The Clinical Importance of Herb-Drug Interactions and Toxicological Risks of Plants and Herbal Products

Approximately 70% of the world’s population has been using medicinal herbs as a complementary or alternative medicine that has grown tremendously in both developed and developing countries over the past 20 years (World Health Organization Drugs Strategy 2002–2005). This increase in consumer demand for medicinal plants contin-ues, although scientific data are rare to create safety and efficacy profiles. Its popularity is also related to easy availability, cost-effectiveness leading to better purchasing power, and various factors that perceive that they are generally safe. Herbs are often administered simultaneously with therapeutic drugs for the treatment of major ailments, and herb-drug interactions (HDIs) increase their potential. The main routes proposed for HDIs include cytochrome P450 (CYP450)-mediated inhibition or induction and transport and flow proteins. In our review, we highlighted herbal medicines used for the treatment of various diseases with pharmacokinetic, pharmacodynamic analysis and case reports together with their adverse effects and herb-drug interactions. Therefore, this review can be used as a quick reference database for physicians and healthcare professionals involved in therapy, aiming to maximize clinical outcomes by reducing the negative and toxic effects of plants along with avoiding herb-drug interactions.


Introduction
Herbal products are considered the best choice as complementary medicine in western countries, especially in the United States and Europe. Annual sales of dietary herbal supplements in the United States increase 6.8% year over year. In addition, China and India are the top export countries, while Hong Kong, Japan, the United States, and Germany are the leading importers. The Confederation of Indian Industry (CII) presented that the market size of the Ayurvedic industry in the country is $ 4.4 billion, and the total market size of the Indian health industry is $ 11.8 billion. There has been an increase in demand for "complementary" medicines, including those of plant origin. In addition, there is a significant increase in the self-administration of herbal medicines among the public. In the context of the growing demand and use of herbal medicines for patients and the public, and the subsequent interests of the regulatory authorities, comprehensive research on the safety and effectiveness of herbal products, including the possibility of interactions when simultaneous application is required, should be encouraged. This is because all herbal medicines and dietary supplements are a complex mixture containing multiple active phyto-components that increase the possibility of herb-drug interaction (HDI). Most people who consume herbal products and supplements do not show this to their pharmacist or doctor, thereby increasing the likelihood of HDI being identified and resolved over time. However, data from recent studies show that there is potential for serious interaction between some commonly used herbs/herbal products and commonly used standard medications [1].
In our review, we highlighted herbal medicines used for the treatment of various diseases with their adverse effects and herb-drug interactions, and stated recommendations for proper use of plants that might prevent possible risks for future incidents.

Toxicological risks of plants and herbal products
General risks associated with herbs and/or herbal products include: • Misidentification without assigning with Latin names. Possible causes of misidentification include contamination of cultivated plants with weeds, and resembling plants mistaken for herbs collected in the wild.
• Contamination with harmful substances such as heavy metals, polycyclic aromatic hydrocarbons, dioxins, as well as natural toxins or microorganisms.
• Interaction with other drugs, such as antagonism or synergism, and medical tests that potentially lead to misdiagnosis.
• Adulteration with other medicinal drugs.
• Intrinsic toxicity caused by the presence of natural toxins, such as aristolochic acids [2].

Nephrotoxicity
The drug or toxin that causes kidney damage when exposed to a certain level cannot pass the excess urine, and the waste product is what is called nephrotoxicity. In this case, there is an increase in blood electrolytes, such as potassium and magnesium. This situation begins temporarily but can be serious if it is not detected before. Blood urea nitrogen (BUN) test and creatinine levels in the blood are two simple tests called as kidney function tests used to detect the nephrotoxicity. For healthy individuals, the normal levels of BUN and creatinine are between 10-25 mg/dl and 0.7-1.4 mg/dl, respectively. The following factors may increase these values: a. Dehydration.
b. Obstruction of blood flow to or from kidney caused by a tumor, stone, or irregular heart rhythms.
c. Nephritis or urinary tract infection.
tetrachloride. In the second category, hypersensitivity reactions, for example, phenytoin reaction, cause an immunoallergic or metabolic idiosyncratic reaction due to fever, rash, eosinophilia and indirect drug reaction for a short time. The second reaction type response rate is variable, for example, halothane [3]. Drug interaction mechanisms: when some drugs are taken at the same time, they react together and cause liver damage. For example, the combination of tylenol with INH, histamine, laniazide, and nydrazide can be hepatotoxic [3].
When hepatotoxicity caused by herbal drug intake is discussed, case rates are often reported. The severity of toxicity varies greatly between mild hepatitis and acute liver failure. The scoring system for allopathic drugs can be evaluated, but not suitable for herbal medicines and needs validation. Many Ayurvedic and Chinese herbal medicines are reported to cause hepatotoxicity. The main hepatotoxic herbs are Cimicifuga racemosa (L.) Nutt., Larrea tridentata (Sessé & Moc. ex DC.) Coville, Scutellaria baicalensis Georgi, Scutellaria lateriflora L., Teucrium chamaedrys L., etc. [3].

Cardiotoxicity
Cardiotoxicity is a term used for damage to the heart or change heart functions. It is a condition where there is a change in the electrophysiological function of the heart or damage to the heart muscle, weakening the heart and causing poor blood circulation. This can be detected by symptoms such as dry, unproductive cough; inflammation in the ankles, hands, feet, and neck vessels; irregular heartbeat; tachycardia; cardiomegaly; weakness; dizziness; etc. [3].

Potential precautions of plants on hypertension
Herbal products are widely used in the general population and many are encouraged for the natural treatment of hypertension. Patients with hypertension often prefer to use these products in addition to or instead of pharmacological antihypertensive agents. Due to the frequent use of herbal products, both consumers and healthcare providers should be aware of the major issues surrounding these products and factors affecting both effectiveness and damages (

Neurotoxicity
The physical brain damage occurred by exposure to neurotoxin is stated as neurotoxicity. Neurotoxin is a substance that causes changes in the nervous system activity by disrupting or killing neurons. Neurotoxicity symptoms are generally emotional disorders, visual impairment, extremity failing, sexual dysfunction, headache, and behavioral alteration. Atropa belladonna, Brugmansia species, Catharanthus roseus, Cannabis sativa L., Conium maculatum L., Coscinium fenestratum (Goetgh.) Colebr., Datura stramonium L., Hyoscyamus niger L., and Papaver somniferum L. are the common medicinal herbs that have potential neurotoxic effects [3].

Psychiatric and neurological adverse effects
Psychiatric and neurological patients often try herbal medicines assuming they are safe. Numerous case reports include various adverse events such as cerebral arteritis, cerebral edema, delirium, coma, confusion, encephalopathy, hallucinations, intracerebral hemorrhage and other cerebrovascular accidents, movement disorders, mood disorders, muscle weakness, paresthesia, and seizures. Some deaths have been recorded. Misuse is caused by toxicity of herbal ingredients, contamination and adulteration, and herb-drug interactions [6] (

Skin toxicity
Cutaneous toxicity is a term used for a pronounced negative effect such as skin irritation, inflammation, or rashes of the epidermal growth factor receptor caused by exposure to a plant, chemical, or environmental factor. Skin consisting of a layer of dead cells and several layers of living cells is the largest organ and a defensive barrier of the body. When irritant influences into the skin, the living cells react due to cause inflammation or dermatitis. Inflammation consists of four parts including redness, pain, heat, and swelling. Skin toxicity can be detected easily as the reaction is observed immediately. The most common sources of skin toxicity are food and cosmetics, and others are medicated lotions, balms, creams, inhalers, and essential oils. Various herbal ingredients are available in all the cosmetics and medicinal products mentioned above. Types of skin sensitization reactions include: Photosensitization dermatitis: it is a cutaneous toxic response caused by exposure to sunlight when a photosensitizer (sunlight sensitive compound) is present in the body and can be detected by sunburn-like reactions in pigment-free areas. Plants such as Agave lechuguilla Torr., Bassia scoparia (L.) A.J.Scott, Hypericum species (St John's wort), Lantana camara L., Tetradymia species, and Tribulus terrestris cause photosensitive dermatitis [3].
There is another type of phototoxic photosensitization caused by contact with some plants. Such a reaction occurs when a photoactive chemical produced by plants touches the skin, and is absorbed and activated by sunlight. Intensity varies depending on time and exposure amount. Anethum graveolens L., Apium graveolens L., Brassica oleracea L., Citrus aurantiifolia (Christm.) Swingle, Daucus carota, Ficus carica, Hypericum perforatum (St. John's wort), Petroselinum crispum, and Ranunculus acris are reported to produce contact photosensitization [3].

Contamination of herbal medicines by tropane alkaloids
Tropane alkaloids that have been known as toxic and hallucinogenic are mainly seen in Solanaceae plants (Atropa belladonna, Hyoscyamus niger, Datura stramonium, etc.). All over the world, anticholinergic poisoning is observed due to the contamination of herbal teas and plants with tropane alkaloids. Tropane alkaloid poisoning can occur after consumption of any medicinal plant from Solanaceae family as contaminants. Globally, almost all reports from 1978 to 2014 include one of the herbs prescribed in herbal teas. Contamination is most likely to occur during harvesting or processing. For herbs, on-site inspection is required to exclude crosscontamination at the retail level and accidental mixing. The diagnosis is confirmed by screening for the presence of Solanaceae species and tropane alkaloids. Since, if these relatively heat-resistant alkaloids contaminate the herbal teas and other herbs in large quantities, significant health hazards may occur, the significance of good agricultural and collection practices (GACPs) for medicinal plants is accentuated by WHO repeatedly. The DNA barcode is also increasingly used to exclude the presence of pollutant (especially toxic species) and product substitution. All suspect cases should be reported to health authorities so that investigations throughout the supply chain and early intervention measures to protect the public can be taken [7].

Herb-drug interactions with the plants including furanocoumarins
Naturally occurring furanocoumarins are abundant in citrus fruits, vegetables, and medicinal herbs from the Apiaceae, Fabaceae, and Rutaceae families. Grapefruitdrug interactions were first discovered by chance in 1989 where 5-fold higher felodipine plasma concentrations were observed. Consumption of grapefruit juice has increased the oral bioavailability of various drugs, including calcium channel blockers (e.g., felodipine, nifedipine), HMG-CoA reductase inhibitors (simvastatin, lovastatin), benzodiazepines (midazolam, triazolam), antihistamines (terfenadines), and immunosuppressants (cyclosporine). In addition, phototoxicity developing with furanocoumarins occurs as a result of exposure to sunlight, following contact with the plant. Phototoxicity results in acute dermatitis, sometimes blisters, and vesicles. In many cases, prolonged hyperpigmentation is observed. Photochemotherapy for a long time with furanocoumarins can also cause cancer (skin and liver) [8].

Toxicity of pyrrolizidine alkaloids
Pyrrolizidine alkaloids (PAs) are common components of hundreds of plant species of unrelated botanical families scattered across many geographical regions of the world. In more than 6000 plants belonging to three large plant families, Asteraceae, Boraginaceae, and Fabaceae, above 660 PAs and PA N-oxides have been identified and about half of them are toxic. More than 10,000 cases of PAs poisoning have been documented worldwide, most of which resulted from exposure to food contaminated with PAs. Acute toxicity from PA is mainly seen in the liver, including hemorrhagic necrosis, hepatic megalocytosis, venous occlusion, liver cirrhosis, and hepatic carcinomas, and chronic exposure to PAs, from herbs/dietary products containing PAs, can lead to kidneys, pancreas, gastrointestinal tract, bone marrow, and brain. It is a worldwide public health problem due to the high risk of human exposure to genotoxic and tumorigenic PAs, and the International Program on Chemical Safety has concluded that PAs are a threat to human health and safety. Regulations have been constituted to restrict its use [8].

Adverse effects of anthraquinone derivatives
Anthraquinone derivatives with a laxative effect appear in a number of plants: Sennae folium, rhei rhizoma, frangulae cortex, and aloe. They have a laxative effect by directly stimulating the colonic smooth muscles. The adverse effects of laxative anthraquinone drugs are more likely to be caused by excessive loss of fluids and electrolytes, especially potassium loss, associated with the use of high doses. Higher doses also drain a larger portion of the colon, and the resulting natural absence of defecation over the next day leads to reuse of anthraquinone. Prolonged use of laxatives due to laxative addiction should be avoided, as it may have a detrimental effect on the intestinal mucosa, leading to a condition known as Melanosis coli. This is usually seen after at least 9-12 months of regular stimulant laxative use. Undesirable effects such as abdominal spasms and pain, urine color change by metabolites, and hemorrhoid congestion are common. A report from China reported that patients with senna leaf tea addiction as laxatives suffer from symptoms of fidgetiness, sleeplessness, dilated pupils, and loss of appetite while consuming 5-9 g of senna daily. Rare cases of hepatic inflammation induced by anthraquinone derivatives have been reported and may be dose dependent. Hypokalemia, which occurs as the effect of long-term use of laxative drugs, strengthens the effect of cardiac glycosides and interacts with antiarrhythmic drugs. Using other drugs (diuretics, adrenocorticosteroids, and licorice) that cause hypokalemia can speed up electrolyte imbalance. Contraindications for anthracene laxatives are intestinal obstruction and chronic intestinal inflammation such as stomach or duodenal ulcer or ulcerative colitis [9].

Adulterations
Many reports on the adulteration of herbal products with synthetic drugs have been systematically reviewed and published with case reports. The list of herbal products and adulterants produced in this way is quite impressive and caused serious side effects ( Table 3). A case with the latest herbal product adulterated is related to a 56-year-old man from Indonesia. While visiting Australia, he was hospitalized in a mixed condition arising from hypoglycemia. He insisted that type II diabetes was controlled only by diet. However, despite dextrose infusions, glucose levels do not normalize. It was eventually discovered that he also received a TCM "Zhen Qi" from Malaysia. It was analyzed and shown to contain glibenclamide. Like that, in some cases, patients were severely damaged. Examples of serious side effects include agranulocytosis, Cushing's syndrome, coma, over-anticoagulation, gastrointestinal bleeding, arrhythmias, and various skin lesions. Due to the adulteration of herbal products with synthetic drugs, adequate and necessary procedures should be applied, and whole herbal products should be analyzed before marketing [10].

Heavy metal contaminations
It is possible to come across heavy metals such as cadmium, cobalt, copper, iron, manganese, nickel, lead, zinc, and mercury in concentrations that are not produced within the framework of certain rules, especially the traditional Chinese herbal preparations. This contamination is probably caused by contamination during drying and preservation. With severe complications that may occur, these types of products are unlikely to cause adverse health effects, even if they are not consumed in large quantities for long periods of time [11].

Herb-drug interactions (HDI)
There are no molecules in nature that have no effect. Therefore, this diversity increases the variety of products while increasing the probability of interaction. If the effect of a drug is changed qualitatively or quantitatively by another substance (herbal medicine/product/ingredient), there is an interaction between these two drugs. It can be said as a rule that two drugs should be present at the same time in the body, especially in the place of interaction, for interaction to occur. But sometimes, if the drug causes a permanent effect on the body, interaction can occur even if such a drug is not found in the body. Interaction is sometimes deliberately created to increase the therapeutic effect of one drug with another drug or to reduce its side effects, which are useful interactions. In other cases, the interaction may occur undesirably as a result of unauthorized use of medicines or when the patient is starting treatment with a particular medication. Sometimes, unpredictable interactions due to new drugs may occur. Drug-related as well as disease-related factors (patient's age, gender, genetic characteristics, pathological condition), such as the posology and method of administration, pharmacokinetic, pharmacodynamic, and therapeutic properties of the drug may cause interactions between medicines and herbal medicines (Figure 1) [12].
It is observed that the use of herbal medicines/herbal products is more common in the geriatric group aged 65 and over, and the use in women in this adult population is higher than in men. Herbs/herbal products/drug interaction is higher in patients using drugs with narrow therapeutic index. Information on herbs-herbal products/ drug/component interactions is based on in vitro tests, in vivo animal experiments, Figure 1. The important risk factors that influence the occurrence of interactions between herbal products and conventional drugs [13]. and case reports. Many mechanisms play a role in these interactions, and interactions are seen in two main types as pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic interactions result in changes in drug absorption, distribution, metabolism, and elimination. These interactions usually occur far away from the drug's effect and lead to a decrease or increase in effect as a result of the change in drug concentration in body fluids. In order to say that there is a pharmacokinetic interaction, the plasma level or half-life of the drug should be determined experimentally. Various interactions such as cytochrome P450, UDP-glucuronyl-transferase (UGTs), and carrier proteins such as P-glycoprotein (P-gp) are thought to play a role in these interactions. Pharmacokinetic interactions are the most common interactions as a cause of undesirable side effects. If the herb or natural products or its secondary metabolites inhibit an enzyme involved in drug metabolism, it may increase the potential for toxic effects, as it will reduce the metabolism of drugs that metabolize the enzyme and turn into an inactive metabolite as a result of metabolism. If the herbal drug induces an enzyme, a decrease in drug effect may be observed, since the metabolism of the drugs that are metabolized by this enzyme and converted into inactive metabolite as a result of metabolism will increase. Likewise, if the drug turns into an active metabolite as a result of metabolism, if the herbal drug induces the enzyme responsible for the metabolism of the drug, an increase in drug effect or toxic effect may be observed as a result of increased effective metabolite concentration [12].
Pharmacodynamic interactions occur when one drug changes the effect of another, that is, an effect opposite or in the same direction, chemically combined with it. That is, if the herbal medicine and drug affect the same receptor or the same site, interaction occurs and a synergic or antagonistic effect may occur. While the effect of the drug increases as a result of the additive effect, the effect of the drug decreases or disappears as a result of the antagonistic effect. The concentration of the drug in body fluids, plasma, is not changed by the second drug. Although most of the drug metabolism is carried out in the liver with cytochrome P450 enzymes, the metabolism of some drugs can be in the blood, kidney, skin, and intestine. Approximately 50 different cytochrome P450 enzymes have been identified. However, a small portion of these enzymes play a role in drug metabolism. Herbal drug-drug interactions are generally pharmacokinetic-type interactions that result from enzyme inhibition or induction [12].
The following are the evaluation parameters used to determine the probability of herb-drug interactions: h. An adverse event has been sufficiently defined.
i. The event ends after stopping the medicine.
j. The activity repeats upon challenge again [3].

Herb-drug interactions in the treatment of cardiovascular disorders (CVDs)
In 2015, an estimated 422.7 million cases of cardiovascular disease (CVD) and 17.92 million CVD deaths were reported worldwide. And most people in the world still prefer complementary and alternative medicine (CAM) as their first treatment option. The consumption of over-the-counter CAM consumption increases the risk of HDI, which endangers the effective medical management of CVD. In cardiac therapy, the narrow therapeutic drug window and a wide range of cardiac drugs available for treatment are also a major cause of concern for HDI. People with chronic diseases often use CAM therapies inappropriately to manage their condition and thereby increase the potential or possibility of HDI formation [1].
This section of our review focuses on plants reported in the literature by preclinical or clinical studies (rats or humans) or cardiovascular drugs with appropriate case reports. These herbs are reported to affect the pharmacokinetics of some cardiovascular drugs through a variety of HDI mechanisms. Reported HDI studies of some plants commonly used for the treatment of CVDs are summarized in

Herb-drug interactions with chemotherapeutic drugs
One of the most important risks associated with the combined use of herbal products and chemotherapeutic agents is herb-drug interactions. Patients with chronic illnesses who use more than one drug have a higher risk. Herb-drug interaction is undesirable in the treatment of cancer due to the perpendicular dose-effect relationship and toxicity of chemotherapeutic agents. The most common mechanism of herb-drug interaction is herbal mediated inhibition and/or stimulation of drug-metabolizing enzymes and/or transport proteins that lead to changes in the pharmacokinetic order of the victim drug. This focus on clinically significant herb-drug interaction should attract public attention, including practitioners, researchers, and cancer chemotherapy consumers ( Table 5) [14].

Herb-drug interactions with attention-deficit/hyperactivity disorder (ADHD) medication
In some pediatric patients with attention deficit/hyperactivity disorder (ADHD), natural products such as herbal medicines are used. Although herbal remedies are thought to be safe when used appropriately, they may contain active ingredients that can interact with concurrently used medications and can lead to adverse events for natural products-drug interactions ( Table 6) [15].

Herbs
Interacting drugs CYP, P-gp induction/inhibition

Herb-drug interactions (HDI) with chronic kidney disease (CKD) medication
Chronic kidney disease (CKD) is defined as abnormalities in kidney structure or function that have been going on for more than 3 months, with adverse health consequences. The prevalence of CKD is estimated to be 8-16% worldwide.  Table 5.
Herbal interaction studies with chemotherapeutic agents conducted in human subjects [14].
Most importantly, patients with CKD are advised to avoid over-the-counter products and herbal medicines according to the Kidney Disease Improving Global Outcome (KDIGO) guidelines. However, several studies have revealed that many patients with CKD have returned to complementary and alternative medicine (CAM) for a desperate treatment. The consumption of unregistered herbal products is more common today because these products can be easily purchased from on-line media, street markets, or stores. It is an alarming trend as it may be linked to an increase in the number of patients with liver and kidney failure in public hospitals. In addition, patients with CKD are at higher risk of developing cardiovascular disease. Most of them are prescribed with antiplatelet and anticoagulants. Anti-platelets and anticoagulants

Herb-drug interactions with menopause medication
Herbal remedies are popular among women to relieve menopausal symptoms such as hot flashes, energy loss, depression, joint pain, and insomnia. As recently reviewed, a variety of herbs used to treat menopausal symptoms can cause herbdrug interactions ( Table 8) [17].

Herb-micronutrient interactions
The ability of some foods to reduce or increase the absorption of various vitamins and minerals has been known for years. Almost half of the population regularly uses some herbal products as a dietary supplement, along with the vitamin and mineral supplements. The use of these products has increased significantly over the past two decades, and a number of clinically relevant herbal drug interactions have been identified during this time. Therefore, it is likely that the mechanisms underlying many herb-drug interactions may also affect micronutrient absorption, distribution, metabolism, and excretion. Not taking these eccentricities into account can negatively affect the outcome and interpretation of any advanced herb-micronutrient interaction studies [18] ( Table 9).

Cimicifuga racemosa
Increase the activity of antihypertensive agents

Angelica sinensis Inhibit platelet aggregation and increase risk of bleeding if co-medicated with anticoagulants
Oenothera biennis L.
Potentially interacts with anti-inflammatory drugs, corticosteroids, beta-blockers, antipsychotics and anticoagulants Trifolium pratense L. Increase the activity of CYP3A4 and alters the metabolism of drugs Humulus lupulus L. Interact with CNS depressants, antipsychotics, hormones and CYP-metabolized drugs

Databases setup for plants/dietary supplements
The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center has developed About Herbs (www.aboutherbs.com), which provides research information, including alleged uses, side effects, and herb-drug interactions for about 284 dietary supplements. Using Google Analytics, they have detected that more than 26,317,000 hits have been recorded since November 2002. According to these data, top 10 plant and/or dietary supplements in 2018 were chaga mushrooms, turmeric, ashwagandha, reishi mushroom, graviola, Active Hexose-Correlated Compound, boswellia, dandelion, green tea, and Coriolus versicolor. In Table 10, based on the literature researches in PubMed, their scientific and common names, plant-drug interactions and their appropriate use in the oncology environment are discussed. In the past 16 years, evidence of the use of these supplements is based on limited studies and mostly preclinical findings. It is important to inform healthcare professionals about popular dietary supplements so that patients can be informed to make decisions that maximize benefits and minimize risks [19] Hereby, important herb-drug interactions have been compiled in Table 11.  May decrease the plasma level of protease inhibitor saquinavir [24,25] Antidiabetic (metformin, chlorpropamide) May occur greater reduction in blood glucose level [26,27] Paracetamol (acetaminophen) May change some pharmacokinetic variables of paracetamol [28] Aloe vera L.
Laxative antidiabetic [20] Corticosteroids and potassium-depleting diuretics Laxative and potassium lowering effect may result in hypokalemia [29,30] Cardiac glycosides and antiarrhythmic drugs May enhance the hypokalemia-related arrhythmia [29,30] Antidiabetics Because of the glucose-lowering effects, diabetic patients should be careful when combining with an antidiabetic agent [31] Cassia senna L.

Less efficacy with
Ginkgo [48] Omeprazole (proton pump inhibitor) May induce the metabolism, and reduce the effect of omeprazole [49] Tolbutamide (an antidiabetic drug) May increase or decrease the hypoglycemic effect of tolbutamide [50] Amikacin (aminoglycoside) Amikacin ototoxicity may enhance [51] Glycyrrhiza glabra Expectorant, antispasmodic and antiinflammatory properties and in treatment of peptic and duodenal ulcers [20] Prednisolone (corticosteroid) Glycyrrhizin increases the plasma concentrations and potentiates pharmacological effects of prednisolone [52,53] Hydrocortisone (corticosteroid) Glycyrrhetinic acid potentiates the activity the topical cutaneous vasoconstrictor effect [54] Dexamethasone (corticosteroid) Dexamethasone induces the mineralocorticoid effects of glycyrrhizin [55] Antihypertensives Mineralocorticoid effects (sodium and water retention and hypokalemia) of plant reduce the efficacy of the drugs that use to lower blood pressure. Hypokalemic effect of the plant may increase the effect of the loop and thiazide diuretics [20] Plants Effect and usage

Hypericum perforatum
To treat depression, seasonal affective disorder, anxiety and insomnia, especially related to menopause [20] Gliclazide (an antidiabetic drug) Increases the apparent clearance of gliclazide [56] Carbamazepine, phenytoin and phenobarbital (antiepileptics) Clinically significant interaction is unlikely, but Hypericum should be used carefully with these antiepileptic drugs [20] Alprazolam, midazolam, triazolam and quazepam (benzodiazepines) Since the main compound hyperforin induces the enzyme CYP3A4, bioavailability may decrease [20,57] Indinavir (protease inhibitor) Nevirapine (nonnucleoside reverse transcriptase) May decrease the antiretroviral drugs and may lead to development of drug resistance [58,59] Cyclosporine, tacrolimus, (Immunosuppressants) May decrease the blood levels and may lead the acute organ rejection in transplant patients [60][61][62] Warfarin and phenprocoumon (anticoagulants) May cause a moderate reduction in the anticoagulant effects of the drugs [20] Simvastatin and atorvastatin (antihyperlipidemic agents) May observe the increasing serum level of total cholesterol [63,64] Nifedipine, verapamil (calcium channel blockers) and talinolol (a β-adrenoceptor blocker) May decrease the bioavailability of drugs [65] Oral contraceptives Associated with increased metabolism of ethinyl estradiol, norethindrone, and ketodesogestrel, and may cause bleeding and unwanted pregnancy [66][67][68][69] Carbamazepine (antiepileptic) Should be considered a mild interaction between carbamazepine and

Hypericum
Sertraline, nefazodone (selective serotonin reuptake inhibitors) May be occurred the symptoms of central serotonergic syndrome [70] Linum usitatissimum L. Demulcent for bronchitis and coughs, and topically used for burns [20] Anticoagulant or antiplatelet drugs In the view of the thought that omega-3 fatty acids such as linolenic acid have antiplatelet effects, should be concerned about the possibility of prolonged bleeding [20] The

Panax ginseng
Adaptogenic [20] Phenelzine (MAO inhibitor) Additive nervous system effect of drug such as headache, tremor, sleeplessness and mania [34] Warfarin (anticoagulant) INR may decrease by concomitant usage [71] Warfarin, heparin, aspirin, and NSAIDs There is no clear data, but due to the antiplatelet components in P. ginseng, it should be avoided concomitant using [32] Caffeine Possible additive stimulant effects [20] Piper methysticum Anxiolytic, sedative, aphrodisiac

Barbiturates and benzodiazepines
Might potentiate the effects of central nervous system depressants [72] Alprazolam (benzodiazepine) Risk of coma due to possible additive effect on GABA receptor [72] Levodopa May reduce the efficacy due to possible dopaminergic antagonism [73] Acetaminophen May enhance the risk of hepatotoxicity [33] Valeriana officinalis Used for stress and insomnia as sedative and anxiolytic [20] Barbiturates Excessive sedation. The active component valerenic acid seems to likely to have the additive effect to phenobarbital [74] Other central nervous system depressants such as benzodiazepines and opioids Possible additive sedative effects [20] Caffeine Possible reverse effect to the sedative effect of Valerian [20] Zingiber officinale To reduce nausea and emesis induced by pregnancy, chemotherapy, and postoperative ileus [75] NSAIDs May reduce the platelet aggregation and enhance the bleeding tendency [33] Nifedipine May potentiate the antiplatelet effects [76] Metronidazole May increase the bioavailability [77] Glibenclamide (antidiabetic) May reduce the blood glucose level [26]

Criteria for risk assessment of herbal products
There have been an increasing number of herbal products as food ingredients or supplements, which are a commercially important part of the health food market. Herbal products can range from whole foods (e.g., cranberry against urinary infections) to pharmaceutical-like preparations in unit dose form, such as tablets, capsules, or drops, and are thought to provide additional benefits beyond basic nutrition. The regulatory position on food supplements is uncertain (food or medicine?), and there is concern about the safety assurance of these products. Several cases of poisoning have been reported with herbal products. In some cases, these were caused by contamination with other plant species, but this is not always the case. In addition, toxic components (e.g., pyrrolizidine alkaloids) are accumulated at different concentrations in different parts of the source plant, and climatic and agronomic differences lead to great variability in the composition [78]. Therefore, it is not possible to provide a simple checklist of suitable tests to ensure the safety of herbal products. International guidelines are available for the safety assessment of herbal product and should be designed to cover all life stages to ensure a lifelong intake that can be consumed without significant health risk [78].
Information relating to herbal product identification, characterization, and standardization: A. Botanical source: identity to family (geographic origin), genus, and species of source plant (with authority), and, if relevant, variety and chemotype; common names as well as part(s) of plant used. Evidence from previous human exposure through food or other sources (ethnobotanical and folk medicine studies). C. Raw material (fresh or dried plant materials): specifications according to standard reference (e.g., herbal Pharmacopoeias), identity tests (macroscopic, microscopic, FT-IR, TLC, GC, HPLC, etc.), quantitative tests (especially constituents related for efficacy and/or toxicity).

E.
Botanical preparation: standardization criteria (markers: active constituents, other related components; plant extract ratio), specifications: levels and range for markers, physico-chemical properties of relevant components; stability, purity criteria by chain control or analysis; microbiological, mycotoxins, pesticides, and environmental contaminants. Nature and level of excipients; formulation methodology, storage conditions should have been specified.
F. End product: formulated product.
G. Specification of the product.
H. Extent of use and estimated intake (posology and method of administration). and integrative health science. This plan has been published to inform the public, healthcare professionals, and health policy makers, with evidence-based information about the usefulness and safety of complementary and integrative health interventions and their role in health care development. The plan uses key research to facilitate understanding of the biological effects, mechanisms of action, effectiveness, and clinical effects of complementary health approaches. Both the WHO and NCCIH plans aim to improve TM and CAM knowledge, including phytotherapy. Therefore, understanding herb-drug interactions and the molecular mechanisms involved in these processes is a way to guarantee safe use of MP and/or HMP. In addition, this can help therapeutic planning and healthcare professionals to recommend the best treatment strategy to use. In this review, some critical issues are also discussed. The botanical identification and labeling of the plant material are important for preventing undesirable health problems. The changes in the scientific definitions of the plants in traditional medicine in time can cause unwanted or toxicologic effects by the usage of the wrong plant. The contamination of the plants with the environmental contaminants (microorganisms, fungal toxins such as aflatoxins, pesticides, and heavy metals), inappropriate preparation process, and interaction of traditional herbs by concomitant or consecutive usage also endanger the safety of herbal medicine for human health. What makes herbal medicine research valuable is that it has the chance to research harmful and toxic plants for developing pharmacologically and therapeutically worth remedies, and to develop medicinal plant combinations as safe and efficient herbal medicines. Standardization and strict control mechanisms are essential to maintain the high quality of herbal products and to prevent from the contaminations for the safety of patients [17].
The following guidelines can be suggested to minimalize the risk of herbal uses: