Virginia Hughes has a nice piece out on generational transmission of……experiences. In this case she focuses on a paper by Dias and Ressler (2014) showing that if you do fear conditioning to a novel odor in mice, the next two generations of offspring of these mice retain sensitivity to that odor.

This led me to mention that there is a story in substance abuse that has been presented at meetings in the past couple of years that is fascinating. Poking around I found out that the group of Yasmin Hurd (this Yasmin Hurd, yes) has a new paper out. I’ve been eagerly awaiting this story, to say the least.

Szutorisz H, Dinieri JA, Sweet E, Egervari G, Michaelides M, Carter JM, Ren Y, Miller ML, Blitzer RD, Hurd YL. Parental THC Exposure Leads to Compulsive Heroin-Seeking and Altered Striatal Synaptic Plasticity in the Subsequent Generation.Neuropsychopharmacology. 2014 Jan 2. doi: 10.1038/npp.2013.352. [Epub ahead of print] [PubMed, Neuropsychopharmacology]

This study was conducted with Long-Evans rats. The first step was to expose both male and female rats, during adolescence, to Δ9tetrahydrocannabinol (THC) at a dose of 1.5 mg/kg, i.p. every third day from Post Natal Day 28-49. No detectable THC was still present in the animals 16 (and 28) days later. The animals were bred at PND 64-68. Parallel Vehicle exposed rats were the comparison.

The resulting pups were fostered out to surrogate mothers in new “litters” consisting of approximately equal male/female pubs and an equal number from the THC-exposed and Vehicle-exposed parents. So this rules out any effects the adolescent THC might have on parenting behavior (that would affect the pups) and mutes any effect of littermates who are offspring of the experimental or control parents.

TransGenerationalTHCheroinThe paper shows a number of phenotypes expressed by the offspring of parents exposed to THC in adolescence. I’ve picked the one that is of greatest interest to me to show. Figure 1d from the paper depicts behavioral data for a heroin intravenous self-administration study conducted when the offspring had reached adulthood. As you can see, under Fixed-Ratio 5 (5 presses per drug infusion) the animals with parents who were exposed to THC pressed more for heroin than did the control group. They were equal in presses directed at the inactive lever and exhibited equal locomotor activity during the self-administration session. This latter shows that the drug-lever pressing was not likely due to a generalized activation or other nonspecific effect.

The paper contains some additional work- electrophysiology showing altered Long Term Depression in the dorsal striatum, differential behavior during heroin withdrawal and alterations in glutamate and dopamine-related gene expression. I’ll let you read the details for yourself.

But the implications here are stunning and much more work needs to be completed post-haste.

We’ve known for some time (centuries?) that substance abuse runs in families. The best studied case is perhaps alcoholism. The heritability of alcoholism has been established using human twin studies, family studies in which degree of relatedness is used and adoption studies. Establishing that alcoholism has a heritable component led to attempts to identify genetic variations that might confer increased risk.

The findings of Szutorisz and colleagues throws a new wrinkle into the usual human study designs. It may be possible to identify another factor- parental drug exposure- which explains additional variability in family outcomes. This would probably help to narrow the focus on the genetic variants that are important and also help to identify epigenetic mechanism that change in response to actual drug use.

On the pre-clinical research side…..wow. Is it via the male or female…or is it both? Does the specific developmental window of exposure (this was adolescent) matter? Does the specific drug matter? Is the downstream effect limited to some substances but not others? Is there a general liability for affective disorder being wrought? Does the effect continue off into subsequent generations? Can it be amped up in magnitude for the F2 generation (and onward) if the F0 and F1 generations are both exposed?

I think if this finding holds up it will help to substantially advance understanding of how An Old Family Tradition can become established. As I posted before:

In his classic song the great philosopher and student of addictive disorders, Hank Williams, Jr., blames a traditional source for increasing the probability of developing substance abuse:

….Hank why do you drink?
(Hank) why do you roll smoke?
Why must you live out the songs you wrote?
Stop and think it over
Try and put yourself in my unique position
If I get stoned and sing all night long
It’s a family tradition!

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.

Pot kills?

February 25, 2014

Apparently pot CAN kill.

 

Hartung and colleagues conclude from two Cases:

After exclusion of other causes of death we assume that the young men died from cardiovascular complications evoked by smoking cannabis….The assumption of fatal heart failure in both cases is corroborated by the acute effects of marijuana, including a marked increase in heart rate that may result in cardiac ischemia in susceptible individuals, lesser increases in cardiac output, supine blood pressure and postural hypotension….We assume the deaths of these two young men occurred due to arrhythmias evoked by smoking cannabis; however this assumption does not rule out the presence of predisposing cardiovascular factors.

h/t:

The Legislative Mandates have been issued for FY 2014.

The intent of this Notice is to provide information on the following statutory provisions that limit the use of funds on NIH grant, cooperative agreement, and contract awards for FY2014.

It contains the usual familiar stuff, of pointed interest is the prohibition against using grant funds to promote the legalization of Schedule I drugs and the one that prohibits any lobbing of the government. With respect to the Schedule I drugs issue, for a certain segment of my audience, I remind you of the critical exception:

(8) Limitation on Use of Funds for Promotion of Legalization of Controlled Substances (Section 509)
“(a) None of the funds made available in this Act may be used for any activity that promotes the legalization of any drug or other substance included in schedule I of the schedules of controlled substances established under section 202 of the Controlled Substances Act except for normal and recognized executive-congressional communications. (b)The limitation in subsection (a) shall not apply when there is significant medical evidence of a therapeutic advantage to the use of such drug or other substance or that federally sponsored clinical trials are being conducted to determine therapeutic advantage.”

I wouldn’t like to find out the hard way but I would presume this means that research into the medical benefits of marijuana, THC and/or other cannabinoid compounds are just fine. I seem to recall reading more than one paper listing NIH support that might be viewed in this light.

What I found more fascinating was a little clause that I had not previously noticed in the anti-lobbying section.

(3) Anti-Lobbying (Section 503)

(c) The prohibitions in subsections (a) and (b) shall include any activity to advocate or promote any proposed, pending or future Federal, State or local tax increase, or any proposed, pending, or future requirement or restriction on any legal consumer product, including its sale or marketing, including but not limited to the advocacy or promotion of gun control.”

there is also another stand-alone section in case you didn’t get the point:

(2) Gun Control (Section 217)
“None of the funds made available in this title may be used, in whole or in part, to advocate or promote gun control.”

I was sufficiently curious to go back through the years and found out that this language did not appear in the Notice for FY 2011 and was inserted for FY 2012. This was part of the “FY 2012 the Consolidated Appropriations Act, 2012 (Public Law 112-74) signed into law on December 23, 2011“. I didn’t bother to go back through the legislative history and try to figure out when the gun control part was added but it looks like something similar that affected the CDC appropriation was put into place in 1996.

So I guess we should have expected the anti-gun-control forces to get around to it eventually?

A reasonably provocative paper which suggests that automobile drivers are impaired at a blood alcohol concentration (BAC) as low as 0.01% has recently appeared.

Phillips DP, Sousa AL, Moshfegh RT. Official blame for drivers with very low blood alcohol content: there is no safe combination of drinking and driving.Inj Prev. 2014 Jan 7. doi: 10.1136/injuryprev-2013-040925. [Epub ahead of print][Pubmed][Publisher]

When I was first told of this finding, my initial curiosity was not so much about the findings but more about the design. It is incredibly difficult to come up with ways to compare drinking driver versus non-drinking driver stats in field studies or data mining retrospectives.

The authors drew data from US traffic fatalities1 recorded in the National Center for Health Statistics database and the Fatality Analysis Reporting System database. The study sought to test the hypothesis that driver BAC would be related to the driver being determined to be solely and officially at blame for the crash. There are numerous factors that were coded for drivers including “under the influence of alcohol, drugs or medication” and “driving on wrong side of the road”. The “under the influence…” factor was dropped from all analyses for the obvious reasons that it would contaminate their test of hypothesis.

This is important for the reader to grapple with his or her most obvious complaint about this design. If the police officer is determining the responsibility and can smell (or otherwise detect) alcohol on one driver, this puts a bias in the outcome measure (responsibility for the crash) that would tend to correlate with the thing being tested (BAC). So the authors focused on the factors that were seemingly unambiguous. Such as “running off road” or “driving wrong way on one-way” versus “unsafe speed for conditions” and other ambiguous factors that depend on a police judgement.

The authors calculated the Sole Official Blame (SOB) as the number of drivers officially and solely blamed for the crash divided by the number of drivers officially assigned no blame for the crash. They also calculated the percentage of drivers blamed solely and officially for the crash divided by the total number of drivers involved. Phillips14-traffic-F1Figure 1 from the paper presents the SOB by the BAC for both male and female drivers. The solid line is the “All Blame Factors” and the dotted line is for the unambiguous factors- the far better measure2, IMO. These data do make a case that fatal crash risk is an essentially linear function of BAC. Importantly, there is no inflection of the curve at either 0.08 or 0.1 BAC which have been the US legal limits during my driving lifetime. The error bars are 95% confidence intervals and they are using lack of overlap of the 95% CI as their inferential statistic indicating a significant difference (they also include a chi-square statistic for the 0.1 BAC vs sober bin). So far, so good. BAC is linearly correlated with the risk of being the sole and officially blamed driver for a fatal accident. [UPDATE: I didn’t originally catch a bit of a dodge the authors are pulling here. The inferential analyses are conducted on the “all blame factors. Then they state “these patterns hold when one considered all blame factors or unambiguous factors”. This “pattern” language is sometimes used to skip over the fact that the inferential analysis didn’t hold up on the other variable(s). This is a big problem, given my questions about the contamination of the blame issue if the officer knows one driver had been drinking alcohol.]

An interesting side-analysis looked at the problem that BAC is not always measured which could introduce a bias. I’m assuming that the first analysis used only verified negative BAC “sober” drivers but it is hard to find this directly stated. Anyway, they looked at the correlation on a state-by-state basis between the SOB “buzzed”, aka 0.1 BAC and SOB sober (which was 2.09 for the overall dataset), and the percent of unmeasured BACs in the fatal crash listing. The correlation was negative, showing that the lower the proportion of unmeasured BACs in a state, the larger the difference between sober and 0.1% BAC drivers in fatal crash responsibility. So if anything, I guess we have to assume that a lower percentage of blood testing results in an underestimate of the crash risk.

The authors next moved on to take a crack at the question of circumstances. In essence it addressed the question of whether people driving at 0.1% BAC are doing so under risky circumstances. At night, for example.
Phillips14-traffic-F3The third Figure from the paper depicts SOB ratio and the Percent Blamed for a subset of two-car crash pairings in which one driver was sober and the other was at a positive BAC. The beauty here is that nondriver circumstances are as identical as you can get for the sober and intoxicated drivers. The authors performed 16 chi-square tests but a quick multiple-comparisons adjustment to the listed p values shows they still survive as all of them being different, BAC vs sober, for SOB and P measures. Odds of being at fault are 60/40 for 0.1% BAC versus sober and about 80/20 by the time you reach two car crashes in which one driver was at 0.08% BAC. Interestingly this is the analysis that appears to show some categorical difference between BAC of 0.1-0.3% and BAC of 0.6-0.8%. They also did a cute little comparison of paired-crashes where one driver was at 0.08 and the other was 0.5-0.7 BAC. The SOB did not differ (95% CI overlap) in this analysis.

As a final note, a bunch of supplementary analyses were provided to try to rule in or out additional driver (sex, race), vehicle (speed and model year) and circumstantial (raining, time, location) factors. The relationship of SOB with BAC persisted.

Probably my largest question about traffic risks conferred by low levels of alcohol consumption is captured by the report of the relative effect size of the “most common driver factors” in Table 1. The “Driving too fast for conditions or in excess of the posted speed limit” factor is a large contributor to SOB ratio in the 0.1-0.7%BAC drivers as well as one of the larger differences from the sober drivers. This underlines a suspicion that those who are willing to drive after a low amount of alcohol consumed are perhaps innately different from those who are not. They might be somewhat more of a risk taker. Here, we’d really want to get at the population that is willing to drive after a drink or two and look at their driving crash risk when they are sober. Methodologically, this is asking for a lot, I realize.

This is only one study, of course. There may be other data out there that show a less continuous function of fatal crash risk to BAC in this range below the current US legal limit. But this is for sure an important study.

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1authors say that there is no sufficiently detailed database for nonfatal crashes, sady.

2Still trying to wrap my head around whether these “unambiguous” factors are in fact uncontaminated by the police officer’s knowledge that one of the drivers had been drinking. Presumably they write up their reports somewhat after they have investigated. Maybe I’m searching for rigor where none is needed but it still bugs me.

I last did this poll in 2009 on the old Sb version of the blog. My readership has changed, medical marijuana has marched on and, most importantly, two US states have finally legalized recreational use of marijuana. A comment on a recent post reminded me of this.

Grumble asked:

I’m not sure why the “how much did usage change” question would be interesting at all. Can’t we just say “of course usage will go up, duh?”

and I replied:

there is a species of denialist cannabis fan (we get them around here now and again) that insists that full legalization will do nothing to use rates. Their rationale is that pot is so easy to get that anyone who wants to smoke pot already does. I counter with the idea that they are biased by their subculture and proffer the counter example of *my* subcultures of interest in which there are tons of people for whom the only reason they do *not* smoke weed, on the odd occasion, is the legal status.

Well, what do you think?

Have at it peeps!

The ONDCP twitter account just posted a very interesting graph on past-month marijuana use rates in the 12-17 year old adolescent population.
TeenMJbyState

This dovetails very nicely with a factoid being twittered today in the #MTF2013 hashtag which is covering the release of the mid-term data from the Monitoring the Future project.

this actually surprised me. That it was so low.

Of course, one’s first suspicion is that states which are liberal enough to pass medical marijuana laws might have adolescent populations that are more likely to smoke marijuana anyway, i.e., regardless of the medical legalization. Be nice to see a workup on teen marijuana use in these states before and after they legalized medical marijuana.

Another legendary figure of substance abuse research has passed away.

Nancy K. Mello was a Professor of Psychology in the Department of Psychiatry at McLean Hospital. Her work spanned across a broad range of psychoactive and/or addictive substances with a focus on treatment medications in the recent years [PubMed].

According to the Obituary in the Boston Globe:

With her husband, Dr. Jack H. Mendelson, she cofounded the Alcohol and Drug Abuse Research Center at McLean Hospital in 1974, and they became leading researchers in the field of substance abuse.

“Their findings on loss of control and mood dysfunction as a result of drinking by alcoholics not only revolutionized scientific understanding of alcoholic drinking behavior, it also stimulated a new generation of behavioral and psychological researchers to apply experimental models to the study of alcoholism,” Dr. Roger Weiss, chief of McLean’s division of alcohol and drug abuse, said in a prepared statement.

Dr. Mello, who was director of McLean’s Alcohol and Drug Abuse Research Center and also taught at Harvard Medical School, died Monday, the hospital said. She was 78; other details, such as the cause of death, were not immediately available.

The conditional probability of dependence on a given drug is a question that is of substantial interest to users, parents of users, public policy makers and heath care providers. After all, if people simply stopped using a drug once a problem arises then many of the negative effects could be avoided. There is a fair degree of correlation between meeting diagnostic criteria for dependence and someone failing to stop using a drug despite clear and growing negative consequences. (Indeed this is one of the dependence criteria). Therefore, we must consider dependence to be a target of substantial interest.

It can be difficult to estimate the conditional probability of dependence in humans because we mostly have cross-sectional data to work with. And so we must infer conditional probability from dividing the currently dependent population by some denominator. Depending on what one uses for the denominator, this estimate can vary. Obviously you would like some population that uses the substance but what represents a level of “use” that is relevant? One time ever? Use in the past 12 months? Use in the past 30 days?

A new paper by van der Pol and colleagues uses a prospective design to provide additional data on this question.

The authors recruited 600 frequent cannabis users, aged 18-30, and assessed them for cannabis dependence at start, after 18 months and after 36 months using the:

Composite International Diagnostic Interview (CIDI) version 3.0 (Kessler and Ustun, 2004), and required the presence of three or more of seven symptoms within the 12-month period since the previous interview (without requiring the presence of all symptoms at the same time). It should be noted that the CIDI includes a withdrawal symptom, which is not included in the DSV-IV manual.

The study defined “frequent” use as 3 or more times per week for 12 months or more. This is important to remember when trying to assess the conditional probability. It all depends on what you construe as an at-risk population. Here, I’d say these were already rather confirmed cannabis fans.

The authors were interested in the very first incidence of dependence and so therefore excluded subjects who had ever met criteria, this left 269 subjects at intake (retention in the study left N=216 at 18 mo and N=199 at 36 mo). This is another point of interest to me and affects our estimation. Three or more times per week for 12 months or more and 45% of them had never previously met criteria for dependence. There are two ways to look at this. First, the fact that a lot of similarly screened users had already met criteria for dependence suggest that this remaining population was at high risk, merely waiting for the shoe to drop. Conversely it might be the case that these were the resistant individuals. The ones who were in some way buffered from the development of dependence. Can’t really tell from this design….it would be nice to see similar studies with various levels of prior cannabis use.

There were 73 cases of cannabis dependence of the 199 individuals who were followed all the way to 36 months, representing a conditional probability of transitioning to dependence of 36.7% within 3 years.

Now, of course the authors were interested in far more than the mere probability of meeting dependence criteria. They assessed a number of predictor variables to find differences between the individuals that met criteria and those that did not. Significant variables included living alone, mean number of prior cannabis use disorder symptoms, a continual smoking pattern per episode, using [also] during the daytime, using cannabis to “cope”, child abuse incidents, motor and attentional impulsivity and recent negative life events. For this latter, followup analysis identified major financial crisis and separation from someone important as driving events.

As the authors point out in the discussion, the predictors differ from those identified from a more general population. This makes sense if you consider that the range on numerous variables has been seriously restricted by their catchment criteria. The amount of cannabis exposure, for example, did not predict transition to dependence in this study–perhaps because it was well over the “necessary if not sufficient” threshold. This underlines my theme that the denominator matters a lot to our more colloquial estimates of the risks of dependence on cannabis.

Another issue identified in the discussion was the choice to start at 18 years of age for the captured population. Cannabis use frequently starts much earlier than this and many studies of epidemiology suggest that initiation of drug use in the early teens, mid teens, late teens and early twenties confers substantially different lifetime risk of dependence. “The earlier someone starts using, the more likely to become dependent” is the general findings. The authors cite a study showing that the mean age of meeting cannabis dependence criteria for the first time is 18. This is at least consistent with the fact that 65% of their collected sample had previously met criteria for dependence. No study is perfect or gives us the exact answer we are looking for, of course.

A final note on estimating the conditional probability of dependence in the population that uses cannabis 3 or more times per week for over a year. Of the original sample, 331 had already met dependence criteria and were excluded because the interest here was on the first time dependent. If we ignore those 70 people lost to followup during the study, and add the 73 to the 331 then we end up with 76% of those individuals smoking that much cannabis who have already, or will soon, meet dependence criteria.

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van der Pol P, Liebregts N, de Graaf R, Korf DJ, van den Brink W, van Laar M. Predicting the transition from frequent cannabis use to cannabis dependence: A three-year prospective study. Drug Alcohol Depend. 2013 Jul 22. pii: S0376-8716(13)00228-7. doi: 10.1016/j.drugalcdep.2013.06.009. [Epub ahead of print]. [Publisher, PubMed]

As you are aware, the National Institute on Alcohol Abuse and Alcoholism has been under the care of an Acting Director for years now as the attempt to merge the NIAAA with NIDA moved along before ultimately being axed by Francis Collins.

A Press Release today announces a new permanent Director has been appointed:

National Institutes of Health Director Francis S. Collins, M.D., Ph.D., announced today the selection of George F. Koob, Ph.D., as Director of the National Institute on Alcohol Abuse and Alcoholism. Dr. Koob is expected to join the NIH in January 2014.

“With his distinguished reputation and vision, I am confident that George will encourage innovative ideas in the basic neurobiology of addiction, and will be dedicated to bridging the gap between our understanding of alcohol abuse, alcoholism, and addiction and developing new, targeted treatments,” said Collins.

As NIAAA director, Dr. Koob will oversee the institute’s $458 million budget, which primarily funds alcohol-related research in a wide range of scientific areas including genetics, neuroscience, epidemiology, prevention, and treatment. The institute also coordinates and collaborates with other research institutes and federal programs on alcohol-related issues and national, state, and local institutions, organizations, agencies, and programs engaged in alcohol-related work.

Dr. Koob comes to the NIH from The Scripps Research Institute, California Campus, where he is Chairman, Committee on the Neurobiology of Addictive Disorders, and Director, Alcohol Research Center. He earned his Ph.D. in Behavioral Physiology at Johns Hopkins University.

Dr. Koob’s early research interests were directed at the neurobiology of emotion, with a focus on the theoretical constructs of reward and stress. His contributions have led to the understanding of the anatomical connections of emotional systems and the neurochemistry of emotional function. Dr. Koob also is one of the world’s authorities on alcohol and drug addiction. He has contributed to the understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and more recently on the neuroadaptations of these reward circuits associated with the transition to dependence.

A quick search of PubMed pulls up some 650 articles including many reviews staking out his “dark side of addiction” orientation to substance dependence.

His wikipedia page indicates that Dr. Koob is on the ISI Highly Cited list and a quick trip to Web of Knowledge shows an h-index of 123.

I think this selection by the NIH indicates a degree of seriousness in the recent RFAs and Supplements designed to advance the”functional integration” of research on alcohol and other drugs. While Koob has had a very substantial amount of work in alcohol over the past years, he has also maintained programs with psychomotor stimulants and opioids.

So any investigators* who were a little suspicious that this “functional integration” stuff was just to soothe feelings over all the wasted time, money and stress of the attempted merger have to walk that cynicism back a bit. The NIH could have easily appointed a pure alcohol type of researcher, even an alcoholism clinician. But the choice of a pre-clinical scientist who has research feet planted across many different substances of abuse sends the signal that there is meat behind the idea of integration.

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*I’ll raise my hand on that one.

There was a twitt from Dirk Hansen today

which pointed to Chen and McCarron in Current Psychiatry. This paper seems to be a set of diagnostic and therapy recommendations and contains an example Case Report.

This triggered a bunch of the usual incredulity, in this case from @drogoteca.
https://twitter.com/Drogoteca/status/394802780591771648
https://twitter.com/Drogoteca/status/394823663318351872

those two are but the tip of this person’s denialist iceberg on cannabis hyperemesis. He or she is quite convinced that this cannot be a real outcome of chronic pot smoking.

It can and is.

For background, I’ve discussed the evidence for a cyclical vomiting syndrome associated with cannabis use here, here and here. Also see Dirk’s post.

For grins I thought I’d see if there were any new Case reports and found several I had not seen before.

Hickey and colleagues (2013) report a Case of Cannabis Hyperemesis Syndrome that was treated with haloperidol:

A 34-year-old man well known to our ED arrived with epigastric pain, nausea, and vomiting for 4 days. He had been unable to tolerate anything orally but reported temporary relief only with long hot showers. He came to the ED that night to be admitted because he knew his symptoms would not improve, and he was always admitted in the past when his symptoms were so severe. He denied fevers, chills, diarrhea, hematemesis, melena, or hematochezia.

The patient’s history was significant for similar symptoms every 2 to 3 months for approximately 10 years. He reported daily cannabis use since 1992, with only short intervals of abstinence resulting in complete resolution of his vomiting. He has been admitted to our hospital from the ED 7 times and had multiple unremarkable diagnostic tests including 3 computed tomographic scans, an esophagogastroduodenoscopy, and several specialty consults. He has also been admitted to several other local hospitals for cyclical vomiting. Other than substance abuse, he has no known psychiatric history. A diagnosis of CHS was finally made in 2012, a few months before this ED arrival.

Mohammed and colleagues (2013) reported a Case (which they are at pains to point out is from the Caribbean) that resolved with abstinence.

A 26-year-old Caucasian male presented to our center with a
1-week history of severe colicky epigastric pain heralded by significant nausea for 3 weeks. He had approximately 20 episodes of bilious vomiting daily with numerous bouts of retching. He admitted to smoking 4 “joints” or marijuana cigars every day for the last 2 years, and denied alcohol and tobacco use. He had 4 similar episodes over the last 6 months. During
these admissions, he was rehydrated and abdominal imaging revealed no abnormalities. His ongoing nausea was relieved
by taking hot showers, of which he took up to 15 times per day, sometimes for more than an hour.

The diagnosis of CHS was made and he was counseled on abstinence from marijuana. Though he refused to enter a substance
abuse program, he remained cannabis-free and on follow-up at 1, 3 and 6 months revealed no recurrence in symptomatology.


Enuh and colleagues (2013)
report a case from the US.

A 47-year-old African American male with a history of epilepsy and drug addiction presented to the hospital with a seizure complicated by nausea, vomiting, and severe abdominal pain. He was known to be diabetic, hypertensive, and addicted to marijuana for 30 years. He smoked two to three “blunts” (cigar hollowed out and filled with marijuana) most days and occasionally up to eight blunts daily. The drug was last taken on the day of his admission.

He immediately went to the bathroom and remained under a hot shower with the exception of two 15-minute breaks for the rest of the day. He believed that a warm shower could relieve his nausea and vomiting. He stated that it made him feel better than medication. Intravenous ondansetron was of limited benefit. It was difficult to persuade him to exit the shower for the rounds and physical examination. Receiving medication and eating were problems because of this compulsive showering. The same event of entrenching himself in the shower had happened 2 months prior to his hospitalization for a grand mal seizure. Abstinence from marijuana during the hospital stay made the patient’s nausea, vomiting, and obsessive warm showering resolve after 3 days.

Not as satisfying as it could be with respect to the workup and the post-hospitalization followup, of course. But interesting.

Sofka and Lerfald (2013) report a series of four Cases. All had histories of chronic cannabis use, all used hot showers to alleviate symptoms and all had negative GI scans and other clinical workups. One individual was reported to have ceased cannabis use and had remained symptom free. The other three were reported as continuing their cannabis use and continuing to have symptoms. Frustratingly, the authors do not specify the followup duration for any of the cases.

Gessford and colleagues (2012) report a Case that is significant for the comment on the efforts to find a cause prior to the identification of CHS:

A 42-year-old Caucasian female, who has routinely been seen at our institution for nausea, vomiting and abdominal pain since 2003, presented with the complaint of nausea, vomiting and abdominal pain. She stated that the symptoms occurred this time after eating four bites of ice cream. …

Her physical exam was normal except for some mild epigastric tenderness which she attributed to her excessive vomiting. Laboratory studies including a comprehensive metabolic panel, amylase, lipase, and complete blood count were normal except for anemia, which had improved since her last admission. Urine studies, including urinalysis, were normal with a urine drug screen positive for delta-9-tetrohydrocannabinol (THC), benzodiazepines and opiates. Abdominal and chest x-rays were normal.

During the course of her admission, further investigation into her history revealed chronic marijuana use. She reported that long hot showers provided the only relief for her pain and nausea. She claimed that she took so many showers that her bathroom was growing excessive amounts of mold and mildew. Research into her medical records revealed an even more disturbing fact: excessive radiation exposure and medical cost. In total, she has had in excess of 97 abdominal x-rays, eight abdominal CT scans, two abdominal MRIs, an abdominal MRA, small bowel follow-through, three gastric emptying studies, four esophagogastroduodenoscopies (EGD), and three colonoscopies. Since 2003 these tests produced two abnormal findings: (1) the two most recent gastric emptying studies at 224 and 180 minutes (gastroparesis) and (2) gastritis/duodenitis on EGD. Throughout her complete sevenyear work-up, celiac sprue, peptic ulcer disease, Barrett’s esophagus, porphyrias, ischemic bowel disease, appendicitis, ulcerative colitis, Crohn’s disease and H. pylori infection have been excluded. The patient’s medical record indicated that since 2005 she has had 97 emergency room visits. Additionally, since 2007 she has had 42 admissions.

Emphasis added. This is a feature of many of the clinical Case Reports that cannot be ignored. The lack of awareness of cannabis as the causal agent is costly. In terms of the dollar costs of diagnosis and care and in terms of the drugs and invasive diagnostic procedures administered to the patient.

I don’t have access to Morris and Fisher (2013) which the Abstract states reports a single Case.

In trolling around on Google I ran across this comment in a pot user forum:

As far as symptoms are concerned, they began about 3 years ago when I would wake up feeling nauseated. Shortly after the nausea started, I’d vomit once and (after smoking) I would feel better. This continued off and on without me giving it much thought until February of this year, when I was floored by intractable vomiting for about 48 hours. I couldn’t keep anything down (not even water), and the only time I felt like I didn’t want to die was when I was in a hot shower. When the vomiting and nausea finally relented after that first episode, I chalked the experience up to acute gastroenteritis. However, about three days later, I woke up feeling nauseated. I went to work as usual, but by noon I was throwing up unstoppably again and had to go home. By the time evening came around, I could eat light food like white rice and slept. But as soon as I awoke the next morning, I had the same stomach pains and nausea. Again I went to work and again the unstoppable vomiting kicked in right around midday. The only thing that brought relief was a hot shower or bath. So long as I was under hot water, I felt alright.

This person details a history of medical workups and a bit of the recur/remit presentation before ending up with his conclusion:

At this point, I have been completely abstinent from ze herb for 5 days and I have already noticed improvement. Although I, too, was skeptical about CHS at first, I just do not know what else could be causing the problem. Although I absolutely love to get high, at my current weight/height (I am 6’1″ and 129lbs now) I am quickly running out of options. If I can’t find a solution to this problem soon, it will literally kill me. And I’ll be damned if I gonna become the first known death directly related to marijuana consumption.

Naturally, the other forum users express the usual incredulity we see from the leegalizeetmon crowd. It’s worth a read.

I also ran across this blog post from a person claiming to be an ER doc:

Since I have become aware of this association between marijuana use and CVS type presentations it has been my “good fortune” to care for nearly a dozen patients in the emergency department who self-reported diagnosis of CVS. Curiously, of these patients about 10 admitted active marijuana use, and the 2 who denied it had positive urine screenings for marijuana. This does not exactly make a case series, but is certainly another interesting observation. Of course, since the prevalence of marijuana use in our Emergency Department seems to approach 100% sometimes, this also may not be a statistically significant association!

I conclude with points I made in prior posts. At the moment, this syndrome is clearly quite rare considering estimates for chronic cannabis users worldwide. Some of this is due to lack of diagnosis..the Case Reports make very clear that an extended history of diagnostic investigation of more usual gastric disorders is typical prior to the identification of cannabis as the causal agent. But even so, very likely this is a rare reaction. Given that, it is not impossible that there is some as-yet-undetermined source of the chronic vomiting that is merely correlated with cannabis use. [In the event your imagination fails you, people tend to suggest moldy weed, herbicide/pesticide and/or contamination from smoking devices as causes.] Nevertheless, it appears to me to be likely that as we accumulate more and more Cases separated by time and place, which involve individual users with a variety of phenotypes and environmental circumstances, which present similar clinical pictures and which seem to have chronic cannabis smoking (not synthetic marijuana products, for example) as the only commonality…. well it becomes very difficult to sustain any alternative hypothesis.

__
Hickey JL, Witsil JC, Mycyk MB.Haloperidol for treatment of cannabinoid hyperemesis syndrome. Am J Emerg Med. 2013 Jun;31(6):1003.e5-6. doi: 10.1016/j.ajem.2013.02.021. Epub 2013 Apr 10. [link]

Mohammed F, Panchoo K, Bartholemew M, Maharaj D.Compulsive showering and marijuana use – the cannabis hyperemisis syndrome.Am J Case Rep. 2013 Aug 23;14:326-8. doi: 10.12659/AJCR.884001. [PMC link]

Enuh HA, Chin J, Nfonoyim J. Cannabinoid hyperemesis syndrome with extreme hydrophilia. Int J Gen Med. 2013 Aug 19;6:685-7. doi: 10.2147/IJGM.S49701. [OpenAccess link]

Sofka S, Lerfald N. Cannabinoid hyperemesis syndrome: A case series. W V Med J. 2013 May-Jun;109(3):20-3.
[link]

Gessford AK, John M, Nicholson B, Trout R. Marijuana induced hyperemesis: a case report. W V Med J. 2012 Nov-Dec;108(6):20-2. [link]

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.

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

I originally posted this Jan 09, 2008 on the old blog and reposted it 12/12/2008 with small improvements over the prior version. It has been one of my more popular posts when it comes to Google hits. You might want to check out a personal recipe for opiate based cough remedy as well.


The US Food and Drug Administration (FDA) began sending warning letters to sellers of so called “bio-identical hormone replacement therapy” today according to an AP report. Apparently the claims for alleviating menopausal symptoms are

not supported by medical evidence and are considered false and misleading.

Needless to say, these “compounded” products are being sold without FDA approval. It’s all a conspiracy man! Dang FDA is a tool of BigPharma trying to keep cheap and effective remedies from the public. Noted tool of TheMan(BigPharmaDivision) Abel Pharmboy has a recent post in which he touches on “cosmeceutical” marketing of drugs and the FDA’s authority to regulate cosmetics under

their regulatory authority is in part ordered by the Federal Food, Drug, and Cosmetic Act of 1938 (and subsequent legislation).

soothingsyrup.jpg
source
This reminds me of the glory days of the quack remedy / patent medicine era and today, from the mouldering archives, we take up a Case Report published by A. B. Hirsch, M.D. [“Mrs. Winslow’s Soothing Syrup. American Medical Journal, 1884, 12(11):504-506] which is available from Google Books here. A footnote indicates that this Abstract was read before the Philadelphia County Medical Society on Sept 17, 1884. Ahh, Mrs. Winslow’s . Used for over 60 years by mothers for their teething children.

Read the rest of this entry »

Apparently this Cory Monteith was kind of a big deal, star of a hit television show and what not. Also a drug addict.

And now dead.

His latest stint in rehab, by reports, was this April.


Vancouver Chief Coroner Lisa Lapointe said the actor had been dead for several hours when his body was discovered.

“Mr. Monteith was found deceased in his room at approximately noon today,” Lapointe said at a news conference late Saturday.

2013 in Memoriam: ‘Glee’ Star Cory Monteith Dead at 31

Acting Vancouver Police Chief Doug LePard said the evidence shows Monteith was last seen returning to his room alone late Friday night.

Although the cause of death is not yet known, police have ruled out foul play. Police said they believe he was alone when he died.

In 2008 we discussed the death of Heath Ledger and upon wondering if he was a drug addict it emerged that we weren’t supposed to discuss his addiction. I have to admit my first thought on hearing this news was…weariness. I wasn’t going to blog it. Luckily, I don’t have to, see the end of the post.

I am, however, very interested to see how much our popular consciousness has changed. Particularly since this poor guy had been open about his struggles with drug use. Is it now okay to start right in with the discussion of how his addiction to drugs led to this? Or at least to speculate? Maybe we will be okay discussing his possible affective disturbances (depression? anxiety? other?) that led to his substance use? Can we discuss this without stigma just like we might discuss Tony Soprano’s bad ticker and Angelina Jolie’s breast cancer risk factors?

I am curious.

In the mean while, there is a fantastic post up at the unlikely activist blog. It talks a little bit about why those of us scientists who are interested in topics of substance use and abuse do what we do.

Over the forthcoming days, the facts and events that led to Mr. Monteith’s death will be splashed over the pages of every newspaper in the land.

His story, however, is played out every day in small communities around this country. He is only one example of a victim of a disease that knows no bounds. The anonymous die every single day in this country because of their disease, and their plight must not be ignored.

Wealth cannot protect someone from an addiction. Neither can talent or beauty. Neither can fame.

And in many cases, even the love of family, friends and a partner cannot stop it.

And in many cases, even the best treatments we have cannot stop it.

The hope for people suffering from this disease is scientific research into the mechanisms, causes and targets of treatment for addiction. It’s why we must put as many resources as we can onto research that aims to stop the needless suffering and deaths of the famous and anonymous alike. We must combine the use of sophisticated brain imaging methods and genetic analyses in human subjects, with molecular and cellular studies in animals. It’s why we must give the victims of this illness the compassion and help they need, just like we do so for people with other preventable illnesses like cancer, HIV/AIDS and diabetes.

Go read it.

UPDATE 07/16/13: The Coroner confirms Monteith’s death due to heroin and alcohol.

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.