Curcumin

Curcumin (chemically known as Diferuloylmethane) is the main active ingredient of the spice Turmeric (Curcuma Longa or JiangHuang) and is the main 'curcuminoid' compound (80% of curcuminoid weight is curcumin^[1]) alongside the other three curcuminoids known as demethoxycurcumin, bisdemethoxycurcumin, and cyclocurcumin.^[2][3] Curcuminoids in general are known to exist in the curcuma genus^[4] (just in highest amounts in curcuma longa) although they are not exclusive to this plant.

Curcumin is the main molecule in the curcuminoid class of molecules (similar to how resveratrol is the main molecule in the stilbene class of molecules), and is most commonly associated with turmeric as that is its largest naturally occurring source

Curcuminoids are known to exist in:

• Turmeric (Curcuma longa or JiangHuang) at around 22.21-40.36mg/g in the rhizomes and 1.94mg/g in the tuberous roots^[4] as well as other curcuma species such as phaeocaulis (0.098mg/g)
• Common Ginger (Zingiber officinale) and shampoo ginger (Zingiber zerumbet)^[5]

Commercially available extracts of 'curcumin' may not be wholly curcumin, but a blend consisting of 77% curcumin (17% demethoxycurcumin, 3% bisdemethoxycurcumin, last 3% not classified but assumed to possess a cyclocurcumin content).^[6] Curcumin can also be referred to as NCB-02 (a standardized mixture of curcuminoids)^[7][8] or E100 (the code for curcumin in the usage of food coloring).^[9]

The structure of curcumin, officially known as diferuloylmethane, is two ferulic acid moeities bound together with an additional carbon (methane) to abridge the carboxyl groups. It can exist in a enol form (pictured below) or a keto form, which is molecularily symmetrical with two ketone groups on the backbone.

The curcumin molecule is bright yellow (as it is used as an industrial food colorant known as E100)^[10][9] and highly lipophilic.^[11] Curcumin is acid stable in the pH of the stomach.^[11]

Curcumin inherently is poorly absorbed when orally ingested by itself^[12] insofar that 8,000 mg of curcumin sometimes fails to significantly increase serum levels^[13] (although other studies note small spikes with 4,000mg^[14] or 8,000mg being able to reach 22-41 ng/mL^[15]). Due to this, modifications to curcumin supplements are investigated to enhance the amount of curcumin that reaches circulation.

A review article investigating the pharmacokinetics of various commercially available curcumin supplements reported that, relative to regular unenhanced curcumin, the bioavailabilities were: NovaSol (185-fold), CurcuWin (136-fold), LongVida (100-fold), Cavacurmin (85-fold), Meriva (48-fold), BCM-95 (27-fold), Theracurmin (16-fold), CurQfen (16-fold), MicroActive curcumin (10-fold), and Micronised curcumin (9-fold).^[16] All values were obtained from studies in human volunteers, will all but three (BCM-95, CurQfen, and MicroActive curcumin) using a double-blind, randomized crossover design.

The combination of curcumin with piperidine from black pepper extract (inhibitor of glucuronidation) is known to increase the bioavailability of curcumin 20-fold when 20mg piperidine is used alongside 2,000mg curcumin.^[17]

Complexing curcumin with phospholipids (a phosphatidylcholine-curcumin complex known as Meriva) can increase its incorporation into lipophilic membranes, increasing C_max and AUC five-fold in rats^[18] and making 450mg Meriva as effective as 4g curcumin in humans (unpublished trial).^[19] Other trials suggest a factor of 29-fold higher absorption in humans, although said enhanced absorption favors demethoxycurcumin rather than curcumin.^[20]

THERACURMIN emulsions (nanoparticles) possesses a 40-fold higher AUC (Area-under-Curve) when compared to basic curcumin power in rats, and a 27-fold higher AUC in humans.^[21] although another study found merely a 10-fold increase in AUC and a 40-fold increase in C_max in rodents.^[22] This increased bioavailability is, in part, due to increased water-solubility.^[23] Usage of nanoparticles can be used up to 210mg without any apparent saturation in absorption, and increase to C_max to 275+/-67ng/mL, an AUC of 3,649+/-430 ng/ml/h, and a half-life of 13+/-3.3 hours.^[23]

Several patented curcumin complexes exist to increase its bioavailability, with the most efficious being (compared to unenhanced curcumin) NovaSol (185-fold), CurcuWin (136-fold), LongVida (100-fold), Cavacurmin (85-fold).

AP-1, a class of transcription factors made of dimerizations of c-Fos, c-Jun and related proteins that is involved with cell proliferation, survival, and differentiation^[24] bind to their receptor on the cell nuclear (TPA response element) to induce effects associated with AP-1.^[25][26] The effects of AP-1 differ depending on the proteins that make it up, but curcumin is able to interfere with the AP-1 released by tumor promoters^[27] and is able to enhance some phase II (anti-oxidant) enzymes by moderating some better AP-1 confirmations.^[28]

Curcumin is also seen as a direct mTOR inhibitor, able to prevent the association of the raptor subset with the TOR protein, inhibiting mTORC1 activity directly without significant influence from AMPK-TSC or Protein Phosphatase A2.^[29][30]

Curcumin can also directly inhibit DNA polymerase lambda,^[31] focal adhesion kinase (FAK),^[32] Src,^[32] p300 (CREB Binding Protein),^[33] Thioredoxin reductase,^[34] Lipoxygenase (LOX),^[35] and tubulin.^[36]

It may also directly affect (negatively) 17beta-HSD3^[37] and 5-alpha reductase.^[38]

Curcumin has been noted to directly and potently inhibit the Glycogen Synthase Kinase-3β (GSK3β) enzyme with an IC₅₀ of 66.3nM.^[39]

Junction points are defined as proteins or receptors that, by their activation or inactivation, influence a great deal of related proteins.

NF-kB, a proinflammatory transcription factor, is inhibited by curcumin via a two-fold mechanism of preventing p65 translocation to the nucleus, and by preventing the degradation of the molecule which holds NF-kB in a dormant state, IkB.^[40] The co-activator of NF-kB, Notch-1, is also suppressed by curcumin although abnormally high levels of Notch-1 can reduce the inhibitory effects of curcumin on NF-kB.^[41] NF-kB moderates over 200 related proteins related to cell proliferation, invasion, metastasis, chemoresistance, and/or inflammation.^[42][6]

As mentioned previously, the proteins of AP-1 are also seen as a sort of junction point mediating cell proliferation and survival.^[24]

The main proteins and molecules that are downstream of NF-kB, and thus are reduced in potency when NF-kB is inhibited, are Bcl-2, Bcl-xL, cyclin D1, interleukin-6 (IL6), cyclooxygenase 2 (COX2) and matrix metallopeptidase-9 (MMP9).^[43][44]

Curcumin inherently exhibits low bioactivity in part due to its low intestinal absorption rate and in part due to rapid metabolism (glucuronidation),^[45] although measures have been taken to enhance absorption including micelle incorporation and nanoformulations.^[46][47]

A phospholipid complex has been noted to increase absorption 3.4-fold relative to curcumin alone in rats,^[48] a micellar surfactant (polysorbate) alone by 9-fold,^[49] phytosomes by 19.2-fold,^[20] and a combination of surfactants with oil^[50] or PLGA-PEG^[51] increasing absorption to 20-fold or greater relative to reference solutions of curcumin.

Alternatively, the absorption can be increased by pairing curcumin ingestion with other lipophilic agents such as the volatile oils naturally occurring in the turmeric plant (6.9-fold^[52]) or traditional preparation with gum ghatti (27.6-fold after processing^[21]) or by enhancing the initially poor water solubility of curcumin by pairing with water soluble carriers (polyvinyl pyrrolidone) and antioxidants^[53] where absorption can be further increased by adding in yet another lipophilic carrier.^[46]

Curcumin is inherently a very lipophilic (fat soluble) supplement, and ingesting curcumin by itself will result in very poor absorption. This absorption can be increased by numerous ways, either by introducing fat soluble components (may stimulate the intestines to produce micelles which carry fat soluble components via lymph) or formulating micelles within a dietary supplement. The water solubility of curcumin may also be enhanced with coingestion of water soluble carriers like polyvinyl pyrrolidone

Due to the poor intestinal absorption curcumin (without augmenting absorption) is effective in reaching colonic tissue. An oral dose of 3.6g curcumin (which has been shown to increase plasma levels to 11.1+/-0.6nmol/L^[54]) is able to increase the levels of curcumin in colorectal tissue to 7.7+/-1.8nmol/g (normal) and 12.7+/-5.7umol/g (malignant).^[54]

If curcumin is left unaugmented and thus poorly absorbed, then it is able to be retained in the colon where it may exert localized effects

Curcumin, due to its lipophilicity, is transported in the blood via transports; most likely binding to human serum albumin.^[55]

Without aiding absorption, an oral dose of 500mg/kg bodyweight in rats results in peak plasma levels of 1.8ng/mL.^[56]

When investigating humans oral dosages of 2, 4, and 8g curcumin daily for 3 months results in circulating levels of 0.51+/-0.11, 0.63+/-0.06, and 1.77+/-1.87uM; respectively. These C_max values were attained around 1-2 hours post-administration and then rapidly declined.^[57] Another human study found that 3.6g of curcumin resulted in levels of 11.1+/-0.6nmol/L an hour after consumption, with the lower dose tested (0.45g) not able to influence serum levels of curcumin;^[54] this dose is about 1/45th the circulating amount of the 4g curcumin dosage in the previous study, and the reason for discrepancy is unclear.^[57][54][19] Higher dosages induce a C_max of 2.30+/-0.26 μg/mL (10g) and 1.73+/-0.19 μg/mL (12g); the reason for the drop in C_max is unknown, but hypothesized to be due to saturation of the transporters.^[58]

Increasing the oral dose to 10g induces an AUC of 35.33+/-3.78 μg/mL, and a 12g dose induces an AUC of 26.57+/-2.97 μg/mL.^[58]

The major metabolites of curcumin in humans are curcumin sulfate (via sulfation enzymes of P450) and curcumin glucuronide (via glucuronidation by P450).^[56][54][58]

In the bile, tetrahydrocurcumin and hexahydrocurcumin have been noted in rats, and to a lesser degree dihydroferulic acid and ferulic acid.^[59]

One study using an intravenous dose of curcumin at 40mg/kg bodyweight in rats noted that the dose of curcumin was essentially cleared from plasma after one hour.^[56]

Curcumin undergoes reduction metabolism to dihydrocurcumin and tetrahyrdocurcum. Further reductive metabolism by alcohol dehydrogenase gives rise to hexahydrocurcumin and hexahydrocurcuminol which are the major metabolites in human and rat liver cells.^[60]

In rats, the protein expression of intestinal CYP3A4 and P-glycoprotein (P-gp) was reduced by treatment of curcumin at a dose of 60 mg/kg/day for 4 days, although CYP3A4 was induced in the liver and kidney.^[61] In rat hepatocytes, protein expression of P-gp was reduced after 72 hours of taking curcumin.^[62] Additionally, an in vitro study in rats examined the effects of everolimus and curcumin on CYP3A4 and P-gp (everolimus is a substrate of CYP3A4 and P-gp). Curcumin significantly decreased the bioavailability of everolimus due to its activation of CYP3A4.^[63] Another study examined the activity of CYP2C9 in humans and CYP2C11 in rat livers when taking curcumin. Curcumin inhibited CYP2C9 in humans and to a lesser effect inhibited CYP2C11 in rats.^[64]

In vitro studies using human enzymes or cells have shown that curcumin inhibits CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2B6.^[65][66] Curcuminoid extract inhibited CYP2C19 > CYP2B6 > CYP2C9 > CYP3A activities with IC₅₀ values ranging from 0.99 to 25.3 μM, while CYP2D6, CYP1A2, and CYP2E1 activities were less affected (IC₅₀ values > 60 μM).^[67] Inhibition of CYP3A4, CYP1A2, and CYP2B6 were due to competitive inhibition, while inhibition of CYP2C9, CYP2C19, and CYP2D6 were due to mixed competitive-noncompetitive inhibition.^[67][65]

Curcumin interacts with many cytochromes p450, including the important CYP3A4, which metabolizes many drugs.

Curcumin has a potential interaction with antiplatelet agents, anticoagulant agents, nonsteroidal anti-inflammatory agents, salicylates, and thrombolytic agents which may cause bleeding.^{[68][69][70][71]} When administering 100mg/kg of curcumin to rats, it increased the concentration of warfarin and clopidogrel but did not alter the anticoagulation rate and antiplatelet aggregation.^[72] However, two cases were identified in a cross-sectional point of care survey which had clinically significant interactions between curcumin and anticoagulant/antiplatelet agents.^[71]

There is also an interaction between vinblastine and curcumin. Vinblastine-induced tumor cell death may be inhibited by curcumin through the microtubule dynamics in which the authors suggest that vinblastine should not be consumed with curcumin.^[73]

In addition, when treating Salmonella typhimurium with ciprofloxacin or cotrimoxazole in animal models, curcumin lowers the antimicrobial efficacy of both drugs.^[74][75]

Curcumin may increase bleeding risk with antiplatelet and anticoagulant agents and decrease the efficacy of vinblastine, ciprofloxacin, and cotrimoxazole.

DHA is a long chain omega-3 fatty acid that is vital for brain development and protection. It is the most prevalent omega-3 fatty acid in brain tissue. ^[76] Several cognitive disorders such as anxiety, depression and Alzheimer's are linked to a dietary deficiency of DHA. ^[77][78][79] DHA may be obtained through the diet or it may be synthesized from dietary precursors such as alpha-linolenic acid, however, it is well known that conversion of alpha-linolenic acid to EPA and DHA is very low. It is especially low in men and conversion of alpha-linolenic acid to DHA is lower than conversion of alpha-linolenic acid to EPA.^[80]

One animal study found that curcumin preserves DHA content in the brain and elevates enzymes that are involved in the synthesis of DHA from its precursors thus, resulting in increased DHA concentrations in both the liver and the brain. ^[81]

Curcumin seems to enhance the synthesis of DHA and increase concentrations in the liver and the brain. This may prove especially useful for those who do not consume fish or supplement fish oil

Curcumin is able to preserve cells in response to glutamate excitotoxicity secondary to acting on the TrkB receptor (molecular target of BDNF)^[82] with peak efficacy appears to occur at 10µM (98.57% of control) and 24 hour pretreatment (99.81% of control);^[82] absolute protection has been noted elsewhere in hippocampal cells with 15µM curcumin.^[83] Since the glutamate-induced decline in BDNF is fully reversed with 2.5-10µM of curcumin^[82] it is thought that this plays a significant role.

The protective effect of curcumin against glutamate-induced toxicity extends to cerebellar granule cells,^[84] hippocampal cells (5-15µM),^[83] and retinal cells (15µM).^[85]

Phosphorylation of the NR1 subunit has been noted to be decreased with 15µM curcumin pretreatment^[85] and the NR2A subunit appears to be upregulated^[83] both of which have been attributed to the reduction in calcium signalling following stimulation with glutamate.^[83][85] AMPA and kainate receptors are unaffected by curcumin treatment,^[83] and the upregulation of NR2A is thought to play a role since protein synthesis is required for neuroprotection.^[83]

Curcumin, at least in vitro appears to be remarkably neuroprotective against glutamate induced cell death, which is either due to a modification of the NMDA receptors or due to preserving BDNF concentrations

One study assess curcumin and cognitive injury noted that, in control rats that were not injured, curcumin at 500ppm was able to increase BDNF levels to approximately 140% of control; this was independent of significant changes to CREB (105%) and phosphorylated CREB (93%).^[86]

In vitro, curcumin can abolish the induction of the NMDA receptor subunit R2B mRNA by corticosterone^[87] when corticosterone is incubated at 0.1mM and curcumin at concentrations as low as 0.62uM;^[88] this may be related to the ability of curcumin in vitro to prevent corticosterone-induced neuronal death.^[88]

Curcumin at 5, 10, and 20mg/kg was fed to rats daily for 21 days, and upon being subject to acute stress and subsequent cognitive testing; curcumin dose-dependently reduced the negative influence of stress on spatial memory with both higher doses (10, 20mg/kg) being significant and slightly less effective than 10mg/kg imipramine.^[88]

Epidemiological studies have found that a correlation exists between mood disorders and obesity. It is believed that a pathophysiological mechanism like inflammation plays a pivotal role in the manifestation of mood disorders.^[89] Thus, the use of curcumin as a treatment for mood disorders, via its anti-inflammatory properties, has been explored.

One animal study found that curcumin decreased anxious behavior in rats.^[81]

A cross-over randomized double-blind placebo-controlled trial among obese individuals was conducted in order to gauge the clinical efficacy of curcumin in treating anxiety and depression.^[90]

Inclusion criteria were those with a BMI > 30, subjects who had 2 > risk factors for coronary heart disease, and those who had LDL-C between 120-160 mg/dL. Thirty-five subjects (mean age: 38.37 ±11.51; 83% females were a part of the trial. Participants were given either capsules containing a mix of 500 mg of C3 Complex, along with 5 mg of bioperine or placebo capsules that were of the exact size and shape, which only contained 5 mg of bioperine. The subjects were required to take two capsules of curcumin a day (1 g) or two capsules of placebo a day for thirty days. The treatment period lasted for thirty days after which the patients were required to switch over to the alternative treatment following a 2-week wash-out interval between the regimens. Psychometric tests such as the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) were administered to each participant at baseline, week 4, 6, and 10 of the trial.

At baseline, the BDI score for the overall study population was 9.89 ± 6.50, which qualifies as mild depression. The BAI score for the overall study population was 28.66 ± 5.80, which qualifies as severe anxiety. The trial found that curcumin had no significant effect on the mean BDI score for the overall study population when compared to placebo (P=0.7), however, it was associated with a significant reduction on the mean BAI score when compared to the placebo group (P=0.03).^[90]

Curcumin seems to be effective in treating severe anxiety in females who are obese

Curcumin has been shown to be a potent anti-depressant in animal models of depression. It exerts these effects via regulation of monoamine neurotransmission, anti-oxidation in the brain, HPA modulation and attenuation of neuroinflammation.^[91]

Some trials have found curcumin to be somewhat effective in reducing symptoms of depression.^{[92][93][94][95]} However, most of the trials that did produce significant effects, lacked placebo groups, utilized small sample sizes, were limited by the use of self-reported psychometric tests or were too short in duration.

A recent randomized, double-blinded, placebo-controlled trial investigated whether curcumin was more effective than placebo at reducing symptoms of depression and whether different doses of curcumin would result in different effect sizes. The study found that curcumin was more effective than placebo in reducing symptoms of depression and this difference was statistically significant. Unlike previous trials, this study utilized a much larger sample size (123 participants) and was 12 weeks in duration. However, the study was not statistically powered to detect differences between the different doses of curcumin, which may explain why the study was not able to conclude whether high doses of curcumin were superior to low doses of curcumin in reducing symptoms of depression.^[96]

Curcumin's anti-inflammatory, HPA-modulating and anti-oxidant effects may be able to regulate some of the systems involved in depression. The evidence in humans currently suggests that curcumin seems to be more effective than placebo in reducing symptoms of depression. However, longer studies, with larger sample sizes and more rigorous designs are necessary.

Curcumin at 500ppm in rats (a dose similar to some anti-Alzheimer's dosages^[97]) for 4 weeks on either a high fat or normal diet who were then subject to a fluid percussion injury noted that the increased oxidation in the brain (139% normal diet, 239% high fat diet; high fat did not induce oxidation without neural injury) was reduced to 45-47% in both groups and BDNF was normalized despite its inherent reduction in neural injury,^[86] and other proteins that tend to be reduced in this form of injury are somewhat normalized with curcumin.^[98] Cognitive performance was declined after injury, and the reduction was attenuated but not normalized.^[86]

Curcumin is able to inhibit aggregation of beta-amyloid proteins in the brain, and thus prevent neural inflammation which would normally be downstream from said aggregation. The former has been noted in vivo^[99] and has been hypothesized to be the reason as to why higher circulating levels of Beta-Amyloid have been noted (statistically insignificant) with curcumin supplementation^[100] as beta-amyloid is prevented from aggregating in the brain,^[101] and thus must circulate somewhere.

Mechanistically, curcumin may be able to reduce Beta-amyloid build-up in neural tissue

In a rodent model with advanced Alzheimer's Disease characterized by beta-amyloid accrual, curcumin was able to attenuate the decline in neural performance and was synergistic with DHA; a component fatty acids from fish oil.^[102] This synergism may be related to how both agents can reduce beta-amyloid aggregation, but by differing mechanisms;^[103][104] some authors hypothesize that this synergism may be further enhanced by exercise^[105] due to an interaction with exercise and fish oil on neuronal plasticity.^[106]

A 6-month trial has been conducted on Curcumin and Alzheimer's, using basic curcumin at either 1 or 4g daily for 6 months in a population of 50+ year old chinese persons suffering from cognitive decline for at least 6 months prior to trial onset. Scores on the MMSE, a rating scale for Alzheimer's, increased progressively in the placebo (indicating cognitive decline) but were mostly static in both curcumin groups.^[100] This trial is limited in statistical power due to its sample size of 27 completions and multiple confounds, however.^[100]

Some therapeutic promise, but evidence is limited

Curcumin (or more specifically, turmeric) has a historical usage for pain relief following trauma.

Curcumin at 400mg (2,000mg of Meriva) in persons with acute algesic episodes appears to have a potency comparable to 1,000mg acetaminophen and 100mg nimesulide (trending to be more potent than acetaminophen yet less potent than nimesulide).^[107] It appeared to start working within two hours (slower than nimesulide) with maximal efficacy at 3-4 hours and a loss of efficacy but not yet normalized within 12 hours.^[107] This same supplement (2g Meriva) seems effective in reducing pain in osteoarthritic persons over three months^[108] and eight months.^[109]

In patients of laparoscopic cholecystectomy (associated with pain and fatigue following the operation) given 500mg curcumin once every six hours noted that supplementation was associated with a reduction in pain as reported by a 100 point VAS (rating scale), where although no difference was noted on day three followup at weeks 1-3 was associated with significantly less (approximately half) the pain.^[110]

High dose curcumin supplementation appears to be effective in treating post-operative pain, arthritic pain, and in persons who suffer from pain routinely. High doses of curcumin seem comparable in potency to some reference drugs

Curcumin is suspected to be able to protect against cardiac hypertrophy, inflammation, and thrombosis via inhibition of the protein p300, a Histone acetyltransferase (HAT) and it's downstream pathways. This inhibition has been shown to prevent heart failure in rats.^[111]

Ex vivo incubation of red blood cells from healthy volunteers in the concentration range of 1-100µg/mL (0.368-36.8µM) noted that 10µg/mL (3.68µM) was able to form echinocytes (small and even spiky protrusions on red blood cells) within 30 minutes, and was deemed to be indicative of a toxic effect.^[112]

Plasma levels of sICAM (involved in the pathology of atherosclerosis^[113]) appear to be very slightly but significantly reduced with 80mg curcumin (bioavailability enhanced form) daily for four weeks in otherwise healthy middle aged persons.^[114]

Via induction of Heme-Oxygenase 1 (HO-1), curcumin can prevent the endothelial (blood vessel) dysfunction associated with high blood glucose in a dose dependent manner and may offer protection from side-effects associated with diabetes.^[115] In an animal model of diabetes, curcumin has also preserved a degree of endothelial health during disease progression (although it was unable to, at 200mg/kg bodyweight, prevent changes).^[116]

This protective effect has also been demonstrated with LPS insult, a pro-inflammatory condition, and curcumin dosed at 50-100mg/kg bodyweight in rats;^[117] changes in endothelial contractility (via TNF-a) have also been reduced with curcumin.^[118]

The concentration of curcumin that induces HO-1 minimally (2μM) also appears to perturb endothelial cell replication, and 100nM curcumin has been noted to cause disproportionate DNA segregation and increase micronucleation.^[119]

Appears to hold protective effects on blood vessels, but its clinical significance is not known; seems promising, and most likely mediated through Heme Oxygenase-1

Supplementation of 150mg curcumin (enhanced absorption) was associated with an increase in blood flow as assessed by flow mediated vasodilation over the course of 8 weeks, the potency being comparable to thrice weekly physical exercise.^[120]

Oral ingestion of curcumin at 0.2% of the rat diet is able to restore the age-related decline in endothelial reactivity and nitric oxide to the levels of a youthful control, although the youthful rats experienced no such benefit.^[121]

Oral supplementation of 80mg bioavailability enhanced curcumin daily for four weeks in otherwise healthy persons has resulted in a significant (about 40%) increase in circulating nitric oxide^[114] which coincided with a similarly large spike in catalase activity.^[114]

In regards to nitric oxide, orally ingested curcumin appears to increase nitric oxide concentrations in serum. This has been noted in humans, and the degree of increase appears to be quite large

Protection from L-NAME induced hypertension^[122] and cyclosporin-A induced endothelial dysfunction^[123] has been noted with curcumin at 200mg/kg or 50-100mg/kg of its metabolite (tetrahydrocurcumin).

One human study using 500mg turmeric thrice daily (22.1mg curcumin each time) has noted significant decreases in blood pressure in persons with nephritis.^[124]

In postmenopausal women given 150mg curcumin daily (colloidal nanoparticles) daily for eight weeks, supplementation was associated with slightly decreased systolic blood pressure (112+/-10mmHg to 107+/-10mmHG) and no changes in diastolic pressure nor heart rate.^[120]

500mg curcumin daily has been shown to reduce triglycerides by 47% (110+/-21mg/dL to 58+/-9mg/dL) over 7 days, while a higher dose of 6g reduces triglycerides by 15% (93+/-13mg/dL to 79+/-11mg/dL); the cause for the lowered efficacy of high doses is not known.^[125] These were seen in otherwise normal weight and healthy young subjects.^[125]

In otherwise healthy postmenopausal women, 150mg curcumin daily (enhanced absorption) has failed to reduce triglycerides^[120] while another study using 80mg of a lipidated form for four weeks in otherwise healthy middle aged persons slightly reduced triglycerides.^[114]

500mg curcumin daily has been demonstrated to reduce total cholesterol levels by 17% while a higher dose of 6,000mg reduces total cholesterol by 5% in otherwise healthy subjects.^[125]

150mg of bioavailability enhanced curcumin in otherwise healthy postmenopausal women has failed to reduce total cholesterol, HDL-C, and LDL-C over eight weeks.^[120]

In liver cells, Curcumin at 20uM appears to activate Adenosine Monophosphate Kinase (AMPK) to the same degree as Metformin (2mM), which is 400-fold more potent on a concentration basis.^[126] Although glucose uptake into cells tends to be secondary to AMPK activation^[127] and has been noted with both Metformin and another potent AMPK activator berberine, this study noted that Curcumin failed to induce glucose uptake, instead noting a trend to reduce glucose uptake.^[126] This inhibition of glucose uptake has been noted elsewhere, where 100uM Curcumin was shown to inhibit insulin-stimulated GLUT4 translocation^[128] despite curcumin twice being shown to not significantly interact with the insulin receptor itself (not cell type specific).^[129][126]

Remarkably potent AMPK activator, yet seems to fail at inducing glucose uptake into cells (and thus undermines many of the inherent benefits of AMPK as it pertains to diabetes)

The effect of curcumin to lower blood glucose was one of the first effects to be seen with curcumin, seen in 1972.^[130]

One of the mechanisms of this blood glucose lowering effect is by stimulating Adenosine Monophosphate Kinase (AMPK) in skeletal muscle, drawing in glucose.^[131] This effect is enhanced with the presence of insulin, and since insulin also activates the PI3K pathway curcumin appears to be synergistic with insulin in regards to reducing blood sugar levels.^[132] Curcumin can also activate AMPK in other cells, such as liver cells^[126] and some cancer cells.^[133]

Curcumin is able to alleviate the downstream inflammatory reactions that occur during times of diabetes and metabolic syndrome in rats^[134] and, vicariously through its anti-inflammatory effects, improve insulin resistance.^[135][134]

Supplementation of curcumin to a prediabetic population over the course of nine months appears to preserve pancreatic function and improve both insulin sensitivity and adiponectin relative to control, and curcumin was able to prevent any occurrence of diabetes during this time frame (whereas 16.4% of control developed it).^[136]

Curcumin has been noted to attenuate lipolysis induced by TNF-α and isoproterenol (representative of catecholamines) in 3T3-L1 adipocytes, which was thought to be secondary to suppression of ERK1/2 activation.^[137] ERK1/2 is known to be regulated by AMPK^[138] which curcumin has been found to activate^[139] (in liver cells, this was noted to be of comparable potency to Metformin but requiring 20uM to Metformins 2mM^[126]); all of these events being similar to the known AMPK activator Berberine.

Fatty Acid Synthase (FAS) is inhibited by Curcumin with an IC₅₀ of 26.8μM (59.1μM in regards to β-ketoacyl reduction); the inhibition was noncompetitive when NADPH was the substrate, but mixed competitive with either acetyl or malonyl Coenzyme A^[140] and had both slow and fast acting components in a concentration and time dependent manner.^[140] 20uM of Curcumin abolished lipid accumulation in isolated 3T3-L1 cells undergoing differentiation, which may have been due to downregulation of PPARγ and CD36;^[140] another study notes that PPARy activation by Curcumin is dependent on AMPK activation.^[139]

Curcumin appears to be a potency activator of AMPK

Inflammation appears to play a role in obesity, particularly one cytokine known as TNF-α; adipose of genetically obese mice overexpress TNF-α which is also seen in adipocytes of overweight individuals^[141] and TNF-α expression appears to negatively correlate with LPL activity.^[142] TNF-α itself does exert lipolytic activity,^[143] so its elevation in obesity may be as a biomarker of underlying dysregulation rather than a per se contributor; the possibility of TNF-α resistance (a phenomena similar to insulin resistance, as TNF-α has its own receptor class on adipocytes^[144]) also being possible.^[145] TNF-α is a potent activator of NF-kB (nuclear receptor) which mediates many of its effects,^[146] and overactivity of NF-kB and TNF-α in adipocytes are both highly correlated with metabolic syndrome and obesity.^[145]

In general, excessive inflammation in adipocytes (assessed by looking at biomarkers thought to be representative of inflammation such as TNF-α) is highly correlated with obesity and metabolic syndrome; interventions which reduce inflammation in adipocytes tend to also be those that can reduce fat mass in persons suffering from excessive inflammation

A reduction in immune cell infiltration in adipose tissue has been noted in vivo when mice are given 3% curcumin in the diet for up to 4 weeks, as assessed by histological examination.^[134]

Curcumin appears to be associated with an increased FOX01 transcription activity and increased adiponectin production in vivo (with higher circulating levels of adiponectin noted in both genetic and diet induced obesity, but lean control mice did not experience an increase);^[134] FOXO1 is known to positively influence adiponectin transcription in fat cells.^[147][148]

Leptin secretion from adipocytes appears to be suppressed with 12 and 24 hour incubation with Curcumin in a concentration and time dependent manner.^[149]

In obese mice given curcumin (3% of feed), despite noting an increase in food intake relative to control; this reduction in body fat was not observed in normal mice.^[134]

In a study on rats, sympathetic activation from circulating fatty acids (commonly seen in obesity) is reduced via curcumin's lipid lowering effects; the resulting state is cardioprotective independent of weight loss.^[150]

Curcumin can also suppress angiogenesis in rat fat cells, a longer term adaptation associated with prolonged obesity.^[151] This is a general mechanism that applies to more cell types as well.^[152]

Through it's anti-oxidant effects, curcumin can ameliorate oxidative damage to skeletal muscle via Ischemia/Reperfusion when preloaded at 100mg/kg (I.P injection) to rats, with a potency greater than vitamin E.^[153] Curcumin also ameliorates the increase in inflammatory cytokines associated with Ischemia/Reperfusion injury.^[153][154]

As for the mechanisms of the above, curcumin (5-10uM) appears to increase Glucose-Regulated Protein 94 (Grp94) expression, which regulates calcium homeostasis; this regulation of calcium homeostasis appears to precede the standard inhibition of NF-kB activation and reduce the state of oxidation when an oxidative insult is produced.^[155] Interestingly, curcumin can also inhibit upregulation and damage from lead via preventing Grp94 upregulation,^[156] and general protection against cadmium as well.^[157]

Curcumin (via injection) is also implicated in increasing the recovery of skeletal muscle capacity associated with deloading, although it was not able to preserve skeletal muscle mass during deloading.^[158] These results differ from earlier ones showing a 100mg/kg oral dose of curcumin in rats was able to reduce muscular atrophy while a higher dose of 250mg/kg actually improved skeletal muscle weight.^[159]

Curcumin is able to inhibit Atrogin1/MAFbx and its subsequent ubiquitin ligase activity in vitro at 25uM,^[160] which induces skeletal muscle catabolism downstream of p38/MAPK induced by TNF-a. This has been confimed in rats with injections of 10-60ug/kg curcumin daily for 4 days which preserved lean mass in the face of LPS, by preventing p38 activation and the subsequent Atrogin1/MAFbx activation.^[160]

Skeletal muscle, via glucose uptake and oxidation, is a tissue regulator of glucose metabolism.

Some fatty acids, such as palmitic acid, can activate (phosphorylize) IRS-1 which causes negative feedback to the insulin receptor and desensitizes muscle cells to insulin-stimulated glucose uptake; curcumin appears to prevent this from occurring.^[161] This effect is shared by green tea catechins.^[161] Improvements in this mechanism of insulin resistance have been seen in vivo with dose-dependent oral doses of curcumin at 50, 150, and 250mg/kg bodyweight.^[162] AMPK activation appears to be a key intermediate in these effects.^[162][131] Beyond acting upon IRS, curcumin may also increase glucose uptake into skeletal muscles by acting on muscarinic acetylcholine receptors and then through PLC and PI3K.^[163]

Curcumin has been implicated in reversing some aberrations in skeletal muscle associated with type II diabetes, such as upregulation of beta-adrenergic receptors and Akt,^[164] the downregulation of NRF2 and Heme Oxygenase-1,^[165] and downregulation of AMPK and CPT-1.^[162] At least one study has suggested that the state of diabetes may be a prerequisite, and although it didn't measure all above parameters it did note no effects of curcumin in non-diabetic mice.^[166]

Curcumin has been noted to sequester superoxide (O_2-) radicals with an IC₅₀ of 5.84μg/mL.^[167]

When comparing 500mg curcumin against 6g curcumin, the anti-oxidative potential of the two does not significantly differ; if anything, 500mg curcumin seems superior due to insignificantly higher AUC of the increase in anti-oxidant abilities as measured by ORAC.^[125] This is thought to be due to a possible pro-oxidant effect of curcumin at higher dosages, seen with other anti-oxidants.^[168][169]

One of curcumin's most well-researched effects on inflammation is inhibiting TNF-a induced activation and nuclear translocation of NF-kB, a protein that influences the genetic code to produce inflammatory cytokines. This has been seen in immune cells after oral ingestion of 150mg curcumin (resveratrol at 75mg, green tea catechins at 150mg, and soy at 125mg as confounders)^[170] but also in isolation in vitro^[171] and in vivo.^{[172][173][174][175]} Activation of NF-kB can increase protein content (amounts) of Cyclooxygenase-2 (COX-2), a pro-inflammatory enzyme; pretreatment with curcumin reduces COX-2 upregulation induced by inflammatory cytokines.^[176] Other pro-inflammatory enzymes that are suppressed by curcumin are iNOS, LOX (directly inhibited), and Phospholipase A2 (directly.)^[177]

Curcumin has also been noted to have a potent suppressive effect on macrophage migration. One recent study using an emulsified form of curcumin (nano-emulsified curcumin, (NEC)) administered to mice by oral gavage at 1g/kg reduced levels of the macrophage recruiting factor monocyte chemoattractant protein 1 (MCP-1) and reduced levels of blood monocytes (a precursor to macrophages). NEC also suppressed macrophage recruitment in a murine model for peritonitis and inhibited the migration of macrophage cell lines in vitro.^[178] The suppressive effects of curcumin on macrophage migration were further demonstrated in another mouse model, where adipose tissue was isolated from mice fed a high fat diet and cultured to obtain adipose-tissue conditioned medium. When RAW 264.7 cells (a macrophage cell line) were treated with the conditioned medium, cell migration increased, which was suppressed by the addition of curcumin to the culture medium.^[179] 1 comment on PubPeer (by: Actinopolyspora Biskrensis)

Curcumin has a potent suppressive effect on macrophage activation and recruitment to sites of inflammation.

Curcumin appears to be able to suppress most adhesion molecules investigated, including E-selectin and P-selectin, ICAM-1, VCAM-1, and ELAM-1, the latter three are due to NF-kB inhibition downstream of Akt.^[180][181]

Curcumin can reduce inflammation through a variety of means; preventing pro-inflammatory signals from acting on the nucleus (NF-kB related), reducing the ability of immune cells to get to sites of inflammation (adhesion related), and reducing the exacerbation of already present inflammation by reducing the activity of inflammatory enzymes (COX2, LOX related).

Curcumin is associated with reducing a variety of inflammatory signals, and a lot of them that are associated with arthritis and inflammatory joints.^[182]

When dosed equally (200mg/kg in rats), curcuminoids from turmeric are 4.6-8.3% more effective than the active components of ginger in suppressing inflammation associated with cytokine release in arthritis.^[183] Both herbs are more potent than indomethacin.^[183]

A pilot study over three months has noted that Meriva is able to improve symptoms of osteoarthritis as assessed by WOMAC by 58%^[108] and a later study with 1,000mg turmeric as Meriva tablets (200mg curcuminoids of 75% curcumin) over eight months noted that the total symptoms of knee osteoarthritis were reduced to 41% of baseline values with improvements in pain, stiffness, and physical functioning (as assessed by treadmill testing).^[109]

Orally administrated curcumin appears to be highly effective in reducing symptoms of knee osteoarthritis, with the potency being comparable to other highly efficacious supplements like Boswellia serrata or S-Adenosyl Methionine

One study found that curcumin was able to suppress replication of the Rift Valley fever virus and its fully virulent form (ZH501) in vitro.^[184] A modification to the IKK-β protein (which inhibits IκBα and serves to enhance NF-kB signalling) keeps IKK-β in an active state and exacerbates inflammatory signalling, curcumin can bind to IKK-β and allow IκBα to suppress NF-kB activation and inflammation, which prevents virus replication.^[184]

Curcumin, at 100mg/kg bodyweight in rats, has been shown to preserve testosterone levels when coadministered with a drug (Metronidazole) that causes testosterone reductions and worsens parameters of sperm.^[185]

Protective effects on the testes have also been noted with curcumin in regards to alcohol, where curcumin (80mg/kg bodyweight) was able to preserve testicle structure and testosterone levels despite alcohol consumption,^[186] most likely though preventing the oxidation of ethanol to acetylaldehyde.^[187] Other compounds that damage the testicles and reduce testosterone, but are protected against by curcumin, include excessive chromium levels^[188] and cadmium.^[189]

When looking at the 17beta-HSD3, the final step in testicular testosterone synthesis, curcumin was found to be a noncompetitive inhibitor with an IC₅₀ of 2.3uM, and brought Luteinizing-Hormone stimulated testosterone levels down to 34% of control at a concentration of 10uM.^[37] This effect was not dose-dependent, and concentrations of 1uM were not significantly different from 0.1uM and control cells.^[37]

Curcumin may also possess inhibitory actions against 5-alpha reductase, the enzyme that converts testosterone into the more potent androgen DHT. The IC₅₀ value is reportedly between 5-10uM.^[38]

Given the above two mechanisms (17beta-HSD3 and 5AR inhibition) are anti-androgenic in nature, it would be prudent to observe in vivo effects of curcumin. The only current study on the matter used injections of PEG-curcumin at 0.5mg (giving a C_max of 7ug/mL to then decline to 1ug/mL) noted a decrease in circulating testosterone levels and function of seminal vesicles, although testicle weight did not decline.^[190]

In regards to aromatase, the enzyme that converts testosterone to estrogen (and thus higher activity would mean a more anti-androgenic profile), curcumin does not directly inhibit aromatase in vitro^[191] but appears to reduce the catalytic activity of aromatase (also known as CYP1A) in mice.^[192] Clinical relevance of these effects is not known.

Curcumin appears to have protective effects on testicular functions, but possesses anti-androgenic activity. The concentration required for inhibition is high, but it appears to occur in vivo when it is met; it is uncertain what oral dose is needed for these effects, but it might occur with superloading and increasing bioavailability. Low doses of curcumin may have no adverse effect whatsoever

In regards to possible anti-estrogen effects, the lack of inhibition on aromatase^[191] but potential to reduce catalytic activity of aromatase^[192] suggests some interactions may exist at this stage. One study comparing normal rats versus a Menopausal model (ovariectomized) noted that 10mg/kg oral ingestion in the normal mice was able to reduce circulating estrogen levels.^[193]

100nM of Curcumin is able to act as an agonist at estrogen receptors in MCF7 breast cancer cells, but has low activation of target genes relative to estradiol, although more potent than quercetin and Enterolactone (from Sesamin).^[194] It is possible that Curcumin may act as a Selective Estrogen Receptor Modulator (SERM) and compete for the more potent estradiol, as it has been noted to reduce estrogen-induced cell proliferation elsewhere (was not tied directly to the estrogen receptor in this study).^[195]

In regards to anti-estrogenic activity, limited but theoretical potential of Curcumin to be antiestrogenic via either reducing the effects of aromatase or via acting as a SERM (not yet wholly established)

A pegylated curcumin derivative (similar bioactivity, designed for injections) at 500mg in rats is able to exert estrogenic effects as assessed by sex organs (uterine changes indicative of estrogenicity in females).^[190]

High doses appear to be estrogenic

Curcumin has the ability to protect DNA from oxidation via the heavy metal arsenic^[196], and this protection has been demonstrated in human trials after oral ingestion 1g of a 20:1 curcumin:piperine (black pepper) combination for 3 months.^[197] Blood lymphocytes were the biomarker for DNA damage.

In rats fed a low dose of curcumin (0.03% of the diet), curcumin was able to prevent formation of adducts in hepatic DNA induced by an injection of the carcinogenic benzo(a)pyrene.^[198] Curcumin also prevented adducts in colonic cells when administered at 2% of the diet with meals.^[199]

One of the mechanisms under investigation for chemoprotective effects of curcumin is the inhibitory effect on NF-kB, a protein that can influence genetic coding and transcription when activated. Normally, TNF-a (a pro-inflammatory cytokine) positively influences NF-kB activity and induces cell growth, survival, and inflammation. Curcumin can inhibit the interaction between the two molecules without reducing TNF-a levels, and aside from the inhibition of cytoprotection the elevated levels of TNF-a can induce cellular death via Fas-associated protein cell death and caspase-8.^[200] This mechanism appears to 'sensitize' cells to cell death induced by TNF-a by inhibiting cellular survival via NF-kB^[201][202] and is most likely due to curcumin's ability to prevent or reduce activation of p38 in the face of other activators.^{[203][204][205]}

Curcumin is also able to suppress a transcription factor associated with NF-kB, the Notch family of proteins; this potentiates the suppressive effects on NF-kB, but Notch-1 overexpression is able to act in reverse and attenuate curcumin's suppressive effects on NF-kB.^[41]

Other notable products downstream of NF-kB that are reduced by curcumin administration are cyclooxygenase-2 (COX-2), cyclin D1, adhesion molecules, MMPs, inducible nitric oxide synthase, Bcl-2, Bcl-xL, and tumor necrosis factor (TNF); most of which are associated with cancer metabolism in some manner.^[44][176] Curcumin appears to directly inhibit IKKβ as the method of reducing NF-kB translocation.^[206]

A second possible molecular target for curcumin is the family of proteins known as Specificity Proteins, which include Sp1, Sp3, and Sp4. These proteins are transcription factors involved in cell growth regulation and survival.^[207] 10-25uM of curcumin in vitro was shown to decrease levels of all three of these proteins in a culture of bladder cells which ultimately led to cell death.^[208] The mechanism of action for curcumin was not fully elucidated, but at least partially involved stimulating proteosomal degradation of these transcription factors.^[208]

In a B-CLL cell culture, curcumin was able to induce apoptosis with an IC₅₀ of 5.5uM while its effects in healthy mononucleated (non-cancerous) cells were associated with an IC₅₀ of 21.8uM.^[171]

Secondary to inhibiting expression of the cytokines CXCL1 and CXCL2 (a downstream effect of NF-kB translocation inhibition), curcumin appears to negatively regulate several factors that can lead to prostatic tumor meta-stasis (COX2, SPARC and EFEMP) which can lead to less metastasis in vivo.^[206] As siRNA inhibition of CXCL1/2 also had these effects, this appears to be the metabolic lever of concern.^[206]

Curcumin was able to arrest bladder cell cancer growth in vitro at concentrations of 10-25uM and induce apoptosis.^[208] This effect was also seen in an in vivo xenograft experiment where bladder cancer cells were transplanted into mice which were then given 50mg/kg injections of curcumin every other day for 18 days; this treatment also led to a reduction in tumor growth.^[208]

Autophagy is a longevity associated process involving selective destruction of damaged cellular organelles, sometimes described as cellular housekeeping or maintenance;^[209][210] autophagy appears to activated by many polyphenols^[211] including curcumin, resveratrol, silybin (from milk thistle), quercetin, and catechin (common, but usually known to be a component of the four green tea catechins).

Curcumin (and the metabolite tetrahydrocurcumin ^[212]) appear to induce autophagy via Akt/mTOR/p70S6K and ERK1/2 signalling pathways (inhibition and activation, respectively^[213]) and so far has been detected in glioma,^[213] uterine,^[214] oral cancer,^[215] and leukemic cells.^[212] In drosophilia, flies with mutations in the osr-1, sek-1, mek-1, skn-1, unc-43, sir-2.1, or age-1 genes fail to have life extension from curcumin^[216] although mev-1 and daf-16 appear to be indepednent.^[216]

Beyond the possible roles in longevity, autophagy promotion from curcumin is thought to be protective against gliomas^[217][218] as glioma cells are resistant to apoptosis but readily destroyed by autophagy.^[219][220] Parkinson's pathology may be attenuated with curcumin via preservation of autophagy^[221]

Curcumin appears to induce autophagy secondary to beneficial modulation of mTOR and ERK1/2 signalling (inhibition and activation, respectively) which may underlie both longevity promoting and select anti-cancer effects

In drosophilia, curcumin can induce longevity via antioxidative properties^[216] independent of caloric restriction yet is not complementary with caloric restriction (suggesting acting upon the same pathway)^{[222][223][224]} with most efficacy at 100mM of the feed.^[222] Interesting, administration of curcumin for an entire lifespan has been shown to have a possible suppressive effect on longevity but administration for youth (drosophilia health span, which is about the first 30% of life) prolonged median and maximum lifespan by 49% while administration during middle age (up to 45% of lifespan) had less promotion and administration in older age (senesence) reduced median lifespan by 4% (although maximum still increased 11%).^[222]

Curcumin has been shown to promote longevity independent of caloric restriction in fruit flies, and appears to have more potency in youth than in older individuals (where some suppressive effects on lifespan are noted)

The metabolite of curcumin, tetrahydrocurcumin, appears to promote longevity in male mice by 11.7% at a dietary intake of 0.2% tetrahydrocurcumin, but is dependent on administration as youth.^[225] This study failed to note an effect when mice started curcumin feeding at 19 months (the above results noted with earlier feeding at the 13th month), suggesting the youth requirement extends to mammals.^[225] Longevity enhancement in mice has been noted elsewhere.^[226]

Conversely, one mouse study has noted a failure of curcumin to enhance lifespan when given at similar doses and times in F1 hybrid mice, despite caloric restriction being effective^[227] and lifetime administration of curcumin (0.2%) starting at 4 months has also failed to promote lifespan in UM-HET3 mice.^[228] Assuming a food intake of around 8.55g/45g bodyweight^[229] and body weights around 45g for the majority of the life^{[227][228][225]} an estimated intake of curcumin daily would be 17.1mg (converting to 380mg/kg bodyweight and an estimated human dose^[230] of 22.8mg/kg or 1.5g for a 150lb person)

There is some promising, but currently mixed, evidence to support the role of curcumin in anti-aging. This may follow the same motifs of requiring ingestion of curcumin in youth or at least prior to midlife,

It is an unproven but attractive theory that curcumin works via Chaperone-mediated autophagy (covered on the Longevity page) due to both being prolongevity yet less effective in aged subjects (due to decreasing LAMP-2A expression)

One double-blinded multicenter study noted that, in conjunction with standard therapy for Ulcerative Colitis, 2g of curcumin daily (1g with two different meals) was able to confer significant protection against colonic inflammation and improve symptoms of Ulcerative Colitis for as long as it was used.^[231] Less mortality and relapse was noted with curcumin usage, but the difference was not significant 6 months after cessation of usage like it was for the 6 months it was being used for.^[231] These effects were seen earlier in both Ulcerative Colitis and Crohn's Disease, two human conditions associated with intestinal inflammation.^[232]

Curcumin appears to be able to reduce diet-induced liver fat builded (steatohepatitis) at 0.15% of the diet which is thought to be secondary to activation of AMPK and induction of PPARα.^[233]

At least one human intervention showed that curcumin was able to suppress diabetic nephropathy (related to kidney function) and decrease proteinuria at a dose of 500mg turmeric (22.1mg curcumin) thrice a day with meals for 2 months.^[234] The mechanism of action appears to be suppressing pro-inflammatory cytokines like TGF-b and IL-8.^[234] These benefits have been shown to extend to nephritis associated with lupus at the same dosing protocol in humans.^[124]

Curcumin exerts this apparent kidney protection via suppressing inflammation and related cytokines or mRNA associated with inflammation (MCP-1, IL-8, NF-kB).^[235] Curcumin at 5mg/kg bodyweight (rats) is able to prevent histological changes (related to macrophage infiltration) in kidney structure associated with experimental LPS injections when administered simultaneously^[235] and in delaying the inevitable progression of renal failure.^[236]

Some protective changes are also present, as curcumin can upregulate Heme-Oxygenase 1 in kidney cells partially via NF-kB suppression^[237] and this mechanism is linked to kidney protection effects.^[238]

Demonstrated to have protective effects on the kidneys in clinical settings, and animal studies suggest this may extend to preventative measures as well

Pairing Curcumin with Piperine, a black pepper extract that is also an inhibitor of glucuronidation enzymes in the intestines and liver, is able to increase bioavailability 20-fold (2000% of baseline values) when 20mg piperine is paired with 2g curcumin.^[17]

The pairing of the two has been demonstrated synergistic in attenuating benzo(a)pyrene toxicity in various tissues^[239][240] as well as mitigating DNA damage.^[241]

Interestingly, this synergism does not seem to apply to preventing hypertension induced by L-NAME; both compounds are effective in attenuating high blood pressure from a lack of Nitric Oxide, but their effects are not even additive.^[242]

Turmeric is the spice that curcumin and other curcuminoids were initially derived from as it is the best natural source of curcumin.

Essential oil compounds of turmeric (turmerones) appear to be either additive or synergistic with curcumin in suppressing dextran sulfate sodium induced colitis, with the combination able to abolish the effects of the toxin.^[243]

At least one study has looked at the effects of each ingredient in isolation and the combination, and in regards to its nematocidal effects the four curcuminoids show synergism with each other.^[2]

Ginger and Turmeric are both plants in the same family of plants, and may have related phytonutrient profiles due to this association.

One study investigating the combination of 6-gingerol enhanced ginger and turmeric topical solution (at 3% and 10% respectively) found enhanced wound healing with both compounds in isolation and slightly better recovery with the combination, although not synergistic.^[244]

The combination appears to be more effective than either compound in isolation in suppressing some adverse blood parameters associated with metabolic syndrome, such as high blood sugar and lipids.^[245]

The soy isoflavones, particularly genistein and daidzein, appear to be synergistic with curcumin as it pertains to reducing androgen receptor content and circulating Prostate-Specific Antigen (PSA) levels in otherwise healthy men; insinuating the combination could be useful against prostate cancer.^[246] The dosages used were fairly low in this study, 40mg of isoflavones (66% daidzein, 10% genistein) and 100mg curcumin daily for 6 months, and dropped PSA from 18.8+/-12.4 to 10.2+/-6.2ng/mL.^[246]

One component of Fish Oil, docosahexaenoic acid (DHA), exert synergistic effects in anti-cancer signalling in breast cancer cells which is apparently unique when looking at the mechanisms of either compound in isolation.^[247] This synergism apparently extends over into each compounds anti-inflammatory effects, and this mechanism extends to EPA.^[248]

Curcumin seems to increase DHA concentration in rats by elevating enzymes that are involved in DHA synthesis. Taking curcumin and ALA seems to enhance this effect likely because ALA is a precursor to DHA.^[81]

Curcumin at 1µM concentration in cancerous leukemia cells has been shown to synergistically enhance the actions of Vincristine, an alkaloid isolated from Madagascar Periwinkle (not to be confused with Vinpocetine, from another species of Periwinkle). This occurred in 4 out of 5 samples when Vincristine was incubated at 10uM.^[171]

Curcumin shows synergism with Rolipram (a potent PDE4 inhibitor); PDE4 inhibitors increase cAMP levels via PKA in cancerous leukemia cells.^[171] Additive in 1 out of 5 tested samples and synergistic in the other four.^[171]

Hydroxylated phenolic compounds are known to interfere with iron absorption via binding iron (in a process known as chelation), which appears to apply to curcumin. Curcumin has been noted to interact with iron in cells (contributing to some effects in the body^[249][250]) and in mice given curcumin (0.2-2.0% of the diet; highest dose correlating to a human dose of 8-12g) alongside a low iron diet (as ferric citrate) the addition of curcumin appeared to exacerbate deficiency symptoms.^[251] This study noted that the higher dose of curcumin only negatively affected the low iron group (around one tenth the standard intake) with normal and higher intakes of iron not being significantly hindered.^[251]

500mg of turmeric, a dose commonly used to spice foods, does not appear to appreciably affect iron absorption.^[252]

Curcumin supplements may be able to bind to iron in the intestines and reduce its absorption, an effect that may not apply to low doses of turmeric applied as a food seasoning and may not be relevant when iron content of the diet is reasonable (only when iron is low do high doses of curcumin seem to interfere with its effects)

Garcinol is a polyisoprenylated benzophenone chalcone molecule that is found in Garcinia Indica, a plant in the mangosteen family of fruits.^[253] It was found synergistic in inducing apoptosis in pancreatic tumor cells with an apparent synergism 2-10 fold higher than the sum of the two.^[254]

Although it has been suggested that curcumin exhibits selective toxicity toward cancer cells without affecting healthy cells, an in vitro study demonstrated that curcumin can induce apoptosis in healthy human T cells at a rate comparable to cancerous leukemia cells.^[255] This effect occurred without any direct DNA damage to the T cells, but instead through activation of the extrinsic p53-independent apoptotic pathway.^[255] This effect was seen to some degree at a curcumin concentration of 15 μM, but was most pronounced at a curcumin concentration of 50 μM.^[255] For comparison, a 3.6 gram oral dose of curcumin raised plasma cucrumin levels to 11.1 nM in one study.^[256] Another multiple dosing study of 10 g of a curcumin found that peak blood levels (not average) reached around 5 μM, although much of it was conjugated after passing through the liver.^[257]

An in vitro study has indicated that curcumin may have effects at high doses that could cause immunosuppression in theory.

In 1993, the National Toxicology Program (USA) reported the toxic and carcinogenic properties of turmeric oleoresin, the organic form of turmeric, which contains a percentage of curcumin (79–85%) similar to that of commercial grade curcumin. Rats and mice were fed diets containing 1,000 to 50,000 ppm of turmeric oleoresin for 3 months and 2 years, and investigators found increased incidences of ulcers, hyperplasia, and inflammation of the forestomach, cecum and colon in male rats and of the cecum in female rats in the 2-year feeding studies. There was an increased incidence of thyroid gland follicular cell hyperplasia in female mice and equivocal evidence of carcinogenic activity in female rats, female mice, and male mice. These conclusions were based on increased incidences of clitoral gland adenomas in female rats, hepatocellular adenomas in female mice, and carcinomas of the small intestine and hepatocellular adenomas in male mice. The increased incidence of carcinomas of the small intestine was observed in mice taking average daily doses of curcumin of ∼0.2 mg/kg.^[258] Additionally, 0.2% curcumin was given to rats over six months resulting in a reduction of iron. However, according to the author, this could be due to long-term supplementation and Western-type diet.^[259]

Two human studies have found that does of up to 12 g of curcumin are safe and well tolerated.^[13][260] When using enhanced formulations to increase circulating levels of curcumin, 1g of MERIVA (Curcumin bound to lecithin) over 8 months is not associated with any side-effects.^[109]

Human studies of curcumin doses up to 12g daily have not found any side-effects.

While the study discussed above did not see DNA damage in T cells, earlier in vitro studies using similar doses of curcumin have found DNA damage linked to curcumin in both peripheral blood lymphocytes^[261] and gastric mucosal cells.^[262] The authors of the study in T cells suggest that the difference between the two studies could be due to the different populations of cells studied in the two experiments, and perhaps the different methods used in assaying DNA damage.^[255]

Another in vitro study in a human fibrosarcoma line has also found evidence of DNA damage starting at curcumin concentrations of 3-8 μM and apoptosis induced at concentrations around 10 μM.^[263]

In vitro experiments have found that curcumin may damage the DNA of human cells.

Curcumin also caused damage and inhibited DNA repair genes including ATM, TR, BCRA1, 14-3-3sigma, DNA-PK, and MGMT mRNA after 48 hours of treatment in mouse-rat hybrid retina ganglion cells.^[264]

In human hepatoma G2 cells, curcumin exhibited dose-dependant damage in both the mitochondrial and nuclear genomes where the mitochondrial damage was more extensive. At higher doses, curcumin damaged DNA.^[265]

An in vitro study examined the effects of curcumin on stages of mouse embryo development. Exposure to 24 μM of curcumin at the early age stage (blastocyst stage) was lethal to all embryos; this stage is equivalent to 3-8 days of gestation in vivo.^[266] Curcumin decreased in vivo mouse oocyte maturation, in vitro fertilization and decreased fetal weight.^[267]

In mice, IV curcumin-PEG reduced live births in mature females and reduced testicular testosterone concentrations and spermatogenesis in mature male mice.^[268][269] Alternatively, a two-generation reproduction study in mice found no effects on reproduction other than a small body weight reduction in pups fed 10,000 ppm (847-959 mg/kg body weight) of curcumin orally.^[270]

The use of IV curcumin may lead to a decrease in fetal weight.

There have been no clinical trials conducted in humans showing toxicity of curcumin. However, examining a 90-day supplementation in rats demonstrated that overdose or long term intake of curcumin could initiate oxidative stress, inflammation, and metabolic disorders possibly causing liver injury.^[271] Additionally, data collected between 2004 and 2013 among 8 US centers in the Drug-Induced Injury Network revealed that 15.5% of hepatotoxicity cases were caused by herbal and dietary supplements. Out of the 130 related cases of liver injury due to supplements, 65% were from non-bodybuilding supplements that occurred most often in Hispanic/Latinos compared to non-Hispanic whites and non-Hispanic blacks. Of the 217 supplement products implicated in liver injury, turmeric was among the 22% of the single- ingredient products.^[272]

Curcumin may cause hepatotoxicity.

In healthy human subjects, dosages of 6g daily have been associated with minor flatulence and a yellowing of the stool, both of which stopped after supplement cessation.^[273] However, it is generally recognized that curcumin does not cause significant short-term toxicity at doses up to 8 g/day.^[13][14] This dose of curcumin is not completely harmless in non-healthy populations; one clinical trial showed that in cancer patients who ingested curcumin at doses ranging from 0.45 to 3.6 g/day for 1–4 months, some adverse effects included nausea and diarrhea and an increase in serum alkaline phosphatase and lactate dehydrogenase.^[274] Doses of curcumin ranging from 500 mg/day to 12 g/day may also produce additional mild side effects, including headache and skin rash.^[14] When given 4 g/day of curcumin, side effects included diarrhea, abdominal distension, and gastroesophageal reflux disease (GERD).^[275] Curcumin has been used at doses higher than 8 g/day in situations in which no effective therapies exist (e.g. advanced pancreatic cancer and other conditions seen in the above-mentioned studies), as toxicity is acceptable in these situations, but no human studies have been conducted to date to test the dose levels which cause long-term toxicity.^[276]

There have also been many cases reported of contact dermatitis with curcumin. However, these are usually in occupational setting where other airborne exposures could have contributed or there are other exposures in general that could have contributed to the dermatitis.^{[277][278][279][280][281][282]}

Curcumin may cause minor GI effects or dermatitis.

A 68-year-old woman with a history of breast and thyroid cancer presented with yellow discoloration on the soles of her feet after ingestion of a 500-mg capsule of turmeric for four months (curcumin is a yellow pigment which is present in turmeric). After cessation of the drug, the yellow color disappeared.^[283]

A case reported contact dermatitis with curcumin in the occupational setting where there could have been other exposures that contributed to the dermatitis.^[277] In addition, two patients reported allergic contact dermatitis after using curcumin-containing chlorhexidine solutions.^[278] Other cases have reported contact dermatitis from curcumin.^{[279][280][281][282]}

There has also been a case of anaphylaxis reported of a woman eating turmeric on three occasions. ^[284]