Sunday, June 27, 2010

Turbocharging the Brain - The Always-On Drug

The checkered legacy of amphetamines prompted neuroscientists and physicians to hail the arrival of modafi nil as a wakefulness-promoting agent with a seemingly more favorable side effect and abuse profile than the amphetamines. The ability of modafi nil (introduced in the U.S. in 1998) to allow people to work long stretches without the need for breaks has turned it into a lifestyle drug for the jet-lagged who attempt to live in four time zones at once.

Jamais Cascio, an associate of the Institute for the Future in Palo Alto, Calif., obtained a prescription for modafi nil from his physician after hearing about it from friends who traveled a lot. On trips overseas, he noticed that it made him feel not only more awake but also sharper. “The perceived increased cognitive focus and clarity was very much of a surprise, but it was a very pleasant surprise,” says Cascio, who has mentioned the drug in some articles he has written. “My experience was not that I’d become a superbrain.
It was more an experience of more easily slipping into a state of cognitive flow, a state of being able to work without distraction.”

Testing has confi rmed some of Cascio’s impressions. In 2003 Sahakian and Robbins found that 60 rested, healthy male volunteers did better on a few neuropsychological measures, such as recall of numerical sequences, but results were unchanged on others. Investigators elsewhere have also found benefi ts for the drug, although, as Cascio noted, it will not make a dunce into a genius. None of these studies, moreover, has tested effects on cognition over extended periods.

Unregulated availability of either modafi nil or methylphenidate also remains unlikely because the drugs tend to affect individuals in different ways. Users with lower IQs appear to derive a large performance boost from modafi nil, whereas those with more innate ability show little or no benefit. With methylphenidate, those having poor working memory improved when tested; those having a naturally higher memory capacity showed much smaller benefits.

As with amphetamines, modafi nil did not emerge from a basic understanding of the underlying biology of how the brain works. Present research shows, however, that the drug seems to involve multiple neurotransmitters, the chemicals that trigger the firing of specific clusters of neurons. The drug’s exact mechanism remains to be elucidated. But recently Nora D. Volkow, director of the National Institute on Drug Abuse, and her colleagues discovered that one of those neurotransmitters is dopamine, the same chemical that is boosted by amphetamines and that imbues those drugs with their addiction potential. “It appears that methylphenidate and modafi nil are very similar in what they’re doing to the dopamine system in the brain, contrary to what was believed,” says Volkow, although she adds that it is not practical to smoke or ingest modafi nil to produce a strong high, so the possibility of abuse is lower. Another roadblock to wider use appeared in 2006, when the FDA rejected the drug as a treatment for ADHD in children because of reports about serious skin rashes.

Repackaging old attention-boosting drugs as cognitive enhancers for students, executives and software programmers may produce only marginal benefits over consuming a double espresso. The question of what exactly is an enhancer has prompted the convening of a group within the American College of Neuropsychopharmacology to discuss the standards that any drug should meet to be classified as a cognitive booster. Ultimately, enhancement drugs may come from another sphere of research. Insights into how we translate a baby’s image or a friend’s name into lasting memories has laid the groundwork for new drugs specifically designed to achieve better functioning in people with Alzheimer’s or other dementias.

Optimism about a new generation of pharmaceuticals derives in part from advances in basic research into the biochemical processes underlying memory formation. More than 30 types of gene-altered mice have demonstrated the ability to both acquire information and store it in longterm memory better than the average mouse. “This is the first time in the history of neuroscience that we have the backbone of the molecular and cellular biology of memory,” says Alcino J. Silva, a neurobiologist at the University of California,
Los Angeles. “What this means for society is that for the fi rst time we can use it to start changing how we learn and remember.”

But truly effective memory drugs are probably a long way off, in part because of the scientific challenges. Most of the 200 gene mutations introduced into mice by researchers worldwide caused deficits. Silva remembers one mouse in his laboratory that illustrated the possible tradeoffs that researchers will confront during development of a cognitive enhancer. The animals learned faster than normal, unaltered mice but were unable to complete an elaborate puzzle administered by the investigators. “If you taught them something simple, they acquired it fast, but for anything more complicated, they couldn’t acquire it,” Silva says. He estimates that it may take decades before drugs from this research are routinely used.

The logistical challenges are daunting as well. Several of the fi rst companies to enter the fray, including ones founded by leading academics, have faltered. In 2004 Science magazine cited four new firms—Sention, Cortex Pharmaceuticals, Memory Pharmaceuticals and Helicon Therapeutics—as exemplars of a trend. Sention went out of business. Cortex is ailing and desperately seeking a partner. Last year Hoffmann–
La Roche purchased at a penny-stock price (less than $1) Memory, co-founded by Nobelist Kandel, after it had experienced layoffs and a number of failed clinical trials. Helicon has survived because of the largesse of billionaire Kenneth Dart, the Styrofoam cup magnate, who was enticed by the prospect of memory drugs—the company has been developing a drug that would modulate a pathway related to glutamate, a neurotransmitter that triggers an intricate cellular signaling path related to the formation of longterm memories.

A sister company, Dart NeuroScience, now handles development of new drug candidates, leaving the job of conducting clinical trials to Helicon. So far Helicon has received more than $100 million in funding but has yet to reach latestage clinical trials for any of its drug candidates. “The way I like to explain this to audiences when I give talks is that when Helicon was formed I thought that I was making memory enhancers for my parents and I had no gray hair,” says Tim Tully, Helicon’s chief scientific officer, who co-founded the company when he was at Cold Spring Harbor Laboratory. “They’re now dead, I’m fully gray, and I’m fully cognizant of the fact that this is a race for me not them.”

Tully, 55, adds that he does not foresee his creations ever becoming the next Viagra or Prozac. “What the media loves to totally ignore is the side-effect potential and jump right to the wild speculation of this as a lifestyle drug,” Tully says. “And I think it’s just missing the mark. The reality is that if you’ve got a debilitating form of memory impairment these drugs may be helpful, but they’re probably going to be too dangerous for anyone else.”

Despite these cautionary tales, drugmakers continue trying to develop cognitive enhancers for Alzheimer’s and other dementias. Among the compounds under consideration are ones that alter the effects of neurotransmitters other than glutamate — including receptors switched on by the nicotine in tobacco (though not the one linked to addiction). One of the reasons that people smoke is because nicotine helps to sharpen attention.

Lessons learned from drugs developed for dementia could lead to agents that ease the milder cognitive problems associated with normal aging, assuming these compounds do not arrive burdened with intolerable side effects. If sufficiently benign, these pills could find their way into college dorms or executive suites. “Within the pharmaceutical fi eld, people recognize that a successful cognitive enhancer could be the bestselling pharmaceutical of all time,” says Peter B. Reiner, a professor of neuroethics at the University of British Columbia.

Source of Information : Scientific American October 2009

No comments: