Jan. 7, 2011 -- As a boy growing up in Covington, Ky., David Nichols played with chemistry sets instead of footballs. By high school, the self-professed "science geek" who made stink bombs for fun recognized his flair for formulas and decided to become a chemist.
Little did he know that the profession that brought him so much happiness would leave him haunted, as drugs he discovered would be misused, causing harm, and even death.
When he started studying for his doctorate in 1969 -- two years after the summer of love -- Nichols was interested in how drugs, such as LSD, acted on the brain.
"It occurred to me: People can take these drugs, and in some people the effects last a moment, but in others it permanently changes them in some way," Nichols said.
Some LSD users have claimed to reach states of superior consciousness and even see God. But others have suffered "bad trips," and even developed permanent psychosis, Nichols said.
"If drugs can change people's perspectives on the world or who they are, they must work in a very fundamental way in the brain," Nichols said.
In the 1980s, Nichols got a research grant to study 3,4-methylenedioxymethamphetamine (MDMA) -- a drug commonly known as ecstasy. At the time, MDMA was being used in psychotherapy.
"When it became clear that it was going to become a controlled substance, I thought maybe we could figure it out how it worked and develop a safe version to allow psychiatrists to continue using it," Nichols said.
To uncover how MDMA worked in the brain, Nichols made analogs -- compounds that were structurally very similar to MDMA, but slightly different. By lopping off pieces of the compound one-by-one, Nichols and colleagues could determine which parts were important for its euphoric effects.
One of the analogs, 4-methylthioamphetamine (MTA), was found to boost the release of the feel-good neurotransmitter serotonin. Certain antidepressants, such as Prozac, improve mood and relieve anxiety by keeping serotonin up in the space between nerve cells. So it was no surprise that, like selective serotonin reuptake inhibitors, MTA also had antidepressant effects in rats.
But after publishing three papers on MTA and its promise in the treatment of mood and anxiety disorders, it emerged that MTA was being made and marketed for a different purpose.
"A colleague told me people were taking MTA tablets called 'flatliners,'" Nichols said.
Flatliners, which were chemically different from MDMA and therefore not considered illicit, were being synthesized by amateur chemists and peddled as "legal highs." At least five people died from taking the drug, Nichols said.
"I was shocked by that," said Nichols, who is now chairman of pharmacology at Purdue University in West Lafayette, Ind. "I had really never thought that people could get killed by something I had worked on."
Nichols knew people were making his compounds, which had never been tested in humans, and selling them as street drugs. The police contacted him asking for samples to use as standards to which drugs seized could be compared. But it really hit home when Scottish drug trader David Llewellyn cited Nichols' work as "especially valuable" to his drug-making business in a 2010 interview with the Wall Street Journal.
"People said, 'You shouldn't be shocked because you knew people were doing this.' But when you see it in print, it's a shock," Nichols said.
When the journal Nature subsequently approached him about writing an essay on the topic, Nichols obliged.
"I have never considered my research to be dangerous, and in fact hoped one day to develop medicines to help people," he wrote in the essay published Jan. 5, 2011. "I have worked for nearly four decades synthesizing and studying drugs that might improve the human condition. I strive to find positive things, and when my research is used for negative ends it upsets me."
As research becomes more accessible through online, open-access journals, researchers increasingly are aware that their audience no longer is restricted to scientific inner circles.
"It gets tricky when every drug dealer, home meth lab and drug cartel gets immediate access to the same information," said Arthur Caplan, chairman of medical ethics at the University of Pennsylvania.
Keeping Science Safe
Studies relating to biological warfare and nuclear weapons are restricted to the public for reasons of national security. But there is no way to keep research like Nichols' -- and the materials necessary to replicate it -- out of malicious hands.
"You publish and I think you just have to hope people use it responsibly," Nichols said, adding that a sophomore organic chemistry student could make MTA with a few hundred dollars of glassware and chemicals. "Before, you would order laboratory equipment from a standard supplier and the DEA could be alerted. But with the Internet, you can order things without much scrutiny."
Caplan thinks measures should be taken to limit the potential for science to do harm. Journals could restrict access to complete formulas and recipes, drug enforcers could be on the lookout for compounds with high potential for misuse, and scientists could think hard about who they share their research with.
"None of these things are perfect." Caplan said. "I'm not saying you can prevent the misuse of scientific knowledge. But at least you could make it tougher for the bad guys."
Although the knowledge that his discovery has killed people -- and may have had yet unknown long-term effects in many more -- haunts Nichols, he plans to continue his research. Understanding the function of receptors in the brain, called G protein-coupled receptors, is the "holy grail of pharmacology," he said. He currently is developing a rat model of schizophrenia that can be used to discover drug targets and develop therapies.
And while Nichols can't help but feel in some way responsible for the harm caused by MTA, the notion that people have a personal responsibility for what they do to themselves has carried some of the weight, he said.
"Young people often feel invincible," Nichols said. "They think, 'Oh, it's legal. I can't get in trouble.' They don't think about whether it will hurt them. One of the messages that I'd like to get out is that a legal high does not equal a safe high -- it just means it's not illegal yet."