Rapamycin (Sirolimus) and Cannabis: Full Interaction Profile

Does cannabis interact with sirolimus?

Sirolimus is a substrate for both CYP3A4 and P-glycoprotein. The label says inducers of either pathway may decrease sirolimus concentrations and inhibitors may increase them. It advises avoiding strong inducers such as rifampin and rifabutin and strong inhibitors such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin, and using caution with weaker modulators [1].

For cannabinoids specifically, the label goes one step further. It names cannabidiol and states that sirolimus blood levels may increase when the two are used together, with close monitoring for sirolimus toxicity and a possible Rapamune dose reduction [1].

What the Rapamune label actually says about cannabidiol

The label has a short section headed Cannabidiol. It contains three statements: sirolimus blood levels may increase with concomitant cannabidiol; prescribers should closely monitor for an increase in sirolimus blood levels and for adverse reactions suggestive of sirolimus toxicity; and a dose reduction of Rapamune should be considered as needed [1]. The Drug Interactions summary at the top of the section also flags therapeutic drug monitoring and dose reduction for cannabidiol by name [1].

That section is written about cannabidiol as a co-administered drug. It gives no dose threshold, no product names and no monitoring schedule, and it does not limit the warning to a particular product or formulation, such as CBD oil [1].

Sirolimus metabolism and exposure

Sirolimus is extensively metabolized in the intestinal wall and liver by CYP3A4, with P-glycoprotein counter-transporting drug back into the gut lumen; seven major metabolites circulate in whole blood [1]. About 92% is plasma protein bound, and the whole-blood to plasma ratio is 36, reflecting extensive partitioning into blood cells [1]. The mean terminal half-life is about 62 hours in stable renal transplant patients, and 91% of radioactivity is recovered in feces [1].

Liver function changes exposure on its own. Mean AUC rises 43% in mild, 94% in moderate and 189% in severe hepatic impairment, and the label reduces the maintenance dose by about one third in mild-to-moderate impairment and one half in severe impairment [1]. Dosing is titrated to a target sirolimus trough range rather than a fixed number of milligrams [1].

Labeled adverse reactions in the renal transplant studies were described as dependent on dose and concentration. The most common (30% or more) include hypertriglyceridemia, hypercholesterolemia, hypertension, peripheral edema, increased creatinine, diarrhea, headache, anemia and thrombocytopenia [1].

The label's one explicit food rule is grapefruit juice, which inhibits CYP3A4-mediated metabolism of sirolimus and must not be taken with Rapamune or used to dilute it [1].

What real-world reports show

Nachnani and colleagues screened 4,600 reports for a 2024 systematic review in Frontiers in Pharmacology and found 31 in which cannabinoids altered the pharmacokinetics of a narrow-therapeutic-index drug, produced adverse events, or both. Those 31 reports involved 16 drugs, 889 subjects and 603 cannabis or cannabinoid users. Warfarin, valproate, tacrolimus and sirolimus were the most widely reported interactions and, in the authors' words, may pose the greatest risk to patients [2].

In 18 of the 31 reports (58%), a clinician uncovered an unexpected serum level of the prescribed drug [2]. The authors note that delta-9-THC and cannabidiol are metabolized by CYP3A4, CYP2C9 and CYP2C19, the same enzymes that metabolize most prescription medicines [2]. These reports document potential interactions, but the review does not establish how much cannabis or cannabinoids change sirolimus levels [2].

Does the form of cannabis matter: smoked, vaped, edible or CBD oil?

The label's cannabidiol statement does not distinguish among smoked, vaped, edible or oil forms [1]. The case-level reports in the 2024 review cover cannabis and cannabinoid products as a group [2].

Low-dose rapamycin and cannabis

Sirolimus is FDA-approved for two things: preventing organ rejection in kidney transplant recipients aged 13 and older, and treating lymphangioleiomyomatosis [1]. Aging, longevity and healthspan are not approved indications, so using rapamycin for them is off-label [1]. Compounded rapamycin is not FDA-approved, and FDA does not verify its safety, effectiveness or quality before marketing [3].

The PEARL trial gave healthy, normative-aging adults 5 mg or 10 mg of compounded rapamycin once weekly for 48 weeks in a double-blind, placebo-controlled design. Visceral adiposity did not change significantly, adverse and serious adverse events were similar across groups, and blood biomarkers stayed in normal ranges [4]. An earlier pilot randomized 25 generally healthy adults aged 70 to 95 to 1 mg daily or placebo; 11 rapamycin and 14 placebo participants completed at least 8 weeks, and the rapamycin group showed significant decreases in hemoglobin, hematocrit and red cell indices [5]. Neither trial was designed to test cannabis [4][5].

Labeled risks relevant to higher sirolimus levels

The boxed warning covers increased susceptibility to infection and the possible development of lymphoma and other malignancies from immunosuppression, and says only physicians experienced in immunosuppressive therapy and renal transplant management should use Rapamune for rejection prophylaxis [1]. The Warnings section adds that oversuppression can increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections and sepsis [1].

Other labeled concerns include hypersensitivity reactions, angioedema, fluid accumulation and impaired wound healing, hyperlipidemia, proteinuria, interstitial lung disease, and a decline in renal function with long-term cyclosporine co-therapy [1].