14. Alcohol 

Alcohol may interact with drugs because it is metabolized in the liver by cytochromes P450 [100]. The interaction may lead to an increased concentration of alcohol and/or drugs in the bloodstream, increasing , , antiepileptics, and hypnotics. Indeed, alcohol consumption may increase the sedative effect of some drugs, induce mood changes, reduce alertness and judgment, and decrease muscle tone, up to the occurrence of coma [101].

Other interactions may occur with the concomitant intake of analgesics (NSAIDs and paracetamol), antibiotics (cephalosporins), antihistamines, antihypertensives (ACE inhibitors, diuretics, beta-blockers), bronchodilators, statins, anticoagulants, and sulfonylureas.

Moreover, alcoholic beverages such as wines and beers contain several flavonoids and polyphenols that could be responsible for food–drug interactions. Among these substances, trans-resveratrol and gallic acid in red wine, and phenolic acids and prenylflavonoids in beer have proven to be potential inhibitors of cytochrome CYP activity [75,102].

The interaction between alcohol and disulfiram is clinically useful to reduce alcohol consumption. Disulfiram inhibits aldehyde dehydrogenase that converts acetaldehyde derived from alcohol into acetic acid. By reducing that biotransformation, the increasing concentrations of acetaldehyde (up to 5–10 times higher than normal) cause symptoms including accelerated heartbeat, a reddened and swollen face, low blood pressure, abdominal cramps, nausea, vomiting, headaches, and hypoglycemia. Interestingly, that effect can also occur with other drugs, such as metronidazole, cephalosporins, sulfonylureas, chloramphenicol, griseofulvin, and quinacrine, which manifest a "disulfiram-like" reaction [103,104]. 

15. Tea 

The content of catechins (especially epigallocatechin) in tea could be responsible for the inhibition of OATP transmembrane transporters, even if that effect was not clinically evident in human trials [78]. The consumption of green tea is not recommended in subjects taking antibiotics, anticoagulants, oral contraceptives, anxiolytics, chemotherapeutic or antihypertensive agents, because catechins can inhibit the OATP1A2 transporter in the intestinal mucosa. Therefore, this affects the absorption of several drugs, as well as nadolol (an antihypertensive beta-blocker), rosuvastatin (statin), chemotherapy agents (erythromycin, levofloxacin, imatinib, methotrexate), antivirals (saquinavir) and other agents (i.e., rocuronium, fexofenadine, thyroxine) [51,105,106]. However, clinical studies of possible interactions between tea and drugs have been carried out on a limited number of subjects [78]. 

16. Coffee 

The scientific literature reports possible interactions between the intake of coffee, or beverages containing caffeine (cola drinks, cocoa), and some drugs. Indeed, the caffeine found in several beverages and foods can interact with different medications in different ways. For example, concomitant intake of caffeine-containing beverages/foods may reduce the effectiveness of hypnotics, drugs for the treatment of urinary incontinence (such as anticholinergics, topical estrogens), and lithium. In other cases, caffeine enhances the effects of the drug, leading to the onset of side effects. For example, caffeine increases (a) the effect of oral warfarin, increasing the risk of bleeding; (b) the stimulation of the sympathetic nervous system by MAO-inhibitors, leading to episodes of cardiac arrhythmias or hypertension; (c) the gastric damaging effects of NSAIDs [107].

Another important interaction occurs with the intake of clozapine, an atypical antipsychotic drug, whose serum concentrations may rise by 20–26% due to the inhibition of the CYP1A2 isoform by the caffeine contained in a 40 mL cup of coffee [107]. On the contrary, the interaction between caffeine and felodipine, which was demonstrated during in vitro studies, was not observed in clinical trials. An important interaction occurs when bronchodilator drugs containing theophylline are administered together with caffeine, because both molecules can accelerate breathing and heart rate, so their concomitant intake is not recommended.

Finally, the concomitant intake of some medications (i.e., oral contraceptives, quinolone antibiotics) may increase serum levels of caffeine which may accumulate, leading to signs and symptoms such as nausea, vomiting, nervousness, anxiety, and tachycardia [108]. In any case, it is important to add that the pharmacokinetics of caffeine are highly variable among individuals, due to polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. So, the entity of interaction with the same drug may change among individuals [109].

17. Milk 

Milk may interfere with some antibiotics, reducing the bioavailability of tetracyclines and fluoroquinolones when administered per os. Indeed, these drugs may form complexes with calcium present in milk and dairy products that can seriously compromise their absorption [78]. 

18. Macronutrients: Proteins and Lipids 

It is well known that the efficacy of medications could be modified when taken per os within the meal, because food components and bioactive compounds may interfere with each other. Research has mainly focused on understanding the chemical mechanisms underlying these interferences. Indeed, high-energy and high-fat meals are more likely to modify gastrointestinal motility and the intestinal absorption of drugs [110]. In particular, high-fat meals may reduce serum concentrations of cycloserine (an antitubercular drug) and esomeprazole (a PPI), or increase the absorption of fat-soluble drugs such as saquinavir and atazanavir (antiretroviral protease inhibitors) [111]. Protein-rich meals can potentially increase serum albumin levels, and/or cytochrome P450 activity and alter the effectiveness of warfarin (as demonstrated by the reduction in the INR ratio). Similar consequences were observed in the case of levodopa because amino acids such as isoleucine, leucine, valine, phenylalanine, tryptophan, and tyrosine compete for the transmembrane transporter that allows drug absorption within the intestinal mucosa; as a result, the bioavailability of the drug is reduced, as is its pharmacological effect. On the contrary, the bioavailability of propranolol is increased when combined with foods, increasing its effects [76]. 

19. Fibers

A fiber-rich meal may alter the absorption of some drugs, depending on the fiber-induced increased gut motility, although studies are scarce and results may be contradictory, due to individual variability [112]. Simvastatin, ezetimibe, pravastatin, and fluvastatin may suffer a reduction in efficacy when assumed in conjunction with a high-fiber intake. Accordingly, the concomitant intake of pectin or oat bran and lovastatin may reduce drug absorption.

20. Food Supplements 

The potential risk of drug interactions exists also for food supplements, because they may contain active molecules (naturally contained or added during industrial processes) that are associated with adverse events. For these reasons, food supplements are generally safe for the general population but are not completely risk-free for medical patients [113]. Some components of food supplements may be pharmacologically active, or act as enzyme inhibitors or inducers, being capable of altering the pharmacokinetics and the effects of drugs [114]. Many studies investigated the interactions between supplements and drugs to overcome the lack of awareness about the potential drawbacks of these products and to motivate caregivers to ask their patients about the use of supplements [115]. The topic is becoming increasingly prevalent, given the growing and widespread consumption of these products in recent years; it is estimated that about 32 million Italians, aged 35–64 years and mostly women, consume food supplements. About 18% of them bought a supplement on the advice of family, friends, the internet, TV, or magazines.

In general, reports on the adverse events attributable to herbal or phytochemical products are quite rare; the effects are generally mild and include headaches, nausea, and fatigue. More serious events, such as liver damage or bleeding, have also been described [114,116]. 

The difficulty in obtaining information on food supplements and drug interaction is represented by the study methodology. Most information comes from preclinical models, whereas the gold standard should be represented by clinical trials. The aim is to identify the interactions, the target enzymes (i.e., CYP isoforms), and transmembrane transporters (i.e., ABC and SLC families) by co-administration of an enzyme-specific probe. Moreover, some natural compounds contained in supplements have been shown to activate nuclear receptors, such as PXR (Pregnane X Receptor) and CAR (Constitutive Androstane Receptor) [117]. These receptors regulate the expression of a set of genes involved in the bioactivation, detoxification, and transport of endogenous and exogenous substances, including drugs [114]. 

21. Herbal Products 

The use of herbal products is common worldwide; unfortunately, there are no efficacy data for many of these compounds and no quality safety regulations, so that "natural" does not always mean "safe". Indeed, many of these products are identified with more than one name and sometimes reflect the plant from which they derive [118,119]. Furthermore, the dose is not regulated and sometimes the composition is not clear; information about the purity of the products is scarce, and very often there are contaminations from heavy metals [120]. Furthermore, herbal compounds such as Hypericum perforatum, Ginkgo biloba, and Salvia chinensis and preparations such as Yin zhi huang (a Chinese herbal product) can activate nuclear receptors, such as PXR and CAR [117]. Among the various compounds that were found to interfere with some drugs, the most known is the Hypericum perforatum, a natural antidepressant remedy also called Saint John's worth. The active ingredient is hyperforin, which can inhibit neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate, and -aminobutyric acid. Moreover, Hypericum can modulate the activity of CYP3A4, CYP2C9, and CYP1A2 isoforms and P glycoprotein, because hyperphorin binds the nuclear receptor that regulates the expression of intestinal CYP3A4 and glycoprotein P. Therefore, 

Therefore, Hypericum perforatum can interact with several medications [121], reducing their degradation and hence increasing their circulating levels and effects: - Immunosuppressants (cyclosporin, tacrolimus); - Anticancer drugs; - Oral contraceptives (ethinyl estradiol, norethindrone, keto desogestrel); - Cardiovascular drugs (anticoagulants, statins, beta-blockers); - Antimicrobials (including anti-HIV, voriconazole); - Antidepressants and anxiolytics (benzodiazepines and buspirone); - Anticonvulsant agents; - Oral hypoglycaemic agents (tolbutamide, gliclazide); - Anaesthetics; - Respiratory (fexofenadine) and gastrointestinal (omeprazole) agents; - Anti-migraine drugs (eletriptan); - Muscle relaxant medications; - Medications used in drug abusers (i.e., methadone).

Ginkgo biloba is another important herbal compound that has been proven to interfere with the effectiveness of some medications [122]. It is used to improve brain performance and reduce fatigue. It is also used in cases of Alzheimer's disease and claudication intermittent, as it can improve cognitive functions in cerebrovascular diseases and peripheral blood circulation [123,124]. The substances contained in the Ginkgo biloba that have pharmaco-logical properties are flavonoids and tripertenic lactones (ginkgolides and bilobalide). As a result, Gingko biloba can reduce platelet aggregation, and act on the CPY2C9 and CYP3A4 isoenzymes, inhibiting the microsomial metabolism of warfarin. Therefore, herbal preparations containing Ginkgo biloba should be avoided in patients treated with antiplatelet or anticoagulant drugs [125,126]. 

The inhibitory action of Ginkgo extract on cytochrome P450 isoforms seems to be responsible for other pharmacokinetic interactions involving the calcium-channel blocker nifedipine and the PPI omeprazole. Other studies have shown that flavonoids contained in Ginkgo can exert an agonist action with the GABA system and a serotoninergic effect, interacting with benzodiazepine and SSRI, respectively [127–129].

Senna preparations (Cassia angustifolia and acutifolia), based on their natural cathartic properties, have the potential to interact with drugs [130]; hence, they should be avoided in association with drugs that may induce hypokalemia, as well as thiazide or loop diuretics, corticosteroids, or with cardiac glycosides, antiarrhythmics, and -blockers [131,132] 

22. Liquorice 

Liquorice is made from rhizomes and roots of the plant named Glycyrrhina glabra. Its excessive consumption can lead to increased arterial blood pressure and hypokalemia [133,134]. This effect is attributable to the metabolite glycyrrhizin acid that reduces the hepatic and renal metabolism of corticosteroids by inhibiting the 11-beta-hydroxysteroid-dehydrogenase enzyme. Consequently, the aldosterone-like activity of cortisol at the renal level increases, inducing pseudo-primary hyperaldosteronism, resulting in hypertension, hypokalemia, metabolic alkalosis,s, and hydro-saline retention. The consumption of this preparation should be avoided during antihypertensive therapy, or with drugs that could cause hypokalemia (i.e., thiazides loop diuretics, and corticosteroids) [130,135]. 

23. Ginseng 

Ginseng includes numerous species of the Araliaceae family. This root is used to obtain different products, such as a coffee substitute drink and supplements. It has antioxidant, antipyretic, cholesterol-lowering, anticancerogenic, and anti-inflammatory properties and it is believed to improve memory function. For this reason, it is used in the case of hypotension, diabetes, gastritis, insomnia, fatigue, and mental stress [136,137]. The use of ginseng is not harmless, even if the intestinal metabolites of its constituents (ginsenosides) on which the beneficial properties depend, may strongly inhibit the cytochrome-dependent metabolism and transmembrane transporters [138,139]. Therefore, consumption of ginseng is not recommended together with certain medications such as anticoagulants (warfarin), phenelzine (IMAO), some chemotherapeutics (imatinib), oral hypoglycemic and insulin, digoxin, anticonvulsant (lamotrigine) and antiestrogenic therapies [140–142]. 

24. Spices 

Spices may also interfere with a drug's metabolism. Recently, a group of Japanese researchers investigated the action of 55 species on the cytochrome system [143]. Interestingly, cinnamon, black and white pepper, ginger, turmeric, and nutmeg may inhibit the activity of CYP isoforms 3A4 and 2C9, which catalyze the biotransformation of many drugs so that their effects are prolonged. For example, turmeric increases the effect of chemotherapy drugs, whereas cloves increase the action of antibiotics. On the contrary, ginger can increase the gastric discomfort of NSAIDs. However, the interactions can be more often detected when spices are taken in high doses, and the drugs have a lower therapeutic index/narrow therapeutic range, as in the case of oral anticoagulants.

25. Black Pepper 

Piperine contained in black pepper inhibits both P-glycoprotein and cytochrome CYP3A4 [144,145], so it can modify the concentration of those drugs that are the substrate of both systems. In particular, P-glycoprotein recognizes as substrates certain chemotherapy pneumatics (etoposide, doxorubicin, vinblastin), digoxin, immunosuppressants, glucocorticoids (dexamethasone), anti-HIV agents, colchicine, tacrolimus, and quinidine. Substrates of CYP3A4 include tricyclic antidepressants (amitriptyline, clomipramine, imipramine), benzodiazepine (alprazolam, midazolam, triazolam), antibiotics (erythromycin, clarithromycin, dapsone), antihistamines (terfenadine, astemizole), calcium-channel blockers (nifedipine, felodipine, diliazem, verapamil), cyclosporin, lovastatin, dexamethasone, carbamazepine, cisapride, ethinyl estradiol, glyburide [143].