A number of herbs are thought to be likely to cause adverse effects. Furthermore, "adulteration, inappropriate formulation, or lack of understanding of plant and drug interactions have led to adverse reactions that are sometimes life threatening or lethal." Proper double-blind clinical trials are needed to determine the safety and efficacy of each plant before they can be recommended for medical use. Although many consumers believe that herbal medicines are safe because they are "natural", herbal medicines and synthetic drugs may interact, causing toxicity to the patient. Herbal remedies can also be dangerously contaminated, and herbal medicines without established efficacy, may unknowingly be used to replace medicines that do have corroborated efficacy. Standardization of purity and dosage is not mandated in the United States, but even products made to the same specification may differ as a result of biochemical variations within a species of plant. Plants have chemical defense mechanisms against predators that can have adverse or lethal effects on humans. Examples of highly toxic herbs include poison hemlock and nightshade. They are not marketed to the public as herbs, because the risks are well known, partly due to a long and colorful history in Europe, associated with "sorcery", "magic" and intrigue. Although not frequent, adverse reactions have been reported for herbs in widespread use. On occasion serious untoward outcomes have been linked to herb consumption. A case of major potassium depletion has been attributed to chronic licorice ingestion., and consequently professional herbalists avoid the use of licorice where they recognise that this may be a risk. Black cohosh has been implicated in a case of liver failure. Few studies are available on the safety of her s for pregnant women, and one study found that use of complementary and alternative medicines are associated with a 30% lower ongoing pregnancy and live birth rate during fertility treatment. Examples of herbal treatments with likely cause-effect relationships with adverse events include aconite, which is often a legally restricted herb, ayurvedic remedies, broom, chaparral, Chinese herb mixtures, comfrey, herbs containing certain flavonoids, germander, guar gum, liquorice root, and pennyroyal. Examples of herbs where a high degree of confidence of a risk long term adverse effects can be asserted include ginseng, which is unpopular among herbalists for this reason, the endangered herb goldenseal, milk thistle, senna, against which herbalists generally advise and rarely use, aloe vera juice, buckthorn bark and berry, cascara sagrada bark, saw palmetto, valerian, kava, which is banned in the European Union, St. John's wort, Khat, Betel nut, the restricted herb Ephedra, and Guarana. There is also concern with respect to the numerous well-established interactions of herbs and drugs. In consultation with a physician, usage of herbal remedies should be clarified, as some herbal remedies have the potential to cause adverse drug interactions when used in combination with various prescription and over-the-counter pharmaceuticals, just as a patient should inform a herbalist of their consumption of orthodox prescription and other medication. For example, dangerously low blood pressure may result from the combination of an herbal remedy that lowers blood pressure together with prescription medicine that has the same effect. Some herbs may amplify the effects of anticoagulants. Certain herbs as well as common fruit interfere with cytochrome P450, an enzyme critical to much drug metabolism.