Dr. Grossi's Blog
Until 1997 the family of compounds collectively known as amphetamines were thought to have been synthesized in Berlin in 1887 (about the same time as valproic acid was synthesized as an organic solvent in France), but A.B. Clements et al. found mescaline, nicotine, and methamphetamine in a species of the Texas acacia bushes (Acacia rigidula). Amphetamines are potent agents that produce their effects by increasing the levels of biogenic amines (dopamine, norepinephrine, and serotonin) in the synapse. Amphetamine binds to all monoamine transporters, but its main behavioral effect is the result of its binding to and blocking the dopamine transporter (DAT). It also enhances the reverse transport of amphetamine from the cell interior to the synapse or extracellular space. It also adversely affects the vesicular storage of dopamine in the cell thus allowing it to accumulate in the cytoplasm. Finally, it inhibits monoamine oxidase A and B (MAO-A and MAO-B) and this results in less breakdown and an accumulation of dopamine in the cell.
The major value of amphetamine is in the treatment of ADHD, although they have a role in narcolepsy (less in the last 12 years) and excessive daytime sleepiness resulting from other drugs, obesity (mostly in the 1950s), or from particular circumstances (military, long haul trucking, student cramming). In the late 1930s, a pediatrician in London who cared for institutionalized, disruptive children was seeking a remedy for the headache which followed the X-ray procedure known as pneumoencephalogram in which air is introduced into the spinal column and when sitting it makes its way to the ventricles in the brain. This allows xrays to be taken and because the air is darker than the surrounding brain a judgment can be made regarding any shift in the brain. Usually after such a procedure the patient experiences a severe headache. What occurred, however, was startling. The patients became much less disruptive, distracted, oppositional and hyperactive. This paved the way for their usage in what became labeled ADHD in the late 1970s. In earlier years it was known as minimal brain dysfunction or hyperactivity of children. I should note that the reinforcing properties of amphetamine were noted in the 1930s and in the following approximate 30 years the drugs were regulated by many countries and they are classified as Schedule II under the Convention of Psychotropic Substances.
What are the effects on the central nervous system (CNS)? Amphetamine crosses the blood-brain barrier and thus quickly reaches the primary sites of action. Behavioral effects include wakefulness, anorexia, hyperactivity, often elation or euphoria, and a generally very pleasant and activated feeling. Adverse effects can include moodiness, aggravation of mood instability, cardiac effects (tachycardia especially) gastrointestinal upset, insomnia, jitters, occasional headache, occasional tics, proneness to crying. Very rarely an amphetamine psychosis may develop. Generally, any of these adverse effects diminish and disappear shortly after discontinuation of the drug. Are there any long-term consequences of amphetamine treatment? The answer is probably not or minimal in comparison to the benefits. Their effects on growth are controversial but the recent consensus is that evidence for growth changes stemming from treatment are lacking. If there were an effect it would undoubtedly be mediated by lower caloric intake and this can usually be easily remedied.
A very rare adverse effect is the development of an amphetamine psychosis. High doses can produce psychotic behavior and thinking indistinguishable from schizophrenia in healthy individuals. Hallucinations, delusions, paranoid thinking, etc. can be present. The current illicit amphetamine epidemic is increasing the incidence of this problem because of the high doses used on the street as well as an element of adverse selection. KeKiten et.al. corrected for prior history of psychotic disorder and still found a prevalence rate of three times the general population. In humans who experience flashbacks, spontaneous recurrence of amphetamine-induced psychosis, there is a concomitant increased plasma norepinephrine and 3-methoxytyramine which are metabolites of DA from the PFC.
And yet, when one considers the relative benefits and liabilities of treatment with amphetamine, the benefits seem to outweigh the risks. While we have not discussed the animal studies with amphetamine or the post mortem studies of amphetamine abusers, it is noteworthy that the elevated risk for substance abuse in individuals with ADHD can be reduced when treatment is initiated during childhood but not adolescence. Accompanying this is a reduction in structural brain pathology. Specifically, unmedicated ADHD children demonstrated smaller brain white matter volume than medicated children, suggesting that stimulant treatment may normalize brain white matter volume.