Cocaine

Systematic (IUPAC) name
methyl (1R,2R,3S,5S)-3- (benzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-carboxylate
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy cat.	C
Legal status	Controlled (S8) (AU) Schedule I (CA) ? (UK) Schedule II (US)
Dependence liability	High
Routes	Topical, Oral, Insufflation, IV, PO
Pharmacokinetic data
Bioavailability	Oral: 33%[1] Insufflated: 60[2]–80%[3] Nasal Spray: 25[4]–43%[1]
Metabolism	Hepatic CYP3A4
Half-life	1 hour
Excretion	Renal (benzoylecgonine and ecgonine methyl ester)
Identifiers
CAS number	50-36-2 Y
ATC code	N01BC01 R02AD03, S01HA01, S02DA02
PubChem	CID 5760
IUPHAR ligand	2286
DrugBank	DB00907
ChemSpider	10194104 Y
UNII	I5Y540LHVR Y
KEGG	D00110 Y
ChEBI	CHEBI:27958 Y
ChEMBL	CHEMBL120901 N
Synonyms	methylbenzoylecgonine, benzoylmethylecgonine, ecgonine methyl ester benzoate, 2b-Carbomethoxy -3b-benzoyloxy tropane
Chemical data
Formula	C17H21NO4
Mol. mass	303.353 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C17H21NO4/c1-18-12-8-9-13(18)15(17(20)21-2)14(10-12)22-16(19)11-6-4-3-5-7-11/h3-7,12-15H,8-10H2,1-2H3/t12-,13+,14-,15+/m0/s1 Y Key:ZPUCINDJVBIVPJ-LJISPDSOSA-N Y
Physical data
Melt. point	98 °C (208 °F)
Boiling point	187 °C (369 °F)
Solubility in water	HCl: 1800-2500 mg/mL (20 °C)
N (what is this?)  (verify)

Cocaine (benzoylmethylecgonine) (INN) is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant.^[5] The name comes from "coca" and the alkaloid suffix -ine, forming cocaine. It is a stimulant, an appetite suppressant, and a topical anesthetic. Biologically, cocaine acts as a serotonin–norepinephrine–dopamine reuptake inhibitor, also known as a triple reuptake inhibitor (TRI). It is addictive because of its effect on the mesolimbic reward pathway.^[6]

Unlike most molecules, cocaine has pockets with both high hydrophilic and lipophilic efficiency, violating the rule of hydrophilic-lipophilic balance. This causes it to cross the blood–brain barrier far better than other psychoactive chemicals.

It is illegal to possess, grow, or distribute cocaine for non-medicinal and non-government-sanctioned purposes in almost all countries. Still it is used extensively throughout the world.

Medical effects[link]

Data from The Lancet suggests cocaine is ranked both the 2nd most addictive and the 2nd most harmful of 20 popular recreational drugs.^[7]

Cocaine is a powerful nervous system stimulant.^[8] Its effects can last from 15–30 minutes to an hour, depending on the route of administration.^[9]

Cocaine increases alertness, feelings of well-being and euphoria, energy and motor activity, feelings of competence and sexuality. Athletic performance may be enhanced in sports where sustained attention and endurance is required. Anxiety, paranoia and restlessness are also frequent. With excessive dosage, tremors, convulsions and increased body temperature are observed.^[8]

Occasional cocaine use does not typically lead to severe or even minor physical or social problems.^[10][11]

Acute[link]

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2009)

With excessive or prolonged use, the drug can cause itching, tachycardia, hallucinations, and paranoid delusions. Overdoses cause tachyarrhythmias and a marked elevation of blood pressure, which can be life-threatening.

Chronic[link]

Side effects of chronic cocaine use

Cocaine hydrochloride

Chronic cocaine intake causes brain cells to adapt functionally to strong imbalances of transmitter levels in order to compensate extremes. Thus, receptors disappear from the cell surface or reappear on it, resulting more or less in an "off" or "working mode" respectively, or they change their susceptibility for binding partners (ligands) – mechanisms called down-/upregulation. However, studies suggest cocaine abusers do not show normal age-related loss of striatal dopamine transporter (DAT) sites, suggesting cocaine has neuroprotective properties for dopamine neurons.^[12] The experience of insatiable hunger, aches, insomnia/oversleeping, lethargy, and persistent runny nose are often described as very unpleasant. Depression with suicidal ideation may develop in very heavy users. Finally, a loss of vesicular monoamine transporters, neurofilament proteins, and other morphological changes appear to indicate a long term damage of dopamine neurons. All these effects contribute a rise in tolerance thus requiring a larger dosage to achieve the same effect.^[13]

The lack of normal amounts of serotonin and dopamine in the brain is the cause of the dysphoria and depression felt after the initial high. Physical withdrawal is not dangerous, and is in fact restorative. Physiological changes caused by cocaine withdrawal include vivid and unpleasant dreams, insomnia or hypersomnia, increased appetite and psychomotor retardation or agitation.^[14]

Physical side effects from chronic smoking of cocaine include hemoptysis, bronchospasm, pruritus, fever, diffuse alveolar infiltrates without effusions, pulmonary and systemic eosinophilia, chest pain, lung trauma, sore throat, asthma, hoarse voice, dyspnea (shortness of breath), and an aching, flu-like syndrome. Cocaine constricts blood vessels, dilates pupils, and increases body temperature, heart rate, and blood pressure. It can also cause headaches and gastrointestinal complications such as abdominal pain and nausea. A common but untrue belief is that the smoking of cocaine chemically breaks down tooth enamel and causes tooth decay. However, cocaine does often cause involuntary tooth grinding, known as bruxism, which can deteriorate tooth enamel and lead to gingivitis.^[15] Additionally, stimulants like cocaine, methamphetamine, and even caffeine cause dehydration and dry mouth. Since saliva is an important mechanism in maintaining one's oral pH level, chronic stimulant abusers who do not hydrate sufficiently may experience demineralization of their teeth due to the pH of the tooth surface dropping too low (below 5.5).

Chronic intranasal usage can degrade the cartilage separating the nostrils (the septum nasi), leading eventually to its complete disappearance. Due to the absorption of the cocaine from cocaine hydrochloride, the remaining hydrochloride forms a dilute hydrochloric acid.^[16]

Cocaine may also greatly increase this risk of developing rare autoimmune or connective tissue diseases such as lupus, Goodpasture's disease, vasculitis, glomerulonephritis, Stevens–Johnson syndrome and other diseases.^{[17][18][19][20]} It can also cause a wide array of kidney diseases and renal failure.^[21][22]

Cocaine misuse doubles both the risks of hemorrhagic and ischemic strokes,^[23] as well as increases the risk of other infarctions, such as myocardial infarction.^[24]

Addiction[link]

Cocaine dependence (or addiction) is psychological dependency on the regular use of cocaine. Cocaine dependency may result in physiological damage, lethargy, psychosis, depression, akathisia, and fatal overdose.

Biosynthesis[link]

The first synthesis and elucidation of the cocaine molecule was by Richard Willstätter in 1898.^[25] Willstätter's synthesis derived cocaine from tropinone. Since then, Robert Robinson and Edward Leete have made significant contributions to the mechanism of the synthesis.

[edit] Biosynthesis of N-methyl-pyrrolinium cation

Biosynthesis of N-methyl-pyrrolinium cation

Biosynthesis of cocaine

Robinson biosynthesis of tropane

Reduction of tropinone

The biosynthesis begins with L-Glutamine, which is derived to L-ornithine in plants. The major contribution of L-ornithine and L-arginine as a precursor to the tropane ring was confirmed by Edward Leete.^[26] Ornithine then undergoes a Pyridoxal phosphate-dependent decarboxylation to form putrescine. In animals, however, the urea cycle derives putrescine from ornithine. L-ornithine is converted to L-arginine,^[27] which is then decarboxylated via PLP to form agmatine. Hydrolysis of the imine derives N-carbamoylputrescine followed with hydrolysis of the urea to form putrescine. The separate pathways of converting ornithine to putrescine in plants and animals have converged. A SAM-dependent N-methylation of putrescine gives the N-methylputrescine product, which then undergoes oxidative deamination by the action of diamine oxidase to yield the aminoaldehyde. Schiff base formation confirms the biosynthesis of the N-methyl-Δ¹-pyrrolinium cation.

Biosynthesis of cocaine[link]

The additional carbon atoms required for the synthesis of cocaine are derived from acetyl-CoA, by addition of two acetyl-CoA units to the N-methyl-Δ¹-pyrrolinium cation.^[28] The first addition is a Mannich-like reaction with the enolate anion from acetyl-CoA acting as a nucleophile towards the pyrrolinium cation. The second addition occurs through a Claisen condensation. This produces a racemic mixture of the 2-substituted pyrrolidine, with the retention of the thioester from the Claisen condensation. In formation of tropinone from racemic ethyl [2,3-13C2]4(Nmethyl-2-pyrrolidinyl)-3-oxobutanoate there is no preference for either stereoisomer.^[29] In the biosynthesis of cocaine, however, only the (S)-enantiomer can cyclize to form the tropane ring system of cocaine. The stereoselectivity of this reaction was further investigated through study of prochiral methylene hydrogen discrimination.^[30] This is due to the extra chiral center at C-2.^[31] This process occurs through an oxidation, which regenerates the pyrrolinium cation and formation of an enolate anion, and an intramolecular Mannich reaction. The tropane ring system undergoes hydrolysis, SAM-dependent methylation, and reduction via NADPH for the formation of methylecgonine. The benzoyl moiety required for the formation of the cocaine diester is synthesized from phenylalanine via cinnamic acid.^[32] Benzoyl-CoA then combines the two units to form cocaine.

Robert Robinson's acetonedicarboxylate[link]

The biosynthesis of the tropane alkaloid, however, is still uncertain. Hemscheidt proposes that Robinson's acetonedicarboxylate emerges as a potential intermediate for this reaction.^[33] Condensation of N-methylpyrrolinium and acetonedicarboxylate would generate the oxobutyrate. Decarboxylation leads to tropane alkaloid formation.

Reduction of tropinone[link]

The reduction of tropinone is mediated by NADPH-dependent reductase enzymes, which have been characterized in multiple plant species.^[34] These plant species all contain two types of the reductase enzymes, tropinone reductase I and tropinone reductase II. TRI produces tropine and TRII produces pseudotropine. Due to differing kinetic and pH/activity characteristics of the enzymes and by the 25-fold higher activity of TRI over TRII, the majority of the tropinone reduction is from TRI to form tropine.^[35]

Pharmacology[link]

Appearance[link]

A pile of cocaine hydrochloride

A piece of compressed cocaine powder

Cocaine in its purest form is a white, pearly product. Cocaine appearing in powder form is a salt, typically cocaine hydrochloride (CAS 53-21-4). Street market cocaine is frequently adulterated or “cut” with various powdery fillers to increase its weight; the substances most commonly used in this process are baking soda; sugars, such as lactose, dextrose, inositol, and mannitol; and local anesthetics, such as lidocaine or benzocaine, which mimic or add to cocaine's numbing effect on mucous membranes. Cocaine may also be "cut" with other stimulants such as methamphetamine.^[36] Adulterated cocaine is often a white, off-white or pinkish powder.

The color of “crack” cocaine depends upon several factors including the origin of the cocaine used, the method of preparation – with ammonia or baking soda – and the presence of impurities, but will generally range from white to a yellowish cream to a light brown. Its texture will also depend on the adulterants, origin and processing of the powdered cocaine, and the method of converting the base. It ranges from a crumbly texture, sometimes extremely oily, to a hard, almost crystalline nature.

Forms of cocaine[link]

Salts[link]

Cocaine is a weakly alkaline compound (an "alkaloid"), and can therefore combine with acidic compounds to form various salts. The hydrochloride (HCl) salt of cocaine is by far the most commonly encountered, although the sulfate (-SO₄) and the nitrate (-NO₃) are occasionally seen. Different salts dissolve to a greater or lesser extent in various solvents – the hydrochloride salt is polar in character and is quite soluble in water.

Basic[link]

As the name implies, “freebase” is the base form of cocaine, as opposed to the salt form. It is practically insoluble in water whereas hydrochloride salt is water soluble.

Smoking freebase cocaine has the additional effect of releasing methylecgonidine into the user's system due to the pyrolysis of the substance (a side effect which insufflating or injecting powder cocaine does not create). Some research suggests that smoking freebase cocaine can be even more cardiotoxic than other routes of administration^[37] because of methylecgonidine's effects on lung tissue^[38] and liver tissue.^[39]

Pure cocaine is prepared by neutralizing its compounding salt with an alkaline solution which will precipitate to non-polar basic cocaine. It is further refined through aqueous-solvent Liquid-liquid extraction.

Crack cocaine[link]

A woman smoking crack cocaine

Crack is a lower purity form of free-base cocaine that is usually produced by neutralization of cocaine hydrochloride with a solution of baking soda (sodium bicarbonate, NaHCO₃) and water, producing a very hard/brittle, off-white-to-brown colored, amorphous material that contains sodium carbonate, entrapped water, and other by-products as the main impurities.

The "freebase" and "crack" forms of cocaine are usually administered by vaporization of the powdered substance into smoke, which is then inhaled.^[40] The origin of the name "crack" comes from the "crackling" sound (and hence the onomatopoeic moniker “crack”) that is produced when the cocaine and its impurities (i.e. water, sodium bicarbonate) are heated past the point of vaporization.^[41] Pure cocaine base/crack is easy to smoke because it vaporizes smoothly, with little or no decomposition at around 98°C,^{[citation needed][dubious – discuss]} which is below the boiling point of water. The smoke produced from cocaine base is usually described as having a very distinctive, pleasant taste.

In contrast, cocaine hydrochloride does not vaporize until heated to a much higher temperature (about 197°C), and considerable decomposition/burning occurs at these high temperatures. This effectively destroys some of the cocaine, and yields a sharp, acrid, and foul-tasting smoke.

Smoking or vaporizing cocaine and inhaling it into the lungs produces an almost immediate "high" that can be very powerful (and addicting) quite rapidly – this initial crescendo of stimulation is known as a "rush". While the stimulating effects may last for hours, the euphoric sensation is very brief, prompting the user to smoke more immediately.

Coca leaf infusions[link]

Coca herbal infusion (also referred to as Coca tea) is used in coca-leaf producing countries much as any herbal medicinal infusion would elsewhere in the world. The free and legal commercialization of dried coca leaves under the form of filtration bags to be used as "coca tea" has been actively promoted by the governments of Peru and Bolivia for many years as a drink having medicinal powers. Visitors to the city of Cuzco in Peru, and La Paz in Bolivia are greeted with the offering of coca leaf infusions (prepared in tea pots with whole coca leaves) purportedly to help the newly arrived traveler overcome the malaise of high altitude sickness. The effects of drinking coca tea are a mild stimulation and mood lift. It does not produce any significant numbing of the mouth nor does it give a rush like snorting cocaine. In order to prevent the demonization of this product, its promoters publicize the unproven concept that much of the effect of the ingestion of coca leaf infusion would come from the secondary alkaloids, as being not only quantitatively different from pure cocaine but also qualitatively different.

It has been promoted as an adjuvant for the treatment of cocaine dependence. In one controversial study, coca leaf infusion was used -in addition to counseling- to treat 23 addicted coca-paste smokers in Lima, Peru. Relapses fell from an average of four times per month before treatment with coca tea to one during the treatment. The duration of abstinence increased from an average of 32 days prior to treatment to 217 days during treatment. These results suggest that the administration of coca leaf infusion plus counseling would be an effective method for preventing relapse during treatment for cocaine addiction.^[42] Importantly, these results also suggest strongly that the primary pharmacologically active metabolite in coca leaf infusions is actually cocaine and not the secondary alkaloids.

The cocaine metabolite benzoylecgonine can be detected in the urine of people a few hours after drinking one cup of coca leaf infusion.

Routes of administration[link]

Oral[link]

A spoon containing baking soda, cocaine, and a small amount of water. Used in a "poor-man's" crack-cocaine production

Many users rub the powder along the gum line, or onto a cigarette filter which is then smoked, which numbs the gums and teeth – hence the colloquial names of "numbies", "gummers" or "cocoa puffs" for this type of administration. This is mostly done with the small amounts of cocaine remaining on a surface after insufflation. Another oral method is to wrap up some cocaine in rolling paper and swallow (parachute) it. This is sometimes called a "snow bomb."

Coca leaf[link]

Coca leaves are typically mixed with an alkaline substance (such as lime) and chewed into a wad that is retained in the mouth between gum and cheek (much in the same as chewing tobacco is chewed) and sucked of its juices. The juices are absorbed slowly by the mucous membrane of the inner cheek and by the gastrointestinal tract when swallowed. Alternatively, coca leaves can be infused in liquid and consumed like tea. Ingesting coca leaves generally is an inefficient means of administering cocaine. Advocates of the consumption of the coca leaf state that coca leaf consumption should not be criminalized as it is not actual cocaine, and consequently it is not properly the illicit drug. Because cocaine is hydrolyzed and rendered inactive in the acidic stomach, it is not readily absorbed when ingested alone. Only when mixed with a highly alkaline substance (such as lime) can it be absorbed into the bloodstream through the stomach. The efficiency of absorption of orally administered cocaine is limited by two additional factors. First, the drug is partly catabolized by the liver. Second, capillaries in the mouth and esophagus constrict after contact with the drug, reducing the surface area over which the drug can be absorbed. Nevertheless, cocaine metabolites can be detected in the urine of subjects that have sipped even one cup of coca leaf infusion. Therefore, this is an actual additional form of administration of cocaine, albeit an inefficient one.

Orally administered cocaine takes approximately 30 minutes to enter the bloodstream. Typically, only a third of an oral dose is absorbed, although absorption has been shown to reach 60% in controlled settings. Given the slow rate of absorption, maximum physiological and psychotropic effects are attained approximately 60 minutes after cocaine is administered by ingestion. While the onset of these effects is slow, the effects are sustained for approximately 60 minutes after their peak is attained.

Contrary to popular belief, both ingestion and insufflation result in approximately the same proportion of the drug being absorbed: 30 to 60%. Compared to ingestion, the faster absorption of insufflated cocaine results in quicker attainment of maximum drug effects. Snorting cocaine produces maximum physiological effects within 40 minutes and maximum psychotropic effects within 20 minutes, however, a more realistic activation period is closer to 5 to 10 minutes, which is similar to ingestion of cocaine. Physiological and psychotropic effects from nasally insufflated cocaine are sustained for approximately 40–60 minutes after the peak effects are attained.^[43]

Coca tea, an infusion of coca leaves, is also a traditional method of consumption. The tea has often been recommended for travelers in the Andes to prevent altitude sickness.^[44] However, its actual effectiveness has never been systematically studied.^[44] This method of consumption has been practiced for many centuries by the native tribes of South America. One specific purpose of ancient coca leaf consumption was to increase energy and reduce fatigue in messengers who made multi-day quests to other settlements.

In 1986 an article in the Journal of the American Medical Association revealed that U.S. health food stores were selling dried coca leaves to be prepared as an infusion as “Health Inca Tea.”^[45] While the packaging claimed it had been "decocainized," no such process had actually taken place. The article stated that drinking two cups of the tea per day gave a mild stimulation, increased heart rate, and mood elevation, and the tea was essentially harmless. Despite this, the DEA seized several shipments in Hawaii, Chicago, Illinois, Georgia, and several locations on the East Coast of the United States, and the product was removed from the shelves.

Insufflation[link]

A man sniffing cocaine

Nasal insufflation (known colloquially as "snorting," "sniffing," or "blowing") is the most common method of ingestion of recreational powdered cocaine in the Western world. The drug coats and is absorbed through the mucous membranes lining the sinuses. When insufflating cocaine, absorption through the nasal membranes is approximately 30–60%, with higher doses leading to increased absorption efficiency. Any material not directly absorbed through the mucous membranes is collected in mucus and swallowed (this "drip" is considered pleasant by some and unpleasant by others). In a study^[46] of cocaine users, the average time taken to reach peak subjective effects was 14.6 minutes. Any damage to the inside of the nose is because cocaine highly constricts blood vessels – and therefore blood and oxygen/nutrient flow – to that area. Nosebleeds after cocaine insufflation are due to irritation and damage of mucus membranes by foreign particles and adulterants and not the cocaine itself; as a vasoconstrictor, cocaine acts to reduce bleeding.

Prior to insufflation, cocaine powder must be divided into very fine particles. Cocaine of high purity breaks into fine dust very easily, except when it is moist (not well stored) and forms "chunks," which reduces the efficiency of nasal absorption.

Rolled up banknotes, hollowed-out pens, cut straws, pointed ends of keys, specialized spoons, long fingernails, and (clean) tampon applicators are often used to insufflate cocaine. Such devices are often called "tooters" by users. The cocaine typically is poured onto a flat, hard surface (such as a mirror, CD case or book) and divided into "bumps", "lines" or "rails", and then insufflated.^[47] As tolerance builds rapidly in the short-term (hours), many lines are often snorted to produce greater effects.

A study by Bonkovsky and Mehta^[48] reported that, just like shared needles, the sharing of straws used to "snort" cocaine can spread blood diseases such as Hepatitis C.

In the United States, as far back as 1992 many of the people sentenced by federal authorities for charges related to powder cocaine were Hispanic American; more Hispanics than non-Hispanic White and non-Hispanic Black people received sentences for crimes related to powder cocaine.^[49]

Injection[link]

Drug injection provides the highest blood levels of drug in the shortest amount of time. Subjective effects not commonly shared with other methods of administration include a ringing in the ears moments after injection (usually when in excess of 120 milligrams) lasting 2 to 5 minutes including tinnitus & audio distortion. This is colloquially referred to as a "bell ringer".^[50] In a study^[46] of cocaine users, the average time taken to reach peak subjective effects was 3.1 minutes. The euphoria passes quickly. Aside from the toxic effects of cocaine, there is also danger of circulatory emboli from the insoluble substances that may be used to cut the drug. As with all injected illicit substances, there is a risk of the user contracting blood-borne infections if sterile injecting equipment is not available or used. Additionally, because cocaine is a vasoconstrictor, and usage often entails multiple injections within several hours or less, subsequent injections are progressively more difficult to administer, which in turn may lead to more injection attempts and more sequelae from improperly performed injection.

An injected mixture of cocaine and heroin, known as “speedball” is a particularly dangerous combination, as the converse effects of the drugs actually complement each other, but may also mask the symptoms of an overdose. It has been responsible for numerous deaths, including celebrities such as John Belushi, Chris Farley, Mitch Hedberg, River Phoenix and Layne Staley.

Experimentally, cocaine injections can be delivered to animals such as fruit flies to study the mechanisms of cocaine addiction.^[51]

Inhalation[link]

Inhalation or smoking is one of the several means cocaine is administered. Cocaine is smoked by inhaling the vapor by sublimating solid cocaine by heating.^[52] In a 2000 Brookhaven National Laboratory medical department study, based on self reports of 32 abusers who participated in the study,"peak high" was found at mean of 1.4min +/- 0.5 minutes.^[46]

Smoking freebase or crack cocaine is most often accomplished using a pipe made from a small glass tube, often taken from "Love roses," small glass tubes with a paper rose that are promoted as romantic gifts.^[53] These are sometimes called "stems", "horns", "blasters" and "straight shooters". A small piece of clean heavy copper or occasionally stainless steel scouring pad – often called a "brillo" (actual Brillo pads contain soap, and are not used), or "chore", named for Chore Boy brand copper scouring pads, – serves as a reduction base and flow modulator in which the "rock" can be melted and boiled to vapor. Crack smokers also sometimes smoke through a soda can with small holes in the bottom.

Crack is smoked by placing it at the end of the pipe; a flame held close to it produces vapor, which is then inhaled by the smoker. The effects, felt almost immediately after smoking, are very intense and do not last long – usually 5 to 15 minutes.

When smoked, cocaine is sometimes combined with other drugs, such as cannabis, often rolled into a joint or blunt. Powdered cocaine is also sometimes smoked, though heat destroys much of the chemical; smokers often sprinkle it on cannabis.

The language referring to paraphernalia and practices of smoking cocaine vary, as do the packaging methods in the street level sale.

Suppository[link]

Little research has been focused on the suppository (anal or vaginal insertion) method of administration, also known as "plugging". This method of administration is commonly administered using an oral syringe. Cocaine can be dissolved in water and withdrawn into an oral syringe which may then be lubricated and inserted into the anus or vagina before the plunger is pushed. Anecdotal evidence of its effects are infrequently discussed, possibly due to social taboos in many cultures. The rectum and the vaginal canal is where the majority of the drug would likely be taken up, through the membranes lining its walls.^{[citation needed]}}}

Mechanism of Action[link]

Cocaine binds directly to the DAT1 transporter, inhibiting reuptake with more efficacy than amphetamines which phosphorylate it causing internalization; instead primarily releasing DAT (which cocaine does not do) and only inhibiting its reuptake as a secondary, and much more minor, mode of action than cocaine and in another manner: from the opposite conformation/orientation to DAT.

The pharmacodynamics of cocaine involve the complex relationships of neurotransmitters (inhibiting monoamine uptake in rats with ratios of about: serotonin:dopamine = 2:3, serotonin:norepinephrine = 2:5^[54]) The most extensively studied effect of cocaine on the central nervous system is the blockade of the dopamine transporter protein. Dopamine transmitter released during neural signaling is normally recycled via the transporter; i.e., the transporter binds the transmitter and pumps it out of the synaptic cleft back into the presynaptic neuron, where it is taken up into storage vesicles. Cocaine binds tightly at the dopamine transporter forming a complex that blocks the transporter's function. The dopamine transporter can no longer perform its reuptake function, and thus dopamine accumulates in the synaptic cleft. This results in an enhanced and prolonged postsynaptic effect of dopaminergic signaling at dopamine receptors on the receiving neuron. Prolonged exposure to cocaine, as occurs with habitual use, leads to homeostatic dysregulation of normal (i.e. without cocaine) dopaminergic signaling via down-regulation of dopamine receptors and enhanced signal transduction. The decreased dopaminergic signaling after chronic cocaine use may contribute to depressive mood disorders and sensitize this important brain reward circuit to the reinforcing effects of cocaine (for example, enhanced dopaminergic signalling only when cocaine is self-administered). This sensitization contributes to the intractable nature of addiction and relapse.

Dopamine-rich brain regions such as the ventral tegmental area, nucleus accumbens, and prefrontal cortex are frequent targets of cocaine addiction research. Of particular interest is the pathway consisting of dopaminergic neurons originating in the ventral tegmental area that terminate in the nucleus accumbens. This projection may function as a "reward center", in that it seems to show activation in response to drugs of abuse like cocaine in addition to natural rewards like food or sex.^[55] While the precise role of dopamine in the subjective experience of reward is highly controversial among neuroscientists, the release of dopamine in the nucleus accumbens is widely considered to be at least partially responsible for cocaine's rewarding effects. This hypothesis is largely based on laboratory data involving rats that are trained to self-administer cocaine. If dopamine antagonists are infused directly into the nucleus accumbens, well-trained rats self-administering cocaine will undergo extinction (i.e. initially increase responding only to stop completely) thereby indicating that cocaine is no longer reinforcing (i.e. rewarding) the drug-seeking behavior.

Cocaine's effects on serotonin (5-hydroxytryptamine, 5-HT) show across multiple serotonin receptors, and is shown to inhibit the re-uptake of 5-HT3 specifically as an important contributor to the effects of cocaine. The overabundance of 5-HT3 receptors in cocaine conditioned rats display this trait, however the exact effect of 5-HT3 in this process is unclear.^[56] The 5-HT2 receptor (particularly the subtypes 5-HT2AR, 5-HT2BR and 5-HT2CR) show influence in the evocation of hyperactivity displayed in cocaine use.^[57]

In addition to the mechanism shown on the above chart, cocaine has been demonstrated to bind as to directly stabilize the DAT transporter on the open outward-facing conformation whereas other stimulants (namely phenethylamines) stabilize the closed conformation. Further, cocaine binds in such a way as to inhibit a hydrogen bond innate to DAT that otherwise still forms when amphetamine and similar molecules are bound. Cocaine's binding properties are such that it attaches so this hydrogen bond will not form and is blocked from formation due to the tightly locked orientation of the cocaine molecule. Research studies have suggested that the affinity for the transporter is not what is involved in habituation of the substance so much as the conformation and binding properties to where & how on the transporter the molecule binds.^[58]

Sigma receptors are affected by cocaine, as cocaine functions as a sigma ligand agonist.^[59] Further specific receptors it has been demonstrated to function on are NMDA and the D1 dopamine receptor.^[60]

Cocaine also blocks sodium channels, thereby interfering with the propagation of action potentials; thus, like lignocaine and novocaine, it acts as a local anesthetic. It also functions on the binding sites to the dopamine and serotonin sodium dependent transport area as targets as separate mechanisms from its reuptake of those transporters; unique to its local anesthetic value which makes it in a class of functionality different from both its own derived phenyltropanes analogues which have that removed and the amphetamine class of stimulants which as well altogether lack that. In addition to this cocaine has some target binding to the site of the Kappa-opioid receptor as well.^[61] Cocaine also causes vasoconstriction, thus reducing bleeding during minor surgical procedures. The locomotor enhancing properties of cocaine may be attributable to its enhancement of dopaminergic transmission from the substantia nigra. Recent research points to an important role of circadian mechanisms^[62] and clock genes^[63] in behavioral actions of cocaine.

Because nicotine increases the levels of dopamine in the brain, many cocaine users find that consumption of tobacco products during cocaine use enhances the euphoria. This, however, may have undesirable consequences, such as uncontrollable chain smoking during cocaine use (even users who do not normally smoke cigarettes have been known to chain smoke when using cocaine), in addition to the detrimental health effects and the additional strain on the cardiovascular system caused by tobacco.

Cocaine can often cause reduced food intake, many chronic users lose their appetite and can experience severe malnutrition and significant weight loss. Cocaine effects, further, are shown to be potentiated for the user when used in conjunction with new surroundings and stimuli, and otherwise novel environs.^[64]

Metabolism and excretion[link]

Cocaine is extensively metabolized, primarily in the liver, with only about 1% excreted unchanged in the urine. The metabolism is dominated by hydrolytic ester cleavage, so the eliminated metabolites consist mostly of benzoylecgonine (BE), the major metabolite, and other significant metabolites in lesser amounts such as ecgonine methyl ester (EME) and ecgonine. Further minor metabolites of cocaine include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p-hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine.^[65] These do not include metabolites created beyond the standard metabolism of the drug in the human body, like for example by the process of pyrolysis such as is the case with methylecgonidine; or the binding of other exogenous subsumed chemicals in administration concurrently with any constituent cocaine molecule conformation in vivo to be enumerated within the user as a conditionate dependant on tertiary measures to form as a novel metabolite too vast in potential instances to account for beyond the tertiary measure of their otherwise notability.

Depending on liver and kidney function, cocaine metabolites are detectable in urine. Benzoylecgonine can be detected in urine within four hours after cocaine intake and remains detectable in concentrations greater than 150 ng/mL typically for up to eight days after cocaine is used. Detection of accumulation of cocaine metabolites in hair is possible in regular users until the sections of hair grown during use are cut or fall out.

If consumed with alcohol, cocaine combines with alcohol in the liver to form cocaethylene. Studies have suggested cocaethylene is both more euphorigenic, and has a higher cardiovascular toxicity than cocaine by itself.^[66][67][68]

A study in mice has suggested that capsaicin found in pepper spray may interact with cocaine with potentially fatal consequences. The method through which they would interact however, is not known.^[69][70]

Detection in biological fluids[link]

Cocaine and its major metabolites may be quantitated in blood, plasma or urine to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Most commercial cocaine immunoassay screening tests cross-react appreciably with the major cocaine metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. When interpreting the results of a test, it is important to consider the cocaine usage history of the individual, since a chronic user can develop tolerance to doses that would incapacitate a cocaine-naive individual, and the chronic user often has high baseline values of the metabolites in his system. Cautious interpretation of testing results may allow a distinction between passive or active usage, and between smoking versus other routes of administration.^[71] In 2011, researchers at John Jay College of Criminal Justice reported that dietary zinc supplements can mask the presence of cocaine and other drugs in urine. Similar claims have been made in web forums on that topic.^[72]

Cocaine as a local anesthetic[link]

Cocaine was historically useful as a topical anesthetic in eye and nasal surgery, although it is now predominantly used for nasal and lacrimal duct surgery. The major disadvantages of this use are cocaine's intense vasoconstrictor activity and potential for cardiovascular toxicity. Cocaine has since been largely replaced in Western medicine by synthetic local anesthetics such as benzocaine, proparacaine, lignocaine/xylocaine/lidocaine, and tetracaine though it remains available for use if specified. If vasoconstriction is desired for a procedure (as it reduces bleeding), the anesthetic is combined with a vasoconstrictor such as phenylephrine or epinephrine. In Australia it is currently prescribed for use as a local anesthetic for conditions such as mouth and lung ulcers. Some ENT specialists occasionally use cocaine within the practice when performing procedures such as nasal cauterization. In this scenario dissolved cocaine is soaked into a ball of cotton wool, which is placed in the nostril for the 10–15 minutes immediately prior to the procedure, thus performing the dual role of both numbing the area to be cauterized and also vasoconstriction. Even when used this way, some of the used cocaine may be absorbed through oral or nasal mucosa and give systemic effects.

In 2005, researchers from Kyoto University Hospital proposed the use of cocaine in conjunction with phenylephrine administered in the form of an eye drop as a diagnostic test for Parkinson's disease.^[73]

History[link]

This section is written like a personal reflection or essay rather than an encyclopedic description of the subject. Please help improve it by rewriting it in an encyclopedic style. (March 2010)

Coca leaf[link]

Coca leaf in Bolivia

For over a thousand years South American indigenous peoples have chewed the leaves of Erythroxylon coca, a plant that contains vital nutrients as well as numerous alkaloids, including cocaine. The coca leaf was, and still is, chewed almost universally by some indigenous communities. The remains of coca leaves have been found with ancient Peruvian mummies, and pottery from the time period depicts humans with bulged cheeks, indicating the presence of something on which they are chewing.^[74] There is also evidence that these cultures used a mixture of coca leaves and saliva as an anesthetic for the performance of trepanation.^[75]

When the Spanish arrived in South America, most at first ignored aboriginal claims that the leaf gave them strength and energy, and declared the practice of chewing it the work of the Devil. But after discovering that these claims were true, they legalized and taxed the leaf, taking 10% off the value of each crop.^[76] In 1569, Nicolás Monardes described the practice of the natives of chewing a mixture of tobacco and coca leaves to induce "great contentment":

When they wished to make themselves drunk and out of judgment they chewed a mixture of tobacco and coca leaves which make them go as they were out of their wittes.^[77]

In 1609, Padre Blas Valera wrote:

Coca protects the body from many ailments, and our doctors use it in powdered form to reduce the swelling of wounds, to strengthen broken bones, to expel cold from the body or prevent it from entering, and to cure rotten wounds or sores that are full of maggots. And if it does so much for outward ailments, will not its singular virtue have even greater effect in the entrails of those who eat it?^{[citation needed]}

Isolation and naming[link]

Although the stimulant and hunger-suppressant properties of coca had been known for many centuries, the isolation of the cocaine alkaloid was not achieved until 1855. Various European scientists had attempted to isolate cocaine, but none had been successful for two reasons: the knowledge of chemistry required was insufficient at the time.^{[citation needed]} Additionally contemporary conditions of sea-shipping from South America could degrade the cocaine in the plant samples available to Europeans.^{[citation needed]}

The cocaine alkaloid was first isolated by the German chemist Friedrich Gaedcke in 1855. Gaedcke named the alkaloid "erythroxyline", and published a description in the journal Archiv der Pharmazie.^[78]

In 1856, Friedrich Wöhler asked Dr. Carl Scherzer, a scientist aboard the Novara (an Austrian frigate sent by Emperor Franz Joseph to circle the globe), to bring him a large amount of coca leaves from South America. In 1859, the ship finished its travels and Wöhler received a trunk full of coca. Wöhler passed on the leaves to Albert Niemann, a Ph.D. student at the University of Göttingen in Germany, who then developed an improved purification process.^[79]

Niemann described every step he took to isolate cocaine in his dissertation titled Über eine neue organische Base in den Cocablättern (On a New Organic Base in the Coca Leaves), which was published in 1860—it earned him his Ph.D. and is now in the British Library. He wrote of the alkaloid's "colourless transparent prisms" and said that, "Its solutions have an alkaline reaction, a bitter taste, promote the flow of saliva and leave a peculiar numbness, followed by a sense of cold when applied to the tongue." Niemann named the alkaloid "cocaine" from "coca" (from Quechua "cuca") + suffix "ine".^[79][80] Because of its use as a local anesthetic, a suffix "-caine" was later extracted and used to form names of synthetic local anesthetics.

The first synthesis and elucidation of the structure of the cocaine molecule was by Richard Willstätter in 1898.^[25] The synthesis started from tropinone, a related natural product and took five steps.

Medicalization[link]

With the discovery of this new alkaloid, Western medicine was quick to exploit the possible uses of this plant.

Used for dental pain in children

In 1879, Vassili von Anrep, of the University of Würzburg, devised an experiment to demonstrate the analgesic properties of the newly discovered alkaloid. He prepared two separate jars, one containing a cocaine-salt solution, with the other containing merely salt water. He then submerged a frog's legs into the two jars, one leg in the treatment and one in the control solution, and proceeded to stimulate the legs in several different ways. The leg that had been immersed in the cocaine solution reacted very differently than the leg that had been immersed in salt water.^[81]

Carl Koller (a close associate of Sigmund Freud, who would write about cocaine later) experimented with cocaine for ophthalmic usage. In an infamous experiment in 1884, he experimented upon himself by applying a cocaine solution to his own eye and then pricking it with pins. His findings were presented to the Heidelberg Ophthalmological Society. Also in 1884, Jellinek demonstrated the effects of cocaine as a respiratory system anesthetic. In 1885, William Halsted demonstrated nerve-block anesthesia,^[82] and James Corning demonstrated peridural anesthesia.^[83] 1898 saw Heinrich Quincke use cocaine for spinal anesthesia.

Today, cocaine has very limited medical use. See the section Cocaine as a local anesthetic

Popularization[link]

Pope Leo XIII purportedly carried a hipflask of the coca-treated Vin Mariani with him, and awarded a Vatican gold medal to Angelo Mariani.^[84]

In 1859, an Italian doctor, Paolo Mantegazza, returned from Peru, where he had witnessed first-hand the use of coca by the natives. He proceeded to experiment on himself and upon his return to Milan he wrote a paper in which he described the effects. In this paper he declared coca and cocaine (at the time they were assumed to be the same) as being useful medicinally, in the treatment of "a furred tongue in the morning, flatulence, and whitening of the teeth."

A chemist named Angelo Mariani who read Mantegazza's paper became immediately intrigued with coca and its economic potential. In 1863, Mariani started marketing a wine called Vin Mariani, which had been treated with coca leaves, to become cocawine. The ethanol in wine acted as a solvent and extracted the cocaine from the coca leaves, altering the drink's effect. It contained 6 mg cocaine per ounce of wine, but Vin Mariani which was to be exported contained 7.2 mg per ounce, to compete with the higher cocaine content of similar drinks in the United States. A "pinch of coca leaves" was included in John Styth Pemberton's original 1886 recipe for Coca-Cola, though the company began using decocainized leaves in 1906 when the Pure Food and Drug Act was passed. The actual amount of cocaine that Coca-Cola contained during the first twenty years of its production is practically impossible to determine.^{[citation needed]}

In 1879 cocaine began to be used to treat morphine addiction. Cocaine was introduced into clinical use as a local anesthetic in Germany in 1884, about the same time as Sigmund Freud published his work Über Coca, in which he wrote that cocaine causes:

Exhilaration and lasting euphoria, which in no way differs from the normal euphoria of the healthy person. You perceive an increase of self-control and possess more vitality and capacity for work. In other words, you are simply normal, and it is soon hard to believe you are under the influence of any drug. Long intensive physical work is performed without any fatigue. This result is enjoyed without any of the unpleasant after-effects that follow exhilaration brought about by alcohol. Absolutely no craving for the further use of cocaine appears after the first, or even after repeated taking of the drug.

In 1885 the U.S. manufacturer Parke-Davis sold cocaine in various forms, including cigarettes, powder, and even a cocaine mixture that could be injected directly into the user's veins with the included needle. The company promised that its cocaine products would "supply the place of food, make the coward brave, the silent eloquent and render the sufferer insensitive to pain."

By the late Victorian era cocaine use had appeared as a vice in literature. For example, it was injected by Arthur Conan Doyle's fictional Sherlock Holmes.

In early 20th-century Memphis, Tennessee, cocaine was sold in neighborhood drugstores on Beale Street, costing five or ten cents for a small boxful. Stevedores along the Mississippi River used the drug as a stimulant, and white employers encouraged its use by black laborers.^[85]

In 1909, Ernest Shackleton took "Forced March" brand cocaine tablets to Antarctica, as did Captain Scott a year later on his ill-fated journey to the South Pole.^[86]

During the mid-1940s, amidst WWII, cocaine was considered for inclusion as an ingredient of a future generation of 'pep pills' for the German military code named D-IX.^[87]

Prohibition[link]

The gears of prohibition began churning long before the Harrison Act was passed by Congress in 1914 – a law requiring cocaine and narcotics to be dispensed only with a doctor's order.^[88] Before this moment, various factors and groups acted on primarily a state level influencing a move towards prohibition and away from a laissez-faire attitude.^[89]

By 1903 cocaine consumption had grown to about five times that of 1890.^[90] Non-medical users accounted for almost the entire increase as cocaine-users extended outside the middle-aged, white, professional class.^[90] Cocaine became associated with laborers, youths, blacks and the urban underworld.^[90]

The popularization of cocaine first began with laborers who used cocaine as a stimulant to increase productivity.^[90] Cocaine was often supplied by employers.^[91] Cocaine was often supplied to African American workers, who many employers believed were better physical workers; cocaine was thought to provide added strength and constitution and according to the Medical News, made blacks “impervious to the extremes of heat and cold.”^[90] However, users of cocaine quickly acquired a reputation as dangerous and in 1897, the first state bill of control for cocaine sales came from a mining county in Colorado.^[92]

The popularization of cocaine use was not confined to African Americans or simple laborers. In Northern cities, cocaine use increased amongst poorer people – in fact, cocaine was often cheaper than alcohol.^[91] In the Northeast in particular, cocaine became popular amongst workers in factories, textile mills and on rail roads.^[93] In some instances, cocaine use supplemented or replaced caffeine as the drug-of-choice to keep workers awake and working overtime.^[93]

This period of increasing cocaine use followed with increasing fears that young children were being preyed upon and forced into cocaine addiction.^[94] Indeed, it was even thought that cocaine was used to seduce young girls away from their homes and cause them to be addicted and dependent upon the substance and therefore fall prey to an inescapable cycle of prostitution.^[95] Fears of the corruption of the youth by cocaine were popular and widespread but there is little evidence to support their veracity.^[94]

Mainstream media reported cocaine epidemics as early as 1894 in Dallas, Texas.^[96] Reports of the cocaine epidemic would foreshadow a familiar theme in later so-called epidemics, namely that cocaine presented a social threat more dangerous than simple health effects and had insidious results when used by blacks and members of the lower class.^[96] Similar anxiety-ridden reports appeared throughout cities in the South leading some to declare that “the cocaine habit has assumed the proportions of an epidemic among the colored people.”^[96] In 1900, state legislatures in Alabama, Georgia and Tennessee considered anti-cocaine bills for the first time.^[96]

Hyperbolic reports of the effect of cocaine on African Americans went hand-in-hand with this hysteria. In 1901, the Atlanta Constitution reported that “Use of the drug [cocaine] among negroes is growing to an alarming extent.”^[97] The New York Times reported that under the influence of cocaine, “sexual desires are increased and perverted … peaceful negroes become quarrelsome, and timid negroes develop a degree of 'Dutch courage' that is sometimes almost incredible.”^[98] A medical doctor even wrote “cocaine is often the direct incentive to the crime of rape by the negroes.”^[98] To complete the characterization, a judge in Mississippi declared that supplying a “negro” with cocaine was more dangerous than injecting a dog with rabies.^[99]

These attitudes not only influenced drug law and policy but also led to increased violence against African Americans. In 1906, a major race riot led by whites erupted; it was sparked by reports of crimes committed by black ‘cocaine fiends.’^[97] Indeed, white-led, race riots spawning from reports of blacks under the influence of cocaine were not uncommon.^[100] Police in the South widely adopted the use of a heavier caliber handguns so as to better stop a cocaine-crazed black person – believed to be empowered with super-human strength.^[101] Another dangerous myth perpetuated amongst police was that cocaine imbued African Americans with tremendous accuracy with firearms and therefore police were better advised to shoot first in questionable circumstances.^[102]

Ultimately public opinion rested against the cocaine user. Criminality was commonly believed to be a natural result of cocaine use.^[103] Much of the influence for these kind of perceptions came from the widespread publicity given to notorious cases.^[89] While the historical reality of cocaine’s effect on violence and crime is difficult to disentangle from inflamed perceptions, it does appear that public opinion was swayed by the image of the violent, cocaine-crazed fiend and pushed over the edge by a few violent episodes.^[103] It was an image of the cocaine-user that carried acute racial overtones.^[89]

Before any substantive federal regulation of cocaine, state and local municipalities evoked their own means to regulate cocaine. Because of the initial lack of targeted legislation, on both federal and state level, the most typical strategy by law enforcement was the application of nuisance laws pertaining to vagrancy and disturbing the peace.^[104] Subsequent legislative actions aimed at controlling the distribution of cocaine rather than its manufacture.^[105] Reformers took this approach in part because of legal precedents which made it easier to control distributors, such as thin the case of pharmacies; state and local boards of hearth or boards of pharmacy often took the place of regulatory bodies for controlling the distribution of cocaine.^[105]

Some states took the position of outright banning of all forms of cocaine sale; Georgia was the first to do this in 1902.^[106] A New Orleans ordinance banned cocaine sales as well but left an ill-defined exception for therapeutic uses.^[105] A more common requirement was to restrict the sale of cocaine or impose labeling requirements. A 1907 California law limiting sale of cocaine to only those with a physician’s prescription resulted in the arrest of over 50 store owners and clerks in the first year.^[105] A 1913 New York state law limited druggists’ cocaine stocks to under 5 ounces. Labeling requirements initially operated on a state level with some states even going so far as to require that cocaine and cocaine-containing products be labeled as poison.^[107]

Eventually the federal government stepped in and instituted a national labeling requirement for cocaine and cocaine-containing products through the Food and Drug Act of 1906.^[107] The next impactful federal regulation was the Harrison Narcotics Tax Act of 1914. While this act is often seen as the start of prohibition, the act itself was not actually a prohibition on cocaine, but instead setup a regulatory and licensing regime.^[108] The Harrison Act did not recognize addiction as a treatable condition and therefore the therapeutic use of cocaine, heroin or morphine to such individuals was outlawed – leading the Journal of American Medicine to remark, “[the addict] is denied the medical care he urgently needs, open, above-board sources from which he formerly obtained his drug supply are closed to him, and he is driven to the underworld where he can get his drug, but of course, surreptitiously and in violation of the law.”^[109] The Harrison Act left manufacturers of cocaine untouched so long as they met certain purity and labeling standards.^[110] Despite that cocaine was typically illegal to sell and legal outlets were more rare, the quantities of legal cocaine produced declined very little.^[110] Legal cocaine quantities did not decrease until the Jones-Miller Act of 1922 put serious restrictions on cocaine manufactures.^[110]

Modern usage[link]

In many countries, cocaine is a popular recreational drug. In the United States, the development of "crack" cocaine introduced the substance to a generally poorer inner-city market. Use of the powder form has stayed relatively constant, experiencing a new height of use during the late 1990s and early 2000s in the U.S., and has become much more popular in the last few years in the UK.^{[citation needed]}

Cocaine use is prevalent across all socioeconomic strata, including age, demographics, economic, social, political, religious, and livelihood.^{[citation needed]}

The estimated U.S. cocaine market exceeded $70 billion in street value for the year 2005, exceeding revenues by corporations such as Starbucks.^[111][112] There is a tremendous demand for cocaine in the U.S. market, particularly among those who are making incomes affording luxury spending, such as single adults and professionals with discretionary income. Cocaine’s status as a club drug shows its immense popularity among the "party crowd".