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.

Keywords: Abuse liability; amphetamine; attention deficit hyperactivity disorder (ADHD); drug formulations; lisdexamfetamine; microdialysis.

Figure 1.

Chemical structures of various biologically active β-phenylethylamines. * Chiral centre. Red: Oxygen atom; White: Hydrogen atom; Black: Carbon atom; Blue: Nitrogen atom.

Figure 2.

Actions comprising the pharmacological mechanism of amphetamine.

Figure 3.

Different mechanisms leading to a 50% reduction in monoamine reuptake produced by a classical reuptake inhibitor versus a competitive substrate (releasing agent).

Figure 4.

A comparison of the effects of the d- and l-isomers of amphetamine on noradrenaline and dopamine efflux in the brains of freely moving rats. The effects of amphetamine’s d- and l-isomers on the extracellular levels of (A) noradrenaline in the prefrontal cortex and (B) dopamine in the striatum of freely moving SHRs measured by intracerebral microdialysis. Each data point represents mean % of baseline ± SEM. (n = 6–11). The vertical arrow indicates the time of administration of drug or saline. *p < 0.05, **p < 0.01, ***p < 0.001 significantly different from appropriate control group according to ANCOVA with Williams’ test for multiple comparisons. Data taken from Cheetham et al. (2007). Note the different doses of the two drugs.

Figure 5.

The effects of administration of d-amphetamine and lisdexamfetamine on the extracellular concentration of dopamine in the striatum and locomotor activity of freely moving rats. Results are adjusted means; n = 5–6 ± SEM. Drug doses are expressed in terms of d-amphetamine free base for both d-amphetamine sulphate and lisdexamfetamine. The vertical arrow indicates time of drug administration. Data analysed by ANCOVA followed by multiple t-test (d-amphetamine) and Williams’ test (lisdexamfetamine). Significantly different from the vehicle-treated control group: Extracellular dopamine: d-Amphetamine (1.5 mg/kg) 0.05 > p < 0.001 at time-points 15–225 min and 255–300 min; Lisdexamfetamine (1.5 mg/kg) 0.05 > p < 0.001 at time-points 30–300 min. Activity: d-Amphetamine (1.5 mg/kg) 0.05 > p < 0.001 at time-points 15–90 min and 285–300 min; Lisdexamfetamine (1.5 mg/kg) 0.05 > p < 0.01 at time-points 60–120 min, 150–180 min and 300–315 min. Data taken from Jackson et al (2011) and Rowley et al (2011).

Figure 6.

A comparison of the mean peak increases in systolic and diastolic blood pressure produced by intravenous versus oral administration of 50 mg lisdexamfetamine. Means are adjusted for differences between the treatment groups at baseline. SEM was calculated from the residuals of the statistical model. Significantly different from appropriate placebo control group: *p < 0.05; **p < ;0.01. p-values for differences to compare to the same treatment by the oral and intravenous routes were obtained by the multiple t-test after fitting the data to a mixed linear model. There were no significant differences between the peak increases in systolic and diastolic blood pressure evoked by 50 mg lisdexamfetamine administered intravenously and orally.