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Cocaine, also known as coke, is a strong stimulant mostly used as a recreational drug. It is commonly snorted, inhaled as smoke, or dissolved and injected into a vein. Mental effects may include loss of contact with reality, an intense feeling of happiness, or agitation. Physical symptoms may include a fast heart rate, sweating, and large pupils. High doses can result in very high blood pressure or body temperature. Effects begin within seconds to minutes of use and last between five and ninety minutes. Cocaine has a small number of accepted medical uses such as numbing and decreasing bleeding during nasal surgery. Cocaine is addictive due to its effect on the reward pathway in the brain. After a short period of use, there is a high risk that dependence will occur. Its use also increases the risk of stroke, myocardial infarction, lung problems in those who smoke it, blood infections, and sudden cardiac death. Cocaine sold on the street is commonly mixed with local anesthetics, cornstarch, quinine, or sugar, which can result in additional toxicity. Following repeated doses a person may have decreased ability to feel pleasure and be very physically tired. Cocaine acts by inhibiting the reuptake of serotonin, norepinephrine, and dopamine. This results in greater concentrations of these three neurotransmitters in the brain. It can easily cross the blood–brain barrier and may lead to the breakdown of the barrier. Cocaine is a naturally occurring substance found in the coca plant which is mostly grown in South America. In 2013, 419 kilograms were produced legally. It is estimated that the illegal market for cocaine is 100 to US$500 billion each year. With further processing crack cocaine can be produced from cocaine. Cocaine is the second most frequently used illegal drug globally, after cannabis. Between 14 and 21 million people use the drug each year. Use is highest in North America followed by Europe and South America. Between one and three percent of people in the developed world have used cocaine at some point in their life. In 2013, cocaine use directly resulted in 4,300 deaths, up from 2,400 in 1990. The leaves of the coca plant have been used by Peruvians since ancient times. Cocaine was first isolated from the leaves in 1860. Since 1961, the international Single Convention on Narcotic Drugs has required countries to make recreational use of cocaine a crime