Histamine (+liberators / DAO inhibitors)

What is it?

Histamine intolerance is not an allergy. Maintz & Novak (2007) frame it as a disequilibrium between the histamine that accumulates and the body's capacity to break it down, with diamine oxidase — DAO — as the main enzyme for histamine arriving in food. Flushing, headache, hives, digestive upset and sometimes low blood pressure follow. Their review sets out that framework and names no food at all, so nothing here places a single food on the strength of it.

Three groups, and only one of them is a measurement

Histamine-rich foods — aged cheese, cured meat, fermented food, fish, alcohol — carry the amine itself. Liberators are said to release the body's own histamine: strawberries, tomatoes, citrus, chocolate. DAO inhibitors are said to block clearance: alcohol, black tea, energy drinks. The second and third groups need reading carefully. Zuberbier (2022), the international EAACI/GA²LEN/EuroGuiDerm/APAAACI urticaria guideline, records that pseudoallergic non-IgE reactions to naturally occurring food ingredients, and in some cases to additives, have been observed in some patients — and that the pseudoallergen-free and low-histamine diets built on that are "controversial and as yet unproven in well-designed double-blinded placebo-controlled studies". Across its 33 pages the word liberator never appears, and no colour is named. So read "liberator" as the grouping an elimination protocol applies, not as a release measured food by food.

Freshness changes the answer more than the food does

Every level on this axis assumes the food is eaten fresh. Histamine accumulates in protein-rich food as it sits — fish, meat, leftovers, ripening cheese — so a food rated safe can stop being safe within hours of cooking or a few days in the fridge. The practical rules follow from that: avoid what is fermented, aged or long-stored, freeze fish and meat rather than leaving them in the fridge if they are not eaten, and treat a cooked dish as less tolerable the longer it is kept. There is no published figure for when that happens.

The doses that have been published

EFSA's Panel on Biological Hazards (2011) gives the only figures on this axis. For a healthy person, no adverse effect at about 50 mg of histamine. For someone with histamine intolerance, the no-effect dose sits "below detectable limits" — which is to say no threshold has been established at all. For tyramine the same opinion gives 600 mg without an MAOI, 50 mg on a third-generation one and 6 mg on a classical one. The opinion also states that the information available was insufficient to carry out a quantitative risk assessment, so these are doses and not rates, and it publishes no figure for any single food.

Medicines are the DAO inhibitor the food lists leave out

Sattler (1985) selected 341 drugs common in intensive care, screened 164 against human and canine DAO and found 61 that inhibit it, spread across every major therapeutic group. None enhanced it. The useful part is that a class does not predict its members: cefotiam and cefuroxime inhibit human DAO while cefotaxime, of the same family, does not. This was enzyme activity in a test tube and in an intensive-care setting, not symptoms at a dinner table, so it is not a reason to stop a prescription — it is a reason to raise it with a doctor when food that used to be tolerable stops being so. No food, drink or additive is in that screen.

Cheese: the name on the label decides less than you expect

Mayer (2010) measured twenty biogenic amines by UPLC in 58 cheeses bought at retail. 13.8 per cent of the samples carried more than 10 mg of histamine per 100 g, 22.4 per cent more than 10 mg of tyramine, and two samples reached about 194 mg of total amines. That is a distribution across one country's shelf and not a value for any variety: there is no cheddar figure and no gouda figure in it, and two cheeses of the same name can sit at either end. Linares (2012) gives the rule behind the spread. Amines form only where three things converge — the substrate amino acids are available, microbes carrying the right pathway are present and active, and the conditions favour decarboxylation — and the levers that decide those are pasteurisation, the starter culture, salt, pH, and the time and temperature of ripening. None of them is printed on the pack. That review explains variability and publishes no figure, so it cannot place a cheese anywhere.

Fermented sausage, where the exposure has actually been estimated

Latorre-Moratalla (2017) built a probabilistic exposure assessment from 474 dry fermented sausages and Spanish consumption data. A meal delivers on average 6.2 mg of tyramine and 1.39 mg of histamine. For a healthy person the risk from these sausages alone is negligible; for someone taking an MAOI there is a 34 per cent probability of passing the 6 mg safe threshold. The figures belong to Spanish portions and to dry fermented sausage: 474 samples become a distribution, not a value for salami or chorizo, and the thresholds are for acute effects rather than the daily tolerance an intolerant reader is managing. Shulman (1989) assayed tyramine in over a hundred disputed foods and concluded that only a very limited number need absolute restriction — all aged cheeses, concentrated yeast extracts, sauerkraut and broad bean pods — with alcoholic drinks appearing safe in moderation. That paper published its conclusion and not the hundred values behind it, so it carries no figure for anything; its list is a narrowing, and the foods in it are the same ones this axis warns about.

What the law covers, and what it does not

Regulation (EC) No 2073/2005 sets three histamine criteria. Fishery products from species associated with a high amount of histidine: nine samples, mean below 100 mg/kg, at most two between 100 and 200, none above 200. The same species after enzyme maturation in brine: 200 and 400. Fish sauce produced by fermentation: a single sample and a 400 mg/kg limit, the highest of the three and the only one with no tolerance. Two things follow. It is a sampling plan on a batch and not a ceiling on a fillet, so one fish above the mean breaches nothing and a compliant lot is not a promise about the piece in your hand. And it covers only histidine-rich species — the scombroids and their relatives, tuna, mackerel, sardine, herring, anchovy — so salmon, trout, carp, hake, plaice and the rest have no legal number at all. The absence of a number is not the absence of a risk: every fish carries histidine, and bacteria act on it when the cold chain breaks. Piersanti (2014) shows what control finds in practice: of 590 batches of fish products sampled by the Italian authorities between 2008 and 2012, across 3 129 determinations, 4.9 per cent were judged non-compliant, and the irregular cases were explained by species, processing and storage rather than by fish being fish. That is a rate of non-compliance across batches, not a histamine content, and the paper names no species.

How to read the SIGHI ratings

Many levels on this axis rest on the SIGHI food-compatibility list. Each entry carries a rating from 0 to 3 and a set of letters: L for a liberator of mast-cell mediators, H for high histamine content, H! for rapid formation, A for other biogenic amines, B for a DAO blocker. In its own words the histamine column does not show histamine content but perceived compatibility, which it says results from several mostly unknown factors that cannot be precisely determined. It is a rating and not a measurement, and no mg/kg figure can be read out of it. It also lists additives by whole families rather than one at a time, which is why a mineral salt or a purified colour appears on this axis at all: the entry records that the family was reviewed, not that a route to histamine was found in that substance.

Source: Maintz L. & Novak N., Am J Clin Nutr 85 (2007) 1185-1196, for the DAO framework this axis rests on — its abstract names no food; Zuberbier T. et al., Allergy 77 (2022), the EAACI/GA²LEN/EuroGuiDerm/APAAACI urticaria guideline, for what the elimination diets do and do not establish — the word liberator appears nowhere in its 33 pages; EFSA Panel on Biological Hazards, EFSA Journal 9:10 (2011) 2393, for the histamine and tyramine doses and for its own statement that a quantitative risk assessment could not be carried out; Sattler J. et al., Agents Actions 16 (1985) 91-94, for DAO inhibition by drugs and its drug-by-drug inconsistency; Mayer H. et al., J Chromatogr A 1217 (2010) 3251-3257, for the distribution of amines across 58 retail cheeses; Linares D. et al., Front Microbiol 3 (2012) 180, for the three conditions amine formation requires; Latorre-Moratalla M.L. et al., Food Chem Toxicol 99 (2017) 78-85, for the exposure figures and the 34 per cent on an MAOI; Shulman K.I. et al., J Clin Psychopharmacol 9 (1989) 397-402, for the narrowing of the restricted list; Commission Regulation (EC) No 2073/2005, Annex I Chapter 1, for the three histamine criteria and their sampling plans; Piersanti A. et al., Food Chem 153 (2014) 7-12, for four years of Italian official-control results; SIGHI — Swiss Interest Group Histamine Intolerance, food-compatibility list, for the rating scale and its stated limit

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