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S-Adenosylmethionine (SAMe) monotherapy for depression: an 8-week double-blind, randomised, controlled trial

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Abstract

Rationale

Dysregulation of the one carbon cycle is documented in depression. Thereby, S-adenosylmethionine (SAMe), a one–carbon cycle nutraceutical compound with a favourable side effect profile, has a theoretical rationale for efficacy. However, further controlled studies are required to confirm SAMe’s efficacy.

Objectives

To test the efficacy of SAMe versus placebo in unmedicated DSM-5 diagnosed (major depressive disorder) (MDD) patients with mild-to-moderate levels of depressive symptoms.

Methods

We conducted an 8-week, double-blind, randomised controlled trial testing 800 mg/day of SAMe monotherapy versus placebo in 49 patients with MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] score 14–25) who were not currently taking antidepressants. One–carbon cycle biomarkers, brain-derived neurotropic factor (BDNF), and relevant single nucleotide polymorphisms (SNPs) were analysed as potential treatment moderators.

Results

A clinically relevant differential reduction from baseline to week 8 of 3.76 points occurred on the primary outcome (MADRS) in favour of SAMe. This however was not significant (p = 0.13) on an adjusted linear mixed model, notwithstanding a medium to large effect size of 0.72. A high placebo response rate of 53% occurred (> 50% reduction on MADRS). Exploratory analyses showed that SAMe was however effective in reducing depression amongst participants with milder depression severity (MADRS ≤ 22, p = 0.045). Response was not moderated by BDNF, SNPs, or one–carbon cycle biomarkers, although increased folate concentrations were correlated with improved symptoms in the SAMe group (r = − 0.57, p = 0.026). The treatment was safe and well tolerated.

Conclusions

Although a differential reduction in depression symptoms between groups was observed in favour of SAMe, the results of this pilot study were not statistically significant.

Trial registration

ANZCTR—Australian New Zealand Clinical Trials Registry; No.: ACTRN12613001299796; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364900

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Acknowledgments

We would like to thank the study participants who contributed to this project.

Funding

This study is funded by a National Health and Medical Research Council (NHMRC) project grant (APP1048222), and is co-sponsored by FIT-BioCeuticals. Jerome Sarris is supported by an NHMRC Fellowship (APP1125000). Michael Berk is supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (APP1059660 and APP1156072). Study sponsors had no role in study design, in the collection and analysis of data, manuscript preparation, nor the decision to submit the paper for publication.

Author information

Authors and Affiliations

  1. NICM Health Research Institute, Westmead, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia

    Jerome Sarris

  2. Professorial Unit, The Melbourne Clinic, Department of Psychiatry, Melbourne University, Melbourne, Australia

    Jerome Sarris, Jenifer Murphy, Georgina Oliver, Lachlan Cribb, Karen Savage, Ranjit Menon & Chee H. Ng

  3. Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia

    Con Stough & Karen Savage

  4. Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    David Mischoulon

  5. Departments of Medical Genetics, Psychiatry, and Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Chad Bousman

  6. Department of Psychiatry, The University of Melbourne, Parkville, Australia

    Chad Bousman & Michael Berk

  7. Faculty of Medicine, Discipline of Psychiatry, Centre for Clinical Research, Royal Brisbane & Women’s Hospital, Herston, The University of Queensland, Brisbane, Australia

    Patricia MacDonald, Laura Adams, Sonia Nazareth, Suneel Chamoli & Gerard J. Byrne

  8. IMPACT SRC, School of Medicine, Barwon Health, Deakin University, Geelong, Australia

    Michael Berk

  9. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia

    Michael Berk

  10. Orygen, The Centre of Excellence in Youth Mental Health, The University of Melbourne, Parkville, Australia

    Michael Berk

Authors
  1. Jerome Sarris
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  2. Jenifer Murphy
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  3. Con Stough
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  5. Chad Bousman
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  6. Patricia MacDonald
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  7. Laura Adams
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  8. Sonia Nazareth
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  9. Georgina Oliver
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  11. Karen Savage
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  16. Gerard J. Byrne
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Contributions

Author Sarris designed the study. Authors Sarris, Byrne, Bousman, Stough, Berk, Ng, Chamoli, Menon, and Mischoulon contributed to the design and write-up of the protocol. Authors Sarris, Bousman, and Cribb designed and implemented the statistical analysis. Authors Murphy, Cribb, MacDonald, Adams, Nazareth, Oliver, and Savage were involved in the data collection and entry. All authors have contributed to and approved the final manuscript.

Corresponding author

Correspondence to Jerome Sarris.

Ethics declarations

The trial had ethics approval (TMC REC: 232; UQ MREC: 2014000702) and is registered with ANZCTR (protocol number: 12613001299796).

Conflict of interest

JS has received honoraria, research support, royalties, or consultancy or travel grant funding from Integria Healthcare & MediHerb, Pfizer, Scius Health, Key Pharmaceuticals, Taki Mai, FIT-BioCeuticals, Blackmores, Soho-Flordis, Australian Natural Therapeutics Group, Grünbiotics, Healthworld, HealthEd, HealthMasters, SPRIM, Elsevier, Chaminade University, International Society for Affective Disorders, Complementary Medicines Australia, Terry White Chemists, ANS, Society for Medicinal Plant and Natural Product Research, Sanofi-Aventis, Omega-3 Centre, the National Health and Medical Research Council, and CR Roper Fellowship. DM has received research support from Nordic Naturals. He has received honoraria for consulting, speaking, and writing from the Massachusetts General Hospital Psychiatry Academy, Blackmores, and PeerPoint Medical Education Institute, LLC. He has provided unpaid consulting for Pharmavite LLC and Gnosis USA, Inc. He has received royalties from Lippincott Williams & Wilkins for published book ‘Natural Medications for Psychiatric Disorders: Considering the Alternatives.’ MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant, and the Harry Windsor Foundation; has been a speaker for Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen-Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay, and Wyeth; and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen-Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer, and Servier. CS has received research grants from Government: Australian Research Council; NHMRC; NDLERF; NIDA; VDLERF; ARC; Vicpolice; Vicroads; Nestle; SFI; Barry Callebaut; Blackmores; Flordis; Zeller; Clover Corporation; Horphag; GSK; Bayer; Pharmalink; Siemens; Securatek; Efamol; Cognis; Integria; Medvet, Cooper Nutrition, and paid strategic consulting advice for SFI, Blackmores, Bayer; ARU, Carlton FC, GSK India. DM has received research support from Nordic Naturals. He has provided unpaid consulting for Pharmavite LLC and Gnosis USA, Inc. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, from PeerPoint Medical Education Institute LLC, and from Blackmores. He has received royalties from Lippincott Williams & Wilkins for published book ‘Natural Medications for Psychiatric Disorders: Considering the Alternatives.’ GJB receives research support from Janssen-Cilag, Eli Lilly, Biogen, NHMRC (APP1104460, APP1095227, APP1063383, APP1048222) and the RBWH Foundation. He owns shares in CSL. He receives royalties from the sale of his books Community Mental Health for Older People and Psychosocial Dimensions of Medicine. He receives licensing fees from the use of his rating scale, the Geriatric Anxiety Inventory. He is employed by the University of Queensland, the Royal Brisbane & Women’s Hospital, and the Repatriation Medical Authority. CN had served as a consultant for Lundbeck, Grunbiotics, Servier, Janssen-Cilag, Wyeth and Eli Lilly, received research grant support from Wyeth and Lundbeck, and speaker honoraria from Servier, Lundbeck, Bristol-Myers Squibb, Organon, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, Astra-Zenaca, Wyeth, and Pfizer.

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Sarris, J., Murphy, J., Stough, C. et al. S-Adenosylmethionine (SAMe) monotherapy for depression: an 8-week double-blind, randomised, controlled trial. Psychopharmacology 237, 209–218 (2020). https://doi.org/10.1007/s00213-019-05358-1

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