AIM: This study aimed to assess the pharmacokinetics, tolerability, safety and exploratory analgesic efficacy of a novel water-soluble oro-buccal nanoparticle spray of a cannabis-based medicine in advanced cancer patients with unrelieved pain. METHODS: The study was a non-blinded single arm, single escalating dose (n=5) [2.5 mg Δ9-THC and 2.5 mg CBD) and multiple escalating doses (up to 5.5 doses)] of a two-stage pilot study in patients diagnosed with advanced cancers and intractable pain (n=25). RESULTS: As the cannabis-based medicine dose increased, maximum plasma concentrations of all analytes were approximately proportional to dose. The bioavailability of 9-THC and CBD in this water-soluble nanoparticle formulation was approximately twice the bioavailability reported for a 9-THC/CBD formulation with ethanol. The water-soluble formulation in the current study resulted in a higher median (min, max) bioavailability of Δ9-THC than CBD (AUC from 2.5 mg each of Δ9-THC and CBD was 1.71 ng mL.h^-1 (1.1, 6.6) and 0.65 ng mL.h^-1 (0.49. 4.1), respectively). Analyte accumulation was not observed. In a subgroup of patients diagnosed with breast and prostate cancer with bone metastases, mean pain scores improvement from baseline was 40% (unadjusted) and 33% adjusted for rescue medication use. For all patients the most commonly reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively and nausea and vomiting that affected 18 (72%) patients. CONCLUSIONS: The water-soluble cannabis-based medicine (NanaBisTM) provided acceptable bioavailability for Δ9-THC and CBD, appeared safe and tolerable in cancer with uncontrolled pain with preliminary evidence of analgesic efficacy.