A communication to the blog raised an issue that is worth exploring in a little more depth. The questioner wanted to know if I knew why a NIH Program Announcement had disappeared.

The Program Announcement (PA) is the most general of the NIH Funding Opportunity Announcements (FOAs). It is described with these key features:

  • Identifies areas of increased priority and/or emphasis on particular funding mechanisms for a specific area of science
  • Usually accepted on standard receipt (postmarked) dates on an on-going basis
  • Remains active for three years from date of release unless the announcement indicates a specific expiration date or the NIH Institute/Center (I/C) inactivates sooner

In my parlance, the PA means “Hey, we’re interested in seeing some applications on topic X“….and that’s about it. Admittedly, the study section reviewers are supposed to conduct review in accordance with the interests of the PA. Each application has to be submitted under one of the FOAs that are active. Sometimes, this can be as general as the omnibus R01 solicitation. That’s pretty general. It could apply to any R01 submitted to any of the NIH Institutes or Centers (ICs). The PAs can offer a greater degree of topic specificity, of course. I recommend you go to the NIH Guide page and browse around. You should bookmark the current-week page and sign up for email alerts if you haven’t already. (Yes, even grad students should do this.) Sometimes you will find a PA that seems to fit your work exceptionally well and, of course, you should use it. Just don’t expect it to be a whole lot of help.

This brings us to the specific query that was sent to the blog, i.e., why did the PA DA-14-106 go missing, only a week or so after being posted?

Sometimes a PA expires and is either not replaced or you have happened across it in between expiration and re-issue of the next 3-year version. Those are the more-common reasons. I’d never seen one be pulled immediately after posting, however. But the NOT-DA-14-006 tells the tale:

This Notice is to inform the community that NIDA’s “Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects” Funding Opportunity Announcements (FOAs) (PA-14-104, PA-14-105, PA-14-106) have been reposted as PARs, to allow a Special Emphasis Panel to provide peer review of the applications. To make this change, NIDA has withdrawn PA-14-104, PA-14-105, PA-14-106, and has reposted these announcements as PAR-14-106, PAR-14-105, and PAR-14-104.

This brings us to the key difference between the PA and a PAR (or a PAS):

  • Special Types
    • PAR: A PA with special receipt, referral and/or review considerations, as described in the PAR announcement
    • PAS: A PA that includes specific set-aside funds as described in the PAS announcement

Applications submitted under a PA are going to be assigned to the usual Center for Scientific Review (CSR) panels and thrown in with all the other applications. This can mean that the special concerns of the PA do not really influence review. How so? Well, the NIDA has a generic-ish and long-running PA on the “Neuroscience Research on Drug Abuse“. This is really general. So general that several entire study sections of the CSR fit within it. Why bother reviewing in accordance with the PA when basically everything assigned to the section is, vaguely, in this sphere? And even on the more-specific ones (say, Sex-Differences in Drug Abuse or HIV/AIDS in Drug Abuse, that sort of thing) the general interest of the IC fades into the background. The panel is already more-or-less focused on those being important issues.  So the Significance evaluation on the part of the reviewers barely budges in response to a PA. I bet many reviewers don’t even bother to check the PA at all.

The PAR means, however, that the IC convenes their own Special Emphasis Panel specifically for that particular funding opportunity. So the review panel can be tailored to the announcement’s goals much in the way that a panel is tailored for a Request for Applications ( RFA) FOA. The panel can have very specific expertise for both the PAR and for the applications that are received and,  presumably, have reviewers with a more than average appreciation for the topic of the PAR. There is no existing empaneled population of reviewers to limit choices. There is no distraction from the need to get reviewers who can handle applications that are on topics different from the PAR in question. An SEP brings focus. The mere fact of a SEP also tends to keep the reviewer’s mind on the announcement’s goals. They don’t have to juggle the goals of PA vs PA vs PA as they would in  a general CSR panel.

As you know, Dear Reader, I have blogged about both synthetic cannabinoid drugs and the “bath salts” here on this blog now and again. So I can speculate a little bit about what happened here. These classes of recreational drugs hit the attention of regulatory authorities and scientists in the US around about 2009, and certainly by 2010. There have been a modest but growing number of papers published. I have attended several conference symposia themed around these drugs. And yet if you do some judicious searching on RePORTER you will find precious few grants dedicated to these compounds. It it no great leap of faith to figure that various PIs have been submitting grants on these topics and are not getting fundable scores. There are, of course, many possible reasons for this and some may have influenced NIDA’s thinking on this PA/PAR.

It may be the case that NIDA felt that reviewers simply did not know that they wanted to see some applications funded and were consequently not prioritizing the Significance of such applications. Or it may be that NIDA felt that their good PIs who would write competitive grants were not interested in the topics. Either way, a PA would appear to be sufficient encouragement.

The replacement of a PA with a PAR, however, suggests that NIDA has concluded that the problem lies with study section reviewers and  that a mere PA was not going to be sufficient* to focus minds.

As one general conclusion from this vignette, the PAR is substantially better than the PA when it comes to enhancing the chances for applications submitted to it. This holds in a case in which there is some doubt that the usual CSR study sections will find the goals to be Significant. The caveat is that when there is no such doubt, the PAR is worse because the applications on the topic will all be in direct competition with each other. The PAR essentially guarantees that some grants on the topic will be funded, but the PA potentially allows more of them to be funded.

It is only “essentially” because the PAR does not come with set-aside funds as does the RFA or the PAS. And I say “potentially” because this depends on their being many highly competitive applications which are distributed across several CSR sections for a PA.

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*This is a direct validation of my position that the PA is a rather weak stimulus, btw.

As always when it comes to NIDA specifics, see Disclaimer.

The Daily Mail is reporting followup toxicity findings in the June 17 death of one Matthew Rybarczyk the after attending a rave party.

The Daily Mail:

There are fears that a string of fatal overdoses this summer have been caused by the toxic substance bath salts after it was pushed to young festival-goers as the party drug ‘Molly’, officials said today.

The substance had been sold to at least one young person as ‘molly’ – a potent form of ecstasy – but was in fact the meth-like street drug bath salts.

Officially known as methylone, it can have similar effects to ecstasy or MDMA on the user.

It has been confirmed as cause of death of a 20-year-old man and is suspected in the deaths of others.

StructureFig-mdma-vs-cathinones450As you can see in this structural diagram, methylone is the cathinone cousin of 3,4-methylenedioxy-methamphetamine (MDMA) which is the canonical psychoactive of both Ecstasy and Molly.I am delighted to see some actual toxicity data followup reporting. Perhaps other sources will have more specifics with regard to the medical examiner’s findings and the various drugs found in the decedent’s blood. For now, however, at least we have something to go on.

And I covered one prior Case Report containing three methylone-related deaths. And as I noted there, we know perfectly well that MDMA itself is capable of killing people.

As we’ve also discussed, MDMA can result in significant medical emergency and death. Yes, really, it is the MDMA.

It would not be at all surprising if methylone deaths were via the same neuropharmacological triggers, see Baumann et al 2012 and Simmler et al, 2013. Certainly what one can glean from the symptoms is very familiar.

I take issue, however, with the Louise Boyle piece in the Daily Mail. We can start from the headline:

Did all these festival-goers die from taking BATH SALTS? One death confirmed as fears others were duped into buying toxic street drug while believing it was ‘molly’

See that? Nice trick. Methylone is a “toxic street drug” while apparently ‘molly’ is no such thing. Bzzzt, wrong. Methylone and MDMA are the same category of thing. Recreational drugs obtained from sources of dubious quality. Trying to distinguish one as a “toxic street drug” as different from the other is silly and nonsensical.

next we have this whopper:

but was in fact the meth-like street drug bath salts

Another report from the NY Post goes down the same path of underinformed sensationalism:

New York club kids who use the party drug Molly … are often being peddled deadly “bath salts” by ruthless dealers,…The dangerous narcotic — which causes a violent, meth-like high — has killed at least one reveler this year and is being eyed in the deaths of two partiers at the Electric Zoo festival on Randall’s Island two weeks ago…Known to drug regulators as methylone

The term “bath salts” is just a nickname. It is no different than Ecstasy, molly, crack, crystal, weed, smack. It has meaning in so far as there is a consensus use of it, but in the absence of consensus it is near meaningless. I would say that at this point in time “bath salts” in the US can mean any of the substituted cathinone drugs. There was a time when I might have said it was semi-uniquely referring to 3,4-methylenedioxypyrovalerone (MDPV) but given the diversity in the market this is no longer correct.

The above referenced papers from Baumann and Simmler, and this additional one from Baumann, should tell the tale about the “meth-like” charge as well. While some of the substituted cathinones could be argued to be “meth-like”, methylone sure isn’t one of them. In fact the neuropharmacology suggests “MDMA-like” if anything. And really, given the most popular cathinones being used to date, it is silly to say that bath salts are meth-like. Mephedrone and methylone are MDMA-like in many ways and MDPV is turning out to be more like cocaine in activity. That’s neuropharmacology, for the most part. When we look at compulsive use and propensity for addiction it in fact looks like methylone (Watterson et al, 2012) and mephedrone (Hadlock et al, 2011; Aarde et al, 2013a; Motbey et al, 2013) might have more reinforcing effect in rodent models than would be expected for a MDMA-like drug (see Schenk 2009; de la Garza et al, 2007 for review). In some of these studies the authors show data suggesting* the “MDMA-like” cathinones might actually be more effective in self-administration than methamphetamine. MDPV appears to generate more compulsive use than does methamphetamine (Watterson et al, 2012; Aarde et al 2013b). So, I suppose if the journalists mean the compulsive-use or reinforcing value as indexed by rat self-administration studies then they might have some defense for the “meth-like” charge. Somehow I doubt they are so informed.

Nevertheless.

When we are talking the acute overdose profile, the symptoms sure sound like MDMA and the relative reinforcing properties are most likely not directly related.

Oh boy. As I was writing this, some tox reporting from the New York Electric Zoo overdoses (it also repeated the methylone finding for Mr. Rybarczyk). James C. McKinley Jr reports at an Arts Beat blog at the NYT:

Toxicology results showed Ms. Rotondo died from acute intoxication after taking pure MDMA, the euphoria-producing drug sold on the street in pill form as ecstasy and in powdered form as molly, said Ellen Borakove, a spokeswoman for the medical examiner’s office.

Mr. Russ had taken a fatal mix of MDMA and methylone, a closely related stimulant that is also often sold under the name molly.

Nice to see some confirmation since there are definitely other drugs to suspect, like PMA and PMMA, when it comes to rave-drug overdoses.

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*there are some methodological questions to be answered. I’d like to see a few more comparisons, myself.

New Case Report from the Maryland Office of the Chief Medical Examiner

Kesha K, Boggs CL, Ripple MG, Allan CH, Levine B, Jufer-Phipps R, Doyon S, Chi P, Fowler DR. Methylenedioxypyrovalerone (“Bath Salts”),Related Death: Case Report and Review of the Literature. J Forensic Sci. 2013 Jul 3. doi: 10.1111/1556-4029.12202. [Epub ahead of print][PubMed, Publisher]

The subject was a 39 year old man with a history of depression, back pain and drug/alcohol abuse. He was found in public talking to himself, delusional. Once admitted to the hospital, he became agitated, tachycardic and hyperthermic (107 degF noted). Although the decedent was positive for diphenhydramine, promethazine, diazepam and nordiazepam the conclusion was….

Based on the investigative, autopsy, and toxicology findings in this case, the cause of death was methylenedioxypyrovalerone intoxication and the manner of death was accident. It is also important to note that his bizarre behavior with life-threatening hyperthermia is consistent with an MDPV-induced excited delirium state in this individual.

Yep.

The peripheral blood level was 1.0 mg/L of MDPV. We’re just starting to see reports so we’ll just have to wait and collect various blood levels that are associated with medical emergency and death to try to get an idea of the danger zone. Of course, there will be no such thing as an absolute threshold, as individual susceptibility and the circumstances will vary.

A new paper from the Fantegrossi laboratory examines the behavioral and physiological effects of the substituted cathinone drug, and “bath salts” constituent, 3,4-methylenedioxypyrovalerone (MDPV) [ Search PubMed ] which is the compound which has dominated the US media reports of averse consequences of bath salts intoxication. To the extent that verification of the drug has been provided in such reports, of course. Additional confirmation can be found here, here.

ResearchBlogging.orgThe current issue of Neuropsychopharmacology has a bath salts image on the cover and contains an article from Baumann and colleagues on MDPV pharmacology (I discussed it here) and this paper from Fantegrossi and colleagues.

William E Fantegrossi, Brenda M Gannon, Sarah M Zimmerman and Kenner C Rice In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity. Neuropsychopharmacology (2013) 38, 563–573; doi:10.1038/npp.2012.233; published online 5 December 2012 [ ArticleLink(free); PDF ]

This is a behavioral pharmacology study in male NIH Swiss mice which first uses drug discrimination techniques to show that when mice are trained to discriminate 0.3 mg/kg i.p. MDPV from saline the subsequent dose response curves for 0.01 to 0.3 mg/kg of MDPV, METH and MDMA are nearly identical. This article has been made freely available so I won’t belabor this part of the study.

Fantegrossi13-mdpvFig4What I wanted to focus on was the radiotelemetry studies of body temperature and locomotion. For reasons related to this classic paper on MDMA from Malberg and Seiden, most investigations of the effects of stimulant drugs in rodents should include some consideration of the role of ambient temperature. Fantegrossi and colleagues examined the effects of 0.3-30 mg/kg i.p. MDPV at both 20°C and 28°C. They showed, first of all, that MDPV produces no change in body temperature when administered at 20°C, but induces temperature elevations in a dose-dependent manner when animals are evaluated at 28°C. Even more interesting is what is shown in Figure 4 which I’ve included here. You can see that the locomotor stimulant effect (total activity counts over 6 hrs; left panel) of MDPV also is more pronounced at the higher ambient temperature with a peak differential observed after the 10 mg/kg i.p. dose (timecourse for this dose shown in right panel). There were also some other interesting phenomenological differences observed with the high ambient temperature condition.

At the highest tested dose of MDPV (30 mg/kg), significant focused stereotypy was observed at 28 1C, but not at 20 1C. Furthermore, four (of six) mice treated with 30 mg/kg MDPV at the high ambient temperature engaged in skin-picking and self-biting, which drew blood, and, in accordance with our IACUC approval, were removed from the study and euthanized. No signs of self-injurious behavior were observed at any dose of MDPV administered at 20 1C.

Repetitive, stereotyped behavior is common with locomotor stimulants and can be observed following high doses of amphetamine, methamphetamine and cocaine among other compounds. So this is probably an expected effect. What was interesting here was the dependency on ambient temperature. Off the top of my head, I can’t remember either the stimulant drug sterotypy literature (which focuses on charcterizing the repetitive behaviors) or the locomotor studies (where the “inverted U” dose effect function often reflects the emergence of stereotyped behavior after high doses) focusing too heavily on the ambient temperature issue. No doubt I could stand to go back and review some papers with a closer eye on the ambient temperature.

This study, however, points a finger at environmental issues when trying to figure out the degree to which the drug MDPV might cause sensational media-friendly outcomes in some users. Studies such as the present one may indicate that factors as subtle as how hot it is the day a person takes a given drug can change the experience from relatively benign into something much more severe. Thus, a dose of a drug which has been taken before by the same user may have highly unpredictable effects just based on this one difference in the situation.

ADDITIONAL READING

Watterson et al 2012 demonstrated intravenous self-administration in rats.
Huang et al, 2012 showed locomotor effects of MDPV on activity wheels in rats.
Fuwa et al 2007 shows dopamine responses with microdialysis and locomotor effects [in Japanese, but the Abstract is in English and the figures are easily interpreted]
Meltzer et al 2006 present monoamine pharmacology on a series of pyrovalerone compounds

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Fantegrossi WE, Gannon BM, Zimmerman SM, & Rice KC (2012). In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology PMID: 23212455

There’s a new Case Report in the Journal of Analytical Toxicology

Adamowicz P, Tokarczyk B, Stanaszek R, Slopianka M. Fatal Mephedrone Intoxication–A Case Report. J Anal Toxicol. 2012 Nov 7. [Epub ahead of print] [PubMed][DOI]

The victim was a 30 year old male, found in a stairwell in a “critical state”. Emergency response was ineffectual and the individual died at the scene. The toxicology testing found his blood and vitreous humour positive for mephedrone (5.5 and 7.1 ug/mL, respectively). There was no alcohol in the individual, no positives on “routine screening analysis” nor any sign of amphetamine, methamphetamine or MDMA. The 2C-B compound initially suspected by police (based on some field assay, looks like) was not confirmed in the powder in his possession nor in tissue samples.

That’s it, short and sweet. The mephedrone (aka 4-methylmethcathinone) killed him.

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Additional reading on the substituted cathinone designer drugs of abuse can be found in my archive.

Related reading on MDMA-induced fatality can be found in the MDMA Archive.

There are two new pharmacological investigations on the substituted cathinone drugs that have been discussed here on occasion.

Each of

Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW.Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products. Neuropsychopharmacology. 2012 Oct 17. doi: 10.1038/npp.2012.204.

and

Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME.Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2012 Aug 17. doi: 10.1111/j.1476-5381.2012.02145.x.

report very similar findings for MDPV, the cathinone that appears most frequently in US newspaper reports.

As a very general rule, the amphetamine class stimulants do a couple of things to enhance the neuron-to-neuron chemical communication that occurs in the brain. The most common and significant effects tend to involve the transporter mechanisms that remove dopamine, norepinephrine and / or serotonin from the synapse, the gap between two neurons. These transporter molecules are an integral part of terminating a signalling event which has been caused by the release of one of these three monoamines from one of the neurons in question. Interfere with the operation of these transporters and a drug can potentiate the magnitude or duration of a given signalling event (i.e., release of one of the dopamine (DA), norepinephrine (NE) or serotonin neurotransmitters).

The amphetamine class stimulants have these properties. As does cocaine. As do therapeutic drugs such as methylphenidate (Ritalin) and Prozac. The term selective serotonin re-uptake inhibitor, SSRI, for Prozac-class antidepressant drugs refers to the transporter, obviously, and also indicates a key thing with the term “selective”. Drugs which have the ability to interact with one of the monoamine transporters tend to interact with the other ones as well. Substantial differences in effect can be associated with differences in the relative ability a specific molecule has to attach to the DAT versus the NET versus the SERotonin transporter (SERT). As one clear example, methamphetamine and MDMA differ in their relative ability to inhibit the SERT….this property of MDMA is associated with many of it’s stimulant-atypical properties relative to other amphetamine-class drugs.

The new studies both show that MDPV blocks all three transporters with much more potent effects at the DAT and NET relative to SERT. As Baumann and colleagues note, MDPV is 50 and 10 times more potent than cocaine (not an amphetamine, we’ll come to this) at DAT and NET respectively. Simmler and colleagues similarly indicate that MDPV is much more potent at DAT than cocaine or methamphetamine which did not qualitatively differ from each other.

So to this point, MDPV looks like a high-potency traditional stimulant. Most effective at the DAT, fairly effective at the NET and with less ability to block the SERT.

Cocaine and the amphetamines diverge at this point because the amphetamines act as a substrate at the transporters. Instead of only interfering and blocking them from doing anything, the amphetamines actually substitute for the neurotransmitter in question and are taken up into the cell. In so doing, they also cause an exchange to happen whereby the transporter moves some neurotransmitter from inside the cell back into the synapse. This transporter mediated efflux contributes to any “regular” release of neurotransmitter mediated through the merging of intracellular sacs (called vesicles) with the cell membrane.

The two papers agree in finding that MDPV has no ability to cause transporter-mediated efflux of dopamine and is therefore best categorized neuropharmacologically as a “pure” blocker (like cocaine) rather than an amphetamine-like transporter substrate.

The Simmler paper adds an in vitro model of blood/brain barrier penetration…in very simple terms the degree to which a molecule is fat-liking versus water-liking can alter the speed at which it can cross cell membranes and get into the brain. This paper used an in vitro preparation of human capillary endothelial cells (that form the blood-brain barrier) to show that MDPV is likely to cross the blood-brain barrier very rapidly, consistent with high lipophilicity predicted from its structure.

The upshot of the two papers is that MDPV shows pharmacological properties consistent with classical stimulants. It shows relatively high selectivity for DAT over SERT and high potency relative to drugs such as methamphetamine or cocaine. In vivo neurochemistry in the Baumann paper confirm that MDPV has potent effects on dopamine levels in the nucleus accumbens, a hallmark of drugs (beyond the stimulants even) which have substantial risk for compulsive use. The only somewhat discordant note for the structure-activity nerds is that MDPV looks so much like the rest of the amphetamines and cathinones that it will be interesting to discover why it doesn’t act as a transporter substrate (Simmler et al included a number of other cathinones and showed that many of them do act as transporter substrates.)

Together these papers suggest that MDPV has high abuse liability with a use pattern characterized by frequent re-dosing much like one sees with cocaine. This is consistent with many self-reports that are emerging from people who use MDPV and therefore, despite the relatively brief time on the “market”, we can predict a cocaine-like dependence problem to emerge for MDPV in the near future.

Sure enough.

The Miami guy who took off all his clothes and attached a homeless guy, including chewing on his face, was not in fact high on “bath salts”.

Lab tests detected only marijuana in the system of a Florida man shot while chewing another man’s face, the medical examiner said Tuesday, ruling out other street drugs including the components typically found in the stimulants known as bath salts.

If you will recall the main stream media reporting up until now, just about every single news item referring to this case referenced speculation from law enforcement sources that this guy was high on “bath salts”.

The commentary to the effect that this case “proved” that we needed to control bath salts now, RIGHT NOW!!!! AIEEEEE!!!!!! was rampant.

I’m sure this case played no role in the recent attempts by Congress to criminalize several drug compounds which were alleged to be components of “bath salts”. As I was just discussing, the only ones to survive the axe of Sen Leahy were 4-MMC and MDPV… but of course the DEA has emergency scheduled these and methylone already.

The DEA, of course, has a process. In which they evaluate the available evidence before moving for a scheduling action. You may not agree with their position on the evidence and you may think they are engaged in an exercise in confirmation. But you cannot deny that they have to come up with …something. Something a little better than “law enforcement officials suspect [insert unusual behavior] was caused by [insert current drug of interest to the MSM and or legislators looking to get some press]”.

The information driven process is superior. At all times. Yes, even for the MSM.

I say it again, wait for the tox results. Before you rush to present your salacious story about the latest event which might possibly have involved a recreational drug. Your credibility demands it.

Last week the US House of Representatives voted to approve a ban on several recreational drugs in the two classes we’ve been discussing of late. Namely the synthetic cannabinoids and the cathinones. They slipped the ban into a bill first called the “Food and Drug Administration Safety and Innovation Act” (Senate version; S.3187) and then, apparently the “FDA User Fee Agreement” (House version maybe) so you can tell they were on the hurry-up about it. As noted in this account from the Bangor Daily News:

The measure combines three bills previously introduced by Sens. Chuck Grassley, R-Iowa, Chuck Schumer, D-N.Y., and Amy Klobuchar, D-Minn. Among the chemicals it would outlaw are mephedrone and methylenedioxypyrovalerone, known as MDPV, which can be used to make bath salts. The bill carries a penalty of up to 30 years for those caught selling the drug.

The lone dissenter in the Senate vote was Sen. Bernie Sanders, an independent from Vermont.

The U.S. Drug Enforcement Administration took emergency action in September 2011 to federally ban mephedrone, Methylone and MDPV and designated the hallucinogenic stimulants a Schedule 1 drug, the same class as heroin and LSD.

I’m having trouble finding anything that specifies exactly what was passed by the House last week but this page S.3190 lists 4-MMC/mephedrone and 3,4-methylenedioxypyrovalerone (MDPV) and then some phenethylamines in the 2C family. These lack the beta-ketone signature of a cathinone so calling them “bath salts” even further confuses the identity issue, I will note. Curiously, methylone (or 3,4-methylenedioxymethcathinone, the MDMA cousin) is not on this list. If anything, the available data tend to suggest this is the one most likely to be a breakout hit in this country…it is already pretty popular in the UK.

Anyway, the news of the day is that Sen Patrick Leahy of VT has blocked the inclusion of the 2C compounds and the resulting bill has passed the Senate with only mephedrone and MDPV included from that class of compounds (apparently all the cannabinoids were included). According to this reporting, a member of his staff said:

“Sen. Leahy has been clear that scheduling controlled substances is not something to be taken lightly.”

“It is not without implication to put a whole lot of chemicals on the federal drug schedule,” he said. “It means putting more people in jail and makes it harder to seek legitimate uses for these drugs. Leahy is most comfortable sticking with what has been carefully considered.”

Here’s how I read this from my perspective as one that has been interested in the effects of the cathinones and has followed the developing scientific literature and, to lesser extent the street seizures and policy initiatives, via published work and discussions with researchers, DEA representatives, NIDA Program Officials and even FDA folks.

I bet they presented actual data on mephedrone and MDPV. Published data and as-yet-unpublished data from laboratories in addition to the public health and law enforcement data. Data that are probably limited but still reasonably convincing. To a CongressCritter. This is the “carefully considered” part.

What I also would predict is that there was comparatively less information about the 2C drugs, if any at all. And the DEA hoped that by calling it all “bath salts” they could criminalize the lot. I would surmise that at best the pro-ban folks based their demands on finding some 2C family compounds in products being sold as bath salts along with, or in a context similar to, substituted cathinone drugs like mephedrone and MDPV.

And I bet Sen Leahy called bullshit on an information disparity.

If this is what happened, I have to issue a pat on the back to him for standing up for the rule of information in making policy decisions.

UPDATE: ok, this appears to be a House bill version that includes a full list. Several cathinones were included in addition to the 2C-? phenethylamines. Interesting. There’s a link which compares it to S.31690 and you can see where the Senate version had just the 4-MMC and MDPV with the 2C-? phenethylamines.

If you’ve been following along my posts on the substituted cathinones you will recall that cathinone is beta-keto-amphetamine. And much like amphetamine, chemists can hang little bits off the core structure to create new and interesting drugs which may offer different subjective experiences. For people who are into that sort of thing. The compound termed “Methylone” is the cathinone cousin of 3,4-methylenedioxymethamphetamine or MDMA. Which we’ve discussed a time or two on this blog. As we’ve also discussed, MDMA can result in significant medical emergency and death. Yes, really, it is the MDMA.

ResearchBlogging.orgA Case Report has just popped up on the preprint queue of the Journal of Analytical Toxicology. In it, Pearson and colleagues detail three cases of fatality involving the methylone compound. For me the interest is the way this slots neatly into the Case Reports on MDMA fatalities, especially given the drug-discrimination paper that was our first introduction to the cathinones on this blog. Although there is great diversity, MDMA cases frequently involve an individual who was “found collapsed” by friends. Emergency medical services are invoked, whereupon the individuals are frequently found with high body temperature, rhabdomyolysis, hyponatremia (dilute blood) and may have seizure-like symptoms. Cardiac arrest is not uncommon during the course of care, as is cascading organ failure. Diversity rules the day. Some individuals have been rave dancing, some have not. Some were exposed to a broad array of other psychoactives. Alcohol, nicotine and cannabis are very common but you also see methamphetamine, caffeine and a list of other stimulant/entactogen/hallucinogen class drugs. The denialists like to point to the other factors as causal, insisting that “pure MDMA” is as safe as sea salt. My position is that the great similarity of clinical courses across the diversity of “other factors” makes it even more convincing that the single shared factor, i.e., MDMA, is the causal factor. ….plus there’s this little thing called the preclinical literature.

As always with Case Reports, the work by Pearson et al. will be less than satisfying. It is only through the gradual building of the Case Reports and the addition of preclinical investigations that we will really know what is going on. But every journey starts with a single step….

The second case is the most canonical, to my eye. A 19 year old woman at a rave was observed to collapse, briefly recover, claim to “not feel well” and then exhibit seizure-like symptoms. She went into asystole en route to the Emergency Department and had a body temperature of 103.9 F. She was found negative for cocaine metabolite, cannabinoids,
opiates, benzodiazepines, phencyclidine, amphetamines, barbiturates, methadone and propoxyphene on immunoassay and positive for methylone and lamotrigine. Wait, what? This anticonvulsant sodium channel blocker is a most interesting finding. Was it being used intentionally (by the user or the tablet manufacturer) to modulate the methylone effect on monoamines? Perhaps. Or was she an epileptic prescribed an anticonvulsant? That would be interesting given this prior MDMA-related Case and the Giorgi et al. 2005 preclinical study.

Case 1 is a little more unusual, if we’re assuming methylone acts much like MDMA. In this case a 23 year old male was acting erratically in public and was detained by the police and transported to the ED. This one sounds a bit more like a classical amphetamine case, with reports of forced restraint, combativeness and, sigh, the strength-of-five*-men thing. Initial symptoms included rhabdomyolysis, a body temperature of 105.9F, seizure and renal failure. After about 3.5 hrs of care a series of cardiac arrest/recovery events culminated in a fatal arrest about 24 hrs after admission. The blood workup detected detected methylone, dextromethorphan, cotinine, caffeine and lidocaine and the Medical Examiner ruled it due to methylone. As we’ve occasionally seen from the outside of the deaths of the rich and famous, the MEs are seemingly going on an assessment of drug levels to reach their decision. One might assume that the levels of the other drugs were considered to be below the threshold for causing a death. Naturally, we are in the purest speculation territory to start dreaming up drug interaction stories. For me, the strength will eventually lie in matching up the constellation of clinical symptoms with all the cases of fatality and medical emergency that involve methylone. I’d like to know a bit more about the dextromethorphan, however, given that it is degraded by the same CYP2D6 hepatic enzyme which degrades MDMA and, presumably, methylone. Dextromethorphan is also capable of causing serotonin syndrome, thus might have the same direction of effect as methylone in this context, i.e., this may support a relatively simple additive-effects conclusion.

The final case is just plain disturbing. A 23 year old male was acting erratically in an after-hours club when management had him secured to a chair in a van outside with plastic wrap. He was left there for 3-4 hours before being discovered. Paramedics found low blood pressure, weak (but rapid) heart rate and convulsions. Upon arrival at the ED, he had body temperature of 107 F and died after about 45 minutes of attempted life support. He had 0.03 g/dL blood alcohol concentration and methylone, in addition to several therapeutics administered in the ER (but might possibly have obscured recreational use of benzodiazepines and synthetic opiates). A positive immunoassay for cannabinoids was not confirmed on followup analysis.

I think you can see that being wrapped in a chair with plastic wrap for 3-4 hours in a van might have possible had effects. I’m most concerned about the physical exertion that might have been going on, much like in Case 1 in which the guy was struggling against police. The body heat has to come from somewhere and muscular exertion (due to intentional activity) could be that somewhere. Note that in Malignant Hyperthermia, seizure-like muscular contraction can provide that same input to the system. This would be relevant to all three cases.

As I mentioned above, this is the beginning of the story. By no means can three Cases nail down a connection with high confidence. But this is all strikingly familiar and dovetails with the aforementioned drug-discrimination finding and a recent report of neuropharmacological similarity of methylone and MDMA. So I’m betting we’ll see more of these Case Reports of medical emergency and death that involve methylone.

And the profiles are going to look just like the ones involving MDMA.
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*well, at least it was five, not ten.

Julia M. Pearson, Tiffanie L. Hargraves, Laura S. Hair, Charles J. Massucci, C. Clinton Frazee III, Uttam Garg, & B. Robert Pietak (2012). Case Report: Three Fatal Intoxications Due to Methylone Journal of Analytical Toxicology

From Springfield MO:

Joshua Amir Nossoughi, 32, of Springfield, died last July in a hospital about two hours after officers confronted him as he tried to break into the Battlefield city hall. During a long effort to catch and subdue him, Nossoughi was unfazed by five separate Taser shocks, pepper spray and two dozen baton strikes to his legs, The Springfield News-Leader reported (http://sgfnow.co/H97QAv).

Officers finally captured the 6-foot-4, 240-pound man and got him into an ambulance, but he was pronounced dead at a hospital. His body temperature was 105 degrees.

“Basically his temperature was too high to sustain life,” Deputy Medical Examiner Tom Van De Berg said.

The autopsy found a compound called MDPV in Nossoughi’s blood and liver.

The case is from Bangor, ME. The initial report quoted an emergency room doctor as saying at least three people in the Bangor area had died from “bath salts”. As per the DEA emergency scheduling action in September, there are at least three synthetic cathinone derivative drugs of concern:

The Administrator of the Drug Enforcement Administration (DEA) is issuing this notice of intent to temporarily schedule three synthetic cathinones under the Controlled Substances Act (CSA) pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The substances are 4-methyl-N-methylcathinone (mephedrone), 3,4- methylenedioxy-N-methylcathinone (methylone), and 3,4- methylenedioxypyrovalerone (MDPV). This action is based on a finding by the Administrator that the placement of these synthetic cathinones into schedule I of the CSA is necessary to avoid an imminent hazard to the public safety.

I had a prior post (lost in the Sb hole, reposted) discussing a bit of frustration with the conflation of two different drug molecules under one street name. Particularly when it comes to the sensationalized media reports.

This is why I’m happy the most recent report is a confirmation from the medical examiner that MDPV was involved in this case in Maine.

The state medical examiner’s office has determined that a man who took bath salts and died at Eastern Maine Medical Center last July overdosed on the synthetic street drug.

Ralph E. Willis, 32, had consumed “a toxic level” of methylenedioxypyrovalerone, or MDPV, a key ingredient of bath salts, Mark Belserene, administrator of the medical examiner’s office, said Wednesday.

I am even more happy that the journalist, Nok-Noi Ricker, requested even more information:

Willis had 150 nanograms per milliliter of MDPV in his bloodstream, a body temperature of 103 degrees and an erratic heartbeat when he got to the emergency room — all side effects of the hallucinogenic stimulant — the report states.

This is great. Usually we have to comb through a very slowly developing and erratic Case Report literature to determine anything at all about real-world, in situ, drug levels, combinations and identities that lead to medical emergency and death. Nice to see a reporter tenacious enough to do the followup beyond the original (and sadly typical) level of “Person dead, Cops say it was [insert drug name here]”.

I am also happy that the journalist includes the caveats. This guy was combative and agitated, from the reporting. So, as another quoted expert mentions, we can’t necessarily conclude that this is all down to a simple equation between plasma levels of the drug and the resulting cardiac complications.

“There are so many factors that go into [a bath salts] death that have nothing to do with the level” of drugs ingested, Karen Simone, a toxicologist and director of the Northern New England Poison Control Center in Portland, said Tuesday. “Maybe it killed him, and maybe it didn’t.”

Physically restraining bath salts users who are severely agitated and in a state of excited delirium can be harmful and even life-threatening because they usually have increased heart rates and high blood pressure, Simone and Dr. Jonnathan Busko, an emergency room doctor at Eastern Maine Medical Center in Bangor, have said.

As I have been mentioning in the case of mephedrone/4-methylmethcathinone, the academic literature has been slow to develop. There are now three pretty interesting papers which take a look at neurochemical, toxicological and behavioral effects of 4-MMC including Kehr et al 2011, Baumann et al, 2012 and Hadlock et al, 2011.

All I’ve been able to drum up* with respect to MDPV is Fuwa et al (PDF). The abstract is in English and the Figures are pretty easy to work out but…any of my readers fluent in Japanese and want to give translation a go?

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*generally available. There were two adjacent posters at the recent ACNP meeting although I couldn’t really get a feel for whether they are close to publication or not. Stay tuned, there will eventually be some more data I would think.

This originally appeared on the Scienceblogs.com version of DrugMonkey and fell into the gap when we closed up shop over there.


The New York Times had a piece up Sunday that was entitled “An Alarming New Stimulant, Legal in Many States“. I was alerted to this by David Kroll who reposted some prior comments at his Take as Directed blog. I’ve been getting some traffic from a BoingBoing linker from Maggie Koerth-Baker to an older post from me so I thought I’d better address a couple of points that jump out at me.
First and foremost, the reader should be extremely cautious whenever there is conflation of two different drugs under one purported street name. Even if they are structurally quite similar and some human reports have overlapping properties. In the case of “bath salts”, there is quite a bit of confusion over whether a news account is referring to 4-methylmethcathinone (4-MMC), methylenedioxypyrovalerone (MDPV), sees no difference between them* or doesn’t know if there is any difference.

Read the rest of this entry »

HR 1254 (pdf) has passed the House.

This Act would criminalize possession of a range of compounds which activate the endogenous cannabinoid CB1 receptor. The language covers several structural classes as well as an extended list of, e.g. the JWH-xxx compounds. In essence this is another attempt on the analog front in which the DEA is not able to move quickly enough on specific new drugs that emerge within a general neuropharmacological class.

The bill also doubles the amount of time the DEA has to generate the support for a final rule, once an emergency action has been invoked.

The House Resolution next addresses 17 compounds in the likely stimulant/empathogen class, with most of them being cathinone derivatives. Readers of this blog will be familiar with the well known 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV) on this list.

One assumes that Chuck Schumer will be leading the charge on this in the Senate and that it will pass in short order…opposition to this sort of legislation is not usually robust among elected politicians.

I have a post up over at Sb News on substituted cathinone stimulants, aka “bath salts” that discusses a Sunday New York Times piece on “bath salts”.

The short version is:

and also this.

[update: the post is now at https://drugmonkey.wordpress.com/2011/07/19/news_on_substituted_cathinone/]

Did I mention I enjoy learning more about the neurobiological and behavioral effects of recreational drugs as well as the development and treatment of addictions?

The College on Problems of Drug Dependence will be holding their annual meeting in Hollywood Florida this upcoming week. I’ve been going through the Itinerary Planner and Program Book to get a preview. There are a few presentations that touch on topics that we’ve blogged about here at the DrugMonkey blog, including

-treating the hyponatremia associated with MDMA-induced medical emergency

vaccination against drug abuse

exercise as a potential therapy for, or antidote against, stimulant drug addiction

-JWH-018 and other synthetic cannabinoid constituents of Spice/K2 and similar “incense” products

-some preclinical studies on mephedrone / 4-methylmethcathinone

-presentations from the DEA on scheduling actions that are in progress

I’m certainly looking forward to seeing a lot of interesting new data over the next week.