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The Journey of Amphetamines

While researching at Berlin University, the Romanian doctoral student Lazar Edeleanu published a thesis involving phenyl-isobutyric acid. His original research detailed the discovery of several novel molecules, including one that would revolutionize medicine. Thought originally to be worthless, he named the molecule phenyl-isopropylamine and moved his research in a different direction.

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Edeleanu’s new discovery soon became a distant memory as nearly 40 years sped by until the molecule resurfaced in a Los Angeles laboratory. While studying asthma, the American pharmacologist Gordon Alles researched ephedrine in hopes of minimizing its side effect profile.

An asthma attack involves narrowing of the airways (bronchioles). Ephedrine’s utility in asthma treatment is as a nasal decongestant and bronchodilator, due to its interaction with ∝ and ? adrenergic receptors. However, ∝ and ? adrenergic receptors have many other physiological functions that result in unwanted systemic side effects.

Alles soon shifted focus from ephedrine and concentrated on a new molecule that he called “beta-phenyl-isopropylamine.” He was unaware that this and Edeleanu’s  decade-old discovery were one in the same.

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The use of humans as test subjects is highly regulated and restricted. However, in 1927, the absence of ethical review boards was at times advantageous in the progress of medical research. And so, as the story goes: on June 3, 1929, Alles injected 50 milligrams of beta-phenyl-isopropylamine and carefully documented its effects. The classic nasal decongestion and bronchodilation of ephedrine-containing asthma medications were evident. He also noted a uniquely enhanced thought process and feeling of well-being. Perhaps it was during this moment of clarity that he also shortened the compound’s name to “amphetamine.”

Despite his best efforts, amphetamine’s utility as an asthma medication was perhaps no better than that of ephedrine–but Alles knew possible applications remained. In recognition of amphetamine’s potential, Alles patented the medicinal use of both amphetamine sulfate and amphetamine hydrochloride in 1932. These preparations soon appeared on pharmacy shelves among cough suppressants, which was perhaps its first over-the-counter use.

Almost simultaneously, the Philadelphia pharmaceutical firm Smith, Kline, and French (SKF) were developing an amphetamine-containing inhaler known as benzedrine. They soon began a partnership with Alles. The benzedrine inhaler, containing a racemic mixture of dextro- and levo-amphetamine, was then patented in 1933.

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A Benzedrine Inhaler

Soon, SKF pharmacologists had far more stimulating plans for amphetamine that were no longer limited to benzedrine. In 1935, amphetamine was heralded as a novel treatment for narcolepsy. Further breakthroughs occurred when amphetamine became the first prescription antidepressant (Benzedrine sulfate). In fact, during the late 1930s, amphetamine became indicated for a staggering 39 conditions (from hiccups to schizophrenia).

Benzedrine Tablets (right)

Benzedrine Tablets (right)

By the end of the 1930s amphetamine gained popularity among the armed forces. In 1938, a Berlin pharmaceutical company began marketing amphetamines under the brand name Pervitin. Inside of just four months, more than 35 million tablets of Pervitin were shipped to German soldiers. The instructions contained within each pack were crystal clear, recommending consumption to “maintain sleeplessness.”

Pervitin Tablets

Pervitin Tablets

 

Germany wasn’t the only country kept safe by an army of amphetamine-fueled drones. Benzedrine tablets were routinely supplied to US servicemen as well, especially for use in aviation.

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While German and American soldiers held their guns close and their amphetamines closer, the allure of amphetamine-based diet pills was also becoming a staple in American households. The largest age group among medical users were those aged 36 to 45 years, 85% of them being women.

As World War II concluded in 1945, the well-documented military use of amphetamines continued at home by over half of a million US civilians. In 1945 alone, SKF maintained a daily production of over a million Benzedrine tablets.

As the patent for Benzedrine would soon expire, SKF quickly devised a clever replacement: Dexedrine. You see, amphetamine’s chirality results in enantiomers that are mirror-images of themselves, known as dextro- and levo-amphetamine. Two non-superimposable forms of amphetamine occur because of a chiral center, which is a carbon bound to four other unique atoms. For amphetamine, the chiral carbon is bound to a benzylic group, an amine (NH2) group, a methyl (CH3) group, and a hydrogen atom.

The Benzedrine inhalers that gained popularity during the 1930s contained a racemic (equal) mixture of both enantiomers. Patent law would prohibit SKF to simply rebrand all of their racemic amphetamine under the name Dexedrine. So, in a flash of genius, the dextrorotatory enantiomer of amphetamine (dextroamphetamine) was isolated in 1976 and branded Dexedrine. Dexedrine became an instant success, generating annual sales that ranged in the millions.

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With the war over, SKF ensured that amphetamine continued to benefit society. Amphetamines, which were at the time still prescribed for weight loss and depression, would soon acquire new indications for use. As an example, SKF introduced a product called Dexamyl, a blend of dextroamphetamine and the barbiturate sedative amobarbital. There was also Ambar, another amphetamine/barbiturate combination. Lastly there was Babar, a clothed elephant who appeared among French children’s books.

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So as to maintain their own weight among the competitive pharmaceutical industry, Obetrol Pharmaceuticals (a division of Rexar, which would ultimately be acquired by Shire Pharmaceuticals) began marketing amphetamines for weight-loss under the name Obetrol. The pill became very popular during the 1950s and 1960s.

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As the 1950s ended, the introduction of monoamine oxidase inhibitors and tricyclic antidepressants quickly replaced amphetamines for the treatment of depression. Regardless, amphetamine growth was far from stunted, even surpassing tranquilizers in popularity.

Amphetamines became prescription-only in 1960. Further legislations during 1965 restricted their manufacture and distribution. Appropriately nicknamed, “uppers”  gained further popularity in the 1960s as over 10 billion amphetamine pills were produced annually in US.

These large numbers attracted further legal attention, and amphetamine soon fell under the radar of the Bureau of Narcotics and Dangerous Drugs (now known as the DEA). In 1971 the Controlled Substances Act declared amphetamine a Schedule II controlled substance. As such, amphetamine was categorized as having a high potential for abuse and dependence but an accepted medical use.

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Despite attempts to regulate its use through prescription, amphetamine continued to be one of America’s most used drugs until the 1980s. Though origins for the sudden change in preferences are unclear, some speculate the sharp decrease in 1980s amphetamine use could be related to the sudden popularity of cocaine.

Thankfully, amphetamine was not forgotten. Years later (1996), amphetamine returned when Shire Pharmaceuticals introduced their latest medication: Adderall. Their newly-patented blend of instant-release amphetamine salts sought to corner the market for ADHD medications (as well as narcolepsy and obesity).

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Adderall’s patented mix of amphetamine salts contains equal parts of amphetamine sulfate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and dextroamphetamine saccharate. Both amphetamine sulfate and amphetamine aspartate monohydrate are racemic mixtures, meaning they contribute equal parts of dextro- and levo-amphetamine to the mix. In contrast, dextroamphetamine sulfate and dextroamphetamine saccharate have been isolated and purified as the dextrorotatory enantiomer, contributing entirely dextro-amphetamine. More simply put, Adderall’s amphetamine salt mix contains 75% dextroamphetamine and 25% levoamphetamine salts.

Instant-Release Adderall Tablets (10 mg)

Instant-Release Adderall Tablets (10 mg)

 

The dextro-amphetamine enantiomer is well-documented as having more centrally acting effects on the nervous system. On the other hand, Levo-amphetamine elicits peripheral nervous system activation to a slightly greater degree (a “body load”).

Adderall was a major success, and soon thereafter in 2001 Shire introduced a time-release preparation known as Adderall XR. Unsurprisingly, the release roughly coincides with patent dates. For instance, 2002 would see Teva begin the manufacture of generic instant-release Adderall. Nevertheless, the introduction of Adderall XR represents a major milestone in the history of amphetamines.

Adderall XR

Adderall XR

 

Table 1: Amphetamine Salt Contents of Adderall XR Capsules

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With extended-release formulations, patients were now able to maintain high serum concentrations of amphetamine throughout the day with a single administration. The extended release properties were not due to molecular changes, but the pill itself was prepared so as to delay half of its contents. Adderall XR is a capsule that contains many small amphetamine-containing beads. The beads are equal parts immediate-release and delayed-release, which delay the release of half of the medication until after 4 hours

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As patent wars continued, Adderall XR went generic during 2009. The following year many generic copies surfaced and they reported their net profit fell to $165.9 million from $213.6 million. Not to be left behind, the FDA had already approved Shire’s latest amphetamine-based medication: Vyvanse.

Vyvanse

Vyvanse

 

Vyvanse (lisdexamfetamine) is unique among amphetamine-based medications, as it is a prodrug. Vyvanse itself is an inactive molecule. When a pill of vyvanse is swallowed, it travels down the esophagus and into the stomach. From there, it enters the small intestine.

The pancreas secretes many digestive enzymes into the small intestine. Among these are enzymes are proteases. Proteases cleave amide bonds, which are commonly found linking amino acids. Following proteolytic cleavage of an internal amide bond, vyvanse is split into independent lysine and dextroamphetamine molecules. Newly liberated dextroamphetamine molecules then begin to absorb into the bloodstream through the intestine.

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5 comments

  1. Good article summarizing the history of amphetamines which demonstrates how ridiculous laws are. The pharm companies kept reformulating from racemic, to dextro, to adderall, to vyvanse – all the while claiming each new one was safer than the previous. Also, constantly coming up with new diagnoses for speed. When they mixed amp with barbituates they were basically pushing addictive drugs, legally, for profit. The pharmaceutical companies in America are one of the most corrupt. They lobby congress, finance campaigns and have officials ( all the way up to president ) in their pockets.

  2. The most wacked out on speed I ever was happened after I had an energy drink sold only in Oregon. A young woman I met told me she called it liquid adderall. I find it hard to believe it’s still being sold but you never know. Anyone from Oregon know the name of that drink and if it’s still available???
    Could the intrepid Kevin write about the mechanism of action of Ibogaine and Salvia Divinorum? Thanks.

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