DARK Classics in Chemical Neuroscience: Cocaine

In this review, we consider the story of cocaine from its humble origins in South America to its status as one of the most abused substances in 21 st century society. The synthesis and biosynthesis of cocaine are discussed, as well as its pharmacokinetics, metabolism, pharmacology, and importance in modern neuroscience and molecular imaging.

CULTURAL AND HISTORIC RELEVANCE

“For there was never any elixir so instant magic as cocaine.”

1

–Aleister Crowley, Cocaine (1917)

The story of cocaine is old. Very old. Fascinating and alluring, but equal parts destructive and tragic, this relatively simple alkaloid has a long and complex past. Cocaine’s history spans millennia, is peppered with enigmatic characters including actors, rock stars, athletes and gangsters, and is full of paradoxes, unimaginable wealth, scandal, murder, passion and intrigue. Cocaine bridges the old world to the new, the practice of modern medicine to the illicit drug market and the drug cartels, one of the largest illegal businesses with one of the largest legal ones, and the means of survival for one society at the expense of damage and destruction to another.

Cocaine is an alkaloid that is produced biosynthetically by Erthroxylum coca ( ), a shrub native to the Andean Highlands and northern parts of the Amazon in South America. Pure cocaine (blow, snow, Charlie, C) is a white powder, and as the hydrochloride salt is water soluble and usually snorted up the nose. “Crack cocaine” (rock, base) is the free base. It is a yellow solid and is usually smoked in a crack pipe ( ). While there are eight possible stereoconformers, only one of them, (R)–(-)cocaine (1), is addictive.2

For thousands of years, indigenous South Americans have consumed coca tea or chewed on dried coca leaves with lime or ash, promoting the release of cocaine in saliva. In addition to the general stimulating and rejuvenating benefits associated with coca, including the alleviation of hunger and thirst, the practice has been used by locals as well as travelers to South America specifically for the relief of altitude sickness.3 These “magical” effects, associated with the slow release of cocaine from chewing or brewing tea, has given the coca plant mythical status amongst the local population. Considered a gift from heaven, it has been referred to as “the divine plant” of the Incas.4 When the Spaniards invaded South America and enslaved the indigenous population, they found that allowing the slaves to chew coca leaves while working made them more affable and likely to do more perilous tasks.5

Since its introduction to modern society, cocaine has captured the imagination and inspired the creativity of artists and scientists alike. Artistic references to cocaine are abundant in literature (Sherlock Holmes by Sir Arthur Conan Doyle,6 The Curious Case of Dr. Jekyll and Mr. Hyde by Robert Louis Stevenson), Hollywood movies (Blow, Traffic, Scarface, Pulp Fiction), TV shows (Narcos, Snowfall), artwork (at the time of writing Banksy’s Snorting Copper is estimated to be worth $1.75 million7) and songs (Cocaine by JJ Cale and made famous by Eric Clapton, Cocaine Blues, different songs with the same title recorded by Johnny Cash and Bob Dylan, Champagne Supernova by Oasis, and Crack City by David Bowie).

In the scientific community, bringing cocaine back to Europe allowed for the first isolation in 1855 by Niemann and the later development of “coca wine” by Angelo Mariani. Vin Mariani ( ) was a Bordeaux wine laced with coca leaves.10, 11 It contained 10% alcohol and 8.5% alkaloid cocaine from the leaves of Erythroxylum coca and, famously, Thomas Edison, Queen Victoria and Pope Leo XIII were reportedly all fans. Subsequently cocaine has proven an addictive target for total synthesis chemists (vide infra), while elucidating the biosynthesis, metabolites and mechanisms of pharmacological action have been of similar interest to biochemists and pharmacologists alike. The latter quickly developed a better understanding of the medicinal properties of cocaine, and backed up the lore of the South American natives with biochemistry. However, the popularization of cocaine at this time can perhaps mostly be attributed to Sigmund Freud, who documented the stimulant and euphoric effects of cocaine in his 1884 publication “A contribution to the knowledge of the effects of cocaine,” which was republished more recently in The Cocaine Papers.12 Freud was also able to show dose-dependent relationship effects of cocaine on mood, hand strength, and measure of perception, and was immensely proud of these discoveries.

The chronicles of coca from the Inca,4 as well as the preliminary scientific investigations from Freud (and others),12 caused the medicinal properties of cocaine to be seized upon, and prescription of cocaine for toothaches ( ), headaches, dyspepsia, gastrointestinal disorders, neuralgia, and melancholy soon followed around the turn of the 20th century. Coca Cola was developed during this period from coca leaves and kola nuts, though the exact recipe remains a secret, and marketed as the “intellectual beverage and temperance drink” during prohibition America.13 Today, Coca Cola obtains coca leaves with a special permit and, although the drink no longer contains cocaine, it remains one of the world’s most valuable companies. Cocaine was also used in solutions of 4 to 20% for local anesthesia, chiefly in ophthalmologic surgery, because of cocaine’s unique ability to block nerve conduction and cause vasoconstriction in mucous membranes.14, 15 Notably, today cocaine remains approved by the US Food and Drug Administration (FDA) as a nasal solution ( ), and is indicated for the induction of local anesthesia of the mucous membranes when performing diagnostic procedures and surgeries on or through the nasal cavities in adults.16

If our story stopped there, then perhaps cocaine would have earned a place in the recent issue of this journal devoted to Classics in Chemical Neuroscience.17 However, since this paper is part of the issue dedicated to Dark Classics in Chemical Neuroscience,18 it is imperative that we acknowledge the other darker side of cocaine. William S. Burroughs described cocaine as “the most exhilarating drug I have ever used,”19 and Dominic Streatfeild concurred: “Cocaine is a sensational drug… Nothing will make you feel as good.”20 This ability to cause pleasure stems from cocaine’s ability to block uptake of neurotransmitters such as dopamine and norepinephrine (see Pharmacology section for more details), and is what makes the drug extremely addictive.21 Perhaps the first description of cocaine addiction was in the popular Sherlock Holmes detective stories, written in the 1880’s by former ophthalmologist Arthur Conan Doyle. In The Adventures of Sherlock Holmes: A Scandal in Bohemia, Dr. Watson describes Holmes as: “…alternating from week to week between cocaine and ambition.”6 Notably, Freud claimed that cocaine could cure medical and physiological ailments, and he treated his morphine-addicted friend with cocaine. His effort was entirely successful in treating the opioid addiction — by replacing it with a cocaine addiction!12 This garnered Freud some negative press and, famously, Friedrich Albrecht Ehrlenmeyer, physician and psychiatrist, accused Freud of having “unleashed the third scourge of humanity,” after alcohol and opioid addiction.22

Despite the early evidence of the addictive properties (or perhaps because of them!), snorting cocaine for recreational use became popular in the early 20th century, and by 1910 the first reports of nasal damage from snorting cocaine appeared in the scientific and medical literature.26 By 1912, thousands of people were dying on an annual basis from cocaine abuse, prompting the United States to ban the drug in 1914.26 The use of cocaine in consumer products was severely lowered in 1914 by the Harrison Narcotics Act, which forbade the use of cocaine in proprietary medicines and required regulation of those involved with the importation, manufacturing, and distribution of cocaine and opium products. Unfortunately, this American law also misidentified cocaine as a “narcotic” which added confusion to any medical usefulness of the natural product.10 In 1970, the Comprehensive Drug Abuse Prevention and Control Act would define cocaine as “Schedule II:” having medical use and a high abuse potential.27 To this day cocaine remains a controlled substance, and is classified Schedule II by the US Drug Enforcement Administration (DEA). The increased control of the substance and the development of local anesthetics based on cocaine (see the Importance in Neuroscience section), have replaced most of the use of cocaine medically.

Abuse of cocaine increased in the 1970’s, with some experts pointing to the demonization of amphetamines as a turning point for cocaine’s popularity. Later in this decade the infamous Medellin cartel kingpin Juan Pablo Escobar ( ), would monopolize the import and sale of cocaine in the United States.28 The incredible story of Escobar’s cocaine empire has been dramatized in movies (Blow) and television (Narcos) and paints a picture of extravagant wealth in Colombia from the coca trade. During his prime, Escobar’s cartel supplied ~80% of the cocaine smuggled into the USA (~15 tonnes per day), turning over almost $22 bn a year in personal income. For this reason, Escobar was dubbed the King of Cocaine, and he was the wealthiest criminal in history. Not only that, but his estimated net worth of ~$30 bn actually made him one of the wealthiest people in the world, too! He was eventually confined to house arrest, but following his escape he died in a shootout in 1993.

In meta-analysis of music, television, and movies, despite more media referencing drug use now than compared to 1968, there are also more mentions of “negative” consequences and side effects of illegal drug use.29–31 Indeed, the biggest tragedy of cocaine’s story is that many of the creative people described above who drew inspiration from the drug also died prematurely as a result of abusing it.32 Thus a number of high profile musicians (Ike Turner, Scott Weiland, Whitney Houston) and entertainers (John Belushi, Philip Seymour Hoffman, River Phoenix, Corey Haim, Chris Farley, Carrie Fisher) ended up dying from a cocaine overdose, or indirect causes likely resulting from cocaine use and abuse.

Perception of cocaine abuse in America and portrayal in the media in the 1970’s and 80’s was decidedly racial; crack cocaine was reported in nightly news segments as always being associated with African American men.33 This largely informed the mandatory minimum sentencing laws, which would greatly affect African American men instead of their Caucasian counterparts.34 Despite the stimulant and euphoric effects being the same between cocaine and crack cocaine (see Pharmacology), there is a significantly higher sentencing law associated with crack.27 The Anti-Drug Abuse Act of 1986 originated the mandatory minimum sentences for those convicted with drugs that exceed an amount for trafficking and not use. Under this law, the eligibility for mandatory minimum for crack cocaine was only 0.005 kg and for powder cocaine 0.5 kg.27 Obviously from the harsher guidelines, significantly more crack cocaine users were sent to jail and this propelled a demonization of crack cocaine over pure cocaine powder. In 2010, the Fair Sentencing Act responded to the complaint that powder cocaine was given preferential treatment; it changed the minimum amounts of crack cocaine to 0.028g, merely closing the weight ratio from 100:1 to 20:1.27 This leniency toward cocaine correlates to shorter prison sentences as well.34 Although changes have been made, it still appears an unjust differentiation between cocaine and crack.

In the last decade, cocaine use has slightly decreased in the United States from 2% of adults aged 18-25 who reported use in 2002, to 1.7% in 2015.35 Overall, 1.9 million people (0.7% of the US population) identify as cocaine users, with 394,000 (0.1%) of those using crack cocaine.36 Despite a small number of users in comparison with opioids (heroin: 0.6 million/prescription opioids: 3.8 million) and cannabis (4 million),35 cocaine is the most highly intercepted drug globally. In 2015 for example, 864 tons of cocaine were seized from an estimated global manufacturing total of 1,125 tons of pure cocaine, produced in Colombia, Bolivia and Peru.36 In response to the increased interception, it is estimated that coca plant cultivation has increased 25% from 2013 to 2015.36 Despite the increase in manufacturing and trafficking risk, the price of cocaine in the United States has hardly changed.37 Cartels control the entire manufacturing process and only pay $10,000 for a kilo of pure cocaine, despite the final markup of that pure kilo being $150,000 when a dealer divides it into gram quantities. Depending on the location, one gram of cocaine is sold for $100-$150.37

The expense, and low purity, associated with cocaine may be attributable to its relatively low popularity compared to other drugs. In the party scene, younger users (aged 13-25) report using 3,4-methylenedioxymethamphetamine (MDMA, molly, ecstasy or E) as a stimulant because it is cheaper in comparison to cocaine for a similar one-time high. For those still using cocaine, most report co-abuse with alcohol and other drugs.38 Unfortunately, the mixing of cocaine with other drugs of abuse can prove deadly. Of the entertainers mentioned above, Philip Seymour Hoffman, John Belushi, Chris Farley and River Phoenix all died after using Speedball (a mixture of cocaine and morphine/heroin).39 The most common co-abuse occurs with drinking alcohol while ingesting cocaine; the metabolism profile changes and results in a more toxic metabolite (see Pharmacokinetics and Drug Metabolism),38, 40–42 and the combination of cocaine and alcohol was responsible for death of baseball pitchers José Fernández and Tommy Hanson, novelist Jacques d’Adelswärd-Fersen and musician Jay Reatard.

This is cocaine’s story, and it is clearly a complex one. As we stated in our introduction, cocaine intersects and connects many different parts of the modern world. Thus, Coca Cola is reliant upon the coca industry and is one of the world’s most valuable companies, with an estimated net worth of $188 bn. Contrastingly, the estimated value of the illegal cocaine market is $88 bn per year. Today it is estimated that ~150,000 hectares of land is used to cultivate coca and with these staggering numbers in mind, clearly the coca producing countries of Colombia, Peru and Bolivia depend upon the crop for their livelihood despite the fact that cocaine is responsible for almost 50,000 deaths per year worldwide. Coca’s importance to the region was known as long ago as the 16th Century when Juan Matiezo de Peralta once remarked: “if there were no coca there would be no Peru,”20, 43 and for this reason a century of cocaine abuse is unlikely to topple a multi-billion dollar industry based on a crop that has been part of a peoples culture for thousands of years. In this review we describe the science underpinning the wealth, power and scandal, the methods behind the money, and the pharmacology of cocaine’s pleasure. The synthesis and biosynthesis of cocaine are discussed, as well as the alkaloids pharmacokinetics, metabolism, pharmacology and importance to modern neuroscience and molecular imaging.