Archive for the 'Drug Abuse Science' category

Repost: The War on Drugs Didn't Work, Eh?

Sep 02 2014 Published by under Cannabis, Drug Abuse Science, Public Health

There's a strawman-tilting screed up over at substance.com from my current favorite anti-drug-war-warrior Maia Szalavitz. She's trying to assert that Trying to Scare Teens Away From Drugs Doesn’t Work.

In this she cites a few outcome studies of interventions that last over relatively short periods of time and address relatively small populations. I think the most truthful thing in her article is probably contained in this quote:

Another study, which used more reliable state data from the CDC’s Youth Risk Behavior Survey, concluded that “When accounting for a preexisting downward trend in meth use, effects [of the Montana Meth Project] on meth use are statistically indistinguishable from zero.”

This points out the difficulty in determining broad, population based outcomes from either personal introspection (where a lot of the suspicion about anti-drug messaging comes from, let's face it) or rather limited interventions. Our public policy goals are broad- we want to affect entire national populations...or at least state populations. In my view, we need to examine when broad national popular behavior shifted, if it did, if we want to understand how to affect it in the future.

The following originally appeared 21 July 2008.


If you are a reader of my posts on drug abuse science you will have noticed that it rarely takes long for a commenter or three to opine some version of "The (US) War on Drugs is a complete and utter failure". Similarly, while Big Eddie mostly comments on the liberty aspects (rather than the effectiveness) of the WoD himself, a commenter to his posts will usually weigh in, commenting to a similar effect.

Now I'm open to all the arguments about personal liberty trade offs, economic costs, sentencing disparities, violations of other sovereign nations and the like. Nevertheless, I'm most interested in the fundamental question of whether the War on Drugs worked. That is, to reduce drug use in the US. For those who believe it has not worked, I have a few figures I would like explained to me.

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10 responses so far

Insinuations, misdirections, straw arguments and obsfucation in drug abuse journalism

Jul 18 2014 Published by under Drug Abuse Science, Public Health

Maia Szalavitz has penned a new article on addiction that has been circulated, credulously and uncritically, on social media by people who should know better. So, once more, into the breech, Dear Reader.

The article in question is Most of Us Still Don't Get It: Addiction is a Learning Disorder is posted at substance.com.

We can start with the sub-header:

Addiction is not about our brains being "hijacked" by drugs or experiences—it's about learned patterns of behavior. Our inability to understand this leads to no end of absurdities.

From whence comes learning if not from experiences? And what is the ingestion of a psychoactive drug if not an experience? She is making no sense here. The second sentence is pure straw-man, particularly when you read the entire piece and see that her target is science, scientists and the informed public rather than the disengaged naive reader.

Academic scientists focused on drug abuse have talked about the learning aspect, of habits and of the lasting consequences of drug experiences since forever. This is not in the least little bit unknown or novel.
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13 responses so far

The most replicated finding in drug abuse science

Ok, ok, I have no actual data on this. But if I had to pick one thing in substance abuse science that has been most replicated it is this.

If you surgically implant a group of rats with intravenous catheters, hook them up to a pump which can deliver small infusions of saline adulterated with cocaine HCl and make these infusions contingent upon the rat pressing a lever...

Rats will intravenously self-administer (IVSA) cocaine.

This has been replicated ad nauseum.

If you want to pass a fairly low bar to demonstrate you can do a behavioral study with accepted relevance to drug abuse, you conduct a cocaine IVSA study [Wikipedia] in rats. Period.

And yet. There are sooooo many ways to screw it up and fail to replicate the expected finding.

Note that I say "expected finding" because we must include significant quantitative changes along with the qualitative ones.

Off the top of my head, the types of factors that can reduce your "effect" to a null effect, change the outcome to the extent even a statistically significant result isn't really the effect you are looking for, etc

  • Catheter diameter or length
  • Cocaine dose available in each infusion
  • Rate of infusion/concentration of drug
  • Sex of the rats
  • Age of rats
  • Strain of the rats
  • Vendor source (of the same nominal strain)
  • Time of day in which rats are run (not just light/dark* either)
  • Food restriction status
  • Time of last food availability
  • Pair vs single housing
  • "Enrichment" that is called-for in default guidelines for laboratory animal care and needs special exception under protocol to prevent.
  • Experimenter choice of smelly personal care products
  • Dirty/clean labcoat (I kid you not)
  • Handling of the rats on arrival from vendor
  • Fire-alarm
  • Cage-change day
  • Minor rat illness
  • Location of operant box in the room (floor vs ceiling, near door or away)
  • Ambient temperature of vivarium or test room
  • Schedule- weekends off? seven days a week?
  • Schedule- 1 hr? 2hr? 6 hr? access sessions
  • Schedule- are reinforcer deliveries contingent upon one lever press? five? does the requirement progressively increase with each successive infusion?
  • Animal loss from the study for various reasons

As you might expect, these factors interact with each other in the real world of conducting science. Some factors you can eliminate, some you have to work around and some you just have to accept as contributions to variability. Your choices depend, in many ways, on your scientific goals beyond merely establishing the IVSA of cocaine.

Up to this point I'm in seeming agreement with that anti-replication yahoo, am I not? Jason Mitchell definitely agrees with me that there are a multitude of ways to come up with a null result.

I am not agreeing with his larger point. In fact, quite the contrary.

The point I am making is that we only know this stuff because of attempts to replicate! Many of these attempts were null and/or might be viewed as a failure to replicate some study that existed prior to the discovery that Factor X was actually pretty important.

Replication attempts taught the field more about the model, which allowed investigators of diverse interests to learn more about cocaine abuse and, indeed, drug abuse generally.

The heavy lifting in discovering the variables and outcomes related to rat IVSA of cocaine took place long before I entered graduate school. Consequently, I really can't speak to whether investigators felt that their integrity was impugned when another study seemed to question their own work. I can't speak to how many "failure to replicate" studies were discussed at conferences and less formal interactions. But given what I do know about science, I am confident that there was a little bit of everything. Probably some accusations of faking data popped up now and again. Some investigators no doubt were considered generally incompetent and others were revered (sometimes unjustifiably). No doubt. Some failures to replicate were based on ignorance or incompetence...and some were valid findings which altered the way the field looked upon prior results.

Ultimately the result was a good one. The rat IVSA model of cocaine use has proved useful to understand the neurobiology of addiction.

The incremental, halting, back and forth methodological steps along the path of scientific exploration were necessary for lasting advance. Such processes continue to be necessary in many, many other aspects of science.

Replication is not an insult. It is not worthless or a-scientific.

Replication is the very lifeblood of science.

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*rats are nocturnal. check out how many studies**, including behavioral ones, are run in the light cycle of the animal.

**yes to this very day, although they are certainly less common now

22 responses so far

CPDD 2014: The XLR-11 synthetic cannabinoid is looking nastier by the day

XLR-11_structureA session on synthetic cannabinoids at the Experimental Biology meeting in April included a talk on nephrotoxicity consequent to use of synthetic cannabinoid products. I covered it in a post. As with a prior report of Cases in Wyoming, the scientist from Oregon reported being able to identify XLR-11 in two of the cases presented. There is not much available on PubMed at the moment regarding the effects of this cannabimimetic. (The XLR-11 structure at the right is courtesy of "meodipt" who submitted it to the Wikipedia page for free use.)

New data presented by Michael Gatch at the recent meeting of the College on Problems of Drug Dependence in San Juan, PR (lovely venue, btw) caught my eye because of an unusual property of XLR-11. Previously, Gatch has looked at a lengthy series of synthetic cathione ("bath salt") drugs in mouse locomotor and rat drug-discrimination assays. This new work is similar, save for the different drug class, so if you want some background reading, that prior paper would be a good complement.

The key, for me, was the drug-discrimination data. This is an assay in which animals are trained to discriminate saline from a reference drug, in this case good old Δ9Tetrahydrocannabinol (THC). In essence the rat is reinforced for responding on one lever if it has received saline just prior to the operant session and on the other lever if it has received THC. Then, on critical test days, you can substitute a dose of some other drug and determine the extent to which the rat responds on the drug-paired versus saline-paired lever. As I've mentioned before, this seems imprecise to the newcomer since seemingly any intoxicant would be scored as "drug" to a rat. Not so. They are actually highly specific in categorizing drugs of similar pharmacological activity.

The interesting thing in the presentation by Gatch was that he showed time-course with bins of about 5 minutes after the start of the session. One drug, XLR-11, popped out as having rapid onset of activity (i.e., full THC responding at 5 min when it takes maybe 10 or 15 for this to occur for THC itself) and a short duration of action (THC-lever responding disappeared after about 15 minutes). I say it popped out because out of a series of cannabimimetic drugs he presented, this one was the only one to have this profile (to my recollection).

This is interesting because in a general sense this tells me two things. First, this is the profile of a drug that is going to engender rapid on/off subjective effects and therefore very likely frequent re-dosing. From a comparative perspective this sounds like enhanced abuse liability to me...i.e., better chances of causing addiction.

The second aspect only hit me when I recalled that XLR-11 was the compound associated with nephrotoxicity. Now, admittedly, it may be the case that XLR-11 itself has a pyrolosis product produced during the smoking of plant matter containing it. But it also strikes me that this rapid on/off pharmacological profile might lead to recreational users simply using more of the products containing this compound than they ever would of products containing some longer acting synthetic cannabinoid. And that might get us back to thinking about what is contained in the various plants used in the products being sold to users.

8 responses so far

The NIH says investigators must incorporate sex-differences analyses in their studies

May 14 2014 Published by under Drug Abuse Science, NIH, NIH funding, Sex Differences

For some reason I am having a DOI error on the actual comment from Clayton and Collins. So until that is resolved, the sourcing is from the journalists who got the embargoed version.

Apparently Janine Clayton and Francis Collins have issued a commentary on a new policy that the NYT describes as:

The N.I.H. is directing scientists to perform their experiments with both female and male animals and include both sexes in sufficient numbers to see statistically significant differences. Grant reviewers will be instructed to take the sex balance of each study design into account when awarding grants.

Yeah, that sounds pretty clear. My studies just doubled...which means really that they were just cut in half. I'm cool with that. I actually agree that it would be good if we did almost everything as a sex-differences study.

There's the money though. Sex difference studies in a behaving animal are not just a doubling as it happens (and as I inaccurately described it just above). From a prior post on this topic entitled: The funding is the science II, "Why do they always drop the females?"

As nicely detailed in Isis' post, the inclusion of a sex comparison doubles the groups right off the bat but even more to the point, it requires the inclusion of various hormonal cycling considerations. This can be as simple as requiring female subjects to be assessed at multiple points of an estrous cycle. It can be considerably more complicated, often requiring gonadectomy (at various developmental timepoints) and hormonal replacement (with dose-response designs, please) including all of the appropriate control groups / observations. Novel hormonal antagonists? Whoops, the model is not "well established" and needs to be "compared to the standard gonadectomy models", LOL >sigh<.

The money and the progress.

Keep in mind, if you will, that there is always a more fundamental comparison or question at the root of the project, such as "does this drug compound ameliorate cocaine addiction?" So all the gender comparisons, designs and groups need to be multiplied against the cocaine addiction/treatment conditions. Suppose it is one of those cocaine models that requires a month or more of training per group? Who is going to run all those animals ? How many operant boxes / hours are available? and at what cost?

Oh, don't worry bench jockeys. According to the NYT article:

Researchers who work with cell cultures are also being encouraged to study cells derived from females as well as males, and to do separate analyses to tease out sex differences at the cellular level.

“Every cell has a sex,” Dr. Clayton said in a telephone interview. “Each cell is either male or female, and that genetic difference results in different biochemical processes within those cells.”

“If you don’t know that and put all of the cells together, you’re missing out, and you may also be misinterpreting your data,” Dr. Clayton added. For example, researchers recently discovered that neurons cultured from males are more susceptible to death from starvation than those from females, because differences in the ways their cells process nutrients.

"Encouraged". Okay, maybe you CultureClowns have an escape clause here. Animal model folks are facing "demanded" language.

Final observations are ridiculous:

But [the new policies] are likely to be met with resistance from scientists who fear increased costs and difficulty in performing their experiments. Studying animals of both sexes may potentially double the number required in order to get significant results.

“There’s incredible inertia among people when it comes to change, and the vast majority of people doing biological research are going to think this is a huge inconvenience,” Dr. Zucker said.

...

Margaret McCarthy, a neuroscientist at University of Maryland School of Medicine who studies sex differences, agreed. “The reactions will range from hostile — ‘You can’t make me do that’ — to ‘Oh, I don’t want to control for the estrous cycle,'” she said.

This has nothing to do with whether a scientist "wants" to or not.

Let me be clear, I want to do sex-differences studies. I am delighted that this will be a new prescription. I agree with the motivating sentiments.

What I "fear" is that grant applications will be kicked in the teeth if they include sex differences comparisons. What I "fear" is that my research programs will be even less productive on the main area of interest, to the tune of a lot of extra work that will simply confirm a lot of what we already know. For example, female rats tend to self-administer more drug than males do. A lot of my colleagues have been working on these topics for a long time. The identification of those areas where it actually matters (i.e., sex difference effects that haven't yet been detected) are going to come along with a lot of negative findings. What I "fear" is that when we are interested in a certain thing, there is a bit of sex-differences literature and the hypothesis is going to be "males and females are the same" or even "females are more/less sensitive to drug" that this is going to bring down the holy hells of reviewer wrath over what hypothesis we are testing.

I fear a lot of things about this. What I don't fear is my own interest in the topic. What I don't fear is the "inconvenience". I don't even fear "difficulty". It just isn't that difficult to add female groups to my studies.

What it takes is additional grant funding. Or tolerance on the part of P&T committees, hiring committees and grant review panels for apparently reduced progress on a scientific topic of interest. And those things are not at all easy to come by.

The funny thing is, we've been taking steps in the lab toward this direction in the past year anyway. So I should be grateful I have at least that little tiny bit of a head start on this stuff.

22 responses so far

ASPET 2014: XLR-11 synthetic cannabinoid associated with nephrotoxicity

Apr 30 2014 Published by under ASPET, Drug Abuse Science, Experimental Biology

This is an overview of a presentation in Symposium 491. Scientists versus Street Chemists: The Toxicity of Designer Marijuana Wed, Apr 30, 9:30 AM - 12:00 PM at Experimental Biology 2014.

Wed, Apr 30, 10:45 - 11:10 AM Clinical and unexplained idiosyncratic toxicity of K2 exposure by G. Buser of the Oregon Health Authority.

One potential health consequence of the use of synthetic cannabinoids is acute kidney injury (AKI) or nephrotoxicity. There have been Case Reports published and there are more cases described in the MMWR report of the US CDC.

Buser indicated that in Oregon the index case for her agency's attention was a 17 yo male who reported to the emergency department where he was found to have abnormal kidney function. He had been smoking a synthetic cannabis product. With such a finding, there are a number of questions: Is it a contaminant? Possibly a toxic solvent used to prepare the product? Toxic constituents of the plant material used for a given product? A hot spot in the product that resulted in an unusually high dose?

This thinking triggered an investigation around the state of OR, in which medical facilities, officers and other public health authorities were queried for cases of unexplained nephrotoxicity in young adults. Buser identified several additional cases in which it appeared from case histories that the smoking of synthetic cannabis products were involved. The author then attempted to secure the clinical course, case histories and any clinical samples collected.

She ended up with 9 cases collected between May-Oct 2012, all male with a median age of 18. Due to the variability in the cases, the onset from last smoking to symptoms was 2 weeks to 30 minutes although Buser cautioned that the case histories derived from friend or the user might not be that reliable.

Affected individuals (also see the above links) tend to suffer from nausea, vomiting and abdominal/flank/back pain. Buser said that in the OR cases, the individuals tended to wait anywhere from 12 hrs to a day after the start of their symptoms, thinking that it would resolve by itself.

The cases typically featured abnormal clinical chemistry (BUN, serum creatinine), proteinuria and kidney biopsies were found to confirm both acute tubular nephritis and interstitial nephritis.

The study interviewed 6 of 9 cases, all were habitual marijuana smokers, had obtained their synthetic cannabis over the counter from convenience stores or head shops and they reported 5 different product brand names. The team was able to secure 2 of the products for testing.

One of the more frustrating issues for a study like this is that the patients reported to Emergency services of some sort a long time after last exposure to synthetic cannabis. So there is a good deal of uncertainty about being able to detect any of the known agents. Nevertheless, one invidual was positive for (1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl) methanone (XLR-11). No other known cannabimimetics were found. This individual happened to be one (of the two) for whom they were able to secure and analyze a sample of the product he had used. It was also positive for XLR-11.

XLR-11 was found in four of the five product samples and four of six patient's specimens in the WY report as well.

It appears to be the case that no other cannabimimetic compounds have been reported in association with acute kidney injury. Obviously, the data are thin and in many cases of AKI, there are no analyses of the product and timing may be such that clinical sample would be negative anyway.

Still, there is enough of a smoking gun here to recommend some preclinical studies on the nephrotoxic effects of XLR-11, as mentioned by Buser.

Buser ended up by observing that in three of the cases there were other people smoking the same product with the affected individual. It was speculated that perhaps there was a hot spot, perhaps those individuals smoked more or perhaps they had an individul liability. With respect to the latter, she noted that two brother pairs were represented in the affected sample. This might point to shared genetic liability for these adverse effects of XLR-11 consumption.

One major takeaway from the presentation is that a specific synthetic cannabinoid might have specific risks for kidney injury. A second major takeaway is that we know far too little about this phenomenon, both from a mechanistic perspective and an epidemiological one. Efforts from public health officials such as Buser can enhance awareness and therefore detection of human cases.

3 responses so far

Experimental Biology 2014: Transgenerational effects of stimulant drugs

This is a summary of a presentation in Symposium 222. Molecular Basis of Addiction: Neurocognitive Deficits and Memory Mon, Apr 28, 9:55 AM - 12:10 PM at the 2014 Experimental Biology meeting.

Mon, Apr 28, 10:25 - 10:40 AM Amphetamine exposure during development causes epigenetic trans-generational changes in drug sensitivity in Caenorhabditis elegant. Authors: Talus McCowan, Bryan Safratowich, Joyce Ohm, Lucia Carvelli

McCowen* presented a study which showed transgenerational effects of amphetamine in a C. elegans model.

Caenorhabditis elegans is a nematode about 1 mm long which has the dubious virtue of having 302 neurons of which a mere 8 are dopaminergic. This makes for a tractable model, particularly when you think you might want to model the entire nervous system.

The model involved Swimming Induced Paralysis (SWIP) which can be induced in a liquid medium by treating the worm with amphetamine. This is a time and dose dependent phenomenon which has been shown to depend on the dopamine transporter and D2/3-like dopamine receptors. Classic targets of the amphetamines.

The study exposed eggs to 500 uM amphetamine or control media for 15 hours. After maturation of the worms, they were subjected to the SWIP test in which it was found that the egg-exposed animals had an enhanced freezing response. In this case it was an increased percentage of the worms freezing in the context of a moderate dose, selected to give parametric range on either side. The authors then examined the F1 generation of worms, which had received no drug treatment up until the SWIP challenge. here it was found that the F1 offspring of the F0 worms exposed to amphetamine during development also had an enhanced response to amphetamine.

The lab is interested in methylation of histones as an epigenetic mechanism that might possibly convey this effect. They found decreases of histone H3 Lys4 trimethylation (H3K4me3) in the F1 offspring of amphetamine incubated worms compared with the offspring of control worms. This was selective as there was no difference in H3K27me3 expression.

Obviously this is just a start, one would think that the advantage of the worm is that you could go out for generations quite readily, in comparison with rodents (see below). So presumably this story will advance by the time we see it in publication. Nevertheless, this joins a growing appreciation of the transgenerational effects of drug. While there are many caveats in translating this to humans, it certainly puts a bright spotlight on familial abuse patterns and our potential targets for explaining them.
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Related: Heritability of Substance Abuse Meets Epigenetics?

*The speaker identified himself as a first year graduate student. I think he did a bang up job of the presentation and of handling the questions.

4 responses so far

Will a dual sigma receptor antagonist / dopamine transporter inhibitor treat stimulant abuse?

This post covers a platform presentation in symposium 222. Molecular Basis of Addiction: Neurocognitive Deficits and Memory (Mon, Apr 28, 9:55 AM - 12:10 PM) at the 2014 Experimental Biology meeting.

803.3/D382 - Preclinical efficacy of the dual sigma receptor antagonist dopamine uptake inhibitor, CM699, as a medication for stimulant abuse

Johnathan Katz of the NIDA Intramural Research program presented an overview of the data and findings that led up to the creation of a new molecule (CM699) that functions a both a dopamine transporter (DAT) inhibitor and a sigma receptor antagonist. As a bit of background, NIDA has spent a tremendous amount of effort trying to use dopamine transporter inhibitors as agonist therapy for stimulant abuse. The theory of agonist therapy is familiar from the nicotine patch and methadone. The outline is that if you have a drug which mimics the abused drug in effect but has different time-course of effect, you may be able to blunt the acute high of the preferred drug and/or method of use. The nicotine patch supplies the identical drug but in a more sustained, slower and less-peaky manner. Methadone is relatively long acting at endogenous opioid receptors, apparently providing relief without the acute euphoric high. A similar strategy has governed attempts to identify compounds which would confer protection against stimulant abuse.

Since the acute reinforcing effect of stimulants such as cocaine and methamphetamine is mediated through the DAT, this was the target of considerable NIDA effort over decades. It has not been a successful effort.

First off, Katz pointed out that calling sigma a "receptor" is bit of a misnomer as it functions as an intracelluar chaperone protein. This molecule hangs out in association with the endoplasmic reticulum but under ligand activation can migrate to modulate the function of membrane bound proteins. One of those is apparently the dopamine transporter.

Another background consideration for the presentation is that cocaine, as Katz noted, blocks the DAT but also has some sigma affinity. The significance of this agonist activity was not made entirely clear in the talk and we should keep in mind that any antagonism of the sigma receptor will also likely remove the sigma-mediated effects of cocaine. This part was not well explicated in the talk.

At any rate, sigma antagonist compounds block the effects of cocaine. Katz described data indicating that the acute locomotor stimulant effect of cocaine can be prevented and that sigma antagonists can attenuate lethality from an otherwise toxic dose of cocaine.

An initial study from Remi Martin-Fardon, however, found that one sigma antagonist (BD1047) did not reduce cocaine self-administration. Katz then tested several additional sigma antagonists to rigorously determine that no, sigma antagonist compounds by themselves did not reduce cocaine self-administration, even cross a wide range of cocaine doses.

Katz next presented data to remind us that the DAT inhibitor methylphenidate (aka Ritalin) not only fails to reduce cocaine self-administration but that it can increase the self-administration of lower per-infusion doses of cocaine.

However, the combination of methylphenidate with any of several sigma antagonists produced an "insurmountable antagonism" of cocaine self-administration. Meaning that across a wide range of per-infusion doses of cocaine, the rats now failed to self-administer. Importantly, these combinations had no effect on food maintained operant responding, no effect on self administration of opioids or direct dopamine D1 or D2 like receptor agonists but did work to suppress methamphetamine self-administration. This indicates the effect is specific to DAT mediated reinforcing effects.

This all led up to the creation of a compound (CM699) that had the ability to both antagonize sigma receptors and to inhibit the DAT. It was found to blunt the dopamine response to acute cocaine, as measured with intracerebral microdialysis. Furthermore, this single compound produced the "insurmountable antagonism" of cocaine self-administration that had been found for the two-drug combinations.

The talk ended with a proposal that the mechanism of action is that sigma antagonism depletes cholesterol from the membrane which promotes an inward-facing conformation of the DAT.

Obviously, Katz is optimistic that this combined-action CM699 compound proves the concept for a stimulant abuse treatment medication. The half-life of this particular compound was only about 4 and a half hours, thus their immediate goal is to get a longer acting compound which both antagonizes sigma and blocks the dopamine transporter. Nevertheless, the chance that it can completely remove the rewarding properties of cocaine supports the idea that combined activity at DAT and sigma is the route to effective agonist therapy for stimulant abuse.

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ASPET 2014: Vaccinating against the effects of nicotine

Apr 27 2014 Published by under Drug Abuse Science, Nicotine

This platform presentation was in symposium 166. New Preclinical and Clinical Perspectives for Smoking Cessation on Sun, Apr 27, 3:00 - 5:30 PM at the 2014 Experimental Biology meeting.

R. I. Desai (University website, PubMed) presented new results from a study of a vaccine designed to attenuate the effects of nicotine.

I previously discussed the principles involved in anti-cocaine vaccination, and NIDA has generated this handy video explainer on the basic principle of vaccination against drugs of abuse

Desai noted at the outset that there have been four anti-nicotine vaccines developed by drug companies with some of them advancing to Phase II or even Phase III trials. As he remarked, they have all been viewed as failures. Nevertheless it is the case that some of the failures have been due to insufficient antibody titer having been produced in a relatively large proportion of the subjects. Thus, it may be that the principle is still sound but that the vaccines need to be improved in terms of generating more consistent, high antibody titers.

This study used the SEL-068 nano particle vaccine described here in abstract form. Although Desai did not hammer home the point in his presentation, one presumes that this new nanoparticle vaccine is hypothesized to generate higher antibody levels in animals.

This particular study used the drug discrimination procedure (see here for description) to evaluate the interoceptive stimulus or subjective properties of nicotine in squirrel monkeys. The animals were trained to discriminate nicotine from saline pretreatment with a stimulus-termination procedure; one lever was correct when nicotine had been administered and the other lever was correct when saline had been administered. Control animals learned the discrimination well within 30 sessions and some evidence of learning could be observed as early as 3-4 sessions of training.

The control animals received vaccination only after the nicotine/saline discrimination had been learned. The training drug was changed to epibatidine ( a nicotine acetylcholine receptor agonist, i.e., similar to nicotine in pharmacological action) during the vaccination to avoid complicating interpretation of the discrimination behavior. After a few weeks of the vaccination treatment, discrimination for epibatidine was high, however the animals were now unable to discriminate the original training dose of nicotine. A follow-up nicotine dose-substitution challenge showed that only a minor rightward shift of the dose-response function had been produced. A slightly higher dose of nicotine engendered over 80% responding on the lever associated with epibatidine (and previously nicotine).

The effect of vaccination could be overcome by slight increases in the dose, at least in animals previously experienced with nicotine.

Interestingly, the animals that were vaccinated prior to the start of any discrimination training did not learn the nicotine discrimination. Over about 30 training sessions, there was no selective responding on the nicotine paired lever when nicotine had been administered. This indicates that the subjective feeling of the training dose of nicotine had been attenuated to the point where it wasn't reliably different from vehicle exposure.

The research team then went on to train the vaccinated group to discriminate epibatidine from saline. In this case, the discrimination was established with about the same time course as was seen for nicotine in the non-vaccinated group. It is structurally different, thus antibodies specific to nicotine that were generated by the vaccine would not be expected to recognize epibatidine. This part of the study shows that the vaccinated animals would still be able to form a discriminative set based on the activity of receptors through which a major part of nicotine's action is conferred.

One of the most interesting outcomes of this study was that the learning of a discrimination based on nicotine could be blocked by vaccination. This tends to suggest that the most effective clinical target will be to vaccinate children before they have any experience with nicotine.

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also see Would you vaccinate against drug abuse?

6 responses so far

Hyperemesis associated with synthetic cannabinoid products

Mar 07 2014 Published by under Cannabis, Drug Abuse Science

As you know, Dear Reader, a cyclical vomiting syndrome is often associated with chronic cannabis smoking. I've written about it a few more times (here, here, here) and you can check out additional posts at Addiction Inbox (here, here). I urge you to read through the comments posted under all of these blog entries. The numbers definitely rival the published Case Reports in number of affected individuals. Clearly there continues to be many folks suffering who go initially undiagnosed.

A Reader sent me a link to a medical diagnosis challenge published in the Well section of the New York Times recently which returned my interest to the topic. Mostly due to the following comment in the solution column:

Sure enough, there it was – two recent case reports describing several regular synthetic marijuana users who developed a syndrome that was indistinguishable from cannabinoid hyperemesis caused by the real stuff.

I had not seen any such reports so I went looking and found one of them on PubMed.

Hopkins CY, Gilchrist BL. A case of cannabinoid hyperemesis syndrome caused by synthetic cannabinoids. J Emerg Med. 2013 Oct;45(4):544-6. doi: 10.1016/j.jemermed.2012.11.034. Epub 2013 Jul 26.

By now, the diagnosis sounds very familiar. A 30 year old man presented at the ED with nausea and vomiting. He reported a prior history of such episodes, including gastro-enterology workups, scans, endoscopies, etc. Nothing that would explain his symptoms was ever found. The patient had found that hot showers relieved his pain and took several showers per day.

Naturally the patient had started using cannabis at the age of 13 and had been smoking several times per day for years.

Up until this point, everything is very familiar.

This particular individual had been cannabis free for 6 months due to legal surveillance under parole. After cleverly determining with over-the-counter tests that synthetic marijuana products (brand names of K2 and Spice were popular early in the cycle and have come to be familiar as semi-generic terms) didn't trigger cannabinoid positives:

...he quickly resumed his daily smoking habits and in the month before presentation was often smoking synthetic marijuana hourly, including waking up several times at night to get high.

The patient claimed that in the 2 months prior to presentation he'd been using "Scooby Snacks (sic)*" brand exclusively and provided some to the research team. This is cool because the team identified the cannabinoids in the product. It contained several, "JWH-018, JWH-073, JWH-122, AM-
2201, and AM-694" and they also found the patient's urine to be positive for JWH-018, JWH-073 and AM-2201.

As a bit of a sidebar, I really don't know why particular combinations are included in various synthetic cannabis products. It is unclear if it is accident of supply, illicit manufacturers who just throw stuff together at random, the end of the batches or something more intentional. There is an interesting paper from the Fantegrossi group (Brents et al, 2013) that suggests the possibility of synergistic effects.

Returning to the case report, on three month followup it was found the patient manged to remain abstinent and reported remission of his symptoms after the first 2 weeks.

Okay, so typical story for cannabinoid hyperemesis syndrome and in this case the patient had been exposed to multiple cannabinoid full agonists instead of delta-9-tetrahydrocannabinol prior to current episode. Of course his history suggests strongly that it was cannabis smoking that created his liability for the episodes in the first place.

One take-away message over the past several years is that we've rapidly gone from a point where nobody knows cannabis can cause a vomiting syndrome to some reasonable awareness. This is fantastic. The greater awareness, the greater the chances of rapid and accurate diagnosis. If you read the case reports you will see extensive and expensive gastrointestinal testing and diagnostic work in the history of many individual patients. Realization on the part of the patients that they should mention their cannabis smoking helps. Realization on the part of medical staff that they should ask about cannabis helps.

Knowledge can be a powerful bit of assistance for health care.

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*more likely Scooby Snax?

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