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 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.

https://twitter.com/NIDAnews/status/413317559824297984

this actually surprised me. That it was so low.

https://twitter.com/drugmonkeyblog/status/413359694183276544

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.

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]

There was a twitt from Dirk Hansen today

https://twitter.com/Dirk57/status/394802566179352576

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.

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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]

Driving test

February 24, 2013

This is from a bit by David Frum:

20121221-074922.jpg

Per this article, the question of private employers dealing with off-hours behavior deemed legal by the State.

Gee… If we only had some way to determine if users of marijuana are likely to be vocationally impaired. If only there were some way to get that information. So that we could come up with some guidelines. And do things based on reasonable approximations of fact rather than agenda based random reaction (on either side).

Wouldn’t that be useful?

What? What’s that you say?

“Science”?

The recent fax (yes, they still call it this despite it arriving via email attachment) from CESAR (Vol 21, Issue 40; October 09, 2012) puts us back on an occasional theme of this blog.
They have adapted data from the latest update from SAMHSA’s National Household Survey on Drug Abuse. This figure shows the number of past year users of selected illicit/recreational drugs.
Interestingly, marijuana use continues to trend up from the approximate plateau of 2002-2007, while use of cocaine is trending downward. Even the nonmedical use of prescription drugs (which has been a big problem overdose-wise) is relatively flat. Rounding slightly, we’re looking at some 30 million past year users of marijuana compared with 4 million past year users of cocaine.

So why is this interesting? Well, as we’ve covered in the past the notion of conditional probability of dependence is a key issue for parents and policy makers and yet we have really poor estimates on that. Direct studies are usually limited in scope and the big-scale epidemiological stuff is too imprecise- i.e., rarely are there good diagnostics of dependence. So we sometimes have to infer things based on, e.g., daily use rates versus annual rates. Something like that. Fortunately the more precise studies and the broader interpretive efforts tend to agree.

Roughly speaking the conditional probability of alcohol dependence is on the order of 4%, for cannabis on the order of 8-10% and for stimulants, including cocaine, on the order of 15%.

So, applying these rough estimates to the past-year data above, we end up with something on the order of 600,000 dependent on cocaine and 2,400,000 dependent on marijuana. If you dropped the estimate of conditional probability for marijuana to the 4% of alcohol, you still end up with 1.2M people dependent on marijuana.

My point, as always, is that the definition and scope of a “drug dependence problem” is going to depend on frame of reference. One important frame of reference in my view is the number of people who are affected. This, btw, is why we think of alcohol dependence as such a huge problem even though just about every estimate suggests the conditional probability of dependence is one of the lowest. Because the percentage of the entire population exposed to alcohol on a regular basis is so large, the number of people who are dependent is relatively large.

A paper in the October issue of the Journal of Psychopharmacology will be of interest to my readership. It looks at the consequences of exposure to an exogenous cannabinoid agonist

Byrnes JJ, Johnson NL, Schenk ME, Byrnes EM. Cannabinoid exposure in adolescent female rats induces transgenerational effects on morphine conditioned place preference in male offspring.J Psychopharmacol October 2012 26: 1348-1354, first published on April 19, 2012 doi:10.1177/0269881112443745 [ PubMed ]

In this study the authors exposed 23 day old (adolescent) female Sprague-Dawley rats to a three day, twice per day regimen of WIN 55,212-2 which is a full agonist at the CB1 receptor. The more familiar exogenous cannabinoid, Δ9-tetrahydrocannabinol (THC) is a partial agonist at the same site. The authors waited until the animals were adult (60 days), bred them and then examined the subsequent male off-spring of these mothers. They assay of interest was the Conditioned Place Preference test which is one common method to assess subjective drug liking in rats and mice.

The idea is to take a chamber which is divided into two or there sections by dividers and doors (in this case it was a three-chamber apparatus). The chambers are differentiated by salient stimuli such as the floor texture or type, wall stripes (horizontal vs vertical), etc. You let the subject explore at will in pre-conditioning baseline studies. Then, you conduct a series of conditioning sessions in which the animal is injected with a drug and then confined in one of the chambers. On other sessions the animal is injected with the drug vehicle only and confined to the other chamber. In this case, there were three active drug and saline conditioning sessions. Finally, on a later test day the animal is allowed once again to freely explore all of the chambers. The amount of time it spends in each chamber is recorded and the relative preference for the drug-paired chamber over the saline-paired chamber can be expressed, typically as a difference in amount of time, or the percentage of the total time, spent exploring the drug-paired chamber.

The figure presents Conditioned Place Preference data for the adult male offspring (WIN-F1) of mothers which were exposed to WIN 55,212-2 in adolescence and in the control group (VEH-F1) of adult male offspring of mothers treated twice a day for three days with the drug vehicle. There were three different place conditioning levels with groups of animals from the VEH and WIN treated dams place conditioned (in adulthood) with saline, 1 or 5 mg/kg of morphine. As expected, the chamber preferences of animals “conditioned” with vehicle were indistinguishable, i.e., they spent approximately equal time in each chamber. Animals conditioned with morphine, however, spent more time in the drug-paired chamber than in the vehicle-paired chamber.

Interestingly, there was a group difference which depended on the maternal treatment. The offspring of the WIN treated mothers appeared more sensitive to the rewarding effects of morphine because they expressed a conditioned place preference after 1 mg/kg training, unlike the adult offspring of VEH exposed dams. Although I’m not showing it here, the study also looked at adolescent male offspring and found a similar enhancement of morphine place-preference conditioning in the offspring of WIN exposed dams.

The translational take-away is pretty clear and fairly frightening. It suggests that one of the reasons for familial patterns of substance abuse may not simply be down to genetic legacy but may have something to do with drug exposures of the mother.

Just as our most fervent defender of pot posted the most scientifically offensive clause in the legalization initiative defeated by California voters:

5. Cannabis has fewer harmful effects than either alcohol or cigarettes, which are both legal for adult consumption. Cannabis is not physically addictive, does not have long term toxic effects on the body, and does not cause its consumers to become violent.[DM- policy statement, false, false, distraction]

a comment on an older post returned our attention to the cannabis hyperemesis syndrome.

The past year I started smoking a lot more than ever before.
I’m 21, and every single morning I wake up with the worst upset stomach. It gets all the way to the point where I’m running to the bathroom to throw up and nothing ever comes out. The doctors think its in my head. Awesome. When this first began happening I would just make myself throw up but once I began it wouldn’t stop for hours and I had to be taken to the emergency room. I feel like I’m dying!! But of course I feel completely better when I go smoke. It’s insane!

So I trotted over to PubMed to see what is new, if anything, with cannabis hyperemesis. I found three new CaseReport publications that I had not seen before including:

Nicolson SE, Denysenko L, Mulcare JL, Vito JP, Chabon B. Cannabinoid hyperemesis syndrome: a case series and review of previous reports. Psychosomatics. 2012 May;53(3):212-9. Epub 2012 Apr 4. PubMed

Luther V, Yap L.A hot bath to calm what ails you: the Cannabis Hyperemesis Syndrome. Acute Med. 2012;11(1):23-4. PubMed

Bagdure S, Smalligan RD, Sharifi H, Khandheria B. Waning effect of compulsive bathing in cannabinoid hyperemesis.Am J Addict. 2012 Mar-Apr;21(2):184-5. doi: 10.1111/j.1521-0391.2011.00209.x. Epub 2012 Feb 7. PubMed

There are a total of 6 individuals reported (20-27 yrs of age, 2 female), all of whom presented to medical services (New York, 4; London, 1; Amarillo, TX, 1) with repeated and severe vomiting. All Cases had been smoking marijuana for many years with at least daily smoking in recent months to years. Five of the cases identify multiple uses per day, the sixth just indicates daily smoking.

Medical workups for all six indicated no other detectable gastrointestinal causes. All six Cases include multiple episodes of repeated vomiting in the past which had resulted in emergency department visits or hospitalizations for that patient.

All six had been using hot showers to control their symptoms, selected quotes from different Cases are illustrative:

he persistently demanded to use our showering facilities…He continued to demand to use the showering facilities, and oddly seemed more settled after bathing.

Several times during the interview, he went to the bathroom to put his head under the hot shower, which he said improved his

Ms. B complained that the hospital showers were not warm enough because the best way to relieve her symptoms was to take extremely hot, hour-long showers four times daily.

Three of the cases have evidence that ceasing marijuana smoking prevented further episodes of cyclical vomiting. Three show evidence that returning to marijuana smoking after abstinence led to recurrence of symptoms. Two cases had no followup evidence.

As this evidence starts to accumulate, we need to remember one thing about the Case Reports which is that there is a severe publication/selection bias in this sort of thing. Physicians’ motivations to publish are not like ours and what strikes one group of physicians to bother to publish a Report is entirely opaque to me. It is, however, likely only the tip of the iceberg. As a second caution, it may also be the case that their is a bias for the publication of “clean” Cases. For only bothering when the individual Case seems to fit this growing profile to a T. Thus, it may make things about this syndrome appear more clear cut, more severe, etc. This goes both ways but one thing I would be concerned about are those Cases that are indeed caused by chronic cannabis use but are not diagnosed because they don’t seem to fit the Case Report literature.

Perhaps hot bathing/showers are not always involved? Perhaps the use history is not as severe as it was for this most recent set of six cases? Perhaps there are some cases in which marginal gastro-intestinal concerns have interacted with a lesser degree of chronic cannabis smoking to push an individual over the threshold to cyclic vomiting symptoms?

There is always the unknown factor. People have proposed unknown toxins in the past…contamination of the cannabis being used. Still not impossible, especially given the apparent rarity of the syndrome. But, I would argue, as the cases occur across time and geography this becomes less likely. You would think that contamination might surround particular drug supplies (in time and space) in a way that might turn up as a geographic patient cluster.

For now, however, the evidence is reasonably strong and it is most certainly growing. Obviously, I think it is well past time for scientists with models that are relevant to emesis to get cranking and start up some studies. Unfortunately rats don’t vomit so it is going to require some specialized animal models, perhaps the ferret.

From here we learn that WA voters are to consider Initiative 502 which would legalize marijuana. For recreational purposes.

Seems to be the same deal as the initiative that failed to pass muster with voters in our dope smokingist, weed growingist and reputably most individual “thing” friendly state of California.

Perhaps the good folks of WA will see it differently.

In my estimation the hook for this (tax money to balance the state budget) poses the same Catch22 which hung the proposition in Cali. Dope smokers don’t like the idea of Marlboro Green becoming the only provider. They fear “regulation and taxation” means corporate profits and no more home growing. Or perhaps that corporatizing and commodifying the product would leave them in a situation similar to the beer industry in the US before microbrews came roaring back. whichever way it went, I think it was a segment of *dope fans*, ironically enough, that doomed the California effort.

It will be interesting to see if the WA folks who like the kinde learn from the prior example and line up in support. (and can be bothered to vote, naturally)

Dirk Hanson‘s post on cannabis hyperemesis garnered another pertinent user comment:

Anonymous said…

My son suffers from this cannabinoid hyperemesis. At this moment he is here at my home on the couch suffering. I have been up with him for 3 days with the vomiting and hot baths. He says this time its over for good. This is our third bout. The first two time we went to ER, they put him on a drip to hydrate him, and gave him some pain medicine and nausea medicine. After a few hours he went home and recovered. This time we went to Urgent Care, put him on a drip, pain med, Benadryl, and Zofran. He felt better. That was yesterday, today we are right back with the nausea, but the Zofran limits the vomiting. I’m hoping tomorrow will be much better. He hasn’t eaten for 3 days. He let me take a video of him at Urgent Care before treatment, and in the video he was heaving and begging himself with tears never to smoke again. My son has smoked for 14 years.

I reviewed several case reports back in 2010. The comment thread was robust (this was originally posted at the Sb version of the blog) and there was considerable skepticism that the case report data was convincing. So I thought I’d do a PubMed search for cannabis hyperemesis and see if any additional case reports have been published. There seem to be at least 17 new items in Pubmed since the Soriano-Co et al 2010 that I referenced in the update.

One in particular struck my eye. Simonetto and colleagues (2012) performed a records review at the Mayo Clinic. They found 98 cases of unexplained, cyclic vomiting which appeared to match the cannabis hyperemesis profile out of 1571 patients with unexplained vomiting and at least some record of prior cannabis use. The profile/diagnosis was created from the prior Case Report literature that I reviewed but unfortunately I can’t get access to this paper to tell you more.

The other thing to think about is the relative increase in case reports in the past year or two. As I think I commented at the time, this is typical of relatively rare and inexplicable health phenomena. The Case Reports originally trickle out…this makes the medical establishment more aware and so they may reconsider their prior stance vis a vis so-called “psychogenic” causes. A few more doctors may obtain a much better cannabis use history then they otherwise would have done. More cases turn up. More Case Reports are published. etc. It’s a recursive process.

I think we’re seeing this at work.

And as more cases emerge, separated in time and space, the denialist position of blaming a contaminated cannabis product (or bad bongs) gets harder and harder to sustain.

The Monitoring the Future study has added the synthetic marijuana products (see here, here, here for additional) to their annual survey. Data on annual use rates are now available for the 12th grader segment. I have taken the liberty of graphing the annual use rates for a selection of the more common drugs in this 2011 dataset.
What you can see (click on the graph to see a bigger version) is that these products are more popular than a host of drugs that have a considerably longer history. These packets of plant material spritzed with one or more full endocannabinoid CB1 receptor agonists (see dr leigh here, here for details) only really appeared on the US market in 2010 in broad availability.

Not too shabby to already be beating these other drugs, eh?

Unfortunately the full monographs aren’t available yet and the update tables for “lifetime” and “30 day” do not appear to include the synthetic marijuana category yet. Nevertheless, it’s a good thing that this drug category has been added to the survey. As we go forward it will be interesting to see if popularity continues or if this was a brief flash in the pan related to broad quasi-licit availability of these products.

These data will also provide a nice comparison to more limited investigations such as this one. Hu et al (2011) report 8% cannabimimetic use in a sample of 852 college students collected in September of 2010.
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The Annual Prevalence table is here.

MtF 2011 update page

To the Maximus Foundation (@FakeWeed)

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