Why Can Amphetamines Be Used to Treat ADHD in Children?

The efficacy of amphetamine in reducing ADHD symptoms and improving functional outcomes has been shown in clinical studies.

How Amphetamine Works to Treat ADHD

Amphetamine is a type of stimulant medication and has been used extensively in ADHD treatment. Other psychostimulants such as methylphenidate, as well as the non-stimulant atomoxetine, are also used to treat ADHD.

The stimulants as a class increase the availability of synaptic dopamine. Therapeutic effects of stimulants include a reduction of the hyperactivity, impulsivity, and inattention characteristic of patients with ADHD, and improvement of associated behaviors, including on-task behavior, academic performance, and social functioning.

Amphetamines are thought to block the reuptake of both norepinephrine and dopamine into the presynaptic neuron and to facilitate neurotransmitter release through reverse transport.

History of ADHD Amphetamine Treatment

It was first noted in the 1930s that amphetamines produced a “paradoxical” relaxing effect in severely disruptive, institutionalized, hyperactive boys, paving the way for its use in the treatment of ADHD.

In 1937, psychiatrist Charles Bradley administered Benzedrine sulfate, an amphetamine, to 30 behavior “problem” children. He observed a spectacular improvement in school performance in half of the children.

In addition to a motivational drive, a large proportion of the patients became emotionally subdued without, however, losing interest in their surroundings.

For example, irritable, aggressive, and noisy children became more placid, easy-going, and interested in their surroundings. Bradley noted that these patients “appeared subdued because they began to spend their leisure time playing quietly or reading, whereas formerly they had wandered aimlessly about antagonizing and annoying others.”

Bradley conducted several subsequent studies after his 1937 study. These studies proved to be an important precursor to studies of amphetamines and their use in conditions such as attention deficit hyperactivity disorder (ADHD).

Contemporary Amphetamine Treatment Efficacy

The initial amphetamine compositions in Bradley’s 1937 study were quite different from the contemporary amphetamine compositions used to treat ADHD currently.

Technological advances now address the need for extended symptom control to manage the entire school or work day, the desire to minimize adverse effects and the need to reduce the potential for diversion and/or abuse of amphetamines.

Amphetamine can be administered twice daily in short-acting (SA) compositions; however, SA compositions have been associated with adherence problems because it is necessary to administer the drug during the school or work day. Thus, once-daily, long-acting (LA) compositions were developed.

For instance, a recent LA composition, lisdexamfetamine (LDX), is a new chemical entity prodrug created by covalently linking an amino acid, lysine, to d-amphetamine, which is then metabolized in vivo to yield d-amphetamine.

In a 2004 research study with 52 children aged 6-12 years with ADHD, researchers found that LDX was significantly more effective than placebo in treating the symptoms of ADHD in school-age children. And treatment effects were seen at 12 hours postdose, the last time point measured.

In addition, the numbers of math problems attempted and correct were significantly greater in LDX-treated subjects. Importantly, clinician ratings also indicated improvement with LDX, with the majority of subjects showing improvement and nearly a third being very much improved.

This study also showed that LDX was generally well tolerated, and no meaningful abnormalities were observed in clinical laboratory data. The safety profile was similar to that seen in other studies with stimulants.

Sources consulted:

Biederman, Joseph, et al. "Lisdexamfetamine Dimesylate and Mixed Amphetamine Salts Extended-Release in Children with ADHD: A Double-Blind, Placebo-Controlled, Crossover Analog Classroom Study." Biological Psychiatry, vol. 62, no. 9, 2007, pp. 970-976.

Faraone, Stephen V., and Jan Buitelaar. "Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis." European Child & Adolescent Psychiatry, vol. 19, 2010, pp. 353–364.

Hodgkins, Paul, et al. "The Pharmacology and Clinical Outcomes of Amphetamines to Treat ADHD: Does Composition Matter?" CNS Drugs, vol. 26, no. 3, 2012, pp. 245-268.

Strohl, Madeleine P. "Bradley’s Benzedrine Studies on Children with Behavioral Disorders." Yale Journal of Biology and Medicine, vol. 84, 2011, pp.27-33.


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