Curcumin Formulations for Better Bioavailability: What We Learned from Clinical Trials Thus Far?

The straightforward ways to address the limitation(s) of curcumin are to enhance its bioavailability, shield it from oxidation and metabolism, and increase its ability to target diseased tissues and/or organs. 18 , 47 One of the main strategies for increasing curcumin’s bioavailability is to utilize adjuvants that can inhibit or delay its metabolism. 18 , 63 Other intriguing innovative formulations that appear to offer longer circulation, improved permeability, and resistance to metabolic processes include liposomes, micelles, nanoparticles, and phospholipid complexes. 18 , 42 , 64 These bioavailable or bioenhanced formulations of curcumin are generally categorized into three different formulations. The classic example of first-generation formulation includes the use of significant amounts of adjuvants such as piperine from black pepper, turmeric oils, or any other natural compounds that were included to inhibit the essential detoxification enzymes such as hepatic aryl hydrocarbon hydroxylase, cytochrome P450, mixed-function oxygenases, and UDP-glucuronyltransferase. 18 , 63 , 65 , 66 The first-generation formulation enhances the absorption time of curcumin by inhibiting or delaying its metabolism. The formulations such as curcumin–piperine, C3 complex–piperine (C3 complex/bioperine), turmeric fiber or oil with curcumin, BCM-95, and Cureit belong to the first-generation category. 44 In the second-generation, emulsifiers such as carbohydrate complexes, polyethoxylated hydrogenated castor oil, lipid complexes, phospholipid complexes, polysorbates, water-dispersible nanopreparations, and spray drying were used to increase the solubility of curcumin. These included BioCurc, Cavacurcmin, CurcuWIN, Hydrocurc, Meriva, Nanocurcumin, Novasol, Theracurmin, and Turmipure Gold. 44 Although increases in plasma curcuminoids levels occur primarily through their conjugated metabolites (glucuronides and sulfates), numerous studies have shown that these conjugated metabolites lack biologically significant effects because of the large size, quick renal elimination, limited membrane, and blood–brain barrier (BBB) permeability. 44 , 67 , 68 For this reason, delivering curcumin in its free form (naturally unconjugated) is essential to maximize its therapeutic effects. The third-generation curcumin formulations including Longvida and CurQfen have solved the issue of “free” curcuminoids bioavailability, membrane permeability, and cellular uptake without the use of artificial emulsifiers like polysorbates. 44 This section details the clinical safety and efficacy of all three generations of curcumin formulations. Different formulations and their composition are listed in Table 1 . Abbreviation: CLDM, Curcumin liquid droplet micromicellar formulation; DHA, Docosahexaenoic acid; EPA, icosapentaenoic acid; HCl, Hydrogen chloride. Early attempts to increase absorption of curcumin included the addition of turmeric oil (BCM-95; BioCurcumax; Curcugreen), a small amount of piperine (curcumin C3 complex) to stimulate the gastrointestinal system, prevent curcumin efflux and inhibit hepatic and intestinal glucuronidation, or as a turmeric oleoresin (Curcugen). 18 , 44 , 55 All of these formulations have shown incremental improvement in curcumin absorption and efficacy clinically ( Table 2 , Figure 1 ). For instance, supplementation with curcumin/piperine (500 mg-2g/day curcumin plus 5–20 mg/day piperine) formulation resulted in a significant reduction in ubiquitin, muscle atrophy F box (MAFbx)/atrogin-1, chymotrypsin-like protease, interleukin 2 (IL-2), TNF-α, INF, IL-6, IL-10, and enhancement in bioavailability, safety, tolerability, and delayed onset of muscle soreness in healthy subjects without adverse side effects. 55 , 69 , 70 Abbreviations: Aa, Aggregatibacter actinomycetemcomitans ; ACPA, Anticitrullinated protein antibody; ACR, American College of Rheumatology; ACT, Asthma control test; ADPKD, Autosomal dominant polycystic kidney disease; AFU, Alpha-L-fucosidase; ALDH, Aldehyde dehydrogenase; ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; AOPPs, Advanced oxidation protein products; APACHE II, Acute physiology, and chronic health 370 evaluation II; AST, Aspartate aminotransferase; BALP, Bone-specific alkaline phosphatase; BANA, N -benzoyl- dl -arginine-2-naphthylamide; BAP, Biological antioxidant potential; BAX, Bcl-2 associated X-protein; BCL-2, B-cell lymphoma 2; BDNF, Brain-derived neurotrophic factor; BMD, Bone mineral density; BMI, Body mass index; BOP, Bleeding on probing; BPH, Benign prostatic hyperplasia; BSE, Boswellia serra extract; BVAS, Birmingham vascular activity score; CA 19–9, Carbohydrate antigen 19–9; CAL, Clinical attachment level; CAT, Catalase; CD40L, Cluster of differentiation 40 ligand; CD133, Cluster of differentiation 133; CDAI, Crohn’s disease activity index; CDSS, Calgary depression scale for schizophrenia; CEA, Carcinoembryonic antigen; CFU, Colony forming unit; CGI-I, Clinical global impressions-improvement score; CGI-S, Clinical global impressions-severity score; CGRP, Calcitonin gene related peptide; CK, Creatinine kinase; CKD, Chronic kidney disease; CK-MB, Creatinine kinase, MB fraction; CLDM, Curcumin liquid droplet micellar formulation; CLDQ, Chronic liver disease questionnaire; CMC, Consecutive menstrual cycle; Coll2–1, Serum type 2 collagen peptide; COPD, Chronic obstructive pulmonary disease; COX-2, Cyclooxygenase 2; COVID-19, Coronavirus disease 2019; CP, Curcumin phytosome formulation; CpAT, COPD assessment test; CRP, C-reactive protein; CRT, Central retinal thickness; CS, Standardized curcumin; CTR, Curcumin formulation with volatile oils of turmeric rhizome; CTx, C-terminal cross-linking telopeptide of type I collagen; Cu, Copper; CUA, Combined unique activity; Cur, Curcumin; CVD, cadiovascular disease; CXCl1, CXC motif chemokine ligand 1; DAS, Disease activity score; DASS-21, Depression, anxiety, stress scale-21; DB, Direct bilirubin; DBP, Diastolic blood pressure; dFLC, Difference between clonal and nonclonal free-light chain; DFP, Deferiprone; DLQI, Dermatology life quality index; DMD, Duchenne muscular dystrophy; DNA, Deoxyribonucleic acid; DOMS, Delayed onset muscle soreness; DSPN, Diabetic sensorimotor polyneuropathy; EEG, Electroencephalogram; EGF, Epidermal growth factor; EPA, Eicosapentanoic acid; ESR, Erythrocyte sedimentation rate; FA, Fatty acid; FEV, Forced expiratory volume; FF score, Fibromyalgia and fatigue rating score; FFA, Free fatty acids; FDDNP, -(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile; FIHOA, Functional index for hand osteoarthritis; FLC, Free-light chain; FLI, fatty liver index; FLIP, FLICE inhibitory proteins; FMD, Brachial artery flow-mediated dilation; FOXP3, Forkhead box P3; FPG, Fasting plasma glucose; FPI, fasting plasma insulin; FSH, Follicular stimulating hormone; FSHD, Facioscapulohumeral dystrophy; FVC, Forced vital capacity; GGT, Gamma-glutamyl transferase; GI, Gingival index; GLA, Gamma linoleic acid; GM-CSF, Granulocyte-macrophage colony stimulating factor; GOT, Glutamate-oxaloacetate transaminase; GPT, Glutamate pyruvate transaminase; GPx, Glutathione peroxidase; GSH, Glutathione; GSK-3β, Glycogen synthase kinase-3 beta; GSRS, Gastrointestinal symptom rating scale; GTP, Guanosine triphosphate; H 2 O, Water; H 2 O 2 , Hydrogen peroxide; HAM/TSP, HTLV-1-associated myelopathy/tropical spastic paraparesis; Hb, Hemoglobin; HbA1c, Hemoglobin A1c; HDL, High density lipoprotein; HDL-C, HDL-cholesterol; HDR, Headache daily results; HIT-6, Headache impact test 6; HNC, Head and neck cancer; HOMA-β, Homeostatic model assessment for pancreatic beta cell function; HOMA-IR, Homeostatic model assessment for insulin resistance; hs-CRP, High-sensitivity C-reactive protein; HSC, Hematopoietic stem cell; HSI, Hepatic steatosis index; HTLV-1, Human lymphotropic virus type-1; IAPP; Islet amyloid polypeptide; IBD, Inflammatory bowel disease; IBS, Inflammatory bowel syndrome; ICAM, Intracellular adhesion molecule; IgM, Immunoglobulin M; IFN, Interferon; iFLC, Involved free-light chain ratio; IFNγ, Interferon gamma; IIEF-5, 5-item version of the international index of erectile function; IL, Interleukin; iNOS, Inducible nitric oxide synthase; IPSS, International prostate symptom score; IPSS-S, International prostate symptom score-storage sub score; IPSS-V, International prostate symptom score-voiding sub score; IR, Insulin resistance; JKOM, Japanese knee osteoarthritis measure; JOA, Japanese orthopedic association, LAP, Lipid accumulation, product; LDH, Lactate dehydrogenase; LDL, Low density lipoprotein; LDL-C, LDL cholesterol; LDLR, LDL receptor; LDSI, liver disease symptom index; LGMD, Limb girdle muscular dystrophy; LH, Leutinizing hormone; LNAA, Large neutral amino acids; LOS, Length of hospital stay; LPA, Lipoprotein A; LV, Left ventricular; MAFbx, Muscle atrophy F-box; ME/CSF, Myalgic encephalomyelitis/chronic fatigue syndrome; MCP-1, Monocyte chemoattractant protein-1; MDA, Malondialdehyde; MDS-UPDRS, Movement Disorder Society sponsored revision of the Unified Parkinson’s Disease Rating Scale; MELD, Model for end-stage liver disease; MetS, Metabolic syndrome; MGI, Modified gingival index; MHb, Methemoglobin; MI, Myocardial infarction; MIDAS, Migraine disability assessment; MIF, Monocyte inhibitory factor; miRNA, Micro RNA; MLH1, MutL homologue 1; MMP, Matrix metalloproteinase; MN, Micronuclei; MPO, Myeloperoxidase; MSM, Methylsulfonyl methane; MSH2, MutS homologue 2; MSQ, Migraine-specific quality of life; MVC, Maximal voluntary contraction; NAC, N -acetylcysteine; NAFLD, Nonalcoholic fatty liver disease; NAIOS, Nutraceuticals with anti-inflammatory, oxidative and nitrosative stress; NF-κB, Nuclear factor kappa B; NLC, Nanostructured lipid carriers; NMF, Natural moisturizing factor; NO, Nitric oxide; NO-adducts, Nitroso-adducts; NP, Nanoparticle; Nrf2, Nuclear factor erythroid 2-related factor 2; NTBI, Nontransferrin bound iron; NT-proBNP, N-terminal pro hormone B-type natriuretic peptide; NUTRIC, Nutrition risk in critically ill; OLP, Oral lichen planus; OM, Oral mucositis; ORR, Objective response rate; OS, Overall survival; OSDI, Ocular surface disease index; OSE, Oxidative specific epitopes; OSF, Oral submucous fibrosis; PAB, Pro-oxidant antioxidant balance; PANSS, Positive and negative symptoms scale; PASI, Psoriasis area severity index; PBE, Pine bark extract; PBI, Papillary bleeding index; PCI, percutaneous coronary intervention; PCOS, Polycystic ovary syndrome; PCr/Pi, Phosphocreatine to inorganic phosphate ratio; PCS, P-cresyl sulfate; PCT, Procalcitonin; PD, Pocket depth; PDT, Photodynamic therapy; PFS, Progress free survival; PGC-1α, Peroxisome proliferator and activated γ receptor coactivator 1 alpha; PGE2, Prostaglandin E2; PI, Plaque index; PhK, Phosphorylase kinase; Pg, Porphyromonas gingivalis ; PMS, Premenstrual syndrome; PPARγ, Peroxisome proliferator-activated receptor gamma; PPBS, Postprandial blood sugar; PPD, Probing pocket depth; ppFEV 1 , Predicted forced expiratory volume in one second; PPFT, Periprostatic fat thickness; PON1, paraoxonase-1; PRL, Prolactin; PSA, Prostate-specific antigen; PSQI, Pittsburgh sleep quality index; PSST, PMS screening tool; PTH, Parathyroid hormone; PV, Prostatic volume; Q max , maximum flow rate; QoL, Quality of life; QUICKI, quantitative insulin sensitivity check index; RA, Rheumatoid arthritis; RAS, Recurrent aphthous stomatitis; REEDA, Redness, edema, ecchymosis, discharge, approximation; REU, Reticular erosive ulcerative score; RF, Rheumatoid factor; rFLC, Free-light chain ratio; RISR, Radiation induced skin reactions; ROM, Range of motion; RORγ t, Retinoic-acid-receptor-related orphan nuclear receptor gamma; ROS, Reactive oxygen species; RT, radiotherapy; SBI, Sulcus bleeding index; SBP, Systolic blood pressure; SCCAI, Simple clinical colitis activity index; sCD40L, Cluster of differentiation 40 ligand; SGRQ, St. George respiratory questionnaire; SF-36, Short form healthy survey; SJC, Swelling joint count; SM, Sulfur-mustard; SMCs, Subjective memory complaints; SOD, Superoxide dismutase; SODA, Severity of dyspepsia assessment; SOFA, Sequential organ failure assessment; Sp, Substance P; SPEED, Standard patient evaluation of eye dryness; SRT, Selective reminding test; SSQOL, Stroke specific quality of life; sVCAM, Soluble vascular cell adhesion molecule; T2D, Type 2 diabetes mellitus; TAC, Total antioxidant capacity; TBARS, Thiobarbituric acid reactive substances; TBUT, Tear-film breakup time; TBX21, T-box transcription factor 21; TC, Total cholesterol; TEWL, Transepidermal water loss; Tf, Tannerella forsythia ; TG, Triglyceride; TGF-β, Transforming growth factor-beta; TIBC, Total iron binding capacity; TJC, Tender joint count; TLC, Total lymphocyte count; TLR4, Toll-like receptor 4; TN, Total nitrite; TNF-α, Tumor necrosis factor alpha; TRP, Tryptophan; TRR, Transferrin receptor; TURB, Transurethral resection of bladder; TURP, Transurethral resection of prostate; UGT, Uridine diphosphate glucuronosyltransferase; uDPYD, Urinary deoxypyridinoline; UIBC, Unsaturated iron-binding capacity; VAS, Visual analog scale; VCAM, Vascular cell adhesion molecule; VEGF, Vascular endothelial growth factor; VO 2 max, Maximal oxygen consumption; WBC, White blood cells; WEC, Hot water extract; WPI; Whey protein isolate; WOMAC, Western Ontario and McMaster Universities osteoarthritis index; Zn, Zinc Broad range of biological activities and molecular mechanisms of first-generation curcumin formulations. The first-generation formulations have shown excellent enhancement in the absorption and cellular uptake of curcumin. Various phase I/II clinical trials demonstrated that these formulations are effective against arthritis, cancer, COVID-19, MetS, NAFLD, and pulmonary diseases by modulating inflammatory cytokines, oxidative stress-related molecules, liver enzymes, and lipid profiles. The figure was created using BioRender.com . In patients with arsenic-induced oxidative stress, this formulation effectively decreased DNA damage, ROS generation, lipid peroxidation, and improved antioxidant capacity. 71 In another study, the administration of curcumin (1.5 mg/day) and piperine (5 mg/day) for 2 months resulted in the efficient alleviation of IL-6 and improvement in forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and asthma control test scores in bronchial asthma patients compared to those who received regular asthma drugs. 72 Moreover, this formulation (1–1.5 g/day curcumin with 5 mg/day piperine) reduced the symptoms including weakness, dry cough, sore throat, sputum cough, ague muscular pain, headache, dyspnea, deterioration, and hospitalized duration in COVID-19 patients without side effects. 73 , 74 Besides, the treatment with this formulation significantly improved mouth opening flexibility, cheek flexibility, and tongue protrusion capacity and suppressed burning sensation in oral submucous fibrosis (OSF) patients compared to placebo (starch and lactose capsules). 75 In another randomized placebo-controlled trial, this formulation was shown to effectively augment GSH levels and decrease erythrocyte MDA levels in pancreatitis patients with no adverse side effects. 76 In addition, it also reduced leptin and TNF-α levels and increased adiponectin levels in T2D patients over 12 weeks of treatment. 77 Curcumin formulation with piperine and ginger ameliorated erythrocyte sedimentation rate (ESR), tender joint count (TJC), swelling joint count (SJC), disease activity score (DAS), and relieved pain and inflammation in rheumatoid arthritis patients. 78 Another study demonstrated that curcumin along with piperine and taurine remarkably suppressed IL-10, AST, ALT, α-L-fucosidase, and miR-21 levels and improved overall survival in hepatocellular cancer patients. 79 Another curcumin/piperine tablet containing other ingredients including propranolol, aliskiren, cilazapril, celecoxib, aspirin, and metformin for 10 weeks enhanced the median survival rate in glioblastoma patients. 80 This treatment was also found to be safe with minimal side effects including indigestion and marginal bradycardia (propranolol effect). 80 Another study employed two tablets of curcumin–spirulina– Boswellia extract (each tablet with 400 mg curcumin, 50 mg spirulina, and 50 mg Boswellia extract) to patients with benign thyroid nodules and reported the reduced nodule area without adverse side events. 81 Also, curcumin and fennel essential oil (FEO) tablets (2 capsules, a total of 84 mg curcumin with 50 mg FEO) caused substantial relief in symptoms and improved quality of life in inflammatory bowel syndrome (IBS) patients. 82 Moreover, the administration of three Oxy-Q tablets (each tablet containing 480 mg curcumin with 20 mg quercetin) repressed polyp size and number without side effects in familial adenomatous polyposis patients (FAP). 83 In another study, a novel curcumin formulation administered as 2 capsules per day (each capsule containing 30 mg curcumin, 100 mg bovine lactoferrin, 15 mg zinc acetate, 100 mg lysolecithin), 600 mg N -acetylcysteine (NAC), and 20 mg pantoprazole inhibited serum pepsinogens, decreased disease severity and improved the cure rate in patients infected with Helicobacter pylori ( H. pylori ). 84 In addition, rectal suppositories of 350 mg curcumin and 80 mg Calendula extract (1 suppository/die, for 1 month) significantly inhibited inflammation compared to those who received a placebo suppository (identical to treatment) without side effects. 85 Yet another formulation, Curcumin Forte (95% curcumin plus 5% piperine formulation) remarkably increased positive and negative symptoms scale (PANSS) and reduced Calgary depression scale for schizophrenia (CDSS) scores in schizophrenic patients with no reported adverse side effects compared to identical colored and sized placebo tablets. 86 Further, washing the mouth with curcumin and chitosan solution (10 mL) three times a day for 2 weeks inhibited Candida activity and achieved a complete response in 80% of denture stomatitis patients. 87 In another study mouthwash containing essential oils and curcumin (MEC) effectively reduced ESR, rheumatoid factor (RF), CRP, anticitrullinated peptide antibody (ACPA), plaque index (PI), pocket depth (PD), clinical attachment level (CAL) and also was found to be well-tolerated in rheumatoid arthritis (RA) patients with periodontitis. 88 C3 complex/bioperine, a curcuminoid extract containing curcumin, desmethoxycurcumin, and bisdemethoxycurcumin in combination with bioperine (piperine), has been demonstrated to be anti-inflammatory, antidiabetic, and antiarthritic agent. 89 − 91 C3 complex/bioperine administered at the dose of 500 mg to 12 g per day for the duration of 7 days to months was safe, tolerated, and effective without any serious side effects. 40 , 89 , 90 , 92 − 104 Moreover, randomized clinical trials have shown that administration of C3 complex/bioperine (1 g/day of C3 complex plus 10 mg/day of bioperine) in patients with metabolic syndrome effectively reduced C-reactive protein (CRP), glucose, glycated hemoglobin (HbA1c), lipoprotein a (LPA), low-density lipoprotein cholesterol (LDL-C), nonhigh-density lipoprotein cholesterol (non-HDL-C), malondialdehyde (MDA), total cholesterol (TC), triglycerides (TG), systolic blood pressure (SBP), diastolic blood pressure (DBP), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), leptin, tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β), and upregulated adiponectin, HDL-C, and superoxide dismutase (SOD) levels compared to placebo containing the same amount of lactose and bioperine in a matched shape, size and color. 92 − 95 The treatment with this formulation was also shown to improve nonalcoholic fatty liver disease (NAFLD) by decreasing alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), hematocrit, erythrocyte sedimentation rate (ESR), iron, hemoglobin (Hb), LDL-C, TC, MCP-1, TNF-α, and epidermal growth factor (EGF). 96 , 97 Besides, C3 complex/bioperine formulation remarkably reduced TG, interleukin 1 beta (IL-1β), interleukin 4 (IL-4), PAB and vascular endothelial growth factor (VEGF), and enhanced zinc/copper (Zn/Cu) ratio in obese subjects. 98 , 105 − 107 In addition, in randomized double-blind clinical trials, oral intake of this formulation (1.5 g/day) for 6 weeks was shown to reduce MDA and oxidative stress levels and upregulated SOD and glutathione (GSH) levels in osteoarthritis patients. 91 , 108 Interestingly, in clinical trials administration of C3 complex (1–1.5 g/day) with bioperine (10–15 mg/day) for 4 weeks showed increased levels of glutathione peroxidase (GPx), SOD, catalase (CAT), and decreased levels of substance P (Sp), visual analog scale (VAS), pruritus severity, dermatology life quality index (DLQI) scores, interleukin 8 (IL-8), high sensitivity CRP (hs-CRP), calcitonin-gene related peptide (CGRP), FEV1, FVC, IL-6, TNF-α, TGF-β, MCP-1, St. George respiratory questionnaire (SGRQ) score and increased glutathione and COPD assessment test (CpAT) scores in patients with sulfur-mustard induced chronic pruritis and pulmonary complications. 89 , 99 , 109 , 110 Ingestion of this complex also showed antidiabetic effects by reducing glucose, C-peptide, HbA1c, ALT, Non-HDL-C, LPA, MDA, and AST and increasing total antioxidant capacity (TAC) and SOD levels in diabetic patients. 90 , 104 , 111 Further, this regimen showed a promising effect in treating critically ill traumatic brain injury (TBI) patients by increasing GPx levels and suppressing leptin, IL-6, CRP, MCP-1, TNF-α, acute physiology, and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, and nutrition risk in critically ill (NUTRIC) score. 100 , 101 It was also shown to be effective in treating premenstrual syndrome (PMS) and dysmenorrhea with a remarkable reduction in AST, direct bilirubin, dysmenorrhea pain, and PMS screening tool (PSST) score and enhancement in vitamin D levels. 102 , 103 This C3 and piperine formulation, however, showed no significant effect on pro-oxidant antioxidant balance (PAB) in NAFLD patients after 8 weeks treatment. 112 Moreover, turmix tablet (300 mg curcumin plus 5 mg piperine) with or without turmix mouthwash for 12 weeks reduced burning sensation, improved mouth opening capacity, and tongue protruding ability in OSF patients. 113 , 114 However, this combination was shown to provide no effects on paracetamol metabolization in healthy subjects. 115 BCM-95 is a novel well established curcumin formulation wherein curcumin is complexed with essential oils from turmeric rhizome, rice flour, vegetable cellulose, vegetable stearate, and silica. 116 BCM-95 has been shown to provide improved bioavailability and increased retention time of curcumin compared to curcumin-lecithin and curcumin-piperine formulations in healthy subjects. 117 Several clinical trials have proven the safety, tolerability, and efficacy of BCM-95 in humans. 117 − 121 BCM-95 is effective in treating multiple myeloma, multiple sclerosis, NAFLD, and prediabetic conditions by reducing BMI, weight, TC, TG, low-density lipoprotein (LDL), inflammatory molecules such as NF-κB, IL-6, TNF-α, and VEGF, liver enzymes including AST and ALT, diseases lesions, and hepatic fibrosis. 118 − 121 BCM-95 treatment increased high-density lipoprotein (HDL), overall remission rate, and physical activity in these patients. 118 − 121 In another study, oral intake of an active natural ingredient formulation (A total of 830 mg formulation consisting of fish oil 250 mg, phosphatidyl choline concentrated sunflower oil 150 mg, silymarin 75 mg, choline bitartrate 35 mg, curcumin 35 mg, D-α-tocopherol 10 mg) capsules (2 capsules/day) for 3 months was shown to be effective in decreasing liver enzymes such as AST, in patients with NAFLD compared to those who received tablet containing the same amount of choline and formulation excipients. 122 This shows that efficacy is attributed to curcumin but not to choline and hence, the anti-NAFLD effect is a stand-alone effect of administered first-generation curcumin formulation. 122 Although, ALT, and gamma-glutamyl transferase (GGT) levels were decreased in these patients after curcumin treatment the reduction was not found to be statistically significant. This formulation has also been shown to be safe and well-tolerated with no reported adverse side effects. 122 It was also shown that administration of another dietary supplement product CartiJoint Forte, a formulation of BCM-95, chondroitin sulfate, and glucosamine hydrochloride, resulted in a significant reduction in VAS score and WOMAC score in osteoarthritis patients with no noticeable adverse events compared to placebo group. 123 Another two novel BCM-95 formulations, CuraMed (552–578 mg of BCM-95 extracted in ethanol 99% (v/v) and 100% ethyl acetate, 49–52 mg volatile oil from C. longa containing 22–23.4 mg aromatic turmerone, and inactive excipients) and CuraMin (350 mg BCM-95, 150 mg of Boswellia serrata Roxb. ex Colebr gum resin extract corresponding to 75% boswellic acids and 10% 3- O -acetyl-11-keto-boswellic acid) have been demonstrated to ameliorate the pain, stiffness, degree of difficulty in moving the knee joint, and to enhance the physical performance in osteoarthritis patients. The placebo used in this study contained calcium phosphate, FD&C yellow 5, FD&C yellow 6, gelatin, magnesium stearate, maltodextrin, silica oxide, and titanium oxide. Both the formulations were found to be safe, well-tolerated, and did not show any serious adverse side effects on these patients. 124 Moreover, CuraMed also reduced postoperative discomfort and pain in periodontitis patients compared to control group who received mefenamic acid. 125 In another study, Curcugreen (dry turmeric rhizomes extracted with ethyl acetate called turmeric oleoresin, precipitated and combined with turmeric essential oil) alone or in combination with zinc was found to be effective in treating obesity by reducing body mass index (BMI), fasting plasma glucose (FPG), HbA1c, insulin, insulin resistance and increasing physical performance capacity compared to zinc with lactose as placebo tablets. 126 Besides, oral spray formulation of curcumin, ArtemiC containing 12 mg artemisinin, 40 mg curcumin, 30 mg frankincense, and 120 mg vitamin C in 1 mL spray when used twice a day for 2 days enhanced the clinical improvement, oxygen saturation and decreased fever and hospitalized duration in coronavirus disease 19 (COVID-19) patients compared to placebo spray (containing the same solvent of ArtemiC except for the active ingredients). 127 No reported adverse effects were observed in this trial. 127 Moreover, curcumin bioactive capsules containing 500 mg/day rutin, 1.5 g/day fish oil (18% EPA and 7% DHA), 50 mg/day curcumin (95% curcuminoids) along with 20 g whey protein isolate (WPI) for 12 weeks has been shown to ameliorate age-related sarcopenia as evidenced by enhanced gait speed and knee extension strength without any serious side effects. 128 In another study, CUC-1 formulation (curcumin with paclitaxel) administered intravenously (300 mg solution/week) increased physical performance and objective responsive rate (ORR) in metastatic breast cancer patients (MBC) (n = 150). 129 However, this intravenous infusion resulted in anemia and hematological grade 3–5 side effects in a few patients (n = 5). 129 Oral intake of two Coltect tablets (each tablet containing 500 mg curcumin, 250 mg green tea, and 100 μg selenium) per day for 8 weeks enhanced the remission rate and suppressed the clinical activity of ulcers in ulcerative colitis patients. 130 This formulation was also found to be safe and well-tolerated among these patients. 130 Another formulation, Curcumall (curcumin C3 95%, turmeric, and ginger dissolved in glycerin and 0.4% alcohol) was shown to have no adverse effects on patients with oral lichen planus (OLP). 131 Additionally, curcumin dispersion amorphous formulation (500 mg/day) was reported to significantly reduce LDL-C, TG, AST, ALT, glucose, and HbA1c, and was safe, well-tolerated, and had no side effects in NAFLD patients. 132 Another study showed that curcumin capsules (Theravalues Co. Tokyo, Japan) containing 0.27% citric acid, 10% Curcumin, 2% other curcuminoids, 54.53% dextrin, 3.2% gum ghatti, and 30% maltose enhanced biological antioxidant potential (BAP), GSH and CAT and suppressed derivatives of reactive oxygen metabolites in healthy subjects with exercise-induced oxidative stress. 133 In addition, the novel curcumin formulation, Cureit/Acumin (46.5% total curcuminoids, 43% total carbohydrates, 5% fiber, 2.4% proteins, 3.2% volatile oil) exhibited enhanced bioavailability than phospholipid and volatile oil formulation of curcumin and was found to be safe without any side effects and improved handgrip strength, weight lifting capacity, walking distance and reduced the creatinine kinase (CK), muscle soreness and time taken to walk the same distance in healthy volunteers. 134 − 136 Another randomized study tested the effectiveness of curcumin essential oil formulation, curcumin phytosomal formulation, and γ-cyclodextrin curcumin formulation on healthy volunteers and reported enhanced curcumin absorption without adverse events. 137 Furthermore, curcuminoid turmeric matrix formulation (50% total curcuminoids, 3% essential oil, 2% protein, 40% total carbohydrate) suppressed CRP, rheumatoid factor (RF), SJC, TJC, ESR, and disease activity scores compared with food-grade starch as placebo in RA patients. 138 In another study, curcumin turmeric oil formulation (440 mg curcuminoid, 38 mg of turmeric oil) reduced mean weight, BMI, waist circumference, FBS, TG, hs-CRP, and increased adiponectin levels in T2D patients compared to administration of the same amount of rice flour as placebo. 139 , 140 Heng and colleagues showed that the application of curcumin alcohol gel reduced phosphorylase kinase activity, TRR, the severity of parakeratosis, and CD8+ T cells in psoriasis patients. 141 Similarly, the application of curcumin gel or curcumin mucoadhesive patch formulation reduced the burning sensation and improved mouth opening capacity in patients with OSF without any adverse side effects. 142 , 143 Another novel curcumin formulation, Infla-Kine containing a proprietary blend of Lactobacillus fermentum extract, lipoic acid, burdock seed, papaya enzyme, zinc, and BCM-95 downregulated inflammatory cytokines such as IL-6, IL-8, NF-κB, and TNF-α thereby improved quality of life in healthy volunteers. 144 Iauril soft gels containing curcumin, quercetin, hyaluronic acid and chondroitin sulfate reduced dysmenorrhea, chronic pelvic pain, and dysuria in patients with endometriosis. 145 Killox, another curcumin formulation, (190 mg curcuminoids, 20 mg resveratrol, 100 mg NAC, 6 mg zinc with the formulation of enterosoma technology) reduced postoperative irritation duration and complications in patients who underwent transurethral resection of prostate, transurethral resection of bladder and with benign prostate hyperplasia (BPH). 146 The formulation did not induce any side effects and it was also found to be safe and well-tolerated in these patients. 146 In addition, LCD capsules (soft gel capsules containing lutein 20 mg, curcumin 200 mg, zeaxanthin 4 mg from marigold flower extract, algal source vitamin D3 600 IU, medium chain TG oil, linseed oil, olive oil, sunflower lecithin, tocopherol and thyme oil) improved Schirmer’s strip wetness length, tear volume, TBUT score, SPEED score, OSDI score, corneal and conjunctival staining score, tear osmolarity, and MMP-9 positive score with comparative safety and no adverse side effects in patients with dry eye syndrome in contrast to soyabean oil as placebo. 147 Moreover, natural product capsules manufactured by Vitacost consisting of 150 mg curcumin, 75 mg resveratrol, and 150 mg epigallocatechin-3-gallate for each 500 mg tablet was shown to reduce TNF-α induced NF-κB activation in healthy volunteers. 148 In another study administration of nutraceuticals with anti-inflammatory, oxidative, and nitrosative stress (NAIOS) containing l -carnitine, coenzyme Q10, curcumin, lipoic acid, quercetin or NAC, glutamine, taurine, and zinc reduced IgM mediated autoimmune responses, fibromyalgia, and fatigue rating and severity of diseases in patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome. 149 Further, PureVida (460 mg of fish oil, 125 mg of Hytolive powder containing 12.5 mg of hydroxytyrosol, 50 mg of curcumin extract) formulation relieved pain and reduced CRP in breast cancer patients with no serious adverse side effects. 150 Another study showed that Reglicem formulation (chromium picolinate 100 μcg Cr, 200 mg curcumin dry extract, 200 mg berberine dry extract, 300 mg inositol, 40 mg banaba dry extract with 1% corosolic acid, silicon dioxide, magnesium stearate, dicalcium phosphate, microcrystalline cellulose) reduced FBS, postprandial blood sugar (PPBS), HbA1c, insulin, homeostatic model assessment (HOMA)-index, TG, TC, and CRP levels in fasting dysglycemia patients. 151 In another clinical trial, hot water extract of curcumin with or without pure curcumin powder for 8 weeks improved the water content of the skin and suppressed trans-epidermal water loss in healthy subjects. 152 Furthermore, Nutrafol women’s capsule formulation (a proprietary blend of clinically tested and bio-optimized phytoactive extracts, vitamins, minerals, and botanicals including standardized extracts of ashwagandha, curcumin, piperine, capsaicin, hydrolyzed marine collagen, hyaluronic acid, organic kelp) augmented hair growth, quality, volume and thickness without any side effects in women with self-perceived hair thinning. 153 Taken together, these results indicated that the first-generation curcumin formulations enhanced the absorption and bioavailability of pure curcumin and were effective against various ailments including autoimmune diseases, cancer, diabetes, hemoglobinopathies, oral diseases, and PMS. Curcumin is readily soluble in fat. Hence, newer formulations have been developed to enhance the solubility of curcumin to enhance its absorption and bioavailability. 18 , 48 Over the years, various technologies have been utilized to enhance its solubility including the usage of polysorbates, phospholipid complexes, liquid droplet nanomicelle, and spray drying. 44 The novel curcumin second and third-generation formulations and their antichronic disease effects have been highlighted in Figure 2 . Novel next-generation formulations of curcumin and their biological effects. The promising next-generation formulations of curcumin including Meriva, Theracurmin, Longvida, and CurQfen have shown various clinical benefits including anticancer, anti-CKD, anti-Crohn’s disease, anti-NAFLD, and antiosteoarthritis activities. The figure was generated using BioRender.com . These second-generation formulations have shown excellent bioavailability and antiarthritic, anticancer, antidiabetic, and antiviral activities in numerous clinical trials ( Table 2 ). For example, oral intake of 500 mg/day novel Actbiome formulation, (curcumin and asafetida complex was incorporated into turmeric fiber) for 8 weeks showed a reduction in IL-10 and gastrointestinal symptom rating scale (GSRS) score and increased fecal bifidobacteria, fecal lactobacilli, and ideal stool form and frequency without any side effects in healthy subjects. 154 Another study showed that a polysorbate formulation of curcumin named BioCurc/CLDM (85% curcumin, 13% desmethoxycurcumin, 2% bisdemethoxycurcumin, lauryl macrogol-32 glycerides, polysorbate-20, dl -alpha-tocopherol, hydroxy prolyl cellulose) (6 tablets, cross-over study) possess excellent absorption and bioavailability and safety in healthy individuals. 155 In addition, cyclodextrin formulation of curcumin known as Cavacurcumin along with omega-3 fatty acids (ω-3 FA), astaxanthin, gamma linoleic GLA, tocotrienols, hydroxy tyrosol, and vitamin D3 resulted in substantial reduction of hs-CRP, and SBP in healthy volunteers. This regimen was also well-tolerated without any adverse side effects. 156 Additionally, curcumin has also been formulated with hydrophilic carriers (CHC) to suppress its hydrophobicity and to enhance its solubility. The CHC formulation has been shown to increase curcumin bioavailability compared to standardized curcumin mixture, phytosomal curcumin formulation, and curcumin-turmeric volatile oil formulation in healthy volunteers. 157 This formulation has also been reported to be safe and did not cause any side effects in both healthy subjects and diabetic patients. 157 , 158 Besides, curcumin phosphatidylcholine along with irinotecan treatment has been shown to delay the disease progression without serious toxicity in patients with solid tumors. 41 Another phytosomal curcumin formulation, Curserin (200 mg curcumin, 480 mg phosphatidylcholine, 120 mg phosphatidylserine, and 8 mg piperine) increased HDL-C and decreased FPG, fasting plasma insulin (FPI), GGT, HOMA for insulin resistance (HOMA-IR), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), lipid accumulation product (LAP), fatty liver index (FLI), TG, non-LDL-C, and hepatic steatosis index (HSI) in obese patients without adverse side effects. 159 In another study, oral intake of curcuminoid micelles capsules containing 20.1 mg curcumin, 3.9 mg demethoxycurcumin, and 0.5 mg bisdemethoxycurcumin was shown to be safe, well-tolerated, and enhanced the bioavailability of curcumin in healthy subjects. 160 , 161 Also, micellar curcumin formulation increased intratumor pH and inorganic phosphate levels in glioblastoma patients with minor side effects. 162 In another study, this formulation was shown to reduce creatinine kinase MB (CK-MB) in myocardial infarction patients. 163 Another phospholipidic formulation FLAVOMEGA containing acetylcarnitine, acesulfame potassium, antiagglomerant, ascorbic acid, baicalin, coenzyme Q10, fructose, green tea catechins, phospholipidic curcumin, skullcap, and sucralose improved muscle strength, performance, and isokinetic knee extension and suppressed CK, reactive oxygen species, valine and free fatty acids in patients with Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy (FSHD), and limb-girdle muscular dystrophy (LGMD). 164 This formulation was also found to be safe, and well-tolerated without causing side effects. 164 Moreover, curcumin polysorbate formulation Flexofytol remarkably reduced Coll2-1, CRP, and global disease assessment activity in osteoarthritis patients in 3 months. 165 In another study, Flexofytol along with Boswellia extract pine bark extract, and methylsulfonyl methane for 12 weeks reduced activity impairment and FIHOA score without any significant adverse effects in osteoarthritis patients. 166 Another formulation HydroCurc consists of 80% curcumin, 17% demethoxycurcumin, and 3% bisdemethoxycurcumin entrapped in a LipiSperse delivery system, was demonstrated to inhibit the formation of thiobarbituric acid reactive substances (TBARS), TNF-α, IL-6, and relieved fatigue. 167 The formulation itself did not cause any side effects and further reduced the iron-induced gastrointestinal (GI) side effects. 167 Also, a single dose of HydroCurc along with maltodextrin enhanced IL-6, and IL-10, and reduced TC, pain, and capillary lactate dehydrogenase during the postexercise period in healthy young men. 168 In another study, Lipocurc formulation was shown to reduce PSA, CEA, and CA 19-9 in patients with advanced metastatic tumors without any side effects. 169 Although, lecithinized curcumin did not affect vitamin E in metabolic syndrome patients, reduced ratio of vitamin E/LDL, vitamin E/TC, and vitamin E/TG were noticed. 170 As mentioned curcumin is least soluble in water with an estimated solubility of 11 ng/mL in alkaline conditions while it is readily soluble in lipids or fats. 43 , 171 , 172 Hence, efforts have been made to develop various lipid or phospholipid curcumin formulations and several of these formulations have shown tremendous potential as therapeutic agents. 173 For example, Meriva, a lecithin delivery method for curcumin, has better tissue dispersion and bioavailability than the unformulated natural substance. 64 , 173 This novel second-generation formulation has been shown to be safe and well-tolerated at a dose of 250 mg/day to 4 g/day for a period of 7 days to 8 months and did not cause any side effects both in healthy subjects and patients. 173 − 192 Moreover, this formation has been shown to ameliorate metabolic disorders including diabetes-associated edema and microangiopathy, hypercholesterolemia, metabolic syndrome, and NAFLD. 176 , 177 , 179 − 184 , 193 − 195 In various clinical trials, this formulation reduced skin flux, peripheral edema, retinal edema, LDL-C, TC, TG, LDL-C, non-HDL-C, uric acid, BMI, waist circumference, hip circumference, AST, ALT, portal vein diameter, liver size, 3-methyl-2-oxovaleric acid, 3-citrate, hippurate, hydroxyisobutyrate, indoxyl sulfate, α-ketoglutarate, kynurenine, methylamine, succinate, trimethylamine, chenodeoxy cholic acid, lithocholic acid, taurocholic acid, leptin, MutL homologue 1 (MLH1), and MutS homologue 2 (MSH2), and increased adiponectin levels, zinc levels, Zinc to copper ratio, PO 2 , visual acuity, microcirculation score, in patients. 176 , 177 , 179 − 184 , 193 , 194 In another study, administration of Meriva (1 g/day) for 3 or 6 months caused a substantial reduction in MCP-1, IL-4, IFNγ, TBARS, p -cresyl sulfate, carbohydrate intake, protein intake, total fiber intake, phosphorus and potassium intake, and gut microbes such as Escherichia - Shigella , Enterobacter verrucomicrobia , Firmicutes, and improved other species of microbes including Lactobacillaceae spp., Lachnoclostridium spp., Lachnospiraceae family, and Prevotellaceae without side effects in patients suffering from chronic kidney diseases. 175 In addition, this formulation showed potential anticancer activities against solid tumors with enhanced safety, tolerability, and minimal adverse side effects. 187 − 189 , 191 , 192 It also improved response rate, stable disease period, inflammation, quality of life, and survival rate, and reduced the burden of chemotherapeutic side effects among these patients. 187 − 189 , 191 , 192 In addition, Meriva mitigated inflammatory markers such as CRP, IL-1β, IL-6, ESR, sCD40L, and sVCAM-1, WOMAC score, Karnofsky scale score, stiffness, negative effects on social function, and boosted physical performance capacity in osteoarthritis with excellent safety and tolerability ( Figure 2 ). 185 , 186 It also reduced the risk of development of T2D and Alzheimer’s disease in adults of age between 30 and 70 years. 190 Another study showed that this formulation (1 g or 4g/day) reduced the severity of gulf war illness disease without any serious side effects. 178 Moreover, Meriva along with fish oil reduced postprandial insulin levels in healthy subjects whereas Meriva with phytosterol reduced cardiovascular disease (CVD) risk in hypercholesterolemia patients. 179 , 196 , 197 In another study, Meriva with anthocyanin has shown improvement in colorectal adenomatous polypos symptoms and it reduced NF-κB and Ki67 levels. 198 Further, another Meriva formulation called Algocur (each tablet contains 1g of Meriva) improved physical performance and reduced pain in men rugby players with osteo-muscular pain. 199 This formulation also showed to be safe and well-tolerated among these men. 199 Wolf and colleagues developed three different lipidated curcumin—NE65, NLC65, and NLC80—formulations reduced trans-epidermal water loss and modulated skin barrier functions in healthy subjects. 200 Another study showed that supplementation of Valdone curcumin soft gel (utilized self-emulsifying drug delivery system) improved clinical response and remission rates in ulcerative colitis patients. 201 Furthermore, topical application of curcuminoid-phosphatidyl choline formulated cream enhanced repigmentation in vitiligo patients. 202 However, another phytosomal curcumin formulation was shown to possess no considerable effect on aryl esterase activities in MetS patients. 203 Also, several studies have also revealed that phospholipidated formulations of both curcumin and curcuminoids were not considerably effective in treating patients with MetS. 204 − 208 Nanoencapsulation or nanoformulation of curcumin is another promising strategy both to increase bioavailability and to decrease curcumin degradation rate in vivo. 23 , 43 Several synthetic and natural polymers, such as chitosan, N -isopropylacrylamide (NIPAAM), N -vinyl-2- polyethylene glycol monoacrylate (NIPAAM [VP/PEG A]), poly(lactic- co -glycolic acid), pyrrolidone, poly(vinyl alcohol) (PVA), and silk fibroin have been developed for curcumin nanoencapsulation. 43 , 209 − 212 Over the years, nanotechnology-based therapeutic delivery methods, including nanoparticles, liposomes, and nanoemulsions, have been developed. 213 , 214 The use of biochemical changes at the tissue microenvironment level in diseased states to initiate and activate drug release has replaced more traditional drug release mechanisms with the controlled-release mechanisms by novel engineered nanoparticle drug delivery systems. 214 , 215 Data indicated that these formulations increased treatment effectiveness while concurrently decreasing harmful side effects. 211 , 212 , 216 , 217 The novel nanocurcumin formulation developed by Exir Nano Sina (Iran) has shown excellent therapeutic efficacy in various diseases such as amyotrophic lateral sclerosis (ALS), ankylosing spondylitis (AS), arthritis, cancer, COVID-19, CVDs, diabetes, infertility, MetS, NAFLD, neurological and psychological disorders without side effects ( Figure 3 ). 195 , 218 − 235 Administration of this formulation for 12 months increased the survival rate in ALS patients. 218 It also reduced RORγ t, IL-17, IL-23, miR-141, miR-155, miR-200, and symptoms in AS patients. 219 The antiarthritic potential of this formulation has been evidenced by its capacity in suppressing CRP, CD4 + and CD8 T + cells, Th 17 cells, B cells, miRNA-155, miRNA-138, miRNA-16 and VAS score, and augmenting Treg cells without any adverse events in the clinical trials involving osteoarthritis and RA patients. 225 , 226 , 236 It was also shown to be effective in treating Behcet’s disease where it improved Treg cells, FOXP3, TGF-β, IL-10, miRNA-25, and miRNA-106b. 237 Molecular targets of curcumin nanoformulations. Increasing lines of evidence suggest that nanoformulations of curcumin possess high bioavailability and safety and are effective against various ailments. These formulations have been shown to inhibit DNA damage, inflammatory cytokines, lipid profile, and reduce amyloid plaque formation in the central nervous system. The figure was created using BioRender.com . Multiple clinical trials have shown its potential in treating COVID-19 disease with admirable safety and tolerability. Nanocurcumin formulation in COVID-19 patients led to reduced levels of GM-CSF, IFNγ, IL-1β, IL-6, IL-17, IL-18, IL-21, IL-23, RORγ t, T-box transcription factor 21 (TBX21), and TNF-α, and induced FOXP3, IL-4, IL-10, IL-35, and TGF-β levels. 238 − 242 It also improved lymphocyte count, oxygen saturation levels, symptoms, and Treg cell frequency and reduced symptom resolution time, hospitalized duration, and mortality rate in COVID-19 patients. 221 , 222 , 238 − 243 Several studies have also revealed the beneficial effects of nanocurcumin formulation in treating critically ill patients with sepsis. Nanocurcumin from Exir-Nano-Sina (Iran) suppressed Bcl-2, inflammatory molecules such as ICAM-1, IL-1β, IL-6, IL-18, TLR-4, TNF-α, and VCAM-1, creatinine, lipid profile, liver enzymes and reduced mechanical ventilation period in these patients. 227 , 244 , 245 In addition, nanocurcumin treatment enhanced clinical response rate and ameliorated radiation-induced dermatitis in various cancers including bladder, head and neck, and prostate cancers. 224 , 246 , 247 It also reduced DNA damage and micronuclei formation in lymphocytes of thyroid cancer patients. 228 Moreover, the antidiabetic properties of nanocurcumin were attributed their capacity in reducing FBG, glycated Hb, insulin, hs-CRP, TC, TAC, TN, LDL-C, VLDL-C, TC/HDL-C, MDA, and augmented insulin sensitivity, TAC, peroxisome proliferator-activated receptor gamma (PPARγ), LDLR, and GSH levels in T2D patients. 248 − 251 It also suppressed neuropathy, depression, and anxiety in T2D-associated peripheral neuropathy patients. 251 , 252 Nanocurcumin supplementation for 10 weeks improved sperm count, sperm motility, and testosterone levels in patients with infertility complaints. 229 This study also showed that nanocurcumin increased testosterone levels and reduced follicular stimulating hormone (FSH), luteinizing hormone (LH), and prolactin levels, although not statistically significant. 229 This formulation has also been shown to decrease TG, HOMA-β, and MDA, and upregulate adiponectin levels and TAC in MetS patients. 230 , 253 Further, treatment with this formulation remarkably reduced the degree of fatty liver, liver enzymes, lipid profile, and inflammatory mediators in patients with NAFLD. 254 This formulation was also effective in treating neurological disorders such as migraine, multiple sclerosis, and Parkinson’s disease and was able to improve disease severity, symptoms, and deregulated miRNAs with no or mild GI side effects. 231 , 232 , 255 − 260 It also reduced pain, severity, lesion area, and burning sensation in patients with various oral diseases including gingivitis, mucositis, and OLP. 247 , 261 − 264 In another study, this formulation enhanced the responsive rate while reducing the positive and negative PANSS subscale score in schizophrenia patients. 233 Further, nanocurcumin formulation from Theravalues Corp., Japan was demonstrated to downregulate IL-6, hs-CRP, MDA, and upregulate IL-10, brain-derived neurotrophic factor (BDNF), and TAC in MetS patients. 265 Furthermore, several other nanocurcumin formulations have also been developed by various laboratories and these formulations have shown tremendous potential in helping healthy subjects and treating various chronic diseases such as arthritis, cancer, NAFLD, neurological disorders, oral diseases, and skin diseases. 266 − 279 Thus, nanocurcumin formulation with enhanced bioavailability and safety has been promising in treating several human diseases. A distinctive example of a submicron crystal dispersion of curcumin known as Theracurmin was reported to have 27-fold higher bioavailability in comparison with pure curcumin. 49 Increasing lines of evidence also suggested its enhanced bioavailability with acceptable safety and mild side effects in healthy subjects and cancer patients ( Figure 2 ). 116 , 280 − 286 It has also been shown to reduce exercise-induced muscle soreness and increased the range of motion. 287 , 288 In postmenopausal women, it reduced brachial SBP. 289 This formulation also improved clinical response rate and lesion healing and reduced endoscopic disease severity in Crohn’s disease patients. 290 In another study, Theracurmin significantly reduced mRNA expression of IL-6 in PBMCs and serum levels of IL-6 in hemodialysis patients. 291 Another salient example of clinical benefits of Theracurmin comes from the trial on osteochondral diseases in which it reduced roughness in the femur bone and stiffness in the knee joint. 292 It also inhibited the raise in oxidized LDL in both COPD and T2D patients. 293 , 294 Collectively, these studies suggest that second-generation formulations of curcumin improved the bioavailability of curcumin and their significance drives the ancillary goal to develop them as therapeutic drugs. An expansive frontier in nutraceuticals is unfolding third-generation curcumin formulation via increasing the bioavailability of “free” curcuminoids without using synthetic polysorbates and/or emulsifiers. 44 , 295 These formulations are well established to have superior absorption, BBB-permeability, cellular uptake, and better tissue distribution. 295 , 296 Based on the published literature, these formulations have greater than 100-fold higher bioavailability compared to pure curcumin. 47 Besides, these formulations are devoid of adulterants and contaminants, making them safer and nongenotoxic and nonhepatotoxic for long-time clinical use. 44 Indeed, third-generation formulations have been developed recently and these formulations include curcumin galactomannan formulation or CurQfen (noncovalent complex between curcumin and fenugreek galactomannans), curcuRouge (Starch and curcumin formulation), Curcuwin Ultra (cellulosic derivatives and curcumin formulation), and Longvida (soy lecithin and curcumin formulation) ( Figure 2 ). 47 , 295 , 297 CurQfen was shown to be safe and well-tolerated and had no adverse side effects have been reported in clinical trials. 44 , 298 − 301 This formulation also improved α- and β-waves of EEG, memory improvement, and reduced choice-based-visual reaction time in healthy subjects. 302 It also improved walking performance, VAS score, and WOMAC score, and inhibited the rise in hs-CRP, IL-1β, and IL-6 levels in osteoarthritis patients. 298 , 301 In addition, its antiobesity and anti-CVD properties were attributed to its increased levels of HDL and reduced levels of homocysteine within 12 weeks of treatment. 300 Besides, to a certain extent, this formulation relieved occupational stress as evidenced by improvement in QoL, SOD, GPx, GSH, and fatigue. 299 In another study, curcuRouge was demonstrated to reduce the neutrophil to lymphocyte ratio without any safety issues in healthy subjects. 303 Another formulation Curcuwin Ultra+ showed enhanced bioavailability and was found to be safe in healthy subjects. 304 Another next-generation formulation with superior bioavailability, Longvida was also elucidated to reduce fatigue, and oxidative stress, tension, and anxiety, and improved mood-related issues, and cognitive functions in healthy individuals with excellent safety and no side effects. 305 − 308 Moreover, clinical trials on obese patients have revealed that Longvida intake improved cerebral artery stiffness, cerebrovascular responsiveness, and lipid profile without side effects. 309 − 311 It has also been shown to be beneficial in treating both OSF and osteoarthritis. 312 , 313 Another illuminating clinical trial evidenced the use of Longvida in detecting amyloid spots in the retina of Alzheimer’s patients and reported that this formulation exhibits a greater capacity to identify these spots in positron emission tomography (PET) scanning compared to conventional amyloid PET in longitudinal evaluation of amyloid risk and neurodegeneration (LEARN) study. 314 Certainly, these clues warrant further investigations on third-generation curcumin formulations as a novel nutraceutical formulation in diagnosing and treating various ailments.

Advances in chemistry and technologies have provided the versatility and tools to develop a range of innovative curcumin formulations with considerable improvement in oral bioavailability and safety. Decades of research on curcumin and its formulations resulted in the increased oral bioavailability of curcumin from 11 ng/mL to 626.98 μg/mL. These curcumin formulations were found to be safe and well-tolerated even at higher doses ranging from 2 g/day to 12 g/day and for a prolonged duration of 6 months to an year. The simplest first-generation formulation with adjuvants to second-generation with polysorbates to third-generation with only natural material have shown tremendous absorption capacity, cellular uptake, and safety not only in diseased but also in healthy subjects providing the evidence of disease prevention and treatment capability of these formulations. As we noted at this time, few of these regimens including curcumin plus piperine combination, BCM-95, nanocurcumin, Meriva, and Theracurmin have been tested clinically and are effective against chronic diseases such as arthritis, autoimmune diseases, cancer, diabetes, endometriosis, hemoglobinopathies, metabolic syndrome, neurological disorders, obesity, oral diseases, psychological disorders, and skin diseases. All the formulations have been shown beneficial effects compared to either placebo such as calcium phosphate, lactose, rice flour, and starch, or the standard care treatment. Major grade 3 side effects, GI intolerability, and hepatotoxicity were reported when curcumin was administered intravenously earlier. Nevertheless, the minor side effects in most of these trials with oral intake of curcumin formulations include cold, irritation, indigestibility, and nausea which in few cases might be attributed to adjuvants and emulsifiers. However, clinical studies are scarce at this time on upcoming and more promising third-generation formulations. Notably, it is advisable to opt for highly bioavailable curcumin formulations that have demonstrated their therapeutic efficacy at a relatively low dosage of 80–500 mg/day. Further, most of the clinical trials conducted were restricted to a small number of patient groups. However, more research is needed to examine the safety and effectiveness of curcumin formulations in both large and diverse patient populations with different phases of the disease. As such, all these formulations cannot be inherently compared due to dissimilarities in the dose, duration of treatment, clinical study design, formulation type, the method used for analysis, and population disparity. Recently, as detailed earlier, curcumin formulation was also used to diagnose the amyloid spots clinically. Therefore, curcumin formulations have significant potential to serve as preventive, diagnostic, and therapeutic entities.

A literature search was carried out using “curcumin and clinical trials” in two different databases, Pubmed and Scopus, until June 2022. Around 458 articles appeared in PubMed and 3622 articles appeared in Scopus for the mentioned keyword. The studies that appeared were analyzed thoroughly for the mentioned keywords. The inclusion criteria applied to select the relevant studies were (a) clinical studies that have used various generations of curcumin formulation; (b) studies on human subjects (both healthy and diseased); (c) full-text manuscripts in English. The exclusion criteria were (a) preclinical studies; (b) studies on the pure form of curcumin; (c) full-text not in English; (d) in silico studies; (e) conference abstracts; (f) review articles; (g) meta-analysis; and (h) case reports. All the relevant articles as per these criteria are included in the table, figures, and text.

Chronic diseases including autoimmune diseases, cancer, cardiovascular diseases, diabetes, hepatocellular, neurological, and renal diseases have persistent high incidence and fatality rates worldwide. 1 , 2 Finding feasible treatment strategies are challenging due to the high prevalence of these diseases and the involvement of several pathways in their development, including JAK/STAT3, JNK, NF-κB, MEK/ERK, p38/MAPK, and PI3K/Akt/mTOR, etc. 1 − 10 Therefore, classical monotarget therapies are insufficient to treat these diseases. Besides, the cost of contemporary pharmaceuticals is high, and have several unfavorable side effects. 7 , 10 , 11 Indeed, there is an increasing need for the development of safer, effective, multitargeted, and cost-effective therapeutic regimens to replace the current harmful and ineffective treatment approaches. A growing body of preclinical and clinical evidence suggests that natural substances derived from diverse plants are potential therapeutic candidates against a wide range of fatal chronic conditions, and their alternative formulations can be employed to boost the bioavailabilities of these substances. 2 , 7 , 10 , 12 − 14 The perennial herb turmeric, Curcuma longa Linn. belongs to the Zingiberaceae family, is indigenous to South Asia’s tropical areas. The rhizomes of this plant have been used for centuries as a remedy for several diseases in the Indian (Ayurveda) and Chinese Medicinal Systems. 15 − 17 Curcumin is a bioactive phytochemical derived from this rhizome. It has traditionally been used as a spice, food preservative, and coloring ingredient. 15 , 18 The chemical name for curcumin is diferuloylmethane (C 21 H 20 O 6 ) and the IUPAC name is (1 E -6 E )-1,7-bis(4-hydroxy-3-methoxy phenyl)-1,6-heptadiene-3,5-dione with a molecular weight of 368.37 g/mol and melting point of 183 °C. The two aryl rings in curcumin are symmetrically connected to a β-diketone moiety by ortho-methoxy phenolic groups. 17 − 21 A pH-dependent keto-enol tautomerism appears in curcumin wherein the stable enol form predominates in an alkaline medium and a keto form in acidic and neutral conditions. 17 In addition, curcumin’s color varies depending on the pH level, yielding a brilliant yellow solution between 2.5 and 7.0, and turning to dark red when the pH rises over that level. 17 , 20 Currently, there are several curcumin-based products available in the market, including pills, ointments, capsules, and cosmetics. 16 , 22 − 24 Turmeric and curcumin have been the established remedies for various ailments, primarily as antiatherosclerotic, antibacterial, anticancerous, antifungal, anti-inflammatory, antioxidant, antithrombotic, and antiviral agents. 22 , 25 , 26 Additionally, a comprehensive analysis of the literature identified curcumin as one of the excellent natural compounds that exhibit analgesic, antirheumatic effects, hypoglycemia, hypolipidemia, hepatoprotective, nephron protective, pulmonoprotective, and cardioprotective activities. 18 , 21 , 27 − 35 Besides, in vitro studies have shown that curcumin modulates several cell signaling pathways, upregulates p53, p21, and p27, downregulates cell survival gene products, and induces apoptosis. 15 , 36 − 39 Numerous clinical studies have demonstrated its outstanding safety, tolerability, and effectiveness even at higher oral dosages, and is currently being sold as a dietary supplement in several countries across the world. 27 , 28 , 40 , 41 Curcumin has not yet been authorized as a drug despite its excellent efficacy and safety, and a key issue for this is the relative bioavailability of curcumin. Research over the last three decades has revealed the poor gut absorption, rapid metabolism, and systemic elimination of curcumin that significantly restricts its bioavailability. 18 , 23 , 42 − 44 Moreover, curcumin is a hydrophobic molecule with a log P of ∼3.2 (octanol-water partition coefficient), making it practically water-insoluble (with a water solubility of only 30 nM). 21 , 45 − 47 Curcumin activity has a reported half-life of 10 min in a phosphate buffer of pH 7.4 which further limits its clinical use. 46 , 47 Even after consuming high amounts of conventional curcumin, very low levels of plasma curcumin were detected. Hence, the overarching goal of all strategies is to increase curcumin’s solubility and bioavailability. 48 − 52 Numerous approaches have been used to improve the solubility and subsequently the bioavailability of curcumin including curcumin-piperine complex, curcumin nanoparticles or nanomicelles, liposomal curcumin, phospholipidated curcumin, and phytosomal curcumin complex. 18 , 42 , 44 , 47 , 53 , 54 Therefore, in the current review, we provide an overview of the bioavailability, safety, tolerability, and efficacy of various curcumin formulations in clinical trials. We have extensively reviewed the completed clinical trials on curcumin formulations of different generations and highlighted their efficacy in treating several chronic diseases. Significant variations in research design, volunteer race, dose, duration, and route of administration were noted. Moreover, we discussed the advantages and limitations of these formulations and highlighted the future perspectives from the podium to clinical practice.

The major findings from curcumin research are the observation of noticeably low serum levels, limited tissue distribution, rapid metabolism, inactive metabolite formation, and rapid clearance/elimination from the body. 18 , 42 , 47 , 48 , 55 Several studies have shown that administration of a large amount of pure curcumin yielded only a trace amount of serum levels of curcumin in rats owing to its poor absorption from the gut. 55 − 60 Curcumin administered orally at 2 g/kg to rats showed a maximum serum concentration of only 1.35 ± 0.23 μg/mL at 0.83 h, whereas the same dosage showed undetectable or extremely low serum levels, i.e., 0.006 ± 0.005 μg/mL at 1 h. 55 Similarly, in another clinical trial, it was shown that administration of 3.6 g of curcumin by the oral route generated serum levels of only 11.1 nmol/L after 1 h. 51 More recently, Yang and colleagues demonstrated that curcumin given intravenously (10 mg/kg) produced a maximum serum level of 0.36 ± 0.05 g/mL, whereas a 50-fold increase in dosage of oral supplement produced only a maximum serum level of 0.06 ± 0.01 g/mL in rats. 56 Besides, following oral treatment of 400 mg of curcumin in rats, Ravindranath et al. demonstrated that only residues of the unmodified substance were discovered in the liver and kidney. 59 This study also showed that 90% of curcumin was noted in the stomach and small intestine at 30 min while only 1% of curcumin was present after 24 h. 59 Another study revealed that administration of radiolabeled (tritium or H 3 ) curcumin at 10, 80, and 400 mg doses resulted in the detection of a considerable amount of curcumin in tissues of rats administered with only 400 mg after 12 days. 58 Also, the percentage of absorbed curcumin remained constant irrespective of the dosage indicating the dose-independent limitations to bioavailability in these animals. 58 Similarly, supplementation of 450–3600 mg of curcumin daily for a week before surgery to patients with colorectal cancer metastases to liver showed no curcumin in their liver tissues. 61 In phase II clinical trial on patients with advanced pancreatic cancer, an oral dose of 8 g/day curcumin resulted in only 22–41 ng/mL of plasma concentration. 62 Further, orally given curcumin (2 g/kg) to rats had an absorption half-life of 0.31 ± 0.07 and elimination half-life of 1.7 ± 0.58 h, albeit in humans, the same dose did not enable the measurement of these shelf life values since most of the levels were below the detection limit at almost all the periods. 55 These studies indicated that the method of administration (whether oral or intravenous) affects the serum levels of curcumin and further suggest that the serum achievable concentrations of curcumin in humans and rats are not exactly comparable. Hence, it is not only imperative to develop bioavailable curcumin but also equally important to find the safety and efficacy of these formulations in humans.