Major flaws in some risk assessments of dietary supplement intake

Key points

  • The critical appraisal in the core national assessments concerning supplemental intake of histidine has had substantial weaknesses


The increasing use of amino acids as food additive and their increasing availability as dietary supplements necessitates assessments of possible negative health effects of intakes that exceed the natural content in foods. In the European Union, the European Food Safety Authority (EFSA) is responsible for risk assessments associated with the food chain, and works closely with international experts, partners and national stakeholders. The EFSA produces scientific opinions and advice that form the basis for legislation and policies in Europe. The scientific opinions have mainly concerned the use of specific amino acids as an additive in animal feed (1).

The EU regulations also include L-histidine among the substances that can be added for specific nutritional purposes to foods for particular nutritional use (2). However, research on the possible hazards and health effects of excess human intakes of histidine is limited. A scientific opinion paper by the EFSA, published in 2008, on the implications for human health of using certain amino acids as a food additive, considered the findings inconclusive concerning histidine. The review was based on four in vitro studies involving histidine (3).

Also national scientific committees, panels and institutes carry out assessments concerning human intake of amino acids and the associated risks, and report to the EFSA. The value and benefits of such an assessment depend on the quality of the critical appraisal of the available research and evidence. Concerning use of histidine as a dietary supplement, only the Spanish and Norwegian food safety committees have carried out risk assessments, in addition to the Institute of Medicine (IoM) in the United States. In this perspective, I have reviewed the risk assessments of histidine as dietary supplement published in the period 2005 – 2015 in light of the original studies of histidine the assessments were based on.


In 2005, IoM issued a report on dietary reference intakes of amino acids based on six studies concerning histidine (or L-histidine) intake in humans, mostly patients (4). The literature search was not described. Two of the studies had small samples (5,6), whereof one did not have a control group (5). One study was on infants (7), and one was published as a letter to the editor describing unpublished observations of four volunteers in a pilot study without a control group (8). The studies are outlined (1-6) in Table 1. Based on these six studies, the IoM concluded that there is tentative evidence in humans that an intake of 4–4.5 grams/day of L-histidine in addition to intake from dietary content does not result in adverse effects, and that the available scientific data were not sufficient to derive an upper limit for the chronic oral intake of L-histidine from supplements (4).

In 2011, the scientific committee for food safety in Norway (VKM) carried out a risk categorisation of high intakes of amino acids. Based on the report by the IoM (2005) described above and two of the studies on humans that were also included in that report (5 & 6 in Table 1), the Norwegian report grouped histidine as a high-risk amino acid because of its direct organ effect on the eyes in high doses (9). This finding originated in the aforementioned letter to the editor, and was reportedly observed in two female participants (8). Details about the literature search were presented in the VKM’s report. However, it was emphasised that the report had several limitations, without further specifications 9.

The scientific committee of the Spanish agency for food safety and nutrition (AESAN) has assessed the use of amino acids, including histidine, as food supplements in two reports (10,11). Concerning studies on humans, both reports refer to the same six studies as appear in the IoM report (1-6 in Table 1). The critical appraisal of adverse effects in humans appears to be more or less a copy of the IoM’s, but with references to the individual studies. In the 2012 report, the committee proposes a maximum daily amount of 750 mg of L-histidine, without providing a rationale for that conclusion (10). The 2013 report, on the other hand, concluded that a maximum daily quantity of 1.12 g of L-histidine as a food supplement is acceptable. The evaluated quantity was based on the authorised level in Italy (11). The description of the literature search was limited to mentioning that the 2012 report included studies published in the period 1971 – 2010, while the 2013 report covered the period 1972 – 2012. AESAN published a third report with the same title in 2015, but this report did not address histidine.

In 2013, the VKM published an assessment of the use of four specific amino acids as food supplement and food additives, including histidine. To complement the IoM’s assessment, their described literature search included the years 2002 – 2012, which did not reveal any new studies reporting adverse health effects on humans. In light of this, the VKM repeated the conclusions made by the IoM. Of studies published before 2002, the assessment only referred to the publication by Geliebter et al. (1981), and mentioned that this publication (which was the letter to the editor) provided the basis for the conclusion in the VKM’s 2011 assessment (12).


The EFSA and the co-operating national committees play a crucial role in communicating advice and describing the risks associated with foods and food supplements to decision makers, legislators, and the public, and their advices should be supported by comprehensive scientific documentation. A critical appraisal should involve a transparent, careful and systematic assessment of the scientific research in terms of its reliability, validity, value and relevance in the particular context, and it is pivotal that the original sources be tracked down and reviewed in order to achieve this, as is recommended in the referencing guidelines.

In conclusion, all five assessments of histidine described above were based on the same six studies on humans. However, the critical appraisals by the involved scientific panels and expert groups had major shortcomings, which led to statements that were not scientifically justified. Only two of the reports included a description of the literature search, and four assessments more or less reproduced the findings by the IoM, apparently relying on a secondary source. All of them failed to mention that the study by Geliebter et al. (1981) was based on only four observations and published as a letter to the editor, and hence was not peer-reviewed. The VKM magnified this flaw by emphasising the findings in that study. It must be acknowledged that the present review has only looked into some of the assessments concerning one dietary substance; a critical look at assessments of other dietary substances may be worthwhile.


  1. European Food Safety Authority. The EFSA Journal. European Food Safety Authority; 2018 [02/04/2018]. Available from:

  2. Commission Regulation (EC) No 953/2009 of 13 October 2009 on substances that may be added for specific nutritional purposes in foods for particular nutritional uses. European Union. OJ L 2009;269:9-19.

  3. Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food, European Food Safety Authority. Amino acids from chemical group 34. Flavouring Group Evaluation 26, Revision 1. EFSA J 2008;790:1-51.

  4. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington DC: The National Academies Press; 2005.

  5. Henkin RI, Patten BM, Re PK, Bronzert DA. A syndrome of acute zinc loss. Cerebellar dysfunction, mental changes, anorexia, and taste and smell dysfunction. Arch Neurol 1975;32(11):745-51.

  6. Schechter PJ, Prakash NJ. Failure of oral L-histidine to influence appetite or affect zinc metabolism in man: A double-blind study. Am J Clin Nutr 1979;32:1011-14.

  7. Zlotkin SH. Nutrient interactions with total parenteral nutrition: Effect of histidine and cysteine intake on urinary zinc excretion. J Pediatr 1989;114(5):859-64.

  8. Geliebter AA, Hashim SA, Van Itallie TB. Oral L-histidine fails to reduce taste and smell acuity but induces anorexia and urinary zinc excretion. Am J Clin Nutr 1981;34(1):119-20.

  9. The Norwegian Scientific Committee for Food Safety (VKM), Panel on nutrition, dietetic products, novel food and allergy. Risikogruppering av aminosyrer. VKM Report 2011:21 [29/03/2018]. Available from:

  10. The Spanish Agency for Food Safety and Nutrition (AESAN). Report of the Scientific Committee of AESAN on the use conditions for certain substances other than vitamins, minerals and plants in food supplements. AESAN-2012-008 [03/04/2018]. Available from:

  11. The Spanish Agency for Food Safety and Nutrition (AESAN). Report of the Scientific Committee of the AESAN on the condition for use of certain substances other than vitamins, minerals and plants in food supplements - 2. AESAN-2013-004 [03/04/2018]. Available from:

  12. The Norwegian Scientific Committee for Food Safety (VKM). Risk assessment of histidine, methionine, S-adenosylmethionine and tryptophan, Opinion of the Panel on nutrition, dietetic products, novel food and allergy of the VKM. VKM Report 2013:10 [02/04/2018]. Available from:

  13. Blumenkrantz MJ, Shapiro DJ, Swendseid ME, Kopple JD. Histidine supplementation for treatment of anaemia of uraemia. BMJ 1975;2(5970):530-33.

  14. Pinals RS, Harris ED, Burnett JB, Gerber DA. Treatment of rheumatoid arthritis with L-histidine: A randomized, placebo-controlled, double-blind trial. J Rheumatol 1977;4(4):414-19.

Table 1. Description of the original studies in the reviewed assessments


Study design

Participant characteristics

Sample size

Dose (grams/day)


Duration of intervention

Main endpoint



1 Blumenkrantz et al. 1975 (13)

Double-blind trial

Chronic uremic or undergoing dialysis. Adults





17.5 weeks


2 Henkin et al. 1975


Anorexia patients





24 days

Taste and smell acuity

3 Pinals et al. 1977 (14)

Double-blind trial

Adult rheumatoid arthritis patients





30 weeks

Rheu-matoid arthritis

4 Schechter and Prakash, 1979

Double-blind, cross-over trial

Healthy adult male





2 x 2 weeks

Taste and smell acuity

5 Geliebter et al. 1981 a

Pilot trial

Overweight adult





2-4 weeks

Taste and smell acuity

6 Zlotkin, 1989





0.100, 0.165, 0.095b


7 days

Urinary zinc excretion

a Published as Letter to the editor. b per kilogram body weight.