Toxicology Reports 8 (2021) 1955–1959

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Toxicology Reports
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An open label, single arm, prospective clinical study to evaluate liver safety
and tolerability of PUREMERIC™ (standardized extract from Curcuma
longa) in healthy subjects
Sudeep HV a, *, Jestin V Thomas b, Vasavi HS a, Shyamprasad K a
a
R&D Center for Excellence, Vidya Herbs Pvt. Ltd, #14A, Jigani I Phase, Bangalore, 560 105 Karnataka, India
b
Leads Clinical Research and Bio Services Private Ltd., Bangalore, India

A R T I C L E I N F O A B S T R A C T

Handling Editor: Dr. Aristidis Tsatsakis Objective: Turmeric is a culinary spice valued since ancient time for its medicinal properties, mostly attributed to
curcumin, the major polyphenol present. The safety of curcumin is well established in humans. However, the
Keywords: tolerability of curcumin is largely determined either in subjects with existing health problems, or in healthy
Turmeric individuals at low doses. More recently the safety of turmeric supplementation is opposed following some case
Curcumin
reports on the occurrence of acute hepatitis due to its consumption.
Safety
Method: Here we have investigated the safety and tolerability of a standardized turmeric extract containing 95 %
Cholestatic hepatitis
Healthy subjects curcuminoids (PUREMERIC™) in an open label, single arm, prospective clinical study. Twelve healthy subjects
aged 18–50 years received 500 mg PUREMERIC capsules twice daily for 90 days.
Results: After PUREMERIC supplementation, the liver function parameters such as aspartate aminotransferase
(AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and direct bilirubin, gamma-glutamyl
transpeptidase (GGT), and lactate dehydrogenase (LDH) were not significantly altered in the serum compared to
baseline. The hematological parameters were within the normal range.
Conclusion: Collectively, these data contradict the turmeric- induced liver damage and establishes the safety of
the extract in healthy individuals.

1. Introduction In the animal safety studies, an oral administration of curcumin up to

3500 mg/kg-BW for up to 90 days did not induce any adverse effects [7].
Turmeric is a spice derived from the rhizomes of Curcuma longa L., Administration of up to 1000 mg/kg B.W. curcumin to rats showed no
(Zingiberaceae). Herbal preparations from turmeric have been used reproductive toxicity as noticed in two successive generations. However,
extensively in Indian traditional medicine in various forms and routes turmeric ingestion is also reported to be associated with liver toxicity in
[1]. Curcuminoids are the major bioactive components of turmeric, some animal species such as mice, and long-term intake in rats [8].
which include curcumin (diferuloyl methane), demethoxycurcumin, and The safety of curcumin has been established through several clinical
bisdemethoxycurcmin. Curcumin is the main active component studies. In a study performed on Indian population, daily oral admin­
responsible for the nutritional and pharmacological activities of istration of 1200− 2100 mg of curcumin for 2–6 weeks did not cause any
turmeric [2]. Curcumin, the major polyphenol in turmeric, has been toxicity [9]. In another study performed on patients with preinvasive
attributed to oxidative stress management and anti-inflammation and malignant or high-risk premalignant conditions, administration of cur­
arthritis [3–5]. cumin up to 8000 mg/kg daily for three months did not induce any toxic
The dietary consumption of turmeric in India accounts for 2–2.5 g/ signs or adverse effects [10]. In a Phase I clinical trial by Sharma et al.,
day in a 60-kg individual, corresponding to an ingestion of approxi­ daily oral administration of curcumin was well tolerated up to 3600 mg
mately 60− 100 mg of curcumin daily and no toxicities or adverse events for up to 4 months in colorectal cancer patients [11]. Majority of clinical
have been reported at the population level [6]. Several systematic studies on curcumin were conducted in populations with existing health
studies have been performed in animals to assess the safety of curcumin. problems [12]. There are only a few reports evaluating the effects of

* Corresponding author at: No. 14A, KIADB, R&D Center for Excellence, Vidya Herbs Pvt. Ltd., Jigani Industrial Area, AnekalTaluk, Bangalore, 560 105, India.
E-mail address: research@[Link] (S. HV).

[Link]
Received 27 July 2020; Received in revised form 19 November 2021; Accepted 30 November 2021
Available online 30 November 2021
2214-7500/© 2021 Vidya Herbs Pvt Ltd. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
([Link]
S. HV et al. Toxicology Reports 8 (2021) 1955–1959

curcumin consumption in healthy human volunteers. DiSilvestro et al. tolerability of PUREMERIC, a proprietary extract prepared from the
reported that a low dose supplementation of curcumin (80 mg/day for 4 rhizomes of C. longa. PUREMERIC is standardized to 95 % curcuminoids
weeks) could exert various health benefits in middle age subjects [13]. as determined by HPLC analysis. Identification of the plant material was
In another double-blind placebo-controlled study, 4-week treatment done at Vidya Herbs Pvt. Ltd., Bangalore, India. Subjects self-
with 80 mg/day significantly improved the cognitive functions in administered 500 mg PUREMERIC capsules orally, in morning and
healthy individuals [14]. Despite the undisputable benefits of con­ night after food. The total treatment period was for 90 days. The subjects
sumption of curcumin, there are some adverse effects reported. In a dose had to record the date, time and amount taken for each administration of
escalation study from Lao et al., 30 % of the subjects administered with a IP in a subject diary.
single dose of 500− 12000 mg experienced minor side effects like diar­
rhea, yellow stool, headache, and rashes [15]. More recently a single 2.5. Study outcomes
case was reported wherein the turmeric supplementation led to the
occurrence of autoimmune hepatitis in a 71-year-old individual [16]. The safety of PUREMERIC was assessed by the clinically significant
These findings necessitate the safety assessment of a higher dose of changes from baseline (V1) to end of treatment (V2) in laboratory pa­
turmeric extract/curcumin over a longer duration in healthy subjects. rameters (liver function, renal function and complete blood count), in­
PUREMERIC™ is a Curcuma longa L. rhizome extract standardized to cidences of adverse effects and serious adverse effects (AE/SAE),
95 % curcuminoids (HPLC method). PUREMERIC was previously eval­ physical examination parameters and vital signs.
uated for acute and sub-chronic toxicity using Wistar rats (data not The primary endpoint of the study was to assess the changes in liver
published). Single dose oral toxicity of PUREMERIC in female Wistar function parameters [Aspartate aminotransferase (AST), Alanine
rats showed that the LD50 of PUREMERIC was more than 2000 mg/kg B. aminotransferase (ALT), alkaline phosphatase (ALP), Gamma-glutamyl
W. The no-observed-adverse-effect level (NOAEL) of PUREMERIC as transpeptidase (GGT), Lactate Dehydrogenase (LDH), Bilirubin (Direct
determined by repeated dose 90-day toxicity study was 1000 mg/kg and Total)] from baseline to end of treatment.
BW. Further, to confirm the safety of PUREMERIC, the current study was The secondary endpoint of the study was to assess the safety of
accomplished in an open label, single arm, prospective clinical trial on PUREMERIC (incidence of AEs/SAEs, Changes in laboratory parameters
healthy human volunteers. (Complete Blood Count, Serum creatinine), physical examination and
incidence of abnormal vital signs.
2. Methods
2.6. Safety measurements
2.1. Study design
The safety evaluation was based on physical examination, vital signs,
An open label, single arm, prospective clinical study was conducted clinical laboratory tests and incidence of AEs. Physical examinations
on 12 healthy human volunteers to evaluate the safety of PUREMERIC. were performed by a physician and included the examination of the
The study was carried out at Anand Multi Specialty Hospital, Vadodara, following: general appearance, eyes, ears, nose, throat, chest/respira­
Gujarat, India. A written informed consent signed by all subjects was tory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/ex­
obtained before the study initiation. After passing the eligibility criteria, tremities, dermatological/skin, thyroid/neck, lymph nodes, and
subjects received PUREMERIC (standardized extract from C. longa con­ neurological/psychiatric systems. All clinically significant treatment-
taining 95 % curcuminoids, capsule form, self-administration), 500 mg emergent findings that were not present at baseline or described in the
orally, twice a day for 90 days. The study included 2 visits over a period medical history were recorded as AEs.
of 90 days. Vital signs observed during the study included systolic blood pres­
sure (SBP), diastolic blood pressure (DBP), pulse rate, and body tem­
2.2. Ethical approval and consent perature at baseline and end of treatment. Fasting blood samples were
collected at visits V1 and V2 to evaluate the efficacy and safety
Study protocol along with informed consent form, and other analytical variables. Haematology parameter analysis included white
appropriate study-related information were approved by Institutional blood cell count, red blood cell count, haemoglobin, mean cell volume
Ethics Committee, Anand Multi Specialty Hospital, Vadodara, India. The and platelet count. Liver function tests included AST, ALT, ALP, GGT,
aspects concerned with the study medications met the requirements of LDH and Bilirubin (direct and total). Serum creatinine level was
Good Manufacturing Practices. Each subject provided the written measured as a function of kidney. All the subjects were monitored
informed consent before the initiation of the clinical study. This trial was throughout the study for any adverse (AEs) or serious adverse events
prospectively registered in Clinical Trials Registry – India (CTRI/2019/ (SAEs).
10/021611 dated 14/10/2019).
2.7. Statistical analysis
2.3. Subjects
The statistical analysis was performed by SPSS 22.0 (SPSS Statistics
Healthy male and female subjects aged 18–50 years with weight for Windows Version 22.0, Armonk, NY, IBM Corp) and are two-sided at
>50 kg and no evidence of any underlying disease were enrolled for this a significant level of 0.05.
study. Subjects suffering from any chronic health conditions (e.g., dia­
betes, hypertension, chronic renal failure, heart, thyroid, and liver dis­ 3. Results
ease) requiring medical treatment were not included in the study. Other
exclusion criteria were drug abusers, smokers, subjects with eating Fig. 1 shows the participant flow chart from subject selection to the
disorder and endocrine abnormalities, subjects undergoing cardiovas­ analysis. Fourteen individuals were screened of which 12 subjects
cular surgery and subjects allergic to herbal products. Subjects not meeting the inclusion criteria enrolled for the study. 2 subjects were
willing and able to give informed consent and not comply with the study failed to meet the eligibility criteria and excluded from the study. All the
procedures were also excluded from the study. 12 subjects completed the study. The mean age of subjects enrolled in
the study was 31.17 ± 5.86 years. This study included all the subjects of
2.4. Intervention Indian origin. There were no significant differences found in the
anthropometric measurements (height, weight and BMI) from baseline
The present study was conducted to evaluate the safety and to the end of study (Table 1).

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S. HV et al. Toxicology Reports 8 (2021) 1955–1959

study. All the 3 subjects used at least one parallel medication during the
study. The medication included paracetamol and oral rehydration so­
lution. None of the subject reported any SAE or was withdrawn from the
study due to AE/SAEs (Table 6).

4. Discussion

The present clinical trial was conducted to evaluate the safety of a

turmeric extract containing 95 % curcuminoids in healthy subjects.
Nevertheless, turmeric is a regularly consumed spice, content of cur­
cumin ingested in such form is lesser than the extract itself [17]. Hence,
there is an absolute requirement of determining the safety of turmeric
extract at higher doses. The available literature document the safety of
turmeric extract and curcumin mostly in patients having health issues
[18–20].
In an open label, single arm pilot study we have demonstrated the
safety of turmeric extract, PUREMERIC having 95 % total curcuminoids
(curcumin, bisdemethoxycurcumin and demethoxycurcumin). There are
several reports on the benefits of curcumin in healthy population. In a
double-blind clinical study from Oliver et al. curcumin at 200 mg dose
administered for 8 weeks significantly improved the endothelial func­
tion in healthy subjects [21]. In another study on healthy individuals
aged 40–60 years, supplementation of low dose of lipidated form of
curcumin (80 mg/day) showed several health benefits [13]. Despite
Fig. 1. Study participant flowchart. having physiological functions there are some adverse effects reported
with curcumin supplementation. More recently, Luber et al., reported
two case studies indicating liver toxicity due to the consumption of
Table 1 turmeric supplement [22]. Here we have rationalized the safety of
Anthropometric assessments of subjects. turmeric supplementation in healthy subjects, specifically measuring
Variable Visit 1 (Baseline) Visit 2 (EOS) p-value # (Visit 1 vs. Visit the liver function parameters.
(Unit) 2) The blood biochemical and hematological parameters were
Weight (kg) 59.72 ± 4.96 59.93 ± 4.90 0.4526 measured of twelve subjects who received 500 mg of turmeric extract
Height (cm) 161.67 ± 6.93 161.67 ± 6.93 – supplementation. AST, ALT and ALP are the predominant blood markers
BMI (kg/m2) 22.83 ± 1.02 22.91 ± 1.09 0.4789 of liver injury. In this study, there was no significant change in the levels
The data were represented as mean ± SD; # p values were compared from of these serum non-specific markers from baseline to the end of study.
baseline using Paired sample t-test. EOS: End of study. The mean AST and ALT levels were found to be not exceeding 40 U/L
following a 12-week consumption of PUREMERIC which clearly indi­
The primary end point analysis included the assessment of liver cated the normal liver function of the participants [23]. Our results
function parameters (Table 2). There were no statistically significant contradict the previous case reports on turmeric-induced acute hepatitis
variations observed in the levels of AST, ALT, ALP, GGT, LDH and bili­ [22].
rubin from baseline to the end of treatment. Further, the serum creati­ Acute hepatitis results from etiologies including alcohol, drugs, or
nine appeared to be in the normal range throughout the study. Summary conditions such as biliary tract dysfunction (cholestatic hepatitis) [24].
of hematological analyses is presented in Table 3. All the evaluated Cholestasis (acute and chronic) in general is presented by elevated AST,
parameters were within the normal range and no significant changes ALT, ALP, and total bilirubin or hyperbilirubinemia associated with
observed from baseline to the end of study. There was no considerable elevated ALP [25–27]. In our study, there was no clinically significant
change in the vital signs measured at baseline and the end of study changes in the serum levels of ALP and bilirubin indicating no signs of
(Table 4). cholestatic liver damage. These data further confirm the safety of
The study participants were monitored for the occurrence of AEs turmeric extract/curcumin consumption. In this study, we have
and/or SAEs throughout the study. Three subjects reported 3 AEs which measured the serum GGT level at baseline and the end of treatment. GGT
included fever and diarrhea, during the study period (Table 5). The is a non-specific serum marker of drug-induced damage to vital organs
outcomes of all the AEs was noted as resolved before the end of the such as liver, brain, pancreas, kidney, heart, and seminal vesicles [28]. A
12-week administration of PUREMERIC did not cause significant

Table 2
Summary of changes in blood biochemical parameters (N = 12 subjects).
Visits
Parameters (Units) Reference range p-value # (Baseline vs. EOS)
Baseline EOS

Aspartate aminotransferase (U/L) 5− 50 28.03 ± 5.70 27.85 ± 5.75 0.8577

Alanine aminotransferase (U/L) 5− 45 31.49 ± 6.17 31.05 ± 6.02 0.6294
Alkaline phosphatase (U/L) 42− 141 91.56 ± 21.61 91.48 ± 26.78 0.9819
Gamma-glutamyl transpeptidase (U/L) 10− 50 28.12 ± 7.54 27.50 ± 6.27 0.6474
Lactate dehydrogenase (U/L) 225− 450 319.53 ± 50.45 314.31 ± 56.04 0.5259
Bilirubin (total) (mg/dl) 0− 1.4 0.93 ± 0.16 0.92 ± 0.13 0.5028
Bilirubin (direct) (mg/dl) 0− 0.6 0.48 ± 0.10 0.44 ± 0.04 0.2691
Serum creatinine (mg/dl) 0.6− 1.4 1.09 ± 0.19 1.05 ± 0.17 0.1298

The data were represented as mean ± SD. # p values were compared from baseline using Paired Sample t-test. EOS: End of study.

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Table 3
Haematology parameter analysis (N = 12 subjects).
Visits p-value # (Baseline vs. EOS)
Parameters (Units) Reference range
Baseline EOS

Total Leukocyte Count (mm3) 4000− 10500 7158.33 ± 1552.39 7183.33 ± 1657.95 0.9039
Red Blood Cell count (million/cmm) 4.6− 6.5 4.91 ± 0.19 4.90 ± 0.23 0.8578
Haemoglobin (g/dL) 12− 17 13.82 ± 0.66 13.71 ± 0.75 0.3034
Haematocrit (%) 35− 54 % 41.19 ± 1.70 41.12 ± 2.15 0.8512
Mean Cell Volume (fL) 80− 96 83.93 ± 1.55 83.98 ± 1.96 0.9086
Mean Cell Haemoglobin (MCH) (pg) 27− 33 28.15 ± 0.89 28.00 ± 0.88 0.3159
MCH Concentration (%) 32− 36 % 33.54 ± 0.82 33.33 ± 0.65 0.1356
Platelet Count (mm3) 150000− 450000 291666.70 ± 53720.38 288916.70 ± 44397.91 0.7496

The data were represented as mean ± SD. # p values were compared from baseline using Paired Sample t-test. EOS: End of study; mm3: Cubic millimetre; g/dl: Gram/
decilitre; fL: femtolitres, 10− 15 L; pg: picograms.

elevation in the serum GGT level.

Table 4
Examination of hematological parameters provides valuable infor­
Vital signs observed during the study (N = 12 subjects).
mation on the potential harmful effect of any foreign substances in the
Visits p-value # (Baseline body [29]. Administration of PUREMERIC resulted in marginal changes
Parameters (Units)
Baseline EOS vs. EOS) of blood parameters.
Temperature (◦ F) 97.74 ± 0.69 98.05 ± 0.30 0.0883 Overall, the findings from our study confirms the safety of orally
Pulse rate (beats/ 73.08 ± 5.25 74.92 ± 3.45 0.2966 ingested turmeric extract (95 % curcuminoids) in healthy adult subjects
minute) and opposes the possibility of any hepatic damage caused by turmeric/
Systolic blood pressure 115.83 ± 9.00 118.33 ± 7.18 0.3388 curcumin supplementation. However, the limitations of this clinical
(mmHg)
Diastolic blood pressure 74.17 ± 6.69 75.00 ± 6.74 0.5862
study include the small sample size and the shorter duration of
(mmHg) treatment.

The data were represented as mean ± SD. EOS: End of study; #: Paired t-test
(Baseline vs End of study). Ethics approval and consent to participate

This clinical trial was approved by Institutional Ethics Committee,

Table 5 Anand Multi Specialty Hospital, Vadodara, India. Subjects meeting all
Adverse events experienced by subjects during the study. inclusion and no exclusion criteria signed a written informed consent
Adverse events Overall (N = 12) n (%) and enrolled in the study.

Total number of AEs reported 3 (25)

Subjects reporting at least one AE 3 (25) Conflict of Interest
Fever 2 (16.67)
Diarrhoea 1 (8.33) The authors declare no conflict of interest.
Total Number of SAEs Reported 0
Subjects Reporting drug-related AEs 0
Subjects Reporting AEs leading to early discontinuation 0 Funding
Number of Deaths 0

Data presented as n (%): Number of subjects (%).

Not applicable

Authors’ contributions
Table 6
Summary of adverse events by severity, causality treatment and concomitant All the authors have read and approved the manuscript. Conceptu­
medication used by subjects during the study. alization: KS; Study design: HVS and TVJ; Study monitoring and coor­
Adverse event term Overall (N = 12) n dination: HVS; writing – original draft preparation: HSV, TVJ and HVS;
(%) review and editing, HVS and KS.
Subjects with atleast one AE 3 (25 %)
Severity
Mild 3 (25 %) Declaration of Competing Interest
Moderate 0 (0)
Severe 0 (0) The authors report no declarations of interest.
Casuality
Related 0 (0)
Not related 3 (25 %) References
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