Menu
×
News
Get Involved
About Us
Our Members
SAFETY OF TURMERIC AND BCM-95

SAFETY OF TURMERIC AND BCM-95 (Curcugreen)

This section begins with evaluations of the safety of turmeric as a common spice, food additive, and as an ingredient used for centuries in traditional, historical medicine. It continues with preclinical toxicological studies and clinical trials conducted on curcumin. More detailed information is given on studies specific to BCM-95.

Turmeric

Turmeric, its essential oil, oleoresin, and/or natural extractives are designated as GRAS (Generally Recognized as Safe) for use as food ingredients and food additives by the United States Food and Drug Administration (US FDA; per 21 CFR 182.10, 182.20).

The American Herbal Products Association’s Botanical Safety Handbook, 2nd ed. lists turmeric as Class 1 (herbs that can be safely consumed when used appropriately) and Interaction Class A (herbs for which no clinically relevant interactions are expected).73 Mills and Bone, in their book The Essential Guide to Herbal Safety,74 list turmeric as Pregnancy Category A (no proven increase in frequency or malformation or other harmful effects on the fetus despite consumption by a large number of women) and Lactation Category C (compatible with breastfeeding). They contraindicate turmeric preparations in cases of obstruction of the biliary tract and advise to consult a health care professional if someone has gallstones. Adverse reactions associated with oral intake are listed as frequent bowel movements and mild gastric discomfort. The authors advise against combining amounts greater than 15 g turmeric powder per day with antiplatelet or anticoagulant medications.

Curcumin

Curcumin Preclinical Toxicity Studies

In systematic studies conducted in rats, dogs, and monkeys at oral doses up to 3.5 g standard curcumin/kg body weight for up to 90 days, no adverse effects were observed.75 No toxicity was observed in 14-day preclinical studies with administration of 2% dietary curcumin (approximately 1.2 g/kg body weight) to rats and approximately 300 mg/kg body weight administered to mice.76,77

Curcumin Reproductive Toxicity Studies

A reproductive study in which curcumin was administered orally to rats in doses up to 1 g/kg body weight daily for two successive generations did not report any toxicity.78

Curcumin Clinical Safety

Phase I clinical studies indicate that curcumin (Curcumin C3 Complex provided by Sabinsa Corporation) is not toxic even at a very high dose of 12 g/day. A dose-escalation study, which aimed to determine the maximum tolerated dose (MTD), administered single doses ranging from 500 mg to 12,000 mg to 24 healthy volunteers. Seven of the subjects reported mild adverse events, including diarrhea, headache, rash, and yellow stools. All symptoms were Grade I toxicity and not related to dose. The MTD could not be determined in this study because amounts more than 12 g were considered to be too large to be consumed comfortably.24

In another dose-escalation clinical study, patients with advanced colorectal cancer received curcumin (Curcumin C3 Complex provided by Sabinsa Corporation) in doses up to 3.6 g daily for up to four months. The reported side effects were minor, with nausea and diarrhea being the most commonly reported complaints.45

Potential Drug Interactions with Curcumin

Anticoagulants

Some preclinical data indicate that co-administration of curcumin with NSAIDs or anticoagulant drugs might result in an increased risk of bleeding.79 Anticoagulant agents include aspirin, clopidogrel (Plavix®), dalteparin (Fragmin®), enoxaparin (Lovenox®, Xaparin®, Clexane®, Oksapar®), heparin, ticlopidine (Ticlid®), and warfarin (Coumadin®, Jantoven®, Marevan®). Curcumin has been shown to have mild anticoagulant properties in assays using human plasma and to prolong bleeding time in a rat-tail transaction assay. Bisdemethoxycurcumin also had anticoagulant activity in these assays, but less so when compared to curcumin.80

Drug Metabolism

Curcumin may interfere with drugs metabolized by the cytochrome P450 (CYP) enzyme system.79 In vitro experiments using recombinant human CYP enzymes, human liver fractions, and human intestinal cell lines indicated that curcumin might affect enzymes involved in drug metabolism. In these experiments, curcumin inhibited sulfotransferase (SULT) enzymes, uridine 5’-diphospho (UDP)-glucuronosyltransferase (UGT), and several CYP enzymes with IC50 (half maximal inhibitory concentration) values ranging from 0.99 to 25 µM.81

To date, only two human clinical studies have explored the effects of standard curcumin on enzymes involved in drug metabolism.‡‡‡ The potential effect of standard curcumin on metabolic enzymes was investigated in healthy Chinese men using caffeine as a probe drug. Sixteen volunteers were recruited for this two-phase study. Initially, 100 mg of caffeine was administered to establish baseline PK measurements. Thereafter, the volunteers received 1,000 mg curcumin (supplied by General Nutrition Centers, Inc. [GNC]; Greenville, South Carolina) once daily for 14 days. On day 15, caffeine was again administered and PK measurements were taken once more. Urinary caffeine metabolite ratios were used to indicate the activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO). Curcumin caused an increase of 49% in CYP2A6 activity and an inhibition of 29% in CYP1A2 activity. There was no significant effect on NAT2 or XO activity.82

 

Table 2. Human Clinical Studies Conducted on BCM-95® (CurcugreenTM)

Reference

Indication

Study Design & Details

Treatment & Dose

Results

Conclusions

MENTAL HEALTH

Sanmukhani et al., 201427

Major depressive disorder (MDD)

R, CM; 6 weeks; N = 45 patients with MDD

3 groups: [1] BCM-95 (500 mg b.i.d.); [2] fluoxetine (20 mg/day); [3] both treatments combined

All groups  HAM-D17; NSD among groups.

BCM-95  MDD symptoms = fluoxetine; no ­ effect with combo.

Lopresti et al., 201428

MDD

R, DB, PC; 8 weeks; N = 52 patients with MDD (18-65 years)

BCM-95 (500 mg b.i.d.) or placebo

BCM-95  IDS-SR30 score 4-8 weeks. No ∆ 0-8 weeks or in STAI trait.

BCM-95  MDD compared to placebo (4-8 weeks only).

Lopresti et al., 201571

 

Secondary analysis of salivary, urinary, and blood biomarkers from Lopresti et al., 2014

 

∆ in urinary markers; no significant ∆ in blood or salivary biomarkers

∆ in urinary biomarkers not related to measurements of depression

Lopresti & Drummond, 201732

MDD

R, DB, PC; 12 weeks; N = 123 patients with MDD (18-65 years)

4 groups: [1] BCM-95 (500 mg b.i.d.); [2] BCM-95 (250 mg b.i.d.); [3] BCM-95 (250 mg b.i.d.) + saffron (15 mg b.i.d.); or [4] placebo

All BCM-95 groups combined  IDS-SR30 & STAI scores 0-12 weeks. No dose effect.

BCM-95  MDD compared to placebo (0-12 weeks). No ∆ in response with half dose. Best response for those with atypical depression.

Rainey-Smith et al., 201633

Cognitive health in older adults

R, DB, PC; 1 year; N = 96 healthy adults (40-90 years)

BCM-95 (500 mg t.i.d.) or placebo

No ∆ in cognition after 1 year. Decline in placebo group at 6 months.

BCM-95 had no effect on cognition after 1 year but may have prevented decline observed in placebo group at 6 months.

Baum et al., 200830

Alzheimer’s disease

R, DB, PC, dose study; 6 months; N = 27 patients with dementia (>50 years)

3 groups: [1] 1 g/day BCM-95; [2] 4 g/day BCM-95; or [3] placebo. All groups 120 mg/day ginkgo leaf extract.

All groups no ∆ in cognition.

BCM-95 had no effect on cognition. Study design flawed as all patients also received ginkgo.

CARDIOVASCULAR HEALTH

Baum et al., 200731

Lipid levels

Secondary analysis of salivary, urinary, and blood biomarkers from Baum et al., 2008

 

All groups no ∆ in lipid levels.

BCM-95 had no effect on lipids. Weak study design as subjects did not have hypercholesterolemia, nor were they fed a high-fat diet.

JOINT HEALTH

Antony et al., 201172

Osteoarthritis (OA)

R, CM; 12 weeks; N = 28 patients with OA of knee (18-65 years)

Rhulief (BCM-95 + BosPure; 500 mg b.i.d.) or celecoxib (100 mg b.i.d.)

Both groups  pain,  distance walked, & range of motion.

Rhulief  OA symptoms = celecoxib.

Chandran & Goel, 201225

Rheumatoid arthritis (RA)

R, SB, CM; 8 weeks; N = 45 patients with RA

3 groups: [1] BCM-95 (500 mg b.i.d.); [2] diclofenac sodium (50 mg b.i.d.); or [3] both treatments combined

All groups  DAS and ACR scores. Only BCM-95  C-reactive protein.

BCM-95 RA symptoms = diclofenac. Only BCM-95  inflammation (C-reactive protein levels).

CANCER CHEMOPROVENTIVE EFFECTS

Das et al., 201026

Oral submucous fibrosis

R, OL; 3 months; N = 48 patients with premalignant lesions

3 groups: [1] BCM-95 (500 mg b.i.d.); [2] turmeric oil (12 drops b.i.d.); or [3] Multinal tabs (spirulina, 500 mg b.i.d.)

BCM-95 & turmeric oil  oral pain & ­ ability to open mouth & eat spicy foods.

BCM-95 & turmeric oil  clinical scores.

Kuriakose et al., 2016

Oral leukoplakia

R, DB, PC; 6 months; N = 223 patients with lesions > 15 mm2 in size

BCM-95 (1800 mg b.i.d) or placebo (cellulose)

BCM-95  size of lesions

BCM-95  clinical scores.

Hejazi et al., 201329

Radiotherapy side effects

R, DB, PC; 20 weeks; N = 40 men with prostate cancer undergoing radiation therapy

BCM-95 (500 mg 6x/day) or placebo (roasted rice flour)

BCM-95  urinary symptoms; no ∆ in effects on bowel or sexual activity.

BCM-95  urinary symptoms due to radiation therapy in men with prostate cancer.

Hejazi et al., 201634

 

Secondary analysis of plasma antioxidant levels from Hejazi et al., 2013

 

BCM-95 ­ total antioxidant capacity and superoxide dismutase.

BCM-95 improved antioxidant status without compromising efficacy of radiotherapy.

CM = comparative

DB = double-blind

OL = open-label

PC = placebo-controlled

R = randomized

SB = single-blind

ACR = American College of Rheumatology criteria

DAS = Disease Activity Score

HAM-D17 = Hamilton Rating Scale for Depression

IDS-SR30 = Inventory of Depressive Symptomatology

STAI = State-Trait Anxiety Inventory

b.i.d. = 2 times daily

t.i.d. = 3 times daily

NSD = no significant differences

∆ = change

 = decreased

­ = increased

Another clinical study examined the effect of standard curcumin on the pharmacokinetics of talinolol, a b-adrenoceptor antagonist (beta blocker) that is used to manage cardiac arrhythmias and hypertension. Talinolol was used as a probe for effects on the P-glycoprotein (P-gp)-related drug transport systems. Curcumin (supplied by Shenwei Pharmaceutical Co.; Shijiazhuang, China) was administered to 12 healthy volunteers for six days. A single dose of 50 mg talinolol was administered one week before the curcumin and on the seventh day following curcumin administration. Concentrations of talinolol were measured in plasma samples. Co-administration of curcumin significantly reduced the plasma levels of talinolol (AUC by 33% and Cmax by 28%) but did not affect the kinetics of absorption (tmax and t½). The authors suggested that curcumin modified P-gp activity in the intestine by occupying receptor sites.83

BCM-95 (Curcugreen)

BCM-95 Preclinical Toxicology

Acute Oral Toxicity — Mice

In an acute oral toxicity study conducted according to international Organisation for Economic Co-operation and Development (OECD) Guideline No. 420, male and female Swiss albino mice (eight to 12 weeks old; 20 to 25 g body weight; five animals per group) were given via gavage 5,000 mg/kg body weight BCM-95 or corn oil as a vehicle control. The animals were fasted for three to four hours prior to oral dosing and one to two hours post-dosing. The animals were observed over 14 days for clinical signs before necropsy. No signs of toxicity were observed at the highest dose tested. Thus, the MTD, minimum lethal dose (MLD), and median lethal dose (LD50) for BCM-95 were all declared to be > 5,000 mg/kg body weight.84

Acute Oral Toxicity — Rats

In an acute oral toxicity study conducted under OECD Guideline No. 420, male and female Wistar rats (eight to 12 weeks old; 160 to 200 g body weight; five animals per group) were given via gavage 5,000 mg/kg body weight BCM-95 or corn oil as a vehicle control. The animals were fasted for three to four hours prior to oral dosing and one to two hours post-dosing. The animals were observed over 14 days for clinical signs before necropsy. No signs of toxicity were observed at the highest dose tested. Thus, the MTD, MLD, and LD50 for BCM-95 were all declared to be 5,000 mg/kg body weight.85

Rat 45-day Study

A 45-day toxicity study was conducted with female Sprague Dawley rats divided into four groups of five animals each. Three doses of BCM-95 mixed with normal rat chow to deliver 100, 250, or 750 mg/kg body weight daily for 45 days were compared to control animals. Physical changes, pharmacotoxic symptoms, body weight, and food intake were measured. The animals were sacrificed after 45 days and hematological, biochemical, and histological analyses were conducted. Continuous administration of BCM-95 did not produce any deaths or physical changes at all doses tested. The increases in body weight were not different from the control animals. There was no change in blood clotting time with any of the doses. There was a trend towards an increase in total leukocyte count, but the differential cell count remained unchanged. There were no changes in serum total protein, albumin, globulin, or glucose levels. In animals receiving the highest dose, serum alkaline phosphatase activity increased. In animals receiving the lowest dose, blood urea levels decreased. There was a dose-related trend towards a decrease in serum cholesterol but no changes in liver cholesterol or serum triglyceride levels. Histopathological evaluations did not reveal any lesions in liver sections. In conclusion, continuous exposure of BCM-95 to female rats for 45 days at doses up to 750 mg/kg body weight was well tolerated by the animals.86

Rat 90-day Study

A 90-day toxicity study (based upon OECD Guideline No. 408) was conducted with Sprague Dawley rats divided into four groups of 20 animals each (10 males and 10 females). Three doses of BCM-95 were mixed with normal rat chow to deliver 100, 500, or 1,000 mg/kg body weight daily for 90 days, administered via gavage. The fourth group of animals were given the vehicle (corn oil) and served as controls. The animals were observed daily for behavior, appearance, and potential signs of toxicity, as well as body weight and food consumption. The animals were sacrificed after 90 days and hematological, biochemical, and histological analyses were conducted. Two additional groups of control and high-dose animals (10 animals in each group) were kept under observation for an additional 28 days. Blood from all study animals was collected and analyzed for hematological and biochemical parameters. Organ tissues also were collected, weighed, and examined using histopathological techniques. There were no treatment-related toxic signs, symptoms, or deaths. There were no differences among groups in mean body weights or food consumption. There were no abnormal hematological findings or biochemical parameters. Organ weights and necropsy results did not show any signs of toxicity. The No Observed Adverse Effect Level (NOAEL) was determined to be > 1,000 mg/kg body weight.87

BCM-95 Genotoxicity — Mutagenicity, Teratology

BCM-95 was determined to be non-mutagenic at an oral dose of 2,000 mg/kg body weight in mice and rats according to the Mammalian Bone Marrow Micronucleus Test and the Mammalian Bone Marrow Chromosome Aberration Test, respectively.88 BCM-95 was also determined to be non-mutagenic in the Ames Test (Bacterial Reverse Mutation Test), when tested in vitro against five strains of Salmonella typhimurium, at concentrations of 1 to 5 mg/plate, with or wihout metabolic activation.89 On the basis of these three tests, BCM-95 can be considered non-mutagenic.

Mammalian Bone Marrow Micronucleus Test

A mammalian erythrocyte micronucleus test (based upon OECD Guideline No. 474) was conducted with mice. This test is designed to detect chromosomal damage caused by a test agent. Visualization of damage to the mitotic apparatus in erythroblasts in bone marrow is facilitated because these calls lack a main nucleus. The frequency of micronucleated polychromatic erythrocytes in animals to which the test agent is given is compared to vehicle controls and a known toxin.

In this experiment, a total of 60 Swiss albino mice were divided into three groups of 20 animals each (10 males and 10 females). The BCM-95 group received one dose of 2,000 mg/kg body weight and the control animals received corn oil, both administrated orally via gavage. The positive control group received cyclophosphamide intraperitoneally at a dose of 40 mg/kg body weight. Half of the animals were sacrificed at 24 hours post-dose and the remainder at 48 hours post-dose. Erythrocytes from the marrow of femur bones were fixed, stained, and examined. There was no observable effect on the micronuclei of the animals that received BCM-95, compared to the negative control. BCM-95 did not show any mutagenic potential, as measured via the micronucleus test.88

Mammalian Bone Marrow Chromosome Aberration Test

A mammalian bone marrow chromosomal aberration test (based upon OECD Guideline No. 475) was conducted in rats. The purpose of this test is to detect structural aberrations induced by test agents. In this experiment, a total of 60 Wistar albino rats were divided into three groups of 20 animals each (10 males and 10 females). The BCM-95 group received a single dose of 2,000 mg/kg body weight and the control animals received corn oil, both administrated orally via gavage. The positive control group received cyclophosphamide via intraperitoneal route at a dose of 50 mg/kg body weight. Half of the animals were sacrificed at 16 hours post-dose and the remainder at 40 hours post-dose. Two hours prior to sacrifice of the animals, they were injected intraperitoneally with colchicine (4 mg/kg body weight). Chromosomes were isolated from bone marrow cells, stained, classified, and scored. No evidence of numerical or structural aberrations was observed in samples from animals treated with BCM-95 or vehicle control. BCM-95 was declared to be non-mutagenic at a dose of 2,000 mg/kg body weight in rats.88

Ames Test (Bacterial Reverse Mutation Test)

The bacterial reverse mutation test is a common screen for genotoxic activity, particularly point mutation. Mutant strains of Salmonella typhimurium that have lost the ability to synthesize histidine are incapable of growing on a histidine-deficient medium, unless a reverse mutation has taken place. Some test agents will exert a mutagenic effect only after they have been metabolized, usually in the liver. For this reason, the test is run with and without metabolic activation.

BCM-95 was tested against five strains of S. typhimurium (TA-98, TA-100, TA-102, TA-1535, and TA-1537), with and without metabolic activation (S-9 liver fraction), at concentrations of 1, 2, 3, 4, and 5 mg/plate (according to OECD Guideline No. 471). Several known mutagens were used as positive controls. The results of all studies with BCM-95 were negative; there was no growth at any of the test concentrations, with or without metabolic activation. The sensitivity of the assay was confirmed by growth in the positive control plates. Under the conditions of this study, BCM-95 was found to be non-mutagenic.89

BCM-95 Human Safety Data

Clinical studies that used a dose of 500 mg twice daily for eight weeks to three months reported that BCM-95 was administered safely.25-28 In another clinical study, BCM-95 was administered in a dose of 4 g daily for six months without significant adverse effects.30 This study explicitly examined biochemical markers for indications of toxicity and is reported in detail below.

Safety parameters were examined in a clinical study with patients with Alzheimer’s disease.30 In this study, patients over 50 years old (N = 27, males and females) with a progressive decline in memory and cognitive function over the previous six months received 1 g or 4 g of BCM-95, powdered curcumin, or placebo, in addition to 120 mg standardized ginkgo leaf extract (no description provided) and any additional treatment deemed appropriate by their physicians. Liver and kidney function was assessed using blood samples obtained at baseline, one month, and six months. The liver function tests included albumin, bilirubin, and ALT (also known as GPT). The kidney function indicators included plasma levels of sodium, potassium, and urea. There were no significant changes in these serum markers for liver and kidney function. Adverse events were mild and distributed among all groups — the largest number in the placebo group (n = 7), followed by the 1-g dose group (n = 6), and the smallest number in the 4-g dose group (n = 2). The most common adverse events were gastrointestinal complaints, followed by respiratory tract infections and falls or dizziness.

Turmeric Curcuma longa
Photo ©2019 Steven Foster

 

Lack of Interaction with NSAIDs

A three-arm study conducted with a total of 45 patients with RA who received BCM-95 (500 mg twice daily), diclofenac sodium (an NSAID; 50 mg twice daily), or both together did not report any interactions between these two treatments.25 There were no changes to hematological or chemical parameters as measured in plasma samples, but effects on coagulation were not specifically measured.

Summary of Safety Information

Toxicological studies conducted with curcumin in rats, dogs, and monkeys at oral doses up to 3.5 g curcumin per kg body weight for up to 90 days did not produce any adverse effects.75 No reproductive toxicity was observed in a study in which curcumin was administered orally to rats in doses up to 1 g/kg body weight daily for two successive generations.78

Phase I human clinical studies indicate that curcumin is not toxic even at a very high dose of 12 g per day. The reported adverse events were mild including diarrhea, headache, rash, and yellow stools. The MTD could not be determined in this study because amounts more than 12 g could not be consumed comfortably.24

BCM-95 has been tested in toxicological studies in rodents and was found to be safe. A study conducted in rats orally administered 100, 500, or 1,000 mg/kg body weight daily for 90 days determined that the NOAEL was greater than the highest dose administered.87 BCM-95 was determined to be non-mutagenic at an oral dose of 2,000 mg/kg body weight in mice and rats.88 BCM-95 did not cause chromosomal aberrations.88

A human clinical study designed to examine safety parameters, in which BCM-95 was administered in a dose of 4 g daily for six months, did not find any significant changes in serum markers for liver and kidney function.30 Adverse side effects were mild and the most common was gastrointestinal discomfort.

The US FDA accepted BCM-95 as Generally Recognized as Safe (GRAS) in a no objection letter dated July 11, 2017 (GRAS Notice No. GRN 000686).90

Drug Interactions

Some preclinical data indicate that co-administration of curcumin with NSAIDs or anticoagulant drugs might result in an increased risk of bleeding.79 In a human clinical study cited above, BCM-95 was co-administered with the NSAID diclofenac sodium without producing any significant adverse effects.25 However, any potential effects of the combination therapy on the risk of bleeding was not part of the evaluation.

Curcumin may interfere with drugs metabolized by the CYP enzyme system.79 The data that support this caution come from in vitro experiments using enzymes and human cell lines. Only two clinical studies have explored the effects of standard curcumin on enzymes involved in drug metabolism. In one study, curcumin caused an increase of 49% in CYP2A6 activity and an inhibition of 29% in CYP1A2 activity. There was no significant effect on NAT2 or XO activity.82 The second study suggested that curcumin modified P-gp activity in the intestine by occupying receptor sites.83 Further studies are needed to determine the clinical significance of these reports.