Reduction in Tamoxifen Metabolites Endoxifen and N-desmethyltamoxifen With Chronic Administration of Low Dose Cannabidiol: A CYP3A4 and CYP2D6 Drug Interaction

Abstract

Background: Cannabidiol (CBD) serves as a promising medicine, with few known adverse effects apart from the potential of drug interactions with the cytochrome P450 system. It has been hypothesized drug interactions may occur with chemotherapeutic agents, but no supporting evidence has been published to date. Case: A 58-year-old female with a history of bilateral breast carcinoma in remission, was treated with tamoxifen for breast cancer prevention for over 6 years. CBD was instituted to treat persistent postsurgical pain, inadequately managed by alternate analgesics. It was postulated that CBD may diminish tamoxifen metabolism by CYP3A4 and 2D6 to form active metabolite endoxifen, which exerts the anticancer benefits. Endoxifen, tamoxifen, N-desmetyltamoxifen and 4-hydroxytamoxifen levels were collected while the patient chronically received CBD 40 mg/day, and after a 60-day washout. Upon discontinuation of CBD 40 mg/day, it was observed that endoxifen levels increased by 18.75% and N-desmethyltamoxifen by 9.24%, while 4-hydroxytamoxifen remained unchanged. Conclusion: CBD at a low dose of 40 mg/day resulted in the potential inhibition of CYP3A4 and/or CYP2D6. Patients receiving CBD and interacting chemotherapeutic drugs, such as tamoxifen, require monitoring to identify possible subtherapeutic response to treatment. Further pharmacokinetic studies are required to ascertain the dynamics of this drug interaction.

Cannabidiol Regulates PPARγ-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells

“…Similarly, CBD may be synergistic with combinatory therapies using such anticancer drugs as doxorubicin or cisplatin [ 42 , 43 ]. CBD has been suggested to possibly reduce drug resistance by long-term clinical treatment with anticancer drugs [ 44 , 45 ].…”

Cannabidiol on the Path from the Lab to the Cancer Patient: Opportunities and Challenges

“…Importantly, CBD targets the cytochrome P450 system and is metabolized by CYP3A4 and CYP2C1 in human liver microsomes (HLMs), giving rise to 6α-OH-, 6β-OH-, 7-OH-, and 4″-OH-CBDs [ 134 ]. A female patient, treated for 6 years with tamoxifen, and, additionally, by CBD, which inhibited CYP3A4/5 and CYP2D6, presented a consequent reduction in N -desmethyltamoxifen and active metabolite endoxifen [ 135 ]. In cancer patients, especially if they have liver diseases or a poor metabolic profile, possible effects of CBD on cytochromes P450, which in turn can affect the pharmacokinetics of conventional anticancer drugs, need to be considered.…”

Over the counter low-dose cannabidiol: A viewpoint from the ACRE Capacity Building Group

“…CBD inhibits cytochrome P450, including the 2D6 and 3A4 hepatic enzymes, and because of this inhibition, the serum concentrations of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, antipsychotics, beta-blockers, opioids, valproate, and clobazam may be increased as these pharmaceuticals are metabolized by these enzymes. Whether this enzyme inhibition is clinically significant with low-dose CBD remains to be determined (Balachandran et al, 2021), although changes in the active component of tamoxifen with CBD in low dose has been described (Parihar et al, 2020).…”