NC legislators aim to clean up “bath salt” omission
Earlier this week, I wrote about on the comprehensive chemistry text in two North Carolina state bills – H12/S9 and H13/S7 – to criminalize distribution, sales, and possession of compounds present in a variety of legal-high, designer drug products.
One bill specifically addressed compounds present in synthetic marijuana compounds whose extensive list included those eponymous JWH compounds synthesized in the laboratory of Clemson University Professor Emeritus, John W. Huffman (featured here). The other bill addressed mephedrone (4-methylmethcathinone; 4-MMC) and other structural analogs of this amphetamine and cathinone derivative.
However, I noted my surprise at the time at the omission of a compound more commonly associated with so-called bath salt products: MDPV, or methylenedioxypyrovalerone. My neuroscience blogging colleague DrugMonkey also remarked to me of his surprise since most other states deal with MDPV in the same legislation with mephedrone/4-MMC because of their structural similarity.
But on Thursday I was tipped off by WRAL-TV Capitol News Bureau Director, Laura Leslie, that a separate bill, Senate Bill 77 (S77), was just filed by State Senator Stan Bingham (R, NC-33) that specifically proposes to criminalize MDPV. Unlike the earlier bills, this one does not appear to currently have a House counterpart so I’m unclear as to how this will be dealt with in the other body. The bill now goes to judiciary committee.
The “bath salt” phenomenon began to grab US media attention in late 2010 as state poison control centers began to receive reports of emergency room visits by people using legal high products that were not synthetic marijuana. According to Mark Ryan, Louisiana Poison Control Center Director, these products are sold under such names as Cloud 9, Ivory Wave, Ocean, Charge Plus, White Lightning, Scarface, Hurricane Charlie, Red Dove and White Dove.
These currently skirt drug laws by claiming “not for human consumption” or as bath salts, plant food, or insect repellent. As with synthetic marijuana products, an advantage of these drugs is that they can’t be detected by the most common urinary drug screens such as the SAMHSA 5 (Quest Diagnostics example here). These products providing those on probation or otherwise subject to mandatory drug testing with a psychoactive alternative to amphetamines or Ecstasy.
TIME Healthland writer, Maia Szalavitz, remarked to me recently of her concern about kids hearing stories about “bath salts” and then trying to smoke Mom’s Calgon. Not a good idea. Trying to do so may indeed, “take me away.”
From a neuropharmacology perspective, even less data are available on MDPV than for mephedrone. MDPV is the 3,4-methylenedioxy derivative of pyrovalerone, a compound first synthesized by Heffe in 1964 and investigated in the 1970s in Europe as an amphetamine-like agent for chronic fatigue. Most recently, investigators from the Massachusetts-based company, Organix, tested a series of pyrovalerone analogs for selective inhibition of dopamine and norepinephrine reuptake transporters, DAT and NET, relative to the serotonin reuptake transporter, in studies toward identifying a treatment for cocaine addiction (J Med Chem 2006, 49, 1420-1432).
The strategy of this search was to identify compounds that are potent at binding DAT (and displacing cocaine) but that cause less actual inhibition of dopamine reuptake. This ratio of the IC50 for inhibition of dopamine reuptake divided by the Ki for binding the DAT is called the discrimination ratio (DR). (For non-pharmacologists, IC50 is the concentration that inhibits a maximal response of a model compound by 50%; the Ki is a measure solely of binding, not function, and indicates the concentration that inhibits maximum binding of a model compound by 50%.)
What’s the significance of this discrimination ratio? Deutsch and Schweri proposed that a DR of 10 or greater is required for functional cocaine antagonism without having the same stimulant effect (J Med Chem 1999, 42, 882−895). In the Organix J Med Chem paper, none of the pyrovalerone analogs had a DR of greater than 5. These data are suggestive that pyrovalerone and its analogs are unlikely to be treatments for cocaine abuse because they have cocaine-like effects.
However, out of all the compounds synthesized for this study, none were the 3,4-methylenedioxy ring-substituted analog, MDPV. I consulted this week with Bryan Roth, MD, PhD, Professor in the UNC-Chapel Hill Department of Pharmacology and principal investigator of the NIMH Psychoactive Drug Screening Program (PDSP). The NIMH contract allows qualified academic investigators to submit new psychoactive compounds for screening against over 50 neurochemical receptors and transporters (current list here). I tried to search the PDSP Ki database for results without success and Dr. Roth confirmed for us on Thursday that MDPV has not yet been tested in the PDSP. I’d be particularly interested in seeing MDPV tested alongside pyrovalerone to see if its profile differs in the same manner as MDMA vs. methamphetamine.
I continue to be fascinated by designer chemistry and legal highs for two reasons. First, is how clandestine chemists are so agile as to stay ahead of not only the legislation and even the science. Much of what is really known about MDPV comes from self-experimentation from human bioassays as detailed at such sites as Erowid and Bluelight. Second, is that the rush to criminalize these compounds is going to place extensive demands on state criminal investigation laboratories. Simply looking at the North Carolina bills for synthetic marijuana compounds and mephedrone analogs, labs are ultimately going to have to develop LC/MS methods for dozens if not hundreds of compounds. In fact, Carmen Drahl, C&EN Associate Editor and blogger at The Haystack, tweeted to me this week that the text of the NC bills almost read like patents in terms of the compound coverage.
But with state governments tightening their belts, I doubt seriously that the additional resources will be available to fund these increased analytical chemistry demands. And even so, chemists are likely to come up with another series of chemicals that are not covered by these new state laws.