Spontaneous Reports of Suspected Adverse Reactions to Ashwagandha: Analysis of Data From the Italian Nutrivigilance System

Dear editor,

Withania somnifera (L.) Dunal, commonly known as ashwagandha or Indian ginseng, has been used in the traditional Ayurvedic and Unani medicine systems of India to treat several disorders. All parts of the plant (i.e., leaves, flowers, seeds, roots) are used, but the root is mostly applied for medical purposes (Mikulska et al. 2023). However, in Europe, the Committee on Herbal Medicinal Products (HMPC) did not adopt a European Union herbal monograph due to the lack of adequate evidence about herbal preparations description and their traditional use (European Medicine Agency‐Committee on Herbal Medicinal Products [HMPC] 2013). In recent years, there has been a growing interest in the potential benefits of ashwagandha as an adaptogen plant, particularly in the field of stress management, cognitive function, and physical performance (Mikulska et al. 2023; Fatima et al. 2024; Lopresti and Smith 2021). Although several preclinical and clinical studies evaluated the biological effects of ashwagandha in different conditions, no adequate investigations on its safety and tolerability have been performed. In clinical studies, ashwagandha has been well tolerated by participants for up to a few months of use (Lopresti and Smith 2021; Tandon and Yadav 2020; Vaidya et al. 2024). Conversely, evidence on the longer‐term safety (i.e., over several months or years) is still lacking even though studies have demonstrated the lack of mutagenic (genotoxic) effects also at high concentrations (Kalaivani et al. 2023). Common side effects are usually mild and include stomach upset, loose stools, nausea, vomiting, and diarrhea (Tandon and Yadav 2020; Lopresti and Smith 2021). However, there is some evidence of more serious side effects associated with ashwagandha use, including those on liver functions. Ashwagandha might also interact with medications, including antidiabetics, antihypertensives, immunosuppressants, benzodiazepines, barbiturates, as well as certain herbs and supplements (Lopresti and Smith 2021; Mikulska et al. 2023).

Currently, in Europe, ashwagandha is regulatory classified as an herbal ingredient used in food supplements. However, EU regulators have questioned its safety, culminating in a recent recommendation for an Article 8 procedure according to Regulation (EC) No 1925/2006 by the Heads of Food Safety Agencies working group “Food Supplements” (Heads of Food Safety Agencies (HoA) Working Group of Food Supplements 2024). Given the uncertainty about ashwagandha's safety profile, this study seeks to improve our understanding by examining spontaneous reports of adverse reactions (ARs) related to natural products containing this ingredient collected by the Italian National Institute of Health.

Since 2002, the Italian National Institute of Health (Istituto Superiore di Sanità, ISS) collects all spontaneous reports of ARs to products of natural origin through the Italian Phytovigilance System (IPS). Currently, anyone can make a report (health professionals, companies, citizens) through the VigiErbe website (www.vigierbe.it). The system allows the collection and analysis of data on clinical characteristics of patients (age, gender, medical conditions), the suspected product, the ARs, motivation for use and concomitant products. ARs are coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reports of ARs containing ashwagandha ( Withania somnifera ) received from January 1, 2002, to November 1, 2024, were analyzed. For the data selection, the names “ashwagandha”, “ Withania somnifera ”, “Indian ginseng”, and “Winter Indian Cherry” were considered. A causality assessment was performed for all the reports, using the modified World Health Organization scale (World Health Organization‐Uppsala Monitoring Centre (WHO–UMC) 2013). Two reviewers (G.M. and I.I.) independently examined and synthesized data from all selected reports into a comprehensive table using standardized data extraction. A third reviewer (S.D.G.) resolved all inter‐reviewer disagreements. The composition of products was reported (Table 1), excluding excipients, as on the label of the package. Continuous data were expressed as median and interquartile range (IQR), while categorical variables were expressed as count or percentages.

TABLE 1.

Principal information on AR reports and causality assessment.

ID/date	Age/sex	Adverse reaction	Seriousness	Suspected product	Concomitant product	Concomitant conditions	Outcome	Dechallenge/rechallenge	Sender	Causality assessment
236/December 2005	64/M	Bleeding gastric ulcer Haemesis Melena	Life threatening	Olimap	Pelvimap Verumap	Prostatic hypertrophy	Recovered	NR/NE	Physician	Unlikely
840/September 2012	72/M	Vomiting Acute diarrhea Hypotension	Not serious	Gunabrain	Esomeprazole Pravastatin	NR	Recovered	+/NE	Physician	Unlikely
906/March 2013	61/F	Dizziness Stunning Disorientation	Not serious	Adrenal Energy Formula	Duloxetine	Colon removal 3–4 years earlier	NR	NR/NE	Physician	Possible
943/June 2013	49/F	Arterial hypertension	Not serious	Perdipeso GTT	Estrogen NOS	Overweight patient (not obese); hypercholesterolaemia	In recovering	NR/NE	Pharmacist	Unlikely
948/July 2013	59/F	Increased transaminase value	Not serious	Oncophyt4	Alprazolam Guna Interferon H	Previous breast carcinoma, currently not undergoing treatment	NR	NR/NE	Physician	Possible
1774/September 2018	53/M	Vomiting Dysentery	Not serious	Recupra	No	No	Recovered	+/+	Pharmacist	Probable/Likely
2198/May 2020	NR/M	Abdominal pain	Not serious	Ashwaganda a	NR	NR	NR	NR/NE	Citizen	Possible
2462/December 2020	55/F	Presyncope Vomiting Diarrhoea	Not serious	Nutriva Nutri Withania	NR	NR	Recovered	+/+	Pharmacist	Probable/likely
2513/January 2021	69/F	Bellyache Excessive sweating	Not serious	Gunabrain	Amplodipine Olmesartan Hydrochlorothiazide Legalon E Citilpea	Hypertension, previouses optic nerve ischemia and gastroenteritis	Recovered	NR/NE	Company	Unlikely
2746/August 2021	58/M	Ventricular extrasystole	Not serious	Dianazen	NR	NR	Recovered	+/NE	Physician	Possible
3043/Aprile 2022	17/M	Syncope Trauma	Hospitalization	Ashwagandha a	NR	NR	Recovered	NR/NE	Physician	Unlikely
3439/March 2023	NR/F	Hypotension Palpitations	Not serious	Quetidia Fast	NR	NR	Recovered	+/NE	Company	Possible
3816/November 2023	33/F	Liver failure Itching Diarrhoea	Hospitalization	Starsu	NR	NR	In recovering	+/NE	Pharmacist	Probable/likely
5924/September 2024	25/M	Headache	Disabling	Ashwagandha (gummies) a	NR	Autism spectrum (Autism Level 1, formerly asperger's syndrome), drug intolerance, cyclic vomiting syndrome, dysthymia, headaches (2009 to 2011), OCD, anxiety disorders, panic attack disorders, major depression (years 2019–2020), involuntary benzodiazepine dependence (clonazepam)	Recovered	+/+	Citizen	Possible
6683/October 2024	54/M	Insomnia	Not serious	Laila Dormibene	Ansioten St. John's wort	Prostatitis and primary insomnia	Not recovered	−/+	Company	Possible

¹

Abbreviations: −: negative; +: positive; d.e.: dry extract; F: female; M: male; NE: not executed; NOS: not otherwise specified; NR: not reported.

^a Composition not otherwise specified.

Adrenal Energy Formula: holy basil, cordyceps, bacopa, and ashwagandha.

Ansioten: l‐theanine 100 mg, Valeriana officinalis d.e. 60 mg titrated in valeric acids 0.48 mg, melatonin 1 mg.

Citilpea: citicoline, palmitoylethanolamide, vitamins A, B6, E.

Dianazen: Withania somnifera (L.) Dunal radix d.e mg 400, magnesium oxide mg 57, vitamin B6 mg 8.4, Crataegus monogyna Jacq. ‐ folium d.e. 3% vitexin mg 350.

Gunabrain: green tea ( Camellia sinensis ) leaves d.e. 98% polyphenols (40% EGCG), W.somnifera root d.e. 5% withanolides.

Gunabrain: C.sinensis (L.) Kuntze, coenzyme Q10, manganese, N‐acetylcysteine, selenium, W.somnifera L. Dunal.

Guna interferon H: homeopathised cytokines: interferon alpha leucocyte.

Laila Dormibene: melatonin 1 mg and 5 dry herbal extracts: chamomile, ashwaganda ( W.somnifera ), lemon balm, valerian, lavender.

Legalon: milk thistle dry extract equal to silymarin 210 mg, vitamin E 18 mg.

Nutriva Nutri Withania: W.somnifera (L.) Dunal radix d.e. 1.5% withanolides mg 800.

Olimap: Guggul (Commiphora mukul Hook.) resin; powder of: Vasa ( Adhatoda vasica Nees) folium, Ginger ( Zingiber officinale Rosc.) rhizome, Long pepper ( Piper longum L.) fructus, Wormwood ( Artemisia absinthium L.) herba c. floribus, Black pepper ( Piper nigrum L.) fructus, stabilizer Gum arabic, powder of: Vidarikand (Pueraria tuberosa (Roxb. ex Willd. DC) rhizome, Cinnamon ( Cinnamomum zeylanicum Blume) cortex, Jatamansi (Nardostachys jatamansi DC.) rhizome, Cardamom ( Elettaria cardamomum White et Mason) semen, Vanslochan ( Bambusa arundinacea Willd.) manna, Grapes ( Vitis vinifera L.) fructus, Gokshura ( Tribulus terrestris L.) herba, Shatavari (Asparagus racemosus (Willd.) Oberm.) radix, Yavani ( Trachyspermum ammi Sprague) fructus, Liquorice ( Glycyrrhiza glabra L.) radix, Garlic ( Allium sativum L.) bulbus, stabilizer: starch, Katuka (Picrorhiza kurroa Royle) rhizoma, Chinese Smilax ( Smilax china L.) radix, Meadow cumin ( Carum carvi L.) fructus, Meshasringi ( Gymnema sylvestre R. Br.) folium, Cumin ( Cuminum cyminum L.) semen, Ashvagandha ( W.somnifera (L.) Dunal) radix, Sigru ( Moringa oleifera Gaertn.) semen, Vidarikand (Pueraria tuberosa (Roxb. ex Willd.) DC) rhizome, Bibhitaki (Terminalia bellerica Roxb.) fructus, Kankola ( Piper cubeba L.f.) fructus, Bilva ( Aegle marmelos Correa) cortex, Musta ( Cyperus rotundus L.) radix, Amalaki ( Phyllanthus emblica L.) fructus.

Oncophyt4: turmeric ( Curcuma longa L.) rhizomes, Grifola umbellata (Polyporus umbellatum Pers.) sporophorum, Boswellia ( Boswellia serrata Roxb.) gummoresin d.e., Cat's claw (Uncaria tomentosa Willd. DC.) bark d.e., Ashwagandha d.e. ( W.somnifera (L.) Dunal) leaves d.e., Green tea ( C.sinensis L. Kuntze) leaves d.e., Parthenium ( Tanacetum parthenium Sch. Bip.) aerial parts d.e.

Pelvimap: NR.

Perdipeso GTT: W.somnifera extract, melon extract, bitter orange, sweet orange.

Quetidia fast: C.sinensis Kuntze leaves d.e. 40% l‐theanine, Passiflora incarnata L. herba cum floribus d.e. 0.5% flavonoids, W.somnifera (L.) Dunal radix d.e. 1.5% withanolides.

Recupra: ashwagandha, rhodiola and centella with vitamins B2 and B6.

Starsu: potassium citrate mg 800, L‐arginine mg 3000, beta alanine mg 500, acetil L‐carnitine mg 500, magnesium chloride mg 210, creatine monohydrate mg 2500, W.somnifera (L.) Dunal leaves d.e mg 300, Eleutherococcus senticosus Maxim. radix d.e mg 300, L‐ascorbic acid mg 100, zinc gluconate mg 5.

Verumap: Sevya ( Vetiveria zizanioides Nash) radix; Sandalwood ( Santalum album L.) lignum powder; Guggul (Balsamodendron mukul Hook.) resin paste; Gokshura ( Tribulus terrestris L.) fructus dry extract (d.e.); Bhumyamalaki ( Phyllanthus niruri L.) herba d.e., Manjistha (Rubia cordifolia L.) radix d.e., Brihatgokshura (Pedalium murex L.) fructus d.e.; Red Sandalwood ( Pterocarpus santalinus L.f.) lignum d.e.; Liquorice ( Glycyrrhiza glabra L.) radix powder, Turmeric ( Curcuma longa L.) rhizome powder; Cloves [ Syzygium aromaticum (L.) Merr. et L. M. Perry] flos powder, Ginger ( Zingiber officinale Rosc.) rhizome powder, Black pepper ( Piper nigrum L.) fructus powder, Long pepper ( Piper longum L.) fructus powder.

From January 1, 2002, to November 1, 2024, 15 spontaneous reports of suspected ARs related to natural products containing ashwagandha were collected (Table 1). Most of the reports were from physicians and pharmacists (N = 10; 67%) followed by pharmaceutical companies (N = 3; 20.0%) and citizens (N = 2; 13%). Although the number of spontaneous reports was low, most of them (N = 9; 60%) have been collected in the last 5 years, suggesting a slight increase in knowledge and use of ashwagandha and, perhaps, awareness of its potential side effects. The median age of people who experienced ARs was 55 years (IQR = 41.0–60.5 years); in two cases the information was lacking. Men were involved in 8 cases (53.3%), women in 7 (46.7%). The ARs reported (N = 27) were mainly related to “Gastrointestinal disorders” (N = 11; 37.9%), “Nervous system disorders” (N = 4; 14.8%), and “Vascular disorders” (N = 3; 10.3%) (Figure 1). Serious reactions occurred in four cases (26.7%). The products containing ashwagandha, potentially involved in ARs, were classified as food supplements (N = 10; 66.7%), herbal products (N = 4; 26.7%), and food (N = 1; 6.6%) (gummies). The information about the reason for use was unknown in 6 cases (40%), among the reported ones it was mainly asthenia/tonic (N = 5; 33.3%). Concerning the composition of the suspected products, ashwagandha was present as the only active substance in 5 cases (ID 2198, 2462, 2513, 3043, 5924) corresponding to 33.3%; in the remaining 10 cases, a combination of ingredients was present, mostly herbal extracts. Particularly, the median number of ingredients was 4, ranging from 1 to 30. In about 26.7% of cases at least one concomitant drug was reported; considering the first ATC level, one drug in the “Alimentary Tract and Metabolism” group, one drug in the “Nervous System” group, and four drugs in the “Cardiovascular System” group were reported. In one case (ID 948), a homeopathic product containing interferon‐alpha leukocyte was reported. Concomitant diseases (33.3%) were indicated in five cases: (i) prostatitis and primary insomnia; (ii) autism spectrum, drug intolerance, cyclic vomiting syndrome, previous headaches, mental disorders, addiction; (iii) hypertension; (iv) hypercholesterolemia; and v) prostatic hypertrophy. Moreover, in two cases a history of cancer (no longer under treatment) and an episode of optic nerve ischemia, respectively, were reported. The analysis of reports showed a lack of data about the duration of use of the products; based on the available information, the median was 20 days (IQR = 1–30 days). In terms of outcome, the clinical condition was mostly “recovered” (N = 9; 60.0%), followed by “in recovering” (N = 2; 13.3%) and “not recovered” (N = 1; 6.7%); the information was lacking in 3 reports (20.0%). Dechallenge resulted positive in 46.7% of cases (N = 7); rechallenge was positive in 4 (26.7%); however, in most cases rechallenge resulted as “not executed,” as ethically expected. The causality assessment was performed for all reports. It was probable/likely in 3 cases (20.0%), possible in 7 cases (46.7%), and unlikely in 5 cases (33.3%).

FIGURE 1.

Frequency of adverse reactions (overall) grouped by system organ class (SOC). Card: cardiac disorders; Ear: ear and labyrinth disorders; Gastr: gastrointestinal disorders; Hepat: hepatobiliary disorders; Infec: infections and infestations; Inj&P: injury, poisoning, and procedural complications; Inv: investigations; Nerv: nervous system disorders; Psych: Psychiatric disorders; Skin: skin and subcutaneous tissue disorders; Vasc: vascular disorders.

Ashwagandha, commonly known as “Indian Winter cherry” or “Indian ginseng,” is one of the most important herbs of Ayurveda and Unani traditional medicines, and it has been starting spread over the western countries; however, its safety profile has not been deeply investigated. The present study aimed to analyse ARs potentially associated with use of ashwagandha, reported to the Italian Phytovigilance System. This is, at our knowledge, the first study describing spontaneous reports of suspected ARs of ashwagandha observed in the Italian population. The reports analyzed (N = 15) were collected from January 1, 2002, to November 1, 2024. Some reactions that deserve particular attention are discussed below.

Particularly, two cases of liver damage were highlighted in our analysis. A 32‐year‐old female experienced liver failure, itching, and diarrhea after taking a food supplement containing ashwagandha, carnitine, and beta alanine for about 10 days (ID 3816). The reaction required hospitalization, with transaminases more than five times the upper limit of normal. The product has been discontinued, and the reported outcome was “in recovery”. Case reports in the literature have documented liver damage reactions (Lim and Barnes 2024) even if the mechanisms by which the plant exerts liver toxicity effects are still unknown. Given that no concomitant medications, supplements, or any underlying conditions were reported and based on the case reports in the literature, the correlation was considered probable/likely. Similarly, a 59‐year‐old female, with previous breast carcinoma, currently not undergoing treatment, experienced an increase of transaminases after the intake of a multi‐ingredient food supplement containing, among others, turmeric ( Curcuma longa ) rhizomes, ashwagandha ( W.somnifera ) leaves, and green tea ( Camellia sinensis ) leaves (ID 948). The patient was also assuming the drug alprazolam and a homeopathic product containing interferon alpha. Hepatic reactions after consuming green tea are well described (Björnsson et al. 2020; Navarro et al. 2017; Menniti‐Ippolito et al. 2020). Moreover, cases of hepatotoxicity after consuming turmeric are reported (Halegoua‐DeMarzio et al. 2023). Considering all these aspects, the causal relationship was judged as possible.

Cases of a potential pharmacokinetic interaction between ashwagandha and medicinal products cannot be excluded. Indeed, ashwagandha has been reported to modulate xenobiotic metabolism by inhibiting both CYP3A4 and CYP2D6 hepatic cytochromes (Siwek et al. 2023). A 61‐year‐old female experienced dizziness after the consumption of a food supplement containing holy basil, cordyceps, bacopa, and ashwagandha, assumed for “chronic stress” (ID 906). The woman was also assuming the drug duloxetine, whose major hepatic metabolic pathways involve CYP1A2 and CYP2D6, so a possible interaction with ashwagandha cannot be excluded. In this regard, the AR is present in the Product Features Summary (dizziness common, disorientation uncommon), so the correlation was judged as possible.

Also, interactions among ingredients of the same product could be associated with the AR onset. In two cases (ID 2746 and 3439), cardiovascular reactions (ventricular extrasystole at rest, palpitations and hypotension) occurred after the intake of a multi‐ingredient food supplement based on ashwagandha. In particular, in the first case, the suspected product also contained Crataegus monogyna Jacq. leaves (3% vitexin), while in the second, the dry extracts of Camellia sinensis Kuntze leaves (40% l‐theanine). There have been reports of cardiac symptoms following the consumption of products containing W. somnifera . Indeed, although cardioprotective effects have been ascribed to ashwagandha, cases of ventricular tachycardia have been documented (Dwivedi et al. 2011; Brown 2018). Moreover, cardiac stimulation has been reported for C. sinensis due to its caffeine content (Batista et al. 2017). Based on these considerations, a pharmacodynamic interaction was hypothesized. Given the lack of information about concomitant therapies or underlying conditions and the positive dechallenge, a possible causal relationship between the supplement and the AR was considered.

In some cases, the reported symptoms could also be explained by the underlying diseases. A 54‐year‐old male experienced a reaction characterized by insomnia (ID 6683). Although, based on the reported information, the rechallenge was positive, it should be outlined that the patient had a clinical history of primary insomnia which could also explain the AR. Moreover, a 25‐year‐old male experienced occasional headaches after assumptions of ashwagandha gummies (ID 5924). In this case, a history of mental and behavioral disorder (autism spectrum, obsessive‐compulsive disorder, anxiety disorders, panic attack disorders, and major depression) along with the assumption of clonazepam, could be related to the AR onset.

Gastrointestinal symptoms could occur after the ashwagandha intake. For example, a 53‐year‐old male experienced vomiting and dysentery after the intake of the food supplement containing ashwagandha, rhodiola, centella, and vitamins, for the relief of stress (ID 1774). Particularly, the patient took one packet of the food supplement in spring 2018 without any reaction. In August, he started again, and 6–8 h after taking the first tablet, he had vomiting and dysentery for a few hours. After 10 days, he took again a tablet and again he had vomiting and dysentery. A Prist test was then executed, revealing an amount of IgE equal to 420 IU/mL (normal value < 200 IU/mL). To note, total IgE increase is a nonspecific datum, and allergic reactions onset is usually immediate and associated with other subjective and objective manifestations (Vara et al. 2016; Anvari et al. 2019). The patient had no other relevant medical conditions and did not assume any other drugs. Mild gastrointestinal symptoms (i.e., diarrhea, vomiting, nausea, and abdominal pain) have been previously reported for ashwagandha (Lim and Barnes 2024; Lopresti and Smith 2021). Considering the positive rechallenge and the absence of concomitant treatments and conditions, the causal correlation was considered likely.

Finally, another important issue is represented by the consumption of ayurvedic products which usually contain several herbal ingredients. In one report (ID 236), a 64‐year‐old male experienced upper and lower gastrointestinal bleeding after the intake of three Ayurvedic products, one of which contained W. somnifera , for prostatic hypertrophy. No alternative causes were reported. The time‐onset of the ARs was consistent with the duration of intake of the three suspected products (approximately 20 days). The composition was only listed for two products with 31 and 8 ingredients, respectively. Therefore, it is not possible to identify one or more substances responsible for the reactions, though some of them may be associated with an increased risk of bleeding (Abebe 2019). Also, contamination with other substances, including heavy metals, cannot be ruled out. Indeed, ayurvedic products often contain heavy metals at concentrations that exceed safety limits, posing potential health risks (Mikulski et al. 2017). Considering the above, the causality assessment was unlikely for W. somnifera .

Analyzing ARs to natural products is more difficult than ethical drugs for several reasons: (1) natural products have a complex composition, which includes different medicinal plants with different compositions, so it is difficult to attribute the reaction to a single component; (2) natural products are frequently consumed in association with ethical drugs: this exposes the subject to the risk of pharmacological interactions; (3) reports of suspected reactions to natural products are often incomplete, which makes it more difficult to establish the causality between AR and intake of the product. Despite these limitations, we attempted to analyse the ARs and establish the causality with the consumption of ashwagandha.

In addition, our study is based on the analysis of the spontaneous reports of ARs related to food supplements; therefore, the underreporting, such as lack of clinical information (i.e., concomitant comorbidities, dosage) should be considered among its limits. Moreover, data on the prevalence of use (denominators) of these products in the general population are not available and, for this reason, ad hoc observational studies are needed. However, the spontaneous reporting system still represents a fundamental monitoring instrument to identify unknown and serious ARs and to detect safety signals not usually assessed within clinical trials.

This study was conceived as an observational retrospective analysis of spontaneous reports collected from the IPS to characterize the safety profile of products containing ashwagandha to identify safety issues from a public health perspective. Our results are coherent with the most commonly reported side effects associated with ashwagandha, which include not only nausea, diarrhea, and drowsiness but also the more serious liver damage (Bjornsson et al., 2020; Ireland et al. 2021; Lubarska et al. 2023; Almuzghi et al. 2024) especially in the case of concomitant use of other natural substances or drugs. Furthermore, several issues related to the composition of the suspected products have been highlighted, such as the fact that several ingredients were often present; thus, it is impossible to determine with certainty the role played by ashwagandha in the observed reactions. Overall, this data reinforces the importance of the Italian Phytovigilance System as a very useful method to monitor food supplements risk signals, also considering that safety studies are not required.

Author Contributions

Ilaria Ippoliti: conceptualization, data curation, formal analysis, writing – original draft, methodology, validation. Silvia Di Giacomo: conceptualization, formal analysis, writing – original draft, validation, methodology. Paola Angela Moro: writing – review and editing, supervision. Francesca Maida: writing – review and editing. Gabriela Mazzanti: writing – review and editing, supervision. Francesca Menniti Ippolito: writing – review and editing, supervision, validation, methodology, project administration. Giuseppe Marano: formal analysis, writing – original draft, validation, methodology.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors disclose no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.