ArticlePDF Available

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



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.
1 3
Toxicology and Environmental Health Sciences (2022) 14:141–145
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
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
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·
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
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
1 3
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
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.
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,
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
1 3
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
Plants have evolved to produce a number of toxic substances
as defence mechanisms against predation from microorgan-
isms (bacteria and fungi), insects and animals [1417]. 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 [1820]. 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
1 3
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,
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).
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.
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,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
1. Ekor M (2014) The growing use of herbal medicines: issues relat-
ing to adverse reactions and challenges in monitoring safety. Front
Pharmacol 4:177. https:// doi. org/ 10. 3389/ fphar. 2013. 00177
2. XXX. https:// www. drugs. com/ npp/ ashwa gandha. html. Accessed
on 200 Sept 2021
3. Bodeker G, Ong CK (2005) WHO global atlas of traditional, com-
plementary and alternative medicine. World Health Organization,
New York
4. Germplasm Resources Information Network (GRIN). Agricultural
Research Service (ARS), United States Department of Agricul-
ture (USDA). https:// npgsw eb. ars- grin. gov/ gring lobal/ taxon/ taxon
omyde tail? id= 102407. Accessed on 20 Sept 2021
5. Kulkarni SK, Dhir A (2008) Withania somnifera: an Indian gin-
seng. Prog Neuropsychopharmacol Biol Psych 32:1093–1105.
https:// doi. org/ 10. 1016/j. pnpbp. 2007. 09. 011
6. Mishra LC, Singh BB, Dagenais S (2000) Scientific basis for the
therapeutic use of Withania somnifera (ashwagandha): a review.
Altern Med Rev 5:334–346
7. Matsuda H, Murakami T, Kishi A, Yoshikawa M (2001) Struc-
tures of withanosides I, II, III, IV, V, VI, and VII, new withanolide
glycosides, from the roots of Indian Withania somnifera DUNAL
and inhibitory activity for tachyphylaxis to clonidine in isolated
145Toxicology and Environmental Health Sciences (2022) 14:141–145
1 3
guinea-pig ileum. Bioorg Med Chem 9:1499–1507. https:// doi.
org/ 10. 1016/ s0968- 0896(01) 00024-4
8. XXX. https:// www. briti sh- suppl ements. net/ produ cts/ clean- genui
ne- ashwa gandha- extra ct- veg- caps-9- 020mg- 22- 54mg- of- witha
ndides. Accessed on 20 Sept 2021
9. Langade D, Kanchi S, Salve J, Debnath K, Ambegaokar D (2019)
Efficacy and safety of Ashwagandha (Withania somnifera) root
extract in insomnia and anxiety: a double-blind, randomized,
placebo-controlled study. Cureus 28(11):e5797. https:// doi. org/
10. 1155/ 2015/ 284154
10. Lopresti AL, Smith SJ, Malvi H, Kodgule R (2019) An investiga-
tion into the stress-relieving and pharmacological actions of an
ashwagandha (Withania somnifera) extract: a randomized, double-
blind, placebo-controlled study. Medicine 98:e17186. https:// doi.
org/ 10. 1097/ MD. 00000 00000 017186
11. Sharada AC, Solomon FE, Devi PU (1993) Toxicity of Withania
somnifera root extract in rats and mice. Int J Pharmac 31:205–212.
https:// doi. org/ 10. 3109/ 13880 20930 90829 43
12. Björnsson HK, Björnsson ES, Avula B, Khan IA, Jonasson JG,
Ghabril M, Hayashi PH, Navarro V (2020) Ashwagandha-induced
liver injury: a case series from Iceland and the US drug-induced
liver injury network. Liver Int 40:825–829. https:// doi. org/ 10.
1111/ liv. 14393
13. Philips CA, Ahamed R, Rajesh S, George T, Mohanan M, Augus-
tine P (2020) Comprehensive review of hepatotoxicity associated
with traditional Indian Ayurvedic herbs. World J Hepatol 12:574–
595. https:// doi. org/ 10. 4254/ wjh. v12. i9. 574
14. Selitrennikoff CP (2001) Antifungal proteins. Appl Environ
Microbiol 67:2883–2894. https:// doi. org/ 10. 1128/ AEM. 67.7.
2883- 2894. 2001
15. Rates SMK (2001) Plants as source of drugs. Toxicon 39:603–
613. https:// doi. org/ 10. 1016/ s0041- 0101(00) 00154-9
16. Vernekar JV, Ghatge MS, Deshpande VV (1999) Alkaline pro-
tease inhibitor: a novel class of antifungal proteins against phy-
topathogenic fungi. Biochem Biophys Res Commun 262:702–707.
https:// doi. org/ 10. 1006/ bbrc. 1999. 1269
17. Priyandoko D, Ishii T, Kaul SC, Wadhwa R (2011) Ashwagan-
dha leaf derived withanone protects normal human cells against
the toxicity of methoxyacetic acid, a major industrial metabolite.
PLoS ONE 6:e19552. https:// doi. org/ 10. 1371/ journ al. pone. 00195
18. Zhang H, Timmermann BN (2016) Withanolide structural
revisions by 13C NMR spectroscopic analysis inclusive of the
γ-gauche effect. J Nat Prod 79:732–742. https:// doi. org/ 10. 1021/
acs. jnatp rod. 5b006 48
19. Vaishnavi K, Saxena N, Shah N, Singh R, Manjunath K, Uthaya-
kumar M, Kanaujia SP, Kaul SC, Sekar K, Wadhwa R (2012)
Differential activities of the two closely related withanolides,
Withaferin A and Withanone: bioinformatics and experimental
evidences. PLoS ONE 7:e44419. https:// doi. org/ 10. 1371/ journ al.
pone. 00444 19
20. Mirjalili MH, Moyano E, Bonfill M, Cusido RM, Palazón J (2009)
Steroidal lactones from Withania somnifera, an ancient plant for
novel medicine. Molecules 14:2373–2393. https:// doi. org/ 10.
3390/ molec ules1 40723 73
21. Han TS, Walker BR, Arlt W, Ross RJ (2014) Treatment and health
outcomes in adults with congenital adrenal hyperplasia. Nat Rev
Endocrinol 10:115–124. https:// doi. org/ 10. 1038/ nrendo. 2013. 239
22. Siddiqui S, Ahmed N, Goswami M, Chakrabarty A, Chowdhury
G (2004) DNA damage by Withanone as a potential cause of liver
toxicity observed for herbal products of Withania somnifera (Ash-
wagandha). Drug Metab Rev 36:1–55. https:// doi. org/ 10. 1081/
dmr- 12002 8426
23. Fu PP, Xia Q, Lin G, Chou MW (2004) Pyrrolizidine alkaloids-
genotoxicity, metabolism enzymes, metabolic activation, and
mechanisms. Drug Metab Rev 36:1–55. https:// doi. org/ 10. 1081/
dmr- 12002 8426
24. Nyekiova M, Ghaderi S, Han TS (2014) Carotenoderma in a
young woman of normal body mass index with hypothalamic
amenorrhoea: a 2-year follow-up case report. Eur J Clin Nutr
68:1362–1364. https:// doi. org/ 10. 1038/ ejcn. 2014. 128
25. Bornstein SR, Bornstein TD, Andoniadou CL (2019) Novel
medications inducing adrenal insufficiency. Nat Rev Endocrinol
15:561–562. https:// doi. org/ 10. 1038/ s41574- 019- 0248-9
26. Prete A, Bancos I (2021) Glucocorticoid induced adrenal insuf-
ficiency. BMJ 374:n1380. https:// doi. org/ 10. 1136/ bmj. n1380
ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Background: Ashwagandha (Withania somnifera (L.) Dunal) is a herb traditionally used to reduce stress and enhance wellbeing. The aim of this study was to investigate its anxiolytic effects on adults with self-reported high stress and to examine potential mechanisms associated with its therapeutic effects. Methods: In this 60-day, randomized, double-blind, placebo-controlled study the stress-relieving and pharmacological activity of an ashwagandha extract was investigated in stressed, healthy adults. Sixty adults were randomly allocated to take either a placebo or 240 mg of a standardized ashwagandha extract (Shoden) once daily. Outcomes were measured using the Hamilton Anxiety Rating Scale (HAM-A), Depression, Anxiety, and Stress Scale -21 (DASS-21), and hormonal changes in cortisol, dehydroepiandrosterone-sulphate (DHEA-S), and testosterone. Results: All participants completed the trial with no adverse events reported. In comparison with the placebo, ashwagandha supplementation was associated with a statistically significant reduction in the HAM-A (P = .040) and a near-significant reduction in the DASS-21 (P = .096). Ashwagandha intake was also associated with greater reductions in morning cortisol (P < .001), and DHEA-S (P = .004) compared with the placebo. Testosterone levels increased in males (P = .038) but not females (P = .989) over time, although this change was not statistically significant compared with the placebo (P = .158). Conclusions: These findings suggest that ashwagandha's stress-relieving effects may occur via its moderating effect on the hypothalamus-pituitary-adrenal axis. However, further investigation utilizing larger sample sizes, diverse clinical and cultural populations, and varying treatment dosages are needed to substantiate these findings.
Full-text available
The use of herbal medicinal products and supplements has increased tremendously over the past three decades with not less than 80% of people worldwide relying on them for some part of primary healthcare. Although therapies involving these agents have shown promising potential with the efficacy of a good number of herbal products clearly established, many of them remain untested and their use are either poorly monitored or not even monitored at all. The consequence of this is an inadequate knowledge of their mode of action, potential adverse reactions, contraindications, and interactions with existing orthodox pharmaceuticals and functional foods to promote both safe and rational use of these agents. Since safety continues to be a major issue with the use of herbal remedies, it becomes imperative, therefore, that relevant regulatory authorities put in place appropriate measures to protect public health by ensuring that all herbal medicines are safe and of suitable quality. This review discusses toxicity-related issues and major safety concerns arising from the use of herbal medicinal products and also highlights some important challenges associated with effective monitoring of their safety.
Synthetic glucocorticoids are widely used for their anti-inflammatory and immunosuppressive actions. A possible unwanted effect of glucocorticoid treatment is suppression of the hypothalamic-pituitary-adrenal axis, which can lead to adrenal insufficiency. Factors affecting the risk of glucocorticoid induced adrenal insufficiency (GI-AI) include the duration of glucocorticoid therapy, mode of administration, glucocorticoid dose and potency, concomitant drugs that interfere with glucocorticoid metabolism, and individual susceptibility. Patients with exogenous glucocorticoid use may develop features of Cushing’s syndrome and, subsequently, glucocorticoid withdrawal syndrome when the treatment is tapered down. Symptoms of glucocorticoid withdrawal can overlap with those of the underlying disorder, as well as of GI-AI. A careful approach to the glucocorticoid taper and appropriate patient counseling are needed to assure a successful taper. Glucocorticoid therapy should not be completely stopped until recovery of adrenal function is achieved. In this review, we discuss the factors affecting the risk of GI-AI, propose a regimen for the glucocorticoid taper, and make suggestions for assessment of adrenal function recovery. We also describe current gaps in the management of patients with GI-AI and make suggestions for an approach to the glucocorticoid withdrawal syndrome, chronic management of glucocorticoid therapy, and education on GI-AI for patients and providers.
With growing antipathy toward conventional prescription drugs due to the fear of adverse events, the general and patient populations have been increasingly using complementary and alternative medications (CAMs) for managing acute and chronic diseases. The general misconception is that natural herbal-based preparations are devoid of toxicity, and hence short- and long-term use remain justified among people as well as the CAM practitioners who prescribe these medicines. In this regard, Ayurvedic herbal medications have become one of the most utilized in the East, specifically the Indian sub-continent, with increasing use in the West. Recent well-performed observational studies have confirmed the hepatotoxic potential of Ayurvedic drugs. Toxicity stems from direct effects or from indirect effects through herbal metabolites, unknown herb-herb and herbdrug interactions, adulteration of Ayurvedic drugs with other prescription medicines, and contamination due to poor manufacturing practices. In this exhaustive review, we present details on their hepatotoxic potential, discuss the mechanisms, clinical presentation, liver histology and patient outcomes of certain commonly used Ayurvedic herbs which will serve as a knowledge bank for physicians caring for liver disease patients, to support early identification and treatment of those who present with CAM-induced liver injury.
Background & aims: Ashwagandha (Withania somnifera) is widely used in Indian Ayurvedic medicine. Several dietary supplements containing ashwagandha are marketed in the U.S. and Europe, but only one case of ashwagandha-induced liver injury (DILI) has been published. The aim of this case series was to describe the clinical phenotype of suspected ashwagandha induced liver injury. Methods: Five cases of liver injury attributed to ashwagandha-containing supplements were identified; three were collected in Iceland during 2017-2018 and two from the Drug-Induced Liver Injury Network (DILIN) in 2016. Other causes for liver injury were excluded. Causality was assessed using the DILIN structured expert opinion causality approach. Results: Among the five patients, three were males; mean age 43 years (range 21-62). All patients developed jaundice and symptoms such as nausea, lethargy, pruritus and abdominal discomfort after a latency of 2-12 weeks. Liver injury was cholestatic or mixed (R ratios 1.4-3.3). Pruritus and hyperbilirubinemia were prolonged (5-20 weeks). No patient developed hepatic failure. Liver tests normalized within 1-5 months in 4 patients. One patient was lost to follow-up. One biopsy was performed, showing acute cholestatic hepatitis. Chemical analysis confirmed ashwagandha in available supplements; no other toxic compounds were identified. No patient was taking potentially hepatotoxic prescription medications, four were consuming additional supplements, in one case rhodiola was a possible causative agent along with ashwagandha. Conclusions: These cases illustrate the hepatotoxic potential of ashwagandha. Liver injury is typically cholestatic or mixed with severe jaundice and pruritus, but self-limited with liver tests normalizing in 1-5 months.
Emerging evidence demonstrates that an increasing number of novel medications have considerable potential to induce adrenal insufficiency. This condition might lead to acute adrenocortical insufficiency, which is potentially fatal; however, the condition could be avoided if clinicians are more aware of the new findings and their implications.
A classic withanolide is defined as a highly oxygenated C28 ergostane-type steroid that is characterized by a C22-hydroxy-C26-oic acid δ-lactone in the nine-carbon side chain. Analysis of the reported (13)C NMR data of classic withanolides with hydroxy groups (C-14, C-17, and C-20) revealed that (1) a hydroxy (C-14 or C-17) substituent significantly alters the chemical shifts (C-7, C-9, C-12, and C-21) via the γ-gauche effect; (2) the chemical shift values (C-9, C-12, and C-21) reflect the orientation (α or β) of the hydroxy moiety (C-14 or C-17); (3) a double-bond positional change in ring A (Δ(2) to Δ(3)), or hydroxylation (C-27), results in a minuscule effect on the chemical shifts of carbons in rings C and D (from C-12 to C-18); and (4) the (13)C NMR γ-gauche effect method is more convenient and reliable than the traditional approach ((1)H NMR shift comparisons in C5D5N versus CDCl3) to probe the orientation of the hydroxy substituent (C-14 and C-17). Utilization of these rules demonstrated that the reported (13)C NMR data of withanolides 1a-29a were inconsistent with their published structures, which were subsequently revised as 1-16 and 12 and 18-29, respectively. When combined, this strongly supports the application of these methods to determine the relative configuration of steroidal substituents.
Hypothalamic amenorrhoea has been shown to be associated with hypercarotenaemia, but no causal link has been established. Many people are unaware of the health implications of carotenoderma. We report on a 36-year-old woman with normal body mass index and with a history of secondary amenorrhoea for 2 years and carotenoderma for 5 years. She had a history of practising a fixed-menu diet of predominantly leafy greens, exercised intensively and had a stressful job. Blood tests confirmed the presence of hypercarotenaemia and hypogonadotrophic hypogonadism. Carotenoderma subsided after 6 months of lifestyle modification, but she remained amenorrhoeic up to 12 months later. Since then, her condition had relapsed up to the time of 2 years of follow-up. We conclude that hypercarotenaemia/carotenoderma and hypothalamic amenorrhoea are manifestations of a constrained lifestyle rather than causally linked. The presence of carotenoderma should alert public individuals and clinicians, especially in primary care, alike for signs of potential health complications including reproductive dysfunction even without weight problems.European Journal of Clinical Nutrition advance online publication, 2 July 2014; doi:10.1038/ejcn.2014.128.
Congenital adrenal hyperplasia (CAH) is a genetic disorder caused by defective steroidogenesis that results in glucocorticoid deficiency; the most common underlying mutation is in the gene that encodes 21-hydroxylase. Life-saving glucocorticoid treatment was introduced in the 1950s, and the number of adult patients is now growing; however, no consensus has been reached on the management of CAH beyond childhood. Adult patients are prescribed a variety of glucocorticoids, including hydrocortisone, prednisone, prednisolone, dexamethasone and combinations of these drugs taken in either a circadian or reverse circadian regimen. Despite these personalized treatments, biochemical control of CAH is only achieved in approximately one-third of patients. Some patients have a poor health status, with an increased incidence of obesity and osteoporosis, and impaired fertility and quality of life. The majority of poor health outcomes seem to relate to inadequate treatment rather than the genotype of the patient. Patients receiving high doses of glucocorticoids and the more potent synthetic long-acting glucocorticoids are at an increased risk of obesity, insulin resistance and a reduced quality of life. Further research is required to optimize the treatment of adult patients with CAH and improve health outcomes.