Curcumin | Cam-Cancer

Curcumin

Abstract and key points

Curcumin or diferuloylmethane is the major constituent and the active component in the spice turmeric (rhizomes of Curcuma longa).  Curcumin is used medicinally as a supplement, and is claimed to have anticancer and chemopreventive properties.  There are two systematic reviews and twenty controlled trials of curcumin for cancer-care available, mostly for supportive care and prevention.  Most studies are small in size and exhibit great heterogeneity. 

Antitumour treatment:

  • There is insufficient evidence to make any statements regarding the efficacy of curcumin as an antitumor agent for any cancer.
  • Preliminary evidence from two studies in colon cancer are promising but require further study.

Supportive care:

  • Curcumin is likely effective at preventing and treating oral mucositis during chemo and/or radiotherapy for head and neck cancer when used topically or orally.
  • Oral curcumin may not be effective at preventing radiation dermatitis, topical application has weak evidence to support its use.
  • Data from poorly designed studies have reported benefit to quality of life during chemotherapy and radiotherapy for mixed cancers with the addition of curcumin.
  • During radiation therapy for prostate cancer, curcumin may reduce urinary symptoms and lower inflammation, but it does not appear to benefit other symptoms or quality of life outcomes.
  • No statements can be made regarding the effect of curcumin on body composition

Prevention:

  • Curcumin is likely effective in treatment of oral submucous fibrosis, however it is not known whether this translates to lower risk of oral cancer.
  • Curcumin has encouraging preliminary research from trials monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, oral leukoplakia, low-grade cervical dysplasia, and elevated prostate-specific antigen, but only few and generally small studies are available.
  • Curcumin has not demonstrated benefit for recurrence of adenomas in people with familial adenomatous polyposis .

Curcumin is generally recognized as safe by the US Food and Drug Administration (FDA) and has been used safely at doses up to 12g daily for several months.

Document history

Summary fully revised and updated in May 2020 by Ellen Conte.
Summary fully revised and updated in April 2014 by Klara Rombauts.
Summary first published in May 2012 authored by Klara Rombauts and Liene Dhooghe.

Citation

Ellen Conte, CAM-Cancer Consortium. Curcumin [online document]. http://cam-cancer.org/en/curcumin. May 28, 2020

What is it?

Description, origin and characterization of the medicinal plant

Curcumin is the main curcuminoid and active component derived from turmeric (Curcuma longa) rhizome.  Curcuminoids, which make up about 3-5% of turmeric rhizome, contain approximately 77% curcumin, 15% demethyoxycurcumin, and 3% bisdemethyoxycurcumin, although commercial preparations may standardize to a higher curcumin content (Adiwidjaja 2017). Turmeric belongs to the ginger family or Zingiberaceae; in Europe turmeric (Curcuma longa) is the most commonly used. Originally from South Asia, turmeric now grows in tropical areas across the world. Mainly its underground parts such as rhizomes and tubers are used. It is also known as Indian saffron, jiang huang, haridra, haldi. Turmeric is the major ingredient of curry powder, a bright yellow-orange food colouring agent (E100), and used as colourant of paper, clothes and cosmetics. (Goel 2020; Jurenka 2009; Govindarajan 1980).

Ingredients and quality issues

Curcuma longa contains:

  • 2-7% volatile oils composed of monoterpenes and sesquiterpenes (mainly ar-, a-, b-turmerone, zingiberene, curcumene, as well as turmerol, zingiberol, curcumol und xanthorrhizol),
  • 3-5% curcuminoids with main component curcumin (diferuloylmethane [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dion]), demethoxycurcumin and bisdemethoxycurcumin,
  • 30-40% starch and other polysaccharides (glycans). (Jurenka 2009; WHO 1999)

Quality issues

Bioavailability of orally administered curcumin is poor; bioavailability-enhanced products are available but vary widely in effectiveness. (Jamwal 2018). An evaluation of turmeric dietary supplement quality in the United States market found that most turmeric products contained curcuminoid content within 80% of advertised, but curcuminoid composition was suggestive of possible use of unlabelled synthetic curcumin in some products. Lead was found in only one product, and residues of toxic class 1 or 2 solvents were within USP-specified limits. (Skiba 2018)

Indications

Curcumin has been used medicinally in traditional Ayurvedic medicine and traditional Chinese medicine for a variety of illnesses, including skin diseases, infections, digestive complaints, meteorism, nausea and vomiting, peptic ulcer, diseases of the gall bladder and liver, inflammatory diseases (Singh 2007), and cancer (Kuttan 1985).  More recently, curcumin has been studied and used for the prevention and treatment  of a variety of conditions.  The best evidence for its use is in inflammatory and metabolic conditions such as arthritis, inflammatory bowel disease, metabolic syndrome, and hyperlipidemia. (Hewlings 2017)

In the management of cancer, curcumin has been claimed to have broad anti-cancer effects including suppression of cancer initiation, progression, and metastases of various cancers, and apoptotic and antiproliferative effects. These effects are thought to be due to curcumins anti-inflammatory and anti-oxidant activities, and effects on various cell-signaling pathways. (Shanmugm 2015; Devassy  2015) 

Mechanisms of action

Curcumin is a pleiotropic compound exerting effects on many signaling pathways in the body. In general, curcumin is a potent anti-oxidant by scavenging reactive oxygen species (ROS), anti-inflammatory through inhibition of ROS-generating cyclooxygenase and lipoxygenase enzymes, anti-proliferative, and pro-apoptotic agent. (Devassy 2015)  Curcumin has been shown to inhibit chemical carcinogenesis in different tissues, and it induces apoptosis in several tumor cell lines. The underlying mechanisms of the antineoplastic properties of curcumin are many, and include: suppression of c-jun and c-fos expression; inhibition of protein kinase C (PKC) and epidermal growth factor receptor (EGFR) tyrosine kinase; suppression of colonic aberrant crypt foci through inhibiting inducible nitric oxide synthase (iNOS); inhibition of cyclo oxygenase-2 (COX-2); inhibition of xanthine oxidase; modulation of Ca+2 and cellular p53 protein; induction of phase-2 detoxification enzymes; inhibition of matrix metallopeptidase 9 (MMP-9) (Lin 2001), inhibition of  vascular endothelial growth factor (VEGF) (Lu 2010), and modulation of various pathways including nuclear factor-kappa beta (NFKB), mitogen-activated protiein kinase (MAPK), notch-1 signaling pathway, nuclear factor-like 2 (Nrf2), Wnt/beta-catenin, and JAK/STAT pathways. (Devassy 2015)

Curcumin may act as a chemosensitizer and radiosensitizer by downregulating various growth regulatory pathways and specific genetic targets, including genes for nuclear factor of B cells (NF-B), signal transducer and activator of transcription 3 (STAT-3), cyclooxygenase 2, protein kinase Akt, antiapoptotic proteins, growth factor receptors, and multidrug-resistance proteins. (Goel 2010)

Application and dosage

Curcumin has most commonly been used orally, although it has also been used topically (Normando 2019; Palatty 2014; Rao 2017), intravaginally (Gattoc 2017) and intravenously (Greil 2018).

Curcumin has low oral bioavailability due primarily to low water solubility, and to a lesser extent poor intestinal permeability and extensive first-pass metabolism (Adiwidjaja 2017).  To improve bioavailability, a variety of approaches have been used and studied including curcumin-piperine complexes, curcumin nanoparticles, cyclodextrin inclusions, curcumin liposomes, and curcumin phospholipid complexes (Jamwal 2018).  A review of curcumin bioavailability of eleven different formulas in healthy volunteers was performed in 2018 (Jamwal 2018) All curcumin formulations significantly increased serum levels compared to unformulated curcumin; relative bioavailability ranged from 6.9 to 185-fold.  The three formulas with greatest relative bioavailability were NovaSol®, CurcuWin®, and LongVida®.  Serum levels as high as 1189.1 ­­+ ng/mL have been detected following oral administration of 410mg NovaSol® formulation, while most other formulas achieve peak concentrations in the range of 100-500ng/mL. Unformulated curcumin has much lower peak plasma concentrations with most studies finding Cmax in the range of 1-10ng/mL. The half-life of curcumin also varies by formulation, ranging from 1-12 hours.  Comparing curcumin pharmacokinetics is challenging due to different dosing, trial designs, analysis methods, and study populations, and thus absolute numbers should be interpreted with caution. Nonetheless, it is clear that bioavailability-enhanced formulas improve absorption and AUC.

After oral administration, curcumin has also been detected in colonic tissue (Irving 2013) and intratumoral brain tissue (Dützmann 2016). In ten patients with glioblastoma (GBM), 1g of micellar curcumin (NovaSol ) 3 times daily for 4 days resulted in detectable intratumoral concentrations of curcumin, DMC, and BDMC; however levels were lower that that found to have a cytotoxic effect in cell culture (Dützmann 2016). Curcuminoids have been detected at mean tissue levels were 48.4 μg/g in the colonic mucosa of patients following 14-days of 2.35g curcumin supplementation (Irving 2013).

Dosing of curcumin varies based on formulation and relative curcumin content (e.g. turmeric powder contains only 3-5% curcumin, TheracurminTM contains 10% curcumin). Turmeric powder has been studied at a dose of 15g daily (Ghalaut 2012). Unformulated curcumin has been studied in doses up to 8g daily for 3 months without significant AEs (Li 2014), and studies in in cancer using unformulated curcumin orally have used 1.4-6g daily (Ryan 2013; Choi 2019). Dosing of bioavailability-enhanced formulas is typically lower, ranging from 80mg-4g (Delavarian 2019).

Regulation and cost

Turmeric is available worldwide as a spice and food supplement and numerous commercial products are available. It is possible to purchase products containing 95% curcumin over the internet; the cost of a monthly supply is about EUR 6 to 18, US$12 to US$36, but prices vary greatly depending on the dose (between 400 and 600 mg) and the amount of capsules (ranging from 60 to 180).

Does it work?

Two systematic reviews (Normando 2019; Al-Maweri 2019) and twenty controlled trials of curcumin for cancer-care have been published. The majority of these trials evaluated chemoprevention in pre-cancerous conditions and supportive care, while only four controlled trials evaluated anti-tumor effects. For a detailed description of all controlled clinical trials (CCTs) please see the Evidence tables.

In general, most studies of curcumin for cancer care are small in size and exhibit great heterogeneity between trials.  There is heterogeneity in curcumin dosing, formulation (e.g. turmeric, curcumin powder, bioavailability enhanced formulas), route of administration (e.g. oral, topical), conventional treatments (e.g. radiation therapy, chemotherapy, targeted therapies, no active treatment), cancer-types, and study outcomes.  

Antitumour treatment

Very few RCTs have evaluated curcumin for antitumour outcomes such as survival, objective tumor response, or cancer biomarkers.  One RCT (Choi 2019), and one single-arm study (Mahammedi 2016) in prostate cancer, two RCTs in colorectal cancer (Howells 2019; He 2011) one matched-control trial in chronic myeloid leukaemia (CML) (Ghalaut 2012), and one single-arm study in pancreatic cancer (Pastorelli 2018) have been published (see Table 1).  

  • There is insufficient evidence to make any statements regarding the efficacy of curcumin as an antitumor agent for any cancer.
  • Preliminary evidence from two studies in colon cancer are promising but require further study.

Description of included studies

Prostate cancer

The only placebo-controlled RCT to date of curcumin monotherapy for men with prostate cancer found somewhat inconclusive results (Choi 2019). The study randomized 97-men who had completed their first cycle of intermittent androgen deprivation (IAD) therapy to 6-months of oral curcumin at 1400mg daily. The primary outcome was duration of first off-treatment, and secondary outcomes included change in PSA and testosterone levels, HRQOL, and safety. There was no significant change in median off-treatment duration, PSA change, testosterone or HRQOL. The curcumin group had a significantly smaller proportion of patients with a PSA increase of >2ng/mL (10.3% vs 30.2%, p=0.0259), and significantly fewer AEs (7/45 vs 16/46, p=0.0349). Ultimately, more research is needed to understand if curcumin has a clinically meaningful difference in treatment outcomes of men with prostate cancer.

A single-arm phase II study in men with castrate-resistant prostate cancer (CRPC) evaluated the effect of docetaxel/prednisone plus curcumin (Mahammedi 2016).  Thirty men received docetaxel/prednisone for 6 cycles combined with 6000mg curcumin daily from day -4 to day +2.  Of 26-men who were evaluated at study end, a PSA response was observed in 59% and an objective partial response in 40%. Treatment was well tolerated, and authors recommended an RCT given the good objective response rate with this combination.

Colorectal cancer

Curcumin as an adjunct to treatment for advanced colorectal cancer has been assessed in two RCTs. In a small RCT (n = 27) of patients with metastatic colorectal cancer receiving FOLFOX, the addition of curcumin resulted in a significant improvement in overall survival (OS) (HR 0.34, p=0.02) and non-significant improvement in progression free survival (PFS) (HR 0.57, p=0.2) compared to FOLFOX chemotherapy alone (Howells 2019). Curcumin was administered at a dose of 2g daily of C3 complex for the duration of FOLFOX chemotherapy (up to 12 biweekly treatments), and was well tolerated. There was no significant change in quality of life (QoL) or neurotoxicity.  The study was open label, not placebo-controlled, and a small sample size, and thus larger placebo-controlled trials are needed.  Another RCT reported body weight gain, reduced serum levels of TNF-α, and an increase in cancer cell apoptosis in 126 colorectal cancer patients receiving 360mg oral curcumin 3-times daily or placebo between biopsy and surgery (He 2011). This demonstrates an anti-inflammatory and possibly anti-cancer effect of curcumin monotherapy in colorectal cancer.  The short treatment and follow-up period limit conclusions that can be drawn.

Chronic myeloid leukemia (CML)

Nitric oxide(NO) levels, a possible marker of carcinogenesis and CML activity, were significantly decreased in 50 patients with chronic myeloid leukaemia receiving 15g imatinib and turmeric powder daily compared to imatinib alone (Ghalaut 2012). The study was not placebo controlled or randomized, and there was no long-term follow up to determine if the decrease in NO lead to clinically meaningful differences in treatment outcomes.

Pancreatic cancer

No controlled clinical trials are available for pancreatic cancer. A single-arm, uncontrolled phase II trial evaluated phospholipid curcumin (Meriva) alongside gemcitabine chemotherapy for 42 patients with advanced pancreatic cancer (Pastorelli 2018). The authors reported a 61.4% disease control rate (27.3% objective response, 34.1% stable disease), progression-free survival of 8.4 months, overall survival of 10.2 months, no changes in QoL, and the treatment was deemed safe and well tolerated. Given this study is uncontrolled and given alongside gemcitabine, conclusions cannot be drawn. However, the authors note that the response rate was comparable to that seen with gemcitabine plus nab-paclitaxel but with less toxicity, and thus further research is warranted. Several phase I studies have used curcumin in patients with advanced pancreatic cancer, often alongside gemcitabine, and found it to be safe and feasible except for some abdominal discomfort with doses of 8g daily (Dhillon 2008; Kanai 2013; Kanai 2011; Epelbaum 2010).

Supportive Care

Several RCTs have evaluated the effect of curcumin on symptoms, side effects, and quality of life in people undergoing treatment for cancer (see Table 2). There is great heterogeneity in trials.

  • Curcumin is likely effective at preventing and treating oral mucositis during chemo and/or radiotherapy for head and neck cancer when used topically or orally.
  • Oral curcumin may not be effective at preventing radiation dermatitis, topical application has weak evidence to support its use but more research is needed
  • Data from poorly designed studies have demonstrated benefit to quality of life during chemotherapy and radiotherapy for mixed cancers with the addition of curcumin, but better quality trials are needed.
  • During radiation therapy for prostate cancer, curcumin may reduce urinary symptoms and lower inflammation, but it does not appear to benefit other symptoms or quality of life outcomes. More research is needed.
  • No statements can be made regarding the effect of curcumin on body composition, more research is needed to clarify

Description of included studies

Oral mucositis

Curcumin has been evaluated for its effect on oral mucositis (OM) during chemo and/or radiotherapy for head and neck cancers in several studies.  A systematic review published in 2019 included four randomized and one non-randomized trials of curcumin applied topically (3 studies used mouthwash, 2 used gel; participants n=217) for treatment and prevention of OM (Normando 2019).  Curcumin was effective at delaying onset of mucositis, accelerating wound healing, reducing the severity of OM, reducing erythema, and reducing pain when compared to povidone-iodine, chlorhexidine, saline, and placebo. Curcumin demonstrated benefit as both a preventative and treatment agent. No meta-analysis was performed due to heterogeneity of formulations, duration, and assessment criteria.

Another subsequently published RCT compared 80mg oral nanocurcumin capsules to placebo for patients (n=32) undergoing radiotherapy for head and neck cancer (Delavarian 2019). Compared to placebo, curcumin delayed the onset of grade 1 OM (p=0.002), significantly reduced severity of OM at all time points, and resulted in significantly less weight loss (p=0.003). Taken together, these studies support the use of oral or topical curcumin for the prevention and treatment of OM during radiation and chemo-radiation for head and neck cancer, but included studies were small and findings need to be confirmed in further well-designed RCTs.

Radiation dermatitis

Curcumin has been studied orally and topically for its effect on radiation dermatitis. A small RCT published in 2013 found that curcumin was effective for reducing radiation dermatitis severity and moist desquamation in a group of 30 women receiving radiation for breast cancer, randomized for curcumin or placebo (Ryan 2013). However, the same author published a much larger RCT in 2018 that did not confirm these findings (Ryan Wolf 2018).  In this study, 686 women receiving breast radiotherapy were randomized to 6g daily curcumin or placebo, and they found that curcumin did not reduce radiation dermatitis severity compared to placebo. There was a non-statistically significant reduction in women with radiation dermatitis severity >3 in the treatment group (7.4% vs 12.9% p=0.082). In both these studies the curcumin was not a bioavailability-enhanced formula, which may impact its therapeutic effect.

Two single-blind RCTs evaluated the effect of a turmeric and sandalwood oil cream applied topically during radiotherapy for head and neck (Palatty 2014) and breast (Rao 2019) cancers respectively. Both studies found that the use of the turmeric-containing cream compared to baby oil applied 5-times daily during radiation therapy significantly delayed the onset and decreased the severity of radiation-dermatitis as measured by the Radiation Therapy Oncology Group (RTOG) score. Investigators were blinded in both studies, but participants were not which is a possible limitation. Additionally, it cannot be ruled out that the sandalwood oil may have some medicinal effect.

Side effects during prostate radiotherapy

Three double-blind RCTs of curcumin in men with prostate cancer receiving external beam radiation have been conducted, looking at a variety of outcomes. One RCT in men with prostate cancer undergoing radiation found that 3g curcumin daily (BCM95) reduced the severity of urinary symptoms compared to placebo, but there were no other significant differences in QoL as measured by EORTC-QLQPR25 (Hejazi 2013).  An RCT in men with prostate cancer undergoing external beam radiation randomized to 3g curcumin (BCM95) daily or placebo found that curcumin improved markers of oxidative stress (increased total antioxidant capacity and decreased activity of superoxide dismutase) and did not impact treatment efficacy (no change in PSA or MRI findings) 3-months post-radiation Hejazi 2016). However the clinical significance of this is not clear.  Finally, an RCT in 64 men randomized to nanocurcumin (120mg/day) or placebo found no significant change in incidence of rectal proctitis (58.1% placebo versus 45.5% curcumin, p=0.313) or other acute radiation toxicities, and no change in treatment outcomes or hematological nadirs (Saadipoor 2019).

Quality of life (QoL) during chemo/radio-therapy

There is some preliminary evidence from two CCTs that curcumin may improve QoL and reduce inflammation (secondary outcome measure) during chemo/radio-therapy for mixed cancers but the trials had many methodological shortcomings and heterogeneous groups, which limit their findings.  One study randomized 80 people receiving adjuvant chemotherapy for solid tumors to curcumin (180mg/day Meriva formula) or placebo for 8 weeks and measured QoL with the University of Washington QoL Index, and serum inflammatory markers (Panahi 2014). Quality of life improved in both groups, but the magnitude of improvement was greater for the curcumin group. A variety of inflammatory markers were reduced in curcumin compared to placebo group, indicating an anti-inflammatory effect of curcumin.  A limitation of the study is that baseline QoL values were different between groups; the curcumin group had lower baseline QoL and thus may have had a greater potential to improve. No long-term follow up was conducted to assess for treatment efficacy. Another study evaluated adverse effects of chemotherapy and radiotherapy in 160 cancer patients taking 1.5g curcumin (Meriva - phospholipid complex) compared to those receiving placebo for 3-months (Belcaro 2014). QoL was significantly better in the curcumin group compared to placebo group for both chemotherapy and radiotherapy, and plasma free radical status was significantly lower in the curcumin group compared to placebo.  However, there are many flaws with this study including an apparent lack of randomization, subjective reporting of symptoms, no mention of blinding, and heterogeneity in the study population. Given the methodological flaws and heterogeneous groups, larger and more long-term trials are required to confirm the possible benefit of adjunctive curcumin with chemotherapy and radiotherapy.

Body composition

A RCT of 126 people with colorectal cancer found improved body weight (gain), reduced serum levels of TNF-α, and an increase in cancer cell apoptosis  with administration of 360mg oral curcumin 3x daily between diagnosis and surgery compared to placebo (He 2011). However, a retrospective matched 1:2 case-control study of curcumin on body composition in patients with advanced pancreatic cancer (22 curcumin treated compared to 44 controls) found that those taking curcumin lost more muscle mass (p < 0.001) and fat mass (p=0.04) than controls (Parsons 2017). Sarcopenic patients treated with curcumin (n=15) had median survival of 169 days versus 299 in sarcopenic controls (p=0.024), no difference in survival among non-sarcopenic patients. However, retrospective studies are weaker designs than prospective RCTs, and thus caution is warranted in interpreting these results.

Prevention

Curcumin has been studied in a variety of precancerous conditions including oral submucous fibrosis (OSF), intestinal adenomas, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), oral leukoplakia, and cervical dysplasia, and in men with elevated screening PSA.  Table 3 provides details on systematic reviews and RCTs of curcumin for pre-cancerous conditions.

  • Curcumin is likely effective in treatment of OSF, however it is not known whether this translates to lower risk of oral cancer.
  • Curcumin has encouraging preliminary research for MGUS and SMM, oral leukoplakia, low-grade cervical dysplasia, and elevated PSA, only few and generally small studies are available.
  • Curcumin has not demonstrated benefit for recurrence of adenomas in people with FAP.

Description of included studies

Oral submucous fibrosis (OSF)

OSF is chronic disease, which can transform to oral squamous cell carcinoma. Goals of treatment are to reduce symptoms, stop progression, and lower risk of malignant transformation. One systematic review of six RCTs and one subsequently published RCT have been published.

The systematic review of six RCTs found that curcumin when compared to other treatments or placebo was effective in managing OSF by reducing symptoms such as pain, and objective signs such as mouth opening (Al-Maweri 2019). One of the included studies evaluated histopathological changes and noted improvement with curcumin.  Dosing of curcumin ranged from 600mg-1000mg daily for 3-6 months, five studies used curcumin tablets while one study used a lozenge. One RCT published in 2018 that was not included in the systematic review found similar results; improved pain, improved objective markers of OSF, and improvements in histological grade and clinical staging in curcumin group compared to placebo (Ara 2019). Despite two RCTs demonstrating improved histopathological features of OSF, there are no long-term follow-up studies to determine if this reduces the rate of malignant transformation and thus exhibits cancer prevention effects. Studies generally were of lower quality with moderate-high risk of bias.

Intestinal adenomas

One RCT evaluated curcumin for reduction in number and size of adenomas in patients with familial adenomatous polyposis (FAP) and found no difference compared to placebo (Cruz-Correa 2018). Forty-four people with FAP were randomized to 1.5g bid curcumin or placebo for 1 year, and were evaluated at baseline, 4 months, 8 months, and 12 months.

Smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance  (MGUS)

One small double-blind controlled cross-over trial randomized 36 people with SMM or MGUS to 4g curcuminoids (C3 complex) daily or placebo for 6 months with a cross-over at 3 months Golombick 2012). After 6 months, patients could enter a 3-month open label extension with 8g of C3 curcumin. Outcomes were markers of free light chairn (FLC) response and bone turnover. While several markers including rFLC, dFLC, iFLC, and uDPYD and serum creatinine decreased on curcumin, most were not statistically significant. The results are encouraging, but more research is needed given the small sample size, short duration of treatment and follow up, and mostly non-statistically significant findings.

Oral leukoplakia

One RCT of 223 people with oral leukoplakia found that 3.6g curcumin for 6 months induced a significant and durable clinical response (leukoplakia size) compared to placebo (Kuriakose 2016). There was no long-term follow up to know if this clinical response translated to reduce oral cancer development, and more research is needed to confirm the findings of this one trial.

Cervical dysplasia

No RCTs have evaluated curcumin for cervical dysplasia, but two single-arm studies have been published.  A single-arm study of oral curcumin for women with low-grade squamous intraepithelial neoplasia (LSIL) was conducted over a 12-week period with promising findings (Joshi 2011).  Women with persistent LSIL after treatment with antimicrobial therapy were given 200mg twice daily of a standardized curcumin extract (NBFR-03) for 12-weeks. Nineteen of 21 women were analyzable; none progressed to high grade, 3 had persistent LSIL, and 16 regressed to atypia, ASCUS, or inflammatory pattern. A 36-month follow-up of 18 of the women was published separately (Joshi 2016). None of the women had progressed to High-grade (HSIL) or cancer, all 15-women who had regressed at the 12-week time-point remained free of LSIL at 36-months. One woman had returned to LSIL at 10-months, but regressed after a second course of curcumin.  A phase I study of intravaginal curcumin found that doses up to 2000mg daily for 14 days of curcumin powder in gelatin capsules was safe and well tolerated (Gattoc 2017).  Among the 13 women treated there were no dose-limiting toxicities and all AEs were grade 1 based on NCI CTCAE Version 4.0. More research is needed from RCTs to know if oral or intravaginal curcumin is effective for the treatment of cervical dysplasia, and if this results in fewer diagnoses of cervical cancer.

Other risk factors

One single-arm, uncontrolled study evaluated the effect of twice daily curcumin supplementation on men with elevated screening PSA.  After 30 days there was a reduction in mean PSA from 6.84 ±3.79 ng/mL to 4.65 ± 2.67 ng/mL (p < 0.0001), and increased PSA free: total ratio from 16.85 ± 3.9% to 19.68 ± 5.35% (p < 0.0036) (Fabiani 2018). Whether curcumin can reduce need for biopsy or have cancer-preventative effects is not known. Reduced DNA damage and improved antioxidant activity were observed in 286 healthy volunteers chronically exposed to arsenic, a carcinogen, when they were given 1g daily of curcumin compared to placebo (Biswas 2010), but whether this translates in to fewer cancers is not known.

Is it safe?

Adverse effects / toxicity

Curcumin and curcuminoids are generally recognized as safe (GRAS) by the FDA (Hewlings 2017). Clinical trials have demonstrated good tolerability and safety in doses up to  8g daily (Bayet-Robert 2010; Cheng 2001; Epelbaum 2010; Hewlings 2017; Kanai 2011) taken for a period of up to 18 months, and in high doses of up to 12g for 3 months (Jurenka 2009; Lao 2006). Possible adverse effects include gastro-intestinal side effects such as diarrhea and nausea (Hewlings 2017; Epelbaum 2010), and a potential for allergic dermatitis related to topical administration (Goel 2008).

Contraindications

There are no known absolute contraindications to curcumin supplementation. There is insufficient data for use in pregnancy and lactation. Caution is warranted with combined use with medications metabolized by CYP 2D6 and 2A6, people on anticoagulant and antiplatelet medications, and people on tamoxifen therapy.  See interactions section for details.

Interactions

Curcumin may interact with some medications due to pharmacokinetic, pharmacodynamics, and additive effects. Preclinical studies have reported alterations in various CYP P450 enzyme function with curcumin, which could lead to interactions with medications (Adiwidjaja 2018).  Curcumin has been reported to inhibit CYP1A2 function and enhance CYP2A6 activity in healthy, male Chinese volunteers (Chen 2010).  Two studies have found no effect of curcumin on CYP 3A4 activity (Fabiani 2018; Al-Jenoobi 2015). A randomized, placebo-controlled six-way crossover study in eight healthy volunteers found that short-term administration of 4g curcuminoids with piperine had no impact on pharmacokinetics of midazolam (CYP3A probe), flurbiprofen (CYP2C9 probe) or paracetamol (UGT and SULT probe) (Volak 2013)  Therefore, curcumoinoids with piperine were deemed unlikely to result in an interaction involving CYP 3A, CYP2C9 or paracetamol conjugation enzymes.  Curcumin may inhibit intestinal ABCB1 transporter, and preclinical data has demonstrated similar results for ABCB2 (Adiwidjaja 2018). 

Curcumin may reduce effectiveness of tamoxifen by altering the metabolism of the prodrug tamoxifen to active endoxifen (Hussaarts 2019). A dose of 1200mg curcumin with 10mg piperine administered 3x daily with tamoxifen reduced endoxifen area under the curve 12.4% (p=0.002) compared to tamoxifen alone. This is consistent with another study that found inhibition of CYP2D6 with curcumin (Al-Jenoobi 2015), which is the enzyme responsible for conversion of tamoxifen to endoxifen.  

Preclinical data has suggested antiplatelet and anticoagulant effects of curcumin and thus possible additive effects with anticoagulant medications (Kim 2012; Goel 2008).  However, human studies have failed to demonstrate a clinically or significantly meaningful effect of curcumin with antiplatelet and anticoagulant medications including acetylsalicylic acid, tipopidine, clopidogrel, warfarin, and dabigatran (Hu 2018; Fung 2017). Caution is warranted until more is known.

In summary, Curcumin may inhibit CYP 1A2 and CYP 2D6 activity, but appears unlikely to have a significant effect on CAYP 3A4 or CYP 2C9 activity. Curcumin likely interacts with tamoxifen. Curcumin is likely safe with anticoagulants, however caution is still warranted. Until more is known, patients should consult with their healthcare provider prior to use of curcumin if they are on any medications.

References

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