The endocannabinoids system (ECS) has garnered considerable interest as a potential therapeutic target in various carcinomas and cancer-related conditions alongside neurodegenerative diseases. Cannabinoids are implemented in several physiological processes such as appetite stimulation, energy balance, pain modulation and the control of chemotherapy-induced nausea and vomiting (CINV). However, pharmacokinetics and pharmacodynamics interactions could be perceived in drug combinations, so in this short review we tried to shed light on the potential drug interactions of medicinal cannabis. Hitherto, few data have been provided to the healthcare practitioners about the drug–drug interactions of cannabinoids with other prescription medications. In general, cannabinoids are usually well tolerated, but bidirectional effects may be expected with concomitant administered agents via affected membrane transporters (Glycoprotein p, breast cancer resistance proteins, and multidrug resistance proteins) and metabolizing enzymes (Cytochrome P450 and UDP-glucuronosyltransferases). Caution should be undertaken to closely monitor the responses of cannabis users with certain drugs to guard their safety, especially for the elderly and people with chronic diseases or kidney and liver conditions.
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. -USA. |
-Capsule (2.5–20 mg). -Oral. |
-Both were effective in CINV and well tolerated while dronabinol was more effective. -Combination is not more effective. |
[27] |
-Dronabinol [Marinol®; (-) trans Δ9-THC] |
-Interventional (retrospective). -Children with malignancy. |
-Solution administered orally (2.5–5 mg/m2 body surface every 6 h as needed). | -Positive responses were reported for 60% of patients. -Prospective trial would be needed to confirm the dronabinol effect in CINV therapy. |
[28] |
-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. |
[29] |
Cancer Pain | ||||
-Sativex® (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. -Phase 3. -UK. |
-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 included dizziness, gastrointestinal disorders and confusion. |
[30] |
-Sativex® (Δ9-THC: CBD at a ratio of 27:25 mg/mL) |
-Interventional (single group assignment) -Phase 3. -UK. |
-Oromucodal spray with a 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 were assessed at the RCT withdrawal visit, 7–10 days later, then monthly, and at the withdrawal or completion of the study. |
[31] |
- Sativex® (Δ9-THC: CBD at a ratio of 27:25 mg/mL) |
-Interventional (Double-Blind, Randomized, Parallel-Group, Placebo-Controlled). -Phase 3. -Multicentric. -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 is still beneficial to secondary endpoints. -No evidence of abuse or misuse was reported. |
[32] |
-No significant difference was reported in advanced cancer patients with chronic uncontrolled pain. | [33] | |||
-Nabiximols (Sativex®; Δ9-THC: CBD at a ratio of 27:25 mg/mL) | -Interventional (Double-Blind, Randomized, Parallel-Group, Placebo-Controlled). -Phase 2. -USA. -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. |
[34] |
-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. |
[35] |
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. |
[36] |
Cannabinoid Based Treatment and Interactions | Affected Transporters and/or Metabolic Enzymes | Experimental Results, Notes and Outcomes | References |
---|---|---|---|
Cannabis, THC, CBD, CBN with either chemotherapy, abuse drugs or medications | -Membrane transporters ABC superfamily (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) -UDP-glucuronosyltransferases (UGTs) |
-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.
|
[19][54][55] |
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.
|
[56] |
Cannabinoids on other drugs | Cytochrome P450 | -CYP3A4 inhibitors and stimulators affect the elimination of Δ9-THC and CBD.
|
[57] |
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).
|
[51][58] |
Synthetic and Phyto-cannabinoids | -Cytochrome P450 -UGTs |
-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-acyl glucuronidation was strongly competitively inhibited by AM-2201, MAM-2201, and EAM-2201. -UGT2B7-mediated naloxone 3β-D-glucuronidation was competitively inhibited by AM-2201.
|
[59][60] |
This work was partially supported by the Maxwell Family Foundation and Cairo University via the mission's sector at the Ministry of higher education, Cairo, Egypt.
This entry is adapted from the peer-reviewed paper 10.3390/medicines6010003