Why Am I Reacting to Everything? How Total Load Sets Off the Mast Cells, with Dr. Bruce Hoffman (Part 1)
This is Part 1 of a two-part conversation episode of The Biology of Trauma® podcast with Dr. Aimie Apigian and Dr. Bruce Hoffman.
You react to everything because your mast cells are responding to your total load, and that load has crossed their threshold. Stress from early trauma or daily life is the largest single trigger, and toxins, processed food and lost natural rhythms add to the same total.
It often starts with one food. Then alcohol, a medication, a supplement, heat, exercise, fragrance, hormonal shifts, stress. The list of what the body tolerates gets shorter while the list of triggers gets longer.
Removing triggers is the usual answer. If that is all we do, the world gets smaller and smaller. The more useful question is why the body became so reactive in the first place, and what role the nervous system plays in setting that threshold.
Dr. Bruce Hoffman, MSc, MBChB, FAARM, IFMCP, practiced integrative and functional medicine in Calgary for 30 years and directed the Hoffman Centre for Integrative Medicine. He specialized in complex chronic illness, including mast cell activation, mold illness and Lyme disease. He is a co-author of the global Consensus-2 paper on diagnosing mast cell activation syndrome.
Mast cells are immune cells that sit where the body meets the outside world, wired closely to the nervous system. Stress, from early developmental trauma or present-day life, is the largest trigger of their activation. They respond to total load, so symptoms come and go as that load changes. A sensitized system can react to the perception of a threat alone, which is why calming the nervous system is part of calming the mast cells.
WHY AM I REACTING TO EVERYTHING?
Your mast cells are reacting to your total load, and the load has crossed a threshold. Dr. Hoffman sees that load rising at every level of life at once.
He names the layers. Environmental: pesticides, glyphosate and a growing toxic load. Physical: ultra-processed food, nutrient gaps, hormone imbalances. And a loss of natural rhythms: indoor living, LED light, rubber-soled shoes, food available around the clock. "And we completely unwilded," he says. He also names non-native electromagnetic fields as a major trigger, a view the research has not yet settled.
Mast cells can also get primed. "Mast cells get primed and they just trigger happy," Dr. Hoffman says. Add another load on top, and even the slightest trigger sets them off. That is how the list keeps growing.
Total load: the combined stress on the body from every source at once, including toxins, food, light and sleep patterns, past trauma and present stress. Mast cells react when the total crosses their threshold.
CAN STRESS TRIGGER MAST CELL ACTIVATION?
Yes. In Dr. Hoffman's experience, stress is the primary and largest trigger of mast cell activation, whether it is present-day stress or early developmental stress.
Early developmental stress sets the stress axis to run high. Norepinephrine and cortisol stay up, and the body stays primed for fight or flight, or drops into dorsal vagal shutdown. In his practice treating chronic complex illness, he found it impossible to work around.
He is clear about what kind of problem this is. "And it's very biological. You know, it's not psychological necessarily. It's biological."
Research supports a stress and mast cell link. In healthy volunteers at KU Leuven, public-speaking stress raised gut permeability in people with a strong cortisol response. The stress hormone CRH did the same, and a mast cell stabilizer blocked that effect.
WHAT HAPPENS INSIDE A CELL WHEN THE BODY SENSES TOO MUCH DANGER?
The cell shifts into a protective shutdown called the cell danger response, and it gets damaged in the process.
A stress response makes the body more efficient. The cell danger response protects the cell and costs it. Free radicals damage the cell membrane and the mitochondria. The damaged cell sends out alarm signals called damage-associated molecular patterns, or DAMPs.
Those signals set off nearby cells and mast cells. Mast cells release chemicals that cause more damage, and that damage goes back to the first cell. The loop keeps itself going. Part of the damage lands on mitochondrial DNA, an emerging area of health research.
Cell danger response: a protective shutdown a cell enters when it senses more danger than it can handle, first described by Dr. Robert Naviaux. Degranulation: a mast cell releasing its stored chemicals, which is what causes symptoms.
HOW DO MAST CELLS CAUSE SYMPTOMS?
Through a very large number of chemical messengers, which Dr. Hoffman groups into three routes.
Allergic. IgE-driven and often histamine-driven: itching, hives, swelling.
Inflammatory. Tryptases, proteases and interleukins.
Growth signaling. Growth factors that Dr. Hoffman links to pain conditions such as endometriosis and fibromyalgia.
Together, with oxidative damage already running high, they feed an ongoing loop of inflammation. His conclusion is that the incoming danger signal has to come down.
WHY WOULD CHILDHOOD TRAUMA SHOW UP IN MY CELLS TODAY?
Unresolved trauma keeps the body in survival mode, and survival mode makes oxidative damage faster than the body can repair it.
Oxidative damage is a normal by-product of making energy. It rises sharply during a survival response and gets repaired when we can rest in a calm, connected state. When that state is out of reach, the damage builds.
Dr. Aimie calls this the thread that runs from complex chronic illness back to childhood: "It literally is the footprint of our past on our present biology."
Many patients carry more than early trauma. Dr. Hoffman rarely met a complex chronic illness patient without it, and most also carried inherited family trauma and medical PTSD from being told nothing biological was wrong.
WHY DO MY SYMPTOMS COME AND GO?
The threshold for a reaction moves every day with total load. One day it is a food. The next it is an airport and a flight at 30,000 feet.
Dr. Hoffman calls this waxing and waning the cardinal feature of mast cell activation. Some people reach a point where they react to everything and sit in a constant inflammatory, shutdown state.
For those most reactive patients, his clinic built self-regulation into care. Under supervision, patients used devices such as HeartMath to self-regulate, received IV saline for dysautonomia or POTS symptoms and mast cell stabilizing medication, and then met the trigger they had reacted to. "It took up to a year, though, Aimie. It wasn't overnight."
Allostatic load: the total wear on the body from all the stress it is carrying at a given time. It changes day to day.
CAN MAST CELLS REACT TO A THREAT THAT ISN'T THERE?
Yes. The perception of threat alone can make mast cells release their chemicals.
"You don't even have to have the threat. You can just think about it and your mast cells degranulate," Dr. Hoffman says. "It's not ... something wrong with the patient."
People who have lived with long-term danger scan constantly, inside and outside the body. When something registers as danger, the stress response fires and mast cells answer. Dr. Hoffman offers a likely mechanism, amygdala and sympathetic activation driving stress hormone release, while noting he cannot be absolutely sure.
Mast cells sit at the blood-brain barrier, on the brain's lining and beside microglia. He cites recent research showing that neurological symptoms, from headaches to brain fog to jaw tightness, are among the most common in mast cell activation.
Neuroception: the nervous system's automatic scan for safety and danger, running below conscious awareness. The term comes from Dr. Stephen Porges.
WHY WOULD ADRENALINE BECOME A TRIGGER?
Dr. Aimie's view is that mast cells can come to expect overwhelm from a stress response, so adrenaline itself starts to act as a cue of danger.
In somatic work this is called coupling. Dr. Aimie describes it this way: "it's almost as if adrenaline itself is now a cue of danger to the mast cells." Cells that could not sustain high stress in the past now respond to smaller amounts.
Dr. Hoffman compares this priming to what happens to microglia after a head injury. Fear of the next reaction adds its own load, and Dr. Aimie sees anticipation alone set off symptoms, especially in caregivers facing a coming loss.
HOW DO MAST CELLS KEEP THE NERVOUS SYSTEM ON ALERT?
Through a loop that runs in both directions.
Nerves release substance P, which activates mast cells. Dr. Hoffman names the receptors involved, including MRGPRX2. Mast cells then activate microglia, the brain's immune cells. The inflammation keeps the nervous system on alert, which sets off more mast cells.
Dr. Hoffman's conclusion: "you've got to down regulate the nervous system while stabilizing the mast cells." Calming the nervous system is part of calming the reactions.
WHY DO I REACT TO THE SUPPLEMENTS MEANT TO HELP ME?
Often the reaction is to the excipients: the dyes, fillers and capsules that carry the ingredient.
Red and blue dyes, gelatin capsules, silica and even "hypoallergenic" fillers can set off a reactive system. Dr. Hoffman points to famotidine (Pepcid), useful short term for mast cell gut symptoms, which comes with many added ingredients.
His approach is to use a compounding pharmacy: start from the raw ingredient, choose a capsule the person tolerates, and use an inert filler when one is needed. He borrows Dr. Afrin's rule: "The cardinal rule of mast cells is try, try and try again. Don't give up."
Excipients: the inactive ingredients in a medication or supplement, such as dyes, fillers, binders and capsule materials.
WHERE DOES HOPE COME FROM FOR SOMEONE THIS REACTIVE?
From a roadmap. Dr. Hoffman takes a three-hour history, looks at every layer involved, and fills in the gaps.
"It changes outcomes because the roadmap creates safety," he says. When patients see that someone knows the path, the hypervigilance cools, and the rest of the work can begin.
Part 2 covers the order he used with his most complex patients, and why the most common starting point can make people worse.
Key Takeaways
People react to more things because mast cells respond to total load, and load is rising at every level of modern life.
Stress, from early developmental trauma or daily life, is the largest single trigger of mast cell activation in Dr. Hoffman's experience.
A cell under too much danger enters the cell danger response, gets damaged, and sends out alarm signals that set off mast cells.
Mast cells cause symptoms through allergic, inflammatory and growth-signaling routes.
Unresolved trauma raises oxidative damage past what the body can repair: the footprint of the past on present biology.
The threshold moves daily with allostatic load, so waxing and waning symptoms are the hallmark.
Mast cells can release their chemicals from the perception of threat alone. In Dr. Aimie's view, adrenaline itself can become a cue of danger.
Mast cells and the nervous system activate each other, so both need calming together.
Reactions to supplements are often reactions to the dyes, fillers and capsules.
A clear roadmap creates safety, and safety cools hypervigilance.
Notable Quotes
"You have immune cells that can be so sensitized from your past unresolved trauma that they are reacting to the thought of being triggered." — Dr. Aimie Apigian
"If we only keep removing triggers, our world just becomes smaller and smaller." — Dr. Aimie Apigian
"You don't even have to have the threat. You can just think about it and your mast cells degranulate." — Dr. Bruce Hoffman
""Oxidative damage is the footprint of our past on our present biology." — Dr. Aimie Apigian
“The threshold is always shifting. It's never static. That's why the cardinal feature of mast cell activation is waxing and waning of symptomatology." — Dr. Bruce Hoffman
"And so we've gone indoors, we switched on the LED lights, we've got our Wi-Fi router, we got rubber-soled shoes. We got refrigerators where we can eat 24/7. And we are completely unwilded." — Dr. Bruce Hoffman
"they're always most commonly suffering from medical PTSD, from being shunted from pillar to post and being told there's nothing biological." — Dr. Bruce Hoffman, on patients with chronic complex illness
"Calming the nervous system is part of calming the reactions of our mast cells." — Dr. Aimie Apigian
"The cardinal rule of mast cells is try, try and try again. Don't give up." — Dr. Bruce Hoffman, citing Dr. Lawrence Afrin
"A roadmap changes outcomes because the roadmap creates safety." — Dr. Bruce Hoffman
Episode Takeaway
More and more people tell me they are reacting to everything. It starts with one food. Then a medication, a supplement, heat, a fragrance, a hard week. The list of what the body can tolerate gets shorter, and the usual answer is a longer list of things to avoid.
I understand why. Avoiding a trigger brings relief. But if we only keep removing triggers, our world just becomes smaller and smaller. I wanted this conversation because I wanted to understand what it takes to help our bodies become more resilient again.
What Dr. Hoffman described is a body carrying a total load. Toxins in our food and homes. Food that feeds us less. Lives lived indoors, away from daylight and the rhythms we were built for. Stress from today, and stress stored from long ago. Mast cells respond to all of it added together, and when the total crosses a threshold, they release their chemicals. That threshold moves every day, which is why a food that was fine on Monday sets off symptoms on Thursday.
The part I most want you to hold is this one. Your mast cells can react to the thought of being triggered. That is real, and it is biological. A body that has lived with danger for a long time keeps scanning for it, and when something registers as danger, the mast cells answer. For some people, it is almost as if adrenaline itself has become the cue. It is as if the cells learned that a stress response ends in overwhelm, so now even a small one reads as a threat.
This is why I talk about the footprint of the past on our present biology. Unresolved trauma keeps us in survival mode, and survival mode creates more oxidative damage than we can repair. That damage is one more signal of danger to the cells, and the loop keeps itself going. It also runs in both directions. The nervous system sets off the mast cells, and the mast cells keep the nervous system on alert.
So calming the nervous system is part of calming the mast cells. The two go together.
In the Biology of Trauma® framework, the work follows an order: safety, then support, then expansion. Dr. Hoffman saw the same thing with his patients. For someone who reacts to everything, that means creating enough safety for the body to stop scanning so hard, and then building capacity from there.
If you recognize yourself here, the Foundational Journey is where that work begins. It builds the safety and capacity the rest of the work depends on. In Part 2, Dr. Hoffman shares the order he used with his most complex patients, and why the most common starting point can make people worse.
Frequently Asked Questions
Why does my body react to everything?
Your mast cells are responding to your total load, and that load has crossed their threshold. Toxins, processed food, indoor living, past trauma and present stress all add to the same total. Past that point, even a small exposure can set off a reaction.
Can stress alone trigger a mast cell reaction?
Yes. Dr. Bruce Hoffman sees stress as the largest single trigger of mast cell activation, and the perception of a threat can be enough. He describes this as a biological response.
Why do mast cell symptoms come and go?
The threshold for a reaction moves with total load, which changes every day. Dr. Hoffman calls this waxing and waning the cardinal feature of mast cell activation.
How are mast cells connected to the nervous system?
Mast cells sit near nerves, at the blood-brain barrier and beside microglia. Nerve signals such as substance P activate mast cells, and mast cell chemicals keep the nervous system on alert, so each drives the other.
Can childhood trauma affect the immune system as an adult?
Early developmental stress sets the stress axis to run high, and unresolved trauma keeps the body in survival mode. That raises oxidative damage, which feeds the loop that sets off mast cells.
Why do I react to supplements and medications?
Often the reaction is to the excipients: dyes, fillers and capsules. A compounding pharmacy can prepare the raw ingredient in a capsule and filler the person tolerates.
Why do headaches and brain fog show up with mast cell activation?
Mast cells sit on the blood-brain barrier and the lining of the brain, next to microglia. When they release their chemicals, the brain's immune cells activate. Dr. Hoffman cites recent research showing neurological symptoms are among the most common in mast cell activation.
In This Episode
00:00 Why are so many people reacting to everything?
02:52 How does early childhood trauma load the mast cells?
05:39 What is the cell danger response?
07:43 How do mast cells cause symptoms?
09:16 Why does childhood trauma show up as oxidative damage today?
11:38 Why do so many chronically ill patients carry medical trauma?
12:32 Why does the trigger list keep getting longer?
14:39 What sets the threshold for mast cell activation?
17:58 Can mast cells react to a threat that is only predicted?
19:47 How does adrenaline become a cue of danger?
22:19 How do mast cells keep the nervous system on alert?
24:10 Why do people react to the supplements meant to help them?
27:21 Why does a roadmap create safety?
Resources and Guides
Get the free Companion Guide to Mast Cell Reactivity. Every term from Parts 1 and 2, explained in plain words in the order it comes up, with the visuals and resource links.
Get The Biology of Trauma book. Chapter 4 covers the cell danger response. Chapter 8 covers microglia and mast cells.
Never Bet Against Occam by Dr. Lawrence Afrin, recommended by Dr. Hoffman.
Mast Cell Activation Syndrome and Excipients, by Dr. Bruce Hoffman.
HeartMath, used in Dr. Hoffman's clinic for self-regulation.
Your Host
Dr. Aimie Apigian, MD, MS, MPH is a double board-certified physician in preventive medicine and addiction medicine with master's degrees in biochemistry and public health. She is the author of The Biology of Trauma, the founder of Trauma Healing Accelerated, and the creator of the Biology of Trauma® framework. She guides self-help individuals and trains practitioners in safely opening up stored trauma that has become biology. Her work came out of her own experience of being a physician with stored trauma she did not recognize as trauma.
Related Episodes
Episode 113: Hidden Triggers: How Mold and Lyme Create A Sensitive and Reactive Personality with Dr. Neil Nathan. For the listener who suspects mold or Lyme sits under the reactivity.
Why Do I Avoid the Doctor Now? Medical Trauma and Post-Intensive Care Syndrome, with Dr. James Jackson (Part 1). For anyone carrying the medical trauma Dr. Hoffman describes.
Research
Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014;16:7-17. The model behind the cell danger loop in this episode.
Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014;63(8):1293-1299. A human study linking psychological stress and the stress hormone CRH to gut permeability through mast cells.
McNeil BD, Pundir P, Meeker S, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519(7542):237-241. On MRGPRX2, a mast cell receptor Dr. Hoffman names.
Schofield JR, Afrin LB. Recognition and management of medication excipient reactivity in patients with mast cell activation syndrome. Am J Med Sci. 2019;357(6):507-511. On reactions to dyes, fillers and capsules.
Transcript
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