Second Draft Statement on the Safety of Ginger Supplement Use in Pregnancy

Annex B - Summary of Studies

TOX/2023/60 Annex B

Last updated: 08 December 2023

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Human Studies

Author/Date	Study type	Study size/No. of Patients at End	Exposure (ginger dose/day)	Study period	Length of Treatment (days)	Main outcome measures	Main results
Chittumma et al., 2007	Randomized double-blind controlled trial.	126/123	Ginger powder capsules (325 mg ×2, 3x/d, = 1950 mg/day)	4 days	4	Change in nausea and vomiting scores (3 symptoms on Rhodes index); occurrence of side-effects	Results showed that ginger is significantly more effective in relieving NVP than vitamin B6 (p < 0.05).
Ensiyeh et al., 2005	Double-blind randomised controlled trial.	70/69	Ginger powder capsules (500 mg 2×/d =1000 mg/day)	3 months	4	Severity of nausea (VAS 0–10); number of vomiting episodes; general response to treatment (5-item Likert scale); occurrence of side-effects or adverse pregnancy outcome	two spontaneous abortions in ginger group, 1 in B6 group; no congenital anomalies observed in babies brough to term.
Fischer-Rassmussen et al., 1991	Double-blind randomised crossover trial	30/27	Ginger powder capsules (250 mg 4 times per day = 1000 mg/day)	11 days	4	Preference of treatment period; relief scores (4-point scoring system); outcome of pregnancy	One spontaneous abortion, One elected. No adverse effects were observed in remaining 25 subjects.
Portnoi, 2003	Not specified	187 pregnant women	Various, not specified	up to 12 months post birth	Minimum of 3 days	Safety and effectiveness of ginger for nausea and vomiting of pregnancy (NVP).	Three major malformations were reported in the ginger group, ventricular septal defect (VSD), right lung abnormality, and kidney abnormality (pelviectasis). One incidence of idiopathic central precocious puberty at age 2 years. No significant difference between the two groups in terms of live births, spontaneous abortions, stillbirths, therapeutic abortions, birth weight, or gestational age
Smith, 2004	Randomized, controlled equivalence trial	291 women, less than 16 weeks pregnant	1.05 g ginger	3 weeks	3 weeks	Ginger verses B6 for the treatment of nausea or vomiting in pregnancy	Three spontaneous abortions in ginger group, 9 abortions in B6 group
Vutyavanich, 2001	Double blind	32	Ginger powder capsules (250 mg 4x/day =1000 mg/day)	5 months	4	Severity of nausea (VAS 0–10); number of vomiting episodes; general response to treatment after 1 week (5-item Likert scale); occurrence of side-effects and adverse pregnancy outcomes	Ginger was significantly more effective than the placebo in relieving the severity of nausea in pregnancy (p = 0.014).
Willetts et al., 2003	Double-blind randomised placebo-controlled trial	120/99	Ginger extract capsules (125 mg 4x/d =1000 mg/day)	8 months	4	Used RINVR to measure frequency, duration, distress caused by nausea, vomiting and retching; long term follow-up for birth outcome	Three spontaneous abortions observed in ginger group

Human studies – Platelet Aggregation

Author/date	Study design	Population/stud size	Study Duration	Exposure	Outcome	Results	Comment
Bordia et al., 1997	Placebo controlled trial	Patients with confirmed myocardial infarction N = 60	3 months. Outcomes measured at: baseline, 1.5 months and 3 months.	Dose: 4g per day Unstandardised capsules	Platelet aggregation— Agonist(s): ADP and Epi;	Ginger had no significant effect on both measures of aggregation	Ginger had no significant effect on blood lipids or blood sugar.
Bordia et al., 1997	No data.	No data.	No data.	No data.	Fibrinogen;	No data.	No mention of randomisation
Bordia et al., 1997	No data.	No data.	No data.	No data.	Fibrinolytic activity	No data.	P value not reported
Bordia et al., 1997	No data.	20	1 day. Outcomes measured at: baseline, 4 hours post-consumption	10 g single dose. Unstandardised capsules	Platelet aggregation. - Agonist(s): ADP and Epi	Reduction of both measures of platelet aggregation when compared to placebo (p <0.05).	No data.
Jiang et al., 2004	Randomized, open label, three-way crossover trial	Healthy male volunteers Age: 20–36 N =12	Total study period: 3x13 days, 14 days washout period between each study period.	Dose: 3.6g (3x 0.4g, 3x per day) Unstandardized capsules Consumed with 25 mg dose of rac-warfarin, consumed once per study period.	Platelet aggregation, Agonist: AA; INR; Plasma warfarin enantiomer protein binding & warfarin enantiomer concentrations Urinary S- 7-hydroxywarfarin	No significant changes in any outcome	P value not reported
Lumb. 1994	Randomised, double-blinded placebo-controlled crossover trial	Healthy male volunteers N=8	Total study period: 2 x 1 day, at least 14 days washout period. Outcomes measured immediately before, 3 hrs, and 24 hrs post consumption of ginger	Dose: 2g (4 x 500 mg) dried ginger per day Unstandardized capsules	Platelet aggregation; - Agonist(s): AA, ADP, collagen, ristocetin, ADP; Bleeding time; Platelet count; Thromboelastography	No significant changes in any outcome at any time point.	No data.
Rubin et al., 2019	Case report	Female, 70 yrs	No data.	48 mg daily Chewable ginger supplement for approx. 1 month	INR - 8.0 approx. 1 month after taking ginger supplement.	INR reduced to 2.6 following cessation of ginger supplementation and pause in warfarin administration	Patient also taking clonazepam 1 mg, metoprolol succinate 25 mg, paroxetine 10 mg, phenytoin 30 mg, rosuvastatin 20 mg, warfarin 7.5 mg, and warfarin 10 mg 10 mg
Srivastava 1989	Open-label single-arm trial	Healthy female volunteers, N = 7	Total study period: 7 days. Outcomes measured at baseline and 7 days post-consumption	Dose: 5g raw ginger per day	Platelet thromboxane B2 production	Ginger consumption resulted in a 37% inhibition of thromboxane B2 production (p<0.01).	No data.
Verma et al., 1993	Randomised placebo controlled trial	Healthy male volunteers; N = 20	Total study period: 14 days, high calorie diet for first 7 days, high-calorie diet and ginger/placebo consumed for next 7 days. Outcomes measured at baseline, 7, and 14 days	Dose: 5g (4 x 625 mg, twice per day); dry ginger powder - Unstandardized capsules Consumed with 100g (2x50g) butter, 2 cups of milk, 8 slices of bread.	Platelet aggregation. Agonist(s): ADP and Epi	Ginger significantly reduced platelet aggregation using both agonists when compared to placebo group (p<0.001).	Platelet aggregation reduced close to baseline but did not decrease further.
Young et al., 2006	Not specified	20	72 days	1 g ginger (+ 10 mg nifedipine)	Synergistic effect of ginger and nifedipine on anti-platelet aggregation in normal human volunteers and hypertensive patients.	Ginger and nifedipine had synergistic effect on anti-platelet aggregation; Ginger increased anti-platelet aggregation effect of nifedipine in all patients	No data.

In vitro studies

Author	Test System	Exposure	Characterisation of test substance	Main outcome measure	Outcome
Abudayyak et al., 2015	Ames: Salmonella typhimurium TA98 and TA100 strains; Cytotoxicity assay: Rat kidney NRK-52E cell line	Cytotoxicity assay: (0.75, 1.50, 3.00, 6.00, 12.00, 25.00, 50.00, and 75.00 mg/ml, genotoxicity: 0.78, 1.56, 3.13, 6.25, 12.50, and 25.00 mg/ml,	Aq, chloroform and MeOH ginger extracts	Cytotoxicity and genotoxicity	Chloroform extract cytotoxic: IC50 = 9.08 mg/ml; aqueous extract mutagenic at all concentrations against T98 strain, in presence of S9 mix
Mohammed et al., 2016	chick embryonic heart micromass; mouse D3 embryonic stem cell systems (ESD3)	0.75–100 uM Micromass assay: 6 days, ESD3: 12 days	6-gingerol	Embryotoxicity	no significant changes in contractile and cellular activity or changes in total protein content in 6-gingerol-treated primary embryonic chick cardiomyocytes.
No data.	No data.	No data.	No data.	No data.	inhibition in contractile activity at 12.5–50 μM
No data.	No data.	No data.	No data.	No data.	Change in both cellular activity and protein content in a dose-dependent manner at high concs (12.5–100 μM)
No data.	No data.	No data.	No data.	No data.	Significant decrease in cardiomyocyte differentiation for all tested concentrations except 0.75 μM in ESD3
No data.	No data.	No data.	No data.	No data.	Significant decrease in cellular activity and protein content of stem cell-derived cardiomyocytes with increased 6-gingerol concentration exposure.
Nakamura & Yamamoto (1982)	Escherichia coli Hs30	Not specified	Juice of ginger rhizome, 6-gingerol	Mutagenicity	ginger juice supressed spontaneous mutation; 6-gingerol mutagenic in isolation
Nakamura & Yamamoto 1983	Escherichia coli Hs30	Not specified	6-shogaol, 6-gingerol	Mutagenicity	[6]-Shogaol was 104 times less mutagenic, at a concentration of 700uM, than [6]-gingerol.
Nirmala et al., 2007	Wistar rats, male	Salmonella typhimurium strains TA 98 and TA 100	Ginger paste and powder, unboiled, boiled, unfried, fried Ames test: Ginger paste: 1, 2 and 3 mg; powder: 0.5, 1 and 1.5 g	Anti-mutagenicity	Anti-mutagenic potential unaltered by treatment of ginger.
Plengsuriyakarn et al., 2012	Cholangiocarcinoma (CCA) cell line 6 (CL-6), hepatocarcinoma (HepG2) and normal human renal epithelium (HRE)	1.95, 3.90, 7.81, 15.62, 31.25, 62.5, 125, and 250 µg/ml	Crude ethanolic ginger extract	Cytotoxicity	IC50 and cytotoxicity 10.95 and 53.15, μg/ml
Sivaswami et al., 1991 (Abstract)	Salmonella typhimurium strains TA 98, TA 100 and TA 1535	Unknown	Essential oil from ginger	Mutagenicity	Non mutagenic
Soudamini et al., 1995	Salmonella typhimurium strains TA 100, 98 and TA 1535	25 and 50 mg/plate	ethanolic mixture of powdered ginger	Mutagenicity	mutagenicity in both TA 1535 and TA 100 at both concentrations
Zaeoung et al., 2005	breast (MCF7) and colon (LS174T) cell lines	Not specified	aqueous extract and volatile oils	Cytotoxicity	IC50 > 39.2 μg/ml

In vivo studies

Author	Test System	Study size	Exposure	Characterisation of test substance	Duration	Main outcome measure	Outcome
Alnaqeeb et al., 2003 (abstract)	Rats, female	Unknown	Oral and intraperitoneal. 50 mg/kg and 500 mg/kg	Aqueous ginger extract	28 days	No data.	Increased levels of serum aspartate aminotransferase (AST) and decreased levels of alanine aminotransferase (ALT) in orally dosed rats
Dissabandara & Chandrasekara, 2007	Sprague-Dawley rats	15 in 3 groups, otherwise not specified	Oral: 500 mg/kg/day and 1000 mg/kg/day during days 5 to 15 of gestation	Powdered ginger extract	Animals treated with ginger for 10 days	Effect of powdered ginger extract administered prenatally on postnatal development	Lower intake of food and water and lower weight gain in ginger treated group
ElMazoudy and Attia, 2018 (abstract only)	ICR mice	Unknown	250, 500, 1000, or 2000 mg/kg bw/d aqueous ginger extract.	Powdered dried ginger root	35-day treatment study; 20 day study (antifertility and abortifacient loss)	Effect on oestrus cycle and implantation in female mice.	Female copulation index was significantly reduced at 2000 and 1000 mg/kg bw/d groups; female pregnancy index significantly decreased at the highest dose. No. of implantation sites and live fetuses in the 2000 mg/kg bw/d group lower than the other treated and control groups.
Hosseini et al., 2015 (abstract only)	Rats, female and male offspring	72 (groups of 9)	Oral: 50, 100 and 200 mg/kg bw during neonatal and perinatal periods	Alcoholic ginger extract	Unknown	Serum testosterone, LH and FSH. Effect on spermatogenic cell lines in male mature offspring rats	Significant increase in testosterone levels and number of spermatogenic cells. Significant reduction in FSH and LH at doses of 100 and 200 mg/kg bw compared to control
Jeena et al., 2011	Wistar rat	30	Oral: 100, 250, and 500 mg/kg per day once daily	Ginger essential oil	13 weeks	Oral Toxicity	No mortaility or abnormal changes observed in relative organ weights w.r.t. body weight. Increase in serum Na levels in male rats treated with 500 mg/kg/d. slight increase in total bilirubin in female rats, along with a decrease in AST and ALT levels. No significant changes in hepatic function parameters (alkaline phosphatase, total protein, albumin and globulin content).
Malik and Sharma, 2011	Wistar rat, male	Not specified	gastric gavage: 250, 500 and 1000 mg/kg, (corresponding to 5, 10 and 20% of the NOAEL of the lyophilised ginger powder (5000 mg/kg)	Lyophilsed ginger juice powder	Experiment 2: 8 weeks. Exp 1&2 not specified	Acute Toxicity	no signs of toxicity or mortality
Plengsuriyakarn et al., 2012	OV and nitrosamine (OV/ DMN)-induced CCA hamsters	90	1000, 3000, and 5000 mg/kg bw/d	No data.	30 days	Acute Toxicity	No data.
Rong et al., 2009	Sprague–Dawley rats, male and Female	40	Gavage: 500, 1000 and 2000 mg/kg bw/day	Powdered Japanese ginger,	37	35 day repeat dose	No increase in mortality. Slightly reduced absolute and relative weights of testes (by 14.4% and 11.5%, respectively) at highest dose.
Shalaby and Hamowieh, 2010	Sprague Dawley rats,	120	Oral, 5 to 17.5 g/kg bw	water or methanolic ginger extract	65 days	Fertility, serum testosterone and acute toxicity	oral Lethal Doses (LD50) of the methanolic and water extracts - 10.25 and 11.75 g/kg bw respectively. No symptoms of toxicity observed at doses up to 5 g/kg bw. Both extracts increased fertility index, sexual organ weight, and sperm motility and count after 65 consecutive days
No data.	No data.	No data.	No data.	No data.	No data.	No data.	Methanolic extract: Testosterone levels increased to 4.08 ± 0.10 and 7.13 ± 0.14 ng/dL (both significant at P < 0.001); Water extract (150 and 300 mg/kg bw): Serum testosterone levels increased 4.06 ± 0.03 and 5.04 ± 0.08 ng/dL (both significant at P < 0.001)
No data.	No data.	No data.	100 and 200 mg/kg bw for 65 consecutive days and water extracts at doses of 150 and 300 mg/kg bw	No data.	No data.	Fertility Index	Mild to moderate degenerative changes of spermatogenic cells, diffuse oedema and incomplete arrest of spermatogenesis. Mild degeneration of spermatogenic cells and slight oedema of interstitial cells in testes of rats orally administered 300 mg/kg bw water extract. LOAEL of 200 mg/kg bw/day for the methanolic extract suggested
Weidner & Sigwart, 2001	Wistar rats, pregnant female	176 (88 Females)	Gastric intubation: 100, 333 and 1000 mg/kg from days 6-15	EV.EXT 33, a patented Zingiber officinale extract (comprising 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, and 8-shogaol (1.9 w/w of the extract))	21 days	teratogenicity	No maternal or developmental toxicity observed
Wilkinson 2000	Sprague-Dawley rats, F	43	Oral, drinking water on days 6-15	20 g/L or 50 g/L ginger tea	20 days	Reproductive and developmental toxicity	Embryonic loss in the treated groups 2x that of the controls. Exposed foetuses found to be significantly heavier than control. No gross structural malformations observed

Effect on CYPs and prostaglandin activity

Author	Test System	Exposure	Characterisation of test substance	Main outcome measure	Outcome
Dugasani et al., 2010	Mouse leukaemic monocyte (RAW 264.7) macrophages and human polymorphonuclear neutrophils (PMN)	1, 3 and 6 uM	[6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol	Compare the antioxidant and antiinflammatory activities of gingerols and their natural analogues to determine their structure–activity relationship and molecular mechanisms.	Dose dependant inhibition of activated PGE2 release. Inhibition reached 58, 66, 73 and 87%, respectively, at 6uM
Jolad et al., 2004	HL-60 cells	Not specified	Ginger constituents: gingerols, shogaols, 3-dihydroshogaols, gingerdiols	Effects of ginger components on LPS-induced PGE2 production	No cytotoxicity demonstrated
Jolad et al., 2005	HL-60 cells	Not specified	Ginger constituents conatining gingerols, shogaols, 3-dihydroshogaols, gingerdiols	Effects of ginger components on LPS-induced PGE2 production	Inhibition of LPS-stimulated PGE2 production (IC50 = 0.05 0.08 ug/ml) with Gingerol fractions
Kim et al., 2012	Human liver microsomes	0.05–5 ug/ml	Aqueous ethanolic ginger extract (30% EtOH)	Inhibitory effect on CYP450-mediated drug metabolism	Concentration-dependent inhibitory effects on CYP2C19; IC50 value of 3.8 g/ml
Kimura et al., 2010;	Human CYP3A4 and CYP2C9 microsomes	Not specified		Inhibitory effect on CYP3A4 and CYP2C9 activity	significant inhibition of CYP3A4 IC50 5.1u g/ml or CYP2C9 IC50 (10ug/ml) activity
Lantz et al., 2007	U937 cells	0.1 ug/ml for 6 hrs	Ginger extract and mixtures of 6-, 8- 10-gingerols and 6-, 8-, 10-shogaols	Effect on inflammatory mediator production	No effect on COX-2 expression
Mukkavilli et al., 2014	Human liver microsomes	Ginger extract: 500 mg/ml (containing 15 mg/ ml 6G, 3.4 mg/ml 8G, 3.9 mg/ml 10G, 3.0 mg/ml 6S); All individual components of gingerols assessed at 100 mM (equivalent to 29 mg/ml 6G, 32 mg/ml 8G, 35 mg/ml 10G and 28 mg/ml of 6S)	Ginger extract: (containing 6-Gingerol, 8-Gingerol, 10-Gingerol, 6-Shogaol). All individual components of gingerols were assessed at 100 mM equivalent to 29 mg/mL 6G, 32 mg/mL 8G, 35 mg/mL 10G and 28 mg/mL of 6S.	Effect of ginger extract and major constituents on CYP P450 enzyme activity	Inhibition of CYP1A2 (IC50 - 221.5 mg/ml) by ginger extract. No effect on CYP2A6; maximum inhibition on CYP2B6: IC50 - 22 mg/ml; IC50 - 122.5 mg/mL against CYP2C8 in the presence of amodiaquine; IC50 - 93.5 mg/mL against CYP2C9, in the presence of diclofenac; Inhibition of CYP3A in the presence of testosterone: no effect in the presence of midazolam

Effect on Platelet Aggregation

Author	Test System	Study size	Exposure	Characterisation of test substance	Main outcome measure	Outcome
Srivas, 1984	Human platelets and rat aorta	No data.	15-20 ul (concentrations not given)	Ginger extracts in water, n-hexane, chloroform, and ethyl acetate	Effect of ginger extracts on in vitro platelet aggregation	Inhibition of arachidonic acid (AA), epinephrine, adenosine diphosphate (ADP), and collagen-induced platelet aggregation
Srivastava, 1986	Platelet rich plasma (no further information given)	No data.	10-20 ul (concentrations not given)	No data.	Effect of ginger and components on platelet aggregation and eicosanoid biosynthesis	Reduced thromboxane formation from exogenous AA; Inhibition of AA, epinephrine, ADP and collagen-induced platelet aggregation
Srivastava 1989	Open-label single-arm trial	Healthy female volunteers, N = 7	Total study period: 7 days. Outcomes measured at baseline and 7 days post-consumption	Dose: 5g raw ginger per day	Platelet thromboxane B2 production	Ginger consumption resulted in a 37% inhibition of thromboxane B2 production (p<0.01).
Suekawa et al., 1986 (abstract only)	Rat hind paw and aorta, rabbits	Unknown	Unknown	6-shogaol	Effect of 6-shogaol on arachidonic acid cascade	Inhibition of carrageenin-induced swelling of hind paw in rats and arachidonic acid (AA)-induced platelet aggregation in rabbits. Inhibition of prostaglandin 12 (PGI2) release in rat aorta. Possibly caused by COX inhibition
Thomson et al., 2002	Sprague-Dawley rats, Adult, F; ex vivo	36	50 mg/kg or 500 mg/kg daily by gavage or intraperitoneally (IP) for 4 weeks	Aqueous ginger extract, equivalent of 500 mg/ml	ex vivo effect of aqueous extract of ginger on the synthesis of thromboxane-B2, prostaglandin-E2, and cholesterol, triglyceride levels in the serum of normal rats	Serum PGE2 reduced and both dose levels; high dose significantly reduced serum TXB2 both orally and IP; A non-significant reduction in the level of TXB2 observed when ginger was injected IP but not significantly different from saline group.
No data.	No data.	No data.	No data.	No data.	No data.	Significant reduction in levels of cholesterol in rats given high dose; No significant change in triglyceride levels with either dose either orally or IP

Herb-drug interactions

Author	Test System	Study size	Exposure	Characterisation of test substance	Duration	Main outcome measure	Outcome
Al-Omari et al., 2012	Albino rat, M	30: 5 groups of 6; 72: 12 groups of 6;	25, 50 and 100 mg/kg bw by gavage; single dose (50 mg/kg bw)and up to one week	Ginger crude extract	Multiple dose: 2 weeks; single dose: 1 week	Effect on glibenclamide and insulin; hypoglycaemic and antihyperglycemic effects in normoglycemic- and streptozotocin-induced (STZ) diabetic rats	Significant decrease in blood glucose level (BGL) in normoglycemic rats after 1 & 2 hrs (50 mg/kg). Significant decrease in non-fasting BGL (N-FBGL) in STZ- diabetic rats
Egashira et al., 2012	Sprague-Dawley rat, M (7 weeks old)	Not specified	10 mL/kg orally	50% ginger juice	1-3 days	interaction between ginger juice and tacrolimus	Significant increase in tacrolimus blood concentrations in rats treated with ginger juice, compared to those treated with water or orange juice
Okonta et al., 2008	Rabbits (3F, 2M)	5	1 ml/kg, orally	Ginger extract	3 days	Effect of ginger on the pharmacokinetics of metronidazole	Significant increase in absorption and plasma half-life; significant decrease in the elimination rate constant and clearance of metronidazole.

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