Methylliberine (Dynamine^®; DYM) and theacrine (Teacrine^®; TCR) are purine alkaloids purported to have similar neuro-energetic effects as caffeine. There are no published human safety data on DYM, and research on TCR is limited. The purpose of this study was to examine the effect of four weeks of DYM supplementation with and without TCR on cardiovascular function and blood biomarkers. One-hundred twenty-five men and women (mean age 23.0 yrs, height 169.7 cm, body mass 72.1 kg; n = 25/group) were randomly assigned to one of five groups: low-dose DYM (100 mg), high-dose DYM (150 mg), low-dose DYM with TCR (100 mg + 50 mg), high-dose DYM with TCR (150 mg + 25 mg), and placebo. Regardless of group and sex, significant main effects for time were noted for heart rate, systolic blood pressure, and QTc (p < 0.001), high-density lipoproteins (p = 0.002), mean corpuscular hemoglobin (p = 0.018), basophils (p = 0.006), absolute eosinophils (p = 0.010), creatinine (p = 0.004), estimated glomerular filtration rate (p = 0.037), chloride (p = 0.030), carbon dioxide (p = 0.023), bilirubin (p = 0.027), and alanine aminotransferase (p = 0.043), among others. While small changes were found in some cardiovascular and blood biomarkers, no clinically significant changes occurred. This suggests that DYM alone or in combination with TCR consumed at the dosages used in this study does not appear to negatively affect markers of health over four weeks of continuous use.