Medicinal Cannabis—Potential Drug Interactions
2. Potential Drug Interactions
3. Effects of Cannabis on Drug Metabolizing Enzymes and Related Drug Interactions
4. Other Potential Drug Interactions
Conflicts of Interest
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|Cannabis Based Treatment||Study Type/Location/n||Dosage/Administration||Efficacy, Tolerability and Notes||References|
|Chemotherapy Induced Nausea and Vomiting (CINV)|
|-Dronabinol [Marinol®; |
(-) trans Δ9-THC) alone or in combination with ondansetron (8–15 mg IV]
|-Interventional (Placebo controlled). |
-n = 64.
|-Capsule (2.5–20 mg).|
|-Both were effective in CINV and well tolerated while dronabinol was more effective. |
-Combination is not more effective.
|-Dronabinol [Marinol®; |
(-) trans Δ9-THC]
-Children with malignancy.
|-Solution administered orally (2.5–5 mg/m2 body surface every 6 h as needed).||-Positive response were reported for 60% of patients. |
-Prospective trial would be needed to confirm the dronabinol effect in CINV therapy.
|-Nabilone with 5HT3 antagonist||-Interventional (retrospective)|
-n = 110 with median age 14 years with malignancy.
|-Oral.||-Adverse effect was reported with minor clinical significance. |
-Poor nausea control in nabilone treated group.
(Δ9-THC: CBD at a ratio of 27:25 mg/mL)
-THC (27 mg/mL)
|-Interventional (Double Blind, Randomized, Parallel Group, Placebo Controlled), n = 177.|
|-Oromucodal spray with maximum Δ9-THC: CBD (130:120 mg/day) or 130 mg/day Δ9-THC alone |
Each actuation is 100 μL.
|-Compared with the placebo, the Sativex treated group showed significant pain relief unlike the Δ9-THC which was non-significant. |
-Reported adverse effects including dizziness, gastrointestinal disorders and confusion.
(Δ9-THC: CBD at a ratio of 27:25 mg/mL)
|-Interventional (single group assignment) |
|-Oromucodal spray with maximum 130:120 mg/day of Δ9-THC: CBD.||-The long-term use is well tolerated without losing pain-relieving effects in terminal cancer-related pain refectory to opioids. |
-Adverse effects and tolerability assessed at the RCT withdrawal visit, 7–10 days later, then monthly, and at the withdrawal or completion of the study.
|- Sativex® |
(Δ9-THC: CBD at a ratio of 27:25 mg/mL)
|-Interventional (Double Blind, Randomized, Parallel Group, Placebo Controlled).|
-n = 399.
|-Oromucodal spray (100 μL per actuation twice daily in the morning and evening with a maximum of 10 sprays for 5 weeks).||-No significant difference was reported in advanced cancer patients with chronic pain (unalleviated with opioids). |
-Nabiximol still beneficial to secondary endpoints.
-No evidence of abuse or misuse was reported.
|-No significant difference was reported in advanced cancer patients with chronic uncontrolled pain.|||
|-Nabiximols (Sativex®; Δ9-THC: CBD at a ratio of 27:25 mg/mL)||-Interventional (Double Blind, Randomized, Parallel Group, Placebo Controlled).|
-n = 360.
|-Oromucodal spray in low (1–4 sprays/day), medium (6–10 sprays/day) and high (11–16 sprays/day) doses.||-Efficacy and safety were reported at low and medium doses against advanced cancer pain. |
-The adverse effects at high doses.
|-Nabiximols (Sativex®, Δ9-THC: CBD at a ratio of 27:25 mg/mL)||-Interventional (Double-Blind, Placebo controlled, Crossover Pilot trial). |
-n = 16.
|-Sublingual spray (7.5–30 mg/day).||-No significant difference was reported against chemotherapy-induced neuropathy. |
-Two-fold reduction of the pain in the responder group with adverse effects.
|Cannabis cigarettes (3.56% Δ9-THC) in combination with opiates||-Interventional (open label).||-Pulmonary administration for chronic pain, including cancer patients.||-Declined chronic pain around 27% in patients receiving oxycodone or morphine analgesics. |
-No serious adverse effects were reported.
|Cannabinoid Based Treatment and Interactions||Affected Transporters and/or Metabolic Enzymes||Experimental Results, Notes and Outcomes||References|
|Cannabis, THC, CBD, CBN with either chemotherapies, abuse drugs or medications||-Membrane transporters ABC super family (glycoprotein P; P-gp, Breast cancer-resistance protein; BCRP, and multidrug resistance protein; MRP1, 2, 3 and 4) |
-Cytochrome P450 (3A, 2D6, 2C9, 1A1, 1A2, 1B1, 2B6 and 2C8)
|-P-gp, BCRP, and MRP1-4 transporters expression were dysregulated by cannabinoids, but in higher concentrations than that usually measured in cannabis smokers. |
-CYP3A was competitively inhibited by THC, CBD and CBN, with CBD being the most potent in a concentration compatible with that in usual cannabis inhalation.
-CYP2D6 was inhibited by THC, CBD and CBN, with CBD being the most potent in a higher concentration than that in usual cannabis consumption.
-CYP2C9 was inhibited by THC, CBD and CBN, with CBD inhibitory effect being dependent on the used substrates.
-CYP1A1, 1A2, 1B1, 2B6, 2C19, 3A4 and 2C8 were strongly inhibited by CBD.
-UGT1A9, and 2B7 were inhibited by CBD.
-UGT1A7, 1A8, and 1A9 were inhibited by CBN.
-UGT2B7 was activated by CBN.
|Δ9-THC, CBD and marijuana inhalation with psychotropic agents||-Cytochrome P450||-CYP2C9 and CYP3A4 were inhibited by Δ9-THC. |
-CYP2C19 and CYP3A4 were inhibited by CBD.
-CYP1A1 and CYP1A2 were induced by marijuana inhalation.
|Cannabinoids on other drugs||Cytochrome P450||-CYP3A4 inhibitors and stimulators affect the elimination of Δ9-THC and CBD.|||
|CBD with antiepileptic drugs||Cytochrome P450 or unknown||Clinical studies of DDI:|
-Non-significant increase of the clobazam plasma level administered with CBD (n = 13 children) due to potent inhibition of CYP2C19.
-Significant change of plasma level of N-desmethylclobazam by CBD co-administration while no significant change in the level of valproate, stiripentol and levetiracetam (n = 24 open label trial).
-All patients showed significant changes of the plasma levels of clobazam, N-desmethylclobazam, rufinamide, and topiramate by increasing CBD doses. The mean therapeutic range was exceeded for clobazam and N-desmethylclobazam; the plasma levels of eslicarbazepine and zonisamide were increased in adults only (n = 39 adults and 42 children).
|Synthetic and Phyto-cannabinoids||-Cytochrome P450 |
|-CYP1A catalysed MROD activity was weakly inhibited by MAM-2201, JWH-019, STS-135, and UR-144. |
-CYP2C8 catalysed amodiaquine N-deethylase was strongly inhibited by AM-2201, MAM-2201, and EAM-2201.
-CYP2C9 catalysed diclofenac hydroxylation and CYP3A-catalyzed midazolam 1′-hydroxylation were inhibited by AM-2201 and MAM-2201.
-CYP2C9 catalysed diclofenac 4′-hydroxylation, CYP2C19-catalyzed [S] -mephenytoin 4′-hydroxylation, and CYP3A-catalyzed midazolam 1′ hydroxylation were strongly inhibited by EAM-2201 (time-dependent inhibition).
-CYP2B6 and CYP2C9 were strongly inhibited by THC, CBN and CBD.
-CYP2A6 was inhibited by THC and CBN (mechanism-based inhibition).
-CYP2D6 was competitively inhibited by CBD.
-CYP1A1 mRNA expression was increased by THC in Hepa-1 cells, but EROD activity in CYP1A1 supersomes was inhibited by THC.
-CYP1A1, CYP1A2, and CYP1B1 were strongly inhibited by CBD (mechanism-based inhibition).
-CYP3A was inhibited by CBD in human liver microsomes.
-CYP2C19-catalyzed [S] -mephenytoin hydroxylation was inhibited by (CBD and THC (Mixed-type inhibition).
-UGT1A9- and UGT2B7 catalysed ethanol glucuronidation were non-competitively inhibited by CBD, and unlike the inclined ethanol glucuronidation in human liver microsome by CBN (dose dependent).
-UGT1A3 catalysed chenodeoxycholic acid 24-acylglucuronidation was strongly competitively inhibited by AM-2201, MAM-2201, and EAM-2201.
-UGT2B7-mediated naloxone 3β-D-glucuronidation was competitively inhibited by AM-2201.
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Alsherbiny, M.A.; Li, C.G. Medicinal Cannabis—Potential Drug Interactions. Medicines 2019, 6, 3. https://doi.org/10.3390/medicines6010003
Alsherbiny MA, Li CG. Medicinal Cannabis—Potential Drug Interactions. Medicines. 2019; 6(1):3. https://doi.org/10.3390/medicines6010003Chicago/Turabian Style
Alsherbiny, Muhammad A., and Chun Guang Li. 2019. "Medicinal Cannabis—Potential Drug Interactions" Medicines 6, no. 1: 3. https://doi.org/10.3390/medicines6010003