History of Psychostimulant Use

Cocaine derives from the coca plant Erythroxylon coca and has a long history as a stimulant (Figure 4.2, Box 4.3). Coca chewing originated in Peru at least as early as 3000 BC. Initially, its use was restricted to royalty but eventually came to the general population following the Spanish conquest to sustain the performance of laborers in the Peruvian silver mines. Cocaine has been used for centuries in tonics and other preparations to allay fatigue, sustain performance, and treat a wide range of ailments. Cocaine once was a component of Coca Cola®. In 1886, the druggist John Styth Pemberton patented a medicine that contained two natural stimulants, cocaine and caffeine, to formulate the syrup base for Coca Cola®. He blended a whole-leaf extract of coca with an extract from the African Kola nut which contains caffeine. Coca Cola® was initially manufactured and marketed as an “intellectual beverage” and “brain tonic,” and until 1903, Coca Cola® contained approximately 60 mg of cocaine per 8 ounce (237 ml) serving. In 1903, soon after the dangers of cocaine were widely publicized, the manufacturer of Coca Cola® removed cocaine from its formulation, although an extract of the coca leaf is still found in the preparation today. However, the only stimulant now found in a typical can of Coke is ∼34 mg caffeine.

Figure 4-2 Erythroxylon coca. [From: Bentley R, Trimen H. Medicinal plants: being descriptions with original figures of the principal plants employed in medicine and an account of the characters, properties and uses of their parts and products of medicinal value. Churchill, London, 1880.]

The therapeutic effects of cocaine were propounded not only by manufacturers of Coca Cola®. In the late 19th century, Dr. Sigmund Freud also advocated the use of cocaine for the treatment of a variety of disorders, including psychiatric disorders and drug addiction. In fact, Freud used cocaine himself but quickly lost his enthusiasm after witnessing his first cocaine-induced psychosis in a colleague (more on cocaine psychoses will be discussed later in this section; see Box 4.4 for a modern example).

Cocaine and other indirect sympathomimetics have been involved in more than one episode of widespread drug abuse, both in the United States and worldwide (Table 4.2, Figure 4.3). Presumably because cocaine was used in numerous tonics and “healthful” preparations, extensive cultivation of cocaine occurred in South America, resulting in extensive exportation to the United States and Europe. With widespread supply, demand followed, and in the United States the first restriction of coca products occurred with the 1914 Harrison Narcotics Act, sponsored by Representative Francis Burton Harrison (Democrat, New York):

“An Act to provide for the registration of, with collectors of internal revenue, and to impose a special tax on all persons who produce, import, manufacture, compound, deal in, dispense, sell, distribute, or give away opium or coca leaves, their salts, derivatives, or preparations, and for other purposes...That it shall be unlawful for any person to sell, barter, exchange, or give away any of the aforesaid drugs except in pursuance of a written order of the person to whom such article is sold, bartered, exchanged, or given, on a form to be issued in blank for that purpose by the Commissioner of Internal Revenue...[but shall not apply to] the dispensing or distribution of any of the aforesaid drugs to a patient by a physician, dentist, or veterinary surgeon registered under this Act in the course of his professional practice [or] the sale, dispensing, or distributing of any of the aforesaid drugs by a dealer to a consumer under and in pursuance of a written prescription issued by a physician, dentist, or veterinary surgeon registered under this Act ... That any person who violates or fails to comply with any of the requirements of this Act shall, on conviction, be fined not more than $2,000 or be imprisoned not more than five years, or both, in the discretion of the court.”

BOX 4.3


Cocaine is derived from the leaves of the coca plant (Erythroxylon coca). Cocaine is an alkaloid found in the leaves of the plant and was first isolated in 1855 by Friedrich Gaedcke of Germany, who originally termed it “erythroxyline.” An improved purification process was published in 1860 by Albert Niemann, who renamed the alkaloid “cocaine.” Nearly 40 years later, in 1898, Richard Willstatter was the first to synthesize the cocaine molecule, beginning with tropinone, and define its chemical structure. Illicit cocaine production involves the extraction of crude coca paste from the coca leaf, purification of coca paste to coke base, and conversion of the base to cocaine hydrochloride. Cocaine hydrochloride can also be synthesized (that is, the process does not begin with a crude extract), in which 2-carbomethoxytropinone is first produced, followed by conversion to methyl ecgonine, and finally benzoylation to cocaine. Licit or pharmaceutical-grade cocaine hydrochloride production generally follows this synthesis procedure but incorporates several more steps that yield cocaine hydrochloride with a purity greater than 99.5% (in contrast to illicit cocaine, which is ∼80–97% pure). Gaedcke F. Ueber das erythroxylin, dargestellt aus den blättern des in Südamerika cultivirten strauches erythroxylon coca. Archiv der Pharmazie, 1855, (132), 141–150. Albert Niemann. Ueber eine neue organische base in den cocablättern. Archiv der Pharmazie, 1860, (153), 129–256. Casale JF. A practical total synthesis of cocaine’s enantiomers. Forensic Science International, 1987, (33), 275.

This legislation, however, may have unwittingly mislabeled cocaine-containing preparations as narcotics (Box 4.5), but the law, for the first time, penalized the possession, sale, and use of cocaine.

In the 1960s, cocaine use rose together with the monetary profits from illegal trafficking. In the 1970s, cocaine was most commonly administered intranasally in a powder form (as cocaine hydrochloride). The perception among users was that such a preparation was safe and non-addictive. In fact, the 1980 edition of the Comprehensive Textbook of Psychiatry stated: “...used no more than two to three times a week, cocaine creates no serious problems. In daily and fairly large amounts, it can produce minor psychological disturbances. Chronic cocaine abuse does not appear as a medical problem.” (Kaplan HI, Freedman AM, Sadock BJ (eds.) Comprehensive Textbook of Psychiatry: Volume 2, 3rd edition. Williams and Wilkins, Baltimore, 1980, pp. 1614–1629).

Cocaine hydrochloride itself cannot be smoked because it is quickly destroyed at high temperatures, and methods were developed to produce a smokeable preparation, in which the base of cocaine is separated from the salt. Termed “freebase” cocaine, such a preparation is very pure and originally appeared in the late 1970s and remained popular through the mid-1980s. Freebase vaporizes at 260°C. When heated, the crystals release vaporized cocaine that can be inhaled. In one process, called freebase extraction, the hydrochloride salt is mixed with buffered ammonia, the alkaloidal (freebase) cocaine is extracted from the solution using ether, and the ether is evaporated to yield cocaine crystals. In another process, cocaine hydrochloride is combined with baking soda (sodium bicarbonate), and the mixture is heated until it forms a solid. This smokeable form of cocaine became available as small, readily smokeable “rocks” and was called “crack” cocaine because the crystals make a crackling sound when heated. Since the mid-1980s, this has been the preferred method of producing smokeable cocaine because it is simpler and safer than the ether extraction method. Today, most of the available crack cocaine in the United States is produced this way.

BOX 4.4


A 29-year-old white married unemployed man came to the outpatient clinic of the hospital with the complaints of marked anxiety and the fear that he was “going insane.” His past history included several arrests and convictions for burglary and aggravated battery, as well as a psychiatric hospitalization a few years ago, when he was diagnosed as having “drug addiction” and a “sociopathic personality.” He admitted using a variety of drugs (heroin, codeine, paregoric) for many years until about a year ago, when he stopped using these drugs and began instead to use Desoxyn (methamphetamine hydrochloride) alone. He related that once or twice a week he would dissolve about 15 tablets of Desoxyn (5 mg strength) into boiled water and then inject the solution intravenously in 2–4 divided doses over a 24 hour period. Following the last injection, he would stay up all night reading books on biology, medicine, and psychology, meditating, or looking at things through a microscope, which he bought a few months ago in order to find out more about the “secrets of Nature.” On examination, he was oriented, coherent and relevant. Almost throughout the interview he kept pulling the hair on the top of his head in a stereotyped manner. Asked why he was doing this, he replied that this was a “tic” he acquired a few months ago. His thought disorder became apparent, as he further explained that a few months ago he came to believe that “twisted” hair in his head may cause cancer of the brain and schizophrenia, and he had to “untwist” it to prevent the occurrence of these illnesses. He was extremely concerned about it, since his father had died of a brain tumor a few years earlier. His preoccupation with “hair” was pervasive. He pointed out that hair and sperm under the microscope look like worms; therefore [sic] they are worms, that the testes are bags of worms, and that the intestines and the brain and the whole human body are just big worms. Ideas of grandiosity and persecution were also present. He called attention to the fact that he was born on July 17, that Caesar’s first name was Julius and that since the Romans celebrated the founding of Rome on the 17th of each month, it was more than likely that Julius Caesar was born on July 17. Since the patient was also Roman (Italian), he reasoned that he was Julius Caesar reincarnated. He expressed the belief that “police agents are everywhere”; he worried about [sic] “what they are doing to our food” and pointed out that the milk is not only pasteurized, but also homogenized, which means that “they poison our genes with milk.” It is of interest that he denied ever having hallucinations. Siomopoulos V. Thought disorder in amphetamine psychosis: a case report. Psychosomatics, 1976, (17), 42–44.
Figure 4.3 (A) Median percentage change in heart rate in humans for 1 h after an intravenous injection of saline or 4–32 mg cocaine. The percentage change was calculated for each dose of cocaine with reference to its own 30 min pre-drug baseline. The saline function represents data collected on day 8 of the experimental series. The shaded region indicates the semi-interquartile range of those data. (B) Median percent change in systolic blood pressure after an intravenous injection of saline or 4–32 mg cocaine. The percent change was calculated for each dose of cocaine from the pre-drug baseline measured during the 30 min prior to the injection of that dose. The saline function represents the data collected on day 8 of the experimental series. The shaded area indicates the semi-interquartile range for those data. These figures show the relative effectiveness and potency of cocaine in producing increases in heart rate and blood pressure. [From Fischman MW, Schuster CR, Resnekov L, Shick JFE, Krasnegor NA, Fennell W, Freedman DX. Cardiovascular and subjective effects of intravenous cocaine administration in hummans. Archives of General Psychiatry, 1976, (33), 983–989.]


History of Cocaine Use and Misuse

3000 B.C.

Cocaine is believed to have originated in the subtropical valleys of the eastern slopes of the Andes or Amazonian subtropical valleys. The earliest archeological evidence from Peru dates coca chewing to 3000 B.C.


Coca chewing was restricted to Incan royalty and religious figures. Coca leaves were used as offerings and were used in cultural and religious ceremonies.


Coca chewing came to the masses following the Spanish conquest. Coca leaves were used by Indian slave laborers in the silver mines to keep themselves alert and working.


Albert Niemann analyzes a sample of Peruvian coca in the lab of Fredrich Wöhler to determine active compound and isolates cocaine.


Coca is touted by Angelo Mariani who developed a coca based wine Vin Mariani. The wine contained no more than 300 mg of cocaine, was very popular, and was marketed as a tonic wine and cure-all.


Karl Koller publishes work on using cocaine as an anesthetic during eye surgery.


Sigmund Freud publishes On Coca. Recommends cocaine use for a variety of illnesses, notably for alcoholism and morphine addiction.


Albert Erlenmeyer publishes a paper denouncing cocaine use as treatment for opioid addiction. Blames Freud for releasing “the third scourge of mankind.”


Freud publishes Craving for and Fear of Cocaine. He admits that cocaine should not be used to treat morphine addiction after his friend Ernst von Fleischl-Marxow experiences severe toxic symptoms of heavy cocaine use.


Pemberton, a patent-medicine maker from Atlanta, produced a wine called Cocaine – Ideal Nerve and Tonic Stimulant. Because of overriding Prohibition restrictions, he launched a nonalcoholic extract of coca leaves and caffeine-rich African Kola nuts in a sweet, carbonated syrup he called Coca Cola.


Coca Cola Company is founded. Coca Cola is touted as a medicinal drink.


Due to negative public sentiment, Coca Cola “decocainizes” its preparation, replacing cocaine with caffeine.


President Howard Taft presents a State Department report on drug use to Congress. Cocaine officially becomes “Public Enemy #1.”

“The illicit sales…and the habitual use of it temporarily raises the power of a criminal to a point where in resisting arrest there is no hesitation to murder. It is more appalling in its effects than any other habit-forming drug used in the United States.”



The Harrison Narcotic Act is passed which tightly regulates the distribution and sale of drugs. Because of public anti-cocaine sentiment the Harrison Act was largely supported and was rather successful.


Cocaine use increases following a backlash against amphetamine use. Stimulant users rediscover cocaine as a “safe” recreational drug. Most use is social-recreational among friends or acquaintances.


Controlled Substances Act passes in United States Congress. Cocaine is made a Schedule II drug by the Drug Enforcement Administration (abusable drugs with officially sanctioned medical uses).


“Freebasing” develops in southern California.


A White Paper issued by the United States government indicated that cocaine is “not physically addictive” and “usually does not result in serious social consequences such as crime, hospital emergency room admission, or death.”


Approximately 20% of those aged 15–25 admit to using cocaine. Drug abuse treatment facilities and hospitals report dramatic increases in cocaine freebase admission.

From: Siegel RK. Cocaine smoking. Journal of Psychoactive Drugs, 1982, (14), 271–359.

BOX 4.5


Strictly speaking, narcotics are drugs such as morphine that blunt, rather than excite, brain activity and produce narcosis (sleepiness), but the term has been more widely used in the legal sense to refer to any drug or substance that affects mood or behavior and is sold for nonmedical, illegal purposes.

Amphetamines were first synthesized in 1887 in Germany and had widespread medical use in the treatment of narcolepsy and a variety of other disorders from 1936 to the mid-1940s. D-Amphetamine was sold over-the-counter in Europe until the 1960s when many cases of acute psychotic schizophrenia-like episodes began to occur. The term amphetamine originates from the chemical name α-methylphenethylamine and includes dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine). The D-isomer is five to 10 times more potent than the L-isomer in producing central nervous system effects. Methamphetamine was first synthesized in Japan in 1893 and is the methylated derivative of amphetamine, in which a methyl group is added to the amphetamine base structure. The methyl group increases amphetamine’s ability to cross the blood–brain barrier, thus hypothetically facilitating its psychoactive effects

There are two isomers, D and L, and the D isomer is much more psychoactive than the L isomer. The L isomer is still the active ingredient in nasal decongestant inhalers like Vicks Vapor inhaler. Although rarely prescribed, methamphetamine (D-methamphetamine; Desoxyn) is approved in the United States for the treatment of attention-deficit/hyperactivity disorder and as a short-term adjunct treatment in a regimen for weight loss based on caloric restriction.

Methamphetamine came into widespread use during World War II to increase the endurance and performance of military personnel. Methamphetamine was sold over-the-counter in Japan as Philopin and Sedrin as a product to fight sleepiness and enhance vitality. At the end of World War II (1945–1955), an epidemic of methamphetamine use occurred in Japan, attributed to dumping military stockpiles of stimulant agents on the open market. Japan had an estimated 550,000 methamphetamine abusers in 1954. Sweden also witnessed an epidemic of abuse of phenmetrazine, an amphetamine-like stimulant, in the 1950s and 1960s. Illegal diversion of amphetamines in the 1960s paralleled the increased use of the drugs on the street, resulting in a cyclical pattern of abuse by users who were known as “speed freaks” (habitual users of amphetamines).

In the 1960s, methamphetamine was synthesized illegally and called “crank,” and it dominated the “speed” (generic term for psychostimulants in the amphetamine grouping) market. Manufacture shifted to the San Diego area in the 1980s with the production of “crystal meth.” Crystal meth is synthesized from ephedrine and iodine and has a crystalline-like appearance when it is pure. The high-purity crystalline form is also termed “ice” because of its resemblance to shards of ice crystals. Both the powdered and crystal forms of methamphetamine are the hydrochloride salt, and in contrast to cocaine, the salt form of methamphetamine can be smoked. Freebase methamphetamine is an oily liquid at room temperature. Smoking methamphetamine became a popular route of administration in the 1980s in Hawaii, the Pacific Coast of the United States, and southern California and subsequently spread to the rest of the United States.

The 2011 United States National Survey on Drug Use and Health from the Substance Abuse and Mental Health Services Administration estimated that 36.9 million people aged 12 and older (14.6%) had ever engaged in cocaine use, and 18.5 million (7.2%) people aged 12 and older had ever engaged in stimulant use. Of those 12 and older, 3.9 million were last-year users of cocaine (1.5%), and 2.7 million were last-year users of stimulants (1.0%). Of these, 11.9 million (4.6%) had used methamphetamine, and 1.0 million (0.4%) were last-year users of methamphetamine. Notable statistics from the survey included the following. In 2011, of those people aged 12 or older who ever used in the last year, 0.82 million (21.1%) showed cocaine abuse or dependence, and 0.33 million (12.9%) showed stimulant abuse or dependence (Substance Use Disorder based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5], criteria), 0.58 million (14.5%) of those who ever used in the last year showed cocaine dependence, and 0.25 million (9.3%) of those who ever used in the last year showed stimulant dependence (DSM-IV criteria; see What is Addiction?).

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