The kava article is still on its way. Part of the delay is that I’ve been rethinking how I do research, prompted by a new Substack feature called the paid subscriber perk. Mine is an invitation to “borrow my notes”: with each article, paid subscribers will receive a PDF of my refined research notes, linked directly at the end of the post, because nobody needs a scavenger hunt.

(If you scroll down, you’ll find my notes for this article!)

Preparing notes for someone else to read has changed how I read. I find myself slowing down, paying closer attention to which details I’d want you to carry into your own reading, and asking more often why a particular finding matters.

That slower way of reading shaped this piece. It grew out of a recent assignment exploring Hashimoto’s thyroiditis and the complementary interventions that have been studied for its management. Paper after paper measured success the same way, through changes in thyroid hormone levels and antibody concentrations. Many of the results were encouraging. Still, I kept returning to a question the data rarely answered: OKAY, good job, acupuncture, BUT how did the patient feel?

You can hand me a laboratory report that looks pristine, and I can still feel like hot garbage that’s been rolling around the streets for three to four business days. Lab values are enormously useful, but they are stand-ins for something harder to measure, and a stand-in can improve while the experience it’s meant to reflect stays exactly the same.

The thyroid literature has been grappling with this very problem. A subset of people with Hashimoto’s continue to experience fatigue, brain fog, cold intolerance, low mood, and sluggish digestion even when their thyroid hormone levels sit comfortably within the normal range.

None of this is an argument against levothyroxine, which remains appropriate and effective for a great many people. (Please don’t adjust your thyroid medication based on something you read on Substack, this included.)

What interests me is the space between two statements we often treat as interchangeable, “your labs are normal” and “you are well,” and what it might look like to take that space seriously.

In this piece:

• What it means to have normal thyroid labs while still experiencing symptoms

• Why TSH reflects the pituitary more than the rest of the body

• How T4 is converted to T3, and what happens when conversion falls short

• The possible role of ongoing autoimmunity

• How food, coffee, and supplements affect levothyroxine absorption

• What the complementary research measured, and what it left out

Location of the thyroid gland

What Do the Labs Tell Us?

Hashimoto’s thyroiditis (also called chronic autoimmune or chronic lymphocytic thyroiditis) is a condition in which the immune system gradually damages the thyroid gland. Lymphocytes, a type of white blood cell, move into the thyroid tissue, and over time the gland can become fibrotic (scarred) and atrophied (shrunken) (Zhang et al., 2025). Both immune cells and antibodies contribute to that damage (Luo et al., 2024). It’s the most common cause of hypothyroidism, an underactive thyroid, in countries with adequate iodine intake, and it affects women at least ten times more often than men (Luo et al., 2024; Zhang et al., 2025). (Yet another category we’re winning, ladies. Lucky us.)

The lab values that come up throughout this piece:

• TSH (thyroid-stimulating hormone): released by the pituitary gland in the brain to tell the thyroid how much hormone to make. When thyroid hormone runs low, TSH rises.

• T4 (thyroxine): the main hormone the thyroid produces. “Free T4” is the portion circulating unbound in the blood and available to tissues.

• T3 (triiodothyronine): the active form of thyroid hormone. Most of it is made from T4 outside the thyroid.

• TPOAb and TgAb: antibodies against thyroid peroxidase and thyroglobulin, two proteins the thyroid uses to make hormone. Their presence tells us the immune system is targeting the thyroid.

These antibodies can show up long before thyroid function declines. Higher titers (the concentration of antibodies in the blood) are associated with greater thyroid damage, which keeps the immune system engaged, a self-reinforcing cycle that may eventually lead to hypothyroidism (Luo et al., 2024).

Once hypothyroidism develops, the standard treatment is levothyroxine (often abbreviated LT4), a synthetic version of T4 (Delgadillo & Agrawal, 2026). It’s typically started when TSH stays elevated or when symptoms appear, and for most people it brings hormone levels back into range and relieves symptoms. Clinicians describe this state as euthyroid, meaning thyroid hormone levels fall within the normal range.

However, for an estimated 5 to 10% of people with Hashimoto’s, fatigue, weight gain, cold intolerance, constipation, and depression persist even after TSH and free T4 return to normal (Zhang et al., 2025). Hormone replacement alone doesn’t seem to resolve these symptoms (Luo et al., 2024), and some people on long-term levothyroxine continue to report trouble with memory, focus, and overall well-being, often with antibody levels that remain elevated.

Five to ten percent can sound modest. Considering how common Hashimoto’s is, though, it represents a lot of people whose lab results and lived experience are telling two different stories. I think that discrepancy deserves to be taken seriously on its own terms.

The editor is currently being significantly annoying and not letting me put a caption to my URL links, so all image sources will be cited in my references, sorry.

What TSH Can and Can’t Tell Us

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I’ve been thinking about this quite a bit lately, especially when it comes to the way we approach herbal medicine as an alternative to pharmaceuticals. There seems to be an expectation that somewhere out there, there’s a plant capable of replacing just about any medication. A botanical counterpart, if you will.

Now, I understand where this comes from. I really do!

There’s a growing distrust of pharmaceutical companies and the industry as a whole, although I’m not particularly interested in opening that can of worms today. I also think many people have experienced the runaround within our healthcare system. They’ve spent years searching for answers, tried treatments that haven’t provided the relief they hoped for, or simply feel that their concerns haven’t been adequately addressed. Eventually, they begin exploring other options, and herbal medicine can offer an opportunity to become more involved in those decisions. I can certainly appreciate that.

I also think we’ve become accustomed to associating particular medications with particular ailments. Great marketing, really. You have a headache? Reach for Advil. Having trouble sleeping? There’s something for that, too. So, when someone becomes interested in herbal medicine, it’s understandable that they might ask, “Well, what’s the natural version of Advil?”

It’s a reasonable question, given how we’ve learned to approach treatment.

Where I think things become a little more complicated is when we begin expecting those alternatives to be therapeutically equivalent.

What Are We Trying to Compare?

I started questioning this approach fairly early on, partly because of my medical background and having endured a rather grueling year of pharmacology. (Those of you who’ve taken pharmacology know exactly what I’m talking about. My sincerest condolences.)

Every medication has its own pharmacokinetic and pharmacodynamic properties, half-life, adverse effects, contraindications, and the list goes on. I KNOW, that’s quite a bit of terminology to throw into one sentence. Don’t worry, I’m not about to make you sit through a pharmacology lecture. I’ve already suffered through enough of those for all of us. BUT these characteristics tell us about how a substance behaves in the body, what physiological processes it influences, and what we can reasonably expect from its use. I’m certainly not suggesting that everyone needs to understand all of these concepts before exploring herbal medicine, nor do I expect every herbal equivalency list to include a complete pharmacological profile. Can you imagine the size of that infographic? ACTUALLY, I would love to see that lol

But I do think we need to consider what we’re comparing.

In cases where a pharmaceutical consists of an isolated compound, we’re attempting to match its effects with those of a botanical preparation containing numerous chemical constituents, each potentially contributing to its overall pharmacological activity. The fact that two substances are used for the same condition doesn’t necessarily tell us whether they act through the same mechanisms or produce comparable clinical outcomes.

That’s a lot information to leave out when we’re telling someone that one can simply replace the other.

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I want to talk about the connection between testosterone and metabolism. And I don’t mean how testosterone itself is metabolized, but rather what happens to metabolic health when testosterone levels start to decline.

Testosterone is involved in quite a few physiological processes, including maintaining skeletal muscle mass, bone health, and reproductive function (Rojas-Zambrano et al., 2025). So when testosterone levels decline, the effects can extend beyond libido and sexual function. Lower testosterone levels have been associated with changes in body composition, central obesity, insulin resistance, type 2 diabetes, dyslipidemia, and hypertension (Tsujimura, 2013). Put several of those together and we’re talking about metabolic syndrome.

There’s a pretty interesting relationship happening between testosterone and metabolic health, so that’s what we’re digging into today.

Here’s what we’re getting into:

• How testosterone levels are connected to metabolic health

• Why obesity, insulin resistance, and low testosterone tend to travel together

• What’s happening physiologically as testosterone declines

• Where herbs like ashwagandha, fenugreek, and ginseng might fit into the picture

• What the human research on herbs and testosterone looks like

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Where Testosterone Meets Metabolism

Metabolic syndrome refers to a group of conditions and risk factors that commonly occur together, including central obesity, insulin resistance, high blood pressure, and abnormal blood lipid levels (Swarup et al., 2024). Visceral fat, the fat stored around the organs in the abdomen, plays a central role in its development. As this tissue expands, it releases inflammatory signaling molecules that can interfere with insulin function and contribute to insulin resistance (Swarup et al., 2024). Waist circumference is one of the measurements used when assessing metabolic syndrome for this reason.

Low testosterone shows up in this same metabolic picture often!

In the European Male Aging Study, men with late-onset hypogonadism had higher BMI and waist circumference, higher triglycerides, systolic blood pressure, glucose, insulin, and insulin resistance, along with lower HDL cholesterol (Tsujimura, 2013). It’s essentially the metabolic syndrome cluster showing up alongside hypogonadism in the same group of men.

Lower testosterone concentrations have also been associated with greater insulin resistance and type 2 diabetes. Around one-third of men with type 2 diabetes have been reported to have late-onset hypogonadism (Tsujimura, 2013).

Testosterone also helps maintain skeletal muscle mass, which brings another tissue into this discussion (Rojas-Zambrano et al., 2025). Skeletal muscle is a major site of glucose uptake in response to insulin, so changes in muscle mass can affect how the body handles glucose. That’s one reason the relationship between testosterone and body composition deserves attention when we’re talking about metabolic health.

As obesity increases, serum testosterone concentrations tend to fall (Tsujimura, 2013). At the same time, expanding visceral fat contributes to inflammatory signaling and insulin resistance (Swarup et al., 2024). You can see how these changes start appearing together: more central adiposity, altered insulin responsiveness, and lower testosterone concentrations.

I hope that makes the overlap between low testosterone and metabolic syndrome a little easier to see.

Reduced testosterone activity is associated with increased fat mass, decreased skeletal muscle mass, and a lower basal metabolic rate (Tsutsumi & Tsuchiya, 2025).

It Goes Both Ways

Low testosterone can predict the development of central obesity and the accumulation of fat around the abdomen. At the same time, higher BMI, central adiposity, and metabolic syndrome can predict lower testosterone levels (Wang et al., 2011).

So we have this relationship where increasing body fat is associated with declining testosterone, and declining testosterone is associated with changes in body composition.

But what’s happening physiologically?

Adipose tissue contains aromatase, the enzyme responsible for converting testosterone into estradiol. As adipose tissue increases, aromatase activity can increase along with it. Higher estrogen signaling may then suppress the hypothalamic-pituitary-gonadal (HPG) axis, which regulates testosterone production (Wang et al., 2011).

There may also be changes happening directly in the testes. Men with obesity and insulin resistance have shown reduced responsiveness of Leydig cells, the cells responsible for producing testosterone, to hormonal stimulation (Wang et al., 2011). So we have potential changes in both the signals regulating testosterone production and the cells responding to those signals.

Testosterone also has a relationship with insulin sensitivity, and there’s a study I want to bring into this discussion.

Researchers withdrew testosterone from hypogonadal men for two weeks and found that insulin sensitivity decreased before there were apparent changes in body composition (Wang et al., 2011). In other words, their bodies became less responsive to insulin even though their body composition hadn’t noticeably changed. That’s interesting because it suggests testosterone may influence insulin sensitivity independently of changes in body fat.

Similar findings have been reported in men receiving androgen deprivation therapy for prostate cancer, where testosterone suppression has been associated with increased insulin resistance and unfavorable changes in blood lipid levels (Tsujimura, 2013).

So we have several physiological processes happening here! Increasing adiposity can affect testosterone regulation, while declining testosterone may influence insulin sensitivity and body composition. You can see how these changes could reinforce one another over time (Wang et al., 2011).

The interconnected relationship between testosterone and metabolic health

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What About the Herbs?

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Alright, let’s talk plants.

Supplements marketed for men’s hormonal health come with plenty of promises about boosting testosterone. A few include: ashwagandha, fenugreek, and ginseng.

But how many of these plants have been studied in humans, and what happens to testosterone concentrations when people take them?

A 2021 systematic review gives us a decent place to start! Researchers examined 32 randomized controlled trials involving 13 different herbs, looking specifically at their effects on testosterone concentrations in men. Of those 32 trials, nine reported statistically significant increases in testosterone. Only six were rated as having a low risk of bias (Smith et al., 2021).

In research, bias refers to aspects of how a study is designed, conducted, or analyzed that could systematically influence its results. Things like inadequate randomization, poor blinding, or missing participant data can affect how much confidence we place in the findings. So when a study has a higher risk of bias, we have to be more cautious about how we interpret its results.

Fenugreek (Trigonella foenum-graecum) and ashwagandha (Withania somnifera) had the most consistent positive findings in the review. Asian red ginseng (Panax ginseng) also showed some promise, although the results varied across studies (Smith et al., 2021).

Many of these trials involved younger, generally healthy men, which is something to keep in mind when we’re talking about age-related testosterone decline and metabolic syndrome. The studies also varied in the herbal extracts they used, how much participants took, and how long they took them.

Even when researchers reported an increase in testosterone, what did that mean for the men participating? Were they feeling any better? Did their body composition or insulin sensitivity improve? Because an increase in testosterone on a laboratory report doesn’t necessarily tell us whether someone’s metabolic health has improved. We need bit more info. An increase in testosterone on a laboratory report tells us something about the herb’s potential hormonal effects. Whether that translates into meaningful improvements in metabolic health is a separate question, and one the available research hasn’t adequately answered.

Okay, herbs:

Ashwagandha (Withania somnifera)

Ashwagandha has become something of a celebrity in the supplement world, especially when it comes to stress, exercise performance, and testosterone. It’s also one of the herbs with some human research behind its hormonal claims!

Clinical trials have explored ashwagandha in men undergoing resistance training, men experiencing stress, and men with fertility concerns. Several reported increases in testosterone concentrations, although the findings varied between studies and populations (Smith et al., 2021).

Ashwagandha contains compounds called withanolides, which have been investigated for their antioxidant and anti-inflammatory activity. Oxidative stress can interfere with testosterone synthesis in Leydig cells, so researchers have been exploring whether ashwagandha’s antioxidant properties could help explain some of its reported hormonal effects. It’s a possible mechanism, although we don’t yet know whether that’s what’s happening in the men taking it (Shypilova et al., 2026).

In research involving infertile men, ashwagandha supplementation has also been associated with reductions in cortisol and oxidative stress, alongside increases in testosterone and luteinizing hormone (LH) (Sengupta et al., 2018).

Cortisol is part of the body’s stress response, which is coordinated by the HPA axis. Testosterone production is regulated through a different hormonal system, the HPG axis. These two systems communicate, and prolonged stress signaling can affect reproductive hormone regulation. Researchers have proposed that ashwagandha may influence this relationship through its effects on stress signaling and reproductive hormone regulation. The mechanisms are still being investigated, though, and much of this research has focused on male fertility (Sengupta et al., 2018).

Researchers have proposed that compounds in *Withania somnifera* may act through GABA-A receptors, potentially increasing the release of gonadotropin-releasing hormone (GnRH) and, subsequently, gonadotropins such as LH and FSH. Ashwagandha may also influence cortisol levels, suggesting possible effects on stress regulation and male reproductive function.

Fenugreek (Trigonella foenum-graecum)

Fenugreek is another plant that comes up frequently in conversations about testosterone, and researchers have explored its effects in several human clinical trials. Some reported increases in testosterone concentrations, although the findings weren’t consistent across every study (Smith et al., 2021).

Some of these trials involved middle-aged men who were overweight or obese, which is relevant given the relationship between excess adiposity, insulin resistance, and testosterone levels.

BUT the trials used different fenugreek extracts, doses, and treatment durations, making direct comparisons difficult. The results from a study using one particular extract can’t necessarily be applied to every fenugreek supplement on the market. We have some encouraging findings for testosterone, although evidence for fenugreek’s effects on metabolic syndrome remains limited (Smith et al., 2021).

Asian Red Ginseng (Panax ginseng)

Asian red ginseng has also been investigated for its effects on testosterone, although the human findings are mixed. And just to clarify, we’re talking about Panax ginseng here, which is a different species from American ginseng (Panax quinquefolius).

In one small trial involving 72 men with metabolic syndrome, researchers reported a modest increase in testosterone after four weeks of supplementation. That’s a relevant population given everything we’ve discussed about testosterone and metabolic health, but four weeks is a relatively short period.

Of the seven ginseng trials included in the systematic review, only one reported a statistically significant increase in testosterone (Smith et al., 2021). So we have an interesting finding in men with metabolic syndrome, but the results across the other studies haven’t been nearly as encouraging.

Fenugreek

Where Does That Leave Us?

Say you’re looking at a study where testosterone levels increased after several weeks of taking an herbal extract. Great! But what does that tell us about metabolic health?

Think about everything we’ve discussed with insulin resistance, abdominal fat, and the hormonal changes that can accompany metabolic syndrome. If testosterone increases, I’d want to know what’s happening to those other measurements, too. Is the body responding to insulin any differently? Has body composition changed? What about blood lipid levels?

Because ultimately, we’re interested in what these hormonal changes mean for metabolic health, and testosterone concentrations alone can only tell us so much.

I’d love to see more botanical trials investigating these relationships, especially in people who already have metabolic syndrome. There’s a lot of interesting physiology here, and I think we’ve barely scratched the surface of what researchers could explore!

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Thanks for reading! 🌻

Until next time,

Agy | The Buffalo Herbalist

Ps: check out my other publications :)

The Herbal Academic

A research notebook exploring herbal medicine through physiology, pharmacology, and science. Expect research breakdowns, paper annotations, evidence literacy, academic rabbit holes, and notes on what I’m reading, learning, and questioning along the way.

By Agy | The Buffalo Herbalist

The Herbal Mythos

Where plants, medicine, history, folklore, astrology, and old ideas about the human body collide.

By Agy | The Buffalo Herbalist

References:

Rojas-Zambrano, J. G., Rojas-Zambrano, A. R., Rojas-Zambrano, A. F., & Barahona-Cueva, G. E. (2025). Benefits of testosterone hormone in the human body: a systematic review. Cureus, 17(2), e78785. https://doi.org/10.7759/cureus.78785

Sengupta, P., Agarwal, A., Pogrebetskaya, M., Roychoudhury, S., Durairajanayagam, D., & Henkel, R. (2017). Role of Withania somnifera (Ashwagandha) in the management of male infertility. Reproductive BioMedicine Online, 36(3), 311–326. https://doi.org/10.1016/j.rbmo.2017.11.007

Shypilova, I., Bolgova, O., & Mavrych, V. (2026). Integrative Natural Approaches for Age-Related Testosterone Decline: a synergistic framework combining exercise, nutrition, and bioactive compounds. Cureus, 18(1), e101276. https://doi.org/10.7759/cureus.101276

Smith, S. J., Lopresti, A. L., Teo, S. Y. M., & Fairchild, T. J. (2020). Examining the Effects of herbs on testosterone concentrations in Men: A Systematic review. Advances in Nutrition, 12(3), 744–765. https://doi.org/10.1093/advances/nmaa134

Tsujimura, A. (2013). The Relationship between Testosterone Deficiency and Men’s Health. The World Journal of Men S Health, 31(2), 126. https://doi.org/10.5534/wjmh.2013.31.2.126

Tsutsumi, T., & Tsuchiya, K. (2025). Testosterone and obesity in an aging society. Biomolecules, 15(11), 1521. https://doi.org/10.3390/biom15111521

Wang, C., Jackson, G., Jones, T. H., Matsumoto, A. M., Nehra, A., Perelman, M. A., Swerdloff, R. S., Traish, A., Zitzmann, M., & Cunningham, G. (2011). Low testosterone associated with obesity and the metabolic syndrome contributes to sexual dysfunction and cardiovascular disease risk in men with type 2 diabetes. Diabetes Care, 34(7), 1669–1675. https://doi.org/10.2337/dc10-2339

We know that phytoestrogens aren’t actually estrogens. They aren’t steroid hormones, but some of them share enough structural similarity with estrogen that they can interact with estrogen receptors in the body. I’ll get much more into what that means, do not worry. Knowing that, though, opens up an interesting question: if phytoestrogens can interact with some of the same receptors as estrogen, can any of estrogen’s specific physiological effects also be seen with phytoestrogens?

There is obviously a LOT of nuance packed into that question. Estrogen has effects throughout the body, phytoestrogens are a pretty broad group of compounds, and sharing a receptor doesn’t automatically mean two substances are going to produce the same biological response. There are a lot of different pathways we could wander down here, so I want to narrow our investigation to one that caught my attention while I was reading: neuroprotection.

Research has proposed several different mechanisms through which estrogen may be neuroprotective. That made me curious about what we know about phytoestrogens along those same pathways:

Can they influence some of the same processes involved in neuronal damage, and if so, are they doing it through the same mechanisms?

That’s what we’re sorting through today!

So here are the questions I’m looking to answer:

• What does “neuroprotective” mean?

• So, how is estrogen neuroprotective?

• Where do phytoestrogens enter the picture?

• What does the research on genistein show?

• Does the gut microbiome change the answer?

• Are we seeing the same neuroprotection as estrogen?

  

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What Does “Neuroprotective” Mean?

Neuroprotection is exactly what it sounds like: protecting neurons and other components of the nervous system from injury or damage.

We can be talking about an acute injury, like the damage that occurs during a stroke, or damage that develops alongside neurodegenerative diseases like Alzheimer’s and Parkinson’s disease (Khushi et al., 2026).

What does “protecting” a neuron look like on a physiological level? Well, it helps to look at what can damage one. If we can identify the processes that contribute to neuronal damage, we can also start to see where something might step in and interfere with that process. Those points become potential targets for neuroprotection.

The ones I want us to focus on today are oxidative stress, inflammation, apoptosis, and excitotoxicity (Khushi et al., 2026).

• Oxidative stress: This happens when the production of reactive oxygen species, or ROS, overwhelms the systems available to manage them. Those reactive molecules can damage cellular components, which makes antioxidant activity one potential avenue for neuroprotection.

• Neuroinflammation: Microglia are the resident immune cells of the central nervous system. When activated, they can release pro-inflammatory cytokines, making microglial activation and inflammatory signaling another target in neuroprotection research.

• Apoptosis: This is programmed cell death, and it involves its own collection of signaling pathways, including caspases and changes in mitochondrial function. We’ll be meeting some of the proteins involved in this process again when we get to genistein!

• Excitotoxicity: Neurons communicate using neurotransmitters, and glutamate is the major excitatory neurotransmitter in the central nervous system. Excessive glutamate activity can lead to too much calcium entering neurons, kicking off a cascade that can ultimately damage or kill the cell (Khushi et al., 2026).

Overview of the mechanisms involved in neuronal damage associated with neurodegenerative diseases.

So, How Is Estrogen Neuroprotective?

When we hear estrogen, most of us probably associate it with the reproductive system. But estrogen is doing quite a bit outside of reproduction too, and there are estrogen receptors throughout the brain! Estrogen signaling has been associated with synaptic plasticity, cholinergic signaling, neuroinflammation, and neuronal survival (Brann et al., 2007; Manasa et al., 2026).

And that connection to neuronal survival is what we’re interested in today :)

Estrogen appears to interact with several of the same processes we just learned can contribute to neuronal damage. It has demonstrated antioxidant activity, for example, which may help limit cellular damage associated with reactive oxygen species. It has also been shown to attenuate activation of NMDA receptors, giving us a potential connection to the excitotoxicity we just talked about (Simpkins et al., 2012).

Our microglia have returned too! Estrogen has been shown to suppress microglial activation and reduce inflammatory responses in experimental models of cerebral ischemia (Brann et al., 2007). So now we have another one of our neuroprotective targets showing up: neuroinflammation.

Then there’s apoptosis. Estrogen can influence cellular signaling involved in whether a neuron survives or progresses toward programmed cell death. ERK and PI3K/Akt are two pathways that show up in this research, and both are associated with promoting cell survival and inhibiting apoptosis (Simpkins et al., 2012). I’m going to leave the signaling alphabet soup there for now, thank you.

The piece I want us to take with us is that estrogen appears capable of influencing some of the cellular machinery involved in keeping a neuron alive.

Can Estrogen Protect the Blood-Brain Barrier Too?

The blood-brain barrier is a really cool piece of anatomy. It creates a highly selective barrier between our circulating blood and the tissue of the central nervous system, tightly controlling what is able to move into and out of the brain. And estrogen may have a role in maintaining it!

The blood-brain barrier is lined by endothelial cells that are connected by tight junctions, which help restrict movement between those cells and maintain the barrier. Claudin-5 is the name of one of the proteins that helps form these tight junctions. Research has shown that estrogen can increase claudin-5 expression as well as endothelial resistance. Pretty cool! Lower estrogen levels have also been associated with increased permeability of the BBB (Manasa et al., 2026). I’d be interested to know whether that relationship is directly connected to changes in claudin-5 expression.

There are also matrix metalloproteinases, or MMPs. These are enzymes capable of breaking down components of the extracellular matrix, and increased MMP activity can contribute to disruption of the BBB. Estrogen has been shown to inhibit MMP activity, giving us another proposed mechanism for how estrogen may help protect the integrity of the blood-brain barrier (Manasa et al., 2026).

The blood-brain barrier (BBB) in a healthy state compared with BBB breakdown.

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Do We See Evidence of Less Neuronal Damage?

Cerebral ischemia is a good example of several of these mechanisms happening at once.

When blood flow to an area of the brain is interrupted, neurons are suddenly deprived of oxygen and glucose, and that can set off oxidative stress, inflammation, excitotoxicity, and eventually cell death. So what happens if estrogen is present? In animal models of cerebral ischemia, estrogen administration has been shown to reduce infarct volume. In other words, researchers found a smaller area of damaged brain tissue following the ischemic injury (Brann et al., 2007).

Most of the evidence we’ve looked at so far is preclinical, though, so we do need to keep that limitation in mind!

Where Do Phytoestrogens Enter the Picture?

Okay, now we can finally add the plants into this!!

Phytoestrogens are naturally occurring, non-steroidal compounds found in plants, and some share structural similarities with 17β-estradiol. That similarity allows certain phytoestrogens to bind to estrogen receptors and influence estrogen signaling in the body (Gorzkiewicz et al., 2021). Phytoestrogen is also a pretty broad term, though. There are several different groups of these compounds, with much of the research into their potential neurological effects focusing on soy isoflavones like genistein and daidzein (Gorzkiewicz et al., 2021).

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When I started planning this series, I thought we might spend some time looking at all the different body systems the HPA axis manages to get its little hands into. And we still might! But as I was working through the research, something else tickled my fancy: the common belief that chronic stress can cause autoimmune disease.

If you’ve spent any amount of time in wellness spaces, you’ve probably heard some version of this. Stress causes inflammation. Chronic stress raises cortisol. Too much cortisol disrupts the immune system. Eventually, autoimmune disease enters the conversation.

But what is the physiology underneath all of that? I wondered.

That’s what we’re investigating in Part 2! Here! Now!

We’re going to look at how the HPA axis and immune system communicate, what can change when stress becomes chronic, and how researchers are trying to understand the relationship between stress physiology, inflammation, and autoimmunity. Along the way, we’re going to ask:

• How does the HPA axis communicate with the immune system?

• What changes when stress becomes chronic?

• If cortisol helps control inflammation, why can chronic stress be associated with more inflammation?

• Can the immune system change the stress response too?

• What does any of this have to do with autoimmunity?

• So what does cortisol look like in people with autoimmune disease?

I tried linking each question in the table of contents to its section below! So if there’s something you want to learn about ASAP, you should be able to click the question above and jump right to it instead of scrolling through the whole article. :) Let me know if it works for you!

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How Does the HPA Axis Communicate With the Immune System?

Cortisol gets talked about so often in the context of stress that we sometimes totally forget it has jobs throughout the body that extend beyond stress! For example, cortisol has a role in helping regulate immune activity. What does that mean? Well, immune cells are responsive to glucocorticoids, including cortisol, which gives the HPA axis a direct line of communication with the immune system (Nunez et al., 2025).

A quick terminology stop before we go any further: glucocorticoids are a class of steroid hormones produced by the adrenal cortex, and cortisol is the primary glucocorticoid in humans. Immune cells express glucocorticoid receptors (GRs), so cortisol released into circulation can reach these cells and bind to receptors inside them. Once cortisol binds to a GR, the receptor changes shape, and the cortisol-GR complex can move into the nucleus of the cell, where it can influence gene transcription (Cohen et al., 2012).

This is one of the ways an endocrine signal from the HPA axis can become a change in immune-cell behavior!

One place we can see this is in the regulation of cytokines. Cytokines are signaling proteins that immune cells use to communicate, and some of them help initiate and coordinate inflammation. Glucocorticoid signaling can reduce the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α (Nunez et al., 2025).

There’s some really interesting molecular biology underneath that effect, involving inflammatory transcription factors such as NF-κB and AP-1. Keep those in your back pocket for right now because we’ll be getting into them a bit later on (Cohen et al., 2012).

Cortisol can also influence where immune cells go throughout the body, which I think is such a cool part of this physiology. This is called leukocyte trafficking. White blood cells are constantly moving between the bloodstream and tissues, and glucocorticoids can change that distribution (Nunez et al., 2025). One example is neutrophil demargination. Some neutrophils are temporarily associated with blood-vessel walls rather than freely circulating in the bloodstream, and glucocorticoids can shift more of those cells into the circulating pool (Cohen et al., 2012).

The effects of glucocorticoid signaling extend across several immune-cell populations, including lymphocytes, macrophages, neutrophils, dendritic cells, and natural killer cells. Depending on the cell type, glucocorticoids can influence aspects of immune-cell trafficking, maturation, and function (Nunez et al., 2025). So when we say that cortisol helps regulate immune activity, we’re describing quite a few different physiological processes happening under that umbrella: changes in inflammatory signaling, changes in what immune cells are doing, and changes in where some of those cells go throughout the body.

ALRIGHT SO: the HPA axis communicates with the immune system through glucocorticoid signaling, with cortisol carrying that signal to immune cells throughout the body. Because those cells can respond directly to cortisol, changes in HPA-axis activity have the potential to change immune activity too!

Glucocorticoids help regulate HPA axis activity through negative feedback at the hypothalamus and pituitary while also reducing the expression of pro-inflammatory cytokines.

What Changes When Stress Becomes Chronic?

In Part 1, we spent a lot of time with the negative feedback loop that helps regulate the HPA axis.

A stressor activates the HPA axis, cortisol is released, and rising cortisol eventually feeds back to the hypothalamus and pituitary to help regulate the response. Once the stressor has passed, that feedback helps bring HPA-axis activity back down.

refresh your HPA axis memory here:

But what happens when stress keeps showing up?

With chronic stress, the HPA axis can be recruited repeatedly over time, and eventually the regulation of the system itself can start to change. Researchers have described alterations in the normal pulsatile and circadian patterns of cortisol secretion, changes in negative feedback, and changes in glucocorticoid-receptor sensitivity (Nunez et al., 2025).

I want to hang out with that for just a quick minute because there are several different parts of HPA-axis regulation that we can look at when we talk about “cortisol.” When we’re trying to understand what chronic stress might be doing to this system, we can look at:

• How much cortisol is circulating: This is probably the piece we’re most familiar with, but cortisol concentration is only one measurement of HPA-axis activity.

• When cortisol is being released: Cortisol follows a circadian rhythm, with concentrations changing throughout the day, and it’s also released in smaller pulses. Chronic stress can disrupt these normal patterns, so two people could theoretically give us the same cortisol measurement at one moment in time while having very different patterns of cortisol secretion across an entire day (Nunez et al., 2025).

• How negative feedback is functioning: Cortisol feeds back to the hypothalamus and pituitary, helping regulate further CRH and ACTH secretion. Changes in that feedback can change how the HPA axis responds and regulates itself over time (Nunez et al., 2025).

• How sensitive cells are to cortisol: Remember those glucocorticoid receptors from the last section? Okay, perfect. Cortisol has to bind to them for many of its effects on immune cells to occur. Chronic stress has been associated with changes in glucocorticoid-receptor sensitivity, so we also have to consider how responsive those cells are to the cortisol signal they’re receiving. A change in receptor sensitivity could change the biological response to cortisol even when the hormone itself is still circulating (Nunez et al., 2025).

Circadian regulation of the HPA axis and cortisol secretion. The suprachiasmatic nucleus (SCN) helps coordinate daily HPA-axis activity, influencing CRH, ACTH, and glucocorticoid secretion across the circadian cycle. The figure also illustrates how chronic stress can disrupt this rhythmic regulation.

If Cortisol Helps Control Inflammation, Why Can Chronic Stress Be Associated With More Inflammation?

Earlier, we saw that glucocorticoid signaling can reduce the production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α (Nunez et al., 2025). Chronic stress can repeatedly activate the HPA axis, which means cortisol continues to be part of the stress response. So if cortisol is helping regulate inflammation, why can chronic stress be associated with more inflammation?

Back to Those Glucocorticoid Receptors

A big piece of this comes back to those glucocorticoid receptors. During chronic stress, immune cells can become less sensitive to glucocorticoids, a phenomenon called glucocorticoid resistance (Nunez et al., 2025). And to understand why that could change inflammation, you can pull NF-κB and AP-1 back out of your pocket now!

When cortisol binds to its intracellular glucocorticoid receptor, the cortisol-GR complex can move into the nucleus of the cell. There, it can interfere with the activity of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), two transcription factors that help regulate the expression of genes involved in producing pro-inflammatory cytokines. Inhibiting their activity is one of the molecular mechanisms through which glucocorticoids can reduce inflammatory signaling (Cohen et al., 2012). The cortisol-GR complex can also interact with glucocorticoid response elements (GREs), which are specific DNA sequences involved in regulating gene transcription. Through this pathway, glucocorticoid signaling can increase the production of anti-inflammatory proteins, including inhibitor of nuclear factor kappa B (IκB) (Cohen et al., 2012).

read more about inflammation & transcription factors here:

IκB gives us a really cool example of what that anti-inflammatory regulation looks like inside the cell as itnbinds NF-κB and keeps it sequestered in the cytoplasm, limiting NF-κB’s ability to enter the nucleus and activate the transcription of inflammatory genes (Cohen et al., 2012). SO! There are multiple points along this pathway where glucocorticoid signaling can influence the inflammatory response.

What Happens With Glucocorticoid Resistance?

Glucocorticoid resistance changes this picture because cortisol can still be circulating and reaching immune cells while those cells have become less responsive to its signal. Reduced glucocorticoid sensitivity can weaken some of the anti-inflammatory effects we just walked through, including the regulation of inflammatory transcription pathways (Cohen et al., 2012).

Human viral-challenge studies give us a really interesting look at this relationship.

In a study of 276 healthy adults, researchers measured chronic psychological stress and glucocorticoid-receptor resistance before exposing participants to a rhinovirus. Greater chronic stress was associated with greater glucocorticoid resistance, and glucocorticoid resistance was associated with a greater likelihood of developing a cold (Cohen et al., 2012).

In a second study of 79 healthy adults, researchers looked more directly at the inflammatory response following rhinovirus exposure. Glucocorticoid resistance measured before infection predicted greater production of IL-1β, TNF-α, and IL-6 afterward. That gives us a mechanism for how chronic stress and increased inflammation can exist in the same physiological picture: if immune cells become less responsive to glucocorticoids, cortisol’s ability to regulate inflammatory signaling can be reduced (Cohen et al., 2012).

Acute and chronic stress can have different effects on immune regulation. Acute HPA-axis activation and glucocorticoid signaling can help restrain pro-inflammatory cytokine production, while chronic stress may be associated with altered glucocorticoid signaling and glucocorticoid-receptor resistance, reducing this regulatory effect and contributing to sustained inflammation. The “prolonged cortisol” pathway shown here represents one proposed model of chronic-stress dysregulation and should not be interpreted to mean that chronic stress universally produces persistently elevated cortisol (Nunez et al., 2025).

Can the Immune System Change the Stress Response Too?

Alright, so up to this point, we’ve covered how the HPA axis communicates with the immune system, right? Cortisol is released, it reaches immune cells, binds to glucocorticoid receptors, and can change what those cells are doing.

But the immune system gets to pick up the phone and talk back!

“Hello, this is the immune system speaking.”

Part of that return message comes through cytokines. Pro-inflammatory cytokines like IL-1, IL-6, and TNF-α can carry information about inflammatory activity to the brain and activate components of the HPA axis (de Brouwer et al., 2010). That means an active immune response can become part of the signaling that activates the HPA axis and ultimately influences cortisol release. The immune system has officially joined the conversation!

Personally, I think this bidirectional communication gives us a much better way to understand the relationship between stress and inflammation because we have signals moving in both directions! When inflammatory signaling continues over longer periods of time, pro-inflammatory cytokines may also contribute to changes in HPA-axis activity (de Brouwer et al., 2010).

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What Does Any of This Have to Do With Autoimmunity?

Okay, now you’re probably like, “Agy, you promised me an article about autoimmunity. CUT TO THE CHASE.”

Immune Tolerance

We’ve talked a LOT about inflammation, but inflammation and autoimmunity aren’t the same thing. Autoimmune diseases involve a loss of immune tolerance toward the body’s own antigens, meaning the immune system begins reacting against components of the body that it would normally recognize as “self” (Nunez et al., 2025).

Immune tolerance is essentially how the immune system learns what belongs to us and what doesn’t. We need an immune system that can recognize and respond to something potentially harmful while maintaining tolerance toward our own tissues. Glucocorticoids can influence this process through their effects on dendritic cells, which are involved in antigen presentation and help shape the immune response that follows. During HPA-axis dysfunction, changes in glucocorticoid signaling may interfere with these effects on dendritic cells and their role in maintaining self-tolerance (Nunez et al., 2025).

learn how this immune tolerance happens in the gut here:

Tregs and Th17 Cells

Regulatory T cells, usually shortened to Tregs, help maintain immune tolerance by suppressing autoreactive immune responses. Under chronic stress and HPA-axis dysfunction, reductions in Treg number and function have been described, along with reductions in IL-10, a cytokine involved in limiting inflammatory responses. T helper 17 cells, or Th17 cells, produce IL-17 and participate in inflammatory immune responses, and increased Th17 activity and IL-17 have also been described in chronic stress and HPA-axis dysfunction (Nunez et al., 2025).

A Bigger Neuroendocrine-Immune Network

There’s another proposed framework I want to bring into this because it widens our view beyond cortisol a bit, which is important.

Researchers have described a neuro-endocrine-immune network in which the nervous, endocrine, and immune systems communicate through hormones, neurotransmitters, neuropeptides, and cytokines. Cortisol is part of that network, along with mediators such as epinephrine, norepinephrine, acetylcholine, substance P, and inflammatory cytokines (Cristal-Lilov et al., 2021).

The basic idea is that these systems normally regulate one another. Stress mediators, autonomic signals, glucocorticoids, and immune mediators participate in feedback relationships. Within the allostatic framework, repeated or prolonged activation can alter those regulatory relationships, and because the system is nonlinear, dysfunction doesn’t necessarily mean that every mediator simply becomes “high” or “low” (Cristal-Lilov et al., 2021).

In the context of autoimmunity, the proposed problem is a loss of coordination between these systems. Neuroendocrine signals may no longer regulate immune activity appropriately for the inflammatory signals being produced, potentially allowing inflammatory and autoreactive immune activity to persist. In rheumatoid arthritis, for example, high levels of inflammatory cytokines would be expected to stimulate the HPA axis, yet cortisol responses have been described as relatively inadequate for the degree of inflammation present (Cristal-Lilov et al., 2021).

This is still a proposed framework. Researchers haven’t established that disruption of this network causes autoimmune disease, or whether some of these changes develop as a consequence of autoimmune inflammation itself.

Autoimmunity

So What Does Cortisol Look Like in People With Autoimmune Disease?

The studies show...well, both low and high cortisol?

I know. Hear me out.

In one recent study of people with systemic lupus erythematosus (SLE) and Sjögren’s syndrome, cortisol measured 60 minutes after waking was lower than it was in healthy controls, suggesting a reduced cortisol awakening response and HPA-axis hyporeactivity. Other studies have found higher cortisol exposure in SLE and higher salivary cortisol in Sjögren’s syndrome, while still others have found no significant difference in HPA-axis activity at all (Uçar et al., 2026).

This is why understanding the physiology is SO important.

Cortisol is only one part of the relationship between stress and inflammation. A stressor can activate the HPA axis and lead to cortisol release, but cortisol isn’t required for an inflammatory response to exist. Immune cells have their own receptors, signaling pathways, transcription factors, and cytokines capable of initiating and sustaining inflammatory activity. We’ve already met a few of them in this article: NF-κB, IL-1β, IL-6, and TNF-α. Inflammatory signaling can even travel in the other direction. Pro-inflammatory cytokines including IL-1, IL-6, and TNF-α can communicate inflammatory activity to the brain and activate components of the HPA axis (de Brouwer et al., 2010).

When we measure cortisol in someone with an autoimmune disease, then, we’re looking at one signal within a much larger conversation between the endocrine and immune systems.

There may also be something else driving the inflammatory response.

Autoimmune diseases are multifactorial, with genetic susceptibility, epigenetic changes, environmental exposures, the microbiome, sex hormones, and neuroendocrine stress pathways potentially interacting in their development and activity (Nunez et al., 2025). The neuroendocrine-immune framework, mentioned above, considers how multiple interacting signals, rather than cortisol alone, may shape immune regulation over time (Cristal-Lilov et al., 2021).

So, a lower cortisol measurement doesn’t automatically mean less inflammation, and a higher measurement doesn’t automatically tell us cortisol caused the inflammation.

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THAT WAS A LOT. I’m sorry! But I’m not, because now you know :)

We covered a TON of physiology here (if you have to go back and read it, totally fine. My eyes are crossing editing this lolol) but I think it leaves us with a much better way to think about the relationship between chronic stress, cortisol, inflammation, and autoimmunity. The HPA axis and immune system are constantly communicating, and chronic stress can change how that communication is regulated.

Once we widen the lens to the larger neuroendocrine-immune network, it also becomes pretty clear why looking at cortisol alone can only tell us so much.

Cortisol can absolutely be one piece of the puzzle. Its secretion patterns can change, glucocorticoid receptors can become less responsive, and glucocorticoid signaling can influence inflammatory pathways and immune regulation. At the same time, immune signals can influence the HPA axis, and autoimmune disease develops within a much larger landscape of genetic susceptibility, immune tolerance, environmental exposures, hormones, and other interacting factors.

So, eek, don’t hate me but I totally think we can give cortisol a little bit of a break as the end all, be all villain.

A high cortisol measurement doesn’t tell us that cortisol caused someone’s inflammation, and a low measurement doesn’t mean inflammation should disappear. The physiology happening around that measurement is a whole lot bigger than one hormone.

Up next, we’re getting into adaptogens!

if you want to read how I went on citation hunt on this topic, read this:

In the final part of this series, we’ll look at what adaptogens are, where they may interact with the stress-response systems we’ve been learning about, and whether they’re really as safe as we’ve been told they are. :)

Until next time,
— Agy | The Buffalo Herbalist & The Herbal Academic

If you enjoyed this article and want to support the work I’m doing here, you can become a paid subscriber. Paid subscriptions help me continue spending the frankly (lolol) unreasonable amount of time I do reading research papers, following citation trails, and turning all of that into articles like this one.

There’s never any pressure to upgrade, though! Reading, sharing, commenting, or sending an article to someone who might enjoy it all help support my work too, and I’m very grateful that you’re here. 🌻

References:

Cohen, S., Janicki-Deverts, D., Doyle, W. J., Miller, G. E., Frank, E., Rabin, B. S., & Turner, R. B. (2012). Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proceedings of the National Academy of Sciences, 109(16), 5995–5999. https://doi.org/10.1073/pnas.1118355109

Cristal-Lilov, A., Ben Salmon, A., & Erez, O. (2021). Mental and physiological structures and mechanisms of overprotection in the aetiology of autoimmune disease. Journal of Medical - Clinical Research & Reviews, 5(8), 1–14.

De Brouwer, S. J., Kraaimaat, F. W., Sweep, F. C., Creemers, M. C., Radstake, T. R., Van Laarhoven, A. I., Van Riel, P. L., & Evers, A. W. (2010b). Experimental stress in inflammatory rheumatic diseases: a review of psychophysiological stress responses. Arthritis Research & Therapy, 12(3), R89. https://doi.org/10.1186/ar3016

Nunez, S. G., Rabelo, S. P., Subotic, N., Caruso, J. W., & Knezevic, N. N. (2025). Chronic stress and autoimmunity: the role of HPA axis and cortisol dysregulation. International Journal of Molecular Sciences, 26(20), 9994. https://doi.org/10.3390/ijms26209994

Uçar, C., İnanç, E., Dişli, F., Yolbaş, S., & Yıldız, S. (2026b). The neuro-immune gap in systemic autoimmunity: Integrated dysregulation of the HPA axis and autonomic flexibility in SLE and Sjögren’s syndrome. Psychoneuroendocrinology, 188, 107863. https://doi.org/10.1016/j.psyneuen.2026.107863

Hey all!

My dad is in town visiting from Florida, so I’ve been spending time with him this week and haven’t had quite enough time to sit down and properly write Part 2 of our HPA-axis series yet. It’s coming next week, I promise!

BUT, the planets aligned and my doctoral coursework handed me the perfect little Field Notes to hold us over in the meantime :)

As you may have noticed by now, I tend to pair what I’m writing about here with whatever I’m currently learning about in my doctoral coursework. One of my discussion assignments this week happened to focus on adaptogens, their potential role in adrenal function, and how one specific adaptogen may influence the HPA axis.

If you read Part 1, you know I pinky promised we’d eventually get to the plants. Apparently, we’re getting a tiny preview!

The prompt specifically used the word enhance when talking about the effects of adaptogens on the HPA axis, which immediately made me wonder... what does it mean to “enhance” the HPA axis physiologically? Are we stimulating it? Increasing cortisol production? Influencing the way the stress response is regulated?

So! Today I want to quickly cover:

• What we mean when we call something an adaptogen

• What “enhancing” the HPA axis could mean physiologically

• One proposed mechanism involving Panax ginseng

• A research literacy side quest that I was NOT expecting this assignment to send us on :) but I'm really happy it did!

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Panax ginseng

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If you’ve subscribed to my little side quest, The Herbal Academic, you probably knew this one was coming. Today, I want to give you guys an overview of the hypothalamic-pituitary-adrenal axis, better known as the HPA axis.

Physiologically, the HPA axis helps coordinate our stress response, and in the herbal world, it has become pretty intertwined with conversations about adaptogens, cortisol, and “adrenal support.”

We’ll get to the herbs, I pinky promise.

As I started putting this article together, though, I realized there was WAY too much physiology involved to squish everything I wanted to talk about into one piece. So, we’re turning this into a little HPA-axis series!

THE AGENDA:

For Part 1, we’re sticking with the axis itself. We’re going to meet the hypothalamus, pituitary, and adrenal glands, follow the hormonal signals that travel between them, and look at how the HPA axis regulates its own activity through negative feedback.

Then, in Part 2, we can zoom out and look at the meat and potatoes, what HPA-axis activity is doing throughout the body, including its connections with metabolism, cardiovascular function, immune activity, and reproductive function.

Part 3 will finally bring us back to the plants, where we can pull out the research on adaptogens and look at what researchers are measuring when they study their effects on the HPA axis.

My goal is to avoid handing you another textbook-like piece where the voice in your head slowly turns monotonous and dull, and before you’ve even scrolled halfway down, you’ve closed the app or browser and moved on with your day. Pointless!

Sound good?! Okay, please take out your notebooks!

(take a minute to look at this diagram before you dive in! you’ll see it later in the article as well)

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Point A: The Hypothalamus

The hypothalamus is a relatively small region of the brain located within the diencephalon, just below the thalamus (Molina, 2023). If you imagine looking at the brain from the side, we’re pretty centrally located, sitting underneath the thalamus and just above the pituitary gland.

That last part is going to be useful for us because the hypothalamus and pituitary work VERY closely together! Work besties!

What Does the Hypothalamus Do?

The hypothalamus is heavily involved in maintaining homeostasis, which is basically our body’s ongoing attempt to keep its internal environment relatively stable. And that’s a MUCH bigger job than it probably sounds like.

To do this, the hypothalamus receives and integrates information from the environment, other areas of the brain, and from within the body. It helps regulate things like body temperature, thirst and fluid balance, food intake and energy expenditure, blood pressure, and our sleep cycle (Molina, 2023). So, yeah. It has its little neuronal hands in A LOT of things!

For the HPA axis, the hypothalamic hormone we need to know is corticotropin-releasing hormone (CRH). The hypothalamus produces a number of other hormones, but for the sake of the scope of this article, CRH is the one you need to remember!

When the HPA axis is activated in response to stress, the hypothalamus releases CRH, which travels through a specialized network of blood vessels connecting the hypothalamus and anterior pituitary (Herman et al., 2016). And when we say “stress” here, we’re talking broadly about a real or anticipated demand that requires the body to make physiological adjustments to help maintain homeostasis. (yes, having to make a very normal, everyday phone call unfortunately totally counts as this type of stress)

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Point B: Pituitary Gland

The pituitary gland is a small endocrine gland located at the base of the brain, where it sits inside a little bony pocket called the sella turcica. I don’t know why, but I’ve always found that kind of adorable? The gland basically gets its own little seat inside the skull.

It’s also connected to the hypothalamus by the pituitary stalk, so our first two pieces of the HPA axis are VERY close neighbors.

The pituitary itself is divided into two main parts: the anterior pituitary and the posterior pituitary. These two regions differ in their structure and in how they communicate with the hypothalamus, and there’s a whole lot of physiology hiding in that sentence that we’re going to graciously leave alone today.

For the HPA axis, we only need the anterior pituitary.

CRH and ACTH

Once CRH reaches the anterior pituitary, it stimulates specialized cells called corticotrophs to release adrenocorticotropic hormone (ACTH).

ACTH is one of several hormones produced by the anterior pituitary, but it’s the one we care about for the HPA axis. Once released, ACTH enters the bloodstream and travels through the systemic circulation until it reaches its target: the adrenal cortex (Kamel-ElSayed & Schwartz, 2023).

So far, we have:

CRH: from the hypothalamus
ACTH: from the anterior pituitary (which is now on its way to the adrenals! lets goooo)

Point C: Adrenal Cortex

We’ve officially made it to the adrenal glands!

These are two small endocrine glands that sit right on top of the kidneys. If you’ve never seen them before, they kind of look like tiny little hats perched on top of each kidney, which I feel makes them seem much less intimidating than they are in an endocrinology textbook. Cuties :)

Each adrenal gland is divided into two main regions: the outer adrenal cortex and the inner adrenal medulla.

Now, both of these regions are involved in our physiological response to stress, but they do very different things. The adrenal medulla is involved in the sympathetic nervous system response and releases catecholamines like epinephrine and norepinephrine, while the adrenal cortex produces steroid hormones, including the glucocorticoids we’re interested in for the HPA axis. There’s a whole physiology lesson hiding in these two little glands alone, and I could VERY easily get distracted by it. So, I will NOT.

For today, we’re staying in the adrenal cortex.

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ACTH and Cortisol

Once ACTH reaches the adrenal glands, it binds to receptors in the adrenal cortex and stimulates the production and release of cortisol, our main glucocorticoid hormone.

Cortisol has gotten a bit of a villain reputation online, which is unfortunate because we very much NEED it. (Do we want a deep dive on cortisol? Physiological/pathophysiological actions?)

During a stress response, cortisol helps make energy available to meet increased physiological demand. It influences glucose metabolism, helps mobilize stored energy, supports cardiovascular function, and temporarily shifts resources away from processes that aren’t as immediately necessary during a stress response (Sheng et al., 2021).

And cortisol’s job extends way beyond stress. It plays a role in metabolism, immune function, cardiovascular regulation, and maintaining normal physiological function throughout the day. (see! not so bad!)

We’re focusing on its role in the HPA axis today, but I don’t want you leaving class thinking cortisol only shows up when something stressful happens!

So now we can add our third hormone:

CRH: from the hypothalamus
ACTH: from the anterior pituitary
Cortisol: from the adrenal cortex

Okay, Let’s Put This All Together

We’ve spent a lot of time following individual hormones around the body, so let’s review really quick:

The HPA axis was activated in response to a stressor, or some kind of real or anticipated demand that required the body to make physiological adjustments.

The hypothalamus responded by releasing CRH, which traveled to the anterior pituitary and stimulated the release of ACTH. ACTH then entered the bloodstream, made its way to the adrenal cortex, and stimulated the production and release of cortisol (Herman et al., 2016; Sheng et al., 2021).

That rise in cortisol helps the body meet the increased physiological demand by mobilizing energy stores, increasing the availability of glucose, supporting cardiovascular function, and temporarily altering processes like immune and reproductive activity (Sheng et al., 2021).

What we’ve been following, then, is a coordinated neuroendocrine response: information about a stressor is translated into a series of hormonal signals that ultimately changes what’s happening throughout the body.

Look at us! We know the HPA axis! Weeee!

The Negative Feedback Loop

Alright, so we’ve released cortisol into circulation. Now we need to make sure we don’t just keep making more and more of it indefinitely. I just want to touch on this really briefly to close because it helps put the WHOLE axis into perspective.

The HPA axis helps regulate its own activity through a negative feedback loop!

As cortisol circulates through the body, some of that signaling makes its way back to the HPA axis through glucocorticoid receptors. We don’t need to get super deep into receptor physiology today, but these receptors give cortisol a way to influence the same pathway that led to its production (DeMorrow, 2018; Herman et al., 2016).

So, as cortisol levels rise, glucocorticoid feedback at the hypothalamus helps reduce CRH activity, while feedback at the anterior pituitary helps decrease ACTH secretion. With less CRH stimulating the pituitary and less ACTH stimulating the adrenal cortex, we’re essentially turning down the signals telling the body to keep producing cortisol (Herman et al., 2016).

Basically, cortisol gets a say in how much more cortisol we make.

And THAT is our negative feedback loop! As the end product of the pathway increases, it feeds back into the system and reduces the signals driving its own production. This helps regulate HPA-axis activity and allows the stress response to move back toward baseline.

Part 2 will pick back up from here!

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I think that’s enough endocrinology for one day! Don’t you?

We now have the basic physiology of the HPA axis under our belts, but there’s still A LOT more to talk about. Cortisol travels throughout the body, where glucocorticoids influence a wide range of physiological processes, including metabolism, cardiovascular function, immune activity, and reproductive function (Herman et al., 2016).

If you feel like this left you itching to learn more, don’t fret! This is what’s coming!

In Part 2, we’ll look at how HPA-axis activity connects with other physiological systems throughout the body and what cortisol is doing once it reaches those tissues.

Then, in Part 3, we can finally bring the plants into the conversation. We’ll look at adaptogens, the HPA axis, and what researchers are measuring when they study these herbs. More importantly, we’ll look at what those findings can tell us, and where we need to be careful about saying more than the research does.

Class dismissed!

If you enjoyed this article and would like to support the work that goes into researching and writing pieces like this, you can become a paid subscriber to The Buffalo Herbalist. Paid subscriptions help give me the time to keep digging into the research, asking more questions, and turning what I learn into something we can all explore together.

And if you’re curious about what I’m researching, reading, and working on between these articles, you can also find me over at The Herbal Academic. That’s my new little behind-the-scenes corner where I share more of the academic side of this work, including the papers I’m reading, research questions I’m chasing, and whatever has currently taken over my brain.

Whether you’re a free or paid subscriber, or you’ve decided to follow me down both rabbit holes, I’m very happy you’re here. Thank you for reading and learning alongside me!

Until next time,
— Agy | The Buffalo Herbalist

References:

DeMorrow, S. (2018). Role of the Hypothalamic–Pituitary–Adrenal axis in health and Disease. International Journal of Molecular Sciences, 19(4), 986. https://doi.org/10.3390/ijms19040986

Herman, J. P., McKlveen, J. M., Ghosal, S., Kopp, B., Wulsin, A., Makinson, R., Scheimann, J., & Myers, B. (2016). Regulation of the Hypothalamic‐Pituitary‐Adrenocortical stress response. Comprehensive Physiology, 6(2), 603–621. https://doi.org/10.1002/cphy.c150015

Kamel-ElSayed, S. A., & Schwartz, J. (2023, May 1). Physiology, pituitary gland. StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK459247/

Molina, P. E. (2023). Endocrine physiology (6th ed.). McGraw Hill.

Sheng, J. A., Bales, N. J., Myers, S. A., Bautista, A. I., Roueinfar, M., Hale, T. M., & Handa, R. J. (2021). The Hypothalamic-Pituitary-Adrenal axis: development, programming actions of hormones, and Maternal-Fetal interactions. Frontiers in Behavioral Neuroscience, 14, 601939. https://doi.org/10.3389/fnbeh.2020.601939

The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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Question 4: How long can dandelion root and yellow dock root be used regularly, particularly for chronic constipation?

Okay! I’ve been sitting on this question for a bit because I really wanted to dig into the research before answering it.

The original question was about the regular use of dandelion root (Taraxacum officinale) and yellow dock root (Rumex crispus) for chronic constipation, with the reader mentioning that she had heard dandelion wasn’t a “forever herb.”

Which immediately made me wonder...what exactly is a forever herb?

Because really, how long can we take an herb? We talk about some plants as being better suited for short-term use and others as being appropriate for longer periods, but I wanted to know what we actually have to support those recommendations for these two plants.

Okay, Let’s Start With Dandelion

Dandelion (Taraxacum officinale) has a pretty long history of use for digestive complaints, including constipation, dyspepsia, flatulence, and loss of appetite (Martinez et al., 2015). So, its appearance here isn’t strange at all. People have absolutely been using this plant for digestive purposes for a very long time.

When I started looking specifically for evidence supporting its use for constipation, though, things got thin pretty quickly.

A 2015 review of Taraxacum found plenty of traditional use, but the authors couldn’t find clinical studies establishing efficacy or dose-response relationships. They also noted that information on dosage, duration of use, and use in specific populations was unavailable (Martinez et al., 2015).

There is some newer research! A 2025 study found that T. officinale increased gastrointestinal motility and fecal output in rats, which sounds pretty relevant to our question (Ali et al., 2025).

Except...they weren’t studying dandelion root.

The researchers used the aerial parts of the plant, extracted with 70% methanol, and administered that extract to rats at doses of 10, 100, and 500 mg/kg (Ali et al., 2025). That gives us some interesting evidence that T. officinale can influence gastrointestinal motility, but we can’t take a methanolic extract of the aerial parts given to rats and use it as evidence for what happens when someone regularly drinks a decoction of dandelion root.

Different plant part. Different preparation. Different population.

So, while dandelion has a long history of digestive use, including for constipation, the research doesn’t give us a nice answer to our original question of how long dandelion root can be taken regularly. And that’s kind of the problem!

So, How Long Can We Take It?

The European Medicines Agency (EMA) has a monograph specifically for dandelion root, recognizing its traditional use for mild digestive complaints, temporary loss of appetite, and increasing urine output. Interestingly, constipation isn’t among the listed indications (EMA, 2022).

When it comes to duration, the EMA recommends consulting a doctor or qualified healthcare practitioner if symptoms persist for longer than two weeks while using dandelion root (EMA, 2022). I’ll admit, when I saw “two weeks,” my little research brain perked right up! Maybe this was where the idea that dandelion shouldn’t be used indefinitely came from?

Buuut monograph doesn’t establish two weeks as the maximum duration of use. The recommendation is about how long someone should continue self-treatment when their symptoms are persisting.

Also, the original AMA question involved a five-year-old, so of course I wanted to know what the monograph had to say about children:

The EMA states that dandelion root isn’t recommended for children under 12 because its use in this age group hasn’t been established due to a lack of adequate data (EMA, 2022).

So...where does that leave us?

We have a LONG history of traditional digestive use, some interesting preclinical research suggesting that T. officinale can influence gastrointestinal motility, and an EMA monograph giving us some guidance around duration of self-treatment. What I couldn’t find was good long-term data giving us a defined duration for regular use of dandelion root.

There’s another problem I have with the statement that “dandelion isn’t a forever herb.”

Which part of the dandelion are we talking about?

Because that isn’t specified. And if I had to make an herbalist/medically trained guess about what someone meant by that statement, my first thought would be the leaves and their action as a diuretic.

Dandelion leaf contains a relatively high amount of potassium, which often comes up when discussing its diuretic action. But I have questions!

1. How much potassium are we getting from the amount of dandelion leaf someone would realistically consume?

2. How much makes it into the preparation?

3. Is that amount enough to compensate for what may be lost through increased urination?

So, my best guess is that the “not a forever herb” thing may have originated from concerns about using dandelion leaf as a diuretic over a long period of time, specifically because of the potential for ongoing fluid loss.

That’s my interpretation, though! And this brings us right back to why plant part matters so much! SO MUCH!

I do not have a direct source for this image, but I wish I did! It’s wonderful!

What About Yellow Dock?

Yellow dock (Rumex crispus) has a long history of traditional use as a laxative, among several other uses (Qian et al., 2024). And unlike dandelion, we have something in its phytochemistry that gives us a little more to work with when we’re trying to understand that use: anthraquinones!

Researchers have identified several anthraquinones in yellow dock root, including emodin, chrysophanol, physcion, rhein, and aloe-emodin (Eom et al., 2020). You may recognize that group of compounds from some of our much more familiar stimulant laxative herbs, which makes their presence in a traditionally laxative plant pretty interesting.

There’s a catch, though. (Why is there always a catch?) How much of those anthraquinones researchers found depended quite a bit on the preparation method. Let me walk you through how:

In one study, researchers first extracted dried yellow dock root with ethanol. They then suspended that extract in water and separated it using n-hexane, dichloromethane, ethyl acetate, n-butanol, and finally water (Eom et al., 2020). Those became the different “fractions” they analyzed.

Basically, they were taking one big extract and separating its compounds into smaller groups based on their chemical properties and which solvents they were more likely to dissolve into.

This let the researchers see that the anthraquinones weren’t distributed evenly across all of those fractions.

And they REALLY weren’t, like really were NOT.

The dichloromethane fraction had the highest total anthraquinone content, followed by the n-hexane fraction, the original ethanol extract, ethyl acetate, and n-butanol. None of the five anthraquinones the researchers measured were detected in the aqueous fraction, though (Eom et al., 2020).

And since our original question was specifically about roots being boiled in water...THIS study doesn’t tell us what would end up in that decoction. Their aqueous fraction was the water-soluble portion left after starting with an ethanol extract and separating it with several other solvents.

They didn’t take yellow dock root, boil it in water the way someone would at home, and analyze the resulting tea.

Truthfully, I really couldn’t find a study that did. I’m not sure the research on a traditional yellow dock root decoction for constipation is out there yet. (If I’m wrong, please please please correct me and drop the study in the comments!) Science likes to make things a bit more complicated, unfortunatelyyyy.

Rumex crispus

But How Long Can You Use Yellow Dock?

This is one place where I did find a much more specific recommendation. YAY!

Ethnobotanist James A. Duke, a longtime USDA researcher and author of the Handbook of Medicinal Herbs, recommends using yellow dock for no longer than 8–10 days (Duke, 2002).

(A little honesty: before researching this article, I hadn’t come across Duke’s work before, but I’m glad I did!)

Duke describes the anthraquinones in yellow dock as laxative compounds that can irritate the gastrointestinal tract. He warns that overuse may cause abdominal cramping and diarrhea, while prolonged use may contribute to hypokalemia and electrolyte imbalance (Duke, 2002).

But I couldn’t find clinical research establishing that 8–10 day limit for yellow dock root. A recent review of R. crispus also calls for more research into its acute, subchronic, and chronic toxicity (Qian et al., 2024).

So, I’d treat 8–10 days as a short-term-use recommendation, rather than a safety cutoff that has been established in clinical research.

But What About the Constipation?

After ALL OF THAT, I personally wouldn’t choose either of these herbs as something to take every day indefinitely for chronic constipation.

With dandelion root, I couldn’t find evidence giving us a clear maximum duration of use. With yellow dock, we have an 8–10 day recommendation from Duke, but we’re missing the clinical research that would establish that as a specific safety cutoff.

For me, though, there’s a bigger issue with using either one as a daily strategy: the constipation is still chronic.

If someone needs an herb every day in order to have a bowel movement, I’d want to start paying attention to what might be contributing. I’d gently introduce more fiber, promote daily movement if they’re able, and start monitoring hydration because, plain and simple, half of us probably aren’t drinking enough water.

I’d definitely pay attention to diet, too! If you want to and you’re able, keeping a food journal for a little while can be really helpful. But you absolutely don’t need a spreadsheet documenting every bite of food you’ve ever eaten. If you can notice how you feel after certain foods, what seems to make constipation better or worse, or any patterns that keep popping up, that’s useful information too. I say that because I personally have an aversion to food journals, like, just let me eat?

And then I’d start asking some bigger questions:

1. Could a medication be contributing?

2. Is gut motility impaired?

3. Is there an underlying digestive issue?

4. Is something else going on that needs to be addressed?

I might also bring in a mucilage-containing herb supportively, just to make things a little more slippery in there and help things along while working on the larger picture. I wouldn’t expect that herb to fix the underlying cause either.

So, for chronic constipation, I’d be much more interested in figuring out why it keeps happening and supporting the things that can help bowel function along the way. The herbs can absolutely be part of that conversation, but I’d want to look at the whole picture, too.

And I guess this is also a small invitation into the kind of thinking I hope to encourage with this publication. It’s really easy to learn herbalism as a series of pairings: this symptom = this herb. Constipation? Find the constipation herbs. Trouble sleeping? Find the sleep herbs. Headache? Find the headache herbs.

Sometimes that can be useful! But I think we can dig deeper than that.

What is happening physiologically? What could be contributing to the symptom? What patterns are showing up around it? What can we support with food, movement, hydration, lifestyle, or other changes? And then, with that bigger picture in front of us, where might an herb fit?

That’s the kind of herbalism I want to teach here. I want us to zoom out, ask more questions, and understand what we’re trying to support before reaching for a plant.

Until next time,
— Agy | The Buffalo Herbalist

References:

Ali, H. Z., Ali, N., Nabi, M., Ali, M., & Jahan, S. (2025). Evaluation of the laxative effects of Taraxacum officinale using experimental animal models. Journal of Ethnopharmacology, 353, 120264. https://doi.org/10.1016/j.jep.2025.120264

Duke, J. A. (2002). Handbook of medicinal herbs (2nd ed.). CRC Press.

Eom, T., Kim, E., & Kim, J.-S. (2020). In vitro antioxidant, antiinflammation, and anticancer activities and anthraquinone content from Rumex crispus root extract and fractions. Antioxidants, 9(8), 726. https://doi.org/10.3390/antiox9080726

European Medicines Agency. (2022). European Union herbal monograph on Taraxacum officinale F.H. Wigg., radix (EMA/HMPC/475726/2020).

Martinez, M., Poirrier, P., Chamy, R., Prüfer, D., Schulze-Gronover, C., Jorquera, L., & Ruiz, G. (2015). Taraxacum officinale and related species—An ethnopharmacological review and its potential as a commercial medicinal plant. Journal of Ethnopharmacology, 169, 244–262. https://doi.org/10.1016/j.jep.2015.03.067

Qian, H., Jia, Y., Zheng, K., Li, C., Shao, J., Wang, J., Xu, H., & Zhou, X. (2024). Rumex crispus L.: A comprehensive review on botany, traditional uses, phytochemistry, pharmacology, and safety. International Immunopharmacology, 143, 113569. https://doi.org/10.1016/j.intimp.2024.113569

And don’t worry! We’re doing this in easy mode!

Alright, in this issue:

• What a virus actually is

• How a virus gets inside your cells

• Viral replication, easy mode

• Where we can interrupt that process

• Why calling an herb “antiviral” doesn’t actually tell us very much

• The Antiviral Herb Guide :)

  

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Okay, So What Is a Virus?

Viruses are strange little things. They aren’t cells, which means they’re built very differently from bacteria, fungi, or the cells that make up our own bodies. At their simplest, viruses carry genetic material, either DNA or RNA, tucked inside a protein shell called a capsid. Some have one more layer on the outside: the viral envelope (Kausar et al., 2021).

This is our cute little piece of stationery; except it’s actually a lipid membrane surrounding certain viruses!

Much of that membrane originally belonged to us. (which is crazy to think about!) Enveloped viruses pick it up from the host cell as newly formed viral particles leave, taking a portion of the cell membrane with them on the way out. Viral proteins embedded within that membrane can then help the virus recognize or interact with the next cells it encounters (Kausar et al., 2021).

Underneath all of that packaging is a pretty major limitation: a virus doesn’t really have everything it needs to reproduce independently. It needs a living host cell to copy its genetic material, make viral proteins, then assemble new viral particles. That dependence on a host is one of the defining features of viruses (Adeosun & Loots, 2024).

So, for something capable of causing this much trouble, a virus is surprisingly dependent on us, right?! Without a host cell to hijack, it can’t make more of itself.

Getting Into the Cell

Before a virus can use a cell to make more of itself, it has to get inside. That starts with attachment, when proteins on the surface of the virus bind to specific receptors on a host cell. Those receptors matter because viruses can’t necessarily infect every cell they encounter. The virus has to be able to recognize and bind to something on that particular cell first (Kausar et al., 2021).

Which, already, is a lot of work for something that can’t reproduce on its own.

Attachment gets the virus to the cell, but now it has to actually cross the membrane. Exactly how it manages that varies between viruses. Some enveloped viruses can fuse their own envelope with the host cell membrane, allowing their contents to enter the cell. Others use endocytosis, a completely normal cellular process where the membrane folds inward and brings material from outside the cell with it (Kausar et al., 2021). In that case, the virus is essentially taking advantage of something the cell already does.

Once inside, there’s still one more layer to deal with. The viral genetic material is tucked away inside its capsid, so that DNA or RNA needs to be released before it can actually be used. This is called uncoating. The capsid is broken apart or removed, leaving the viral genome accessible inside the host cell (Kausar et al., 2021).

So, our virus has now found a cell it can infect, attached itself, made it across the membrane, ditched its packaging, and deposited its genetic material inside.

All of that just to get through the front door. Jeez Louise.

SARS-CoV-2 virus entry into the cell

Viral Replication, Easy Mode

Okay, our virus is inside the cell, its genetic material is unpacked, so now we get to the whole reason it went through the trouble of getting in there in the first place. It needs to make more viruses!!

This can get complicated FAST because viruses don’t all replicate the same way. Some carry DNA, others carry RNA, plus there are different enzymes and strategies involved depending on the virus we’re talking about. We absolutely do not need all of that today, thankfully.

For easy mode, what matters is that the virus now has access to a living cell, along with all the cellular resources it was missing on its own.

The viral genome needs to be copied so every new virus gets its own set of genetic instructions. Viral proteins have to be produced too, since those will eventually become the structural pieces of new viral particles or carry out jobs the virus needs during replication. Viruses rely heavily on the host cell to make this happen, while some also bring or produce specialized enzymes of their own to complete particular steps (Kausar et al., 2021). Your cell, which was minding its own business moments ago, has essentially been recruited into manufacturing viruses, involuntarily. Rude.

Once enough copies of the genome and viral proteins have been made, those pieces can start coming together into new virus particles. Those newly assembled viruses eventually leave the cell, giving them the opportunity to find more susceptible cells and run the whole process again (Kausar et al., 2021).

So, viral replication on very easy mode:

Get inside → unpack → copy the genome → make viral proteins → assemble new viruses → get out.

There’s a tremendous amount of molecular biology stuffed into those six little steps, but that’s enough for what we need today :)

Steps in the viral replication cycle.

So, What Are We Trying to Stop?

Now that we have a virus successfully making copies of itself, we can look back at that whole process and see something useful: there are quite a few places where it could potentially be interrupted.

Depending on the virus, an antiviral might interfere with:

• Attachment and entry: The virus has to bind to a susceptible host cell before it can get inside. Interfering with that interaction can stop the infection process before the viral genome ever enters the cell.

• Uncoating: Once inside, the virus still has to release its genetic material from its protective capsid. Prevent that from happening and the genome stays packaged away instead of becoming available for replication.

• Genome replication: The viral DNA or RNA has to be copied to make new viruses. Some antivirals interfere with this process or with the viral enzymes required to carry it out (Kausar et al., 2021).

• Viral protein production and processing: A copied genome isn’t enough. The virus also needs proteins to build new viral particles or perform specific jobs during replication, which gives us another part of the process to interfere with (Kausar et al., 2021).

• Assembly and release: All of those newly made pieces still have to be assembled into complete virus particles, then successfully leave the cell. Interrupt either step or you can interfere with the virus spreading to more cells.

• The virus itself: Some substances demonstrate direct virucidal activity, meaning they act directly on virus particles. This is different from interfering with something the virus does once it has already entered a host cell (Adeosun & Loots, 2024).

• The host response: Not every antiviral effect has to involve attacking the virus directly. Some compounds influence cellular signaling or parts of the immune response involved in antiviral defense (Adeosun & Loots, 2024).

So, when we say something is “antiviral,” I don’t want you to automatically picture “supporting the immune system” or “stimulating immune function.” Those can absolutely be part of the picture, but now we know there are a whole lot of other places where a plant or one of its constituents might interfere with the process.

We can get way more specific than that!

When you’re choosing herbs or explaining their actions to someone else, you can talk about an extract interfering with viral attachment to a host cell. You can point to a constituent that inhibits an enzyme required for viral replication, or explain that an antiviral effect happens directly against the viral particle before it ever enters the cell.

Instead of stopping at, “this herb has antiviral activity,” you can actually say, “This plant has been studied for its ability to interfere with viral replication by inhibiting an enzyme the virus needs for that process.” 😎

Look at you talking mechanisms!

Now We Can Talk About the Plants

Okay! Finally, the herbs!

Plant extracts and their constituents have been studied at several points in the viral life cycle, including attachment and entry, replication, viral protein activity, cellular signaling, plus direct activity against the virus itself (Adeosun & Loots, 2024).

The research gets messy pretty quickly, though, because “plant” can mean a lot of different things in a paper. Sometimes researchers are testing a whole extract, while other studies pull out one constituent and test that on its own. There are cell studies, animal studies, computational models, plus some human research scattered throughout the literature. cue Agy’s head spinning. All of those can tell us something useful, but they aren’t giving us the same kind of evidence.

And when we’re looking at an isolated constituent, we have to be careful about how far we carry that finding. If a compound from a plant inhibits a viral enzyme in a cell study, we can’t automatically give that activity to every preparation of the whole herb. The concentration used in the study matters, the extraction matters, absorption matters, plus we have to account for what happens to that compound after we actually swallow it.

I know, I know. I sound like a broken record about this. Phytochemistry matters!

So I put everything into a guide for you:)

The Antiviral Herb Guide takes the mechanisms we just went through and organizes the plants around them, with the virus studied, what preparation or constituent was actually tested, plus the level of evidence behind it. I wanted something you could pull up when you see “antiviral” attached to an herb and actually figure out what that means.

So again: we’re getting REALLY specific here. This isn’t an exhaustive or complete guide by any means! It was created to give you a head start in understanding what to look for when you’re researching on your own.

Download it here:

If you enjoyed this free Field Notes and have been thinking about upgrading, this is a lovely time to join us. Your subscription gives you access to this guide, the rest of The Library, plus the paid deep dives!

And, of course, it helps fund my ongoing habit of opening a research paper because I had one small question and resurfacing several hours later with an entire PDF and/or article :) Whoops.

Until next time,
— Agy | The Buffalo Herbalist

PS: I’m going to be taking the time to update and revamp The Library this week and next as it’s very clearly been collecting a few cobwebs.

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References:

Adeosun, W. B., & Loots, D. T. (2024). Medicinal plants against viral infections: A review of metabolomics evidence for the antiviral properties and potentials in plant sources. Viruses, 16(2), 218. https://doi.org/10.3390/v16020218

Akbari, A., Bigham, A., Rahimkhoei, V., Sharifi, S., & Jabbari, E. (2022). Antiviral polymers: A review. Polymers, 14(9), 1634. https://doi.org/10.3390/polym14091634

Kausar, S., Khan, F. S., Rehman, M. I. M. U., Akram, M., Riaz, M., Rasool, G., Khan, A. H., Saleem, I., Shamim, S., & Malik, A. (2021). A review: Mechanism of action of antiviral drugs. International Journal of Immunopathology and Pharmacology, 35, 20587384211002621. https://doi.org/10.1177/20587384211002621

Melkikh, A. V. (2022). Viruses, immunity and evolution. Biosystems, 220, 104761. https://doi.org/10.1016/j.biosystems.2022.104761

Perera, W. P. R. T., Liyanage, J. A., Dissanayake, K. G. C., Gunathilaka, H., Weerakoon, W. M. T. D. N., Wanigasekara, D. N., Fernando, W. S. K., Rajapaksha, R. M. H., Liyanage, R. P., & Perera, B. T. (2021). Antiviral potential of selected medicinal herbs and their isolated natural products. BioMed Research International, 2021, 7872406. https://doi.org/10.1155/2021/7872406

Okay, first, let's get you familiar with the virus itself, and then we'll get into the fun stuff :) Well, its honestly all fun stuff in my opinion!

This was incredibly enlightening for me to research. All the dots seem to be there just STARING AT US, blinking in anticipation, but we’re just patiently waiting for science to find the lines to connect them all.

ALSO don’t forget to grab your notebooks and be prepared to come back to this a few times. It’s a bit dense, but I didn’t want to leave anything out. :)

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What Is EBV?

If you’re an adult reading this, there’s a very good chance EBV is already living in your body right now (kind of a wild thing to sit with, honestly). It infects somewhere around 90 to 95% of adults worldwide (Shabnam and Khan, 2026), making it one of the most common viruses on the planet!

EBV is a member of the herpesvirus family, technically classified as a B-lymphotropic gammaherpesvirus, or human herpesvirus 4 (HHV-4) if you want the formal, fancy name (Shabnam and Khan, 2026). Most of us pick it up in early childhood, and childhood infection is usually so mild it comes and goes without anyone noticing. No fever, no drama, nothing. In adolescence, though, first exposure carries much higher odds of actually making you sick. Around 30 to 70% of teens and young adults infected for the first time develop infectious mononucleosis (Draborg et al., 2013), the “kissing disease” most of us have at least heard of by name (Shabnam and Khan, 2026).

How It Gets In

EBV’s main route in is saliva, which is why infectious mononucleosis earned the “kissing disease” nickname. The virus enters through the oropharynx, the back of your throat, and works its way into the surrounding tissue before finding its real target: B cells, the immune system’s antibody factories (Draborg et al., 2013). Saliva isn’t the only way in, though. Sexual contact, organ transplantation, and blood transfusion can all transmit EBV as well (Shabnam and Khan, 2026), so this isn’t purely a childhood-cooties situation.

But once it reaches a B cell, EBV stops behaving like the virus you’d probably picture in your head.

dramatic pause for effect

Model illustrating the infection of EBV in human.

How It Hides

Once inside of us, EBV has two very different ways it can behave. It can enter an active, or lytic, cycle, where it uses the infected cell to produce new copies of the virus that can go on to infect other cells. But EBV can also do something that explains how an infection you picked up as a kid can still be hanging around decades later: it can go latent.

During latency, the viral genome literally curls itself into a loop, forming a circular piece of DNA called an episome that sits inside the nucleus of the B cell, separate from your own chromosomes. Then EBV starts shutting things down. Depending on the stage of latency, most of its genes get switched off, and in resting memory B cells, viral protein production can become extremely limited or even undetectable (Draborg et al., 2013). SO! Now you’ve got a B cell carrying the entire EBV genome around inside of it while giving the immune system very little indication that anything unusual is happening. Sneaky.

But just hiding inside the cell isn’t enough. EBV also has to keep that cell alive.

B cells carry a protein called Bim, whose job is to trigger apoptosis, essentially cellular self-destruction, when something inside the cell has gone wrong. Very useful when the cell in question is carrying around an entire viral genome! EBV, naturally, would prefer that not happen. Through epigenetic changes, it can suppress the gene responsible for making Bim, turning down this self-destruct signal without actually changing the underlying DNA sequence (Paschos et al., 2009). Less Bim means less pressure for that infected B cell to undergo apoptosis, giving the cell, and the EBV genome sitting inside of it, a better chance of sticking around.

And it can stick around for a VERY long time. EBV establishes this reservoir inside the memory B-cell population, which is how a virus you may have picked up before you could even spell Epstein-Barr can still be sitting there decades later.

Latency in EBV

How Your Immune System Keeps EBV Contained

Of course, EBV isn’t getting away with all of this completely unopposed. A huge part of keeping the virus under control comes down to T cells, particularly CD8+ cytotoxic T cells, which can recognize and destroy infected cells (Draborg et al., 2013).

For those T cells to know what’s happening inside a cell, they need a way to actually see in there. That’s where MHC I comes in. Almost every nucleated cell in your body displays MHC I molecules on its surface, and those molecules hold up tiny pieces of proteins from inside the cell for CD8+ T cells to inspect (Wieczorek et al., 2017). If those pieces look normal, carry on. If one of them is viral? Now the immune system knows something is in there that absolutely shouldn’t be.

EBV, naturally, has found ways to interfere with this too. During active infection, it can disrupt the MHC I antigen-presentation pathway, reducing how effectively viral proteins get displayed to CD8+ T cells (Draborg et al., 2013). And during latency, EBV creates a different problem altogether by keeping its viral protein production extremely limited. Fewer viral proteins being made means fewer obvious signs of infection for the immune system to catch.

So, there’s this constant push and pull happening in the background. Your T cells are keeping watch over EBV-infected cells, while EBV is doing everything it can to give them as little to work with as possible. For most people, the immune system maintains that balance remarkably well, which is how you can carry EBV for the rest of your life without ever knowing it’s there.

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What Molecular Mimicry Is, and EBNA1’s Role in It

One of EBV’s more interesting tricks involves molecular mimicry, where something made by the virus resembles something made by us. EBV takes advantage of that resemblance in a couple of different ways.

One is functional mimicry, where EBV makes its own version of a human protein that can do a very similar job. EBV actually carries the instructions for making a viral version of IL-10, one of our own anti-inflammatory cytokines (I know, what the heck). This viral IL-10 can suppress interferon-gamma production and dampen CD8+ cytotoxic T cell responses, the very cells we just talked about that help keep EBV-infected B cells under control (Draborg et al., 2013). IMPOSTER!

But there’s another kind of mimicry that becomes especially interesting when we start talking about autoimmune disease. Here, a viral protein resembles one of our own proteins closely enough that an immune response meant for the virus can cross-react with our own tissue. Your body builds an immune response against an EBV protein, completely correctly, but if part of that viral protein looks enough like something your own cells make, some of those antibodies or T cells may recognize both (Shabnam and Khan, 2026).

Your immune system is working off of bad information. :(

Side-by-side 3D models comparing how viral gp350 (green, left) and endogenous C3d (pink, right) map onto the B-cell receptor CR2 (gray).

And keep the concept of molecular mimicry in your back pocket during your immunology studies, because this is NOT just an EBV thing! Other pathogens are capable of doing this too.

Alright, now remember from earlier that when EBV goes dormant, it shuts down most of its genes and keeps only a small amount of viral activity going? One of the proteins that can stick around during latency is called EBNA1, or Epstein-Barr nuclear antigen 1. This one is especially interesting when we start looking at autoimmune disease (Shabnam and Khan, 2026).

In lupus, for example, parts of EBNA1 resemble Ro (SSA), one of the autoantigens targeted by the immune system in SLE. Antibodies produced against EBNA1 can cross-react with Ro, meaning the same antibody can recognize both the viral protein it was originally made to target and one of your own proteins (Draborg et al., 2013). From there, something called epitope spreading can happen, where an immune response that started against one small target gradually expands to recognize additional parts of the same protein, and eventually other proteins too (Fahlquist-Hagert et al., 2023). What started as a response against EBV has now widened into an autoimmune response against multiple targets.

EBNA1 doesn’t seem to have just one human look-alike. In MS, researchers have found cross-reactivity between EBNA1 and anoctamin-2, or ANO2, a protein expressed in the central nervous system. Antibodies against ANO2 are found more often in people with MS than in controls, and experiments have shown that antibodies recognizing ANO2 can also recognize a specific region of EBNA1 (Shabnam and Khan, 2026). Same viral protein, completely different human target.

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When EBV Wakes Back Up

So, what happens when EBV stops hiding?

Remember that latency isn’t permanent in the sense that EBV gets locked away inside a B cell and can never become active again. The virus can switch back into its lytic cycle, start producing new viral particles, and begin infecting other cells again. This is EBV reactivation!

Researchers still don’t have a complete picture of what makes that switch happen every time, but part of it comes down to the normal life cycle of the B cell itself. When a latently infected B cell differentiates into a plasma cell, the cellular changes involved in that process can activate EBV’s lytic program and push the virus back into active replication (Draborg et al., 2013). Reactivation can also happen spontaneously, during periods of acute or chronic stress, or alongside infection with another pathogen (Tarasco et al., 2025).

A lot of this comes back to the balance we talked about earlier between EBV and the immune system. If that balance gets disrupted, the conditions that were keeping a latent infection under control can change. Both immune suppression and an excessively inflammatory immune response have been associated with reactivation, which sounds a little backwards at first because those are opposite ends of the immune spectrum (Tarasco et al., 2025). But either one can interfere with the coordinated immune response that normally keeps EBV contained.

And we actually have a very big, very recent example of what that can look like: COVID-19.

Factors associated with EBV reactivation.

Read more

• Where the alarm system sits and what sets it off

• Why tissue swells, and what leaves the vessel first

• The loop that keeps inflammation escalating

• How your body shuts the whole thing down on purpose

• What chronic inflammation looks like at the tissue level

I had to memorize this piece by piece, cell by cell, for a course conference (more like an oral exam) for my immunology course this semester. It was interesting that I was studying this the same week I got stung by a bee on my finger (DIABOLICAL). It was fun to actually kind of SEE it happening in realtime, even though I know all of us have experienced a cut, a bug bite, a scratch, etc.

We all know what it looks like, but ever wonder what’s happening inside that cut? What our immune cells are doing? How they’re acting? What causes all the swelling and itchiness?

Wonder no more, my friends, let me explain it all to you!

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Phase One: Initiation

Okay, so let’s say you slice your finger open on the lid of a can. THE WORST.

Two things come in on that lid. Bacteria ride through the break in your skin. Right alongside them, a bunch of your own cells get crushed in the process, spilling their insides out into the surrounding tissue. Your body picks up on both of these using two separate sensing systems, each one watching for a different kind of trouble.

The cells doing the watching were already there before you even opened the can. Macrophages, dendritic cells, and mast cells (often termed “resident cells”) sit parked in your tissues on guard.

What does this mean? Well, they’re kind of decked out in receptors called PRRs, or pattern recognition receptors, and these are what pick up on trouble and sound the alarm to get the inflammatory response started (Roh & Sohn, 2018).

So, what counts as trouble? The bacteria riding in on that can lid are covered in PAMPs, or pathogen-associated molecular patterns, and they’re pretty self-explanatory, right? The PRRs recognize molecular patterns that come from pathogens, which could be LPS (lipopolysaccharide) from gram-negative bacteria, or even the little tail some bacteria use to swim around (flagellin). These are things our human cells just don’t make!

Then we’ve got DAMPs (also self-explanatory), damage-associated molecular patterns, coming from all those cells that were just sliced open by the sharp lid. Here the PRRs recognize things like ATP or mitochondrial DNA :( , the normal stuff that’s supposed to stay INSIDE the cell but sets off the alarm the moment it turns up OUTSIDE (Roh & Sohn, 2018).

This is why you’ll see swelling when you sprain your ankle, for example. No visible damage, no way for any outside bacteria to GET IN, but you still end up with some inflammation.

In the scenario we’re working with, though, you get both....sorry :(

PAMPs and DAMPs

The Mast Cell Opens

Remember those resident cells? Yeah? Okay, let’s focus on mast cells. And I know, you’ve probably heard all about them with the MCAS discourse online, but here, they’re not really our enemy. I’ll explain!!

So, the second the mast cell “senses” trouble, it degranulates, which is really just the fancy way of saying it dumps out everything inside of it: histamine, serotonin, leukotrienes, proteases, and cytokines like TNF-α and IL-1 (Granger & Senchenkova, 2010). And I literally mean the “second,” because this whole thing happens in seconds. Histamine is the one I want to zero in on here, because it reaches the endothelial cells lining your blood vessels and tells them to contract (Granger & Senchenkova, 2010).

Those cells are normally standing shoulder to shoulder, holding hands, sealing the vessel wall TIGHT. Now they’re scrunching up, letting go of each other, letting little gaps open up all along the blood vessel wall.

This leads to what’s called “increased vascular permeability,” meaning more things are able to get in and out of the blood vessel. And we want this to happen! (More on that coming up.) Histamine working on our vessels is actually what’s behind the swelling. Plasma proteins are the first thing to squeeze through those gaps into your tissue, and water follows right behind them (Granger & Senchenkova, 2010).

Meanwhile, In the Nucleus

While the mast cell was doing its thing in a matter of seconds, those resident cells that first caught the PAMPs and DAMPs have been working on something a whole lot slower behind the scenes.

Their PRRs switched on a protein called NF-κB, which heads straight into the nucleus and starts flipping genes on (Liu et al., 2017). Those genes code for the next big wave of the response: pro-inflammatory cytokines and chemokines like IL-1, IL-6, IL-12, and TNF-α (Liu et al., 2017). None of this stuff was sitting pre-packed and ready like the mast cell’s stash. The cell has to build every single one of these from scratch, which is exactly why this part takes hours instead of seconds. The chemokines are basically a flare going up into the sky, and the neutrophils are the ones who come running.

NF-κB target genes involved in inflammation development and progression.

Phase Two: Amplification

Alright, so initiation got the ball rolling. Now amplification is what turns a small, contained response into something big enough to actually deal with the threat.

Those neutrophils we called in don’t just show up, do their job, and file out. As they arrive and get to work, they release their own batch of signaling molecules, the same kind of cytokines and chemokines that called them in the first place. So the first responders are basically radioing for backup, and that backup shows up and radios for even more. One cell calls in ten, those ten call in a hundred, and the whole thing snowballs. Yikes.

A feedback loop like this, a response that feeds itself and keeps building instead of staying flat, is what makes amplification its own phase. And it’s exactly what you want when there’s a real threat, because a handful of cells was never going to be enough to clear a wound full of bacteria. You need the crowd.

The neutrophils are the muscle. They swarm the site, gobble up bacteria, and dump out enzymes and reactive molecules that kill off invaders (Filippi, 2019). It’s messy, effective work, and it’s a big part of why an inflamed area gets hot, swollen, and tender. You’re feeling the crowd doing its job.

But a response that only knew how to grow would be a disaster, right? Something has to eventually tell everyone to stand down. Aaand that’s exactly where we’re headed next.

Amplification Loop

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Phase Three: Resolution

Okay so the threat is handled! The bacteria are cleared, the wound is under control, and now your body has the opposite problem on its hands: a site absolutely packed with neutrophils that showed up ready to fight, with nothing left to fight. You can’t just leave that crowd standing around, because all those enzymes and reactive molecules they’ve been flinging will start chewing through your own tissue if nobody calls them off. So resolution is where the body winds everything down and clears out the mess.

Resolution is an active program, something the body switches on deliberately, with its own dedicated set of signals (Sugimoto et al., 2016). It runs a full shutdown sequence here, every bit as coordinated as the ramp-up was. A fresh crew of molecules called pro-resolving mediators clock in, and their job is to call off the recruitment, so that “send backup” signal from phase two finally goes quiet and no new neutrophils get waved in.

The neutrophils already on-site are pretty short-lived to begin with, so once the reinforcements stop arriving, the crowd starts thinning out on its own. Then the cleanup crew rolls in. Macrophages move through the area and clear away all the spent, dying neutrophils, tidying up the site (Ge et al., 2022). Clearing those dead cells does something extra, too, because eating them flips a switch inside the macrophage. It shifts from its aggressive, inflammatory M1 setting into a much calmer M2 setting, where it stops pumping out attack signals and starts releasing soothing, anti-inflammatory ones like IL-10 instead (Ge et al., 2022). The same cell that was running the war is now running the cleanup, calling for peace instead.

Once the mess is cleared and those calming signals are flowing, your tissue can finally start to rebuild, and everything settles back to baseline. That is a healthy inflammatory response from start to finish: it fires up right when you need it, does the messy work, and shuts itself off once the job is done.

Resolution Phase

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When Inflammation Won’t Shut Off

Everything so far describes inflammation working the way it’s supposed to. It fires, it does its job, it shuts down. Sometimes, though, that last step doesn’t happen, and the response that was meant to be temporary just keeps running. This is chronic inflammation, and it sits behind a huge number of long-term diseases.

Think back to that cleanup crew for a second, because a lot of chronic inflammation traces to the cleanup going wrong. When the macrophages can’t clear the dead cells fast enough, or the clearing process breaks down, those dead neutrophils pile up and rupture instead of getting cleared away (Ge et al., 2022). All the toxic contents they were holding spill straight into the tissue. To your body, that spill reads as fresh damage: new DAMPs, new alarm signals, another round of recruitment. The very thing that was supposed to end the response ends up feeding it.

Without that cleanup, the macrophages never get the message to change. That soothing M2 program, the one that produces IL-10 and starts calming everything down, only comes online when the macrophage receives the right signal, and eating those dead cells is the signal. No cleanup, no signal, so the M2 genes never get transcribed. The macrophages stay in their aggressive, inflammatory M1 mode, and the site stays hot (Ge et al., 2022). Now damage and repair are both running at once, indefinitely, with neither one ever finishing.

When tissue is caught in that loop of constant injury and constant attempted repair, the repair signals keep telling your fibroblasts to lay down collagen into a site that never heals. Fibroblasts are the connective-tissue cells that produce collagen and the other structural proteins making up the extracellular matrix, the scaffolding your tissues are built on. Here they just keep building, with no signal telling them to stop. Over time all that excess collagen accumulates as scar tissue, a process called fibrosis, and it slowly stiffens and reshapes the tissue until the organ can no longer work the way it used to (Chimenti et al., 2022).

So the story of inflammation comes down to balance. You want a response strong enough to protect you but smart enough to know when to quit, firing hard when a threat appears and then standing down once the work is done. Your body is good at the firing part. Staying well depends just as much on the shutting down, on that whole resolution program running the way it should and pulling the response to a close.

Pathogenesis of fibrosis.

We started with a single cut on a can lid, and from there your body ran an entire operation: resident cells spotting the intruders, mast cells throwing open the vessel walls, a crew of neutrophils swarming in to fight, then a careful, deliberate shutdown that cleared the mess and handed the site over for repair.

That’s initiation, amplification, and resolution, each phase flowing into the next.

So much of whether this protects you or harms you comes down to the ending. All that firepower stays safe only because the body has an equally strong system for standing down, so when that standing-down fails, the same response that defended you begins wearing at your own tissue, which is why the stopping carries just as much of the work as the starting ever did.

If this piece helped inflammation click for you, the biggest way to support the work is to consider a paid subscription.

I’m keeping it free because this foundation should be available to anyone, and paid members are what make that possible, so I can keep publishing work like this without putting the important pieces behind a paywall.

Every subscription helps keep this accessible for everyone.

If you found this useful or helpful, please like, comment, restack, or share it with someone who’d enjoy it! It really means a lot.

Until next time,

— Agy | The Buffalo Herbalist

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References:

Chimenti, I., Sattler, S., Del Monte-Nieto, G., & Forte, E. (2022). Editorial: Fibrosis and inflammation in tissue pathophysiology. Frontiers in Physiology, 12, 830683. https://doi.org/10.3389/fphys.2021.830683

Ge, Y., Huang, M., & Yao, Y.-m. (2022). Efferocytosis and its role in inflammatory disorders. Frontiers in Cell and Developmental Biology, 10, 839248. https://doi.org/10.3389/fcell.2022.839248

Granger, D. N., & Senchenkova, E. (2010). Inflammation and the microcirculation. Morgan & Claypool Life Sciences. https://www.ncbi.nlm.nih.gov/books/NBK53374/

Liu, T., Zhang, L., Joo, D., & Sun, S. (2017). NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2(1), 17023. https://doi.org/10.1038/sigtrans.2017.23

Roh, J. S., & Sohn, D. H. (2018). Damage-associated molecular patterns in inflammatory diseases. Immune Network, 18(4), e27. https://doi.org/10.4110/in.2018.18.e27

Sugimoto, M. A., Sousa, L. P., Pinho, V., Perretti, M., & Teixeira, M. M. (2016). Resolution of inflammation: What controls its onset? Frontiers in Immunology, 7, 160. https://doi.org/10.3389/fimmu.2016.00160

I wrote this paper for my doctoral program. It’s about Sjögren’s syndrome and mucosal dysbiosis, specifically how the disease affects the microbiome (are we surprised?) across the different organ systems it touches.

This post will not contain an edited version in my Substack educator voice. It’ll stay as is, exactly as I submitted it, and I won’t be adding the usual graphics I use for visualization. Fair warning: this is going to read VERY dry. Academia calls for rigor that gets straight to the point, and you’ll see that here. I love writing these kinds of paper AND for Substack, as it allows me to dip my toes into both voices, it’s fun for me!

I feel like I'm showing you guys the other side of me and it’s a little vulnerable!

What I found while writing this was actually super interesting, though. Sjögren’s affects multiple organ systems, and it was fascinating to see how the microbiome in each of those areas gets disrupted differently. Even in the EYEBALLS. Integrative therapies are included too.

Let me know what you think! And if this sounds interesting to you and you’d like a more digestible version, just say the word :) your wish is my command!

I really feel like I missed my calling as a microbiologist or something. The CHOKEHOLD our microbiome has one me is CRAZY.

ALSO: I've disabled the AI detection scan on this post. Dense academic writing tends to trip those tools up and get flagged as 'AI-generated' even when it's not, and I'd rather not have a flawed detector attached to something I worked hard on and submitted for my doctorate, nor do I really want this work uploaded to the program itself, to be completely honest. I hope you understand.

Quick side note: I just wanted to remind everyone about the Skool community I’ve been (very, very) slowly growing!

Substack is always going to be my spot for long-form deep dives, but over on Skool, we get to mix things up a bit. Think more video presentations, narrated slide decks, mini-breakdowns, more community vibes :)

The content topics are pretty much the same, but the formats are way more versatile and interactive. I’d love for you to join us over there too!

Come hang out with us here:

Skool Community!

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• What oral tolerance is and why your gut cannot function without it

• How your body sorts a harmless antigen from a dangerous one

• The cells that carry that decision out and make it stick

• Why tolerance travels through the whole body while inflammation stays put in the gut

• How a few common plants support the gut barrier, and how licorice constituents drove its effect on regulatory T cells

Okay so, I decided on this topic while studying for my immunology course conference, where I had to learn the ins and outs of it (like I had to memorize the whole thing).

Learning how the body tells friend from foe, particularly in the gastrointestinal tract, was fun because it let me connect a few dots between this topic and past research I’ve done, specifically on autoimmunity and Treg cells. I wanted to share this topic and explain it because I know a lot of us deal with food sensitivities and allergies, and since the food quality in the US isn’t really the best, it helps to understand why our bodies react the way they do to an organic piece of bread compared to something store bought and highly processed. I know you know what I mean.

I’m going to walk you through what happens cellularly, AND a few herbs to help the process along. :)

Okay, So How Much Is Your Gut Handling?

Let’s start here, with the numbers, because they’re a little unhinged…

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The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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We all see what’s happening right now, whether it’s through our TV screens or through the actual first-hand experience of stepping outside and breathing it in. The sky takes on that flat, weird hazy color, the sun turns a strange apocalyptic shade of orange, and within an hour your eyes are stinging, your nose won’t settle, and there’s a scratch at the back of your throat, but you know you aren’t sick

The air quality apps light up with numbers most of us never paid attention to before (or knew existed?!), and suddenly we’re all checking them the way we check the weather.

So today I want to slow down and work through what this is. We’re going to cover:

• What particulate matter is and where it comes from

• Why its size is the whole story when it comes to the danger it poses

• What it does to your airways and your body once you breathe it in

• How to think about herbal support and prevention in a way that maps onto that physiology

My goal is that you leave this piece understanding the why and the what of wildfire smoke, so that when you reach for a supportive herb or set up an air purifier in your bedroom, you’re doing it from a place of understanding rather than guessing.

Before we get into any of that though, it helps to have a reference point for the numbers we’re all watching, because the Air Quality Index is the tool telling us how concerned to be on any given day. (I know you’ve seen this plastered on the news and weather apps) The EPA calculates it for five major pollutants regulated under the Clean Air Act, and particulate matter is one of them (Friis, 2018). The scale runs from 0 to 500, where higher numbers mean more pollution and more risk, and the guide below breaks down who needs to be careful and what to do as the number climbs.

Air Quality Index guide for particulate matter. Source: U.S. Environmental Protection Agency (2014).

During a wildfire smoke event, the number climbing through those upper bands is largely being driven by the fine particulate matter we’re about to get into, so the AQI is really giving us a live readout of how much of that particulate is in the air around us.

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Breaking Down the Smoke

Particulate matter is the term for the mix of tiny solid particles and liquid droplets suspended in the air we breathe, and during a wildfire event that mix is made of soot, smoke, dust, and finely divided material carried along in the air (Friis, 2018). Those particles are rarely just inert specks, because they carry polycyclic aromatic hydrocarbons and volatile organic compounds along with them, and it’s largely those chemical passengers that drive the toxic effects we’re concerned about (Crinnion & Pizzorno, 2018).

Wildfire smoke is a particularly messy version of this, combining particulate matter with a whole range of trace gases (Rizzo & Rizzo, 2024). And it reaches far more of us than you might expect, because recent estimates attribute 25% of the fine particulate matter in the air across the United States to wildfires, with 95% of the population breathing wildfire smoke for at least one day a year (Rizzo & Rizzo, 2024).

When it comes to how particulate matter behaves once it’s in the body, size drives almost everything, so it helps to picture the scale we’re working with. A single human hair runs somewhere around 50 to 70 microns across, and the particles we classify as air pollution are only a fraction of that width (Friis, 2018). PM10 covers the coarser particles, the ones larger than 2.5 microns and ranging up to 10, while PM2.5 covers the fine particles from 0.1 to 2.5 microns, and finer still are the ultrafine particles at 0.01 to 0.1 microns (Friis, 2018). The smaller a particle gets, the easier it slips past the body’s normal defenses to settle deep in the lungs, and once it’s down there, if it doesn’t dissolve, our clearance mechanisms struggle to move it back out (Friis, 2018). That is where the real trouble starts, and where we’re headed next.

Size comparison of PM2.5 and PM10 particles against a human hair and fine beach sand. Source: U.S. Environmental Protection Agency.

Why Size Is the Whole Danger

Particulate matter smaller than 10 microns is readily absorbed in the lungs and then distributed throughout the body (Crinnion & Pizzorno, 2018). The smallest of these particles don’t stay where they land, and the distances they travel are hard to overstate.

When researchers measured ultrafine particulate in the livers of rats 18 to 24 hours after exposure, the levels in the liver were five times higher than in the lungs the particles had entered through (Crinnion & Pizzorno, 2018). Sit with that for a second, please. Five times higher, in the liver, in about a day. When we think about breathing in smoke, our minds go straight to the lungs, and that makes complete sense, because the lungs are the door it comes in through. What that liver finding tells us is that the door is not the destination, and the organ taking the biggest hit may be one we weren’t thinking about at all. Keep the liver in the back of your mind, because it’s going to come back around when we talk about support.

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In this issue:

• How the immune system fights a virus: why the misery of being sick is the response working correctly

• The off switch: the built-in brake that shuts inflammation down once the threat is cleared, and the protein that runs both the accelerator and the brake

• What drives the damage: how cleanly you shut the response down, not only how much virus you had

• What persists in Long COVID: the altered T-cell populations and immune mediators still circulating long after the virus is gone

• Brain fog: the inflammasome, cytokine, and blood-brain barrier story underneath it

• Post-exertional malaise: what’s happening in the muscle tissue itself, and why being out of shape doesn’t explain it

Next issue: the plants! I’m testing out splitting this into parts, because from the feedback I’ve been getting, smaller and more digestible posts land better, and honestly, I agree. I wish Substack had a cleaner way to organize a series, but I’ll figure something out. Next issue will get into which plants have research behind them for Long COVID, where that research is strong, and where it runs out, and I may even go a little crazy and put together some PDFs for you. It’s been a while :) I’m pretending I don’t have a lot on my plate, so please don’t told me to it lol!

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* Read in a dramatic, deep, narrator-style voice *
The following is based on a true story lol

I got COVID in the summer of 2020, back when the strain going around was still fully capable of humbling a person, and it knocked me out for three horrific, agonizing weeks.

I should mention that I rarely get sick, and I mean rarely. I don’t think I’ve ever actually had the flu, I don’t get colds, and while some of this is probably immunological good fortune, a lot of it is that I am an introvert who does not particularly want to leave the house, which turns out to be a wildly underrated infection control strategy. So, three weeks of my lungs hurting, my eyeballs actively attempting to vacate their sockets, insomnia stacked on top of an exhaustion I did not know was available to me, and all of it completely alone because it was 2020 and nobody was coming inside anybody’s house, was deeply destabilizing.

My dad would drive an hour after work to leave groceries at my door, and I would stand behind the glass and wave at him like a sad Victorian orphan. My stepdad once actually came inside to bring me groceries and I cried, openly, with real tears, because a fellow human being was standing in my kitchen. That entire period was trash, and I would like to formally request that we never do it again.

Anyway.

After those three weeks I was in the clear, thankful it was behind me, hopeful that my body had learned something useful from the whole ordeal and stockpiled whatever immune cells it might need next time, and I took an enormous deep breath through my finally unobstructed nostrils and went on with my life.

For a lot of people, that is not where the story ends.

They test negative and go back to work, and then months later they are standing in their own kitchen holding a coffee mug with absolutely no memory of what they walked in there to do, or they take the dog around the block and spend the next two days horizontal, or they find themselves reaching for words that used to be automatic and coming up with nothing. Their heart races when they stand up too fast. They are tired in a way that sleep does not touch, and every lab their doctor runs comes back looking perfectly, infuriatingly normal.

The virus left, but it seems like something else stayed.

What Your Immune System Is Doing When You Feel Like Garbage

Let’s go back to the couch, back to that bus-hit feeling, and follow what’s happening inside you while you’re lying there.

Somewhere in your body a cell has just been infected, and I want you to picture how that goes down, because the virus is not kicking in the door like the Kool-Aid man. The virus is an assassin. It’s covert, it’s silent, it slips inside without your cell registering a thing, and once it’s in there it starts using your cell’s own equipment to build copies of itself. Hacker of the year. Your cell is sitting there doing its job, running its ordinary operations, with absolutely no idea that it’s equipment has been turned against it and is now churning out virus on someone else’s orders.

So, what are we supposed to do with that? How does the body track down an intruder it cannot see?

Thankfully we do have something in the arsenal, and they’re called pattern recognition receptors (Chakravarty et al., 2023). They sit inside the cell and scan for molecular patterns that have no business being there, like a blip showing up on the radar in a stretch of space that’s supposed to be empty.

What they’re looking for, essentially, is a shape. Viral genetic material carries structural features that your own genetic material doesn’t, and these receptors have evolved to recognize those features and nothing else. Your cell can’t identify the virus by name, it has no idea what it’s up against, and it technically doesn’t need to. It just needs to notice that there’s nucleic acid in here wearing the wrong outfit.

And when they do notice, they set off a signaling cascade that activates two transcription factors working together, IRF3 and NF-κB (Chakravarty et al., 2023). These two divide the labor between them, and they’re doing very different jobs, which is where things start getting good.

Viral replication cycle.

IRF3 is the one that goes directly after the virus, driving the production of interferons and the interferon-stimulated genes, which inhibit a huge range of viruses by making it physically harder for them to copy themselves (Chakravarty et al., 2023). NF-κB, meanwhile, is the one bringing the inflammation, switching on the genes that summon immune cells to the scene, open up the blood vessels, and turn the local tissue into somewhere no pathogen wants to be (Chakravarty et al., 2023).

And NF-κB, my friends, is the one you feel. The aching, the fever, the swelling, that specific sensation of your body having been repossessed overnight and handed over to someone with much worse taste than you. All of that misery is inflammation doing precisely what it evolved to do, and as much as it ruins your week, it’s a large part of why you eventually get better.

In COVID specifically, the acute response mobilizes substantial quantities of pro-inflammatory cytokines along with inflammatory cells like neutrophils and macrophages, and it generates virus-specific CD4+ T cells, CD8+ T cells, and B cells, all of them working to clear the pathogen and limit its replication (Bohmwald et al., 2024). So, while you’re lying there feeling like you’ve been personally cursed, nothing is broken. Your body is pouring an enormous amount of energy into a defense operation, and the misery is the price of running that operation at full throttle. (Would it kill it to be a little more discreet about the whole thing? Apparently yes.)

Inflammation feeling terrible is not the problem, then. It feels terrible on purpose, and it's supposed to. The part I want to dig into is what happens after, when the virus has been cleared and the whole thing is supposed to wind down and go home.

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The Off Switch

Inflammation cannot run forever, and your body knows it.

It earns its keep in the early days of an infection, when the threat is live and the tissue needs defending, and then those same inflammatory genes turn on you in the later stage, driving cytokine storm and cell death (Chakravarty et al., 2023). What protected you on day two starts costing you on day twelve. The body has to have some way of calling the whole thing off before it gets there, and it does, and the mechanism is a little bit delightful.

Remember IRF3? The one we just met, out there driving the antiviral response and calling in the interferons? Turns out it’s been moonlighting. It has a second job, one that Chakravarty et al. (2023) call RIKA, and the job is to grab NF-κB and refuse to let go. How romantic.

Let’s slow down for this one though: NF-κB is a transcription factor, which means it can only do anything at all if it can physically get into the nucleus, since the nucleus is where the genes live and switching genes on is the entire point of its existence. What IRF3 does is intercept it out in the cytosol, which is the fluid filling the inside of the cell, everything sloshing around outside the nucleus, and pin it there. NF-κB never makes it to the door. The inflammatory genes it was on its way to switch on stay switched off, and the cytokines it would have summoned, IL-1β and TNF-α among them, never show up in the numbers they otherwise would have (Chakravarty et al., 2023).

So, IRF3 is out here running the antiviral response with one hand and holding inflammation back with the other. The accelerator and the brake, same protein, same cell, same infection. (Multitasking icon, frankly.)

Chakravarty et al. (2023) also make a point about what drives the damage. Virus-induced inflammation causes disease on its own, separately from viral load. How sick you get, and how much damage you walk away carrying, tracks with how cleanly you shut the response down, not only with how much virus you had in you.

Two people can clear the same infection and come out of it with very different bodies, and a lot of that difference lives in the ending.

RIKA, a new anti-inflammatory function of IRF3. IRF3 is widely known for its transcriptional function involving the production of IFNβ and ISGs which antagonize various stages of viral replication

What Stays Behind

For most people, the ending goes fine. The virus gets cleared, the brake comes on, inflammation packs up its things and goes home, and you get your body back. Yay!

But for others, the response never fully stands down. :(

The rest of this one is for paid subscribers.

Below the line, we get into what that failed shutdown does once it settles into tissue: how inflammation crosses a barrier your brain spent your whole life protecting, what your microglia start doing when nobody tells them to stop, and why the muscle of someone with Long COVID looks different from the muscle of someone who simply stopped moving.

Paid subscribers keep this work possible, and it unlocks the full archive, the Body System Index, and the Materia Medica Index while you’re at it.

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The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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The AMA is not, and never will be, a replacement for a consultation. I cannot and will not answer personal or individualized health questions. Where a question is specific to one person, I’ll answer the general version of it instead.

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Question 1: What herbal remedies should I use, and which should I avoid, with an overactive bladder, to soothe and regulate the pressure and urgency?

Before I get into the herbs, it helps to understand what's actually going on with an overactive bladder, because that's what the whole approach is built around. At its simplest, an overactive bladder is a signaling problem, where the bladder tells your brain it's full and urgent long before it actually is. Researchers trace that faulty signal to a few different places (Chen et al., 2024). Sometimes it starts in the urothelium, the lining of the bladder, which is studded with sensors that can become overactive and fire off urgency messages they shouldn't. Sometimes it's the detrusor, the muscular wall of the bladder itself, contracting when it isn't supposed to. And sometimes it comes from higher up, in the nerves and the brain that process those signals and decide how loud the urge feels. Often, it's some combination of all three, layered on top of other contributors like inflammation, hormonal shifts, or anxiety, which is why an overactive bladder rarely traces back to a single cause (Chen et al., 2024).

Pathogenesis of OAB

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This article is a prime example of my researched deep dives. I start by explaining the physiology behind the topic, walk you through the actual research papers (and no, as you’ll see, I don’t cherry-pick studies to strengthen a claim. If I have questions about a paper, I’m going to show you exactly why. This publication isn’t here to sell you on herbs. It’s here to show you what’s out there, no fluff.), and then we look at what an herb is actually doing according to the evidence. These pieces are long, so please feel free to save this and come back to it whenever you’re ready.

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At some point in the last decade, a very specific story about aging started showing up pretty much everywhere.

It usually gets introduced with the exact same analogy: They’re like the plastic caps on the ends of your shoelaces! AND btw the shoelace caps are called AGLETS so this is basically MY topic to write about!

We are told that every time your cells divide, those little caps fray a bit. When they get too short, the cell stops dividing, you age, and everything goes downhill. The marketing pitch that follows is almost entirely predictable: Buy this incredibly expensive extract of Astragalus root, grow your aglets back, and live forever! YAY!

It sounds beautiful, empowering, and incredibly simple. See you in 500 years!

Buuuuut if medical research has a golden rule, it’s that biology is never simple. Those tiny plastic shoelace caps aren’t a design flaw the body forgot to fix. They are actually part of a highly coordinated, brilliant defense system.

Today, we are going to look at the physiology: why your cells shorten their fuses on purpose, how stress gets under your skin to burn through them, and what happens when supplement marketing stretches clinical trials past their breaking point.

The Mitotic Clock: Why Your Cells Have Fuses

So, what are telomeres, actually?

Your DNA is organized into chromosomes, and those chromosomes are linear, meaning they have ends. The problem with having ends is that every time a cell copies its DNA to divide, the enzyme doing the copying can’t quite finish the job. It needs a primer to get started and can only work in one direction, so a small stretch at the very tip of each chromosome gets left behind every single round (Vaziri et al., 1994; López-Otín et al., 2023). This is called the end-replication problem, and your body has been dealing with it since before you were born.

The solution is a buffer zone. Your chromosomes are capped with long repeating stretches of non-coding text, the sequence TTAGGG over and over, thousands of base pairs deep, sitting between your actual genetic code and the edge that keeps getting nibbled (Vaziri et al., 1994). Those buffers are your telomeres. They’re sacrificial by design, because the alternative would be losing functional DNA with every division, and that’s not something you survive for long.

Telomere

Now think about how much cell division your body is actually running. You’re replacing cells constantly, in your skin, your gut lining, your blood, pretty much anywhere tissue needs to be maintained or repaired. Your bone marrow alone keeps a small population of stem cells on permanent duty, and those cells are responsible for generating your entire supply of red blood cells, white blood cells, and platelets, every single day, for your entire life (Vaziri et al., 1994). That’s an almost unreasonable amount of cellular division, and every single round shaves a little more off the telomere.

Back in 1994, Vaziri et al. (1994) tracked telomere length across human life, from fetal tissue to umbilical cord blood to adult bone marrow from donors ranging from 16 to 58 years old. They found that telomeres shortened by roughly 9 base pairs per year of donor age in vivo, and when those same cells were cultured and asked to divide, they lost about 37 base pairs per population doubling. Every cell in your body is carrying a record of how many times it's divided, written into the length of its own telomeres.

When those telomeres shorten far enough, the chromosome ends uncap, genomic stability falls apart, and the cell is forced into one of two exits: apoptosis, which is programmed self-destruction, or senescence, which is permanent cell cycle arrest (López-Otín et al., 2023). The cell either kills itself or locks up forever. And as we're about to get into, both of those outcomes are the point.

Attrition as Defense

Telomeres act as potent tumor suppressors by limiting proliferation (Barnes et al., 2022).

Your cells are constantly bombarded by chemicals, replication errors, and environmental toxins, all of which threaten genome integrity and stability, meaning your DNA’s ability to stay accurate and intact across every round of copying (López-Otín et al., 2023). If a cell picks up mutations that tell it to multiply uncontrollably, its shrinking telomere is the thing that stops it. The fuse burns down, the cell hits a wall, and the runaway replication ends before it can go anywhere.

Now, your body does have a tool that can rebuild telomeres: an enzyme called telomerase. It’s a specialized reverse transcriptase that uses its own RNA template to add telomeric DNA back onto the chromosome ends (Epel et al., 2004; López-Otín et al., 2023). Pretty elegant, right? But most of your somatic cells don’t express it, and that’s on purpose (López-Otín et al., 2023). Your body would rather let those fuses burn down than risk a cell that can copy itself forever. Because when cells do find a way to bypass that arrest signal and flip telomerase back on, that’s typically what you’re looking at in cancer progression (Vaziri et al., 1994). Telomerase reactivation shows up in more than 80 percent of human tumors (Canale & Andreassi, 2025).

So, when a supplement company tells you their pill is a systemic telomerase activator designed to override this safety mechanism in every cell of your body, I want your first reaction to be a healthy dose of caution, not a visualization of your next thousand years on this earth.

Telomere attrition | Source unknown

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How Life Stress Gets Under the Skin

If somatic cells keep telomerase turned off, what causes some people’s fuses to burn down way faster than others? Chronological time is only part of it, because the biological environment matters immensely, and your mind is directly wired to that environment. ,

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Hi! Another bite-sized herbal medicine goodness for you :)

In this issue:

• What secretory IgA does at the mucosal barrier

• Where your body manufactures it

• How fiber, vitamin A, and ginger each turn up production

• The plot twist about which ginger compounds did the work

I picked IgA off a list of antibody isotypes for a discussion post in my doctoral coursework, partly because (as you may have noticed by now) I have a slight obsession with how much our gut influences every other system in the body. As I was annotating the sources, I immediately knew I wanted to share this with you all. If you like this info and want me to over the other immunoglobulins, just let me know!

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Where IgA Comes From

A surprising amount of your IgA is made in Peyer’s patches, which are clusters of lymphoid tissue tucked into the wall of the small intestine.

Min et al. (2023) describe the intestinal mucosa as holding more than 80% of the body’s activated B cells, which makes the gut the single largest antibody-producing structure you have! Inside the Peyer’s patches, dendritic cells release signaling molecules like IL-6 that tell B cells to mature into plasma cells and begin secreting IgA. The entire production line for your mucosal defense sits right there in the gut wall.

Peyer's Patch + Immune System

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