A look at what has actually been studied on DAO enzyme and histamine intolerance, where menopause research fits into that picture, and what remains unresolved.
DAO research is a relatively young field, and the number of controlled human trials is still small. This piece sets out what has actually been tested, where the emerging research on menopause and histamine fits into that picture, and, just as importantly, what has not been established yet.
What Has Actually Been Tested in Human Trials?
Diamine oxidase (DAO) is the enzyme responsible for breaking down histamine arriving from food in the gut, before it is absorbed.1 A handful of small clinical trials have looked at supplementing it directly.
- Histamine intolerance symptom scores. An open label pilot study followed 28 patients taking DAO capsules before meals for four weeks. Symptoms improved significantly during supplementation, then rose again during a DAO free follow up period.2
- Migraine. A randomised, double blind trial of 100 patients with episodic migraine and confirmed DAO deficiency found a greater reduction in headache duration in the DAO group than placebo, along with reduced use of migraine medication.3
- Chronic spontaneous urticaria. A crossover trial of 22 patients, 20 of whom completed it, found DAO supplementation was associated with reduced urticaria activity scores specifically in those with low baseline serum DAO.4
- Fibromyalgia. A double blind, placebo controlled trial in 100 women, published in 2023, examined DAO supplementation alongside standard therapy.5
- Insomnia. A 2025 randomised, double blind trial examined DAO supplementation alongside AOC1 gene variants and sleep outcomes.6
A larger trial is currently underway, enrolling 400 patients to test DAO supplementation, from both porcine and plant sources, against a low histamine diet over three months, specifically designed to address the small sample sizes and short durations of the earlier work above.7
The Evidence Gap Between Porcine and Plant DAO
Almost all of the trial data above used porcine kidney protein extract, the animal derived source. Plant derived DAO, typically from sprouted mung bean or pea, is a newer and vegan suitable alternative, but research on it has focused mainly on isolating and characterising the enzyme in a laboratory setting rather than testing it in people.
Open questions remain about its specificity for histamine over other diamines, and how stable its activity remains once formulated into a supplement.8 This is a genuine evidence gap rather than a minor caveat, and it is worth knowing which source underlies any claim you come across.
DAO, Histamine and Menopause: What Does the Research Show?
Menopause is one of the more interesting emerging threads in histamine research, though it is important to be precise about what has actually been studied versus what is theorised.
The mechanistic case starts with oestrogen and progesterone's documented effects on mast cells, the cells responsible for releasing histamine internally, a separate process from the dietary histamine that DAO acts on. Oestrogen has been shown to prime mast cells toward greater histamine release, while progesterone appears to have something of an inhibitory effect on the same cells.9
As oestrogen fluctuates and progesterone declines through perimenopause and menopause, that balance shifts. This is the basis for the hypothesis that histamine related symptoms may become more noticeable during this life stage for some people.
This is a genuinely active research thread, but it is a hypothesis built from mechanistic and hormonal research, not from large trials specifically testing DAO supplementation in a menopausal population. No published trial to date has isolated menopause as a study group for DAO supplementation.
What exists is a plausible biological mechanism connecting hormonal change to histamine handling generally. It is worth watching, but it is not yet a settled clinical picture.
What Is Not Yet Established?
It is worth stating clearly what the current evidence does not support. A 2023 placebo controlled challenge study found that only around 15% of people who suspected they had histamine intolerance actually reacted to ingested histamine under blinded conditions, a reminder that self suspected sensitivity and confirmed histamine intolerance are not the same thing.10
A related 2024 study looking at DAO gene variants in people with histamine intolerance symptoms, and a 2024 review of the wider field, both concluded that no single test, whether DAO blood activity, urinary histamine metabolites or genetic variants, reliably confirms or rules out histamine intolerance on its own.11, 12
The consistent message across this research is that histamine intolerance looks like a multifactorial process involving genetics, diet, gut microbiome, hormone levels and stress, rather than a single measurable deficiency. That matters for how the DAO trials above should be read. They show specific, measured improvements in specific study populations, under specific protocols.
They do not establish DAO as a treatment for migraine, urticaria, fibromyalgia, insomnia or menopausal symptoms, and none of the researchers behind them claim otherwise. What they show is that DAO, as a mechanism, deserves the growing research attention it is currently getting.
When Should You Speak to a GP or Herbalist?
If you are noticing new symptoms such as flushing, headaches, hives or digestive upset around perimenopause or menopause, speak to your GP or pharmacist first. Many of these symptoms overlap with other conditions, and with menopause itself, so it is worth ruling those out.
You can also book a free 15 minute consultation with a Napiers herbalist. Our herbalists include practitioners who focus on women's health, and they can talk through your diet, your symptoms and what you have already tried.
If you are looking for a simpler introduction to how DAO works and which foods are high in histamine, read What Is DAO Enzyme? And if you are weighing up whether a supplement could be right for you, our guide Should I Take DAO Enzyme? covers what to consider first.
Frequently Asked Questions
Does menopause cause histamine intolerance?
There is no evidence for a direct causal claim like that. What research shows is that oestrogen and progesterone influence mast cell behaviour, which is a plausible mechanism for histamine related symptoms shifting around perimenopause and menopause for some people, not an established diagnosis or a guaranteed effect.9
Has DAO supplementation been trialled specifically in menopausal women?
Not yet, as a defined study population. Existing DAO trials have focused on histamine intolerance, migraine, chronic urticaria, fibromyalgia and insomnia in mixed age adult samples.2, 3, 4, 5, 6
Why is DAO research still described as early stage?
Because most trials so far are small, single centre and short in duration, limitations the researchers themselves point out. A larger, longer trial designed to address exactly this is currently underway.7
Is there a reliable test to confirm histamine intolerance?
Not currently. Research has found that DAO blood activity, urinary histamine metabolites and genetic variants each fail to reliably confirm or rule out histamine intolerance on their own, and a 2023 placebo controlled challenge study found that most people who suspected they had it did not react to ingested histamine under blinded conditions.10, 11, 12
Why might histamine symptoms change around menopause?
One theory is that shifting hormone levels affect mast cells, the cells that release histamine inside the body. Oestrogen appears to encourage histamine release, while progesterone may have a calming effect on the same cells.9
As that balance changes through perimenopause, some people may notice histamine related symptoms more. This is still a hypothesis rather than a proven explanation.
Is plant DAO backed by the same evidence as porcine DAO?
Not yet. Almost all of the human trials used DAO from pig kidney, while plant DAO from sprouted pea or mung bean has mostly been studied in the laboratory.8
How long did people take DAO in the trials?
Most of the trials ran for a matter of weeks. The pilot study on histamine intolerance followed people for four weeks, and the larger trial now underway runs for three months.2, 7
References
- Comas-Basté, O. et al. (2020). Histamine Intolerance: The Current State of the Art. Biomolecules. mdpi.com
- Schnedl, W.J. et al. (2019). Diamine oxidase supplementation improves symptoms in patients with histamine intolerance. Food Science and Biotechnology. ncbi.nlm.nih.gov
- Izquierdo-Casas, J. et al. (2019). Diamine oxidase (DAO) supplement reduces headache in episodic migraine patients with DAO deficiency: a randomised double-blind trial. Clinical Nutrition. diposit.ub.edu
- Yacoub, M.R. et al. (2018). Diamine Oxidase Supplementation in Chronic Spontaneous Urticaria: a Randomised, Double-Blind Placebo-Controlled Study. International Archives of Allergy and Immunology. karger.com
- Okutan, G. et al. (2023). Exogenous Supplementation with DAO Enzyme in Women with Fibromyalgia: a Double-Blind Placebo-Controlled Clinical Trial. Journal of Clinical Medicine. mdpi.com
- Ferrer-Garcia, J. et al. (2025). Effect of diamine oxidase (DAO) enzyme dietary supplementation in subjects with insomnia symptoms and single nucleotide polymorphisms of the AOC1 gene: a randomised double-blind placebo-controlled study. Sleep Health. ncbi.nlm.nih.gov
- Duelo, A. et al. (2025). Study Protocol for a Prospective, Unicentric, Double-Blind, Randomised, and Placebo-Controlled Trial on the Efficacy of a Low-Histamine Diet and DAO Enzyme Supplementation in Patients with Histamine Intolerance. Nutrients. mdpi.com
- Comas-Basté, O. et al. (2020). Lyophilised legume sprouts as a functional ingredient for diamine oxidase enzyme supplementation in histamine intolerance. LWT. sciencedirect.com
- Bonds, R.S. and Midoro-Horiuti, T. (2013). Estrogen effects in allergy and asthma. Current Opinion in Allergy and Clinical Immunology. ncbi.nlm.nih.gov
- Bent, R.K. et al. (2023). Placebo-Controlled Histamine Challenge Disproves Suspicion of Histamine Intolerance. Journal of Allergy and Clinical Immunology: In Practice. pubmed.ncbi.nlm.nih.gov
- Duelo, A. et al. (2024). Pilot Study on the Prevalence of Diamine Oxidase Gene Variants in Patients with Symptoms of Histamine Intolerance. Nutrients. ncbi.nlm.nih.gov
- Jochum, C. (2024). Histamine Intolerance: Symptoms, Diagnosis, and Beyond. Nutrients. ncbi.nlm.nih.gov
