Effect of L-Methylfolate Supplementation on Sleep for Patients with Reduced Methylenetetrahydrofolate Reductase Activity

Abstract

Introduction

Clinicians have limited options outside controlled substances to address sleep disturbance, which left untreated can negatively affect patient outcomes in cardiovascular health, mental health, immunologic function, and more. For some, genetic factors may influence sleep disturbances. L-methylfolate, the active form of folate, plays a critical role in regulation of monoamine neurotransmitters known to have significant impact on sleep regulation: dopamine, serotonin, norepinephrine. Single nucleotide polymorphisms of the enzyme methylene-tetrahydrofolate-reductase are common and can impact monoamine production. The goal of this study was to evaluate effects of L-methylfolate supplementation on sleep in a cohort with reduced methylene tetrahydrofolate reductase (MTHFR) activity.

Methods

A retrospective cohort of patients being treated with L-methylfolate in a concierge medical clinic setting was studied. Patients presenting with sleep complaints were evaluated using the Patient-Reported Outcomes Measurement Information System at baseline. Patients with known MTHFR polymorphisms at either C667T and/or A1298C were recommended 5 mg of L-methylfolate daily and were reevaluated at 2 wks, at 4 wks, and at 8 wks of supplementation. Statistical comparisons were made utilizing ANOVA and T-test comparisons.

Results

Ten were included in the final cohort: six male and four female, average age 43 ± 16 years. Beginning at wk 2, average sleep disturbance improved significantly by −6.94 points (p = 0.005) and by 8 wks, all patients had improvement with a −14.34 change in disturbance from baseline (p = 0.001).

Conclusion

Improvement in sleep disturbance was seen in both low and intermediate function phenotypes. L-methylfolate may be useful for improving sleep in patients with MTHFR polymorphism.

Keywords:

• Activated folate
• L-methylfolate
• MTHFR polymorphisms
• pharmacogenomics
• sleep

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Author Contributions (using CRediT taxonomy, https://credit.niso.org): Dr. Alex Carmon: data curation, formal analysis, investigation, methodology, project administration, resources, visualization, writing original draft. Dr. Russel Amato: formal analysis, methodology, resources, software, visualization, writing review and editing. Dr. Seema Patel: formal analysis, methodology, resources, software, writing review and editing. Dr. Shannon Finks: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, writing review and editing.

Author disclosures

All authors have fulfilled the criteria for authorship and have seen and approved the submitted version. Authors were responsible for recognizing and disclosing any financial or other interest that could be perceived to bias their work, acknowledging all financial support and any other personal connections. No author reports a conflict of interest. While pharmacogenomic information was available for all patients included in this cohort, there was no requirement that the genetic information be obtained from Genomind. Neither Genomind nor any of its scientists had any role in the study protocol or in the medical management of patient care at Züp Medical Services. No funding was received or given in the conceptualization through writing of this article. This original manuscript has never been published before. The authors will release the copyright should the manuscript be accepted for publication.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Notes on contributors

Alex S. Carmon

Dr. Alex S. Carmon is lead pharmacist practicing at ZüpMedical Services in Memphis, Tennessee. She earned her PharmD degree from the University of Tennessee College of Pharmacy and completed her Pharmacy Practice Residency at ZüpMedical Services under the direction of Dr. Shannon Finks. Her research interests include how pharmacogenomic information can influence patient response to drug and nutraceutical therapies.

Russell J. Amato

Dr. Russell J. Amato received his PhD in Pharmacology at Louisiana State University School of Medicine and completed his postdoctoral fellowship within the Vanderbilt Center for Neuroscience Drug Discovery. He has over a decade of experience in developing novel therapeutics for neuropsychiatric diseases including drug abuse, depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD). His strong background in both genetics and psychiatric disease informs his work as Senior Medical Science Liaison at Genomind.

Seema M. Patel

Dr. Seema M. Patel is a Board Certified Psychiatric Pharmacist and is Medical Science Liaison at Genomind. She earned her PharmD from Philadelphia College of Pharmacy and completed a psychiatric pharmacy residency at Virginia Commonwealth University Health System. Her experience includes working with and treating patients with psychiatric disorders utilizing pharmacogenomic data in clinical practice.

Shannon W. Finks

Dr. Shannon W. Finks is a Professor at the University of Tennessee College of Pharmacy. She is Board Certified in Pharmacotherapy and in Cardiovascular Pharmacotherapy and has more than twenty five years experience providing care for patients in both hospital and clinic settings. She currently owns and operates a concierge medicine clinic where patient treatment plans including prescription, nutraceutical, and vitamins are individualized, using genetic information where possible.