CBD and everolimus or sirolimus: why do drug levels rise?

Medicines and the importance of the interaction

From peer-reviewed publications and drug labels: the warning. The same warning also appears in the interaction checker.

How does the interaction happen?

Everolimus and sirolimus are broken down by the CYP3A4 enzyme in the liver and the gut wall, and they are carried by P-gp (P-glycoprotein: a transporter that pumps a drug from gut cells back out). So substances that affect CYP3A4 or P-gp can change how much of these medicines, taken by mouth, reaches the blood. (Everolimus (Zortress) prescribing information §7.1 and §12.3, Sirolimus tablets prescribing information §7)

In the drug-level study, CBD raised the peak level of everolimus and its total amount in the blood (AUC), but it did not change how fast it is cleared from the body (its half-life). Approved CBD had also not changed the level of midazolam, which is broken down by CYP3A4. For this reason, the European product information considers that the effect comes not from the liver but from CBD slowing P-gp in the gut, which increases the amount of everolimus that passes into the blood. (EMA Epidyolex prescribing information 4.5 and 5.2, FDA Epidiolex label §12.3 (05/2026), PMID 37132402)

No controlled interaction study has been done with sirolimus. The prescribing information states that because sirolimus is also carried by P-gp, its level may rise with CBD when it is taken by mouth; in the series of patients with TSC, sirolimus levels also rose. (EMA Epidyolex prescribing information 4.5, FDA Epidiolex label §7.2 (05/2026), PMID 31924480)

What we don't know: The drug-level study was done with approved CBD, and the prescribing information for everolimus states that the effect of other CBD products on everolimus levels is unknown. It is also unclear how the effect changes with the daily amount of CBD; in one case, the everolimus level fluctuated with the CBD dose even though the everolimus dose stayed the same. (Everolimus (Afinitor) prescribing information §7.1, PMID 31539915)

What do studies and official drug information say?

Each finding shows the type of evidence it rests on. A case report describes a single patient; it does not prove cause and effect.

1. Drug-level study

   Drug-level study: everolimus rose about 2.5-fold (2023)

   Healthy adults first took a single dose of everolimus (5 mg). After a one-week break, they started approved CBD at 12.5 mg/kg twice a day and took the same everolimus dose again on the fifth day of CBD. With CBD, the peak blood level of everolimus and its total amount in the blood rose about 2.5-fold; its half-life stayed largely unchanged. The authors recommended monitoring everolimus levels and reducing the dose as appropriate when the two are used together.

   Source: PMID 37132402, FDA Epidiolex label §12.3 (05/2026), EMA Epidyolex prescribing information 5.2

2. Case series

   mTOR inhibitor levels rose in 25 patients with TSC (2020)

   Researchers reviewed the records of 25 patients who were taking everolimus (18 patients) or sirolimus (7 patients) for tuberous sclerosis complex and had CBD added to their treatment. In 76% of the patients, the drug level rose markedly after CBD; the median increase was 9.8 ng/mL for everolimus and 5.1 ng/mL for sirolimus, and in some patients the level doubled or tripled. Side effects occurred in 40% of the patients (most often diarrhea); none were severe. The authors noted that lowering the dose in advance when starting CBD could be considered in patients prone to the medicine's side effects.

   Source: PMID 31924480

3. Case report

   Everolimus levels fluctuated in a child (2019)

   In a 6.5-year-old girl with TSC whose everolimus level was stable at 4–5 µg/L, CBD was added to her treatment (200 mg a day). Six weeks later, the level had risen to 12 µg/L; even though the everolimus dose was cut in half, it rose as high as 16 µg/L. Later, while the everolimus dose stayed the same, the level ranged from 1.7 to 12.3 µg/L depending on the CBD dose. The child had no side effects.

   Source: PMID 31539915

4. Official drug information

   Prescribing information for approved CBD (US and Europe)

   Both documents recommend monitoring everolimus levels and adjusting the dose accordingly when CBD is started in someone taking everolimus. If everolimus is to be started in someone already on a stable dose of CBD, a lower starting dose and level monitoring are recommended. For sirolimus, there is a general warning about drugs carried by P-gp: the level may rise, and drug-level monitoring and a dose reduction should be considered. The dose decision is made by the doctor who prescribes the medicine.

   Source: FDA Epidiolex label §7.2 (05/2026), EMA Epidyolex prescribing information 4.5

5. Official drug information

   Prescribing information for everolimus and sirolimus themselves (US)

   The prescribing information for the everolimus used in cancer and TSC recommends reducing the everolimus dose when it is used with approved CBD and measuring the blood level 2 weeks after starting or stopping CBD; it states that the effect of other CBD products is unknown. The prescribing information for the everolimus and sirolimus used in transplant care also recommends closely monitoring drug levels and side effects that suggest toxicity when they are used with CBD, and reducing the dose if needed.

   Source: Everolimus (Afinitor) prescribing information §2.8 §2.11 and §7.1, Everolimus (Zortress) prescribing information §5.22 and §7.1, Sirolimus tablets prescribing information §5.21 and §7.5

6. Systematic review

   Systematic review: sirolimus among the most frequently reported (2024)

   In a systematic review of 31 publications reporting cannabinoid interactions with medicines that have a narrow therapeutic range, sirolimus, along with warfarin, valproate and tacrolimus, was among the most frequently reported drugs and those that may carry the greatest risk for patients. Information on mTOR inhibitors came mainly from the series of patients with TSC.

   Source: PMID 38868665

What is monitored?

• Everolimus or sirolimus level: the trough level in the blood (just before the next dose) is measured when CBD is started, when the amount of CBD changes and when CBD is stopped; the prescribing information for everolimus recommends doing this about 2 weeks after starting or stopping CBD. Your doctor decides when to measure it. (Everolimus (Afinitor) prescribing information §2.8, Sirolimus tablets prescribing information §2.5 and §7.5, FDA Epidiolex label §7.2 (05/2026))
• Signs of side effects: mouth sores, diarrhea, signs of infection such as fever and chills, a new or worsening cough, shortness of breath or chest pain. If you notice any of these, tell your doctor right away. (Everolimus (Afinitor) patient information, PMID 31924480)
• Blood and urine tests: everolimus can affect kidney function; when used in transplant care, it can also raise blood fats and protein in the urine, and this risk increases at high levels. Your doctor monitors these regularly. (Everolimus (Afinitor) patient information, Everolimus (Zortress) prescribing information §5.11 and §5.12)
• What is in the product: the interaction was shown with approved CBD; in over-the-counter CBD products, the amount of CBD on the label may not be accurate and the product may contain THC. Check the CBD and THC content of the product you use on its label and its certificate of analysis. (Everolimus (Afinitor) prescribing information §7.1, NIH NCCIH) How to read a label and certificate of analysis

Frequently asked questions

References

Last reviewed: October 27, 2026. On this date, each source was opened and checked against the related sentence.