TABLE 6.

Interaction between calcineurin inhibitors, mTOR inhibitors, and cannabis.

Drugs	Probability	Severity	Observed effects	Patient outcomes	Recommendation	References
Calcineurin inhibitors
Cyclosporine (CYP3A4 inhibition)	Defined	Not applicable	Stable cyclosporine levels; specific data was not reported	Adverse effects were reported in the subjects from the cyclosporine cohort (n = 2). These included dry mouth, nausea, dizziness, drowsiness, and episodes of intermittent heat. Dizziness was reported in the female participant (n = 1) Optimal pain control was observed within the cyclosporine + CBD cohort	Concomitant use of CBD and cyclosporine is well tolerated and can be administered together. Weekly follow‐up is advised for the first month of combination therapy, then fortnightly or monthly follow‐up as per the condition of the patient Optimal doses of CBD or cyclosporine should be titrated for each patient due to the probability of mild adverse effects	16
Tacrolimus (Victim—CYP3A4 inhibition)	Defined	Not applicable	An initial decrease in the tacrolimus level was noted (n = 1), which normalized after 1 week. Data on tacrolimus levels were not specified	Notable adverse effects included persistent nausea (n = 1) as well as elevated tacrolimus and SrCr levels (n = 1). Doses of CBD and tacrolimus were then reduced in the respective cases. Other adverse effects reported by subjects in the tacrolimus cohort (n = 5) were dizziness, drowsiness, and a few episodes of intermittent heat Partial improvement of pain management was noted in the subjects (n = 4). There was no improvement in pain control when CBD was co‐administered in the remaining subject	Concomitant use of CBD and tacrolimus is well tolerated and can be administered together. Weekly follow‐up is advised for the first month of combination therapy, then fortnightly or monthly follow‐up as per the patient's condition Optimal doses of CBD or tacrolimus should be titrated for each patient due to mild adverse effects	16
	Defined	Minor to moderate (58.3%–241%)	A case report of a 32‐year‐old female showed baseline tacrolimus levels of 3.9–8.4 ng/mL. On Day 164, the dose‐normalized tacrolimus level had increased by approximately three‐fold, resulting in a reading of 13.3 ng/mL SrCr level increased to 2.4 mg/dL (baseline was 1.2 mg/dL) on Day 124 of the study. Tacrolimus doses were withheld 7 days later with SrCr level decreased to 1.5 mg/dL. An increment of tacrolimus dose to maximum was trialed in which SrCr level increased on Day 282	Signs of tacrolimus toxicity, particularly a rise in SrCr levels	Close monitoring of tacrolimus trough levels is needed when CBD is added as an adjunctive treatment. Dose reduction is warranted when SrCr increases from baseline with close observation	17
mTOR inhibitors
Everolimus (Victim—CYP3A4 inhibition)	Defined	Moderate (180%)	Median increase of everolimus level by 9.8 ng/mL as compared with baseline	Doses of mTOR inhibitors were reduced due to the linear relationship between the drug levels and the risk of toxicity The main adverse effect reported was diarrhea (n = 10). Other adverse effects included abdominal pain, swelling ankle, drowsiness, worsening acne, worsening and severe mouth ulcers, sinusitis, and elevated levels of liver enzymes	Close monitoring of several important parameters (e.g., mTOR inhibitors plasma levels, relevant parameters, and adverse effects) with particular care is warranted during the CBD initiation Dose reduction in CBD should be considered pre‐emptively when the patient is known to be prone to mTOR inhibitor toxicity	18
Sirolimus (Victim—CYP3A4 inhibition)		Minor (70%)	Median increase of sirolimus level by 5.1 ng/mL as compared with baseline