Cannabidiol Elevates mTOR Inhibitor Levels In Tuberous Sclerosis Complex Patients

Abstract Background The mTOR inhibitors everolimus and sirolimus have activity against multiple manifestations of tuberous sclerosis complex (TSC) and are approved to treat astrocytomas, angiomyolipomas, lymphangioleiomyomatosis, and epilepsy. Cannabidiol is a novel anticonvulsant medication. There is a lack of information regarding drug-drug interactions between mTOR inhibitors and cannabidiol in clinical practice. Methods Chart review of TSC patients treated with an mTOR inhibitor (everolimus, sirolimus) and cannabidiol . Clinical information, mTOR inhibitor and cannabidiol dosing, concomitant antiepileptic drugs, laboratory and adverse events were reviewed before and after initiation of cannabidiol. Results 25 patients were treated with cannabidiol and an mTOR inhibitor (18 everolimus, 7 sirolimus). All mTOR inhibitor levels were drawn as troughs. Levels were significantly higher in 76% patients after cannabidiol treatment (p=0.0003). Median change from baseline was +9.8 ng/mL for everolimus and +5.1 ng/mL for sirolimus. Adverse events occurred in 40%, with diarrhea being the most frequent adverse event occurring, in three patients. No severe adverse events occurred during the treatment period. Conclusions Cannabidiol resulted in increased serum levels of everolimus and/or sirolimus. Some patients experienced doubling or tripling of their mTOR inhibitor trough following the addition of cannabidiol. In some cases, this resulted in clinical toxicity, as well as laboratory abnormalities. Awareness of this interaction can lead clinicians to evaluate serum levels and other safety laboratory studies more closely, and thereby avoid potentially significant adverse effects. In patients known to be prone to mTOR inhibitor toxicity, preemptive reduction in dose may be warranted upon initiation of cannabidiol.