By Keith Williams, Ph.D. - Business Manager, Analytical Standards Europe, Cayman Chemical

Coca and cocaine have been used by humans for around 5,000 years. Originally consumed by chewing leaves, there are few if any reports of it causing significant social harm until it was isolated and purified in the 1800s. Since its isolation and purification, cocaine has changed from a medical curiosity to a substance in massive demand for illicit consumption over the past 200 years. What is the background of the evolution of this drug, and what catalysts promoted its use in early days?

Early Use of Cocaine

Cocaine is a plant alkaloid present in the leaves of Erythroxylum coca, a plant originating in South America. Its use as a stimulant was accepted by native South Americans well before the arrival of Spanish conquistadors in 1532. The Spanish quickly realised there were economic advantages to the cultivation of coca and encouraged its cultivation through the development of plantations. And, as governments do, they also introduced taxation systems to allow payment in coca leaves. Although the leaves were exported from South America to Europe, little and unreliable amounts of active cocaine were actually present in the leaves once it arrived as much of it degraded during the journey.

The 1800s

Due to lack of high-quality leaf material in Europe, little further research was done until the mid-1800s. Albert Niemann in 1860 published his doctoral thesis where he detailed the extraction of cocaine from 27 kg (60 lbs) of leaves collected specifically for this purpose on a South American expedition.^1,2 He noted the tongue numbing sensation of the purified drug, but this local anaesthetic effect was not reported again until almost 13 years later by Dr. Alexander Bennet.³

In Bennet’s publication, he complains that

“In this country [United Kingdom] the coca leaves are rare and even in Paris where they can be obtained, they are very expensive.”

These costs and paucity of quality material continued to block significant research following the isolation of the active component until 1885, when Koller published on the local anaesthetic effects of cocaine, and Freud published the first of his cocaine papers Uber Coca.^4,5 These were facilitated by a reliable supply of cocaine from what was then a relatively young, rapidly growing chemical company, Merck. With this reliable supply, other scientists were able to replicate the work. This was the turning point for the accepted use of cocaine as a local anaesthetic. Karch details in his book A Brief History of Cocaine that sales from Merck expanded from one pound in 1883 to 3,179 pounds in 1884 and then 158,352 pounds in 1886.⁶ Cocaine is still used today and is listed in the pharmacopoeias of the US as well as those of other countries.

Stimulant Effect of Cocaine

Although the local anaesthetic effect is beneficial to medicine, coca leaves were originally used for their stimulant effect. There are many anecdotal reports of individuals, groups of workers, or soldiers using coca leaves to enhance their stamina or performance. In fact, the coca leaf achieved almost mythical status in increasing an individual’s endurance that its use was actively encouraged in certain areas.

For example, Edward P. Weston was a notable pedestrian, who competed in extreme, long-distance walking races in late Victorian times and openly admitted the use of coca leaf during these events but claimed that it had minimal effects.^7,8 He came to prominence in 1861, when he walked from Boston to Washington DC in 10 days and 10 hours (478 miles) following a bet on the presidential election. He also undertook a tour of Europe between 1876 and 1884, and in London in 1876, he took part in an ultramarathon completing 115 miles in just 24 hours.

The social use of cocaine primarily originates in coca wines, a formulation described as a cocaine base dissolved in wine. With its origins in France, it was popularised by Angelo Mariani and involved some early examples of celebrity endorsements, including the Pope and European royalty. Mariani undertook what could be described as a modern marketing campaign to promote his products, and Karch also provides an overview of this.⁶ Mariani was the cousin of a noted ear, nose, and throat surgeon, Charles Fauvel, who used cocaine in his practice at least 20 years before Koller. Fauvel, for whatever reason, has never been truly recognised for his pioneering use.

Mariani Tonic Wine - lithography by Jules Chéret, 1894, via http://www.bmlisieux.com/litterature/bibliogr/mariani.htm.

Popularisation and Regulatory Control of Cocaine

Following the reports by Koller and Freud, demand for cocaine rapidly increased as it was actively promoted by a number of reputable drug and chemical manufacturers. Production of pure cocaine soared from 500 grams annually to more than hundreds of kilograms to meet this demand.

It should be remembered that at that time, cocaine was still not regulated as a controlled substance in the way it is today, so there were few legal restrictions to customer demand. To give an idea of scale, Karch reports that one manufacturer produced on average three tonnes annually in the 26-year period leading up to World War I.⁶ To meet this market need, a large quantity of coca leaves was required. While some of it came from South America, significant quantities were also available from plantations developed in Asia. There, plantations continued to operate into the 1940s. After they ceased operation, production contracted back to South America where it originated.

The World Wars

The stimulant effect of coca and cocaine was well known by the early 1800s, and there had been suggestions for its use in military situations as early as 1824.⁹ A number of senior military commanders noted the effects of coca leaves, and later of cocaine itself. Burroughs, Wellcome, & Co. produced a series of products under its “TABLOID” brand. One in particular was a mixture of cocaine and caffeine that was labelled:

“Allays hunger and prolongs the power of endurance

Directions.- One to be dissolved in the mouth every hour when undergoing continued mental strain or physical exertion.” ¹⁰

This product as well as other similar products were extensively used by the British military during World War I after noting their impact on various Antarctic expeditions in 1910-1912. Similar products were also used by other combatants. Kamieński also details use by the German, French, and Australian military, both in infantry and airmen.

A large quantity of the raw material for these pharmaceutical preparations was from the Netherlands, who as a country remained neutral during this conflict. The Dutch company Nederlandsche Cocaïnefabriek (NCF) was established in 1900 to exploit the coca plant.⁶ The raw material was sourced from Dutch colonies in Asia where the coca plant was a different strain, producing a higher cocaine yield overall. At the height of the war, the NCF production was between 20,000 and 30,000 kg annually, with demand primarily driven by military requirements. NCF continued to exist as an independent company until the 1960s when it was acquired by Organon, and the combined organisation was renamed Koninklijke Zwanenberg-Organon (KZO). KZO itself disappeared when it merged with the fibre producing company Algemene Kunstzijde Unie (AKU) to become AKZO, and then later Akzo Nobel N.V.¹¹

Legal Control of Cocaine

As with other plant-based, pure-drug substances, concerns started to develop in the early 1900s for the impact of cocaine on society. The Harrison Narcotics Tax Act in the US was one of the earliest attempts to control cocaine specifically.¹² The reaction of the public in the UK to soldiers returning from the front in World War I with cocaine (and morphine) addictions led to the introduction of the Dangerous Drugs Act of 1920.¹³ These early examples of country-specific drug controls led to international regulation through the League of Nations. One consequence was the impact of the 1928 International Opium Convention on Dutch cocaine production. The requirement for cocaine only to be produced for recognised, legitimate use significantly restricted opportunities for cocaine production and had a significant impact on Dutch manufacturers who had become predominant in this area.¹⁴ Also, around this time, international regulations were introduced requiring country-specific statistical reporting of drug manufacturing. This eventually led to the current situation where the United Nations, through the International Narcotics Control Board, now monitors the enforcement of restrictions on the trade of defined narcotics and psychotropic substances using similar statistical reporting.

Cultural Impact and Shifts in Production

Between the wars, cocaine continued to be used licitly and illicitly, and its effects and use were mentioned in popular culture. For example, Cole Porter refers to the stimulant effect in the song “I Get A Kick Out of You”, originally from the 1934 Broadway musical “Anything Goes.” As the Netherlands withdrew from cocaine manufacturing, Dutch-owned plantations in Asia were replaced, to a large degree, by Japanese-led production. It was a highly profitable business whose manufacture levels were systematically under-reported to the League of Nations. This under-reporting formed part of the basis for the Tokyo War Crimes Trials.⁶

After World War II, the loss of legitimate or state-sponsored production in most countries resulted in contracting the production base back to the continent of origin, namely South America. Use dropped dramatically, before accelerating again towards the 1960s, particularly in the US. This growth has continued internationally with 140.4 tonnes being seized in the EU in 2017 alone.¹⁵ This quantity far exceeds what is reported as being used legitimately in the early 1900s.

There has been no publicly declared use of cocaine for military purposes since World War II. That has not stopped military service personnel from using the drug recreationally, like many others in society.¹⁶ The military’s interaction with cocaine has transferred more to a law enforcement function. For example, a recent press release highlighted the collaboration between the Royal Navy in the Caribbean with US law enforcement and US Coast Guard in seizing 1.4 tonnes of cocaine.17 The influence of cocaine (and other regulated substances) on governments and regimes directly or through their foreign policy continues to exist to this day, and the consequences of such state-supported covert actions were examined in detail in the Kerry report from 1988.¹⁸

Cocaine Effects and Modes of Action

Cocaine use has three noted effects: local anaesthetic, vasoconstrictor, and stimulant. The local anaesthetic effect is associated with cocaine blocking voltage-gated sodium channels and consequently increases the threshold required to trigger action potential in a neuron.¹⁹ This restricts an individual’s ability to respond to painful stimuli. The stimulant effect is enacted through the binding of cocaine to three transporter proteins, namely the norepinephrine transporter (NET), the dopamine transporter (DAT), and the serotonin transporter (SERT or 5-HTT), and inhibition of neurotransmitter uptake, prolonging their action.²⁰ This prolonged action also forms the basis for the tolerance to cocaine reward and sensitization to cocaine toxicity.

Cocaine Metabolism

The principal metabolites/breakdown products of cocaine are illustrated in the below figure. Two of the metabolites, ecgonine methyl ester and benzoylecgonine, are produced without the requirement of any other external influence. Cocaethylene is only produced with the concurrent use of ethanol, and methylecgonidine (AEME) is a pyrolysis product formed when crack cocaine is smoked. When administering drug tests, the presence or absence of these metabolites can be used to identify the various routes of ingestion and help to explain the veracity of explanations given to account for positive drug test results.

Metabolism of cocaine.

Recent Developments in Cocaine

There is always a desire from law enforcement agencies to identify the original growing location of coca leaves, as there is no robust evidence to suggest that there is any large-scale synthetic production of cocaine. A lot of work over the last 20 years has used isotope ratio-mass spectrometry to identify specific and new growing locations in South America.²¹ Possibly more surprising, there is little evidence to suggest that there have been any significant novel psychoactive substances that have been specifically manufactured to directly replace cocaine, although there is some evidence to support the hypothesis there was at least a partial replacement by mephedrone in certain populations.¹⁶

Available from Cayman

Cayman offers numerous analytical standards and reference materials for the identification of cocaine. It is important that we provide these materials in a format that is useful to customers. Based on recent feedback, we are very pleased to announce that our cocaine reference materials are now available in a larger 50 mg size. Custom and bulk sizes are also available upon request. You can request a quote by contacting sales@caymanchem.com.

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References

1. Niemann, A. Ueber eine neue organische base in den cocablättern. Archiv der Pharmazie153(2), 129-155 (1860).

2. Niemann, A. Ueber die einwirkung des braunen chlorschwefels auf Elaylgas. Liebigs Annalen der Chemie und Pharmacie 113(3), 288-292 (1860).

3. Bennett, A. An experimental inquiry into the physiological actions of theine, caffeine, guaranine, cocaine, and theobromine. Edinb. Med. J.19(4), 323-341 (1873).

4. Honegger, H. and Hessler, H. Discovery of local anesthesia by Karl Koller. I. Klin. Monbl. Augenheilkd.157(3), 428-438 (1970).

5. Freud, S. Uber Coca. Wein Centralblatt fur die ges Therapie.2 (1884); Also available as translation in Shaffer, H. Uber Coca: Freud’s Cocaine discoveries. J. Subst. Abuse Treat. 1(3), 205-217 (1984).

6. Karch, S.B. A Brief History of Cocaine. CRC Press, Boca Raton, FL (1998).

7. https://en.wikipedia.org/wiki/Edward_Payson_Weston

8. Weston, E.P. Mr. Weston on the use of coca leaves. Lancet 107(2742), 447 (1876).

9. Kamieński, Ł. Shooting Up: A History of Drugs in Warfare. Hurst (2017).

10. Wellcome Collection. “Forced march” tabloid brand, Burroughs Wellcome Co. Retrieved from https://wellcomecollection.org/works/vp7vwfjm

11. https://en.wikipedia.org/wiki/Harrison_Narcotics_Tax_Act

12. https://en.wikipedia.org/wiki/Dangerous_Drugs_Act_1920

13. http://www.worldlii.org/int/other/LNTSer/1928/231.html

14. European Monitoring Centre for Drugs and Drug Addiction. European Drug Report (2019).

15. Bird, S.M. The importance of the British Army’s slick drug-testing operations. Clinical Pharmacist(10)1 (2018).

16. https://www.southcom.mil/MEDIA/NEWS-ARTICLES/Article/2076222/coast-guard-uk-royal-navy-us-law-enforcement-seize-cocaine-in-the-caribbean-sea/

17. Subcommittee on Terrorism, Narcotics and International Operations. Drugs, law enforcement and foreign policy (1989).

18. Mathews, J.C. and Collins, A. Interactions of cocaine and cocaine congeners with sodium channels. Biochem. Pharmacol.32(3), 455-460 (1983).

19. Ritter, J.M., Flower, R., Henderson, G., et al. Rang and Dale’s Pharmacology, 9th Edition, Elsevier, Edinburgh (2019).

20. Mallette, J.R., Casale, J.F., Jordan, J., et al. Geographically sourcing cocaine’s origin–delineation of the nineteen major coca growing regions in South America. Sci. Rep. 6, 23520 (2016).