Folic acid, the synthetic form of vitamin B9, has spent the past few years riding a wave of cautious optimism in psychiatry. In 2022, a large American study published in JAMA Psychiatry reported that periods covered by folic acid prescriptions were associated with a striking 44 percent reduction in suicide attempts and episodes of intentional self-harm, igniting widespread interest in the idea that a cheap, over-the-counter vitamin might become a genuine tool for suicide prevention. Now a nationwide Swedish study, presented at the European College of Neuropsychopharmacology (ECNP) annual congress in Munich, is tempering that enthusiasm. The new analysis, drawing on sixteen years of data from all 21 Swedish regions, finds that the association between folic acid dispensing and suicide-related deaths is far messier than the earlier work suggested, with effects that appear to diverge sharply by sex and age group and no statistically significant signal at all among women.

To understand why researchers have been drawn to folic acid in the first place, it helps to look at the biology. Vitamin B9 is a central player in one-carbon metabolism, a biochemical network that supplies methyl groups for the synthesis of DNA, the metabolism of amino acids and, crucially, the production and regulation of neurotransmitters in the central nervous system, including monoamines such as serotonin and dopamine that are intimately involved in mood regulation. Folate status has been repeatedly linked to depression, to markers of inflammation and to suicidal behaviour in observational research, and low folate levels have been found in subsets of people with affective disorders. Because the vitamin is inexpensive, widely available, easy to administer and largely free of serious side effects, it has long been considered a biologically plausible candidate for a low-threshold preventive intervention, one that could in principle reach vulnerable people without the stigma, cost and access barriers associated with conventional psychiatric care.

The 2022 JAMA Psychiatry findings seemed to give that plausibility empirical teeth. By linking prescription records to episodes of self-harm in a large American population, the study’s authors reported that months in which patients had folic acid coverage were associated with substantially lower rates of suicide attempts and intentional self-harm. The result generated headlines and, according to the researchers behind the new Swedish work, genuine interest in prescribing folic acid to groups considered at elevated risk. But the study was observational, meaning it measured associations in existing data rather than randomly assigning treatment, and it left open the perennial question that haunts all such research: did the vitamin reduce risk, or were people who happened to receive prescriptions simply different in ways that mattered?

The Swedish team, led by Professor Jussi Jokinen of Karolinska Institutet and Umeå University, set out to test whether the folic acid signal would hold up in a different health system, a different population and a different outcome measure. Rather than tracking suicide attempts, they examined suicide-related deaths among young adults, an age band in which suicide remains a leading cause of mortality. The researchers analysed openly available nationwide data covering the period from 2006 to 2021, encompassing all 21 Swedish regions. Among people aged 20 to 29 years, the dataset included 3,463 suicide-related deaths, of which 2,693 were classified as suicides and 770 as deaths from events of undetermined intent, a category that often includes cases where suicidal intent could not be formally established.

The results, presented by Jokinen together with colleagues A. Mert and A. Desai Boström, did not point in a single direction. Among men aged 20 to 24, higher annual folic acid dispensing rates were associated with a higher concentration of suicide-related deaths, the opposite of what a simple protective story would predict. Yet among men aged 25 to 29, folic acid dispensing was associated with a decrease in suicide-related deaths, echoing the direction of the American findings. Among women, no statistically significant associations emerged at all. This patchwork of divergent, sex- and age-specific patterns is precisely what makes the new study difficult to reconcile with a straightforward causal narrative in which folic acid supplementation uniformly lowers suicide risk.

Jokinen was careful to frame the findings in terms of caution rather than alarm. Our results should not be interpreted as evidence that folic acid increases suicide risk, he said. What they do suggest is caution. Observational associations between prescriptions and suicidal behaviour can be difficult to interpret, because people who receive a treatment may differ in important ways from people who do not. That distinction between association and causation sits at the heart of the debate. The Swedish analysis compared regional dispensing patterns with regional mortality counts rather than following individual people who did or did not take folic acid, an ecological design that can reveal population-level signals but cannot determine whether the vitamin itself affected any single person’s risk.

The researchers highlight one methodological trap in particular: confounding by indication. Folic acid is prescribed for a variety of reasons, from confirmed deficiency and anaemia to supporting treatment of depression, and some of the medical, psychiatric or behavioural circumstances that lead a clinician to recommend supplementation may themselves be linked to suicide risk. In such a scenario, a folic acid prescription may function as an indicator of underlying health circumstances rather than as the cause of the observed outcome. A region or subgroup with more psychiatric morbidity might both dispense more supplements and experience more suicides, producing an apparent association that has nothing to do with the vitamin’s pharmacology. The same logic, running in the opposite direction, could also mask genuine protective effects in some groups. These limitations, the authors emphasise, mean the findings should be read as a signal warranting further investigation, not as evidence for either a beneficial or a harmful causal effect of supplementation.

Jokinen stressed that the Swedish results do not directly contradict the earlier American work, because the populations, outcomes and study designs differ in fundamental ways. Earlier work raised the important possibility that folic acid might be associated with reduced suicidal behaviour, he said. Our study does not directly contradict that work, because the populations, outcomes and study designs are different: it shows that the picture is not straightforward. Before folic acid can be discussed as a suicide-prevention strategy, we need individual-level longitudinal studies that can account for why it was prescribed and for patients’ clinical characteristics. It means the jury is still out. He added that the findings should not prompt any changes in the clinical use of folic acid, and that clinicians and researchers should resist interpreting prescription-outcome associations as proof of a direct protective effect. The key next step, he argued, is individual-level longitudinal research linking folic acid prescriptions to treatment indications, psychiatric and medical diagnoses, other medications, substance use and, ideally, biological folate measures, which would help determine whether the observed associations reflect an effect of the vitamin itself or the characteristics of the patients for whom it is prescribed.

Independent commentators see the study as a useful corrective to premature enthusiasm. Dr Xenia Gonda of Semmelweis University in Budapest, who was not involved in the work, said the findings underline that suicidal behaviour is not a single, biologically uniform phenomenon. Understanding its diverse neurobiological pathways, and how these may differ by sex and age, is essential if we are to identify new, more precisely targeted opportunities for prevention also at the population level, she said, noting that this is particularly important for potential interventions such as folic acid, which is inexpensive, widely available, easy to use and free from the high thresholds and stigma often associated with accessing psychiatric care. At the same time, she cautioned, accessibility and biological plausibility do not establish efficacy, and the authors are right to emphasise that observational findings cannot demonstrate either a causal role for folic acid in the development of suicidal behaviour or a protective effect of supplementation. The observed sex- and age-related differences, she argued, are especially valuable because they highlight the need to move beyond one-size-fits-all models in both suicide research and psychiatric prevention.

For now, the practical takeaway for patients and clinicians is one of continuity rather than change: nothing in the Swedish data justifies altering how folic acid is prescribed, and nothing in it supports adding the vitamin to suicide-prevention protocols on the strength of current evidence. What the study does deliver is a methodological warning shot for the field. Suicide prevention research is crowded with interventions that looked promising in observational data and failed under stricter scrutiny, and the folic acid story now illustrates how the same exposure can produce opposite associations in adjacent subgroups of the same country over the same period. The authors are preparing a manuscript for submission to a peer-reviewed journal, and the work has not yet undergone peer review, so the findings should be treated as preliminary. Until individual-level, longitudinal studies with proper accounting for prescribing indications and clinical characteristics are completed, the question of whether vitamin B9 can meaningfully reduce suicide risk remains, as Jokinen put it, an open one, with the jury still deliberating.

Subject of Research: Association between folic acid supplementation and suicide-related deaths among young adults in Sweden

Article Title: Study questions benefit of folic acid (vitamin B9) supplementation in reducing suicides

Article References: Study questions benefit of folic acid (vitamin B9) supplementation in reducing suicides. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: folic acid, vitamin B9, suicide prevention, suicidal behaviour, observational study, confounding by indication, ECNP Congress, Karolinska Institutet, JAMA Psychiatry, young adults, psychiatry, Sweden