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 To make this change, NIDA has withdrawn PA-14-104, PA-14-105, PA-14-106, and has reposted these announcements as PAR-14-106, PAR-14-105, and PAR-14-104.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.