Folic acid, other B-vitamins or magnesium for autism

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SBU Enquiry Service

Consists of structured literature searches to highlight studies that can address questions received by the SBU Enquiry Service from Swedish healthcare or social service providers. We assess the risk of bias in systematic reviews and when needed also quality and transferability of results in health economic studies. Relevant references are compiled by an SBU staff member, in consultation with an external expert when needed.

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Published: Report no: ut202509 Registration no: SBU 2025/427

Question

What effects do folic acid, other B-vitamins or magnesium have on children and adolescents with autism?

PICO

  • Population: children and adolescents with an autism diagnosis
  • Intervention: folic acid, other B-vitamins or magnesium (oral administration)
  • Comparison: placebo or waitlist
  • Outcome: change in core symptoms, measured by assessment instrument; adverse effects

Method

A systematic literature search was performed using the following databases: Medline (Ovid), Scopus, Embase, and the international HTA-databasse.Two authors independently assessed the abstracts of all identified studies.

Risk of bias in relevant systematic reviews was assessed using an assessment tool based on AMSTAR.

Identified literature

One relevant systematic review with low risk of bias were identified [1]. The results and conclusions are presented in Table 1. In 15 relevant systematic reviews, the risk of bias was considered to be high, therefore the results and conclusions are not reported [2-16].

Table 1 Systematic reviews with low/moderate risk of bias.
Included studies Population, Intervention, Control Outcomes
Siafis et al, 2022 [1]
Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis
143 RCTs in total 

Relevant studies:
1 RCT on folinic acid
(n, total=48)
USA

1 RCT on vitamin B12
(n, total=57)
USA		 Population:
Children/adolescents (125 RCTs) and adults (18 RCTs) with ASD 

Children/adolescents:
Median age: 8.23 years (6.26–9.51), min/max of mean age 3.62–14.64 years. 

Intervention:
Pharmacological (n=41) and dietary supplement (n=17) treatments 

Control:
Any other drug, dietary-supplement or placebo		 Primary outcomes:
 Change in core symptoms of ASD, measured with validated rating scales:
  • Social-communication difficulties
  • Repetitive behaviours
  • Overall core symptoms
Authors' conclusion:
Folinic Acid:
“…there were some indications of improvement by […] folinic acid […], yet they were imprecise based on limited data and not formally statistically significant” 

Vitamin B12:
“…vitamin-B12 […] not found to be efficacious for core or associated symptoms”.

References

  1. Siafis S, Ciray O, Wu H, Schneider-Thoma J, Bighelli I, Krause M, et al. Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis. Mol Autism. 2022;13(1):10. Available from: https://doi.org/10.1186/s13229-022-00488-4.
  2. Bozzatello P, Novelli R, Montemagni C, Rocca P, Bellino S. Nutraceuticals in Psychiatric Disorders: A Systematic Review. Int J Mol Sci. 2024;25(9). Available from: https://doi.org/10.3390/ijms25094824.
  3. Choi H, Kim JH, Yang HS, Kim JY, Cortese S, Smith L, et al. Pharmacological and non-pharmacological interventions for irritability in autism spectrum disorder: a systematic review and meta-analysis with the GRADE assessment. Mol Autism. 2024;15(1):7. Available from: https://doi.org/10.1186/s13229-024-00585-6.
  4. Colak H, Sariyer ET, Nogay NH. The effect of nutritional interventions reducing oxidative stress on behavioural and gastrointestinal problems in autism spectrum disorder. Int J Dev Neurosci. 2023;83(2):135-64. Available from: https://doi.org/10.1002/jdn.10254.
  5. Gogou M, Kolios G. The effect of dietary supplements on clinical aspects of autism spectrum disorder: A systematic review of the literature. Brain Dev. 2017;39(8):656-64. Available from: https://doi.org/10.1016/j.braindev.2017.03.029.
  6. Hoxha B, Hoxha M, Domi E, Gervasoni J, Persichilli S, Malaj V, et al. Folic Acid and Autism: A Systematic Review of the Current State of Knowledge. Cells. 2021;10(8). Available from: https://doi.org/10.3390/cells10081976.
  7. Lam NSK, Long XX, Li X, Saad M, Lim F, Doery JC, et al. The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review. Biomed Pharmacother. 2022;146:112541. Available from: https://doi.org/10.1016/j.biopha.2021.112541.
  8. Li YJ, Ou JJ, Li YM, Xiang DX. Dietary Supplement for Core Symptoms of Autism Spectrum Disorder: Where Are We Now and Where Should We Go? Front Psychiatry. 2017;8:155. Available from: https://doi.org/10.3389/fpsyt.2017.00155.
  9. Liu Y, Yang Z, Du Y, Shi S, Cheng Y. Antioxidant interventions in autism spectrum disorders: A meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2022;113:110476. Available from: https://doi.org/10.1016/j.pnpbp.2021.110476.
  10. Maniram J, Karrim SBS, Oosthuizen F, Wiafe E. Pharmacological Management of Core Symptoms and Comorbidities of Autism Spectrum Disorder in Children and Adolescents: A Systematic Review. Neuropsychiatr Dis Treat. 2022;18:1629-44. Available from: https://doi.org/10.2147/NDT.S371013.
  11. Pancheva R, Chamova R, Marinov D, Toneva A, Dzhogova M, Eyubova S, et al. Therapeutic diets and supplementation: exploring their impact on autism spectrum disorders in childhood – A narrative review of recent clinical trials. Res Autism Spectr Disord. 2024;112. Available from: https://doi.org/10.1016/j.rasd.2024.102352.
  12. Prades N, Varela E, Flamarique I, Deulofeu R, Baeza I. Water-soluble vitamin insufficiency, deficiency and supplementation in children and adolescents with a psychiatric disorder: a systematic review and meta-analysis. Nutr Neurosci. 2023;26(2):85-107. Available from: https://doi.org/10.1080/1028415X.2021.2020402.
  13. Rossignol DA, Frye RE. Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. J Pers Med. 2021;11(11). Available from: https://doi.org/10.3390/jpm11111141.
  14. Rossignol DA, Frye RE. The Effectiveness of Cobalamin (B12) Treatment for Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. J Pers Med. 2021;11(8). Available from: https://doi.org/10.3390/jpm11080784.
  15. Vasconcelos C, Perry IS, Gottfried C, Riesgo R, Castro K. Folic acid and autism: updated evidences. Nutr Neurosci. 2025;28(3):273-307. Available from: https://doi.org/10.1080/1028415X.2024.2367855.
  16. Zhou MS, Nasir M, Farhat LC, Kook M, Artukoglu BB, Bloch MH. Meta-analysis: Pharmacologic Treatment of Restricted and Repetitive Behaviors in Autism Spectrum Disorders. J Am Acad Child Adolesc Psychiatry. 2021;60(1):35-45. Available from: https://doi.org/10.1016/j.jaac.2020.03.007.

Literature search

Upplysningstjänsten har gjort sökningar i databaserna Medline (Ovid), Scopus och Embase, samt i INAHTA1:s databas för HTA2-rapporter. Vi har även handsökt publikationer på webbsidor för regionala HTA-organisationer och myndigheter.

Sökningen har begränsats till systematiska översikter.

Nedan redovisas sökningarna som gjorts i de vetenskapliga databaserna.

Medline via OvidSP 10 April 2025

Title: Folic acid or other B-vitamins for children and adolescents with autism
Search terms Items found
Population:
1. exp Autism Spectrum Disorder/ 48 131
2. (autis* or asd or asperger*).ti,ab,kf,bt. 88 668
3. 1 or 2 91 861
Intervention:
4. exp Vitamin B Complex/ 161 797
5. ((vitamin adj2 (B* or M or G or H)) or thiamin* or riboflavin* or niacin* or pantothen* or pyridox* or biotin* or cyanocobalamin* or cobalamin* or folic or folinic or folate or folacin or folvite or pteroylglutamic).ti,ab,kf,bt. 214 970
6. 4 or 5 289 148
Study types: systematic reviews and meta-analysis / randomized controlled trials3
7. ((Systematic Review/ or Meta-Analysis/ or Cochrane Database Syst Rev.ja. or ((systematic adj4 review) or "meta analys*" or metaanalys*).ti,bt,ab.) not (editorial/ or letter/ or case reports/)) 531 981
Final result
8. 3 and 6 and 7 80
/ = Term from the MeSH controlled vocabulary; .sh = Term from the MeSH controlled vocabulary; exp = Term from MeSH including terms found below this term in the MeSH hierarchy; .ti,ab = Title or abstract; .tw = Title or abstract; .kf = Keywords; .kw = Keywords, exact; .bt = Book title. NLM Bookshelf; .pt = Publication type; .ja = Journal abbreviation; .af = All fields; adjn = Adjacent. Proximity operator retrieving adjacent words, adj3 retrieves records with search terms within two terms from each other; * or $ = Truncation; “ “ = Citation Marks; searches for an exact phrase

1. International Network of Agencies for Health Technology Assessment (INAHTA)

2. Utvärdering av hälso- och sjukvårdens (och i SBU:s fall socialtjänstens) metoder (engelska: Health Technology Assessment)

3. Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision); Ovid format. The Cochrane Collaboration; 2008. Available from: https://training.cochrane.org/handbook/current/chapter-04-technical-supplement-searching-and-selecting-studies#section-3-6-1. with modifications: the following terms are added: clinical trial, phase iii.pt. ; randomised.ab. ; ("Phase 3" or "phase3" or "phase III" or P3 or "PIII").ti,ab,kw.

Medline via OvidSP 10 April 2025

Title: Magnesium for children and adolescents with autism
Search terms Items found
Population:
1. exp Autism Spectrum Disorder/ 48 131
2. (autis* or asd or asperger*).ti,ab,kf,bt. 88 668
3. 1 or 2 91 861
Intervention:
4. Magnesium/ 71 494
5. magnesium.ti,ab,kf,bt. 75 651
6. 4 or 5 117 915
Study types: systematic reviews and meta-analysis / randomized controlled trials4
7. ((Systematic Review/ or Meta-Analysis/ or Cochrane Database Syst Rev.ja. or ((systematic adj4 review) or "meta analys*" or metaanalys*).ti,bt,ab.) not (editorial/ or letter/ or case reports/)) 531 981
Final result
8. 3 and 6 and 7 15
/ = Term from the MeSH controlled vocabulary; .sh = Term from the MeSH controlled vocabulary; exp = Term from MeSH including terms found below this term in the MeSH hierarchy; .ti,ab = Title or abstract; .tw = Title or abstract; .kf = Keywords; .kw = Keywords, exact; .bt = Book title. NLM Bookshelf; .pt = Publication type; .ja = Journal abbreviation; .af = All fields; adjn = Adjacent. Proximity operator retrieving adjacent words, adj3 retrieves records with search terms within two terms from each other; * or $ = Truncation; “ “ = Citation Marks; searches for an exact phrase

4. Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision); Ovid format. The Cochrane Collaboration; 2008. Available from: https://training.cochrane.org/handbook/current/chapter-04-technical-supplement-searching-and-selecting-studies#section-3-6-1. with modifications: the following terms are added: clinical trial, phase iii.pt. ; randomised.ab. ; ("Phase 3" or "phase3" or "phase III" or P3 or "PIII").ti,ab,kw.

Scopus via scopus.com 10 April 2025

Title: Folic acid or other B-vitamins for children and adolescents with autism
Search terms Items found
Population:
1. TITLE-ABS-KEY ( autis* OR asd OR asperger* ) 154 767
Intervention:
2. TITLE-ABS-KEY ( ( ( vitamin W/2 ( b* OR m OR g OR h ) ) OR thiamin* OR riboflavin* OR niacin* OR pantothen* OR pyridox* OR biotin* OR cyanocobalamin* OR cobalamin* OR folic OR folinic OR folate OR folacin OR folvite OR pteroylglutamic ) ) 487 918
Study types: systematic reviews and meta-analysis / randomized controlled trials
3. TITLE-ABS-KEY ( ( systematic  W/2  review )  OR  "meta analy*"  OR  metaanaly* ) AND (EXCLUDE (DOCTYPE, “le”) OR EXCLUDE (DOCTYPE, “ed”) OR EXCLUDE (DOCTYPE, “ch”) OR EXCLUDE (DOCTYPE, “cp”))   796 923
Final result
4. 1 and 2 and 3 188
TITLE-ABS-KEY = Title, abstract or keywords (including indexed keywords and author keywords); ALL = All fields; W/n = Within. Proximity operator retrieving terms within n words from each other; PRE/n = Precedes by. Proximity operator, the first term in the search must precede the second by n words; LIMIT-TO (X) = Includes only results of specified type, e.g., publication type or time range; DOCTYPE = Publication type; “re” = review; “le” = letter; “ed” = editorial; “ch” = book chapter; “cp” = conference proceedings; * = Truncation; “ “ = Citation Marks; searches for an exact phrase

Scopus via scopus.com 10 April 2025

Title: Magnesium for children and adolescents with autism
Search terms Items found
Population:
1. TITLE-ABS-KEY ( autis* OR asd OR asperger* ) 154 767
Intervention:
2. TITLE-ABS-KEY ( magnesium ) 454 736
Study types: systematic reviews and meta-analysis / randomized controlled trials
3. TITLE-ABS-KEY ( ( systematic  W/2  review )  OR  "meta analy*"  OR  metaanaly* ) AND (EXCLUDE (DOCTYPE, “le”) OR EXCLUDE (DOCTYPE, “ed”) OR EXCLUDE (DOCTYPE, “ch”) OR EXCLUDE (DOCTYPE, “cp”))   796 923
Final result
4. 1 and 2 and 3 49
TITLE-ABS-KEY = Title, abstract or keywords (including indexed keywords and author keywords); ALL = All fields; W/n = Within. Proximity operator retrieving terms within n words from each other; PRE/n = Precedes by. Proximity operator, the first term in the search must precede the second by n words; LIMIT-TO (X) = Includes only results of specified type, e.g., publication type or time range; DOCTYPE = Publication type; “re” = review; “le” = letter; “ed” = editorial; “ch” = book chapter; “cp” = conference proceedings; * = Truncation; “ “ = Citation Marks; searches for an exact phrase

Embase via Elsevier 10 April 2025

Title: Folic acid or other B-vitamins for children and adolescents with autism
Search terms Items found
Population:
1. 'autism'/exp 112 355
2. autis* OR asd OR asperger*:ti,ab,kw 144 081
3. 1 or 2 464 814
Intervention:
4. 'vitamin b group'/exp 295 816
5. (vitamin NEAR/2 (b* OR m OR g OR h)) OR thiamin* OR riboflavin* OR niacin* OR pantothen* OR pyridox* OR biotin* OR cyanocobalamin* OR cobalamin* OR folic OR folinic OR folate OR folacin OR folvite OR pteroylglutamic:ti,ab,kw 436 520
6. 4 or 5 464 814
Study types: systematic reviews and meta-analysis / randomized controlled trials
7.  ('systematic review'/de OR 'meta analysis'/de OR [cochrane review]/lim OR (((systematic NEAR/4 review) OR 'meta analys*' OR metaanalys*):ti,ab)) NOT ('case report'/de OR 'editorial'/it OR 'letter'/it OR 'note'/it)) 776 946
Final result
8. 3 and 6 and 7 199
/de = Term from the EMTREE controlled vocabulary; /exp = Term from the EMTREE controlled vocabulary, including all narrower terms in the hierarchy; ti = Title; ab = Abstract; kw = Author keywords; it = Publication type; NEAR/n = Near. Proximity operator retrieving terms within n words from each other; * = Truncation; ‘ ‘ = Citation Marks; searches for an exact phrase

Embase via Elsevier 10 April 2025

Title: Magnesium for children and adolescents with autism
Search terms Items found
Population:
1. 'autism'/exp 112 355
2. autis* OR asd OR asperger*:ti,ab,kw 144 081
3. 1 or 2 464 814
Intervention:
4. 'magnesium'/exp 114 410
5. magnesium:ti,ab,kw 92 899
6. 4 or 5 114 420
Study types: systematic reviews and meta-analysis / randomized controlled trials
7. ('systematic review'/de OR 'meta analysis'/de OR [cochrane review]/lim OR (((systematic NEAR/4 review) OR 'meta analys*' OR metaanalys*):ti,ab)) NOT ('case report'/de OR 'editorial'/it OR 'letter'/it OR 'note'/it)) 776 946
Final result
8. 3 and 6 and 7 39
/de = Term from the EMTREE controlled vocabulary; /exp = Term from the EMTREE controlled vocabulary, including all narrower terms in the hierarchy; ti = Title; ab = Abstract; kw = Author keywords; it = Publication type; NEAR/n = Near. Proximity operator retrieving terms within n words from each other; * = Truncation; ‘ ‘ = Citation Marks; searches for an exact phrase

International HTA Database 10 April 2025

Search terms Items found
1. Autis*  
2. Diet*or Supplement* or foli* or folate or vitamin or magnesium  
3. 1 or 2 0*
* No relevant records were identified in English or any other Scandinavian language
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