Adrenal hypofunction associated with ashwagandha (Withania somnifera) supplementation: a case report

Abstract

Objective
The use of herbal medicinal supplements has gained huge popularity world-wide, but scientific evidence of their effectiveness and safety remains scarce. Ashwagandha ( Withania somnifera ) is one such product, claimed to alleviate pain and anxiety by lowering circulating cortisol levels. Withanolides, which are the principal bioactive compounds of ashwagandha, are naturally occurring steroids and may suppress adrenal function. Here, we describe the effect of ashwagandha on adrenal function of a 41-year-old woman with a low body mass index and who suffered chronic pain and lethargy.

Methods
Adrenal function was assessed by the short Synacthen test (SST) during and after treatment with ashwagandha supplementation.

Results
Whilst taking daily ashwagandha supplement (21.4 mg of Withanolides), for ten weeks, a SST showed a minimal response to 250 μg of an intramuscular injection of Synacthen (tetracosactide): cortisol levels at T 0min = 287 nmol/l, T 30min = 289 nmol/l, and T 60min = 328 nmol/l; from a morning baseline cortisol level of 480 nmol/l prior to taking the supplement. Ashwagandha was discontinued for two weeks, and a repeat SST was performed showing a completely normal adrenal response: cortisol level at T 0min = 275 nmol/l, T 30min = 623 nmol/l and T 60min = 674 nmol/l.

Conclusion
Ten weeks of ashwagandha supplementation was associated with adrenal hypofunction, which was reversible after a two-week break. Individuals taking ashwagandha should be aware of this potentially detrimental effect. Future studies are suggested to assess whether long-term treatment with ashwagandha could lead to permanent suppression of adrenal function, and to elucidate the effects of ashwagandha compounds on adrenal steroidogenic pathway and hypothalamic–pituitary–adrenal axis.

Full text

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Toxicology and Environmental Health Sciences (2022) 14:141–145
https://doi.org/10.1007/s13530-022-00122-z
ORIGINAL ARTICLE
Adrenal hypofunction associated withashwagandha (Withania
somnifera) supplementation: acase report
ChristopherH.Fry1· DavidFluck2· ThangS.Han3,4
Accepted: 9 January 2022 / Published online: 14 February 2022
© The Author(s) 2022
Abstract
Objective The use of herbal medicinal supplements has gained huge popularity world-wide, but scientific evidence of their
effectiveness and safety remains scarce. Ashwagandha (Withania somnifera) is one such product, claimed to alleviate pain and
anxiety by lowering circulating cortisol levels. Withanolides, which are the principal bioactive compounds of ashwagandha,
are naturally occurring steroids and may suppress adrenal function. Here, we describe the effect of ashwagandha on adrenal
function of a 41-year-old woman with a low body mass index and who suffered chronic pain and lethargy.
Methods Adrenal function was assessed by the short Synacthen test (SST) during and after treatment with ashwagandha
supplementation.
Results Whilst taking daily ashwagandha supplement (21.4mg of Withanolides), for ten weeks, a SST showed a mini-
mal response to 250μg of an intramuscular injection of Synacthen (tetracosactide): cortisol levels at T0min = 287nmol/l,
T30min = 289nmol/l, and T60min = 328nmol/l; from a morning baseline cortisol level of 480nmol/l prior to taking the supple-
ment. Ashwagandha was discontinued for two weeks, and a repeat SST was performed showing a completely normal adrenal
response: cortisol level at T0min = 275nmol/l, T30min = 623nmol/l and T60min = 674nmol/l.
Conclusion Ten weeks of ashwagandha supplementation was associated with adrenal hypofunction, which was reversible
after a two-week break. Individuals taking ashwagandha should be aware of this potentially detrimental effect. Future stud-
ies are suggested to assess whether long-term treatment with ashwagandha could lead to permanent suppression of adrenal
function, and to elucidate the effects of ashwagandha compounds on adrenal steroidogenic pathway and hypothalamic–pitui-
tary–adrenal axis.
Keywords Ayurveda· Dietary supplements· HPA axis· Hypocortisolism· Short Synacthen test· Steroidogenesis·
Toxicity
Introduction
Over the past four decades, the use of herbal medicinal
products and supplements has gained huge popularity world-
wide. These products are sold on the Internet and in health
shops, but many are not rigorously tested for their effective-
ness and safety by clinical trials. Individuals with symp-
toms of generalised bodily pain and anxiety are particularly
attracted to these supplements [1]. Ashwagandha (Witha-
nia somnifera) extract is one such herbal product marketed
globally [2, 3]. Although commonly known as ashwagandha,
it has been called by some ten other names. An evergreen
shrub, ashwagandha is a genus of flowering plants in the
Solanaceae (nightshade) family, and most of it is grown in
South Asia, the Middle East and North Africa, but may also
be found in Southern Europe and the Mediterranean [4].
* Thang S. Han
thang.han@rhul.ac.uk
1 School ofPhysiology, Pharmacology andNeuroscience,
University ofBristol, BristolBS81TD, UK
2 Department ofCardiology, Ashford andSt Peter’s NHS
Foundation Trust, Guildford Road, ChertseyKT160PZ,
Surrey, UK
3 Department ofEndocrinology, Ashford andSt Peter’s NHS
Foundation Trust, Guildford Road, ChertseyKT160PZ,
Surrey, UK
4 Institute ofCardiovascular Research, Royal Holloway,
University ofLondon, EghamTW200EX, Surrey, UK

142 Toxicology and Environmental Health Sciences (2022) 14:141–145
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This plant has been used for thousands of years as a medici-
nal herb in traditional Ayurvedic medicine (Ayurveda).
Withanolides, which are the principal bioactive compounds
of ashwagandha, are naturally occurring steroids. About 35
steroidal withanolides, along with 12 steroidal alkaloids and
several sitoindosides have been isolated from ashwagandha
[5–7].
In modern days, ashwagandha is advertised widely for its
apparent “multiple beneficial effects on a number of organs
including the central nervous and endocrine systems, as
well as the ability to alleviate pain by its anti-inflammatory
property and generate calming effects by lowering adrenal
steroids”. However, similar to many other herbal medicinal
products, adverse effects of ashwagandha on humans have
not been well documented [2]. Here, we describe the effect
of ashwagandha on the adrenal function of a woman.
Results
Case presentation
A 41-year-old woman was reviewed in the Endocrine clinic
on 4 May 2021. She had a two-year history of generalised
bodily pain sustained from a road traffic accident. To relieve
pain she was treated with the tricyclic antidepressant ami-
triptyline at 25mg a day (amitriptyline has no known effects
on the steroidogenic pathways), and she had never taken
opioid-based drugs or steroids. She had been taking an oral
contraceptive pill (OCP) but stopped one year previously.
She had regular periods whilst not taking OCP. She had
no history of weight loss and was always slim (body mass
index = 17.5kg/m2). She did not smoke or drink alcohol
excessively. Her thyroid function and basic haematological
and biochemical parameters were normal; lyme borreliosis
was also excluded (Table1). A short Synacthen test (SST)
to exclude adrenal insufficiency was suggested. Whilst SST
was being arranged, the patient inadvertently visited the
phlebotomy department where a morning random cortisol
was done, showing a level of 480nmol/l. The formal SST
was performed on 12 August 2021. To our surprise, the
baseline cortisol level had dropped to 287nmol/l, whilst
the response to 250μg of an intramuscular injection of Syn-
acthen (tetracosactide) was minimal (T30min = 289nmol/l,
and T60min = 328nmol/l).
On direct questioning, the patient’s symptoms remained
unchanged. However, it became apparent that shortly after the
initial consultation in May 2021, the patient began to conduct
Internet search on health topics relating to the adrenal glands.
She discovered a number of websites selling ashwagandha root
extract, which was advertised for its “anti-inflammatory prop-
erty and ability to lower cortisol levels, leading to reduction
of pain and stress”. The patient ordered this product (Clean
Ashwagandha, British Supplements, UK) [8] and took one
capsule twice a day up to the end of August 2021 (two cap-
sules = 858.6mg ashwagandha extract, containing 21.4mg
Withanolides, plus 95.4mg of the manufacturer’s uptake
blend). Therefore, the patient was taking ashwagandha for ten
weeks by the time she had the first SST. Ashwagandha was
discontinued for two weeks and a repeat SST was performed
on 14 of September showing a completely normal adrenal
response to Synacthen: cortisol level at T0min = 275nmol/l,
T30min = 623 nmol/l and T60min = 674nmol/l (Fig.1). The
adrenocorticotropic hormone (ACTH) level at baseline
(T0min) of this second SST was normal at 11ng/l (reference
range: < 50ng/l).
Table 1 Physiological and biochemical characteristics of the patient
prior to taking ashwagandha supplement
* Weight = 50 kg, height = 1.69 m; †Some centres accept a random
cortisol level of > 450nmol/l as normal
Patient characteristics Parameters Reference range
Age, years 41 –
Body mass index, kg/m217.5* 20–25
Systolic/diastolic blood pressure,
mmHg
120/75 < 160/90
Morning cortisol, nmol/l 480 > 550†
Thyroid stimulating hormone, mU/l 2.09 0.35–4.78
Haemoglobin, g/l 124 115–165
Creatinine, µmol/l 60 < 60
Alanine transferase, U/l 25 10–49
Calcium, mmol/l 2.26 2.2–2.6
Ferritin, μg/l 169 15–250
Borrelia burgdorferi IgG Not detected –
Fig. 1 Cortisol levels measured prior to, during treatment and after
discontinuation of treatment with ashwagandha

143Toxicology and Environmental Health Sciences (2022) 14:141–145
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Discussion
Summary
We present a case whose adrenal function was suppressed
during the period when the patient was taking ashwagandha,
which was reversed to normal function after discontinuation
of this herbal product. As far as we are aware, this is the
first observation of temporal changes in adrenal function, as
assessed by SST, during and after stopping supplementation
with ashwagandha. This case highlights the ability of ash-
wagandha to suppress adrenal function in a relatively short
duration (ten weeks), but could be reversed after two weeks
of discontinuation.
Clinical implications
There is a lack of scientific evidence of the effectiveness and
safety of ashwagandha for treating any disease, and accord-
ing to expert review from www. drugs. com website, trials
supporting its clinical use in humans are limited [2]. Animal
studies suggest it has effects on the immune, endocrine and
central nervous systems, and inflammatory conditions. There
are a handful of randomised controlled trials (RCT) from
India [9, 10]. A recent RCT of sixty healthy Indian adults
showed supplementation with 240mg of ashwagandha
extract once daily for 60days led to a reduction in the Ham-
ilton anxiety rating scale (P = 0.040) and morning cortisol
levels (P < 0.001) compared with placebo [10]. The major
flaws with such study were that there was no valid medical
reason for lowering anxiety or cortisol levels of volunteers
who were described as healthy adults. Cortisol reduction
should indeed be interpreted as an adverse effect of ashwa-
gandha rather than benefit. The subnormal adrenal response
totetracosactide (assessed by SST) observed in our patient
could potentially lead to serious health consequences due to
the inability of the patient to mount a response to an acute
stress, such as a major illness or infection. As far as we are
aware, there is no existing literature on dynamic endocrine
tests of adrenal function (such as SST) during and after tak-
ing this supplement.
Adverse effects
A number of potential toxic actions associated with ash-
wagandha have been comprehensively reviewed and
described by experts, including clinicians and pharmacists,
on the www. drugs. com website [2]. Studies with Wistar rats
showed that repeated injections of ashwagandha extract, at a
dose of 100mg/kg body weight for 30days, led to reduction
in the weights of adrenals, thymus and spleen [11], whilst
hepatotoxicity effects of ashwagandha have recently been
reported in humans [12, 13]. Dosing in humans is variable,
ranging from 120mg to 2g a day. Contraindications and
interactions and its use in pregnancy and lactation have not
been well documented, but adverse effects are scarcely or
inappropriately reported in human studies. For example,
in two recent RCTs, one reported “no adverse events” [9]
whilst the other inadequately monitored treatment safety by
full blood counts and lipids [10]. Since there is no exist-
ing published literature on adrenal function amongst peo-
ple taking ashwagandha, it is not possible to determine if
this herbal product affects the adrenal function differently
in people of different age, sex, body composition or ethnic
background.
Mechanisms
Plants have evolved to produce a number of toxic substances
as defence mechanisms against predation from microorgan-
isms (bacteria and fungi), insects and animals [14–17]. A
large number of plants, including ashwagandha, used in
herbal medicines possess this toxic property. The witha-
nolides from ashwagandha contain a highly oxygenated C28
ergostane-type steroidal nucleus with C22-hydroxy-C26-oic
acid δ-lactone in a nine-carbon side chain, and oxidised to
form a six-membered lactone ring [18–20]. It is possible
that the steroidal compounds from ashwagandha, such as
withanolides and alkaloids, may have a direct effect on adre-
nal function. Adrenal steroidogenesis is complex, involv-
ing a pathway of precursor hormones that require specific
enzymatic steps [21], the genes that encode the enzymes
involved in the control of steroid biosynthesis may be inter-
rupted by withanolides and alkaloids, giving rise to adrenal
hypofunction. A recent study has shown that withanone, a
bioactive constituent of withanolides found in ashwagandha
extract, may cause deoxyribonucleic acid (DNA) damage
by forming adducts to DNA. Withanone also forms adducts
with amines, which are reversibly detoxified by glutathione
(GSH) but may cause DNA damage when the GSH sys-
tem is overwhelmed by excessive levels of withanone [22].
Studies have also found that alkaloids from a number of
herbal medicines react with DNA, causing cellular toxicity
or genotoxicity (damage to the genome), leading to struc-
tural alterations of the genetic material through induction
of DNA binding and cross-linking, as well as chromosomal
abnormalities [23].
The effects of steroidal compounds from ashwagandha
may extend to higher neuroendocrine centres controlled by
the hypothalamus and pituitary. The hypothalamic-pitui-
tary axis is known to be vulnerable to stress from restricted
dietary practice and excessive exercise [24] and a number
of drugs including exogenous steroids and opioids [25]. It
is plausible that the steroidal withanolides and alkaloids

144 Toxicology and Environmental Health Sciences (2022) 14:141–145
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from ashwagandha could suppress the hypothalamic–pitui-
tary–adrenal (HPA) axis, in a similar way that exogenous
corticosteroids (used to treat chronic inflammatory condi-
tions) do to the HPA axis, leading to hypoadrenalism [25,
26].
Patient perspective
The patient expressed that she would take greater caution
before considering taking any dietary supplements in the
future. She would do thorough research on independent
sources and consult with healthcare professionals.
Materials andmethods
Information for demographic factors and medications and
physiological measurements were obtained from clinical
history and examination. Blood was taken for biochemis-
try and haematology investigations. Adrenal function was
assessed by SST: the levels of cortisol were obtained at base-
line (prior to Synacthen injection), and at 30min and 60min
after an intramuscular injection of 250μg of Synacthen into
the deltoid muscle. An incremental rise of cortisol level by
at least 200nmol/l or a peak cortisol of > 550nmol/l was
considered as a normal adrenal response. The SST was
performed whilst the patient was taking ashwagandha and
two weeks after coming off this supplement. Analyses were
performed using SPSS Statistics for Windows, v.25.0 (IBM
Corp., Armonk, NY, USA).
Conclusion
This study shows that a relatively short course of ashwa-
gandha is associated with adrenal hypofunction, which was
reversible after two weeks of discontinuation of supplemen-
tation. Individuals taking ashwagandha should be aware
of its detrimental effects. Future studies are suggested to
assess whether long-term treatment with ashwagandha could
lead to permanent suppression of adrenal function. Further
invitro and invivo studies are necessary to elucidate the
effects of ashwagandha compounds on adrenal steroidogenic
pathway and HPA axis.
Acknowledgements We are thankful to our patient for her thorough
discussion of her condition and to consent that her case be published
in a peer-reviewed scientific medical journal. We are also grateful for
additional information on ashwagandha provided by Master Alas-
dair KF Han (St Christopher's Preparatory School, Middlesex), and
Professor Michael EJ Lean (Department of Human Nutrition, Univer-
sity of Glasgow) for his insightful comments.
Declarations
Conflict of interest Christopher H. Fry, David Fluck and Thang S. Han
declare that they have no conflicts of interest.
Ethical approval This study does not require NHS Research Ethics
Committee approval since it involves secondary analysis of anonymised
data. This study was conducted in accordance with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
Statement of human and animal rights This article does not contain
any studies with animals performed by any of the authors.
Statement of authorship TSH reviewed the topic related literature and
wrote the first draft, interpreted the data and revised the manuscript.
CHF and DF checked, interpreted results and commented on the manu-
script. All authors critically revised the manuscript and agree to be
fully accountable for ensuring the integrity and accuracy of the work
and read and approved the final manuscript.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
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