Abstract Background Tamoxifen is frequently used in the adjuvant treatment of hormone sensitive breast cancer. Unfortunately, tamoxifen can lead to bothersome side effects resulting in non-adherence in 40% of patients. Patients searching for relief from these side effects are increasingly turning to cannabinoids such as CBD. However, since tamoxifen is mainly metabolised by CYP2D6, and CBD is suggested to be an inhibitor of CYP2D6, the use of CBD might affect tamoxifen pharmacokinetics (PK). Since the effect of CBD on both tamoxifen PK as tamoxifen-related side effects has never been investigated, the aims of this study were to determine the pharmacokinetic interaction between CBD and tamoxifen, and to subsequently investigate whether there is a beneficial influence of CBD on tamoxifen-related side effects. Methods Patients had to be treated with tamoxifen for at least 3 months, have steady-state endoxifen levels >16 nM (conservative threshold) and experience tamoxifen-related side effects. PK sampling was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen area under the curve (AUC) fell within the [-20%; +25%] interval (n = 15, two-sided α 0.05, β 0.20). In addition, endoxifen PK was analyzed for each CYP2D6 phenotype separately. The effect of CBD on side effects was evaluated with the FACT-ES questionnaire (n = 25, two-sided α 0.05, β 0.20). An improvement > 0.5 times standard deviation (SD) of baseline score was considered clinically relevant. Last, potential side effects of CBD were assessed. Results In this study 15 patients were included for PK analysis and 24 patients for side effect analysis. Endoxifen AUC decreased after CBD by 12.6% (90% CI -18.7%, -6,1%) but remained within bio-equivalence boundaries. The decrease seemed more pronounced in patients with intermediate (IM) CYP2D6 phenotype (-20.8%, 90% CI -26.4%, -14.8%, n = 8) compared to normal CYP2D6 phenotype (-2.2%, 90% CI -11.1%, 7.6%, n = 7). There was no difference in tamoxifen AUC (with or without CBD). On average, the endocrine sub-scale of the FACT-ES improved with a clinically relevant improvement of 8.3 points (95% CI 4.9 – 11.7) after using CBD (baseline SD = 12.8). CBD itself has a mild toxicity profile with few side effects in 10 of 24 patients. Side effects were headache (n=2), dry mouth (n=3), fatigue (n=3), gastroesophageal reflux (n=1), abdominal pain (n=1) and nausea (n=1) and all graded CTCAE 1. Conclusions As endoxifen levels with or without CBD remained within bio-equivalence boundaries and CBD-oil might have a positive effect on tamoxifen-related side effects, it could be considered in case of treatment-related side effects. However, caution is needed in patients with IM or poor metabolizer CYP2D6 phenotypes. Citation Format: Sanne Buijs, Louwrens Braal, Stefan Buck, Noud F. van Maanen, Lonneke van der Meijden-Erkelens, Heleen Kuijper-Tissot van Patot, Esther Oomen-de Hoop, Lotte Saes, Sophia van den Boogerd, Liesbeth Struik, Quirine van Rossum-Schornagel, Ron Mathijssen, Stijn Koolen, Agnes Jager. CBD-oil: a potential solution in case of severe tamoxifen-related side effects [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-08.