there is a term that has been quietly spreading through wellness culture for the last decade. you may have seen it on instagram, heard it from a naturopath, read it in a supplement brand's copy.
adrenal fatigue.
it's a good description of a real feeling. the flat energy. the tiredness that doesn't lift even after a full night's sleep. the sense that your body's ability to handle pressure has quietly diminished. the feeling, as one physician put it, of being wired but tired — never fully alert, never fully calm.
the problem is that "adrenal fatigue" is not, clinically, a real diagnosis. and the supplement industry has exploited that ambiguity for years, selling products that sometimes — according to a study published in Mayo Clinic Proceedings — contain undisclosed thyroid hormones and steroids.
so when a physician at the Osher Center for Integrative Health at Northwestern University publishes a paper in The American Journal of Medicine — one of the oldest and most respected clinical journals in the united states — specifically arguing that there is a real, diagnosable, treatable condition that "adrenal fatigue" has been clumsily pointing at all along, it is worth paying attention.
the paper is called An Integrative Approach to HPA Axis Dysfunction: From Recognition to Recovery. it was published in 2025. this is our attempt to translate it for the people who should read it but will never make it through 13 pages of endocrinology.
first: what is the HPA axis, actually
HPA stands for hypothalamic-pituitary-adrenal. these are three glands that form a chain of command inside your body for handling stress.
something stressful happens. your hypothalamus — a small region in the brain — sends a chemical signal to your pituitary gland. the pituitary sends a signal to your adrenal glands, which sit on top of your kidneys. the adrenals release cortisol. cortisol floods the body, sharpening focus, raising blood pressure, mobilising energy. then — in a healthy system — cortisol feeds back to the brain and says okay, enough. the whole system dials back down.
this is a beautiful, elegant mechanism. it evolved over millions of years. it is very good at handling the kind of stress it was designed for — acute, physical, finite. the lion. the flood. the famine.
the system was not designed for the kind of stress most of us actually live with. chronic, low-grade, unresolvable. the inbox. the performance review. the slow bleed of never quite being done. not a lion. just everything, all the time, with no obvious endpoint.
when stress is chronic, the HPA axis doesn't break. it adapts. and that adaptation — the paper argues — is precisely the problem.
the adaptation that looks like health
under chronic stress, several things happen to the HPA axis that are not immediately visible but are consistently measurable.
the first is cortisol rhythm flattening. a healthy cortisol pattern has a sharp peak in the morning — you wake up alert, clear-headed, energised — and a steady decline toward evening, reaching its lowest point around midnight. in people with chronic HPA dysregulation, this curve flattens. the morning peak blunts. the evening trough rises. the person is never quite sharp. never quite calm. wired but tired is not a metaphor. it is the literal cortisol curve.
the second is glucocorticoid receptor downregulation. when cortisol is chronically elevated, the body protects itself by reducing the number of receptors that respond to it. the person becomes cortisol-resistant — less reactive to stressors, but also less capable of peak performance and recovery. from the outside this can look like emotional stability. it is not. it is biochemical flattening.
the third is what the paper calls HPA hypo-responsiveness. paradoxically, chronic activation eventually makes the system underreactive. the amplitude narrows. the person cannot access high arousal states without external stimulation — caffeine, pressure, deadlines — but also cannot access genuine rest. the system is stuck in a narrow band in the middle, running at reduced capacity in both directions.
the 3am wake. the exhaustion that doesn't lift. the coffee that no longer works the way it did at 28. the recovery that takes the whole weekend now instead of a night.
same.it is not in your head. and it is not adrenal fatigue.
the paper is careful to make a distinction that matters. HPA axis dysfunction is a real, measurable, clinically meaningful pattern of altered cortisol rhythms and impaired stress resilience. it is not the same as adrenal insufficiency — a serious condition where the adrenal glands cannot produce cortisol at all, which requires urgent medical treatment. and it is not the same as "adrenal fatigue," which the paper describes as an inaccurate descriptor that has generated more confusion than understanding.
what it is, the paper argues, is a complex dysregulation — influenced by chronic psychological stress, diet, sleep quality, gut health, inflammation, environmental exposures, and hormonal balance — that manifests as a recognisable cluster of symptoms that have historically been dismissed, minimised, or attributed to something else entirely.
fatigue. insomnia. mood disturbances. poor stress tolerance. brain fog. weight changes. the sense that you are operating below your own baseline.
these are not character flaws. they are not consequences of not trying hard enough. they are the downstream effects of a stress regulation system that has been running in a mode it wasn't designed for, for longer than it should.
what makes it worse — and what makes it better
the paper reviews the full landscape of what contributes to HPA dysfunction. some of it is not actionable — genetic variations, early life stress, childhood adversity. these influence the system at a level that no supplement or sleep schedule will fully correct.
but much of it is. the paper identifies several areas where evidence-based intervention has demonstrated measurable effects on cortisol patterns and stress resilience.
sleep is not optional and not negotiable. poor sleep is both a cause and a consequence of HPA dysregulation — elevated cortisol disrupts sleep architecture; disrupted sleep elevates cortisol the next day. deep sleep specifically is when the HPA axis performs the cortisol suppression that resets the system overnight. without it, the morning peak never fully recovers.
exercise is a cortisol modulator — but the dose matters. moderate intensity exercise, around 150 minutes per week, enhances stress resilience through adaptive HPA activation. excessive intensity or duration — sessions over 90 minutes, inadequate recovery — does the opposite. it is possible to exercise in a way that worsens HPA dysfunction. more is not always better.
diet has a more direct relationship with cortisol than most people realise. high glycemic load diets — refined carbohydrates, rapid sugar spikes — increase insulin, which stimulates cortisol secretion. deficiencies in magnesium, B vitamins, zinc, and vitamin C all impair adrenal and neuroendocrine function. irregular meal timing — skipping breakfast, eating late at night — disrupts the cortisol rhythm directly.
the gut has a bidirectional relationship with the HPA axis that the paper gives significant attention. gut dysbiosis — an imbalance in gut microbiome composition — can activate the HPA axis and alter stress responses. conversely, chronic cortisol elevation impairs gut microbiome health. this is a loop, not a one-way street.
on adaptogens — what the evidence actually says
this is the section most relevant to what we're building at pause n play, so we want to be precise about what the paper claims and what it doesn't.
the paper devotes a full section to adaptogenic herbs — defining them as natural substances that help the body adapt to stress, support homeostasis, and promote resilience — and reviews the clinical evidence for each.
ashwagandha has the strongest evidence base of any adaptogen reviewed. systematic reviews support its ability to reduce cortisol levels and improve stress resilience. the paper cites doses of 125-500mg once or twice daily, standardised to withanolide content. it notes that ashwagandha is particularly suited to people experiencing anxiety and insomnia due to its calming mechanism — it works on the cortisol sensitivity axis, not as a stimulant or sedative.
rhodiola rosea works differently. its mechanism is through monoamine modulation — it addresses mental and physical fatigue, enhances performance under stress. the paper positions it as better suited to people experiencing exhaustion and cognitive fatigue than to those with primarily anxiety and sleep symptoms. ashwagandha for the ⏸ stuck. rhodiola for the ▶ stuck. this is not arbitrary — it reflects genuinely different pharmacological mechanisms.
the paper also reviews holy basil (tulsi), panax ginseng, and licorice root — all with varying levels of evidence, mostly smaller clinical studies and preclinical data.
the paper is clear that adaptogens are not a replacement for addressing the underlying drivers of HPA dysfunction. they are supportive — tools to assist resilience while the deeper work of sleep, movement, nutrition, and stress management is also being done. they are also not all equal. quality of extract, standardisation of active compounds, and dose all matter. the supplement market is poorly regulated and the distance between a clinical-grade ashwagandha extract and a generic capsule is larger than most labels suggest.
a word about "adrenal support" supplements
we want to name this directly because it is important.
the paper cites a study from Mayo Clinic Proceedings that tested over-the-counter "adrenal support" supplements available in health stores. the researchers found that many contained undisclosed active hormones — including cortisol, cortisone, thyroid hormone (T3), and androstenedione — that were not listed on the label.
this is not a fringe finding. these are widely available products being sold to people who are already in a state of hormonal dysregulation. the paper explicitly advises clinicians to avoid recommending these products. we would say the same to anyone reading this.
the reason to understand the HPA axis is not to find a supplement to fix it. it is to understand what's actually happening in your body — and to make choices that support a system that has been quietly running in an adapted state for longer than it should.
the thing the paper says at the very end
the paper closes with a paragraph that we found unexpectedly moving for a clinical research study.
it notes that healthcare providers themselves are at risk — that the high levels of chronic stress common in clinical practice contribute to HPA axis dysregulation in the people doing the treating. it asks them to prioritise their own wellbeing, to recognise their own vulnerability, to engage in self-care strategies that sustain their health.
it is, in its way, an acknowledgment that the system the paper describes does not discriminate. it doesn't care how much you know about cortisol. it doesn't care how high your status is, how hard you have worked, how disciplined you have been.
chronic stress, run long enough, changes the system. and the first step toward changing it back is understanding what has actually been happening.
if this sounded less like a paper and more like a description of the last few years — that's the point. it isn't a character flaw. it's a system doing exactly what systems do under sustained pressure. it adapts. and adapted dysregulation can be moved.
same.