From herbal hope to hormonal havoc: chronic ashwagandha use and HPA axis suppression

Abstract

Summary

This case report describes a 55-year-old postmenopausal woman who presented with Cushingoid features and progressive weight gain over a year. Evaluation revealed low basal cortisol levels and a suboptimal response to the ACTH stimulation test, indicative of adrenal insufficiency. Further investigation into her medication regimen uncovered her consistent use of approximately 950 mg of ashwagandha daily for over a year, prescribed by a local practitioner for symptomatic relief of bilateral knee osteoarthritis. A review of the existing literature suggested a potential cortisol-suppressing effect of ashwagandha, leading to the establishment of a causal link between the patient’s symptoms and her consumption of the ashwagandha extract. She was advised to discontinue the alternative medication and commenced on hydrocortisone replacement, adjusted for her body surface area. A three-month follow-up indicated that her hypothalamic–pituitary–adrenal (HPA) axis suppression had not yet reversed, necessitating continued hydrocortisone supplementation and bimonthly monitoring of her basal and stimulated cortisol levels. This case report underscores the perils of unsupervised exposure to poorly understood compounds prevalent among the general public. It also highlights the role of online platforms and social media in promoting unverified practices and treatments with spurious claims of efficacy and safety, often in contrast to well-researched, modern treatment regimens. Through this case report, we would like to stress upon the importance of imposition of stringent regulations on social media and websites that disseminate unverified information. Furthermore, we emphasize that incentivizing and promoting health literacy among the general population is an urgent imperative.

Learning points

• Clinicians should be familiar with commonly used herbal remedies and their potential endocrine and systemic effects, particularly in the context of unexplained hormonal dysfunction.

• Cushingoid features and secondary adrenal insufficiency in the absence of exogenous steroid use should prompt clinicians to enquire specifically about herbal supplement intake, including dose, formulation, and duration.

• Both clinicians and the public should be aware that excessive doses and prolonged use of ashwagandha can lead to Cushingoid features and sustained suppression of the HPA axis.

• The widespread belief that ‘natural’ always equates to ‘safe’ needs to be actively challenged through public education campaigns and clinician-led counseling. Herbal products can cause deleterious health effects and are not inherently benign.

• There is a pressing need for health authorities to establish evidence-based guidelines for the safe use of ashwagandha and other commonly used herbal products, including daily dose limits and duration.

• International regulatory oversight and policies are essential to counter the growing misinformation around traditional and alternative medicines, especially on digital and social media platforms.

Background

The global use of herbal and nutraceutical preparations has increased substantially, fueled by a perception of being ‘natural and therefore safe’. These are used for a wide spectrum of conditions, from minor ailments such as the common cold to chronic, progressive degenerative diseases for which conventional medicine may not offer curative options or adequate symptom control. Of these, the overuse of non-steroidal anti-inflammatory drugs and steroids is common.

As endocrinologists, we routinely encounter cases of exogenous steroid abuse. Adrenal insufficiency and exogenous Cushing’s syndrome due to herbal remedies adulterated with synthetic glucocorticoids are not uncommon and well-documented in clinical practice. However, endocrine dysfunction arising from the intrinsic hormone-modulating properties of herbal compounds remains under-recognized and under-reported, often due to incomplete history-taking and lack of awareness among clinicians.

Perhaps due to these lacunae in clinical awareness and appropriate history pointers, there have been only two documented case reports describing adrenal hypofunction secondary to ashwagandha (2022 and 2024), underscoring its novelty and the need for heightened clinical vigilance (1, 2).

Withania somnifera (Ashwagandha) is promoted widely across regions – including outside the Indian subcontinent – as an ‘adaptogen’ and is available in capsules, tablets, powders, and poly-herbal syrups with heterogeneity in extraction and withanolide concentration (3). While short-term clinical trials with standardized ashwagandha extracts have shown modest cortisol-lowering effects and subjective stress benefit, the long-term endocrine consequences of chronic, high-dose consumption remain incompletely characterized. Data regarding dose thresholds, duration beyond which HPA-axis modulation becomes clinically relevant, and recovery kinetics are especially limited (4).

Our case therefore highlights a clinically important issue: in patients presenting with unexplained Cushingoid features or low cortisol in the absence of documented steroid exposure, directed questioning regarding herbal supplement intake – specifically dose, brand, and duration – is essential. Recognizing herbal agents such as ashwagandha as potential contributors to HPA-axis dysfunction is relevant not only in regions where Ayurveda originates but increasingly in developed settings, given the globalized nutraceutical market.

Case presentation

A 55-year-old postmenopausal woman with no prior comorbidities presented with complaints of progressive weight gain (10 kg over one year) and facial puffiness noticed by her family over the preceding six months.

She had a history of severe bilateral knee and ankle pain for two years, which had worsened over the past three months. On orthopedic evaluation, she was diagnosed with osteoarthritis in both knees and a complete tendoachilles tear with hematoma in the right ankle. She denied easy bruising, proximal muscle weakness, headaches, or visual disturbances indicative of pituitary pathology, and she exhibited no signs of other chronic illnesses.

The patient reported extensive use of over-the-counter medications, including alternative therapies from a local hospital, for her persistent joint pain. On examination, she exhibited Cushingoid facies (Fig. 1), although there was no evidence of ecchymosis or abdominal striae. Her vital signs and systemic examination were within normal limits.

Figure 1.

A picture of our patient showing ‘moon facies’ typical of Cushing’s syndrome.

Given the strong suspicion of exogenous steroid use – common in our clinical setting – we advised her to bring all medications used over the past year, including prescribed, over-the-counter allopathic, and alternative therapies. On review, no steroid preparations were found. However, careful inspection of her alternative medicines revealed the presence of various herbal compounds, the most notable and recurring one being Withania somnifera, commonly known as ashwagandha in contemporary Ayurvedic medicine.

She had been consuming approximately 950 mg of Withania somnifera daily for the past year via at least three different syrups and two types of tablets (Fig. 2). Other components included Tribulus terrestris (Gokshura) at 350–400 mg/day, Asparagus racemosus (Shatavari) at 300 mg/day, and Terminalia chebula (Haritaki) at 250–300 mg/day.

Figure 2.

Picture showing the alternative medications being used by the patient. These include traditional medicines in the form of capsules, powders, and syrups.

Investigation

Routine hematological and biochemical tests – including complete blood count, serum electrolytes, liver, and renal function tests – were within normal limits. A metabolic workup showed subclinical hypothyroidism (Thyroid stimulating hormone: 7.19 µIU/mL) with normal total T3 and T4 levels; anti-TPO antibody was positive. She was also diagnosed with new-onset diabetes mellitus (HbA1c: 6.5%, fasting blood sugar: 97 mg/dL, postprandial sugar: 157 mg/dL).

Her early morning serum cortisol levels, measured twice, were both <0.5 μg/dL. ACTH measured 16 pg/mL (reference: <46 pg/mL). An ACTH stimulation test with 250 μg of Synacthen revealed suboptimal cortisol responses, with levels of 2.89 μg/dL at 30 min and 3.68 μg/dL at 1 h.

Given the strong clinical suspicion of medication-induced HPA axis suppression, a literature review was undertaken, which identified only two previously published case reports implicating Withania somnifera (ashwagandha) in adrenal hypofunction. No other Ayurvedic components appeared to be plausible causes. In light of the patient’s prolonged intake of high dose of ashwagandha and corroborative clinical and biochemical findings, a diagnosis of exogenous Cushing’s syndrome with HPA axis suppression attributable to ashwagandha use was made.

Treatment

The patient was counseled regarding the adverse effects of long-term alternative medication use and advised to discontinue all such therapies. She was initiated on thyroxine supplementation and hydrocortisone replacement therapy, along with lifestyle modifications (a balanced diet and regular physical activity) to manage her new-onset diabetes.

Outcome and follow-up

Her follow-up was complicated by poor adherence due to ongoing pain and a continued tendency to seek alternative medications. An orthopedic consultation was obtained to optimize pain management, and she was re-counseled to cease alternative therapies and resume hydrocortisone replacement. After six months of therapy, her basal serum cortisol continued to be suppressed at 0.48 μg/dL. She was advised to continue hydrocortisone and to return for a follow-up evaluation after two months.

Discussion

Ashwagandha (Withania somnifera) is a widely recognized herbal medication used in Ayurveda, Unani, and Chinese medical systems. This small shrub, a member of the Solanaceae family, is native to the Indian subcontinent and is also found in southern Europe, Africa, and Australia (3). Traditionally used as a rejuvenative agent in Ayurveda, ashwagandha has demonstrated several therapeutic benefits in short-term studies, including stress reduction, lowered cortisol levels, improved cognition, enhanced cardiorespiratory endurance, and increased hemoglobin. It is also credited with promoting vitality, improving mitochondrial function, and exerting anti-inflammatory and antioxidant effects, which contribute to overall cellular health (4).

Additional studies indicate improvements in sleep quality among individuals with non-restorative sleep, insomnia, and anxiety (5). By improving mitochondrial health, it can lead to better energy production and endurance. It is believed to promote healthy aging and reduce fatigue levels. Its potential endocrine benefits reported are perimenopausal estrogen balance, boosting testosterone levels, improving libido, thyroid hormone modulation, and blood glucose stabilization (6).

Extracts of ashwagandha are derived from the roots, leaves, or a combination of both, and the concentration of bioactive compounds varies depending on the plant part used, as well as factors such as the growth phase, season, and geographic location. The major active ingredients include withanolides – naturally occurring steroidal lactones – along with alkaloids, saponins, sitoindosides, phenolic compounds, flavonoids, and triethylene glycol. The pharmacological effects of Withania somnifera are primarily attributed to two withanolides: withaferin A and withanolide D (7).

Ashwagandha is popularly marketed as an adaptogen – compounds that enhance the body’s non-specific resistance to stress and reduce sensitivity to stressors, thereby supporting adaptation and prolonging the resistance phase. The hypothalamic–pituitary–adrenal (HPA) axis plays a central role in stress regulation, along with the autonomic nervous system and immune pathways. In response to stressors, the HPA axis triggers the secretion of cortisol into the circulation.

Adaptogens are thought to exert their effects, in part, by modulating adrenal activity. Although the precise mechanisms through which these compounds lower cortisol levels remain incompletely understood, they are believed to act both directly – by interacting with glucocorticoid receptors and influencing the HPA axis – and indirectly, through sedative and hypnotic effects via modulation of gamma-aminobutyric acid (GABA) (5). Adrenal steroidogenesis involves various precursor hormones and specific enzymes, and withanolides and alkaloids may interfere with the genes encoding these enzymes, potentially leading to adrenal hypofunction (8).

A recent meta-analysis confirmed that ashwagandha significantly reduces cortisol levels in stressed individuals, although studies vary in dosage, formulation, and duration (30–110 days). Lopresti et al. (9) evaluated 240 mg/day of ashwagandha extract (84 mg withanolide glycosides) for 15 days in 60 mildly anxious but otherwise healthy adults. The intervention led to significant reductions in anxiety and depression scores, along with a 23% drop in morning cortisol levels (vs 0.5% in placebo). Male participants also showed an 8.2% decrease in DHEA-S, compared to a 2.5% increase in the placebo group. Similarly, Pandit et al. (10) conducted an 8-week double-blind, placebo-controlled study evaluating doses of 125, 250, and 500 mg of Withania somnifera extract, all of which resulted in improved psychological scores and reduced cortisol levels compared to placebo.

The consistent cortisol-lowering effect of ashwagandha, though seem beneficial in short-term studies, raises important concerns regarding HPA axis suppression when used chronically or in high doses – particularly given the lack of established guidelines on optimal daily dosage and safe duration of use. Supporting this risk, Fry et al. (1) reported adrenal insufficiency in a 41-year-old woman after 10 weeks of consuming 858.6 mg/day of ashwagandha extract influenced by online promotional content, with recovery of adrenal function observed two weeks after discontinuation. In a more severe instance, Patel et al. (2) reported a 37-year-old woman who was admitted with profound hyponatremia due to adrenal insufficiency after two years of combined use of ashwagandha and Lion’s mane extract.

In our patient, prolonged intake of 950 mg/day for one year – far exceeding the doses typically used in clinical trials – was associated with the development of Cushingoid features, significant weight gain, and pronounced suppression of the HPA axis. Notably, the adrenal insufficiency persisted even six months after cessation of the supplement, in contrast to a previously reported case where recovery occurred within a shorter time-frame. This suggests a possible cumulative, dose- and duration-dependent effect of ashwagandha on adrenal function. Given the widespread and often unsupervised use of ashwagandha, this case underscores the urgent need for studies to determine safe thresholds for dosage and duration.

An additional possibility to consider in cases of adrenal suppression associated with herbal remedies is adulteration with synthetic glucocorticoids or inclusion of animal-derived adrenal tissue, which has been described in the literature as a mechanism for exogenous steroid exposure through complementary medicines. In our patient, all preparations used over the preceding year were physically reviewed, and no glucocorticoids or adrenal extracts were declared in the listed constituents. While laboratory content analysis was not feasible and, therefore, adulteration cannot be absolutely excluded, the temporal association with sustained high-dose ashwagandha intake, coupled with previously published reports, supports a pharmacological effect of ashwagandha itself as the most plausible explanation in this case.

Common adverse effects of ashwagandha include sleepiness, gastrointestinal discomfort, and diarrhea, whereas less common events encompass dizziness, hallucinations, cough, decreased appetite, nausea, hyperacidity, skin rashes, weight gain, and the potential precipitation of thyrotoxicosis. Hepatic dysfunction – including both cholestatic and hepatocellular injury – has also been documented (5). In light of emerging evidence, HPA axis suppression should be recognized as a serious adverse effect of prolonged or unsupervised ashwagandha use.

Conclusion

Ashwagandha, when consumed in excessive doses or over prolonged periods, may lead to Cushingoid features and HPA axis suppression. There is an urgent need to define safe daily dosages and maximum duration of use to prevent adverse outcomes. Healthcare professionals and the general public must be informed of these potential risks, and the unsupervised use of ashwagandha should be discouraged. Clinicians should consider ashwagandha-induced HPA axis suppression in patients presenting with unexplained Cushingoid features, particularly when there is no history of pharmacological steroid use. A thorough review of all medications, including herbal supplements, is essential for timely diagnosis and prevention of serious, potentially fatal consequences.

Declaration of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details and clinical images was obtained from the patient.

Author contribution statement

JJ, SK, BA, and SM were involved in clinical assessment, patient management, and literature review. All authors contributed equally to the conceptualization, drafting, and critical revision of the manuscript. SK served as the corresponding author and coordinated manuscript submission. All authors have reviewed and approved the final version of the manuscript.