Since we ended last year with a post on legal highs – and who decides which analogs are illegal – we logically begin this year, the International Year of Chemistry, with further discussion of synthetic, psychoactive intoxicants.
Today, Nature published an excellent commentary from Dr. David E. Nichols, entitled, “Legal highs: the darker side of medicinal chemistry.” Nichols, a distinguished chair in pharmacology at Purdue University’s College of Pharmacy, reflects on how he is haunted by the deaths that could be tracked back to unintended human use of compounds he and his group have synthesized in the course of legitimate biomedical research. Other scientists whose work has been used for nefarious purposes are likely to share these feelings, both in neuropharmacology and other areas of biological and physical sciences.
Even in my area of natural products and dietary supplements, several colleagues and I have had our work co-opted by herbal manufacturers to sell their goods, most often in the form of overinterpreting in vitro data to make false claims for human use. The listing of the full citations of our associated papers – or even investigator photographs – on manufacturer web pages to imply that we academic scientists have supported their product claims.
However, the same use of synthetic chemistry publications by chemists skirting federal drug laws is a far more serious issue that Nichols addresses in the Nature commentary. Back in October, we discussed here the views of Nichols on one’s scholarly work in neuropharmacology being adopted by the legal highs industry following a Wall Street Journal article by Jeanne Whalen. In fact, Nichols cites that WSJ article in his Nature commentary where his work was described by a Dutch legal highs entrepreneur:
He (David Llewellyn) and his chief chemist get ideas for new drugs by scanning scientific literature. They pay particularly close attention to new papers published by scholars known for researching mind-altering, psychoactive substances.
David Nichols, a pharmacologist at Purdue University, has been especially valuable, Mr. Llewellyn says. Through his work studying brain receptors, Dr. Nichols has developed a range of psychoactive substances. His papers give a full description of the drugs he’s using, including their chemical makeup. This provides Llewellyn and others with a roadmap for making the drugs.
Our colleague Drugmonkey notes that Nichols is a legend in the study of MDMA, or Ecstasy. In fact, Nichols provided other researchers with experimental quantities of this compound early in its history. The work on this and other compounds that modulate serotonergic and dopaminergic pathways in the brain was driven by trying to investigate novel therapeutics, understand the basis of substance addiction, or understand basic mechanisms of disease. But Nichols’ work is unavoidably well-known to the “alternative-chemistry” community – Nichols even has a web page dedicated to him at Erowid.org, one of the go-to sources for non-judgmental information on psychoactive substances. Nichols also coined the term, “entactogen,” to more accurately describe the psychoactive effects of MDMA (relative to the more common term, “empathogen”). Dr. Nichols has dedicated much of his life to truly understanding these kinds of compounds and how they might help us understand and treat human disease.
The Other Chemistry
Inevitably, every chemist who works on psychoactive compounds is a target for their published work to be mined by entrepreneurs wishing to make a buck on not-yet-illegal compounds. Many of these chemists are characterized as “kitchen chemists” or otherwise amateurs, but I wonder just how many highly-trained but unemployed chemists (even ACS members) might be exercising their talents in the legal highs industry. Perhaps Chemjobber could run a survey.
But one essential point about published schemes is that, in most cases, complete safety data is not available for every compound synthesized – most legal high manufacturing proceeds on little more than animal efficacy data. Some dangers might be predicted from the mechanisms of action but, by and large, true risks do not appear until compounds are “field tested” by recreational drug enthusiasts.
I feel for Dr. Nichols when he expresses his sadness at the deaths of individuals who used one compound that was investigated in three of his papers, 4-methylthioamphetamine (MTA):
My laboratory had shown that rats perceived the effects of MTA as being like those of ecstasy. It seemed that that was the sole motivation for its illicit production and distribution to humans. I was stunned by this revelation, and it left me with a hollow and depressed feeling for some time. By 2002, six deaths had been associated with the use of MTA. It did not help that I knew some of these fatalities were associated with the use of multiple drugs, or had involved very large doses of MTA. I had published information that ultimately led to human death.
The social responsibilities of the scientist
Nichols is truly honorable in thinking so responsibly about his work. His compassion and concern reminds me of other scientists whose consciences might have been even more deeply troubled by how their work was used. I can’t imagine the emotional struggle experienced by the nuclear physicists who worked on the science of the atomic bombs that ultimately led to the 1945 obliteration of Hiroshima and Nagasaki and deaths of about 250,000 human beings within four months of the blasts. J. Robert Oppenheimer, most often credited as “father of the atomic bomb,” was noted in his 1967 NYT obituary as having said:
“Scientists are not delinquents,” he added. “Our work has changed the conditions in which men live, but the use made of these changes is the problem of governments, not of scientists.”
And as with governments, so goes the rest of humanity. And this is where Nichols should let himself off the hook. Nichols’ intentions are pure: the chemical investigation of compounds that may lead to new therapeutics or otherwise inform how the brain works. The traditionally open access to literature in print form (if you went to an academic library) and chemical searching on the web has made it easier for enterprising individuals to seek out synthetic schemes for interesting organic molecules. While our work is made public to fellow scientists, it is now increasingly available to the public. Inevitably, our science will be used by others for business and profit. The ethics of the business approach and concern for “consumers” are issues beyond our control.
Nichols notes briefly in his commentary as to whether one should restrict publication on some compounds that are likely to be unsafe or readily-abused. Such an approach would risk the potential benefit that might be reaped down the line if, for example, a much better antidepressant can be made from a published compound.
And how would we know even what to hold back? I think of the well-known case of the meperidine analog, MPPP, that became popular in the late 1970s and early 1980s. The compound itself carries the typical risks of opioid overdose but the real problem came in when chemists took shortcuts on the published synthetic route, producing small amounts of a contaminant pro-neurotoxin, MPTP. We now know that MPTP can be metabolized in dopaminergic neurons to MPP+, a compound that destroys these cells and produce symptoms of Parkinson’s disease. Should a chemist then also feel responsible for problems resulting from a sloppy adaptation of their synthetic scheme? What about carryover of toxic solvents and reactants? Whose fault is that?
Where to draw the line on personal freedom
In fact, what responsibility do scientists and companies share in more extensive influences of their products on human health. We don’t have alcoholic beverage companies repenting for the addiction of millions and the deaths of several hundred thousand in the US each year. We don’t have fast food companies lamenting that their products contribute to heart disease, obesity, and diabetes. In fact – and I think about this issue as a former pharmacy school prof like Dr. Nichols – what about pharmacies that sell alcohol and tobacco products? I don’t hear much discussion these days of how irresponsible and unprofessional this practice is.
Why? Because of individual choice and autonomy. Just as people have the choice to eat a triple-stack-mac-attack, people have the choice whether or not to take an intoxicating substance – legal or not. Dr. Nichols did not force recreational drug enthusiasts to take any of his compounds but the information and opportunity was out there for them to do so. Just like alcohol. Just like tobacco. Just like the pound of steamed shrimp dipped in butter that I’ll be eating today, cholesterol be damned.
I’m not saying that we shouldn’t take responsibility for our science. Indeed, some scientists in the neuropharmacology arena might be a bit too flippant about their attitudes towards drugs of abuse. Attitudes about alcohol use at drug abuse research meetings could be more measured. I’m also equally guilty in sometimes being too light-hearted about natural products that can be taken for psychotomimetic effects. But while we have a responsibility to support the ethical use of science, we cannot control how it is used. I’m far more concerned about the potential impact of publishing the 1918 H1N1 influenza A RNA sequence than I am of the synthetic schemes Dr. Nichols has published over the last 35 years.
Chemistry, psychology, and economics
As both student and professor, I’ve observed that some college chemistry majors with an interest in non-alcoholic intoxicants will always begin to recognize the contribution of their discipline to other recreational substances. The realization that a peer-reviewed literature exists with wide-open descriptions of how to synthesize psychoactive substances tempts many a student to embark on their own independent projects. This is nothing new. It went on before I went to school and still happens today – although many current students fail to avail themselves of the pre-1966 literature not available online that requires a physical trip to the library.
And people have used intoxicating substances as far back as can be documented. People are going to take mind-altering substances regardless of laws prohibiting or permitting use of such substances. Today, no matter what laws have been passed, the US counts over 15 million people with alcohol dependence and a roughly equal number of people who have tried an illegal substance. Alcohol and tobacco, illegal drugs, and misuse of legal drugs all have potentially lethal consequences but the use of each involves some degree of personal choice. What my colleagues are trying to study in the substance dependence field is why some people and not others become addicted to substances even in contexts where access is equivalent. Treating or managing substance dependence is one of medicine’s major challenges.
The combination of personal responsibility and choice together with personal risk of dependence is central to arguments for and against the legal highs industry and, more broadly, drug enforcement policy.
The legal highs industry is certainly made easier with the advent of internet retailing and the real-time agility of legal highs marketers is facilitated by the web. Convenience stores have also made it more, uh, convenient for young adults to access legal highs and these economic times have driven some store owners into this product area – one Texas store owner remarked earlier this year that she was selling between $8,000 and $10,000 per month of synthetic marijuana incense products. You’ve got to move a lot of Gatorade and beef jerky to match those numbers.
Already, one can purchase legal-alternatives to newly-illegal synthetic marijuana products because the industry is staying ahead of the regulators. In fact, one could argue that drug regulations are forcing legal highs manufacturers to dig even deeper into the literature to pull out more and more compounds with less and less known safety characteristics.
I very much admire and respect Dr. Nichols for coming out and discussing his personal feelings about how his science is used. The longer you’re in this business, the more likely it is that your science will be used for purposes you did not intend. You can only operate in the most responsible manner possible without hindering the free exchange of scientific advances and ideas.
Nichols, D. (2011). Legal highs: the dark side of medicinal chemistry Nature, 469 (7328), 7-7 DOI: 10.1038/469007a
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