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Mephedrone in the U.S.

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.

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:

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?

12 Comments

  • Oct 20th 201015:10
    by JJM

    Reply

    This isn’t my field (analogs of illegal drugs). However, fluorine can often be substituted for hydrogen to produce an equally effective product that is not regulated. For example, adding fluorine to the 4-methyl group of mephedrone would probably still produce an active drug. I recall someone at one of the major chemical companies going to jail for selling fluorinated analogs of controlled substances in the mid to late 80s.

    Do note that F is not as good replacing H as many early articles in enzymology would have you think. In particular, they often claimed that the C-F bond is almost as short as a C-H bond (true) but the radius of F is much greater; so it is not quite an “invisible” substitution. There is also the substantial electronegativity of F to consider; which can be a reason for using it.

    • Apr 13th 201203:04
      by Steve

      Reply

      Fluorine (and fluoride compounds) are deadly poisons that inhibit cellular energy generation via mitochondrial interference.

      When in doubt, don’t do it, that’s all I can say.

      I’ve got experience with this stuff – and it’s bad. Real bad. Fuck all you’s guys who want to say otherwise – just wait, it’ll getcha.

      Do NOT smoke this shit. Seriously, for the good of man, I post this – I make it a point to not leave too many comments just lying around the ‘net, especially about, erm, touchy subjects like this, for lack of a better description – but on this, I just can’t keep my mouth shut (or fingers from the keys) – please, just trust me, you don’t want to go through what I’ve been through – the sickness that comes and the withdrawl during detox (I self-detoxed, by drinking lots of water, maintaining electrolytes, taking a multivitamin + b12 regimen, Milk Thistle (1000mg x 4 daily) and eating lots of soups – and of course, NOT using) is not worth the temporary euphoria, and the shit’s way too expensive besides – and if you make it yourself and use it to “get around the cost”, don’t worry, it WILL cost you in the end – much more than you ever imagined, especially as you develop tolerance and attempt to make stronger blends.

      This will destroy you. Maybe not today, maybe not tomorrow, but sometime – caveat emptor, do whatever the Hell you want, but consider the following: these people don’t care what you do either, as long as you pay them. End of story.

      • Apr 13th 201203:04
        by Steve

        Reply

        Addendum – I was mainly talking about Spice(s), but this shit will kill you too. Don’t have any experience with “meph”, that I KNOW of, but I do know that this shit has been added to Spice(s) as well, so yeah. Watch out.

  • Oct 24th 201022:10
    by John

    Reply

    just a correction: this took place in Raleigh, N.C. on Hillsborough Street, not in the town of Hillsborough. Hillsborough Street is the main drag for N.C. State University.

    Good article otherwise

    • Oct 24th 201023:10
      by David Kroll

      Reply

      John, thanks for the correction. I re-read the article and, sure enough, I misread Hillsborough St as the town of Hillsborough. I’ve corrected the post above to note that the incident occurred in Raleigh.

  • Nov 10th 201012:11
    by CashMoney

    Reply

    Did Shulgin ever play around with the cathinones? His nomenclature is blocking this uninformed individual from figuring that out from my copy of PHiKAL…

    • Oct 6th 201122:10
      by Isomer Design

      Reply

      There are no cathinones among the 179 PiHKAL title compounds. However, his latest work, the Shulgin Index, Vol 1, does include several cathinones, in particular DMAP(2-(Dimethylamino)-1-phenylpropan-1-one), methcathinone and methylone (beta-keto MDMA). The 126 title compounds can be seen at shulginindex.info.

      As an aside, why is synthesising something that is not a controlled substance nor an analogue of a controlled substance “circumventing” the law rather than complying with it? Was Huffman’s research circumventing the law?

      • Oct 7th 201106:10
        by David Kroll

        Reply

        As an aside, why is synthesising something that is not a controlled substance nor an analogue of a controlled substance “circumventing” the law rather than complying with it? Was Huffman’s research circumventing the law?

        Good questions – I like the idea that one is equally complying with the law. My definition comes from intent. Huffman did not synthesize the compounds to spray on herbal products and sell to kids to may have had no experience with any illicit drug.

  • Feb 20th 201111:02
    by Synchronium

    Reply

    Bit of a late comment, but for the record, 3-fluoromethcathinone and 4-fluoromethcathinone (one of which earned the nickname flephedrone) are equally efficacious, equipotent and tended not to make people turn blue or savage the nostrils!

    The actual packaged “products” favoured this over mephedrone.

  • Dec 5th 201111:12
    by Marc Stied

    Reply

    Do note that F is not as good replacing H as many early articles in enzymology would have you think. In particular, they often claimed that the C-F bond is almost as short as a C-H bond (true) but the radius of F is much greater; so it is not quite an “invisible” substitution.

  • Apr 25th 201202:04
    by Maquiagem

    Reply

    Since this article was written in 2010 and the research has advanced, just a quick update:

    Cannabimimetic activity was blamed for things that they did not do. The individuals involved in the latest research proved that it should and will be legal to become “legally high”.

    Thank you for your thoughts and research.

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