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Cocaine - Where The Party Ends
By Nathaniel Evans

There once was a monkey who was locked up in a cage in a laboratory in the early 1990's. This monkey did not mind his incarceration for he was given the only drug that laboratory animals prefer to food, water, and sex. This monkey was reinforced to press a bar for an intravenous dose of cocaine. As time went by and Curious George (the monkey) pressed his bar for cocaine, something seemed to be changing. Curious George noticed that he had to press the bar more times to receive the same amount of cocaine than he did previously. Curious George did not care. If allowed to self-administer as much cocaine as he wanted, George would kill himself by overdose. At the end of the study Curious George had pressed his bar more than 12,800 times to r eceive a single dose of cocaine (Barclay 2003).

The effect that cocaine has on monkeys is similar to its effect on humans. The only difference is that most humans have the ability to self administer until death. 51% of the United States population have at some time in their lifetimes used marijuana, cocaine, heroin, prescription sedatives, stimulants or hallucinogens. 15% have used one or more of these in the last twelve months. The overall expenditures of U.S. citizens, other than caffeine, as of 1990 are: $50 billion on alcohol, $40-50 billion on cocaine, $35 billion on tobacco, $30 billion on prescription and over the counter psychotropics, $25 billion on marijuana, and $20 billion on the rest, for a total of $200 billion. For comparison, the United States spends $ ×450 billion on medical care, $250 billion for non-drug recreation, and $100 billion for automobiles. In terms of health there are 400,000 deaths from tobacco, 100,000 from alcohol, 5,000 from prescription drugs, and 3,500 for the other remaining drugs except for marijuana, which there are zero, every year (Perrine 1996).

21 million U.S. citizens have tried some form of cocaine in their lifetimes. 855,000 use it at least once a week. Every day 5,000 U.S. citizens try cocaine for the first time. The use of cocaine is very dangerous, not only for its toxic effects on the body but also for the unknown composition and purity of the cocaine bought on the streets. Purity levels range from bag to bag, and so the cocaine user does not know how much p █ure cocaine is actually ingested. This implies that two lines of the same size may contain different amounts of cocaine. One line might be a lethal dose, where the other one may not induce any effects. Therefore it is not safe for a user to deduce his/her tolerance level. The lethal threshold of the heart may decrease with every use, therefore this self diagnoses is dangerous. There are four factors that determine the effects of a drug upon an individual. The first one, is the individual. Each individual is a unique biological organism in respect to personality and psychology. The mental set of the individual is a very influential factor as well as the setting that the drug is taken. The fourth factor is the pharmacology of the drug it self. This last factor is what will be looked at in the following hydrolysis of cocaine. In order to understand cocaine, we must look at its history, the physiology of the human brain, and the effects it has on the body when ingested alone and with other drugs.

It is very common with drug users to mix their drugs of choice. There are two major types of drug interactions. Drugs may act on each other to potentiate each others effects, called synergism. When cocaine and heroin are mixed they cause a synergistic effect. The 9second major way that drugs can interact is that one can act as therapeutic antagonist and nullify the effects of the other. This is seen in the the emergency care of heroin overdoses with the use of Narcan. The most common combination of drugs seen in emergency rooms across the U.S. is alcohol and cocaine. One of the most dangerous combinations is cocaine and heroin, called a speedball. Both of these combinations have not been fully studied and need more research to understand and prevent their lethal effects. They will be reviewed in the following chapters of this paper.

Chapter 1
The History of Cocaine

The coca plant grows wild in the Andes of South America, Indonesia, Thailand, and parts of China and Asia. Originally from the mountains in Columbia and Bolivia, the coca plant has an interesting his ótory that has effected the lives of many people. The first known crops of coca were set aside by the Incas. They chewed the coca leaf for stamina when working the fields, hunting and gathering food, and in times of famine and war. Radio carbon dating of coca chewing paraphenelia found in Chili and Ecuador was aged at 2,000 years old (Karch 1998). Inca coca production was never used for a source of revenue. The coca leaf was too hard to preserve and transporting also proved to be a problem. This all changed, as many things did, with the arrival of the Europeans.

The King of Spain began handing out land grants and coca crops became plantations. The Incas became slaves and workers on the plantations. The Spanish found coca to be very helpful. They gave the indigenous people who worked on their plantations and mines as much coca leaf to chew as they wanted. The coca leaf increased the stamina as well as decreased their appetite. In 1545, silver was discovered in the Andes at an elevation of 14,000 feet. Although the living conditions were very harsh at this elevation, coca thrived there and in turn became a commodity. Coca leaves were supplied in surplus to the miners. Against religious beliefs, the Spanish tolerated and supported the drug trade for two reasons. One, the coca production was taxed and made the Spanish government a lot of money, and two, King Phillip II believed that the silver mines could not survive with it. Coca production persisted in South America, regardless of fluctuations of any sort (including political and economical changes) for hundreds of years and is still growing there.

In the beginning of the 19th century the European scientific community became interested in the coca plant. Many explorations to South America provided information about the coca leaf and many other exotic plants. The uses of the coca plant particularly intrigued the European community. In 1841, Sir William Hooker was appointed the director of the Royal Botanical Gardens in Kew. Hooker revived King George the III's and Sir Joseph Banks' vision of the botanical gardens. Their vision was to grow as many exotics as possible and to send the plants to as many botanical gardens across the British Empire as possible. They believed that plants had much to teach the scientific world and so the more people who studied and experimented with them, the better.

In 1869, Hooker received coca seedlings. It took forty years before the coca plants grown in Kew were morphologically identical to the mother plants described by the explorers who had collected the seeds in the 1850's expedition to South America. Seeds from these plants were shipped to the botanical research stations across the British Empire (India, Africa, Ceylan, and Jamaica). The seeds were not sent to the Dutch controlled Java. In Java the Dutch had found a much more potent strain of the coca plant from previous expeditions (Karch 1998).

In 1860, Albert Nieman isolated cocaine hydrochloride from coca leaves by a process that is still used by the drug lords of today (Karch 1998). At this time the medical community was interested in the psychoactive properties of the coca leaves. It took 25 years before cocaine was discovered to be an effective local anesthesia. This was due to the lack of raw materials. The coca leaves contain 0.5-1% cocaine hydrochloride. The leaves were, at the time, very hard to package and ship with out loosing potency. By the time the leaves made it back to England they had lost all po tency due to rot. This proved a problem until Nieman had found an easy way of making coca paste. This process was used in South America and the coca paste was shipped without losing any potency and it took up a lot less space.

As cocaine became more popular, studies were done in the latter part of the 19th century that showed coca leaves prolonged and induced endurance and strength. This increased the interest of the commercial community who began to experiment with the coca leaves. In the 1880's, Vin Mariani invented coca-wine (Karch 1998). Vin Mariani became very famous for his wine due to his publicity and self promotion. Mariani was a very smart capitalist and used celebrities to promote his wine by sending them free cases of it. Even the pope was used to endorse Mariani's product.

This was the first documented use of cocaine and alcohol together. This combination made the coca-wine very famous because of the synergistic effects of mixing cocaine and alcohol. Coca-wine became popular and and imitations of Mariani's wine were made with higher contents of cocaine. They got higher concentrations of cocaine by soaking coca leaves directly in the wine. This extra process gave the wine a bad taste due to some of the impurities in the coca leaves themselves. At this time there were not strict guidelines that determined the difference between an alcoholic beverage and a medicine. Taste was the determining factor. If an imitation coca-wine had a high concentration of cocaine and had a bad taste the wine was recognized as a medicine. If the coca-wine had a good taste it was labeled as an alcoholic beverage and the equivalence of a liquor license was needed to sell it (Karch 1998).

In the early part of the 1880's, Karl Koller discovered cocaine to be a very effective local anesthesia for eye surgery. This was cocaine's first medical use. Cocaine was then used as a local anesthesia for many other surgeries and allowed many procedures to be done that were thought to be impossible. This includes gastrointestinal, rectal, tooth, and throat surgery. Henry Noyes, an interested scientist, attended a conference on Koller's work in Britain and then sent his account of the conference to New York. This letter was published on October 11, 1884 in the "New York Medical Record". This letter greatly increased the legitimate demand of cocaine for medical purposes. One American cocaine production company, Merck, increased its production of cocaine from 3/4 lb in 1883 to 3,179 lbs in 1884 to 158,352 lbs in 1886 (Karch 1998).

Cocaine was also used as a remedy for shyness, nervousness, and stage fright. It was also prescribed for treatment of morphine addicts. Cocaine has the opposite effects of morphine and therefore was thought to be a perfect remedy for the morphine addict. In 1884, Sigmund Freud published his first and most famous article "On Coca" which promoted cocaine and gave seven uses of it. Freud stated that cocaine could be used as a mental stimulant, possible treatment of some digestive disorders, appetite stimulant for wasting disease, treatment of alcohol and morphine addiction, treatment for asthma, an aphrodisiac, and a local anesthesia.

Freud's essay was widely accepted across the United States and Europe and within months physicians were treating morphine addiction with cocaine. Within six months of the publication of Freud's article, hospitals across these two countries were full of morphine and cocaine addicts. Many articles were published against the use of cocaine for the treatment of morphine addiction after this. After much pressure from the scientific community Freud published another article defending himself and conceded the argument with the method of intake. He said that the doctors had administered the cocaine intravenously rather than orally and this had caused the intense addictive properties (Karch 1998).

Cocaine was very popular in the medical community and was widely accepted by the general public,in the late part of the 19th century and it wasn't until the beginning of the 20th century that unhealthy aspects were understood and widely known. In 1886, the first recorded death due to an injection of cocaine for rectal surgery occurred. Before the invention and use of the hypodermic needle there were no deaths due to cocaine use. Because of the low content of cocaine hydrochloride in the coca leaves it is virtually impossible to overdose. Other problems began to arise with the use of cocaine. Seizures were induced in some cases where too much cocaine was used. Eye infections were very common when cocaine was used in eye surgery. Dentists also had problems because when cocaine was injected into the gums it went directly into the blood stream. The amount that they were injecting into the gums was too much and proved to be very dangerous. In one case, a women went in to get a tooth pulled and five minutes after her injection she had a massive heart attack and died ten minutes later. It turned out that she, as a child, had rheumatic fever which had caused heart problems and increased her heart attack risk. These consequences were disregarded in the beginning, but as time progressed the medical community began to lose interest in the drug (Karch 1998).

At the turn of the century, cocaine could be purchased over the counter at almost any pharmacy. It was also sold in intravenous kits, tooth drops, coca-wines and as a powder in the open markets on the streets. At this time, the percentage of the population of the country who was using cocaine was greater then than it is now. The total number of cocaine and heroin fatalities in 1912 was 5,000; that is double the amount of fatalities that occur now with four times the population. The trend of fatalities due to cocaine use changed from anesthesia deaths to recreational deaths. In 1924, the American Medical Association appointed a panel investigating deaths due to local anesthesia. By this time other local anesthesias had been isolated. The panel found that cocaine was responsible for fifty percent of local anesthesia deaths. They recommended that the dosage of cocaine administered be decreased and to stop injecting it all together (Karch 1998).

As time progressed through the turn of the 20th century, the recreational use of cocaine was beginning to become noticed by the governments of many countries. In 1912, the Hague Agreements were made between fourteen countries to limit the production of opium, heroin, and cocaine for legitimate use only. Negotiations continued on through WWI on how to implement these sanctions. From 1885 until the end of WWI, the legitimate production of cocaine steadily increased. By the end of WWI, the medical community had begun to lose interest in cocaine's medical use and so the legitimate demand for cocaine began to decrease. The cocaine production companies continued to increase their production in spite of the knowledge that a growing portion of their product was being funneled to the Black Market. The League of Nations issued the Limitations Act of 1925 which required each country to file a yearly report estimating the medical needs for that country and limit the imports to that amount. Many companies found loopholes because the Limitations Act did not set uniform requirements for all of the signatories (Karch 1998).

Many laws were also being passed in the U.S. during this time. In 1914, the first American anti drug law was passed called the Harrison Narcotic Act. This classified cocaine as a narcotic. This also stated that cocaine could only be used as a local anesthetic. All 48 states passed similar laws that year. The manufacture and distribution of cocaine became highly regulated by the government. From this time until the 1970's, the perception of cocaine continued to turn negative due to the many medical errors, over doses, and the availability of more effective and safe drugs.

During the 1970's, there was a resurgence of cocaine because of the new nightclub disco lifestyle. In the mid 1970's, crack cocaine appeared and became very popular in the inner city. This is because crack is reported to give a very good high and also it is very cheap due to the cutting process. The use of cocaine traveled from the night club scene into Wall Street as the 1980's arrived. Executive life required more long hour weeks and cocaine became very useful. The cost dropped dramatically due to the new demand of the drug and this in turn increased the amount of users. From 1974-1982, cocaine users increased from 5.4 million users to 21.6 million users. From 1977-1979, the number of people who used some form of cocaine at least once a month increased from 1.6 million to 4.3 million users, and by 1985 this number had reached 5.7 million. From 1985-1991 the number dropped due to the drug war from 5.7 million to 3.6 million users. Since 1991, cocaine and crack use has continually increased (Nadelson 1999).

Chapter 2
The Physiology of the Brain

The history of cocaine is important to understand because it is ingrained in our culture. Cocaine is a strong drug and produces many effects on the human body. The high is felt in the brain. In order to understand the effects of cocaine, the brain must be examined. The neuron is a key structure in the stimulation of the brain. Neurons contain the body's natural chemicals called neurotransmitters. Neurons are usually divided into three different parts: the cell body or soma, the dendrites, and the axon. The cell body contains a nucleus surrounded by ribosomes, mitochondria and the other usual components of a cell. Most of the metabolic work of the neuron happens in the cell body. The cell body is covered with synaptic receptors in some neurons.

The dendrites are branching fibers that extend from the cell body to the periphery. They receive the information for the neuron. The surface of the dendrites are also lined with synaptic receptors, which are the site specific areas that the neurotransmitters go to induce their effects. The greater the surface area of the dendrites, the greater the amount of information that they can receive. Sometimes information is passed from dendrite to dendrite. There are approximately one hundred thousand dendrites per neuron.

The axon is the information sender of the neuron. It is a thin fiber of constant diameter that is usually longer than t xhe dendrites. The axon can transverse several centimeters in the brain and has multiple branches so as to be able to communicate with other neurons by the release of the neurotransmitters. The axons also convey impulses to glands and muscles. The end of each of the branches of the axon swell up creating the presynaptic terminal. This is the point at which the neuron releases the neurotransmitters. The presynaptic terminals contain many mitochondria because of the amount of energy used in synthesizing and releasing the chemicals (Perrine 1996).

The signaling between neurons happens at the synapse. There are eight major chemical events that occur at the synapse. The neurons synthesize vesicles (the carriers of the neurotransmitters) and the chemicals that act as neurotransmitters. The neurotransmitters are then transported by the neuron down the axon via vesicles. Pep ╔tide neurotransmitters must come from the cell body, whereas non-peptide neurotransmitters can be synthesized along the axon. The electrochemical action potential then travels down the axon and causes calcium to enter the cell at the presynaptic terminal. This action potential is the depolarization of the neuron. As the calcium enters the neuron it invokes the release of the neurotransmitter at the synaptic cleft (the space between the presynaptic and post synaptic terminals). This is called exocytosis. The molecules that are released attach to receptors and alter the activity of the post synaptic neuron. The molecules are then separated from the receptors and sometimes are converted into inactive chemicals. In some cells, as many of the neurotransmitters as possible are taken back into the presynaptic cell, called reuptake. In some cells the vesicles are also recycled and sent back up the axon to the cell body (Kalat 2001).

The receptor site theory is a very important theory for understanding how drugs interact with the body. Drugs act at specific locations in tissues and organs. Drugs must be able to attach to site specific cells (receptor sites) by virtue of their size, shape, and chemical electrical property. Receptor sites receive endogenous chemicals in daily life, such as adrenaline and hormones. Drugs sometimes mimic these endogenous chemicals and induce the same effects; usually they are longer and more intense due to the higher concentration of the drug. The body has many different types of receptor sites. Receptor sites are in enzymes and are located at the synapse. They are proteins and are not rigid. This means that they sometimes can change their form a little bit in order to accommodate the drugs. There are nine ways that a drug can effect the neurotransmitter signal at the synapse. A drug can increase or decrease the neurotransmitter synthesis. It can inhibit or enhance neurotransmitter transport to the presynaptic storage vesicles. It can modify the storage and the release of neurotransmitter in the vesicles. A drug can accelerate or retard the degradation of the neurotransmitter within the synapse. Drugs can block reuptake of neurotransmitter from the synapse. They can mimic the neurotransmitter and act as an antagonist at the receptor site. They can block the receptor all together. They can also affect the up or down regulation of the receptor (Perrine 1996).

Several slightly different types of drugs may be able to activate the same receptor site and cause a biological response. Drugs compete with each other, if they are present at the same time and can bind to the same receptor site. The drug with the most molecules and the highest affinity (binding power) wins and binds to the receptor site. Affinity is defined by the size, shape, and chemical property of the drug. The better the drug fits in the receptor site the higher affinity it has. Affinity is also involved in how long the drug remains active in the body.

When a drug is ingested it travels through the blood stream to the receptor sites. If there is enough ×f the drug to saturate the receptor sites and induce the release of neurotransmitters, a drug action occurs. Eventually, the drug is displaced from the receptor sites in a number of ways: a drug that has a higher chemical affinity is present, the drug may be broken down by enzyme catalyzed destruction in the receptor site, and/or the drug has reached a low enough concentration, due to excretion, that no noticeable biological response occurs. Another dose of the drug is then needed to resaturate the receptor sites and cause a biological response (Liska 1994).

The main organ involved in drug metabolism is the liver. The kidneys, gastrointestinal tract, and blood plasma also contribute to the metabolism of drugs in the body. There ar ¤e three ways that the liver metabolizes drugs. One, the drug can be changed chemically by hydrolysis. The metabolites of the initial drug may be inactive or pharmacologically active. Two, the drug can be conjugated or chemically linked to a normal body substance. This product is pharmacologically inactive and more water soluble. The kidneys are able to excrete this product because it is water soluble. Third, the drug can be altered by oxidation or salt formation to become more water soluble and thus dealt with by kidney excretion. This third way chemically changes a fat soluble substance to a water soluble product (Liska 1994).

There are five different pathways that drugs are excreted out of the body. The most important pathway is through the urine. In order for the drug to be excreted by the kidneys through the urine, it must be water soluble or chemically transformed into a water soluble product. Drugs are also excreted in the feces, in perspiration, saliva, and breast milk, as vomit, and by exhalation on the breath. The last pathway by exhalation on the breath is significant only if the drug is a highly volatile compound, most of which are fat soluble, such as alcohol (Liska 1994).

In order for a drug to reach the central nervous system it must pass through the blood-brain barrier. This barrier is the fat covered membranes that surround the capillaries in the brain. The capillaries in the brain have almost no pores which contributes to this barrier effect. This is because the cells in the brain are not regenerated as quickly as the rest of the cells in the body so the body has to protect them more. There are two categories of molecules that can pass through the blood-brain barrier passively without active transport. They are small uncharged molecules (such as oxygen and carbon dioxide) and fat soluble molecules (Liska 1994).

Chapter 3
Cocaine and its Journey Through the Body

Erthrorylan coca is a woody shrub with bright green leaves and red berries. It provides three to four harvests per year. The leaves can be harvested by the third or fourth year of growth, and can produce leaves for twenty years. The leaves have a 0.5 to 1% concentration of the alkaloid cocaine. The alkaloid cocaine is a very powerful inhibitor of the reuptake of the insect-specific neurotransmitter octopamine. This inhibition of the reuptake of octopamine causes the insect to overdose on its own octopamine, acting as a natural pesticide. This is why the coca plant contains this alkaloid in the first place.

Cocaine hydrochloride is synthesized from the coca leaf. The coca leaves are soaked in a dilute solution of water and an alkali, usually lime, for three to four days. Alcohol is added which takes the cocaine hydrochloride from the leaves into the solution. When alcohol is not available, or too expensive as in the current illegal production in South America, kerosene or gasoline is used. The leaves are then discarded. A dilute solution of sulfuric acid is added. Then lime or ammonia is added to neutralize the acid, causing the dissolved cocaine hydrochloride to solidify and sink to the bottom. The excess liquid is poured off and the crude cocaine is allowed to dry in room air. This crude cocaine is then shipped and purified through a separate process. (pg 76 Karch 1998)

Five hundred kilograms of coca leaves is worth 500 dollars in South America. A farmer chemist can prepare one kilogram of cocaine base from these leaves, worth 1,500 dollars. One kilogram of cocaine base yields one kilogram of cocaine hydrochloride worth 4,000 dollars in South America and 40,000 dollars in the United States. Each time the cocaine changes hands it is cut with many different kinds of chemicals. A few of them are procaine, lidocaine, mannitol, inositol, phenylpropanolamine, baby laxative, and laundry detergent. The original sample reaches the streets with a purity level of roughly sixty-three percent and a street value of 100, 000 dollars (Liska 1994).

Crack cocaine is synthesized from cocaine hydrochloride through a cutting process. Cocaine hydrochloride is mixed with sodium bicarbonate and lidocaine and is dissolved in water and heated. The alkaline soda converts the water soluble form into a water insoluble free base which then floats to the surface and is skimmed off the top. The dry product is hard and porcelain like. When heated, the mixture makes a crackling noise, hence the term crack. Crack is a mixture of different substances but has a very high purity level averaging above 80%. Crack is then placed in a pipe and heated to a vapor and inhaled. It is termed smoking, but the substance isn't actually combusted. Crack is much easier to heat to a vapor than cocaine hydrochloride. When cocaine hydrochloride is burned most of the drug is destroyed before it reaches the body. When crack is smoked it is immediately absorbed into the blood stream and is not limited by the vasoconstrictive properties of cocaine, delivering a larger dose of the drug to the brain in a shorter time period than snorting or injecting cocaine. There is no evidence of smoking cocaine until the early 1980's. One kilogram of crack is worth 135,000 dollars on the streets ( Liska 1994).

The intensity and addictivity of a high is determined by how quick and how much of the drug reaches the brain. When cocaine is ingested orally some chemical break down occurs in the stomach and liver before it reaches the brain. When cocaine is snorted it causes all of the blood vessels it comes into contact with to constrict. This constriction limits the blood flow to the cartilage and causes deterioration due to a of lack of oxygen in the cells. Repeated use can cause the septum to become perforated. The first septum deterioration was documented in 1910. When the effects of cocaine subside, blood supply is restored and the tissue swells causing a stuffy, runny, and irritated nose. The first documented use of snorting cocaine hydrochloride was in 1905. This is the next quickest method of ingestion. When cocaine is diluted in water and injected into the blood stream it reaches the brain rapidly, causing an intense high. This is the second quickest method of ingestion. The quickest way to get the most amount of cocaine to the brain is smoking crack. Crack is the most addictive form of cocaine (Karch 1998).

Cocaine is a psychomotor stimulant, a strong local anesthetic, and a vasoconstricter. Cocaine use can cause sudden cardiac death, heart attack, irregular heartbeat, and heart muscle tissue damage. It induces the heart to pump quickly and forcefully. It also constricts the blood vessels, which causes the heart to work even harder, which lea Vds to fibrillation. This is where the heart stops pumping effectively and quivers. The harmful effects on the heart increases significantly if the user is a tobacco smoker. Animal testing at the National Institute of Health shows that the anesthetic effect can sensitize the brain in such a way that repeated use of smaller doses can cause seizures and in some cases sudden death. The brains threshold for seizure and sudden death is lowered with repeated use (Liska 1994).

To feel a sensation, an electrical impulse travels through the central nervous system to the brain. The impulse is passed from one neuron to the next using ions to stimulate the release of the neurotransmitters. When cocaine is used as a local anesthetic it inhibits the ions in the nervous system from moving along the neuron. No pain is experienced as the ions do not trigger the release of the neurotransmitter and the message does not reach the brain.

Cocaine effects three neurotransmitters: dopamine, norepinephrine and seratonin. Cocaine effects the reuptake of both norepinephrine and dopamine. Both of these are catecholamines which account for the natural excitation and alertness of the body. Since these catecholamines are blocked from being recycled back into the presynaptic terminal, they are present at the synapse at a higher concentrati on and for a longer time which stimulates the brain to euphoria. Dopamine mainly stimulates the amygdala and the nuclear accumbens, both of which are areas in the brain that are responsible for the feelings of pleasure. Chronic use of cocaine depletes dopamine in certain areas of the brain, which causes intense cravings. Cocaine will have stimulating effects wherever norepinephrine acts as a neurotransmitter in the body (Liska 1994).

Cocaine effects the central nervous system, the limbic system, the respiratory system, and the cardiovascular system. Moderate doses of cocaine increase blood pressure, body temperature, breathing, and heart rate, whereas high doses cause death due to the overworking of the heart. Humans sometimes show tremors and convulsions w █hich lead to central nervous system collapse at high doses. Overall brain activity increases when cocaine is taken. Repeated exposure to cocaine damages the limbic system, which increases the susceptibility to a type of seizure that closely resembles epilepsy. Researchers believe that this repeated change in brain activity alters the brain structure over time (Nadelson 1999).

With the escalating chronic use of cocaine toxic effects develop such as tachycardia, hypertension, formication (cocaine bugs), visual hallucinations, and paranoid psychosis. There are cases where young individuals with excellent health have sudden cardiac death due to cocaine use. The toxic effects on the heart are not fully understood but are thought to be caused by the temporary arrhythmia induced by cocaine. Cocaine in high doses can cause intense spasm in the coronary arteries which in some cases induces either a short episode of angina or myocardial infarction. One of the major problems with cocaine is that in small doses angiospasms are provoked.

Cocaine or crack use in the early stages of pregnancy can cause stillbirths and miscarriages. When used later in pregnancy, premature birth may occur. When a baby is exposed to cocaine either in the womb or through breast milk, they are more susceptible to birth defects and mental retardation. Babies who have been exposed to cocaine do not nurse or cuddle well and are irritable and unresponsive. They are also ten times more likely to die of sudden infant death syndrome (Perrine 1996).

The effects of cocaine are short lived. For example, increase in heart rate only lasts about sixty minutes and declines thereafter; this is due to the rapid hydrolysis of cocaine to two deesterfied metabolites, benzoylecgonine and ecgonine methyl ester. Benzoylecgonine and methanol are the products of the cleavage of the methyl ester function. Ecgonine methyl ester and benzoate are the products of the cleavage of the benzoyle group. Cocaine is metabolized by common esterases or simple non enzymatic hydrolysis. Both benzoylecgonine and ecgonine methyl ester are not active stimulants. Benzoylecgonine does have strong vasoconstrictive properties and may contribute to the toxic side effects of cocaine use. One-third of cocaine related deaths occur two to five hours after cocaine administration; this is two half lives of cocaine, which suggests that cocaine as well as the metabolites are responsible for the toxic effects. The intensity of the high and toxic effects of cocaine are dependent on the body's microsomal cocaine-metabolizing enzymes, called human liver cocaine carboxylesterases. 80-90% of cocaine is metabolized by ester hydrolysis; the rest is degraded by N-demethylation to norcocaine, which is followed by oxidation to N-hydroxynorcocaine, and excreted via the kidneys. In the presence of ethanol, the human liver cocaine carboxylesterase catalyzes the ethyl transesterfication of cocaine to cocaethylene. The duration and magnitude of both the desirable and undesirable 3effects of cocaine are relative to the amount of these enzymes present in the body when cocaine is ingested (Bosron 1997).

Chapter 4
Mixing drugs: cocaine and alcohol, cocaine and heroin

The use of cocaine and alcohol is the most common co-use of any drugs seen in the emergency rooms of the country. Studies show that 77% of cocaine users commonly ingest alcohol during cocaine use, while 30% ingest alcohol every time. Alcohol ingestion is known to diminish the undesirable effects of cocaine such as migrane-like headaches, cocaine bugs, teeth grinding, sleeplessness, and anxiety. Cocaine also diminishes the undesirable effects of alcohol, such as drowsiness, dizziness, and impaired motor skills. This practice of mixing cocaine and alcohol is becoming a health concern because the co-use increases the risk of cocaine-related morbidity and mortality. In animals pretreated with alcohol, the metabolism of cocaine to norcocaine, norcocaethylene, and norbenzoylecgonine increased. These metabolites also increase the hepatotoxicity. Ethanol also increased the concentration of cocaine in the liver and decreased it in the heart; Although the brain, lung, kidney, and spleen concentrations were not effected. Data indicates that cocaine-related sudden death increases eighteen fold with co-users.

The human liver cocaine carboxylesterase catalyzes the ethyl transesterfication of cocaine to a pharmacologically active metabolite, cocaethylene, but only in the presence of ethanol. Ethanol has many different effects on the body when used with cocaine. Ethanol is also found to inhibit cocaine methyl esterase activity, which is the hydrolysis of cocaine to benzoylecgonine. Benzoylecgonine's vasoconstrictive effects may contribute to the migrane-like vasospastic headaches. Ethanol diminishes these effects by limiting the production of that metabolite, which likely contributes to co-use (Dean 1997).

Cocaethylene is thought to alter the subjective experience, in addition to enhancing toxicity to the body more than cocaine itself. First, this is supported by the identification of cocaethylene in the urine, blood, brain, and liver obtained by autopsy from individuals who died from cocaine-induced effects. Second, when administered under controlled conditions, cocaethylene produced similar but milder and more pleasurable subjective effects than cocaine. Cocaethylene has a half life three to five times longer than cocaine and is eighteen to twenty-five times more l  ikely to cause sudden death (Andrews 1997). There is a comparable affinity of cocaethylene to cocaine for the dopamine transporter in human striatal membranes, which explains some of the similarities of the subjective effects. This means that cocaethylene occupies the dopamine transporters with the same amount of drug affinity as does cocaine. Since the dopamine receptor sites are occupied by cocaethylene, cocaine continues to remain at the synapse for longer and in higher concentrations. Cocaethylene has a lower affinity for seratonin uptake sites and for norepinephrine transporters, which explains the differing effects.

When combined, cocaine and alcohol are more toxic to the body than when taken separately. Research has shown that combined use of cocaine and alcohol leads to an increase in heart rate that is higher than when each were taken alone. When cocaethylene and cocaine were administered separately, cocaethylene was found to have less stimulating effec yts on the heart and body than cocaine. That shows that production of cocaethylene by the co-use of alcohol and cocaine is not solely responsible for the increase of the stimulating effects. Cocaethylene also demonstrated a slower clearance and a larger volume of distribution (Hart et al. 2000). The simultaneous use also leads to a 30% increase of cocaine levels in the blood, but not of alcohol levels (Pennings et al. 2002). The co-use produced a greater sense of euphoria than when taken separately. When taken together each drug acts as an antagonist of one anothers side effects encouraging the user to continue ingesting both drugs, which may lead to the ingestion of lethal amounts.

In canines, cocaethylene caused hypertension and increased systematic vascular resistance. It decreased myocardial function, slowed cardiac conduction, and was arrythmogenic at high concentrations. Cocaethylene's toxicity did not appear to be mediated by effects on coronary blood flow (Wilson and French 2002).

There might be as many as eight different classes of opiate receptors. Their locations parallel nerve pathways known to be involved in mood and the perception of pain. It is unknown how opiates produce their pharmacological effects. Opiates, especially heroin, are strong depressants. When mixed with cocaine, the effects of both heroin and cocaine are potentiated. In studies conducted with rats made to self administer a speedball (heroin/cocaine), a synergistic effect on the dopamine concentrations in the nuclear accumbens was observed. When cocaine was administered alone there was a 400 %increase in the dopamine concentration in the nuclear accumbens. When heroin was administered alone there was no significant increase observed. When a speedball was self-administered there was a 1000% increase. The process by which this happens is not fully understood (Hemby et al. 1999).

A study using mice concluded that speedball self administration via lever press, had reinforcing effects. It showed that speedball combination produced cocaine like effects in the early part of the drug induced activity, followed by a locomotor profile corresponding to the average of both drugs. This effect was not observed in either drug alone (Polis and Gold 2001).

Using a progressive ratio schedule of drug reinforcement, the relative reinforcing value of a speedball was compared in the rat. Break points (the level that illicited a response) were determined for cocaine and heroin alone and a cocaine and heroin combination. At these lower doses the speedball had a significant effect, compared to the effects of cocaine and heroin alone which were identical to those of saline (the control of the study). This indicates that there is a synergistic effect of the co-use of cocaine and heroin (Duvauchelle et al. 1998).

One study compared speedball users with non-speed ball users on global measures of depression and anxiety and modal groupings of personality characteristics. Compulsive speedball users showed a greater propensity of depression, trait anxiety, and related symptomology. These results agree with the descriptions of severe pathology associated with speedball use (Malow et al. 1992).

Conclusion

The history of cocaine has shown that cocaine has been a U.S. commodity since the time it was discovered. It was the first local anesthetic and liberated surgical exploration in many different ways. It became very dangerous because the amounts that were used were excessive. Almost all of the current local anesthetics are derivatives of cocaine. Intravenous use of cocaine was determined very early in cocaine's history to be toxic and dangerous.

The effects of cocaine are understood for the most part. Cocaine has been studied for a long time due to its medical importance. It has been shown to be very cardiotoxic, when used in an uncontrolled setting. The recreational use was inspired at the beginning of the twentieth century with the use of the many different cocaine products such as coca-wine, tooth drops, and intravenous kits. Cocaine has many enjoyable euphoric effects and that is why it is such a problem. The many dangerous side effects are not taken into consideration by the recreational users. The sudden death factor of cocaine would logically outweigh any high. As shown in laboratory animals the only drug that they prefer to food, water, and sex, is cocaine. This is also true for some addicted users.

The main problem with cocaine is that there is no controlled way of taking it. The product that reaches the streets is not pure cocaine and contains many unknown substances. The amount of human liver cocaine carboxylesterases is also unknown and therefore the user has no way of projecting how much is a safe dose. The other unknown that is of most importance is the relative lethal threshold of the heart. The user never knows what amount of cocaine will cause lethal effects. The user usually thinks that if they do a smaller amount it is safe; this is not true.

These toxic effects only increase when other drugs are ingested with cocaine, which is very common in the recreational use of cocaine for many reasons. One main reason is that most of the time the combination of two or more drugs increases the euphoria experienced. The other reason is that one drug may work as an antagonist in the side effects of the other drug. When mixing cocaine and alcohol several things happen. One, there is a creation of a new psychoactive metabolite, cocaethylene. Cocaethylene has not been studied enough to show any concrete evidence on how it effects the body. There are studies that show it has a longer half life than cocaine. This may be due to the fact that the enzymes in the liver have a harder time breaking it down because of the addition of the ethyl group. Ethanol also slows down the breakdown of cocaine into benzoylecgonine. There needs to be more studies done on cocaethylene and the effects of ethanol on the journey of cocaine through the body.

The synergistic effects observed in the combination of heroin and cocaine, called a speedball, are not yet understood. There are very few studies done on this combination. It has been found that the dopamine concentrations in the nuclear accumbens are synergistically increased in the speedball user. This may be due to both cocaine and heroin acting on the same neuron to release dopamine, causing the neuron to double release. When taken in conjuction with herion, cocaine's stimulating effects may be reversed. The reversal occurs when the concentration of cocaine in the blood stream reaches a high enough level. Current research done on this drug combination has not yet determined the specific level of cocaine concentration. This is very dangerous because heroin is also a depressant. The result is a super depressant and the body slows down to a point where breathing and heart rate may stop and death will follow (Blachford and Krapp 2003). Most of the studies only look at the subjective effects of the drugs. Since the opiate pathways in the brain are not understood it is hard to study the combination of an opiate and any other drug.

Further studies need to be done on these drug combinations. There is a large amount of drug abuse and because of the current punitive approach to the drug war, there is no effort going into drug education. Efforts are solely directed at drug busting and incarceration. We need to examine this approach because the drug war has not produced any significant change.

Bibliograpy
Books

Blachford, S.L., and Krapp, K. 2003. Drugs and Controlled Substances, Information for Students, Michigan: Thomson Gale, Inc.
Bosron, W. F., Dean, R.A., Brzezinski, M.R., and Pindel, V.E. 1997. Human Liver Cocaine Carboxylesterases, in Rapaka, R.S., Chiang, N., and Martin, B.R. NIDA Research Monograph 173: Pharmacokinetics, Metabolism, and Pharmaceutics of Drugs of Abuse, Rockville: NIH Publication.
Dean, R.A., Bosron, W.F., Zachman, F.M., Zhang, J., and Brozezinski, M.R. 1997.
Effects of Ethanol on Cocaine Metabolism and Disposition in the Rat, in Rapaka, R.S., Chiang, N., and Martin, B.R. NIDA Research Monograph 173: Pharmacokinetics, Metabolism, and Pharmaceutics of Drugs of Abuse, Rockville: NIH Publication.
Holmes, A. 1999. Psychological Effects of Cocaine and Crack Addiction, Philadelphia:Chealsea House Publishers.
Kalat, James W. 2001. Biological Psychology, Toronto: Wadsworth.
Karch, Stephen B. M.D. 1998. A Brief History of Cocaine, Boca Raton: CRS Press.
Liska, K. 1994. Drugs and the Human Body, New York: Macmillan Publishing Company.
Perrine, D. M. 1996. The Chemistry of Mind-Altering Substances, Washington: American Chemical Society.
Silverman, R. B. 1992. The Organic Chemistry of Drug Design and Drug Action, San Diego: Academic Press, inc.

Journals

Andrews P. 1997 Cocaethylene Toxicity. Addict Dis 16(3):75-84.
David V., Polis I., McDonald J, and Gold L.H. 2001 Intravenous Self-admini ×stration of Heroin/Cocaine Combinations (Speedball) Using Nose-poke or Lever-press operant Responding in Mice, Behav Pharmacol 12(1):25-34.
Duvauchelle C.L., Sapoznik T., and Kornetsky C. 1998 The Synergistic Effects of Combining Cocaine and Heroin ("Speedball") Using a Progressive-ratio Schedule of Drug Reinforcement. Pharmacol Biochem Behav 61(3):297-302.
Hart C.L., Jatlow P., Sevarino K.A., McCance-Katz E.F. 2000 Comparison of Intravenous Cocaethylene and Cocaine in Humans. Psychopharmacology 149(2):153-62.
Mallow R.M., West J.A., Corrigan S.A., Pena J.M., and Lott W.C. 1992 Cocaine and Speedball Users: Differences in Psychopathy. Journal of Substance Abuse Treatment 9(4):287-91.
McCance-Katz E.F., Kosten T.R, and Jatlow P. 1998 Concurrent Use of Cocaine and Alcohol is More Potent and Potentially More Toxic Than Use of Either Alone. Biol Psychiatry 15;44(4):250-9.
Mello N.K., Negus S.S., Lukas S.E., Mendelson J.H., Sholar J.W., and Drieze J. 1995 A Primate Model of Polydrug Abuse: Cocaine and Heroin Combinations, Journal of Pharmacology and Experimental Therapeutics 274;3:1325-1337.
Pennings E. J., Leccese A. P., Wolf F. A. 2002 Effects of Concurrent Use of Alcohol and Cocaine, Society for the Study of Addiction to Alcohol and Other Drugs, Addiction 97, 773-783.
Scott E., Hemby, Conchita C., Dworkin S. I., and Smith J. E.1999 Synergistic Elevations in Nucleas Accumbens Extracellular Dopamine Concentrations During Self-administration of Cocaine/Heroin Combinations (Speedbal) in Rats. Journal of Pharmacology and Experimental Therapeutics 288;1: 274-280.
Wilson L.D., and French S. 2002 Cocaethylene's Effects on coronary Blood Flow and Cardiac Function in a Canine Model, Toxicol Clin Toxicol 40;5:535-46.

Nathaniel Evans is a graduate of Chamisa Mesa High School (1999) and Antioch College (Yellow Springs, Ohio) 2003. He graduated with Honors in Biology.
A Senior Project

April 2003