I have published 8 books, 2 Epilepsia supplements and over 250 articles since 1962, covering the fields of epilepsy, neurology, neuropsychiatry, metabolic diseases (mainly folate and vitamin B12), and history of medicine, neurology, psychiatry, epilepsy and the NHS.
The most recent publications are:
Folate, vitamin B12, one carbon metabolism and the nervous system: Excess folic acid is potentially harmful
Journal of the Neurological Sciences. 476 (2025) 123627
Folate, vitamin B12 and one carbon metabolism are fundamental to genetics and epigenetics, and to nervous system development and brain health at all ages. The neuropsychiatric complications of deficiency or inborn errors of folate and vitamin B12 are well documented but there has been controversy about whether excess folic acid is also harmful to the nervous system, especially in the presence of vitamin B12 deficiency.
There is now substantial and consistent clinical, epidemiological and experimental evidence that excess folic acid is potentially harmful to the nervous system. Recent experimental evidence confirms that both folate deficiency and excess impair cortical neurogenesis and is greatest when vitamin B12 deficiency is combined with excess folic acid. Excess folic acid increases the demand for vitamin B12 and aggravates the block in the folate cycle resulting from vitamin B12 deficiency. The balance between folate and vitamin B12 is crucial to methylation and to genetics and epigenetics. Both folate deficiency and excess may impair cellular differentiation and nervous system development by hypomethylation or hypermethylation of genes. In countries with folic acid fortification policies many subjects are exposed to excess folate. The long term genetic, epigenetic and transgenerational implications are yet to be clarified. The safe UL of folic acid should be reconsidered in relation to the vitamin B12 status of individuals and populations. The combination of a natural folate together with vitamin B12 would greatly improve the benefits and reduce the harms of current fortification policies.
Junlong Chen and Jialin Liu
Rethinking folic acid fortification: A call for nuanced strategies and broader investigations
Journal of the Neurological Sciences. 476 (2025) 123678
Abstract
This comment letter responds to Edward H. Reynolds’ comprehensive review on folate, vitamin B12, one‑carbon metabolism, and nervous system health. While commending the review’s insights into the potential neurological harms of excess folic acid, especially with vitamin B12 deficiency, we expand on several critical areas. We emphasize distinguishing synthetic folic acid’s neurotoxicity from natural folates, urging further comparative studies. We highlight the underexplored long-term consequences of supraphysiological folic acid exposure in children and adolescents during critical neurodevelopment. The profound implications of transgenerational epigenetic effects from ancestral folate status are stressed, demanding urgent investigation in human cohorts. Crucially, we address the practical challenges of revising global fortification policies, noting the significant logistical, economic, and regulatory hurdles in shifting from folic acid to natural folate forms combined with vitamin B12. We conclude by advocating for a nuanced, multi-pronged approach to fortification, urging reconsideration of the folic acid UL, enhanced population surveillance, and continued research to balance benefits of neural tube defect prevention with potential harms of excess folate.
I thank Professors Junlong Chen and Jialin Liu for their appreciative
endorsement of my review and conclusions [1] and for highlighting 4
aspects in particular. I will comment on each point below.
Messina C.
When more is less: The neurological pitfalls of excess folic acid. Journal of the Neurological Sciences.
Response When more is less: The neurological pitfalls of excess folic acid. Response Journal of the Neurological Sciences.
Fortification, folate and vitamin B12 balance, and the nervoussystem. Is folic acid excess potentially harmful?
Edward H. Reynolds, Agata Sobczyńska-Malefora, Ralph Green
European Journal of Clinical Nutrition August 14, 2025
The benefits of folic acid fortification are well known but less understood or acknowledged is the growing evidence of potential harms to the nervous system from excess folate, primarily because of a combination of fortification and/or high and sustained intake of folic acid supplements. We have summarised the historical, clinical, epidemiological and experimental evidence accumulated over the last 60 years in the pre and postfortification eras, which consistently and substantially suggests that excess folate, in particular in folic acid users, can have direct harms to the nervous system, especially in the presence of vitamin B12 deficiency. The harms are related both to the dose and duration of exposure to excess folic acid. Recent experimental evidence suggests that impaired cortical neurogenesis with excess folic acid is similar to that of folate or vitamin B12 deficiency and greatest when folate excess is present with vitamin B12 deficiency. Excess folate leads to a fall in vitamin B12 levels and aggravation of the block in folate metabolism resulting from vitamin B12 deficiency. The balance between folate and vitamin B12 is crucial to the functioning of one carbon metabolic pathways, the methylation cycle and ultimately to DNA and RNA structure and function, genetic and epigenetic stability. Vitamin B12 deficiency is an independent risk factor for NTDs and accounts for the increased risk of
NTDs in some countries where B12 deficiency is more common than folate deficiency. A more prudent and balanced approach to fortification with folic acid, or preferably a natural reduced folate, combined with vitamin B12 would potentially improve the benefits and reduce the harms, including epigenetic and transgenerational risks, associated with current public health policies.
Folate, vitamin B12, one carbon metabolism and the nervous system: Excess folic acid is potentially harmful
Epilepsia 2024 7th October
The origins and early development of the ILAE/IBE/WHO Global Campaign Against Epilepsy: Out of the Shadows.
Epilepsia Open 2023
The International League Against Epilepsy (ILAE)/International Bureau for Epilepsy (IBE)/World Health Organization (WHO) Global Campaign Against Epilepsy was launched in Geneva and Dublin in the summer of 1997. The second phase of the Campaign was launched by a major event in Geneva, led by WHO Director General Dr. Gro Harlem Brundtland in February 2001. Since then, the Campaign has been gathering momentum around the world culminating in the WHO General Assembly Resolution (WHA 68.20) on Epilepsy in May 2015 supported by 194 countries. Recently, the World Federation of Neurology and other neurological non-governmental organizations (NGOs) have joined forces with the Epilepsy Campaign, leading to the WHO General Assembly Resolution (WHA 73.10) in May 2022 promoting a 10-year Intersectoral Global Action Plan (IGAP) for Epilepsy and Other Neurological Disorders. I was privileged to serve as the first Chairperson of the Global Campaign Against Epilepsy and this year all my documents and correspondence relating to the Campaign have been delivered to the Wellcome Collection in London. These are the basis for this detailed account of the origins and early development of the Campaign. I describe the events leading to the birth of the concept, planning for the Campaign, the launch, development, and the achievements of phase one. This first phase focused on awareness raising, education, and involvement, especially within WHO, ILAE, and IBE, including a series of five Regional Public Health meetings and Declarations on Epilepsy. In 1999, the WHO raised the status of the Campaign to the highest level, the first ever for a Non-Communicable Disease, resulting in the high profile launch of phase two in 2001, paving the way to the continuing global momentum and achievements, including the 2015 and 2022 WHO Resolutions.
Neurology 2024 15th July
Teratogenesis, perinatal, and neurodevelopmental outcomes after in utero exposure to antiseizure medication
Edward Henry Reynolds| Department of Clinical Neurosciences | King’s College London, UK
We read with great interest the revised AAN, AES, and SMFM guidelines.1 The guidelines are inadequate for several reasons.
First, there is a lack of awareness or understanding of: (1) the impact of so many frontline AEDs, notably valproate, on folate 1-carbon metabolism and therefore on genetics and epigenetics, and (2) the fundamental role of the folate and methylation cycles in fetal, embryo, and child development.2,3
The harmful effects of valproate on the developing nervous system and on the positive regeneration responses of injured neurons to folate are both transmitted transgenerationally to unexposed offspring. This implies that both are impacting genetic and epigenetic processes.4,5
Additionally, it is highly unlikely that 400 micrograms of folic acid daily is an adequate periconceptual protective dose in the presence of AEDs. At the very least, people with epilepsy who are taking valproate and who are contemplating pregnancy should be offered the safe upper tolerable dose of 1mg (possibly more, pending further studies).2 Folic acid is an unnatural synthetic compound that must first be reduced to enter the folate cycle, for which there is limited capacity in the human body. It is probable that naturally reduced folates such as folinic acid or methyl folate (the transport form across the blood-brain barrier) will provide better protection, especially if combined with vitamin B12. The folate cycle and vitamin B12 work in symmetry. Excess folate increases the demand for vitamin B12, a shortage of which is also a risk factor for congenital and developmental defects.
Finally, we have known of the congenital risks associated with AEDs for 40 years, and have known the impact of AEDs on folate 1-carbon metabolism for even longer. Research in this area has been painfully slow and deserves a greater sense of urgency and investment.
References
Pack AM, Oskoui M, Roberson SW, et al. Teratogenesis, perinatal, and neurodevelopmental outcomes after in utero exposure to antiseizure medication. Neurology. 2024;102(11):e209279. doi: 10.1212/WNL.0000000000209279.
Reynolds EH, Green R. Valproate and folate: congenital and developmental risks. Epilepsy Behav. 2020;108:107068. doi: 10.1016/j.yebeh.2020.107068
Reynolds EH. Antiepileptic drugs, folate and one carbon metabolism revisited. Epilepsy Behav. 2020;112:107336. doi: 10.1016/j.yebeh.2020.107336
Martin M, Hill C, Bewley S, MacLennan AH, Braillon A. Transgenerational adverse effects of valproate? A patient report from 90 affected families. Birth Defects Res. 2022;114:13-16. doi: 10.1002/bdr2.1967
Patel, MJ, Hogan KJ, Rizk E, et al. Ancestral folate promotes neuronal regeneration in serial generations of progeny. Mol Neurobiol. 2020;57:2048-2071. doi: 10.1007/s12035-019-01812-5
Broussolle E, Reynolds EH, et al.
Charcot’s international visitors and pupils from Europe, the United States, and Russia
Journal of the History of the Neurosciences 2024 26th June
Abstract: The foundation by Jean-Martin Charcot (1825–1893) of the Salpêtrière School in Paris had an influential role in the development of neurology during the late-nineteenth century. The international aura of Charcot attracted neurologists from all parts of the world. We here present the most representative European, American, and Russian young physicians who learned from Charcot during their tutoring or visit in Paris or Charcot’s travels outside France. These include neurologists from Great Britain and Ireland, the United States, Germany and Austria, Switzerland, Russia, Italy, Spain, Belgium and the Netherlands, Scandinavia and Finland, Poland, Bohemia, Hungary, and Romania. Particularly emblematic among the renowned foreign scientists who met and/or learned from Charcot were Charles-Edouard Brown-Séquard, who had interactions with Paris University and contributed to the early development of British and American neurological schools; John Hughlings Jackson, who was admired by Charcot and influenced French neurology similarly as Charcot did on British neurology; Silas Weir Mitchell, the pioneer in American neurology; Sigmund Freud, who was trained by Charcot to study patients with hysteria and then, back in Vienna, founded a new discipline called psychoanalysis; Aleksej Yakovlevich Kozhevnikov and almost all the founders of the Russian institutes of neurology who were instructed in Paris; and Georges Marinesco, who established the Romanian school of neurology and did major contributions thanks to his valuable relation with Charcot and French neurology.
The origins and early development of the ILAE/IBE/WHO global campaign against epilepsy: Out of the shadows.
Epilepsia Open 2023 23rd October
Abstract: The International League Against Epilepsy (ILAE)/International Bureau for Epilepsy (IBE)/World Health Organization (WHO) Global Campaign Against Epilepsy was launched in Geneva and Dublin in the summer of 1997. The second phase of the Campaign was launched by a major event in Geneva, led by WHO Director General Dr. Gro Harlem Brundtland in February 2001. Since then, the Campaign has been gathering momentum around the world culminating in the WHO General Assembly Resolution (WHA 68.20) on Epilepsy in May 2015 supported by 194 countries. Recently, the World Federation of Neurology and other neurological non-governmental organizations (NGOs) have joined forces with the Epilepsy Campaign, leading to the WHO General Assembly Resolution (WHA 73.10) in May 2022 promoting a 10-year Intersectoral Global Action Plan (IGAP) for Epilepsy and Other Neurological Disorders. I was privileged to serve as the first Chairperson of the Global Campaign Against Epilepsy and this year all my documents and correspondence relating to the Campaign have been delivered to the Wellcome Collection in London. These are the basis for this detailed account of the origins and early development of the Campaign. I describe the events leading to the birth of the concept, planning for the Campaign, the launch, development, and the achievements of phase one. This first phase focused on awareness raising, education, and involvement, especially within WHO, ILAE, and IBE, including a series of five Regional Public Health meetings and Declarations on Epilepsy. In 1999, the WHO raised the status of the Campaign to the highest level, the first ever for a Non-Communicable Disease, resulting in the high profile launch of phase two in 2001, paving the way to the continuing global momentum and achievements, including the 2015 and 2022 WHO Resolutions.
John Hughlings Jackson and Thomas Laycock: Brain and Mind.
World Neurology, 2023 August-September
John Hughlings Jackson and Thomas Laycock: Brain and Mind – Laycocks influence on British Neuropsychiatry
Royal College of Psychiatrists 2023 November p18
Health effects of poor housing : Medical profession has a role
British Medical Journal 2023 20th May; 381: p1043
Dear BMJ Editor,
Dobson asks why it’s fallen to the medical community to act on the detrimental health effects of poor housing (Editor’s Choice, 1 April).
For most of the past century the medical profession has acted on the effects of poor housing. My father, a GP, was the medical officer of health for an urban district council in Monmouthshire. He worked with two councillors to ensure the health of the community in the home, school, and workplace. Annual reports from medical officers of health improved local housing and influenced housing policy.
Sadly, public health has been greatly run down and centralised. Medical officers of health no longer exist, and GPs rarely visit homes. Taking a social history was one of the first things I learnt in medical school. There is, and should be, a role for the medical profession in acting on the health effects of poor housing. The profession needs reminding of this.
Edward H. Reynolds, consultant neurologist, London
Subject: Health Warning
Letter published in the Times newspaper 2022 23rd December
Sir, I worked for 54 years in the frontline of the NHS at tertiary, secondary and primary levels (Health Warning, December 21st). It is clear to me that standards of care have been falling since the NHS and Community Care Act of 1990, when Service principles were subordinated to or in constant tension with Business and market principles. Since then the NHS has become increasingly centralised and bureaucratic. Collaboration, communication and continuity of care have been undermined, with increasing concerns about patient safety and staff morale, aggravated by increased demands and inappropriately reduced capacity. Among the solutions should be a return to a predominantly professionally led and locally organised Service with Government support as envisaged and implemented by Aneurin Bevan and the founders of the NHS.
Edward Reynolds
Dr. Edward H. Reynolds MD FRCP FRCPsych
Former Consultant Neurologist to the Maudsley and Kings College Hospitals, Epsom Hospital and the Integrated Care Partnership, Epsom.
Past President of the International League Against Epilepsy
How to avoid harmful national quarantines: primary care led local public health: a historical perspective.
JRSM 2022; 115:12-15