It causes a high, alleviates pain, reduces nausea, and is being investigated for numerous other medical conditions.
11-hydroxy-tetrahydrocannabinol (11-OH-THC)
Major metabolite of THC. It appears to be more psychoactive than THC itself. It’s primarily created by CYP2C9-dependent metabolism of THC.
11-nor-9-carboxy-tetrahydrocannabinol (11-COOH-THC)
Major excreted metabolite of THC. It is not psychoactive, and is primarily created by CYP3A4-dependent metabolism of 11-OH-THC.
Tetrahydrocannabivarin
A minor plant cannabinoid that has been studied for the treatment of some metabolic and addictive disorders.
APPENDIX B: KI TABLE
Table of Ki values for cannabinoids’ inhibition of various CYP enzymes. The Ki provides an indication of the potency of inhibition, with smaller Kis implying a smaller dose is necessary to cause CYP inhibition. The Kis are best used to understand the relative potency of CYP inhibition. The Ki only suggests the dose of a cannabinoid that causes
inhibition—it does not indicate the duration of the effect. It also depends on the second drug used to measure CYP activity.
All numbers are Kis in μM.
† Cannabinoid was a more potent inhibitor when given before the second drug.
* Ki not calculated. Potency notably lower than CBD’s potency.
** Only caused induction, not inhibition. In these studies, a fixed dose of 120mg/kg was used.
^ The upper bound came from an experiment with a deceased human’s liver, which may have had a polymorphism in the CYP2C9 gene. The lower bound used purified enzyme
Figure of five common plant cannabinoids. The “pentylresorcinol” or “olivitol” moiety is highlighted in red. Both the free hydroxyls as well as the 5-carbon chain contribute to inhibition of most CYPs, although olivetol on its own is a much weaker inhibitor
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Dr. Yaakov Waxman – scientific
consultant of MOYADDR of immunology, postdoctoral fellow in Prof. Raphael Meshulam’s laboratory at the Hebrew University of Jerusalem.
