In recent years, Diamine oxidase (DAO) supplements have gained increasing attention in the fields of nutrition, gastroenterology, and integrative medicine. This surge in popularity has been largely driven by growing awareness of histamine intolerance—a condition often misdiagnosed or underrecognized—and the crucial role of DAO in its management. As science continues to unravel the biochemical underpinnings of food sensitivities, allergic reactions, and inflammatory responses, understanding the function of DAO and the potential benefits of supplementation is becoming increasingly important.

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Understanding Histamine and Its Role in the Human Body

Histamine is a biogenic amine involved in several physiological processes. It plays a critical role in immune responses, acts as a neurotransmitter in the central nervous system, and regulates stomach acid secretion and vascular permeability. It is naturally present in various foods and also produced endogenously by mast cells, basophils, and certain bacteria in the gut.

Figure 1. Left: Structure of histamine. Right: Mast cells.

Despite its beneficial roles, histamine can also become problematic. When accumulated in excess, it may lead to a condition known as histamine intolerance, which manifests in a variety of symptoms ranging from migraines and hives to gastrointestinal disturbances and cardiovascular irregularities. Unlike allergic reactions, which involve immunoglobulin E (IgE), histamine intolerance is non-immunological and primarily results from an imbalance between histamine levels and the body's capacity to degrade it.

The Role of Diamine Oxidase (DAO) in Histamine Degradation

Diamine Oxidase is the primary enzyme responsible for breaking down extracellular histamine, especially that which is ingested through food. It is predominantly produced in the small intestine, kidneys, and placenta. When functioning properly, DAO rapidly degrades histamine before it enters systemic circulation.

Figure 2. Pathway of histamine degradation. (1) Normal histamine degradation pathway by diamine oxidase (DAO) and HNMT. (2 + 3) Potential mechanisms responsible for the development of histamine intolerance in patients with AE. (2) Enhanced histamine levels might lead to a high histamine degradation mediated by DAO and blockage of DAO by imidazole acetic acid. (3) Substrate inhibition on DAO might occur by elevated histamine levels. (Maintz et al., 2005)

Causes of DAO Deficiency

The efficiency of DAO can be influenced by several factors:

• Genetic polymorphisms in the AOC1 gene (which encodes DAO)
• Chronic intestinal inflammation (e.g., Crohn's disease, celiac disease)
• Medications that inhibit DAO (such as NSAIDs, certain antidepressants, and antihypertensives)
• Nutritional deficiencies, particularly in copper, vitamin B6, and vitamin C, which serve as cofactors for DAO activity

When DAO production or activity is impaired, even histamine levels from modest dietary sources can become problematic, resulting in the aforementioned symptoms of histamine intolerance.

What Are DAO Supplements?

DAO supplements are oral formulations containing exogenous diamine oxidase, typically derived from porcine kidney extract. These supplements are designed to assist the body in breaking down histamine from food before it enters the bloodstream. They are usually taken shortly before meals and are marketed as "digestive aids" or as part of protocols for managing histamine intolerance.

Mechanism of Action: How DAO Supplements Work

DAO supplements are not absorbed systemically. Their action is confined to the intestinal lumen, where they degrade histamine from ingested food before it can cross the gut barrier into circulation. This localized mechanism ensures that supplementation directly targets dietary histamine rather than endogenous histamine produced by mast cells or basophils.

Importantly, DAO does not interfere with other histamine metabolic pathways, such as the one governed by histamine N-methyltransferase (HNMT), which operates primarily in the central nervous system. Thus, DAO supplements provide a targeted approach to histamine management with minimal systemic interaction.

Key Benefits of DAO Supplements

Relief from Histamine Intolerance Symptoms

The most well-established benefit of DAO supplementation is the alleviation of histamine intolerance symptoms. These symptoms can include:

• Gastrointestinal issues such as bloating, diarrhea, and abdominal pain
• Dermatological reactions like flushing, hives, and itching
• Neurological symptoms including headaches, migraines, and dizziness
• Respiratory symptoms such as nasal congestion and asthma-like reactions

Clinical and anecdotal evidence suggests that DAO supplements can reduce the severity and frequency of these symptoms when used appropriately alongside a low-histamine diet.

Support for Individuals with Gastrointestinal Disorders

Conditions such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and leaky gut syndrome often coincide with histamine intolerance. Inflammation and mucosal damage in these disorders may reduce endogenous DAO production. Supplementing with DAO can help restore balance and provide symptomatic relief, particularly in patients whose digestive symptoms are triggered by high-histamine foods.

Complementary Support for Food Sensitivities

While histamine intolerance is not a true food allergy, it can exacerbate or mimic allergic reactions. Individuals with multiple food sensitivities may experience cumulative histamine effects, making diagnosis and treatment challenging. DAO supplements, by reducing overall histamine load, can improve tolerance to a broader range of foods and reduce false positive responses in allergy testing.

Improved Quality of Life

For individuals suffering from chronic, unexplained symptoms, especially those that fluctuate with dietary intake, the introduction of DAO supplementation can be life-changing. Greater freedom in food choices, reduced medication dependency, and alleviation of symptoms such as fatigue and brain fog can collectively lead to a substantial improvement in overall well-being and mental health.

Evidence Supporting DAO Supplementation

Case 1: Diamine oxidase supplementation improves symptoms in patients with histamine intolerance

Schnedl et al., 2019. doi:10.1007/s10068-019-00627-3

This open-label pilot study investigated the effect of oral diamine oxidase (DAO) supplementation in 28 patients with histamine intolerance (HIT), a condition linked to excess histamine in the body. Participants took DAO capsules before meals for 4 weeks, followed by a period without supplementation. Symptom severity was assessed using a questionnaire covering 22 symptoms across four categories.

The results showed a significant improvement in all symptoms and their intensities during the supplementation phase. When DAO supplementation was stopped, symptom scores increased again. The study concludes that oral DAO supplements can significantly reduce both the presence and severity of HIT-related symptoms.

Figure 3. Scatter-plot of symptoms sum-score of the most common and diagnostic 5 GI symptoms (bloating, postprandial fullness, abdominal pain, belching and diarrhea) for HIT throughout the study period of 8 weeks. Oral supplementation of DAO from visit 1 to visit 3 (V1 to V3); no oral DAO from visit 3 to visit 5 (V3 to V5). (Schnedl et al., 2019)

Case 2: Diamine oxidase supplement reduces headache in episodic migraine patients with DAO deficiency: A randomized double-blind trial

Izquierdo-Casas et al., 2019. doi:10.1016/j.clnu.2018.01.013

This randomized, double-blind study evaluated the effectiveness of diamine oxidase (DAO) enzyme supplementation as a preventive treatment for migraines in patients with DAO deficiency. One hundred participants with episodic migraines and confirmed low DAO activity were divided into two groups, receiving either DAO supplements or a placebo for one month. Key clinical outcomes assessed included the duration and frequency of migraine attacks, pain intensity, and the use of triptan medications.

The study found a statistically significant reduction in migraine duration among patients taking DAO supplements, with average pain hours decreasing from 6.14 to 4.76. In contrast, the placebo group experienced a smaller, non-significant reduction. Additionally, fewer patients in the DAO group required triptan medication, although the number of attacks and pain intensity scores were similarly reduced in both groups. No adverse effects were reported with DAO use. The results suggest DAO supplementation may help shorten migraine duration in patients with DAO deficiency, though longer-term studies are needed to confirm its efficacy.

Figure 4. Box plot for the duration of migraine attacks (in hours of pain) in placebo and DAO groups one month before (C1) and after one month of treatment (C2). The bottom and top of the box (interquartile range) are the percentile 25 and the percentile 75, respectively. Central line represents the median. Lines extending vertically from the boxes (whiskers) indicate variability outside the interquartile range. Outliers are plotted as circles and extreme outliers as asterisks. (Izquierdo-Casas et al., 2019)

How to Use DAO Supplements Effectively

• Timing and Dosage: DAO supplements are typically taken 15 to 30 minutes before meals, especially those suspected to be high in histamine. Dosages range from 4,000 to 20,000 HDU (Histamine Degrading Units), depending on the product and individual response.
• Combining with a Low-Histamine Diet: DAO supplementation is not a license to consume unlimited histamine-rich foods. For best results, it should be used as an adjunct to a low-histamine or histamine-liberator-restricted diet. Examples of high-histamine foods include aged cheeses, smoked meats, fermented products, alcohol, and certain fruits and vegetables.
• Monitoring and Adjusting: Because individual responses vary, it is advisable to monitor symptoms and adjust both diet and supplement regimen accordingly. Working with a healthcare practitioner—ideally one familiar with histamine-related disorders—is recommended for optimal outcomes.

Safety and Side Effects

DAO supplements are generally well-tolerated. Since the enzyme acts locally in the digestive tract and is not absorbed into the bloodstream, the risk of systemic side effects is low. However, certain considerations should be noted:

• Allergic Reactions: Individuals allergic to pork should avoid porcine-derived DAO.
• Pregnancy and Lactation: While the placenta produces high levels of DAO naturally, supplementation during pregnancy should only occur under medical supervision.
• Drug Interactions: Though rare, it's wise to consult a physician if taking medications known to affect histamine metabolism.

Limitations and Considerations

DAO supplements are not a panacea. They do not address histamine produced internally due to mast cell activation or allergic reactions. Furthermore, variability in supplement quality, dosing standardization, and labeling accuracy remains an issue in the nutraceutical market.

Additionally, there is a need for broader awareness and diagnostic criteria for histamine intolerance. DAO testing, while available, is not yet standardized or widely accepted in clinical practice, making diagnosis and treatment often a matter of trial and error.

In summary, diamine oxidase supplements represent a valuable tool in the management of histamine intolerance and related conditions. By enhancing the breakdown of dietary histamine, they provide relief for a wide spectrum of symptoms affecting multiple body systems. Though not without limitations, their safety profile, targeted mechanism of action, and growing clinical evidence make them a compelling adjunct for individuals struggling with unexplained food reactions, migraines, or gastrointestinal symptoms.

As awareness continues to grow and research evolves, DAO supplementation may become a standard recommendation for patients with functional gut disorders, chronic inflammatory states, and idiopathic hypersensitivity reactions. Until then, informed usage, underpinned by clinical reasoning and dietary awareness, remains the cornerstone of effective histamine management.

Creative Enzymes offers high-quality DAO enzymes sourced from pea sprouts and porcine kidney, suitable for various applications. Contact us for any questions or requests!