RTI scientists solving forensic, designer drug mysteries
Sep09

RTI scientists solving forensic, designer drug mysteries

Catching up on my reading this Sunday morning, I’m beaming with pride on the collective accomplishments and coverage of some old friends and colleagues. Kerstin Nordstrom, a AAAS Mass Media Fellow with the Raleigh News & Observer, had a nice story on 3 September about the work of Dr. Peter Stout at RTI International. You old-timers will know this non-profit entity as Research Triangle Institute, home to the discoveries of Taxol and camptothecin by Wall and Wani and colleagues. Kerstin, or Dr. Nordstrom I should say as she holds a PhD in physics, interviews RTI’s Dr. Peter Stout on the institute’s forensic analytical chemistry capabilities with regard to the “designer drug” industry. Yes, here we go again with my long-running commentary on the “synthetic marijuana,” “herbal incense,” “plant food,” and “bath salts” products that have recently taken a direct hit from “Operation Log Jam,” a coordinated, federal operation to shut down the industry. In my post on the federal takedown, I referred to a paper by Stout’s RTI colleagues where mass defect filtering was used to identify unknown analogs of known illegal compounds, particularly the JWH group of cannabimimetic naphthoylindoles (Anal. Chem., DOI:10.1021/ac300509h). (Addendum: That paper was also covered nicely in the 15 June C&EN by Erika Gebel.) Coincidentally, both Kerstin and Peter are dear to me – hence the following disclosures before singing the praises of the article: Peter earned his Ph.D. in molecular toxicology from Dr. Jim Ruth’s lab at my former home, the Department of Pharmaceutical Sciences at the University of Colorado Denver’s Skaggs School of Pharmacy. My time at RTI’s Natural Products Laboratory (2002-2008) overlapped with Peter’s hiring. As an aside, I had not known Peter was hired until he saw a cart outside of my laboratory with my name and hunted me down, guessing there weren’t many Krolls in biochemical pharmacology. An equally lighthearted observation is that Peter has almost completely shaved his head as long as I’ve know him; I’m certain that’s a coincidence with his dissertation research project, “Mechanisms of Drug Disposition into Hair.” Disclosure #2: Kerstin is a fellow graduate of the 2011 Santa Fe Science Writing Workshop and serendipitously ended up here in the Triangle for her AAAS Mass Media Fellowship. What I like about the story is how both of them describe analytical techniques in relatively approachable language: Kerstin on HPLC: For liquid chromatography, an unknown chemical is pushed through a pipe. The pipe is filled with tiny silica particles – 1 to 10 micrometers in size – that attract some molecules and repel others. Each chemical has a different attraction, and so some, attracted to the grains, go slower than...

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DEA jams synthetic marijuana and “bath salts” industry
Jul28

DEA jams synthetic marijuana and “bath salts” industry

With all the discord in Washington these days, it’s rare to see several US governmental organizations working together to address a significant public health problem. This week, the US Drug Enforcement Agency (DEA) mobilized Operation Log Jam, an unusual and highly-coordinated action with six other federal agencies aimed to shut down the synthetic designer drug industry in 109 US cities. The products targeted were of two broad classes: 1) synthetic marijuana “incense” products comprised of naphthoylindole cannabimimetic compounds first synthesized by John W. Huffman’s lab at Clemson in the mid-1990s, and 2) “bath salts” or “plant food” products containing the stimulant/empathogen mephedrone (4-methylmethcathinone) or the stimulant MDPV (3,4-methylenedioxypyrovalerone). This compilation of posts on synthetic marijuana and, to a lesser extent, “bath salts” serves as a good primer on the subject. These products were sold widely on the internet, headshops, and convenience stores and were associated with 13,000 poison control calls last year, 60% of which were in individuals under 25. Disturbing acute and chronic side effects have been reported by users that include severe anxiety and paranoia, unnerving hallucinations, and even heart attacks. Several specific compounds were criminalized by an emergency DEA action and numerous state and local laws over the last two years. Still, products continued to be available containing compounds not explicitly criminalized, with marketers claiming legal status. Commenters here and elsewhere have argued that this industry would go away if marijuana would simply be decriminalized in the US. Earlier this week, TIME Healthland writer Maia Szalavitz made a good argument for this (or at least FDA regulation of recreational drugs) in the context of Operation Log Jam. Comprehensive action I find two aspects of this initiative quite unique since I began covering the synthetic formerly-legal highs phenomenon. First, Operation Log Jam aimed to address every level of the synthetic designer drug industry: manufacturers, wholesalers, and retailers. From the DEA press release: As of today [26 July], more than 4.8 million packets of synthetic cannabinoids (ex. K2, Spice) and the products to produce nearly 13.6 million more, as well as 167,000 packets of synthetic cathinones (ex. bath salts), and the products to produce an additional 392,000 were seized. In addition, $36 million was also seized in the raids. Among the federal agencies involved was the US Postal Service since the internet-marketed products are sometimes shipped via regular mail. US Customs and Border Protection acted to target the flow of compounds synthesized non-domestically into the country. And, of course, the IRS was involved to, “trace the path of illicit drug proceeds by identifying the financial linkages among the various co-conspirators,” as indicated by Richard Weber, Chief, IRS Criminal...

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K2 Synthetic Marijuana: Heart Attacks, Suicides, and Surveillance
Nov14

K2 Synthetic Marijuana: Heart Attacks, Suicides, and Surveillance

Sixteen-year-old boys having heart attacks. Blog reports of deaths and suicides. And a little known chemistry and public health resource mobilized to identify “legal highs.” The chemical and biological phenomenon that is “synthetic marijuana” continued to develop over the last week as we learn more about these products from the medical and public health communities. Most notably, pediatric cardiologists reported in the journal Pediatrics on three cases of Texas teenagers who experienced myocardial infarctions – heart attacks – after using a synthetic marijuana product (DOI: 10.1542/peds.2010-3823). (Many thanks to Dr. Ivan Oransky, Executive Editor at Reuters Health, for providing us with primary information after their own excellent report by Frederik Joelving). Brief background Sold under names like K2 or Spice as “incense” or “potpourri” and labeled as “not intended for human consumption,” these products are laced with one or more synthetic psychoactive compounds that were published in 1990s work studying structure-activity relationships on cannabinoid receptors. The vast majority of the synthetic work was done in the laboratory of Dr. John W. Huffman, now professor emeritus of the Department of Chemistry at Clemson University, with his compounds know by “JWH-” nomenclature. The US Drug Enforcement Agency secured emergency prohibition of five of these compounds late last year, spurring “legal highs” manufacturers to reformulate second-generation Spice products containing related compounds not explicitly designated as illegal. Although the DEA does have the authority to prosecute sale and possession of these analogs, such action is rare. To learn more, we’ve put together a compilation of our synthetic marijuana posts for the reader’s further reference. Adolescent heart attacks In this week’s advance Pediatrics publication, the three cases – all in 16-year-old boys – were seen at the UT-Southwestern Medical Center in Dallas within three months of one another. The common presentation was a 3- to 7-day history of chest pain with myocardial infarction confirmed by electrocardiographic and biochemical endpoints (ST elevation in the inferolateral leads and substantial increases in cardiac troponin-I released into the bloodstream). As you might predict, heart attacks are extremely rare in otherwise healthy 16-year-olds. But marijuana itself is known to cause cardiac effects, with rare cases of myocardial infarction. In the discussion of the Pediatrics report, Dr. Arshid Mir and colleagues describe literature extending back to 1979 (DOI: 10.3109/15563657909010604) on the increased risk of cardiac disturbances, including myocardial infarction, within the first hour of marijuana use. Increased heart rate is a well-recognized effect of marijuana that is mediated by increased sympathetic nervous system outflow to the heart. This 1976 paper in Circulation describes how the majority of this tachycardia can be prevented by premedication with the non-selective beta-blocker, propranolol. But what about...

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Synthetic marijuana for pharmacists
Feb24

Synthetic marijuana for pharmacists

As a former pharmacy professor, I’m honored that a couple of our old and new blogposts have been picked up by colleagues at the University of Texas at Austin College of Pharmacy. Clinical Assistant Professor and drug information specialist, Jennifer Seltzer, PharmD, and her intern, Tiffany LaDow, PharmD, included us in their online durg information alert entitled, “‘Spice’ It Up – A New Way to Get High: What Pharmacists Need to Know.” This type of distillation by LaDow and Seltzer is representative of exactly the kinds of briefs I used to enjoy writing for the Colorado Pharmacists’ Society and are what motivated my establishment of this blog when I was out of academia. I always found that practicing pharmacists appreciated these kinds of timely alerts complete with the basic science underlying these developments. My only suggestion to my pharmacy colleagues is that they might care to embed hyperlinks in their reference list. I’m not being entirely self-serving (although I appreciate the readership). If you’re going to go through the trouble to reference blogposts and other peer-reviewed references complete with the URLs, just embed the URLs for easy clicking. In fact, one of the URLs in the reference list has a spacing issue that improperly directs the readers when copying-and-pasting. Nevertheless, thank you for directing Texas pharmacists to our humble little blog! Thanks to TIME Healthland writer and author, Maia Szalavitz While we’re on this topic, I also need to thank science journalist, Maia Szalavitz, for citing our work yesterday in the widely-read TIME Healthland blog where she is a regular contributor. “Outlawing ‘Legal Highs:’ Can Emergency Bans Hinder Drug Development?” addresses the often-overlooked consequences of broadly assigning compounds to Schedule I of the US Controlled Substances Act: Compounds that may not have been adequately studied for therapeutic benefit might never be fully investigated if relegated to this most-restricted status. By definition, Schedule I compounds have no known medical benefit. However, if they are not studied for medical benefit, none will be found. In support of this notion, Szalvitz cited a 2005 Journal of Neuroscience paper from a Spanish neurodegeneration research group led by Dr. Maria de Ceballos at Madrid’s Cajal Institute. Following from work showing that senile plaques from Alzheimer’s disease patients express cannabinoid CB1 and CB2 receptors, the investigators showed that synthetic cannabinoids can prevent β-amyloid peptide-induced activation of microglial cells, known to produce inflammatory mediators that are neurotoxic. Preventing an major neurodegenerative disease with psychoactive compounds might not necessarily lead to a major therapeutic advance. However, the basic pathophysiology of Alzheimer’s disease and other neurological disorders can certainly be advanced by access to these research tools. DEA...

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Strong chemistry in NC bills banning legal highs
Feb12

Strong chemistry in NC bills banning legal highs

On Wednesday, two bills passed unanimously in the North Carolina State Senate that would outlaw synthetic cannabimimetics and mephedrone. These compounds are currently sold as Spice incense (e.g., K2, Black Mamba) or “bath salts” (e.g., Ivory Wave), respectively. (Many thanks to WRAL-TV Capitol Bureau Chief Laura Leslie and fellow blogger DrugMonkey for alerting me to these bills via Twitter.). Legislatively, similar bills have been passed and laws enacted in states and municipalities around the US while a proposed scheduling rule by the federal drug agency, the DEA, languishes in an administrative and legal morass. The synthetic marijuana bill, House Bill 12 (Senate 9) and the mephedrone bill, House Bill 13 (Senate 7), were originally both put forth in the NC House by co-sponsors led by Representative George Cleveland (R, NC-14) of Jacksonville, North Carolina, home to the US Marine base Camp Lejeune. Cleveland himself is a retired, 25-year US Marine. The US military has been far ahead of other state and federal agencies in prohibiting use of these chemicals and associated products. But for readers of this blog, the part of the NC bills that most impressed me was the exhaustive and near-encyclopedia listing of chemicals to be outlawed under the bills. For example, while the DEA has proposed to only regulate five compounds (and implied prohibition of structural analogs), take a gander at this list: The following controlled substances are included in this schedule: (6) Synthetic cannabinoids. – Any material, compound, mixture, or preparation that contains any quantity of the following substances, their salts, isomers (whether optical, positional, or geometric), homologues, and salts of isomers and homologues, unless specifically excepted, whenever the existence of these salts, isomers, homologues, and salts of isomers and homologues is possible within the specific chemical designation: a. Naphthoylindoles. Any compound containing a 3‑(1‑naphthoyl)indole structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1‑(N‑methyl‑2‑piperidinyl)methyl, or 2‑(4‑morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent. Some trade or other names: JWH‑015, JWH‑018, JWH‑019, JWH‑073, JWH‑081, JWH‑122, JWH‑200, JWH‑210, JWH‑398, AM‑2201, WIN 55‑212. b. Naphthylmethylindoles. Any compound containing a 1H‑indol‑3‑yl‑(1‑naphthyl)methane structure with substitution at the nitrogen atom of the indole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl, 1‑(N‑methyl‑2‑piperidinyl)methyl, or 2‑(4‑morpholinyl)ethyl group, whether or not further substituted in the indole ring to any extent and whether or not substituted in the naphthyl ring to any extent. c. Naphthoylpyrroles. Any compound containing a 3‑(1‑naphthoyl)pyrrole structure with substitution at the nitrogen atom of the pyrrole ring by an alkyl, haloalkyl, alkenyl, cycloalkylmethyl, cycloalkylethyl,...

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