How Does Histamine Connect to Cancer?

Researchers in Finland, Sweden, and Switzerland have shown how the most aggressive form of brain cancer, glioblastoma, can be stopped in its tracks by an antihistamine drug that triggers a form of cell death caused by leaky lysosomes. Though this was a mouse study as most initial studies are, it is very promising. Headed by Pirjo Laakkonen, PhD, at the University of Helsinki, the studies demonstrated an association between the fatty acid binding protein – mammary-derived growth inhibitor (MDGI) and poorer prognosis in patients.

MDGI shuttles fatty acids into cells where they, among other things, become integral components of lysosomal membranes. Lysosomes are little organelles inside our cells that contain numerous digestive enzymes that remove waste and recycle worn-out cellular parts to help keep a cell alive. Healthy lysosomal membranes enclose these enzymes and release them inside the cell only when necessary. If we could destabilize these membranes, we could spill the content of the lysosomes (the digestive enzymes) into the cell and essentially stimulate apoptosis (cell death).

The study focused on Glioblastoma, one of the most aggressive brain cancers we face. The team’s studies found that blocking the MDGI gene (thereby NOT allowing fatty acids into the cell as readily) in glioblastoma cell lines disrupted fatty acid transport into cells and their incorporation into lysosomal membranes, which compromised lysosomal membrane composition and integrity, resulting in lysosomal membrane permeabilization (LMP). LMP is an intracellular cell death pathway triggered when the lysosome contents leak into the cell. The team’s subsequent studies in cell lines and in live mice found that treatment with the anti-histamine Clemastine (Dayhist, Dayhist Allergy, and Allergy Relief), an older type of antihistamine that can cross the blood-brain barrier, effectively mirrored the effects of MDGI, triggering LMP and causing glioblastoma cell death, without harming healthy cells.

In non-brain tumors where crossing the blood-brain barrier is not an issue, theory may admit that any anti-histamine, drug or natural histamine blockers, may illicit the same response in many tumors. Should all cancer patients go on anti-histamine medications or histamine blocking nutrients? That remains to be answered with more studies but this looks very promising!

Through further experiments the investigators showed that MDGI was essential to glioma cell survival. Glioma cells engineered to overexpress MDGI also grew more aggressively and invasively than non-engineered tumor cells following implantation into experimental mice. Conversely, silencing the MDGI gene dramatically reduced the viability of patient-derived glioma cells and blocked cell proliferation. Human glioblastoma cells lacking MDGI were also unable to form tumors when transplanted into mice. “These results demonstrate a dose-dependent effect of MDGI silencing on glioblastoma cell growth and viability.”

See more on this study here:

Histamine’s double-edged sword

Our body has two distinct methods of clearing things that could bring it harm: our immune system kills living toxins (bacteria, viruses, parasites…) and our detoxification pathways clear non-living toxins (chemicals, heavy metals, drugs…). We have one other system that sits somewhere in the middle between the immune and the detoxification systems that helps with both: the mast cells.

Mast cells make a chemical called histamine, which has numerous, distinct, beneficial roles. As part of the immune response, histamine doesn’t kill bad guys itself. It draws fluid to tissues by rendering capillaries more permeable making it easier for immune killer cells to ‘ride the waves’ to a nasty bacteria to destroy. Histamine’s immune and detoxification connection runs deep as its functions vary depending on tissue site and specific receptors on the outside of cells to which it binds.

In the brain, histamine can keep us awake, is involved in our reflex reaction to pain, temperature changes, vibration, and hormone balance. It affects our appetite, helps control gastric secretions helping balance blood pH, and serves as a gatekeeper for neurotransmitters that balance mood, concentration, and focus. (1-4) This makes sense if you think about it. If exposed to an infection, a chemical irritant, something that stimulates pain, or a dangerous vibration felt in the legs or feet, one would need to wake the brain to increase circulation, and flee such harm, buffer the blood to maintain life, and alert us to possible threat.

Histamine so serves in “flight or fight” mechanism to ensure life. It’s role in the periphery demonstrates this as well. If histamine attaches to one receptor (there exists 4 main histamine receptors, H1, H2, H3, and H4 with different functions) it is vasoconstrictive enabling quick movement of blood to extremities to fuel muscles for a quick ‘get away’. Attaching to a different receptor, histamine dilates small vessels and constricts the bronchial tubes as an immediate protective “freeze” mode. It enhances a hypersensitivity to harmful stimuli creating its most known response – the histamine rash and itch. This would serve to keep us safe from poisonous fauna and teach us that those berries are possibly not edible.

However, histamine, when created in excess, over a period of time, will create an environment of chronic inflammation, disturbing cell-to-cell communication and thereby changing its function. Cell function is dependent on their interaction with the environment. If we think of individual cells as people, an organ could be equivalent to a crowded stadium gathered to observe a football game. Communication to your friend seated next to you may be relatively easy during slow play and more challenging when the home team is guarding the one yard line. The roar lifts, chants of “de-fence” try to drown out the opposing quarterback’s play call, and one can barely hear themselves think as you stand, scream, cheer, and cover your ears. A touchdown is scored and silence calms the saddened crowd. All sit. Equilibrium ensues.

If we could liken this scenario to cells in the milieu of the body with thousands upon thousands of conversations taking place, sodas being ordered from barkers selling cold beer and peanuts, opposing fans arguing, people shuffling between rows and hundreds of other activities we would need to envision a million stadiums with hundreds of millions of observers to understand the complexity of the human body. Think of how difficult is communicate when the opposing team has the ball at the one-yard line and this is similar to a cell receiving correct information in a chaos of chronic inflammation.

When histamine levels increase both within and between the cells, causing fluid to accumulate, our body responds with an intricate system to remove the water and regain equilibrium. It signals a special gene called the HNMT gene to make an enzyme that quickly drops histamine levels and fluids decrease accordingly. The crowd sits during a lull in the game. So it is, when we are exposed to allergens, histamine is released, bringing a washing of fluid, the HNMT gene makes its histamine-degrading enzyme, and tissues are cleansed, the cells are bathed, and balance is achieved. This cycle of the histamine cleanse helps us get rid of things that we eat and breath that are not beneficial.

Histamine’s relationship with the stress response brings a bit of clarity on how the system can go wrong. In its protective role in the “flight, fight or freeze” response, histamine is released with an up-tick of the sympathetic nervous system (SNS). The SNS controls adrenal output and cortisol release. When we perceive danger, SNS stimulation protection raises blood pressure, shunts blood to extremities, and dilates pupils enabling us to best survive the assault. All functions considered non-essential to survival are suppressed. Our brain conserves energy. One need not reproduce when chased by a tiger – shut that down. A tiger is going to eat me; who cares if I die from mercury poisoning in ten years, shut down detoxification! I’m soon to be food to a predator, stop all wasted energy on digestion, immune function and fighting chronic disease.

By now you’re probably understanding how the modern, chronic predators of running a business, raising a family, stressful, abusive relationships, paying the bills and filling out tax forms can influence cell communication and our ability to fight disease. One could argue that modern society has created its own tigers and even rewards the increased productivity gained by the chase. The downfalls of such a system are evidenced in the rise of chronic disease including cancer.

Higher histamine levels together with its stimulation of the H4 cell receptors have been reported in many different tumors including melanoma, colon, pancreatic, and breast cancer. Moreover, histamine content increased unequivocally in other human cancer types such as ovarian, cervical and endometrial carcinoma in comparison with their adjoining normal tissues suggesting the participation of histamine in carcinogenesis.

Histamine’s story worsened when recent studies noted that most malignant cell lines express their own histamine-synthesizing enzyme, L-histidine decarboxylase (HDC) and contain high concentrations of endogenous histamine that can be released to the spaces between the cells (5).

Why would a cancer cell want to create commotion and disturb communication between itself and the body? One might theorize that histamine may regulate diverse biological responses related to tumor growth. Growing cancers require angiogenesis, cell invasion, migration, differentiation, stunted apoptosis and modulation of the immune response, indicating that histamine may be a crucial mediator in cancer development and progression. Many cancers have even revealed a much higher concentration of histamine receptors on their cell membranes, further suggesting that histamine stimulates proliferation.

This paper is to reveal, once again, that no bodily function should be labeled as “good” vs “bad”. It is an imbalance, usually due to some environmental force acting on the body, that creates undesirable circumstances. If the imbalance tips histamine levels towards cancer proliferation, how can we target histamine in cancer therapy? One would immediately think that pharmacological anti-histamines might be in order however, anti-histamine medications only target H1 and H2 histamine receptors. So, while they may reduce a stuffy nose, they do nothing to help a cancer patient. Novel approaches need to be investigated to help target H4 receptors, alter and their ligands (.

Here are a few ideas:

  • The use of DAO enzyme both orally and as a rectal suppository. DAO is the specific enzyme made by the HNMT gene in the tissues as well as the ABP gene in the gut cavity. The problem with oral dosing has been its failure to be absorbed and enact any benefit to the tissues. Genetic aberrations (SNPs) or defects (mutations) may result in a lesser ability to produce such enzyme, a decreased capacity to clear histamine and a tendency to histamine related disorders including (possibly) cancer.
  • The DAO enzyme requires flavin adenine dinucleotide (FAD) as its cofactor and FAD requires the B-vitamin riboflavin (B2) for its synthesis. So, adding a whole-food source of B2 may also be in order.
  • A novel use of Rife frequencies in an attempt to regain the normal synchronicity of over-productive mast and basophil cells.
  • Use of relatively higher dose, unique enzymes (beta glucanase, chitinase, xylanase, alpha galactosidase, phytase, astrazyme, serratiopeptidase, peptidases, and proteases) orally to aide in the reduction of histamine stimulating antigens in the digestive tract, break biofilms (histamine-responsible) surrounding the cancer, and help bond to receptor sites on the cancer.
  • Coupling nutritional therapies with Sauna Therapy which has been shown to decrease mast cell activation (6)
  • Stimulation of parasympathetic receptors to reduce sympathetic dominance and lower histamine release.
  • Employing the Fasting Mimicking Diet (FMD) as well as Time Restricted Eating (TRE).
  • Cognitive, mindful, meditation and prayer.
  • A deeper look at genetic pathways gives us other clues to assist DAO production. The HNMT and ADH genes require supplemental zinc, vitamin C, magnesium, and thiamine.
  • Quercetin, a natural compound found in apples, onions, and capers is a wonderful natural histamine reducer. Unfortunately, it is poorly absorbed (about 1%) so use as a suppository may prove more beneficial.
  • Holy Basil, Milk Thistle, and EGCg (from green tea extract), Aloe, Bromelain, Stinging Nettle, Pine Bark Extract, Marshmallow Root, Bitter Orange, and Licorice can be helpful as may Ellagic acid found in raspberries, strawberries, walnuts, mango kernel, and pomegranate.


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  1. Panula P, Chazot PL, Cowart M, et al. (2015). “International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors”. Rev67(3): 601–55.
  2. Wouters MM, Vicario M, Santos J (2015). “The role of mast cells in functional GI disorders”. Gut65: 155–168. doi:10.1136/gutjnl-2015-309151. PMID 26194403.
  3. Blandina, Patrizio; Munari, Leonardo; Provensi, Gustavo; Passani, Maria B. (2012). “Histamine neurons in the tuberomamillary nucleus: a whole center or distinct subpopulations?”. Frontiers in Systems Neuroscience.
  4. Maguire JJ, Davenport AP (29 November 2016). “H2receptor”. IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 20 March 2017.
  5. Bartholeyns and Fozard, 1985; Garcia-Caballero et al., 1994; Engel et al., 1996; Rivera et al., 2000; Falus et al., 2001; Pós et al., 2004
  6. Beneficial effect of sauna therapy on severe antihistamine-resistant chronic urticarial, Eli Magen MD, Leumit Health Services, and Allergy and Clinical Immunology Unit, Barzilai Medical Center, Ashkelon, affiliated with Faculty of Health Sciences, Ben-Gurion University of Negev, Beer Sheva, Israel