Can cannabis use induce drug interactions? Are there any reports of cannabis use resulting in drug interactions in post-transplant patients?

Comment by InpharmD Researcher

While the metabolism of exogenous cannabinoids (e.g., THC, CBD) is not fully elucidated, data suggests cannabis use can produce clinically significant drug interactions, particularly in transplant patients taking calcineurin inhibitors. In vitro data suggests THC is metabolized by and can inhibit CYP3A4, CYP2C9, CYP2C19, while CBD is a substrate of CYP2C19 and CYP3A4. Cannabinoids can also inhibit P-gp, leading to increased levels of certain medications (e.g., calcineurin inhibitors). Case reports have documented this interaction between CBD and tacrolimus, requiring decreased tacrolimus doses to prevent toxicity. A meta-analysis of observational data suggests cannabis users may have a significantly higher rate of graft failure following kidney transplant.

Background

A statement from the American Heart Association warns that information on the safety and efficacy of cannabis use are limited by decades of illegality, particularly in the United States. While there may be potential benefits, cannabis also has the potential to induce drug-drug interactions. In vitro experiments suggest tetrahydrocannabinol (THC) has the potential to inhibit CYP3A4, CYP2C9, CYP2C19, and CYP2D, while cannabidiol (CBD) has the potential to inhibit CYP3A4/5, CYP2C19, CP2D6, and CYP1A2. Tetrahydrocannabinol can also induce CYP1A2, particularly when smoked. Cannabinoids can also inhibit systemic transport proteins, such as P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP). This risk of interactions may be clinically significant in transplant patients taking calcineurin inhibitors. A list of potential interactions and pharmacokinetic mechanisms can be found in Table 1. [1]

While not completely characterized, the metabolism of exogenous cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), appears to be predominately hepatic. In vitro and animal data show THC is primarily metabolized (oxidized) via CYP2C9, CYP2C19, and CYP3A4 before undergoing glucuronidation. Metabolism can also occur in extrahepatic tissue that expresses CYP450 enzymes, such as the brain, lungs, and small intestine. Similarly, CBD is metabolized primarily via CYP2C19 and CYP3A4, but it can also go through CYP1A1, CYP1A2, CYP2C9, and CYP2D6. Over 100 metabolites of TCH have been identified, but the psychoactivity and further metabolism of these compounds is not known. These metabolites are believed to also be metabolized via CYP2C9 and CYP3A4. Studies also suggest cannabinoids may be weak inhibitors of CYP2C9 and CYP3A4. In vitro data also suggest THC and CBD can inhibit P-glycoprotein (P-gp)‐mediated drug transport, suggesting cannabis use can potentially affect the absorption and distribution of coadministered medications. [2], [3], [4]

A 2021 review for transplant clinicians recognizes that as cannabis becomes more legally and socially acceptable, transplant centers will need to develop comprehensive policies to address its use. Clinical practice guidelines for transplant candidate evaluation consistently recommend psychosocial assessment to include substance use/abuse; however, they do not specifically address cannabis use and its management. The review authors conducted a survey of transplant centers and found one-third of responding centers have a policy where a patient’s marijuana use is not discussed (survey response rate 27.4%). The authors recommend programs develop an atmosphere where open communication regarding cannabis use is welcomed. They also recommend medical cannabis be treated as any other medication with special attention to drug-drug interactions and therapeutic monitoring around drug initiation/change weekly for one month and then monthly thereafter. While human data regarding cannabis-related drug interactions is scarce, limited research suggests the potential for clinically significant pharmacokinetic interactions between cannabis and immunosuppressants. [5]

A meta-analysis on the use of cannabis in post-kidney transplant patients estimates the overall usage in this population is around 3.2% although many centers deny cannabis users the opportunity for transplantation. Four observational, cohort studies were included in this analysis (two from Sweden, one from USA, and one from Australia), comprising 55,897 transplant recipients; the study from Australia was a large database analysis (n= 52,689). The results of this meta-analysis found that cannabis use was not significantly associated with all-cause allograft failure (OR, 1.31; 95% CI, 0.70 to 2.46; I2 = 71%) or mortality (OR, 1.52; 95% CI 0.59 to 3.92; I2 = 15%). However, cannabis use was significantly associated with an increased risk of death-censored graft failure (OR 1.72; 95% CI, 1.13 to 2.60; I2 = 43%). A possible reason for the results seen may be due to an interaction via CYP3A4 leading to toxic levels of calcineurin inhibitors; high calcineurin inhibition levels are known to cause thrombotic microangiopathy, arteriolar hyalinosis, striped patterns of tubular atrophy, and interstitial fibrosis. Limitations of this analysis include the substantial heterogeneity between the studies, one study including a larger amount of patients than the others, the possibility of cannabis use underreporting, no information on dose adjustments, and potential publication bias. [6]

Relevant Prescribing Information

Dronabinol. Prescribing information. Akorn; 2022.
Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-hydroxy-delta-9-THC, are present in approximately equal concentrations in plasma. Published in vitro data indicates that CYP2C9 and CYP3A4 are the primary enzymes in the metabolism of dronabinol. CYP2C9 appears to be the enzyme responsible for the formation of the primary active metabolite
Dronabinol is primarily metabolized by CYP2C9 and CYP3A4 enzymes based on published in vitro studies. Inhibitors of these enzymes may increase, while inducers may decrease, the systemic exposure of dronabinol and/or its active metabolite resulting in an increase in dronabinol-related adverse reactions or loss of efficacy of dronabinol capsules. Monitor for potentially increased dronabinol-related adverse reactions when dronabinol capsules are co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).
Dronabinol is highly bound to plasma proteins, and therefore, might displace and increase the free fraction of other concomitantly administered protein-bound drugs. Although this displacement has not been confirmed in vivo, monitor patients for increased adverse reactions to narrow therapeutic index drugs that are highly protein-bound (e.g., warfarin, cyclosporine, amphotericin B) when initiating treatment or increasing the dosage of dronabinol capsules.

Epidiolex (cannabinol). Prescribing information. Greenwich Biosciences; 2022.
Coadministration of cannabinol with orally administered everolimus, a P-gp and CYP3A4 substrate, results in an approximately 2.5-fold increase in mean Cmax and AUC of everolimus. When initiating cannabinol in patients taking everolimus, monitor therapeutic drug levels of everolimus and adjust the dosage accordingly. When initiating everolimus in patients taking a stable dosage of cannabinol, a lower starting dose of everolimus is recommended, with therapeutic drug monitoring. Increases in exposure of other orally administered P-gp substrates (e.g., sirolimus, tacrolimus, digoxin) may be observed on coadministration with cannabinol. Therapeutic drug monitoring and dose reduction of other P-gp substrates should be considered when given orally and concurrently with cannabinol.

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Can cannabis use induce drug interaction? Are there any reports of cannabis use resulting in drug interactions in post-transplant patients?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Summary of Potential Drug-Drug Interactions With Cannabis
Cytochrome P450 Enzyme	Medication Effect	CBD Effects	THC Effects	Examples of Potentially Interacting Drugs/Substrates	Suggested Clinical Intervention
CYP 1A2	Substrate	↑ Substrate concentration	↓ Substrate concentration	Chlorpromazine, clozapine, cyclobenzaprine, duloxetine, haloperidol naproxen, olanzapine, propafenone, theophylline, tricyclic antidepressants	Monitor for signs of either therapeutic failure or adverse effects; consider modifying substrate dose on the basis of cannabis preparation
CYP 2C9	Substrate	↑ Substrate concentration	Conflicting data; unknown	Burprenorphine, fluvastatin, celecoxib, losartan, naproxen, phenobarbital, montelukast, phenytoin, rosiglitazone, rosuvastatin, sulfonylureas, valsartan, warfarin	Consider decreasing dose of substrate; monitor INR for warfarin within 3 d; monitor free phenytoin levels
CYP 2D6	Substrate	↑ Substrate concentration	↑ Substrate concentration	Antidepressants (eg, amitriptyline, citalopram, nortriptyline), antipsychotics (eg, clozapine, haloperidol, risperidone), antiarrhythmic (eg, amiodarone, dronedarone, flecainide, propafenone), β-blockers (eg, carvedilol, metoprolol), opioids (eg, codeine, morphine, tramadol), valproate	Consider decreasing dose of substrate; monitor for adverse reactions; monitor QTc for antidepressants and antiarrhythmics; monitor free valproate levels
CYP 2D6	Inhibitor	↑ CBD concentration	↑ THC concentration	Desipramine, paroxetine, quinidine, ritonavir, sertraline	Consider decreasing dose of cannabis product
CYP 3A4	Substrate	↑ Substrate concentration	↑ Substrate concentration	Benzodiazepines, dihydropyridine calcium channel blockers (eg, amlodipine, felodipine), CNIs (eg, cyclosporine, tacrolimus), PDE5 inhibitors (eg, sildenafil), propafenone, statins (except pravastatin and rosuvastatin), zaleplon, zopiclone, zolpidem	Consider decreasing dose of substrate
	Inhibitor	↑ CBD concentration	↑ THC concentration	Antiarrhythmic (eg, amiodarone, dronedarone, quinidine), azole antifungals (eg, ketoconazole, itraconazole, posaconazole), non-dihydropyridine (eg, diltiazem, verapamil), macrolides (eg, clarithromycin, erythromycin), protease inhibitors (eg, ritonavir, indinavir, nelfinavir, saquinavir, telaprevir, atazanavir, boceprevir, lopinavir), tyrosine kinase inhibitors, valproate	Consider decreasing dose of cannabis product
	Inducer	↓ CBD concentration	↓ THC concentration	Carbamazepine, cimetidine, phenytoin, phenobarbital, pioglitazone, rifampin, St. John’s wort, topiramate	Consider increasing dose of cannabis product
CYP 2C19	Substrate	↑ Substrate concentration	↑ Substrate concentration	Antidepressants (eg, amitriptyline, citalopram, bupropion), antiseizure (eg, clobazam, diazepam, phenytoin, phenobarbital, clopidogrel), proton pump inhibitors (eg, omeprazole, pantoprazole)	Consider decreasing dose of substrate; monitor for adverse effects; for clopidogrel, consider using alternative antiplatelet; monitor free phenytoin levels
	Inhibitor	↑ CBD concentration	↑ THC concentration	Chloramphenicol, felbamate, fluoxetine, fluvoxamine, isoniazid, protease inhibitors (eg, ritonavir, indinavir, nelfinavir, saquinavir, telaprevir, atazanavir, boceprevir, lopinavir)	Consider decreasing dose of cannabis product; monitor for adverse effects
	Inducer	↓ CBD concentration	↓ THC concentration	Carbamazepine, ketoconazole, phenytoin, phenobarbital, rifampin, rifampicin, St. John’s wort	Consider increasing dose of cannabis product; monitor for adverse effects
UGT 1A9	Substrate	↑ Substrate concentration	No data	Acetaminophen, canagliflozin, dabigatran, dapagliflozin, haloperidol, ibuprofen, irinotecan, mycophenolate mofetil, propofol, regorafenib, sorafenib, valproic acid	Consider decreasing dose of substrate; monitor for adverse effects
UGT 2B7	Substrate	↑ Substrate concentration	No data	Carbamazepine, hydromorphone, ezetimibe, ibuprofen, losartan, lovastatin, naproxen, simvastatin, valproate	Consider decreasing dose of substrate; monitor for adverse effects
CBD, cannabidiol; CNI, calcineurin inhibitor; CYP, cytochrome P450; INR, international normalized ratio; PDE5, phosphodiesterase type 5; THC, Δ-9- tetrahydrocannabinol; UGT, uridine 5’diphospho-glucoronosyltransferase

References:

Adapted from: Page RL 2nd, Allen LA, Kloner RA, et al. Medical Marijuana, Recreational Cannabis, and Cardiovascular Health: A Scientific Statement From the American Heart Association. Circulation. 2020;142(10):e131-e152. doi:10.1161/CIR.0000000000000883

Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus
Design	Case report
Case presentation	A 32-year-old female patient on tacrolimus (5 mg twice daily) for interstitial nephritis was started on cannabidiol (CBD) for refractory epilepsy. Her dose was titrated to 20 mg/kg/day over 10 days (2,000 mg in divided doses twice daily). Laboratory findings were within the normal limits prior to starting CBD on day 100 of tacrolimus therapy. On day 114, serum creatinine (SCr) increased to 1.92 mg/dL (from 1.2 mg/dL at baseline) and peaked at 2.4 mg/dL on day 124. Tacrolimus was held, and SCr decreased to 1.5 mg/dL on day 133. Tacrolimus was restarted at 3 mg twice daily. On day 164, an approximate three-fold increase in dose-normalized concentration was seen. The dose of CBD was increased to 25 mg/kg (2,900 mg/day) as she responded well for epilepsy control; however, SCr was increased again, leading to a further reduction of tacrolimus dose (0.5 mg twice daily). Cannabidiol de-challenge was not performed due to concerns of uncontrolled seizures. There were no changes in her concomitant medication therapy, including the formulation of tacrolimus. The patient and caregiver reported no changes in diet and medication adherence.
Study Author Conclusions	The authors report this is the first case showing a significant interaction between purified CBD and tacrolimus. However, they note that due to insufficient evidence, the interaction between CBD and CYP-450 isoforms, including CYP3A4, remains unclear. Additionally, the binding sites of CYP3A4 may impact the inhibitory effect of an agent; however, CBD’s binding site on CYP3A4 has not yet been identified. Inhibition of P-glycoprotein (P-gp) by CBD is another possible mechanism to explain the increase in serum tacrolimus concentrations. This is a single case report, which provides limited quality evidence. The lack of CBD de-challenge/rechallenge is also a limitation. However, evaluating other factors (e.g. concomitant medications, changes in adherence, diets) to rule out other causes for changes in tacrolimus levels is a strength.

References:

Leino AD, Emoto C, Fukuda T, Privitera M, Vinks AA, Alloway RR. Evidence of a clinically significant drug-drug interaction between cannabidiol and tacrolimus. Am J Transplant. 2019;19(10):2944-2948. doi:10.1111/ajt.15398

High on Cannabis and Calcineurin Inhibitors: A Word of Warning in an Era of Legalized Marijuana
Design	Case report
Case Presentation	A 67-year-old man with relapsed follicular lymphoma was admitted for allogeneic hematopoietic stem cell transplant. Continuous tacrolimus infusion drip at 1.8 mg/kg was started two days before the transplant with a goal serum tacrolimus level of 8-12 ng/mL. The drip was decreased to 1.0 mg/kg due to consistently high tacrolimus concentrations above the target goal. Ten days post-transplant, the patient admitted to taking edible marijuana gummies. On day 14 after transplant, tacrolimus levels while on 1.0 mg/kg continuous infusion were therapeutic despite a positive cannabis screen and the patient was placed on tacrolimus 1 mg by mouth twice daily. Tacrolimus levels spiked to 43.8 ng/mL on day 21 after transplant, so the dose of tacrolimus was decreased to 0.5 mg by mouth twice daily. Even with the dose decrease of tacrolimus, the patient's tacrolimus levels continued to increase and peaked at 45.8 ng/mL on day 23 after transplant. Tacrolimus administration was then discontinued after the peak. During this time, the patient also started to show signs of tacrolimus toxicity including diarrhea, body stiffness, tremors, and altered mental status. The patient was transferred to the intensive care unit where he soon became stable. On day 28 after transplant, his tetrahydrocannabinol (THC) screen returned negative and the patient was resumed on tacrolimus on day 31 after transplant after holding the tacrolimus for a total of 10 days.
Study Authors' Conclusions	Exogenous cannabinoids, such as TCH and cannabidiol (CBD), are known to inhibit P-glycoprotein (Pgp) and CYP3A enzymes. The combination of cannabinoids and tacrolimus can lead to increased tacrolimus levels in the blood. The P-glycoprotein and CYP3A inhibition pose a serious concern for the need to regulate or at least monitor cannabis use in patients receiving tacrolimus after stem cell transplant. Furthermore, there may be a benefit to obtainin a urine toxicology screen on these patients before starting the immunosuppressant tacrolimus in order to better adjust the dosage and predict serum concentration.

References:

Hauser N, Sahai T, Richards R, Roberts T. High on Cannabis and Calcineurin Inhibitors: A Word of Warning in an Era of Legalized Marijuana [published correction appears in Case Rep Transplant. 2018 Sep 6;2018:7095846]. Case Rep Transplant. 2016;2016:4028492. doi:10.1155/2016/4028492

Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay
Design	Open-label feasibility study; (N= 7)
Objective	To assesses the effect, safety, and possible drug interactions in kidney transplant patients treated with cannabidiol (CBD) for chronic pain
Study Groups	Kidney transplant patients with chronic pain (N= 7)
Inclusion Criteria	Adult kidney transplant patients (at least one year prior) with chronic pain who requested to associate CBD for their analgesic treatment
Exclusion Criteria	Patients suffering an acute rejection episode, humoral rejection episode, or acute infection within the last 6 months.
Methods	Doses were increased from 50 to 150 mg twice a day for 3 weeks (not further detailed). At medical visits, creatinine, blood count, liver function, liver enzymes, and drug levels were determined every 48 hours the first week and once a week thereafter. Each visit included a physical examination, evaluation of adverse effects daily report form, blood count, liver function test, liver enzymes, creatinine, and calcineurin inhibitors plasma determination.
Duration	3 weeks
Outcome Measures	Creatinine, blood count, liver function, liver enzymes, and drug levels Pain Score Index and Limitation Perception
Baseline Characteristics	Individual Patient Baseline Characteristics and Results (Day 1 / Day 21)
	Patient	1	2	3	4	5	6	7
	Age	75	58	61	60	60	73	65
	Sex	Female	Male	Female	Male	Male	Female	Male
	Pain Cause	Fibromyalgia	Osteoarticular	Fibromyalgia	Osteoarticular	Osteoarticular	Osteoarticular	Neuropathic
	Creatinine (mg/dL)	1.10 / 1.04	1.03 / 1.12	0.92 / 0.89	1.14 / 1.16	1.94 / 2.8	2.07 / 1.95	2.39 / 2.36
	Hemoglobin (g/dL)	11.4 / 10.7	13.4 / 13.1	12.4 / 12.9	15 / 14.3	11 / 10.2	11.5 / 10.9	14.7 / 14.8
	Leucocytes (mm3)	3990 / 4370	7080 / 8960	4480 / 5280	8830 / 10850	7420 / 6360	12900 / 11760	10100 / 12600
	Platelets (103 m3)	185 174	215 237	182 199	248 245	189 174	306 265	157 213
	TGO and TGP (mg/dL)	14 and 11 / 14 and 10	14 and 18 / 16 and 22	20 and 12/ 19 and 12	16 and 9 / 12 and 8	16 and 11 / 15 and 11	16 and 11 / 15 and 11	19 and 16 / 16 and 19
	Tacrolimus (ng/mL)	10.1 / 6.5	7.4 / 2.8	14.4 / 16.7	9.7 / 9.8	7.8 / 13.8	--	--
	Cyclosporine (ng/mL)	--	--	--	--	--	355 / 332	261 / 291
	TGO/TGP, glutamic oxaloacetic transaminase/glutamic pyruvic transaminase.
Results	Patient	1	2	3	4	5	6	7
	Pain score Day 1/ Day 21	5 / 3	2 / 2	1 / 2	4 / 3	6 / 6	6 / 1	8 / 2
	Limitation Perception Day 1/ Day 21	Moderate/Mild	None/None	None/None	Mild/Mild	Moderate/ Moderate	Moderate/None	Severe/None
	Pain score (1 - 10) Limitation perception: none, mild, moderate, severe
Adverse Events	Common Adverse Events: nausea, dry mouth, dizziness, drowsiness, hot flashes (frequency not specified)
	Serious Adverse Events: N/A
	Percentage that Discontinued due to Adverse Events: None
Study Author Conclusions	During this follow-up study, we found mild adverse effects reported during CBD use that required the individualization of treatment, especially titration of the optimal dose for each patient. There were no serious adverse effects reported. In general, the CBD was well-tolerated and there was no need to discontinue the treatment. Although a longer follow-up with more patients is required to draw conclusions about clinically relevant pharmacokinetic interactions between CBD and calcineurin inhibitors, we consider that these data are sufficient to recommend a weekly follow-up during the first month and a biweekly or monthly follow-up on a case-by-case basis.
InpharmD Researcher Critique	Neither efficacy nor safety of CBD in kidney transplant patients can be established from this small, open-label study. Only baseline and the final concentrations of transplant-related immunosuppressive were reported. Clinical impact of CBD use on cyclosporine or tacrolimus remains unclear.

References:

Cuñetti L, Manzo L, Peyraube R, Arnaiz J, Curi L, Orihuela S. Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant Proc. 2018;50(2):461-464. doi:10.1016/j.transproceed.2017.12.042