When people describe what depression and chronic anxiety actually feel like in the body, they rarely talk about neurotransmitters. They talk about being wired and exhausted at the same time. Waking at 3 a.m. with a racing heart. Feeling braced for a threat that never quite arrives, day after day, until the bracing itself becomes the problem. A lot of that experience traces back to one system: the HPA axis, the hormonal machinery that runs the human stress response.

Because ketamine has become a meaningful option for treatment-resistant depression, anxiety, and PTSD—conditions in which the stress system is frequently out of tune—a reasonable question follows. Does ketamine actually do anything to cortisol and the HPA axis? The answer is yes, but in ways that are more interesting and less tidy than a simple “it lowers your stress hormones.” We think it’s worth explaining honestly, because the real picture is more reassuring than the oversimplified version.

What the HPA Axis Does

HPA stands for hypothalamic-pituitary-adrenal. It describes a three-step hormonal cascade that governs how the body responds to stress. When the brain perceives a threat, the hypothalamus releases corticotropin-releasing factor (CRF). CRF signals the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then travels to the adrenal glands, which sit atop the kidneys, and prompts them to release cortisol—the hormone most people associate with stress.

In a healthy system, this cascade is self-correcting. Cortisol rises to meet a challenge, then feeds back to the brain to shut the response off once the threat has passed. The whole loop is supposed to be brief. Cortisol also follows a natural daily rhythm, peaking in the early morning to help you wake and get moving, then tapering across the day to its lowest point at night.

The trouble in chronic depression, anxiety, and PTSD is that the off switch stops working well. The system stays partly activated. Cortisol runs elevated or loses its normal rhythm, and the feedback that’s supposed to calm everything down becomes blunted. Researchers describe this as HPA axis dysregulation, and it’s one of the more consistently observed biological features across stress-related mental health conditions.

Why Chronic Cortisol Elevation Matters for the Brain

Cortisol isn’t a villain. In the short term it’s essential, sharpening attention and mobilizing energy. The problem is duration. When cortisol stays high for months or years, it begins to wear on the very brain regions that regulate mood and memory.

The hippocampus, a structure central to memory and emotional regulation, is densely populated with cortisol receptors and is particularly vulnerable. Prolonged cortisol exposure is associated with reduced dendritic complexity and impaired neuroplasticity in this region—essentially, the brain’s capacity to form and maintain healthy connections gets compromised. This overlaps directly with what we describe in our piece on how ketamine works, where the loss of synaptic connections is a core feature of the depressed brain.

So there’s a plausible link worth taking seriously: chronic stress drives cortisol up, sustained cortisol erodes neuroplasticity, and reduced neuroplasticity is part of what keeps depression entrenched. If ketamine’s signature effect is rapidly restoring neuroplasticity, then the stress system is a natural place to ask whether ketamine also helps reset the upstream driver.

What Ketamine Actually Does to Cortisol

Here’s where honesty matters. The short-term and long-term stories are different, and conflating them causes confusion.

In the short term, a single ketamine infusion can raise cortisol around the time it’s given. This isn’t surprising. The dissociative experience is novel, the setting is clinical, and the body often reads the whole event as physiologically arousing—at least the first time. A transient rise in cortisol during or shortly after an infusion is a normal acute response, not a sign that anything is going wrong.

Over a full course of treatment, the picture shifts. As depression and anxiety symptoms improve—sleep stabilizes, the constant sense of threat eases, rumination quiets—the chronic overactivation of the HPA axis tends to settle along with the symptoms. In other words, ketamine may not lower cortisol by acting on the adrenal glands directly so much as by relieving the underlying psychological state that was keeping the stress system switched on in the first place. The hormonal improvement appears to ride along with the clinical improvement.

Chronic stress leads to overactivation of the HPA axis, which increases corticotropin-releasing hormone and cortisol while decreasing the expression of glucocorticoid receptors—the very receptors the brain relies on to switch the stress response off. — Reviewed in PMC, “Inflammation, stress and depression: ketamine’s therapeutic profile,” 2023

The 2024 Finding That Changes the Question

One of the more useful recent studies on this topic was published in 2024 in the Journal of Affective Disorders. Researchers measured baseline levels of three HPA axis hormones—CRF, ACTH, and cortisol—in 42 participants with treatment-resistant depression enrolled in a randomized, placebo-controlled, crossover trial of intravenous ketamine. The question was straightforward: do a person’s starting stress-hormone levels predict whether ketamine will work for them?

The answer was no. Baseline CRF, ACTH, and cortisol levels did not moderate ketamine’s antidepressant effects. You could not look at someone’s stress hormones beforehand and forecast their response.

We find this genuinely reassuring, and here’s why. A common worry among people with long histories of severe, chronic stress is that they’re somehow “too far gone”—that their system is so dysregulated nothing will reach it. This finding pushes against that fear. Ketamine appeared to work across a range of stress-hormone profiles, which suggests its antidepressant mechanism doesn’t depend on starting from a particular hormonal baseline. The study did note one secondary observation: people with longer-lasting depressive episodes tended to have lower ACTH and CRF, a hint at how prolonged depression may reshape the stress system over time. But that pattern didn’t translate into worse ketamine response.

Timing, Rhythm, and Why the Research Looks Messy

If you go looking through the literature, you’ll find studies that seem to disagree about whether ketamine raises, lowers, or doesn’t change cortisol. A lot of that apparent inconsistency comes down to when measurements were taken.

Because cortisol follows a daily rhythm, a sample drawn at 8 a.m. carries different meaning than one drawn at 4 p.m. Research has shown that the stress-hormone response to ketamine itself can vary depending on the time of day it’s administered relative to that rhythm. Add in differences in dose, whether it’s racemic IV ketamine or esketamine, and how long after the infusion blood was sampled, and you have plenty of room for studies to look like they conflict when they’re really just measuring different moments.

For patients, the practical takeaway is simpler than the research debate: we don’t time infusions around cortisol readings or check stress hormones to decide who’s a candidate, because the evidence doesn’t support doing so. The clinical decision rests on your history, your symptoms, your medications, and your goals—not on a lab value that the science says won’t predict your outcome anyway.

How This Connects to PTSD and Anxiety Treatment

The HPA axis is especially relevant in PTSD, where the stress response is, almost by definition, miscalibrated. People with PTSD often show distinctive HPA axis patterns, and the felt experience—hypervigilance, exaggerated startle, a body that won’t stand down—maps onto a stress system stuck in the on position. Our work with ketamine for PTSD and ketamine for anxiety is partly about giving an overtaxed stress system room to recalibrate, alongside the neuroplasticity effects that let new, less fear-driven patterns take hold.

This is also one reason the period after each infusion matters so much. The neuroplastic window—the stretch of heightened brain malleability following treatment—is a time when calming the stress response and reinforcing it through rest, integration, and supportive routines can compound the benefit. A more regulated HPA axis and a more plastic brain are not separate goals. They reinforce each other.

An Honest Summary of Where the Science Sits

We don’t want to overstate this. The research on ketamine and the HPA axis is still developing, much of the mechanistic detail is unsettled, and a good deal of it comes from small samples. What we can say with reasonable confidence is this:

If you’ve spent years feeling like your body has forgotten how to stand down, that’s not a character flaw or a sign you’re beyond help. It’s a recognizable physiological pattern, and it’s one of the things careful treatment is meant to address. We’re a small team in Franklin, and we’d be glad to talk through your specific situation and whether ketamine is a sensible next step.