Ritalin may work better as purer compound

Half of every dose of the drug Ritalin, taken by an estimated 2 million children with attention deficit-hyperactivity disorder (ADHD), may 
contribute nothing to its therapeutic effect, while possibly adding to its side effects, say researchers at Brookhaven National Laboratory in 
Upton, N.Y. 

 Ritalin contains equal amounts of two molecular forms, or enantiomers, of the compound methylphenidate. They possess most of the same 
chemical properties, but structurally they are mirror images of each other. According to the Brookhaven analysis, one enantiomer is much more 
potent than the other and is responsible for Ritalin's beneficial effects of improving attention and reducing impulsivity.

 Yu-Shin Ding, Joanna S. Fowler, and Nora Volkow tested the two forms separately to see how well each binds to receptor molecules in the 
brain. They labeled methylphenidate with a radioactive tracer, carbon-11, and injected small doses into two volunteers. Using positron 
emission tomography (PET), the researchers could take images of the brain and see where the drug accumulated.

 The scans revealed a "dramatic difference," says Ding. They showed that the form of methylphenidate known as the d-threo enantiomer targets 
the parts of the brain -- the basal ganglia -- involved in the drug's therapeutic effect. In contrast, the mirror image l-threo enantiomer 
distributes itself nonspecifically over the entire brain.

 Ding presented the group's findings at a meeting of the American Chemical Society in Dallas this week and proposed using the d-threo 
enantiomer alone in treating ADHD. The less effective enantiomer may contribute to Ritalin's side effects, including insomnia or loss of 
appetite, or to long-term complications such as liver damage, speculates Ding. Researchers would need to perform additional studies to 
determine whether it plays a detrimental role.

 Previous studies have indicated that the two enantiomers of methylphenidate cause different behavioral responses in patients, but the 
Brookhaven study visually establishes where the drug acts in the human brain, says William F. Trager of the University of Washington in 
Seattle.

 Methylphenidate acts by increasing the amount of the neurotransmitter dopamine in the brain. Nerve cells release dopamine, then control its 
abundance by reabsorbing it and breaking it down. Methylphenidate blocks the reuptake of dopamine, making more of the neurotransmitter 
available to bind to receptors and exert its effects on behavior. The d-threo form appears to block dopamine uptake better than the l-threo 
form.

 One of the most infamous examples of the mirror image property, or chirality, is the drug thalidomide. Widely prescribed for pregnant women 
in Britain as an antinausea treatment in the late 1950s, only one enantiomer was beneficial; the other caused birth defects. In general, 
Trager says, "it's much better to give just one enantiomer because you've eliminated all other variables." Even if one form is inactive, it 
may interfere with the working form.

 Many issues must be considered when designing a drug. Administering Ritalin as a single enantiomer may not be necessary, says Trager, since 
the body seems to metabolize the mirror-image molecules differently, thereby enriching the blood with the more potent form. Also, the 
pharmaceutical company may choose not to separate enantiomers since the process adds to manufacturing costs.

 On the other hand, because metabolism varies among people, "you're always sure of giving the right dose to that individual by giving the pure 
enantiomer," Trager adds. Today, many new drugs are produced as pure enantiomers from the start because companies have available advanced 
chemical synthesis and separation techniques.