Unlike most other studies, this one used oral, low doses of amphetamine - the same doses that children receive for ADHD - to make a more realistic assessment of whether such dosing could cause brain damage. Other studies use higher doses injected into the body or brain which is not only unnatural and not the current practice for low-dose ADHD treatment but also overwhelms any potential limiters that prevent damage such as absorption rate, transport carrier saturation or metabolism. It was found that such dosing does indeed produce brain damage:Amphetamine Treatment Similar to That Used in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder Damages Dopaminergic Nerve Endings in the Striatum of Adult Nonhuman PrimatesFull PDFAbstract:Pharmacotherapy with amphetamine is effective in the management of attention-deficit/hyperactivity disorder (ADHD), now recognized in adults as well as in children and adolescents. Here we demonstrate that amphetamine treatment, similar to that used clinically for adult ADHD, damages dopaminergic nerve endings in the striatum of adult nonhuman primates. Furthermore, plasma concentrations of amphetamine associated with dopaminergic neurotoxicity in nonhuman primates are on the order of those reported in young patients receiving amphetamine for the management of ADHD. These findings may have implications for the pathophysiology and treatment of ADHD. Further preclinical and clinical studies are needed to evaluate the dopaminergic neurotoxic potential of therapeutic doses of amphetamine in children as well as adults.
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neuropsychiatric illness, afflicting 3 to 9% of school-age children and 1 to 5% of adults worldwide (Leung and Lemay, 2003; Biederman and Faraone, 2004; Wilens et al., 2004). For years, psychomotor stimulant drugs have been the mainstay of ADHD treatment (Greenhill et al., 2002; Fone and Nutt, 2005), and in the last decade, their use has increased substantially (Olfson et al., 2003; Robison et al., 2004). Of the various stimulant drugs used in the treatment of ADHD, amphetamine is among the most often prescribed (Greenhill et al., 2002; Fone and Nutt, 2005), both in children and adults (Wilens et al., 2004; Dodson, 2005).
As the use of amphetamine in the treatment of ADHD has increased, a large body of preclinical data has accrued indicating that amphetamine has the potential to damage brain dopamine-containing neurons in experimental animals. In particular, animals treated with amphetamine develop lasting reductions in striatal dopamine, its major metabolite dihydroxyphenylacetic acid (DOPAC), its rate-limiting enzyme tyrosine hydroxylase, its membrane transporter (DAT), and its vesicular transporter (VMAT2) (Gibb et al., 1994; McCann and Ricaurte, 2004). Anatomic studies indicate that lasting dopaminergic deficits after amphetamine are due to damage of dopaminergic nerve endings in the striatum, with sparing of dopaminergic nerve cell bodies in the substantia nigra.
Despite these preclinical data and growing awareness of potential long-term adverse effects of stimulant ADHD medications (Volkow and Insel, 2003; Fone and Nutt, 2005), there has been little expressed concern over possible dopaminergic neurotoxicity in humans receiving amphetamine for the treatment of ADHD. In large measure, this appears to be due to the fact that, as noted by various authors (Vitiello, 2001a,b; Greenhill et al., 2002; Fone and Nutt, 2005), doses, routes, and regimens of administration used in amphetamine neurotoxicity studies in animals differ significantly from those used in the treatment of ADHD.
The purpose of the present study was to determine whether amphetamine treatment, similar to that used clinically in the therapy of adult ADHD, produces long-term effects on brain dopaminergic neurons in adult nonhuman primates. Initial studies used baboons as experimental subjects because their size (20–30 kg) allows for administration of amphetamine at an absolute dose similar to that used in ADHD. To further simulate the clinical use of amphetamine, we trained baboons to self-administer amphetamine by mouth. We tested a 3:1 mixture of dextro- and levo-amphetamine, because one of the more common formulations used in the treatment of ADHD consists of a combination of 75% dextro-amphetamine and 25% levo-amphetamine. In a final set of studies, we used squirrel monkeys to test the species generality of our findings.
Edited by Isochroma-Reborn, 02 December 2012 - 12:35 AM.