Franco C, Sciatti E, Favero G, Bonomini F, Vizzardi E, Rezzani R. Essential Hypertension and Oxidative Stress: Novel Future Perspectives. Int J Mol Sci. 2022 Nov 21;23(22):14489. doi: 10.3390/ijms232214489. PMID: 36430967.
Oxidative stress and inflammation have been identified as contributors to hypertension and cardiovascular disease. With melatonin known to be a powerful free radical scavenger and anti-inflammatory agent, the authors of this article carried out a randomized clinical trial to understand if melatonin (1 mg per day for 12 months), would impact individuals with essential hypertension. The authors found that arterial stiffness and total antioxidant capacity improved significantly, as did endothelial function, though not to statistical significance, in those taking melatonin in combination with hypertensive therapy.
Our comments/takeaway from the article
We understand that essential hypertension has a complex pathology with many factors that impact development including but not limited to genetics, diet, and stress, and are aware that one therapy option is not a likely solution to this disease that impacts billions of people worldwide. With arterial stiffness being an indicator of cardiovascular morbidity and mortality, any improvement can be of clinical value.
While the lowest physiological dose of melatonin (0.3 mg/day) was not utilized in this study, the use of the low dose of 1 mg/day may provide insight into dosing considerations of melatonin for hypertension, as other studies have utilized 5-10 mg/day for hypertension and endothelial function.
This relatively small, randomized clinical trial included 23 individuals, 16 who supplemented melatonin (1 mg/day) to their hypertensive therapy and 10 who continued with their current hypertensive therapy only. The authors note that most studies on the use of melatonin in hypertensive patients include 5-6 mg of melatonin conducted over 90 days, however, they chose 1 mg/ day as “…(according to the Ethics committee, 1 mg/ die is the maximum dosage that should be administered as an addition to the pharmacological anti-hypertensive therapy…”
At the 1 year follow-up, 9 individuals were unable to return due to COVID-19 restrictions, leaving 11 patients from the melatonin-supplemented group and 3 from the control group.
Newly diagnosed with essential hypertension (<1 year)
Hypertensive therapy was started and would not be modified during the study
No other cardiological or metabolic comorbidities (including fasting blood glucose < 100 mg/dL, total cholesterol < 200 mg/dL, and triglycerides < 150 mg/dL)
Regular sleep/wake rhythm (no shift work)
Patients were assessed at baseline and 1 year later, measuring blood pressure, total antioxidant capacity (TAC) level, peripheral arterial tonometry (PAT), and pulse wave velocity. Of note, the authors state that TAC (as measured in plasma), is possibly associated with changes in oxidative stress and vascular damage. PAT is an assessment of endothelial function.
The melatonin supplemented group showed significant improvement (p=0.022) in arterial stiffness and rigidity with the control group worsening or staying the same. While improvements in endothelial function and blood pressure were observed in the treated group, neither were of statistical significance. Total antioxidant capacity (TAC) decreased (p=0.041) in the melatonin group, remaining unchanged in the control group, with the authors noting, “in a situation of altered oxidative balance, the plasma antioxidant system activates in a compensatory sense, shutting itself down when oxidative stress is reduced.”; suggesting that melatonin improved oxidative stress status. No adverse events/effects were noted during this trial.
Validity and reproducibility of some of the testing methods, with potential mathematical errors
Small number of individuals in the study
Lack of follow up on the entire starting population of the study
Other limitations noted in our review:
Specific details about the hypertensive therapies used by the participants were not defined.
It is not clear if the authors accounted for diet and lifestyle or other factors that may have impacted results.
Exploring additional inflammation markers such as Lpa, LpPLA2, hsCRP or others may have been beneficial is assessing outcomes.
The authors conclude that the need for additional therapies for essential hypertension, including adjuvant options such as melatonin are needed. While limitations are present, this trial could provide the basis for future studies to be conducted that include a larger population, using melatonin therapy, that is reported to have a very small number of side effects.
Article review completed by Kim Ross, DCN
Content reviewed by Deanna Minich, PhD
November 28, 2022