This document discusses potential interactions between cannabinoids used for medical purposes (e.g. dronabinol, nabilone) and various cancer therapeutics that are metabolized by the CYP450 enzyme system. It finds that dronabinol and nabilone are moderate inhibitors of CYP3A4, the most abundant CYP enzyme, and lists several chemotherapeutics metabolized by this enzyme. This could increase plasma concentrations and prolong effects of co-administered drugs. The document concludes more research is needed, as certain populations may face higher risks due to genetic CYP polymorphisms affecting drug metabolism.

1. Investigating CYP450 interactions
between cannabinoids and
cancer therapeutics
OhSynNAPse!
Cyrus Ruediger, Megha Majumder, Nawara Ahmed, Albert Fang, Victoria Riel

2. Increasing Cannabinoid Usage
CB1
and CB2
receptors
phytocannabinoids
● Recreational use
● Therapeutic use
○ Analgesic
○ Epilepsy management
○ Increase appetite
○ Reduce nausea
Denver Post

3. Classic Cannabinoids
Δ-9-tetrahydrocannabinol (THC),
dronabinol
nabilone cannabidiol (CBD)

4. Cannabinoid Metabolism
Conjugated
to glucuronide
and excreted
Reduced
psychoactivity
Not psychoactive
*Psychoactivities poorly defined
CYP2C9
CYP2C9
CYP3A4
CYP2C9
Baselt et al., 2004 Jiang et al., 2011

5. Competition for CYP450 Metabolism
Pool of CYP450 enzymes
responsible for drug
metabolism
cannabinoiddrug
Metabolized drugs
(Altered biological activity or
Excretion)

6. (CBD)
Yamaori et al., 2011
CYP2D6activity
Cannabinoids can Competitively Inhibit CYPs

7. What synergistic or antagonistic interactions result
from the consumption of marijuana and related
cannabinoids in conjunction with chemotherapeutics
prescribed for any cancer in susceptible individuals?
Research Question:

8. Methods

9. Predicted Interacting Chemotherapeutics
Interacting
Cannabinoid
Interacting Cancer Therapeutic Reported CYP Interactors with Therapeutic (Stitch, CTD)
nabilone Ifosfamide
1A1, 1A2, 2A13, 1B1, 2A6, 2B1, 2B6, 2C9, 2C18, 2C19, 2C8, 2D6,
3A1, 3A4, 3A5, 3A7
dronabinol Ifosfamide *see above
dronabinol Flutamide
11A1, 11B1, 17A1, 19A1, 19B2, 1A2, 1B1, 20A1, 27A1, 2A1, 2A2,
2B3, 2C13, 2C19, 2C23, 2C24, 2C9, 2D1, 2D3, 2D4, 2D6, 2F4, 2J3,
2J4, 39A1, 3A18, 3A2, 3A4, 4A1, 4A3, 4B1, 4F4, 4V3, 51, 7A1, 8B3
dronabinol Capecitabine 2B6
dronabinol Fluorouracil 2A6, 2B1, 2F1, 2S1, 3A4, 51A1
dronabinol Teniposide 2C19, 3A4, 3A5
dronabinol Octreotide 11A1, 19A1, 3A13, 51
dronabinol Mitotane 11A1, 11B1, 17A1, 19A1, 1A1, 1A2, 2B2, 2B6, 2C19, 2D6, 3A4

10. CYPs interactors involved
drug metabolism
Ifosfamide Flutamide Capecitabine Fluorouracil Teniposide Octreotide Mitotane
1A1 ✘ ✓ ✘ ✓
1A2 ✓ ✓
3A4 ✓ ✓ ? ✓ ✓✘
3A5 ✓ ✓
2B6 ✘ ? ✘
2C9 ✓ ✓
2C19 ✓ ? ? ✘
2D6 ✓ ? ✘

11. Cancer Therapeutic Reported CYP Interactors with Therapeutic (Stitch, CTD)
Lenalidomide N/A
Nilotinib N/A
Pemetrexed N/A
Bortezomib 1A2, 3A4, 2C19
Abiraterone 17, 2D6, 3A4, 21A2, 11B1
Ibrutinib N/A
Capecitabine N/A
Everolimus N/A
Control Chemotherapeutics

12. Known Interactors

13. Cannabinoid-metabolizing CYP450 enrichment
n.s.
(positive control)

16. Nabilone / Dronabinol
- Does not serve as a 5-HT3 antagonist
- a moderate inhibitor of CYP3A4
→ which means that it might increase plasma
concentrations of co-administered medicinal
products that are metabolized through CYP3A4
(ie the chemo agents such as
cyclophosphamide, cisplatin, doxorubicin, etc.)
→ Increased plasma conc
→ the drug is damaging the cells for longer
→ serotonin is continually released
→ 5HT3 receptor agonism
→ prolonged transmission of vomit
signal from damaged region to brain
→ stimulation of vomiting center
→ vomiting

17. Example Chemotherapy Cycle (Lymphoma)
Cannabinoidal
therapeutic (oral)

18. Conclusions
● Marijuana-drug interactions are poorly reported because marijuana has only emerged
recently as a potential commercial therapeutic, and exploring THC-based drugs as a
solution to chemo-induced emesis was abandoned in the 80s due to legal controversies
and few studies conducted to determine adverse effects between the THC-based drugs
and the chemotherapeutics.
● The general consensus in the scientific community is that concurrent use of
cannabinoids with various drugs does not result in any clinically significant adverse
effects; however, due to the increase widespread usage of marijuana, both clinically
and recreationally, more research is needed to identify potential sources of herb-drug
interactions, particularly within susceptible populations. →

19. Which populations may be susceptible to increased adverse effects as a
result of nabilone or dronabinol intake between chemotherapy sessions?
Superfluous aside: Why does this question matter?
→ Polymorphic character of these CYPs and genetic predisposition to CYP mutations
may provide an explanation as to why certain populations are more affected and/or
experience more adverse outcomes when their emesis is treated with a THC-based
potentially-CYP-inhibiting drug like Nabilone and dronabinol.
Distribution of genetic polymorphisms of genes encoding drug metabolizing enzymes &
drug transporters -- Umamaheswaran, Kumar, and Adithan

20. CYP3A4
The Great
Oxidizing
Metabolizer

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