**5.4 Turmeric toxicity**

Turmeric has GRAS status in the United States [74]. Through a toxicological assessment, the European Food Safety Authority (EFSA) has recommended curcumin daily intake be ≤3 mg/kg body weight per day (180 mg/day in 60 kg individuals) [75]. In 2–year oral feed studies, turmeric oil at 79–85% curcumin showed no biological significantly differences in hematology, clinical chemistry (liver and kidney function markers), and urinalysis parameters, but showed to potentially cause carcinogenicity in mice and rats especially in females at doses ≥100 mg/kg body weight in rats and 300 mg/kg body weight in mice [76]. However, the EFSA concluded that curcumin is not carcinogenic and studies have demonstrated the benefits of curcumin as an adjunct treatment of cancer [77]. High daily dose of curcumin might cause hepatotoxicity. In rats, 25 and 100 mg/kg body weight for 90 days of curcumin induced liver injury through the generation of reactive oxygen species and pro-inflammatory cytokines as well as reduced antioxidant and detoxifying enzymes SOD and GST [78]. Similarly, 5% turmeric via diet for 90 days in female Wistar rats and 0.2% turmeric via diet in female Swiss mice was hepatotoxic. Human equivalent dose for these rodent studies ranged from 250 mg curcumin/day to 1 g–50 g turmeric/day [79, 80].

#### **5.5 Turmeric pharmacokinetics**

Turmeric constituents have shown to inhibit p-glycoprotein in vitro and in vivo models [81]. Inhibition of p-glycoprotein can lead to increased bioavailability of drugs [82]. Curcumin is primarily eliminated in the feces with little renal excretion in a rat study [76]. In a pharmacokinetics study with healthy adults, turmeric reduced the bioavailability of the beta-blocker talinolol [83]. Curcumin was safe and effective when combined with glyburide in patients with type 2 diabetes. Better cholesterol and glycemia control without hypoglycemic side effects were observed. Curcumin increased AUC but did not change Cmax of glyburide [84]. In rats, curcumin increased the Cmax, AUC0-t and half-life of amlodipine – an antihypertensive drug [85]. Amlodipine is metabolized by CYP3A4 in humans [86]. Curcumin inhibits several hepatic CYP enzymes including 3A4, 1A2, 2B6 (competitive type of inhibition), 2D6 and 2C9 (non-competitive inhibition) in human recombinant cytochrome P450s [87]. However, it is been suggested that these effects are not clinically significant due to poor bioavailability of curcumin. In fact, in a pharmacokinetics study in healthy volunteers, 4 g curcuminoids +24 mg piperine to enhance bioavailability did not affect Cmax, AUC, clearance, or half-life of drugs metabolized by CYP3A, CYP2C9, and UGT, SULT conjugation enzymes [88].

*Safety Review of Herbs and Supplements in Heart Disease, Diabetes, and COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.96811*

### **5.6 Turmeric safety summary**

Turmeric is safe and effective at doses ≤250 mg curcumin/day. Higher doses are associated with hepatotoxicity and potentially carcinogenicity. Doses as low as 70–250 mg curcuminoids/day has shown to be effective in metabolic disorders and COVID-19. Although turmeric inhibits cytochrome P450 enzymes, these effects seem to be clinically negligible. Caution when taken with drugs that are substrates of p-glycoprotein in order to avoid drug overdose. Although turmeric has hypoglycemic effects and might cause side effects such as fainting when combined with antidiabetic medications, this combination has shown to be safe in clinical trials.
