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:

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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.

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

The Daily Mail:

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

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

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

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

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

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

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

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

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

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

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

next we have this whopper:

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

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

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

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

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

Nevertheless.

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

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

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

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

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

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

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 »

A new blog on drug toxicology has recently appeared and I think some of my Readers will want to bookmark The Dose Makes The Poison.

What is it about? Well, the Intro post indicates:

So, a long time ago in a land far, far away, a brilliant scientist named Paracelsus (who is considered by many a toxicologist throughout time, to be the ‘Father of Toxicology’) wrote:

“Alle Dinge sind Gift, und nichts ist ohn Gift; allein die Dosis macht, dass ein Ding kein Gift ist.”

Trudat! A few more posts have appeared already….

….TV Shows Aren’t The Real World

Even though it doesn’t really make sense, I still want this mass spec! The sample that was analyzed was gastric contents of a decedent. It identifies “chicken stock”, coffee, and cocoa!


Analogue or not an analogue: that is the question!

Currently, cases involving the determination of a controlled substance analogue involve dueling chemists, toxicologists and pharmacologist as there is no consensus in the scientific community regarding what exactly is a controlled substance analogue. Typically, the prosecuting attorneys will have consultation and testimony from the DEA chemists or toxicologists/pharmacologists while the defense will have consultation and testimony from chemists and toxicologists/pharmacologists from other entities. The decision boils down to opinion vs. opinion.

A discussion on the Twitts today returned me to this old post. I can’t believe I’ve never reposted it.

This was originally published on the ScienceBlogs.com version of the blog on 2/292008.

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I have a tendency to refer to data from the Monitoring the Future study with some frequency. Unfortunately I’ve been too lazy to post the critical data figures for your entertainment. Until today DearReader.
One example of which I am particularly fond, is what I call the “Len Bias effect” on the public perception of “risk” associated with casual use of cocaine. I refer to this so often because of the casual sneering response I (and others of my approximate generation) retain for the “Just Say No” program championed by Nancy Reagan in the mid-80s. The MtF data suggest to me at any rate that our “gut feeling” that these types of programs are stupid should be more nuanced.

Read the rest of this entry »

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

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

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

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

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

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

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

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

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

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