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Amphetamine: the story on HearLore | HearLore
Amphetamine
In 1887, a Romanian chemist named Lazăr Edeleanu synthesized a chemical compound in Germany that would eventually reshape modern medicine and culture, yet its true nature remained hidden for four decades. He named it phenylisopropylamine, a clear, volatile liquid with a strong amine odor, but the stimulant properties of the substance were completely unknown at the time. It was not until 1927 that Gordon Alles independently resynthesized the compound and reported its sympathomimetic effects, revealing that the drug could stimulate the central nervous system. This discovery laid the groundwork for the first pharmaceutical product, Benzedrine, which Smith, Kline and French began selling as an inhaler in late 1933 to treat nasal congestion. The drug quickly expanded its medical applications to treat narcolepsy, obesity, low blood pressure, and chronic pain, marking the beginning of a complex relationship between humanity and a powerful chemical agent.
War And The Black Market
During World War II, the strategic value of amphetamine became undeniable as both Allied and Axis forces distributed the drug extensively to soldiers to enhance performance and maintain alertness during long campaigns. The substance was used to keep troops awake for days, improve reaction times, and suppress the need for food and sleep, effectively turning the drug into a weapon of war. As the addictive properties of the drug became known, governments began to place strict controls on its sale, leading to the Controlled Substances Act of the early 1970s which classified amphetamine as a schedule II controlled substance in the United States. Despite these regulations, the drug found its way into the hands of people from diverse backgrounds, including authors, musicians, mathematicians, and athletes who sought its cognitive and physical benefits. In the decades following the war, amphetamine was illegally synthesized in clandestine labs and sold on the black market, with approximately 5.9 metric tons of illicit amphetamine seized within European Union member states during 2012 alone. The street price of illicit amphetamine within the EU ranged from 10 to 20 euros per gram, highlighting the persistent demand for the substance despite legal restrictions.
The Brain And The Body
Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways. The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on monoamine transporters. At therapeutic doses, the drug causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, decreased appetite, elevated heart rate, and increased muscle strength. However, larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown, while very high doses can result in psychosis, which rarely occurs at therapeutic doses even during long-term use. The drug's ability to modulate monoamine transporters involves phosphorylation, in which activated protein kinases attach a phosphate group to a specific amino acid residue on the transporter protein, shifting transporter function into an efflux-permissive state that causes the reverse transport of cytosolic monoamines into the synaptic cleft.
Lazăr Edeleanu synthesized amphetamine in 1887 while working as a Romanian chemist in Germany. He originally named the compound phenylisopropylamine and described it as a clear volatile liquid with a strong amine odor.
When was the stimulant effect of amphetamine discovered?
Gordon Alles independently resynthesized the compound and reported its stimulant effects in 1927. This discovery revealed that the drug could stimulate the central nervous system and laid the groundwork for the first pharmaceutical product Benzedrine.
What is the chemical formula of amphetamine?
Amphetamine has the chemical formula C9H13N and exists as two enantiomers known as levoamphetamine and dextroamphetamine. It is a methyl homolog of the mammalian neurotransmitter phenethylamine and exists as a racemic 1:1 mixture of these two enantiomers.
When was amphetamine classified as a schedule II controlled substance?
The Controlled Substances Act of the early 1970s classified amphetamine as a schedule II controlled substance in the United States. This classification followed the recognition of the drug's addictive properties and its extensive distribution during World War II.
How does amphetamine affect the brain at therapeutic doses?
At therapeutic doses amphetamine increases the concentrations of dopamine and norepinephrine in the brain by altering monoamine transporters. This process causes emotional and cognitive effects such as euphoria increased wakefulness and improved cognitive control.
Which drug is approved for binge eating disorder as of July 2024?
Lisdexamfetamine is the only USFDA and TGA approved pharmacotherapy for binge eating disorder as of July 2024. It converts to dextroamphetamine which increases dopaminergic and noradrenergic neurotransmission in the prefrontal cortex.
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage, but in humans with attention deficit hyperactivity disorder, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth. Reviews of magnetic resonance imaging studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia. A nine-month randomized controlled trial of amphetamine treatment for ADHD in children found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity. Additionally, a 2024 meta-analytic systematic review reported moderate improvements in quality of life when amphetamine treatment is used for ADHD, while another review indicated that lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult. Approximately 80% of those who use these stimulants see improvements in ADHD symptoms, with children with ADHD who use stimulant medications generally having better relationships with peers and family members, performing better in school, and having longer attention spans.
The Dark Side Of Addiction
Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction. Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of accumbal ΔFosB, a molecular switch and master control protein for addiction. Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior with further increases in its expression. While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction. Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction, as it decreases psychostimulant self-administration and reduces the reinstatement of drug-seeking. A Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine noted that when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose, with withdrawal symptoms persisting for weeks with a marked crash phase occurring during the first week.
The Mod Subculture And The Dance Floor
A notable part of the 1960s mod subculture in the UK was recreational amphetamine use, which was used to fuel all-night dances at clubs like Manchester's Twisted Wheel. Newspaper reports described dancers emerging from clubs at 5 a.m. with dilated pupils, as the drug was used for stimulation and alertness, which they viewed as different from the intoxication caused by alcohol and other drugs. Dr. Andrew Wilson argues that for a significant minority, amphetamines symbolized the smart, on-the-ball, cool image, and that they sought stimulation not intoxication, greater awareness, not escape, and confidence and articulacy rather than the drunken rowdiness of previous generations. Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is considered to have a high potential for misuse in a recreational manner since individuals typically report feeling euphoric, more alert, and more energetic after taking the drug. Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate it or subsequently dissolve it in water and inject it, with immediate-release formulations having a higher potential for abuse via insufflation or intravenous injection due to a more favorable pharmacokinetic profile and easy crushability.
The Chemistry Of Control
Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N, and it exists as two enantiomers: levoamphetamine and dextroamphetamine. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers. At room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste. Frequently prepared solid salts of amphetamine include amphetamine adipate, aspartate, hydrochloride, phosphate, saccharate, sulfate, and tannate. Dextroamphetamine sulfate is the most common enantiopure salt. The drug is also the parent compound of its own structural class, the substituted amphetamines, which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and norephedrine, both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while norephedrine is a positional isomer of amphetamine that differs only in the placement of the methyl group.
The Future Of Treatment
As of July 2024, lisdexamfetamine is the only USFDA- and TGA-approved pharmacotherapy for binge eating disorder, with evidence suggesting that its treatment efficacy is underpinned at least in part by a psychopathological overlap between binge eating disorder and ADHD. Lisdexamfetamine's therapeutic effects for binge eating disorder primarily involve direct action in the central nervous system after conversion to its pharmacologically active metabolite, dextroamphetamine. Dextroamphetamine increases dopaminergic and noradrenergic neurotransmission in the prefrontal cortex, a region of the brain that regulates cognitive control of behavior. Similar to its therapeutic effect in ADHD, dextroamphetamine enhances cognitive control and may reduce impulsivity in patients with binge eating disorder by enhancing the cognitive processes responsible for overriding prepotent feeding responses that precede binge eating episodes. A 2025 meta-analytic systematic review of 113 randomized controlled trials found that stimulant medications were the only intervention with robust short-term efficacy, and were associated with lower all-cause treatment discontinuation rates than non-stimulant medications. The field of pharmacomicrobiomics, which studies the interactions between drugs and the human microbiome, has identified the first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, in 2019, suggesting that the gut microbiota may play a significant role in the metabolism and efficacy of amphetamine.