Mephedrone in the U.S.
In a news item last week, two young men found dead in Hillsborough Raleigh, North Carolina, were described by police as having been taking the recreational drug, mephedrone. Known to chemists as 2-methylamino-1-p-tolylpropan-1-one, 4-methylmethcathinone (4-MMC), or 4-methylephedrone, the compound is a semi-synthetic derivative of the natural product cathinone found in the shrub, Catha edulis - better known as khat.
My blogging colleague and substance abuse expert, DrugMonkey, has had an extensive series of posts on mephedrone since it became widely-used - and now outlawed - in much of Europe. Like amphetamine, these compounds are believed to enhance the release of dopamine in the brain but surprisingly little pharmacology is available in the literature. A PubMed search for "mephedrone" currently returns about two dozen papers that speak mostly to legality and use trends.
Natural products have always figured prominently among drugs of abuse - alkaloids with central nervous system penetration have been used as intoxicants since ancient times and remain popular today.
To stay ahead of drug enforcement regulatory authorities, clandestine chemists have endeavored to scour the scientific literature for old synthetic schemes - preferably in non-English journals - to make chemical analogs to create legal highs. In the US, the response of the Drug Enforcement Agency (DEA), was to promote within the Controlled Substances Act the Federal Analogue Act of 1986 that made illegal any "analog" of a known Schedule I substance (for those outside the US, Schedule I compounds are those forbidden for any medical use). In fact, the paper most often cited online for the first mephedrone synthesis is Bulletin de la Societé Chimique de France 1929;45: 284–286.
Most recently, we have witnessed the circumvention of the Analogue Act with the popularity of K2, Spice, or other synthetic marijuana products that contain naphthoylindoles with activity toward cannabinoid receptors. These compounds emerged from work in the laboratory of John W. Huffman at Clemson in the 1990s and are important research chemicals because they have cannabimimetic activity while being structurally unrelated to cannabinoids.
In fact, this structural dissimilarity is one reason for the popularity of synthetic marijuana products: they cannot be detected in most urinary drug screens for THC used in employment and probation monitoring. Huffman's compounds, JWH-018 being the most popular, are illegal in most of Europe and are increasingly under scrutiny in the US, now illegal in 15 states with legislation pending elsewhere in municipalities and other states. Even where currently legal, local law enforcement officials are asking convenience store owners to take K2, Spice, and Black Mamba products off their shelves. And the US military has made such products illegal for use or possession.
My K2 posts at my previous blogs have been the most widely-read posts of anything I've ever written, with sustained traffic at my ScienceBlogs entries that exceeds that of my two current blogs. The interest in these products is simply remarkable. And why would retailers legally sell the product? Here's one answer from the Victoria (Texas) Advocate last month from an article tellingly in the business section:
The methcathinones, such as mephedrone (above), are based on the amphetamine structure with the exception of the ketone. Although more polar and with less propensity to cross the blood-brain-barrier, the additional 4-methyl substitution enhances lipophilicity.
For many local proprietors of the incenses, finding customers who want to purchase the product is not a problem.
Donna Shook, owner of D&D Novelties, said she racks in $8,000 to $10,000 a month from incense sales alone.
"It's going big time. It's even surpassing porn and adult toys," said Shook. "I mainly sell it because there has been a huge request among my customers."
But the safety is what seems to be driving lawmakers and law enforcement authorities to support new legislation. Poison control center reports around the US commonly cite synthetic marijuana products as causing severe anxiety and paranoia, seizures, and in a few cases, the products have been associated with deaths. The availability on the internet of pure JWH compounds, not just the herbal incense products spiked with the chemicals, may be the cause for the uptick in adverse reaction reports. In the case of mephedrone, we have two cases of deaths here in North Carolina that are associated with, but not yet causally linked, to the chemical. A similar case occurred in Sweden last year but was later associated with the use of other drugs that caused the fatality. But even Huffman noted in an interview earlier this year that once compounds are outlawed, chemists will move on to others.
Purely from an academic standpoint, I've been intrigued by those creative clandestine souls who apply their synthetic expertise - and a reverence for the chemical literature - to stay one step ahead of regulatory authorities. Former Dow chemist, Alexander "Sasha" Shulgin, is perhaps the best known of these enthusiasts, going so far as to publish two widely-read books on synthetic procedures and experiential accounts of compound use, achieving the status of near-deity among enthusiasts.
When psychoactive natural products were outlawed, new chemistry (or new attempts at old chemistry) aims to circumvent the law. And while the Analgoue Act was designed to prospectively undermine such activities, new compounds continue to rear their heads.
I'm curious as to when this unusual branch of chemistry got started. Of course, Albert Hoffman synthesized LSD while at Sandoz in Basel but his intent was to make potential pharmaceuticals, not an illicit drug.
Do readers have any recommendations on scholarly, historical sources that address the advent of designer drugs/legal highs?