Objectives: The objective of this study was to assess cannabidiol-enriched cannabis extraction product (CBDEP) efficacy in patients with Parkinson’s disease (PD). Materials and Methods: Forty patients with PD were randomly assigned to the sublingual CBDEP (n = 20) or placebo (n = 20) group. All patients were prescribed a low initial dose with gradual titration within 2 weeks based on individual response – including side effects – followed by 6 weeks of stable dosing. The primary outcome was the Unified Parkinson’s Disease Rating Scale (UPDRS) score. The secondary outcomes were as follows: Quality of life (QOL) evaluated by the EQ-5D-5L, timed up and go (TUG) test, 5 times sit to stand (FTSTS) test, gait velocity, hospital anxiety and depression scale (HADS), renal and liver function indices, and adverse events. All outcomes were measured at baseline and at 8 weeks. The generalized estimating equation adjusted for baseline scores was used to compare the values at baseline and at 8 weeks, and between the groups. Results: Four patients were lost to follow-up (CBDEP group, n = 1; placebo group, n = 3) and 36 were included in the analysis (CBDEP group, n = 19; placebo group, n = 17). The CBDEP group received mean cannabidiol and tetrahydrocannabinol dosages of 15.59 ± 5.04 mg/day and 0.61 ± 0.19 mg/day, respectively. No significant differences were found between the groups in terms of the UPDRS, TUG test, FTSTS test, gait velocity, HADS-anxiety, and HADS-depression. The placebo group had significantly improved EQ-5D-5L scores for QOL (P = 0.004). The CBDEP group showed significantly improved blood urea nitrogen (BUN), serum albumin, serum globulin levels, and albumin/globulin ratio (P = 0.037, P < 0.001, P = 0.011, and P = 0.002, respectively) compared with the placebo group. Neither group had serious side effects. Conclusion: No evidence was found that CBDEP can reduce disease severity or improve functional performance, anxiety, or depression in PD. However, CBDEP is safe and can improve the levels of BUN, serum albumin, serum globulin, and albumin/globulin ratio in patients with PD. Trial Registration: Thai Clinical Trials Registry (registration number: TCTR 20210303005).