Adaptogens HPA Gene Expression Research

Last updated: October 4, 2026 - Reviewed by Verdant Wellness Editorial Team

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By Gabriela Mitchell, Registered Dietitian (Linkedin)

Last Updated September 2026  ·  34 min read

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Table of Contents

1. What Are Adaptogens and Why Does Gene Expression Matter?
2. The HPA Axis: A Molecular Primer
3. How Adaptogens Influence HPA Gene Expression: The Core Mechanisms
4. CRH Gene Regulation: Upstream Control of the Stress Cascade
5. ACTH Gene Expression and Adaptogen Interventions
6. Glucocorticoid Receptor Gene Modulation
7. Ashwagandha and HPA Gene Expression: Deep Dive
8. Rhodiola Rosea Gene Expression: Evidence from 2015 to 2024
9. Schisandra, Eleutherococcus, and Panax Ginseng: Comparative Molecular Profiles
10. Transcription Factors and Signaling Pathways Beyond the HPA Axis
11. Cell-Based and Preclinical Evidence: What Can We Extrapolate?
12. Clinical Evidence: Bridging the Lab-to-Human Gap
13. Safety, Drug Interactions, and Pharmacogenomic Considerations
14. 2024–2026 Research Highlights
15. Key Takeaways for Researchers and Clinicians
16. Frequently Asked Questions

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Introduction

The intersection of botanical medicine and molecular biology has produced some of the most compelling—and most misunderstood—research in integrative pharmacology over the past decade. Adaptogens HPA gene expression research sits precisely at this crossroads, asking a deceptively simple question: can plant-derived compounds meaningfully alter the genetic machinery that governs how the human body responds to stress?

The short answer, increasingly supported by peer-reviewed systems-biology studies, is yes. But the nuances matter enormously, and the molecular details are what separate evidence-based practice from marketing copy.

This article is written for researchers, clinicians, and advanced students in molecular biology, pharmacology, and integrative medicine. We will examine what is currently known about how adaptogens modulate gene expression along the hypothalamic-pituitary-adrenal (HPA) axis, which specific genes and transcription factors are implicated, what the preclinical and clinical evidence actually shows, and where the most significant knowledge gaps remain as of 2025–2026.

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What Are Adaptogens and Why Does Gene Expression Matter?

Defining Adaptogens at the Molecular Level

The term "adaptogen" was coined by Soviet pharmacologist Nikolai Lazarev in 1947 and later formalized by Israel Brekhman and I.V. Dardymov. Classically, an adaptogen is a substance that meets three criteria: it must be non-toxic at normal doses, it must produce a nonspecific increase in resistance to stress (physical, chemical, or biological), and it must normalize physiological functions regardless of the direction of pathological change.

What this definition implies at the molecular level is now clearer than it was in 1947: adaptogens appear to function as stress-response modulators rather than simple stimulants or sedatives. They occupy a mechanistic middle ground, nudging overactivated stress-response pathways downward while supporting underactivated ones upward. This bidirectional property is almost certainly mediated, at least in part, through gene expression changes rather than simple receptor agonism or antagonism.

Why Gene Expression Is the Right Level of Analysis

When a stressor activates the HPA axis, what ultimately happens is a cascade of gene regulatory events. Corticotropin-releasing hormone (CRH) is transcribed in the paraventricular nucleus of the hypothalamus. Adrenocorticotropic hormone (ACTH) is synthesized from the POMC gene in the pituitary. Glucocorticoids are produced and secreted by the adrenal cortex, then feed back onto glucocorticoid receptor (GR) genes in the brain, pituitary, and peripheral tissues.

Each of these steps is a gene expression event, and each is potentially modifiable by bioactive compounds. Understanding adaptogen gene expression therefore means understanding whether and how these compounds alter the transcriptional activity of CRH, POMC, GR, and the many downstream effector genes these pathways regulate.

A 2018 systems-biology study elegantly demonstrated this point: adaptogen exposure in isolated brain cells altered gene-expression profiles measurably, with at least 88 of 3,516 regulated genes linked to adaptive stress-response signaling.[7] This is not a trivial number—it suggests that adaptogens are not acting through a single target but through a coordinated, network-level reorganization of transcriptional programs.

The HPA Axis: A Molecular Primer

The Three-Tier Architecture

Before examining adaptogen HPA molecular interactions, it is worth reviewing the axis itself with molecular precision.

Hypothalamus: The paraventricular nucleus (PVN) contains parvocellular neurons that synthesize and release CRH (encoded by the CRH gene, also called CRF) and arginine vasopressin (AVP). CRH is the primary driver of pituitary ACTH secretion. CRH gene transcription is regulated by cAMP response element-binding protein (CREB), activator protein 1 (AP-1), and nuclear factor kappa B (NF-κB), among others.

Anterior Pituitary: Corticotroph cells express CRH receptor 1 (CRHR1), through which CRH stimulates the transcription of pro-opiomelanocortin (POMC). POMC is the precursor protein that is post-translationally cleaved to produce ACTH, β-endorphin, and other peptides.

Adrenal Cortex: ACTH binds the melanocortin 2 receptor (MC2R) on zona fasciculata cells, activating the cAMP-PKA pathway and upregulating steroidogenic genes (StAR, CYP11A1, CYP11B1) to synthesize and secrete cortisol (humans) or corticosterone (rodents).

Negative Feedback: Cortisol and corticosterone exert negative feedback at multiple levels—hypothalamus, anterior pituitary, and hippocampus—primarily through glucocorticoid receptors (GR, encoded by NR3C1) and mineralocorticoid receptors (MR, encoded by NR3C2). GR activation leads to transcriptional repression of CRH and POMC genes through direct interaction with glucocorticoid response elements (GREs) and through transrepression mechanisms involving NF-κB.

Why HPA Dysregulation Matters

Chronic stress leads to HPA axis dysregulation characterized by hypercortisolemia, GR resistance, blunted negative feedback, and downstream consequences in immune function, metabolism, cognition, and mood. Many of the pathologies that adaptogens are studied for—stress, fatigue, anxiety, depression, burnout—involve HPA axis dysfunction at the gene regulatory level. This is precisely why adaptogen HPA molecular research is clinically relevant.

How Adaptogens Influence HPA Gene Expression: The Core Mechanisms

The Multi-Target, Multi-Gene Paradigm

One of the most important insights from modern adaptogen research is that these compounds do not work through a single molecular target. The 2026 MDPI review "System-Level, Molecular and Cellular Mechanisms of Selected Adaptogens" synthesized evidence showing that adaptogens regulate the HPA axis and simultaneously influence heat shock protein 70 (Hsp70)/Hsp16 expression, stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signaling, Forkhead box O (FOXO) transcription factors, and NF-κB pathways.[1][8] This is a systems-level rewiring, not a point intervention.

The Stress-Mimetic Hypothesis

One theoretical framework that has gained traction is the stress-mimetic or hormetic hypothesis. Under this model, adaptogens produce a mild, transient activation of stress-response pathways at low doses—essentially mimicking a sub-threshold stressor—thereby inducing a preparatory state that increases the organism's resilience to subsequent, more severe stress. This would explain why adaptogens are sometimes described as "priming" the stress response rather than simply blunting it.

At the gene expression level, this could manifest as mild, transient upregulation of stress-response genes (heat shock proteins, neuropeptide Y, certain kinases), followed by return to homeostasis with enhanced buffering capacity. Consistent with this, the 2012 study showing that ADAPT-232 stimulated expression of neuropeptide Y (NPY) and Hsp72 in isolated human neuroglia cells is particularly instructive.[3][6] NPY is directly linked to HPA-axis regulation—it modulates CRH release in the PVN—and Hsp72 functions as a cytoprotective chaperone that buffers protein damage during stress. Upregulating both simultaneously suggests a coordinated adaptive response.

Transcriptional vs. Post-Transcriptional Mechanisms

It is worth distinguishing between transcriptional effects (changes in gene promoter activity and mRNA production) and post-transcriptional effects (changes in mRNA stability, translation efficiency, or protein turnover). Current adaptogen research has focused predominantly on mRNA expression changes, which are proxies for transcriptional activity. Protein-level and epigenetic studies are less common but are beginning to appear in the literature.

CRH Gene Regulation: Upstream Control of the Stress Cascade

CRH as the Master Stress Transcription Target

CRH gene expression in the hypothalamic PVN is arguably the most upstream molecular event in the HPA stress cascade that can be meaningfully targeted pharmacologically. Reducing CRH mRNA levels would theoretically attenuate the entire downstream cascade—less ACTH secretion, less cortisol/corticosterone production, and reduced exposure of peripheral tissues to glucocorticoids.

Several adaptogens demonstrate precisely this effect, and the adaptogen CRH gene relationship is one of the better-documented molecular findings in this field.

Evidence from Schisandra and Rhodiola

A pivotal 2015/2016 study examined the effects of Schisandra chinensis and Rhodiola rosea on HPA-axis gene expression in stressed rats. The results were striking: both adaptogens significantly decreased CRH mRNA expression in the hypothalamus and reduced serum corticosterone levels. Additionally, both attenuated the stress-induced increase in hypothalamic c-Fos mRNA.[12]

c-Fos is a proto-oncogene and immediate-early gene that is rapidly upregulated by neuronal activation, including HPA-axis activation. Its reduction by adaptogen treatment suggests that the adaptogens were not merely acting downstream (at the level of corticosterone secretion or clearance) but were genuinely dampening the upstream neuronal activation that drives CRH gene transcription.

The simultaneous reduction in CRH mRNA and corticosterone is mechanistically coherent: less CRH transcription leads to less CRH peptide release, which leads to less ACTH secretion, which leads to less corticosterone synthesis. This is the adaptogen CRH gene pathway operating as a coordinated system.

Molecular Mechanisms of CRH Gene Suppression

How do adaptogens suppress CRH gene transcription? Several mechanisms have been proposed:

1. Enhanced glucocorticoid receptor sensitivity: If GR signaling is enhanced, glucocorticoid negative feedback on CRH transcription would be more efficient, reducing CRH gene activity even at normal glucocorticoid levels.

1. NPY-mediated inhibition: As noted, adaptogens upregulate NPY expression. NPY acts presynaptically to inhibit CRH release and can also reduce CRH gene transcription through Y1 receptor-mediated pathways.

1. NF-κB suppression: CRH gene transcription is partially driven by NF-κB during inflammatory stress. Adaptogens that suppress NF-κB activity (many do) would therefore reduce CRH transcription under inflammatory conditions.

1. Reduced SAPK/JNK activity: Stress-activated kinases phosphorylate transcription factors (including c-Jun, a component of AP-1) that drive CRH gene expression. SAPK/JNK inhibition by adaptogens would therefore reduce AP-1-driven CRH transcription.

ACTH Gene Expression and Adaptogen Interventions

POMC Transcription and Its Regulation

Adrenocorticotropic hormone is derived from the POMC gene, whose transcription in pituitary corticotrophs is primarily driven by CRH acting through CRHR1 and cAMP/CREB signaling. Understanding the adaptogen ACTH gene relationship therefore requires understanding POMC regulation.

POMC transcription is activated by CREB phosphorylation following CRH-induced cAMP elevation, and it is repressed by glucocorticoids acting through GR. Chronic stress, which dysregulates GR sensitivity, can therefore lead to persistently elevated POMC transcription and ACTH secretion even in the presence of high cortisol—the classic pattern of hypercortisolemia with blunted feedback.

Ginseng and ACTH Gene Normalization

The 2026 MDPI review specifically cites ginseng as normalizing HPA-axis function in rats exposed to chronic unpredictable mild stress (CUMS), with effects on ACTH, corticosterone, and BDNF gene expression.[8] The inclusion of BDNF (brain-derived neurotrophic factor) is notable: BDNF is a downstream target of glucocorticoid signaling in the hippocampus, and its reduction during chronic stress is mechanistically linked to hippocampal atrophy and depression-like behavior.

The normalization of ACTH expression by ginseng in CUMS-exposed rats—a well-validated animal model of chronic stress—suggests that ginseng's effects extend to the pituitary level of the axis, not merely to peripheral corticosterone production or glucocorticoid receptor function.

ADAPT-232 and the Neuropeptide Dimension

The 2012 study on ADAPT-232 (a combination of Rhodiola rosea, Schisandra chinensis, and Eleutherococcus senticosus) in human neuroglia cells provides complementary evidence. While this study did not measure ACTH or POMC mRNA directly, it demonstrated upregulation of NPY, which, as noted, modulates CRH release and therefore indirectly regulates ACTH secretion.[3][6] This positions adaptogens as modulators of the entire CRH-ACTH-cortisol cascade, not merely one node.

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Glucocorticoid Receptor Gene Modulation

GR Gene Expression: The Feedback Hub

The glucocorticoid receptor (GR), encoded by the NR3C1 gene, is the primary molecular mediator of glucocorticoid negative feedback in the HPA axis. GR expression in the hippocampus, prefrontal cortex, and pituitary is critical for shutting down the stress response after acute activation. Reduced GR expression or GR resistance—common consequences of chronic stress—impairs this feedback and perpetuates HPA hyperactivity.

Understanding the ashwagandha GR gene relationship and how other adaptogens affect GR expression is therefore clinically and mechanistically important.

Ashwagandha and Glucocorticoid Receptor Signaling

Ashwagandha (Withania somnifera) contains a diverse array of bioactive withanolides, including withaferin A, withanolide A, and withanolide D. Several of these compounds have been shown to interact with GR signaling, either directly or indirectly.

At the molecular level, ashwagandha extracts have been reported to:

• Modulate NR3C1 expression: Animal studies have shown changes in GR mRNA levels in stress-relevant brain regions following ashwagandha treatment, with some studies reporting restoration of stress-reduced GR expression.

• Suppress NF-κB-driven transcription: Many of the genes that glucocorticoids suppress (pro-inflammatory cytokines, adhesion molecules) are NF-κB targets. Withaferin A has documented NF-κB inhibitory activity, meaning it may functionally mimic aspects of GR-mediated transrepression even through GR-independent pathways.

• Reduce hypothalamic CRH expression: By mechanisms partially mediated through enhanced GR sensitivity, ashwagandha HPA gene effects include reduction of CRH mRNA in stressed animals—consistent with restored negative feedback.

The Significance of Ashwagandha GR Gene Research

The ashwagandha GR gene connection matters clinically because GR resistance is increasingly implicated in treatment-resistant depression, burnout syndrome, and long-COVID fatigue. If ashwagandha can partially restore GR expression or sensitivity in stressed individuals, it would theoretically improve the efficiency of endogenous negative feedback and reduce the need for exogenous glucocorticoid-based interventions.

This remains an active area of investigation, and most of the current evidence is preclinical. However, the mechanistic plausibility is strong, and the clinical trial data on ashwagandha's cortisol-reducing effects in humans—though often measuring serum cortisol rather than GR gene expression directly—are consistent with a GR-sensitizing mechanism.

Ashwagandha and HPA Gene Expression: Deep Dive

Withanolides as Gene-Expression Modulators

Ashwagandha's bioactive withanolides are steroidal lactones structurally related to glucocorticoids. This structural similarity is not coincidental—it likely underlies some of ashwagandha's ability to interact with GR-mediated gene expression pathways. Withanolide A, in particular, has been shown to have neuroprotective and stress-modulating effects that are at least partially attributable to gene expression changes.

Key Genes Modulated by Ashwagandha in HPA Research

A review of the current ashwagandha HPA gene literature identifies the following gene targets as most consistently reported:

| Gene | Direction of Effect | Biological Significance | |------|-------------------|------------------------| | CRH | Downregulation in chronic stress | Reduces upstream HPA drive | | NR3C1 (GR) | Upregulation/normalization | Restores negative feedback | | BDNF | Upregulation | Neuroprotection, hippocampal plasticity | | Hsp70 | Upregulation | Cytoprotection, protein quality control | | NF-κB target genes | Downregulation | Anti-inflammatory | | c-Fos | Attenuation of stress-induced increase | Reduced immediate-early neuronal activation |

Human Clinical Correlation

Multiple randomized controlled trials have demonstrated significant reductions in serum cortisol in humans taking standardized ashwagandha extracts (typically KSM-66 or Sensoril formulations). While these trials measured cortisol protein levels rather than CRH or GR gene expression directly, the cortisol reductions are consistent with upstream gene expression changes.

A 600 mg/day KSM-66 trial published in the Indian Journal of Psychological Medicine found a 27.9% reduction in serum cortisol compared to placebo. The mechanistic question—whether this reflects reduced CRH transcription, enhanced GR sensitivity, altered adrenal steroidogenesis, or some combination—remains to be resolved by studies that combine clinical cortisol measurement with molecular biomarker analysis.

Rhodiola Rosea Gene Expression: Evidence from 2015 to 2024

Salidroside and Rosavin: The Primary Bioactives

Rhodiola rosea gene expression research has been shaped by studies of its two primary bioactive compound classes: rosavins (rosavin, rosin, rosarin) and phenylpropanoids (particularly salidroside/tyrosol). Both compound classes have demonstrated effects on stress-response gene expression, though their precise molecular targets differ.

The 2015/2016 Rodent Study: CRH and Corticosterone

As detailed in the CRH section above, the 2015/2016 study comparing Schisandra chinensis and Rhodiola rosea demonstrated significant decreases in both CRH mRNA expression and serum corticosterone in stressed rats.[12] This established Rhodiola as an adaptogen CRH gene modulator with measurable downstream effects on corticosterone production.

The attenuation of c-Fos mRNA increase is particularly valuable from a molecular standpoint. c-Fos is activated within minutes of neuronal stimulation and serves as a molecular marker of neuronal activity. Its reduction by Rhodiola treatment indicates that the adaptogen was capable of dampening acute neuronal stress activation at the gene-expression level, not merely producing post-hoc anti-inflammatory effects.

The 2024 Mouse Study: Region-Specific Brain Effects

A 2024 study on repeated Rhodiola rosea root extract administration in male Balb/c mice reported lower corticosterone levels and altered stress-responsive gene expression, with particularly notable region-specific effects in the hippocampus and prefrontal cortex.[13]

The regional specificity is important. The hippocampus and prefrontal cortex are the two brain regions most critical for glucocorticoid negative feedback and cognitive regulation of the stress response, respectively. Hippocampal GR density is a key determinant of HPA-axis recovery after stress, and prefrontal cortex function is essential for cognitive appraisal that modulates the HPA response to psychological stressors.

Finding that Rhodiola gene expression effects are concentrated in these two regions suggests a targeted action on the highest-level regulatory nodes of the HPA axis, rather than nonspecific effects on stress-response genes throughout the brain.

Rhodiola and NPY: The 2012 ADAPT-232 Connection

The 2012 ADAPT-232 study, which included Rhodiola rosea as one of three components, demonstrated NPY upregulation in human neuroglia cells.[3][6] While the contribution of each component cannot be fully disentangled from combination studies, Rhodiola is considered a major contributor to this effect based on single-herb studies. NPY upregulation in hypothalamic circuits would provide ongoing inhibitory modulation of CRH release, creating a self-reinforcing attenuation of HPA drive.

Schisandra, Eleutherococcus, and Panax Ginseng: Comparative Molecular Profiles

Schisandra chinensis: Lignans and HPA Gene Regulation

Schisandra's primary bioactives are dibenzocyclooctadiene lignans (schisandrin A, B, C; schisandrol A, B). These compounds have documented effects on cytochrome P450 enzymes, NF-κB signaling, and glucocorticoid metabolism. In the context of adaptogen HPA molecular research, Schisandra's most documented gene-expression effects include:

• Reduction of CRH mRNA in the hypothalamus (2015/2016 study, as detailed above)[12]
• Reduction of c-Fos mRNA, suggesting reduced neuronal activation
• Modulation of corticosterone production at the adrenal level
• Anti-inflammatory effects through NF-κB pathway suppression

Eleutherococcus senticosus: Eleutheroside Effects on Stress Genes

Eleutherococcus senticosus (Siberian ginseng) contains eleutherosides, particularly eleutheroside B (syringin) and eleutheroside E. These compounds have been shown to:

• Modulate glucocorticoid receptor signaling in immune cells
• Reduce NF-κB-dependent gene transcription
• Influence heat shock protein expression (part of the broader adaptogen transcription response pattern)
• Contribute to NPY upregulation in the ADAPT-232 combination context

Eleutherococcus is notable for being one of the original adaptogens studied by the Soviet research group, and its molecular pharmacology is better characterized in terms of receptor binding and enzyme effects than in gene-expression profiling specifically.

Panax Ginseng: Ginsenosides and ACTH Normalization

Panax ginseng's ginsenosides (Rg1, Rb1, Rd, Rg3, among others) are among the most extensively studied adaptogenic compounds. Their gene-expression effects relevant to HPA regulation include:

• ACTH and corticosterone normalization in CUMS rats: As noted in the 2026 review, ginseng normalizes HPA-axis function by regulating ACTH, corticosterone, and BDNF gene expression in chronically stressed rats.[8] This multi-target effect—spanning pituitary ACTH, adrenal corticosterone, and hippocampal BDNF—suggests systemic HPA-axis normalization rather than single-target intervention.

• GR expression modulation: Several ginsenosides have been shown to interact with GR, either as partial agonists/modulators or through effects on GR gene expression. Rg1, in particular, has documented effects on hippocampal GR mRNA levels in stress mode ls.

• BDNF upregulation: Ginseng-mediated BDNF upregulation is significant because BDNF is a downstream target of glucocorticoid signaling and a mediator of stress-resilience. Its normalization by ginseng treatment provides a mechanistic link between HPA-axis gene regulation and neuroplastic outcomes.

Comparative Summary Table

| Adaptogen | Primary Bioactives | Key HPA Gene Targets | Evidence Level | |-----------|-------------------|---------------------|----------------| | Ashwagandha | Withanolides | CRH↓, GR↑, BDNF↑, NF-κB targets↓ | Preclinical + limited clinical | | Rhodiola rosea | Salidroside, Rosavins | CRH↓, corticosterone↓, NPY↑, c-Fos↓ | Preclinical, cell-based | | Schisandra | Schisandrin lignans | CRH↓, c-Fos↓, NF-κB targets↓ | Preclinical | | Panax ginseng | Ginsenosides | ACTH↓, corticosterone↓, BDNF↑, GR modulation | Preclinical | | Eleutherococcus | Eleutherosides | GR modulation, Hsp70↑, NF-κB↓ | Preclinical, cell-based |

Transcription Factors and Signaling Pathways Beyond the HPA Axis

Adaptogen Transcription: The Broader Signaling Network

One of the most important findings from modern systems-biology approaches to adaptogen research is that HPA-axis gene expression is embedded within a broader network of stress-response transcription. The 2018 systems-biology study that identified 88 regulated genes in stressed brain cells exposed to adaptogens found effects extending far beyond the classical CRH-ACTH-cortisol cascade.[7][2]

Specifically, the study reported effects on upstream neurohormones in both HPA and hypothalamic-pituitary-gonadal (HPG) pathways, including corticotropin-releasing hormone, urocortin, and gonadotropin-releasing hormone 1 (GnRH1). It also found changes in prolactin receptor (PRLR) and toll-like receptor 9 (TLR9) expression.[2] This cross-pathway modulation suggests that adaptogens influence a coordinated stress-neuroendocrine network, not simply the HPA axis in isolation.

SAPK/JNK Pathway: The Cellular Stress Kinase

Stress-activated protein kinases, including JNK (c-Jun N-terminal kinase), are activated by cellular stressors (oxidative stress, heat shock, cytokines, UV radiation) and phosphorylate transcription factors including c-Jun, ATF-2, and p53. These transcription factors in turn regulate apoptosis, inflammatory gene expression, and stress-response gene transcription.

The 2026 review identifies SAPK/JNK pathway modulation as a key mechanism of adaptogens.[1][8] By reducing SAPK/JNK activity, adaptogens would:

• Decrease AP-1-driven transcription of inflammatory and stress-response genes
• Reduce JNK-mediated phosphorylation of IRS-1 (relevant to metabolic stress signaling)
• Attenuate JNK-driven apoptosis in stressed neurons

FOXO Transcription Factors: Longevity Meets Stress Resilience

FOXO (Forkhead box O) transcription factors are regulated by insulin/IGF-1 signaling through AKT-mediated phosphorylation and nuclear exclusion. When AKT activity is low (as during caloric restriction or cellular stress), FOXO factors are nuclear and transcriptionally active, driving expression of genes involved in stress resistance, autophagy, and longevity (including GADD45, MnSOD, SIRT1).

The modulation of FOXO transcriptional activity by adaptogens, noted in the 2026 review, is particularly interesting from a hormetic perspective.[1][8] It suggests that adaptogens may tap into the same molecular programs that underlie the stress-resistance benefits of caloric restriction and exercise—without requiring the physiological demands of those interventions.

NF-κB: Inflammation, Immunity, and HPA Cross-Talk

NF-κB is a master transcription factor for inflammatory and immune gene expression, but its relationship with the HPA axis runs in both directions. Glucocorticoids suppress NF-κB through GR-mediated transrepression, while NF-κB itself drives CRH transcription during inflammatory states. This bidirectional relationship means that adaptogens suppressing NF-κB activity will reduce inflammatory cytokine production and simultaneously reduce inflammatory-state CRH transcription—a dual benefit highly relevant to stress-related pathology.

Heat Shock Proteins: Hsp70 and Hsp16 as Stress-Response Amplifiers

Heat shock proteins function as molecular chaperones that facilitate proper protein folding, prevent aggregation of stress-damaged proteins, and regulate the activity of numerous signaling molecules. Hsp70 (and its inducible isoform Hsp72) expression is rapidly induced by stressors and serves as a cellular cytoprotectant.

Both the 2012 ADAPT-232 study and the 2026 review identify Hsp70/Hsp72 upregulation as a consistent feature of adaptogen action.[3][6][1][8] This is consistent with the hormetic hypothesis: adaptogens produce mild stress-mimetic activation that primes the heat shock response, enhancing cellular resilience to subsequent, more severe stressors.

Hsp70 also plays a direct role in GR regulation: it is part of the GR chaperone complex (along with Hsp90 and other co-chaperones) required for maintaining GR in a ligand-competent conformation. Upregulating Hsp70 could therefore enhance GR function and improve glucocorticoid negative feedback efficiency.

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Cell-Based and Preclinical Evidence: What Can We Extrapolate?

The Evidence Pyramid for Adaptogen Gene Expression

A clear-eyed assessment of the current literature requires acknowledging that the majority of adaptogen HPA gene expression evidence is preclinical—derived from cell culture studies and animal models. This is not unusual for mechanistic pharmacology research, but it is important context when communicating findings.

The evidence hierarchy for adaptogen gene expression research currently looks like this:

1. Cell-based studies (human neuroglia, isolated brain cells): Provide mechanistic detail about specific gene targets but lack physiological context
2. Rodent studies (acute and chronic stress models): Provide in vivo HPA-axis context but involve pharmacokinetic and pharmacodynamic differences from humans
3. Human clinical trials: Measure downstream outcomes (cortisol, self-reported stress) but rarely include gene-expression endpoints

Interpreting the 2018 Systems-Biology Study

The 2018 study that found 88 of 3,516 regulated genes in isolated brain cells altered by adaptogen exposure is an important data point that requires careful interpretation.[7] Cell-based studies allow precise control over exposure conditions and enable comprehensive gene-expression profiling (the 3,516 genes likely represent a genome-wide or transcriptome-wide screen), but they cannot account for:

• Blood-brain barrier penetration of adaptogen compounds
• First-pass metabolism and biotransformation
• Pharmacokinetic distribution to specific brain regions
• The dynamic, oscillatory nature of in vivo HPA-axis regulation

Nevertheless, finding 88 stress-response-related genes altered by adaptogen exposure in a single experiment is substantial evidence for meaningful transcriptional activity. The question for future research is which of those 88 genes are most consequential in the in vivo context.

Rodent Models: CUMS and the Corticosterone Endpoint

The chronic unpredictable mild stress (CUMS) model, used in the ginseng study cited in the 2026 review[8], is among the best-validated animal models for HPA-axis dysregulation and depression-like behavior. CUMS rats show elevated ACTH and corticosterone, reduced BDNF, anhedonia (measured by sucrose preference), and behavioral despair—a profile that closely mirrors clinical burnout and depression.

The finding that ginseng normalizes ACTH, corticosterone, and BDNF gene expression in CUMS rats is therefore a significant preclinical finding with plausible human relevance. Whether similar gene-expression normalization occurs in humans is the critical translational question.

Balb/c Mice in the 2024 Rhodiola Study

The 2024 Rhodiola rosea study using male Balb/c mice[13] adds value by using a repeated-administration paradigm (more clinically relevant than single-dose studies) and by examining region-specific brain effects. Balb/c mice are commonly used in stress research because they show an anxiety-prone phenotype that makes HPA-axis responses robust and measurable.

The hippocampal and prefrontal cortex specificity of Rhodiola's gene-expression effects in this study is a particularly noteworthy finding, as it points toward clinically meaningful neural circuits rather than diffuse, nonspecific effects.

Clinical Evidence: Bridging the Lab-to-Human Gap

What Clinical Trials Actually Measure

Most clinical trials of adaptogens measure:

• Serum or salivary cortisol (morning values, diurnal slope, or area under the curve)
• Self-reported stress, fatigue, or mood (via validated scales such as PSS, PANAS, MFI-20)
• Cognitive performance metrics
• Biomarkers of inflammation (CRP, IL-6)

Very few clinical trials include gene-expression endpoints, primarily because obtaining hypothalamic or pituitary tissue is impractical. Peripheral blood gene-expression profiling (from peripheral blood mononuclear cells, PBMCs) is feasible and increasingly used in clinical pharmacology, but it may not fully reflect central HPA-axis gene expression.

Ashwagandha Clinical Data: Cortisol as a Proxy for HPA Gene Activity

The clinical trial literature on ashwagandha and cortisol is among the strongest in the adaptogen field. Multiple RCTs have demonstrated significant cortisol reductions in stressed adults taking standardized ashwagandha extracts:

• A 2019 RCT (Chandrasekhar et al. follow-up) reported significant reductions in serum cortisol at 8 weeks in high-stress adults taking 240 mg of ashwagandha extract
• A 2012 study (Chandrasekhar et al.) found significant reductions in stress scores and serum cortisol with 300 mg twice daily of KSM-66

While these studies do not directly measure CRH, ACTH, or GR gene expression, the consistent cortisol reductions across multiple studies are consistent with upstream gene-expression changes in the HPA axis.

The Translation Gap and Future Directions

The most significant gap in current adaptogen research is the absence of studies that simultaneously measure:

1. Adaptogen plasma exposure (pharmacokinetics)
2. HPA-axis gene expression in accessible tissues (PBMCs, hippocampal extracellular vesicle miRNA as a proxy)
3. Downstream cortisol output
4. Clinical outcomes (stress, fatigue, cognitive function)

Such studies would close the mechanistic loop and allow definitive attribution of clinical effects to specific gene-expression changes. The 2025 systems-biology/network-pharmacology review on adaptogens in long-lasting brain fatigue[11] called for precisely this kind of integrative study design, noting that current evidence supports the HPA-axis gene-expression hypothesis but that direct human evidence remains limited.

Safety, Drug Interactions, and Pharmacogenomic Considerations

General Safety Profile

Most adaptogens studied in clinical trials have favorable safety profiles at recommended doses. However, their gene-expression effects—particularly on GR signaling, NF-κB, and CYP450 enzymes—create several important considerations for clinical use.

Glucocorticoid Interactions

Given that adaptogens modulate GR gene expression and glucocorticoid signaling, they have theoretical potential to interact with exogenous glucocorticoid medications (prednisone, dexamethasone, inhaled corticosteroids). GR-sensitizing effects could theoretically enhance glucocorticoid effects, while competitive interactions at GR could attenuate them. Clinical data on this interaction is very limited; caution is warranted in patients on systemic corticosteroid therapy.

Immunosuppressant Interactions

The NF-κB suppressive activity of several adaptogens creates potential for interaction with immunosuppressant medications that work through overlapping pathways. Schisandra, in particular, is a well-documented CYP3A4 and P-glycoprotein modulator and has documented interactions with tacrolimus and other calcineurin inhibitors. This is clinically relevant for transplant patients or those on immunosuppressive regimens.

HPA-Axis Modulation in Adrenal Insufficiency

Adaptogens that reduce CRH and corticosterone production are theoretically contraindicated in primary or secondary adrenal insufficiency, where the HPA axis is already suppressed. Reducing CRH or ACTH gene expression in a patient with marginal adrenal reserve could precipitate adrenal insufficiency symptoms. This remains theoretical but warrants clinical vigilance.

Pharmacogenomics

The NR3C1 gene (GR) is highly polymorphic, and several common variants (BclI, N363S, ER22/23EK) alter GR sensitivity and HPA-axis reactivity. Individuals with GR hypersensitivity variants may respond more strongly to adaptogen GR-modulating effects, while those with GR hyposensitivity variants may show blunted responses. This pharmacogenomic dimension is unexplored in adaptogen research and represents an important future direction.

Pregnancy and Hormonal Considerations

The HPG pathway cross-talk identified in the 2018 systems-biology study—including effects on GnRH1 and PRLR gene expression[2]—suggests that adaptogens may have hormonal effects beyond the HPA axis. This is relevant for pregnant or breastfeeding women and for individuals with hormonal conditions. Ashwagandha, in particular, has been associated with thyroid hormone changes in some studies and is generally not recommended during pregnancy.

2024–2026 Research Highlights

2024: Rhodiola and Region-Specific Brain Gene Expression

The 2024 repeated-administration Rhodiola rosea study in Balb/c mice[13] represents one of the most methodologically sophisticated recent studies in this area. Key findings:

• Corticosterone was significantly reduced compared to stressed controls
• Stress-responsive gene expression was altered in both hippocampus and prefrontal cortex
• Effects were specific to repeated administration, not observed with single doses
• Regional specificity (hippocampus > prefrontal cortex > other regions) suggests targeted action on HPA feedback circuits

This study underscores the importance of chronic administration models in adaptogen research—consistent with how adaptogens are used clinically.

2025: Systems-Biology Analysis of Adaptogens in Brain Fatigue

The 2025 network-pharmacology review[11] applied systems-biology methods to map adaptogen targets against the molecular pathways implicated in long-lasting brain fatigue. Key contributions:

• Confirmed that adaptogens' anti-fatigue effects are substantially mediated through HPA-axis gene-expression modulation
• Identified network hubs where adaptogen compound targets intersect with stress-response gene networks
• Called for integrative clinical studies that combine gene-expression profiling with fatigue biomarkers

2026: The MDPI Systems-Level Review

The 2026 MDPI review[1][8] is the most comprehensive recent synthesis of adaptogen molecular mechanisms. Key contributions to HPA gene expression understanding:

• Confirmed that adaptogens regulate HPA-axis function at the gene-expression level across multiple animal models and cell systems
• Established Hsp70/Hsp16, SAPK/JNK, FOXO, and NF-κB as key downstream pathway targets
• Provided the most detailed current account of ginseng's ACTH, corticosterone, and BDNF gene normalization in CUMS rats[8]
• Framed adaptogen action as a systems-level reorganization of stress-response transcription rather than single-target pharmacology

The 88-Gene Signature: A Research Frontier

The finding from the 2018 study that at least 88 genes are regulated by adaptogen exposure in brain cells[7] provides the foundation for a potentially high-value research program: defining a molecular signature of adaptogen action in accessible human biospecimens (blood, saliva, biopsy). If a subset of these 88 genes proves robustly regulated by adaptogen treatment in humans, it could serve as a mechanistic biomarker for adaptive stress resilience—a tool with both research and clinical utility.

Key Takeaways for Researchers and Clinicians

Summary of the Evidence

Based on the current literature, the following conclusions can be drawn with reasonable confidence:

1. Adaptogens alter gene expression in stress-relevant pathways. The evidence for this is strongest from cell-based and animal studies, with 88+ genes identified in a single systems-biology study as regulated by adaptogen exposure.[7]

1. CRH gene downregulation is one of the most consistent findings. Both Schisandra and Rhodiola have demonstrated CRH mRNA reduction in stressed rodents, with concurrent corticosterone reductions and c-Fos attenuation.[12]

1. The HPA-axis effects are multi-nodal. Evidence points to effects at the hypothalamic (CRH, c-Fos, NPY), pituitary (ACTH/POMC), adrenal (corticosterone), and feedback (GR, hippocampal BDNF) levels.[7][8][12][13]

1. Multiple signaling pathways are involved. Hsp70, SAPK/JNK, FOXO, and NF-κB are all implicated in adaptogen action, consistent with a systems-level mechanism rather than single-target pharmacology.[1][8]

1. The most recent data reinforces region-specific brain effects. The 2024 Rhodiola study showing hippocampal and prefrontal cortex specificity[13] aligns with the known neurobiology of HPA feedback regulation.

1. Clinical evidence is supportive but mechanistically limited. Human trials show consistent cortisol reductions with ashwagandha, Rhodiola, and other adaptogens, but direct gene-expression measurement in humans remains rare.

Research Gaps and Future Directions

• Human gene-expression studies using PBMC transcriptomics or neuro-inflammatory biomarkers alongside clinical outcomes
• Pharmacogenomic studies examining how NR3C1 variants moderate adaptogen responses
• Epigenetic studies examining whether adaptogen-induced gene expression changes involve DNA methylation or histone modification
• Combination studies examining how multi-adaptogen formulations (like ADAPT-232) produce gene-expression profiles different from single herbs
• Dose-response gene-expression studies to establish hormetic dose windows for optimal HPA-axis modulation

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Frequently Asked Questions

What are adaptogens, and how do they affect the HPA axis?

Adaptogens are plant-derived compounds (and some fungi) that increase non-specific resistance to stress without causing significant toxicity. They affect the HPA axis primarily by modulating gene expression at multiple levels: reducing CRH transcription in the hypothalamus, normalizing ACTH and POMC expression in the pituitary, and restoring glucocorticoid receptor sensitivity in the hippocampus and prefrontal cortex. Their effects extend beyond direct hormone-level changes to the underlying transcriptional programs that regulate how the body responds to and recovers from stress.

Which adaptogens have the strongest evidence for gene-expression effects?

Based on the current literature, Rhodiola rosea and Schisandra chinensis have the strongest and most mechanistically detailed evidence for HPA-axis gene expression effects, particularly for CRH mRNA reduction and corticosterone normalization. Panax ginseng has robust evidence for ACTH and BDNF gene expression normalization in chronic stress models. Ashwagandha has the strongest clinical cortisol data but relatively less direct gene-expression evidence compared to the other three.

Do adaptogens change cortisol or corticosterone levels in humans or only in animals?

Both. In animals, multiple studies have demonstrated significant reductions in corticosterone in stress models following adaptogen treatment, with concurrent gene-expression changes confirming the mechanism. In humans, well-conducted RCTs have demonstrated significant serum cortisol reductions with ashwagandha (multiple trials) and Rhodiola (several trials). The human evidence is more limited in mechanistic depth—most clinical trials do not include upstream gene-expression endpoints—but the cortisol reductions are consistent with the animal gene-expression findings.

What genes and pathways are most often reported in adaptogen HPA research?

The most consistently reported gene targets include:

• CRH (corticotropin-releasing hormone) — typically downregulated
• NR3C1 (glucocorticoid receptor) — typically normalized/upregulated in stress-reduced states
• POMC/ACTH — typically normalized
• BDNF — typically upregulated
• c-Fos — typically attenuated stress-induced increase
• NPY (neuropeptide Y) — typically upregulated
• HSPA1A/HSPA1B (Hsp70/Hsp72) — typically upregulated
• NF-κB target genes — typically downregulated

Key signaling pathways include SAPK/JNK, FOXO, NF-κB, and heat shock response.

Is the evidence clinical, preclinical, or cell-based?

The majority of mechanistic gene-expression evidence is preclinical (animal models) or cell-based. Clinical trials predominantly measure downstream cortisol levels and patient-reported outcomes rather than gene expression directly. The 2018 systems-biology study[7] used isolated brain cells, providing mechanistic detail but limited physiological context. The 2024 Rhodiola study[13] and the ginseng CUMS data[8] are animal studies. Direct human gene-expression studies in this field are rare and represent a significant research gap.

Which studies are most relevant for stress, fatigue, or anxiety?

For stress: The Schisandra/Rhodiola CRH mRNA study[12] and the 2024 Rhodiola corticosterone study[13] are most directly relevant. For fatigue: The 2025 systems-biology review on adaptogens in brain fatigue[11] and the ADAPT-232/NPY study[3][6] are most relevant. For anxiety: The ashwagandha GR gene and cortisol literature is most relevant, as HPA hyperactivity is central to anxiety pathophysiology. Ginseng's BDNF normalization data[8] is relevant for all three conditions, given BDNF's role in stress resilience and cognitive function.

Are there safety concerns or drug interactions with adaptogens?

Yes, several are worth noting:

• Glucocorticoid medications: GR-modulating adaptogens could theoretically interact with exogenous glucocorticoids
• Immunosuppressants: Schisandra is a CYP3A4 modulator with documented interactions with tacrolimus and similar drugs
• Thyroid medications: Ashwagandha has been associated with thyroid hormone changes; caution in patients on thyroid treatment
• Adrenal insufficiency: Adaptogens reducing CRH/ACTH gene expression could be problematic in patients with marginal adrenal reserve
• Pregnancy: Generally not recommended due to hormonal effects including potential HPG pathway modulation

How do Rhodiola, ginseng, Schisandra, and Eleutherococcus compare mechanistically?

Each adaptogen has a somewhat distinct molecular profile:

• Rhodiola primarily targets CRH gene expression and shows strong region-specific hippocampal/prefrontal effects; also contributes to NPY upregulation
• Ginseng has the most comprehensive evidence for multi-nodal HPA normalization (ACTH, corticosterone, BDNF) and GR interaction through ginsenoside mechanisms
• Schisandra shows strong CRH and c-Fos suppression, with additional CYP450 enzyme effects that distinguish it pharmacokinetically from other adaptogens
• Eleutherococcus has more limited gene-expression evidence but demonstrates GR modulation and Hsp70 induction consistent with the broader adaptogen class

In combination (as in ADAPT-232), these adaptogens may produce synergistic gene-expression profiles that exceed what any single herb achieves alone—a hypothesis supported by the robust multi-gene effects observed in the ADAPT-232 combination studies.[3][6]

Conclusion

The field of adaptogens HPA gene expression research has matured considerably from its Soviet-era origins into a discipline engaging with contemporary molecular biology tools: transcriptomics, systems biology, network pharmacology, and region-specific brain expression profiling. The current evidence supports a model in which adaptogens act as systems-level modulators of stress-response gene networks, with particular efficacy at the level of CRH gene expression, glucocorticoid receptor function, and downstream neuroprotective genes like BDNF and Hsp70.

The most important conclusion from the 2018–2026 research period is that adaptogen action cannot be reduced to a single molecular target or a single gene. The identification of 88 regulated genes in a single systems-biology study[7], the multi-pathway summary from the 2026 review[1][8], and the region-specific brain effects of the 2024 Rhodiola study[13] all point toward a coordinated, network-level molecular response that is qualitatively different from conventional single-target pharmacology.

For researchers, the priority research directions are human gene-expression studies, pharmacogenomic analyses, and epigenetic profiling. For clinicians, the current evidence supports the use of well-characterized adaptogen extracts for stress-related HPA dysregulation, with the understanding that the molecular mechanisms underlying clinically observed cortisol reductions involve gene-expression changes at multiple levels of the HPA axis.

The molecular biology of adaptogens is not simple—but it is increasingly coherent, and the picture emerging from the best recent research is one of a sophisticated, evolutionarily ancient relationship between plant compounds and the mammalian stress-response transcriptome.

References cited correspond to numbering as follows: [1] MDPI Pharmaceuticals 2026 systems-level review; [2] 2018 study neurohormone pathway data; [3] 2012 ADAPT-232 neuroglia study; [6] NPY/Hsp72 component of 2012 study; [7] 2018 systems-biology gene-expression profiling; [8] Ginseng CUMS/ACTH/BDNF normalization data from 2026 review; [11] 2025 brain fatigue network-pharmacology review; [12] 2015/2016 Schisandra/Rhodiola CRH study; [13] 2024 Rhodiola Balb/c mouse study.

This article is intended for educational and research purposes. It does not constitute medical advice. Consult a qualified healthcare provider before beginning any supplement regimen, particularly if you are taking prescription medications or have a diagnosed medical condition.