Amphetamine, past and present – a pharmacological and clinical perspective

Abstract

Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine’s diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine’s distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed.

Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia

“…Dopamine (DA) is a neurotransmitter that is well-known to elicit wakefulness (11). Although stimulants that increase extracellular DA levels such as methylphenidate and amphetamine are commonly used to treat attention deficit hyperactivity disorder (12), these drugs also promote arousal (13)(14)(15)(16), and are effective for treating sleep disorders such as narcolepsy (17). Patients with Parkinson's disease have degenerative loss of DA neurons in both the ventral tegmental area (VTA) and substantia nigra (SN) (18), and excessive daytime sleepiness is a common symptom of this disease (19).…”

Adolescent d -amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects during adolescence and cocaine abuse risk during adulthood

“…The differential effects of adolescent damphetamine, atomoxetine, and methylphenidate on cocaine-seeking behavior in adulthood might relate in part to differential long-term effects on DAT function within PFC, as reviewed above. It is probable that additional neurochemical adaptations contribute to the long-term effects of ADHD medications on cocaine abuse risk, such as changes at postsynaptic receptors or norepinephrine and serotonin transporters, to which d-amphetamine also potently binds and reverses transport [43,125]. However, future investigations are needed to investigate these changes in SHR.…”

“…d-Amphetamine was selected for the focus of the current investigation rather than l-amphetamine or the racemic mixture, as the d-isomer is more potent than the l-isomer in modulating dopamine transmission [43,44], and alleviates more ADHD-related symptoms [45]. Whereas both methylphenidate and damphetamine inhibit DAT and NET function, d-amphetamine also reverses transport [46], leading to greater increases in extracellular dopamine than methylphenidate at therapeutically relevant doses [47].…”

Accelerated quantification of amphetamine enantiomers in human urine using chiral liquid chromatography and on-line column-switching coupled with tandem mass spectrometry

“…Its powerful stimulatory action does not only provide therapeutic efficacy, but it also responsible for AM's adverse effects and high potential for recreational abuse. As a result of the United Nations Convention on Psychotropic Substances of 1971, AM became a controlled substance in many countries and is available for treatment by prescription only [1][2][3]. Nevertheless, AM abuse is widespread, with global AM seizures fluctuating between about 20 and 33 tons annually since 2009 [4].…”

“…Currently available pharmaceutical formulations of AM, on the other hand, primarily contain either S-AM (e.g. Dexedrine [1,2]. Thus, the determination of the enantiomeric composition of AM in biological samples may help to distinguish between the illicit consumption of street AM and the legitimate use of AM medication, which is of great relevance in clinical and forensic toxicology.…”