DrugMonkey

Visit Blog Website

20 posts · 18,498 views

Peer-reviewed work under discussion includes topics related to substance abuse, neuropharmacology and cognitive neuroscience.

DrugMonkey
20 posts

Sort by: Latest Post, Most Popular

View by: Condensed, Full

  • May 15, 2012
  • 11:25 AM
  • 72 views

Methylone, or beta-keto-MDMA, also causes fatality

by DrugMonkey in DrugMonkey

A series of 3 Cases of fatality wherein methylone consumption was found causal by the Medical Examiner... Read more »

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. info:/

  • August 19, 2011
  • 03:36 PM
  • 490 views

Racial Disparity in NIH Grants: Priority Scores

by DrugMonkey in DrugMonkey

Unless you have been hiding under a rock, my NIH-focused Reader, you will have heard of the explosive findings of Ginther et al (2011) who reported on an analysis of racial and ethnic disparity in the review and funding of NIH grant applications.

There is a lot to discuss about these findings. A LOT. Well beyond the scope of one or even six blog posts. Commentary from the Office of Extramural Research, the NIMH and the Chronicle of Higher Education are worthwhile reads and there is a bit on National Public Radio as well. Blogger Bashir suggests* that these data prove that if you are African-American you have to be twice as good to succeed.

I'm going to jump right into some grant review geekery. I'm sure you are shocked.
These data are graphed from Table S1 and represented as percentages. I was interested in this Table, and motivated to re-graph the raw number, because of a curiosity about qualitative outcome. In my view the qualitative breakdown for scores is "likely fundable", "could be picked up by Program" and "triaged". These are moving targets across fiscal years, different study sections (the paper did not evaluate the percentile ranks used for funding decisions) and different Institutes or Centers of the NIH (which could have different score/pay relationships). Nevertheless, 100-150 maps reasonably well onto "fundable" and 151-200 onto the grey zone in which Program could possibly make a funding exception.

As a reminder, the old scoring system of the NIH (in place during the 2000-2006 interval used for the paper) went from 100 (best possible score) to 500 (worst possible score). Streamlining ("triage") procedures that were in place meant that approximately half of the applications were not discussed at the study section meeting (based on the preliminary evaluation of the three assigned reviewers) and did not receive a panel-voted score ("Unscored" on the graph). In theory this meant that scores above about 250 should be rare. However, any proposal could be pulled up for discussion if any member of the panel wanted to do so, therefore there might be some initially poor-scoring proposals that received a correspondingly poor voted score. In addition, proposals that seemed initially promising might have flaws revealed during the discussion that drove their score down well past the putative line for initial streamlining.

Black applications are more likely to be triaged and less likely to be placed in the first two best-scoring bins. The disparity even continues into the "no way fundable" zone of 201-250. I'm interested in this because one hypothesis might be that when it comes to that last little push into the obviously-fundable territory, black applicants are not being favored. That might predict a boost in the just-missed-score bins. Not so. There really is a disproportionate triage burden here.

Supplementary Figure S1 provides pretty decent evidence that there is no disparity in funding outcome for a given priority score- so the decisions Program staff make to pick up a gray zone application (or, rarely, to pass over a highly scoring application) do not appear to play a role in the overall disparity effect.

I am also struck by this summary of the findings on grant submitting behavior:
On average, investigators had three to four Type 1 R01 grant applications each. We found that blacks and Asians resubmitted more times before being awarded an R01 (2.01, P

Together, these data indicate that black and Asian investigators are less likely to be awarded an R01 on the first or second attempt, blacks and Hispanics are less likely to resubmit a revised application, and black investigators that do resubmit have to do so more often to receive an award.

Emphasis added. You will recognize these as topics dear to my default advice to submit a lot of proposals, to revise and resubmit and generally to make friends with the process. I've occasionally had to smack down old school outdated advice to not revise triaged or even fairly poorly-scoring apps that were discussed.

You will also recall that at the same time I advise people to make use of the process as it stands, I complain that this default get-in-line-noob stuff puts a higher burden on the younger investigators. Maybe it places a similar burden on African-American applicants in some systematic way. Perhaps because of their job places and a lack of local support for spending a lot of time on a low-percentage behavior like grant submitting. Or maybe because there is a linear function of how much revising you have to do and your eventual learned-helplessness response of stopping swimming.

Perhaps this just points at the grantsmithing parts of how to effectively respond to criticism. Maybe African-American scientists are less likely to have good grant mentoring effectively available to them (no matter the type of employment location, remember they controlled for that).

Well, those are my thoughts for the day. This is a big issue that should be a big wake up to the NIH. I do hope this is not a mere flash in the pan that gets ignored. Likewise, I do hope we are not discussing the same disparity 5 or 10 years in the future and similarly wringing our hands.
__
Ginther, D., Schaffer, W., Schnell, J., Masimore, B., Liu, F., Haak, L., & Kington, R. (2011). Race, Ethnicity, and NIH Research Awards Science, 333 (6045), 1015-1019 DOI: 10.1126/science.1196783

*I hope the NIH is listening. If I am not mistaken this is coming from a postdoc who identifies on blog as African-American. Regardless of the outcome of upcoming analyses and pilot investigations mentioned by Tabak and Collins, there is going to be a HUGE perception problem. The NIH needs to take this just as seriously as resolving whatever obstacles and biases have resulted in the grant award disparity. ... Read more »

Ginther, D., Schaffer, W., Schnell, J., Masimore, B., Liu, F., Haak, L., & Kington, R. (2011) Race, Ethnicity, and NIH Research Awards. Science, 333(6045), 1015-1019. DOI: 10.1126/science.1196783  

  • August 18, 2011
  • 02:47 PM
  • 472 views

Active metabolites of JWH-018 may contribute to effects of K2/Spice, etc.

by DrugMonkey in DrugMonkey

A recent paper from Brents et al. (PubMed) presents the data that we've been hearing about for the past several months. I think leigh of the Neurodynamics blog (see posts on THC and cannabimimetic/JWH-018 pharmacology), may have been the first to report seeing these data at a meeting and then I ran across them at CPDD this past June.

As many of you are fully aware by now, the past couple years has witnessed the emergence of broad popular use of "synthetic marijuana" or cannabimimetic products. They have been retailed widely as small (usually 3g) packets of various plant materials sprayed with a growing list of synthetic drugs which all seem to have full agonist properties at the endocannabinoid 1 receptor subtype (CB1). A series created by J. W. Huffman have been commonly reported, thus you will see reference to the compounds themselves, JWH-018, JWH-073, JWH-081, etc. Public health concern has been expressed given that these products can cause dependence similar to that of delta9-THC, are involved in acute-intoxication traummatic incidents and are reported in online forums (see comment threads to the linked blog posts for example) to a lot of weird and scary (for cannabis-experienced users) subjective effects. Abel Pharmboy and I have found the web search traffic to our first posts on K2/Spice, JWH-018, etc to be unrelenting. The DEA took action, placing five of the more commonly identified synthetic cannabinoids on Schedule I, making the products containing them illegal to sell in the headshops, cigar shops and convenience stores that had been providing these products.

Brents and colleagues have examined the pharmacological properties of 6 metabolites of JWH-018 that have previously been reported to occur in the urine of users in "appreciable amounts". To quickly overview, many recreational and therapeutic drugs (not to mention a host of other exogenous compounds that you ingest) are broken down in the body prior to elimination in urine or feces. They are metabolically altered from the parent drug to one or more metabolites which may have pharmacological activity similar to the parent drug, activity that differs from the parent drug or be essentially inactive. Understanding the effects of a drug, therefore, often can be enhanced by determining whether any metabolites are pharmacologically active.

Figure 2This figure from the paper shows the ability of several compounds to displace radiolabeled CP-55,940 (a selective CB1 ligand, i.e., it binds to these receptors) using mouse brain membranes. The Ki values are the lowest concentrations of the test compounds which displace the radiolabeled CP compound. The unlabeled CP is the most effective, achieving displacement at the lowest concentration. JWH-018 competes for the receptor at a lower concentration than does THC, which has been previously reported. The interesting thing here is that three metabolites of JWH-018 are approximately equal to THC and two are even more effective.

The paper also reports the effects of the M1 metabolite in vivo. Back before the endocannabinoid receptors were identified around the early 90s there was no direct pharmacological way to determine if a novel compound was likely to be similar to THC. So behavioral pharmacologists (primarily Billy Martin, Jenny Wiley and colleagues at VCU) came up with the Tetrad Test of likely cannabinoid action. These four items were catalepsy, analgesia, hypomotility and hypothermia. The Brents paper reports on two of these effects in mice.

Figure 4

Figure 5

These figures show that THC, JWH-018 and the M1 metabolite all reduce locomotor activity and body temperature in the mouse. More importantly, pretreatment with the antagonist AM-251 reverses these effects, providing evidence that it is a selective pharmacological activity at the CB1 receptor.

All in all a nice demonstration that at least one, and likely several, of the metabolites of JWH-018 that have been identified in human users are active. They have pharmacological properties similar to the parent compound and therefore may contribute to the overall effects of the drug.

This means that the next steps will be to determine the distribution and elimination of the metabolites. If they don't get past the blood-brain barrier very well or are very rapidly eliminated from circulation the effects may be unimportant, however some metabolites may last in circulation much longer than the parent. In this latter case, inferences based on the pharmacokinetics of JWH-018 would be an underestimate.

Since there are a host of synthetic cannabinoid compounds being reported in retail products, it will be interesting to see if those result in active metabolites as well.
__
Brents LK, Reichard EE, Zimmerman SM, Moran JH, Fantegrossi WE, & Prather PL (2011). Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity. PloS one, 6 (7) PMID: 21755008... Read more »

Brents LK, Reichard EE, Zimmerman SM, Moran JH, Fantegrossi WE, & Prather PL. (2011) Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity. PloS one, 6(7). PMID: 21755008  

  • June 7, 2011
  • 06:57 PM
  • 569 views

Do epidemiological data on exercise and substance abuse support prescriptions for prevention?

by DrugMonkey in DrugMonkey

A Twitt from the Foundation for Alcohol Research (@AlcoholResearch) today struck my attention. It sounded to me like the usual slippery slope of creating human health prescriptions from limited scientific findings.
Teen athletes may drink more, but smoke less & use fewer drugs. How do you lessen your teen's risk? http://bit.ly/mysWna

The link is to their newsletter which overviews a paper by Terry-McElrath and O'Malley, currently in pre-print at Addiction. The overview is pretty straightforward, based closely on the paper and eschews the problem with the Twitt, which was the question as to whether you could "lessen your teen's risk". So I am mostly mollified.

The paper in question reports data from a survey of over 11,000 US high school seniors (classes of 1986-2001), captured as seniors and then followed longitudinally until age 26. These data were collected as part of the Monitoring the Future study which we discuss quite frequently on this blog.

The key focus of this paper is on the amount of physical activity the surveyed HS seniors reported at first contact. The Participation in Sports, Athletics or Exercising (PSAE) measure was derived:
...by asking, "How often do you actively participate in sports, athletics or exercising" (1=never, 2=a few times a year, 3=once or twice a month, 4=at least once a week, 5=almost every day). The other questions of interest to this analysis were the ones relating to past-30-day use of various recreational drugs. This is a part of the MtF dataset that we have discussed now and again. I like it better than the past-12-month and Lifetime measures because it gets us away from the population who has just sampled a drug once or twice and biases it more for those who use the substance occasionally-to-often, for lack of a better concept.

The drug analysis used frequency of use for marijuana/cannabis, alcohol and tobacco smoking. Other illicit drugs other than marijuana were combined into a single dichotomous variable because they occur at a much lower frequency.

There is a lot of correlational statistical foofraw involved in something like this, I'll omit the details for this purpose. At the end of the selected study window (with the sample aged 26 with 4 followup surveys attempted), the authors ended up with a sample of 40,424 individuals.

The key results were that
-alcohol use at 18 was positively associated with PSAE (see below for a clue as to why)
-rate of change in alcohol and PSAE from 18-22 did not co-vary, there was a positive relationship from 22-26 years of age.
-increasing PSAE values from 18 to 25 were associated with decreased cigarette use.
-increasing PSAE values from 18-22 were associated with decreased marijuana and illicit drugs other than marijuana but there was no relationship from 22 to 26.

Another paper from this group took a related focus and provides some additional valuable context. Terry-McElrath, O'Malley and Johnston examined PSAE and drug use just within the middle- to high-school population (8th, 10th, 12th grades). It doesn't get at the question of lasting impact but it is perhaps more relevant to the question of acute intervention during the teen years and what can/cannot be accomplished. These analyses took into account participation in school-centered athletics separately from a more global estimation of exercise/physical activity and found that the frequency of exercise was related to decreased past-30-day and binge alcohol use in high school. In contrast, increasing athletic team participation was associated with increased alcohol use. A similar relationship held for smokeless tobacco use. The exercise and athletic team participation frequency measures were both negatively associated with tobacco and marijuana smoking.

This latter paper really brings to a fine point the prescriptive query in the motivating Twitt. If you push your teen onto a sports team, these data suggest that s/he will be more likely to drink alcohol and use smokeless tobacco products. If you push your kid into less team oriented endeavors, the more they work out, the less likely they are to use cigarettes, marijuana or alcohol.

That's the best read. But of course we know, in the back of our minds, that these are just correlations in both of these papers. There are a whole host of factors which influence sports / team / exercise participation in high school and then additional ones as one grows into young adult hood. There are other factors which may influence how seriously a given teen takes their participation in team sports, which team sport they select and how much exercise it requires, etc. For all we know, there is nothing there in the nature of a direct neurobiological connection between increased activity and decreased drug use/liking whatsoever.

Perhaps the factors which cause your kid to work out also cause her to disdain drugs? [personal anecdote: two major factors kept me from ever trying marijuana in adolescence- one of which was my assumption that the smoking part would be detrimental to my performance in the aerobic sporting endeavors that was in to at the time.]

This brings me to two additional papers which have the benefit of removing the social and other extraneous factors. In a paper that was reviewed by Scicurious at Neurotic Physiology awhile ago, Cosgrove and colleagues gave rats access to a running wheel until they were "stable" (not specified). They next permitted the rats to self-administer cocaine. The key manipulation was when they presented the rats with the simultaneous opportunity to respond for drug or run on the wheel. The amount of cocaine taken dropped significantly (in females, similar but nonsignificant outcome in males). Almost there. Smith and colleagues nailed it down even better. They allowed female rats access to a running wheel for 6 weeks and then trained them to self-administer cocaine. This was a between-groups study (unlike Cosgrove et al) and they showed that the exercised rats took less cocaine (two different per-infusion doses under a Progressive Ratio schedule) than did the sedentary rats.

These, in combination with the epidemiological data, are the start of something. Together they start to get us closer to something like an ability to make a prescriptive decision that if we make our teens exercise more we may have an impact on their propensity to use recreational drugs.
__
Terry-McElrath YM, & O'Malley PM (2011). Substance Use and Exercise Participation Among Young Adults: Parallel Trajectories in a National Cohort-Sequential Study. Addiction (Abingdon, England) PMID: 21561496
also see

Terry-McElrath YM, O'Malley PM, & Johnston LD (2011). Exercise and substance use among American youth, 1991-2009. American journal of preventive medicine, 40 (5), 530-40 PMID: 21496752... Read more »

Terry-McElrath YM, & O'Malley PM. (2011) Substance Use and Exercise Participation Among Young Adults: Parallel Trajectories in a National Cohort-Sequential Study. Addiction (Abingdon, England). PMID: 21561496  

Terry-McElrath YM, O'Malley PM, & Johnston LD. (2011) Exercise and substance use among American youth, 1991-2009. American journal of preventive medicine, 40(5), 530-40. PMID: 21496752  

  • April 29, 2011
  • 02:53 PM
  • 650 views

On discovering new medicines

by DrugMonkey in DrugMonkey

A link from writedit pointed me to a review of drugs that were approved in the US with an eye to how they were identified. Swinney and Anthony (2011) identified 259 agents that were approved by the US FDA between 1999 and 2008. They then identified 75 which were "first in class", i.e., not just [...]... Read more »

Swinney, D., & Anthony, J. (2011) How were new medicines discovered?. Nature Reviews Drug Discovery, 10(7), 507-519. DOI: 10.1038/nrd3480  

  • February 23, 2011
  • 05:28 PM
  • 992 views

R.I.P. Charles Robert Schuster, Ph.D.

by DrugMonkey in DrugMonkey

An towering figure of the substance abuse research fields has passed away. According to a note posted to an ASPET mailing list, Charles Robert Schuster, Ph.D. suffered a fatal stroke on Feb 21 in Houston Texas. NIDA Director Nora Volkow has also posted a notice to the NIDA-grantees mailing list.

The CPDD biography of Dr. Schuster is a brief overview of his career.
After six years in the Department of Pharmacology at the University of Michigan, he joined the Departments of Psychiatry, Pharmacology, and Behavioral Sciences and founded the University of Chicago´s Drug Abuse Research Center. In 1986, Dr. Schuster was appointed the Director of the National Institute on Drug Abuse, a position he held until 1992. In January of 1995, Dr. Schuster was appointed as a Professor in the Department of Psychiatry and Behavioral Neurosciences at Wayne State School of Medicine and the Director of the Substance Abuse Research Division.

One of the most fundamental and lasting advances of Dr. Schuster was the development of the self-administration model of drug reinforcement. Bob Schuster was one of the first to demonstrate that animals would work to receive intravenous infusions of drug and he was a major player in several of the initial observations on the reinforcing properties of recreational drugs through the 1960s and 1970s.

James R. Weeks published in 1962 that female rats would press a lever to receive intravenous infusions of morphine. Schuster and his colleagues were the first to adapt this method to nonhuman primates, getting started at approximately the same time as Weeks (there are references to Abstract presentations from Weeks as early as 1960 or 1961).
Clark, Schuster and Brady (1961) implanted two rhesus monkeys with internal jugular vein catheters and demonstrated that the monkeys would press a telegraph key for saline infusions. Furthermore, the provision of drinking water to the animals decreased the amount the monkeys would press the key, suggesting that this behavior was sensitive to "drive" (this term for motivation was popular then). The authors quite naturally speculated that this model would be useful for "experimental analysis of the reinforcing properties of many pharmacologic agents". Was it ever...

Thompson and Schuster (1964) reported that rhesus monkeys would work for intravenous infusions of morphine. This report references a "Technical Report" of their own dated July of 1962, for priority purposes one assumes :-). In the first experiment, three male rhesus monkeys were made dependent on morphine by means of four daily injections (7 mg morphine sulfate per kg bodyweight ) for 30 days. Thereafter, the monkeys were trained on a Fixed Interval-Fixed Ratio chained schedule in which they first had to complete an FI2min (first response after 2 min) to produce a stimulus light during which a FR25 (25th response completed ratio) was in place to obtain a morphine infusion. In this experiment the per-reinforcer dose available every 6 hrs (7 mg/kg) was the same as that used to induce dependence. The experimenters then showed that 24 hr discontinuation (after establishing stable responding) resulted in an increased response rate during the FI and decreased latency to complete the FR when drug was again available. Likewise, pretreatment with the opiate antagonist nalorphine also increased FI responding and speeded completion of the FR. Finally, a pre-session injection of morphine decreased the behavioral output for self-administered morphine as a function of the pre-session morphine dose. In short, they had provided the necessary demonstration that monkeys would "work for drug", showing that it functioned as a reinforcer in the classical operant behavioral paradigm.

This work had a lasting and substantial influence on the course of laboratory research on the reinforcing properties of drugs, as well as the brain mechanisms (structural, chemical, physiological) that were involved in reward and reinforcement. Drug mediated or otherwise. A PubMed search for "(rhesus OR macaque OR saimiri) AND (self-injection OR self-administration)" pulls up 769 references which can all be attributed to the methodological and experimental work of Dr. Schuster in the early 1960s. Many of these papers are authored by Dr. Schuster and his immediate colleagues and trainees. Unfortunately the Neurotree entry for Charles Schuster is woefully underpopulated. I was hoping to give you a sense of the degree to which he is the scientific father, grandfather and likely great-grandfather of so many people who have made seminal observations in substance abuse. Perhaps the field will be encouraged to complete this tree as a tribute to his professional life.

Dr. Volkow's email referenced one of Dr. Schuster's findings that anticipated, by at least a decade, a novel approach to therapy for drug abuse. I mentioned vaccination for cocaine abuse here and here. In the latter post I mentioned an attempt in the late 1970s to generate immunizations against opiate dependence. Yes, this was the work of Dr. Schuster. Bonese and colleagues (1974) trained a rhesus monkey to self-administer heroin or cocaine (on alternate days). Following immunization with a conjugate vaccine that produced antibodies capable of binding morphine, the monkey self-administered the same amount of cocaine as before, but wouldn't work for heroin. Increasing the per-infusion dose in steps, it was found that a 16-fold increase in per-infusion dose was required to restore self-administration. The animal thereafter reached an intake level of drug in the 2 hour session that was about 10-fold higher than the pre-immunization baseline. These studies anticipated a series of cocaine-vaccination studies in rats in the early 1990s that has then generated a more or less continual body of research into vaccines for cocaine, nicotine and methamphetamine abuse/dependence. Clinical trials are ongoing for cocaine and nicotine vaccines.

These are but two of the methodological and scientific veins that owe their origins in large part to the efforts of Dr. Schuster. There are his many, many trainees and academic descendants who are perhaps an equally important part of his legacy. I have not even touched upon his tenure as the Director of NIDA with the concomitant influence he had upon drug-abuse science in that role.

Suffice it to say that Dr. Schuster contributed greatly during his professional lifetime to our understanding of substance use, abuse and dependence. For that we are grateful and we celebrate the contributions of this scientist.

__
Clark, R., Schuster, C., & Brady, J. (1961). Instrumental Conditioning of Jugular Self-Infusion in the Rhesus Monkey Science, 133 (3467), 1829-1830 DOI: 10.1126/science.133.3467.1829

THOMPSON T, & SCHUSTER CR (1964). MORPHINE SELF-ADMINISTRATION, FOOD-REINFORCED, AND AVOIDANCE BEHAVIORS IN RHESUS MONKEYS. Psychopharmacologia, 5, 87-94 PMID: 14137126

... Read more »

Clark, R., Schuster, C., & Brady, J. (1961) Instrumental Conditioning of Jugular Self-Infusion in the Rhesus Monkey. Science, 133(3467), 1829-1830. DOI: 10.1126/science.133.3467.1829  

THOMPSON T, & SCHUSTER CR. (1964) MORPHINE SELF-ADMINISTRATION, FOOD-REINFORCED, AND AVOIDANCE BEHAVIORS IN RHESUS MONKEYS. Psychopharmacologia, 87-94. PMID: 14137126  

Bonese KF, Wainer BH, Fitch FW, Rothberg RM, & Schuster CR. (1974) Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature, 252(5485), 708-10. PMID: 4474602  

  • September 30, 2010
  • 07:33 PM
  • 1,230 views

Recreational Mephedrone Brief (09/30/10)

by DrugMonkey in DrugMonkey

Mephedrone, or 4-methylmethcathinone, is a recreational drug that got very popular in the UK in recent years, no doubt due to it being legal to sell and possess up until April of this year. There is not a tremendous amount known about the pharmacology of this drug at present, however we can deduce quite a [...]... Read more »

Sammler EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, & O'Riordan JI. (2010) A harmless high?. Lancet, 376(9742), 742. PMID: 20801405  

  • September 19, 2010
  • 12:59 PM
  • 1,259 views

Mephedrone (4-Methylmethcathinone) appearing in "Ecstasy" in the Netherlands

by DrugMonkey in DrugMonkey

A crash in the MDMA market filled by 4-MMC?... Read more »

Brunt TM, Poortman A, Niesink RJ, & van den Brink W. (2010) Instability of the ecstasy market and a new kid on the block: mephedrone. Journal of psychopharmacology (Oxford, England). PMID: 20826554  

  • August 18, 2010
  • 02:46 PM
  • 1,236 views

Recreational Mephedrone Brief (8/18/10)

by DrugMonkey in DrugMonkey

sourceThe recreational drug 4-methylmethcathinone (4-MMC; aka mephedrone, MMCAT) was legal in the UK up until mid April of this year. I had previously covered the only work in a behaving animal model that I could find, a paper using drug-discrimination techniques to evaluate the discriminative stimulus (aka, subjective) properties of several cathinone derivative compounds (but [...]... Read more »

Torrance H, & Cooper G. (2010) The detection of mephedrone (4-methylmethcathinone) in 4 fatalities in Scotland. Forensic science international. PMID: 20685050  

  • July 23, 2010
  • 11:55 PM
  • 730 views

MDMA for PTSD: The first peer-reviewed clinical trial report

by DrugMonkey in DrugMonkey

My readers will recall that I have blogged now and again about ongoing efforts to get 3,4-methylenedioxymethamphetamine (MDMA), the psychoactive compound preferentially sought as Ecstasy in recreational users, approved as a medication to be used in psychotherapy. The initial attempts have focused on the treatment of Post-Traumatic Stress Disorder. PTSD is a seriously debilitating condition and we may not have sufficient resources and knowledge to deal with, e.g., an anticipated uptick due to the current wars that the US is prosecuting.

I introduced the MDMA/PTSD Phase I clinical trials here, noting
The short version of the theory is that the subjective properties of MDMA (empathic, inhibition lowering, etc) are consistent with helping people in difficult psychotherapeutic situations (such as for post-traumatic stress disorder (PTSD) and, supposedly, end stage cancer anxiety) make therapeutic breakthroughs during a limited number of treatment sessions of talk therapy. This is not proposed as a chronic medication like a selective serotonin reuptake inhibitor (SSRI). The funny thing is, I approve of the concept of moving forward with clinical trials based on the available evidence.

Why not? I mean PTSD can be a very devastating psychological issue and if there are treatment-resistant cases that can benefit from a limited number of MDMA exposures, great.

I concluded that particular post with this observation.
As is general practice in medicine, sometimes there are going to be risks associated with therapy. Sometimes quite substantial risks can be acceptable if the alternative is bad. However we get ourselves into a world of trouble, sometimes even losing a perfectly helpful medication, if we are not as honest as possible, up front, over the actual risks. My subsequent attentions have been lavished upon what I see as a lack of recognition/admission of potential risk factors associated with intake of MDMA, particularly in context of the trend for pushing the doses ever upward as the clinical trials continue.

I have also been critical of what I saw as rather half-baked mechanistic theorizing for how MDMA might produce a therapeutic effect. After all, if this is neurobiologically real there should be a mechanistic explanation for why this drug is so special. How is it better than an antidepressant or stimulant? Or a traditional hallucinogen for that matter? MDMA shares pharmacological properties will all these drug classes, albeit in its own unique constellation of pharmacocomplexity.

In other posts I've covered issues related to drawing inferences about likely human outcomes from the doses used in animal studies here andhere. These observations follow on from an earlier discussion of how we should view the doses of MDMA being used in the context of the likely range of human subjects-from an average sized adult woman to a large male warfighter.


There was aready an interesting preview of the study to be found in a non-peer reviewed protocol made available by the research team. It is nice, however, to finally see the peer-reviewed article by Mithoefer and colleagues appear in the Journal of Psychopharmacology. This study is described in the Introduction as being a "pilot Phase II" trial. This means we are not merely looking at the safety and useful dose range (as with a Phase I trial) but are interested in efficacy. Does the proposed medication actually work? This is a "pilot" I suppose because traditionally 20-30 subjects would be a Phase I trial and a Phase II really expects more like 100 or more.

The authors do speculate on the potential mechanism of action in the Introduction but it is unsatisfying, as with that prior paper. Yes, the indirect serotonin agonist properties are linked to the subjective properties- properties that seem to include empathy, openness to others, lack of fear, etc. A perfectly reasonable-sounding psychodynamic effect, no doubt, but then what is so special about MDMA? They speculate on the oxytocin enhancement that is a downstream effect of serotonin release and about fear conditioning circuitry of the ventromedial PFC and amygdala. Again, I'm not seeing why MDMA is so special.

The design of this study examined 20 PTSD patients who met SDM-IV-R criteria for crime- or war-related Post-Traumatic Stress Disorder and had a Clinician Administered PTSD Scale (CAPS) score of 50 or greater (moderate to severe symptoms). In addition, patients had to have had a minimum prior course of 6 mo of psychotherapy and 3 mo of treatment with either a Selective Serotonin Reuptake Inhibitor (SSRI; e.g., prozac) or Selective Norepinephrine Reuptake Inhibitor (SNRI) compound. Individuals visited the clinic on at six occasions- a baseline evaluation, two experimental therapy sessions, followup evaluation visits 3-5 days after each therapy session and a final evaluation 2 months later.

Twelve patients (10 F) were assigned to MDMA-treatment (125 mg initial dose; 4 rec'd 62.5 mg supplemental dose 2-2.5 hrs later) and 8 (7 F) to inactive placebo treatment conditions. The average age was about 40 years and all subjects were described as Caucasian. There was only a single individual whose index trauma was combat stress (assigned to MDMA) and the majority were sexual assault and childhood sexual or physical abuse.

Figure3: Time 1: less than 4 weeks
before first experimental session;
Time 2: 3-5 days after first experimental
session; Time 3: 3-5 days after second
experimental session; Time 4: 2 months
after second experimental sessionAs depicted in Figure 3 from the article, the CAPS scores declined in both groups, however to a much greater extent in the MDMA-assigned group. Main effects of Time and Treatment Group, as well as the interaction, were reported in the statistical analysis.

So yes, this study shows efficacy of MDMA treatment in the course of a structured psychotherapeutic session for PTSD.

In terms of major limitations to this study, the first has to do with blinding of the treatment condition. I don't really wish to go into expectancy, confidence in the efficacy of the therapeutic modality (ala E. Fuller Torrey), placebo effects and all that. Suffice it to say that for the highest confidence we would wish for successful blinding. It failed utterly in this study, perhaps unsurprisingly. The therapists identified the treatment condition for all subjects and 19/20 of the patients correctly identified the condition they were in. Not blinded in the least. This does not make the study useless, it just puts an additional consideration into our interpretation.

A second moderate limitation is that the subjects were treatment resistant and had previously been on SSRI medications. Since these chronic treatments induce some degree of plasticity of the serotonergic system, and a major effect of MDMA is on serotonin systems and indeed the Reuptake mechanism for which SSRIs are named, well, there are some things to think about. Throw in the original lack of response to SSRI and one wonders about the pre-therapy state of these patients' serotonergic function relative to those who respond to SSRI therapy. Not a huge knock on this early stage study of course. I mean, if you are going to get a recreational drug with known neurotoxic and acute toxicity risk approved as adjunct it is going to have to beat existing medications in some way. Starting with the population that remains untreated despite the best current therapy is an obvious place to start. Still, from a neuropharmacological standpoint it makes this study le... Read more »

Mithoefer MC, Wagner MT, Mithoefer AT, Jerome I, & Doblin R. (2010) The safety and efficacy of { /-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England). PMID: 20643699  

  • April 16, 2010
  • 04:58 PM
  • 963 views

Don't t-a-a-a-a-a-a-aze me bro!

by DrugMonkey in DrugMonkey

sourceA report in Popular Science (authored by Jeremy Hsu) points to a recent paper published in Academic Emergency Medicine. In this, Dawes and colleagues report on an investigation on the effects of TASER on sheep intoxicated with methamphetamine (MA). I was alerted to this by Damn Good Technician who wanted a little bit of context for what would seem to be a WTF? kind of study.

The study was conducted in Dorset sheep who were anesthetized, and administered 0, 0.5, 1.0 or 1.5 mg/kg of methamphetamine HCl (curiously from dissolved Desoxyn, the approved pharmaceutical product) in an IV infusion. The drug treatment was a between subjects factor (N=4 per group) and animals were monitored for "continuous blood pressure, heart rhythm (one-lead), pulse oximetry, and capnography... Arterial blood sampling was performed at baseline, 30 minutes after the administration of the methamphetamine, and after each exposure from a TASER X26".

To answer the question of why?, and for appropriate background on the science try a PubMed search for "cardiac TASER". I note a study in which 5 sec of TASER didn't cause cardiac damage or symptoms in law enforcement trainees and another showing minimal cardiac effects on law enforcement volunteers after vigorous exercise. Also of interest are the case studies of atrial fibrillation in a previously healthy adolescent and recovery of a teen in TASER induced asystole. These, a mini-review by the Dawes group and other searched papers should give you some context and support from the feeling you might have from half-remembered MSM reports over the years that TASER is suspected of being somewhat less than "safe".

What I'm not finding right away is very much about the drug intoxicated suspect who might be TASER'd by law enforcement. Remember this guy? My best estimate was that he was acutely intoxicated with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") although that might be one of my blog interests talking. You might also wish to consider some papers found by searching PubMed for "methamphetamine cardiac toxicity", "methamphetamine vetricular fibrillation" and "methamphetamine heart attack".

Together this background would seem to identify a situation crying out for additional study.

It is worth noting right off the bat, given the comments following the Popular Science Article, that these studies were conducted (in the US) by research scientists under Institutional Animal Care and Use Committee approval and the usual Federal regulatory, and other, oversight mechanisms1.

Methodologically, the study examined four different TASER shock durations starting with a 5 sec continuous shock that seems to be the standard in human investigations. This study included 15, 30 and 40 sec intermittent shocks in which the longest continuous duration was 20 sec. If you watch the end of the Cochella video, these might seem to be more realistic conditions to test over the published studies in law enforcement volunteers I mentioned above. This consideration ties back into why we need to resort to animal models instead of just using law enforcement volunteers. The case reports identify some cases of serious harm to the TASee and the research literature reports essentially no (consistent?) harm. To cross this bridge we need to set up experimental conditions that seem more likely to get us closer to ones that will cause harm. That changes the ethical calculus for human subjects' research versus animal research. Also, the combined effect of a stimulant drug and TASER might be presumed to be additive- again, problematic for human subjects research.

The MA doses were physiologically significant in this model, even though subjects were under anesthesia.
All animals given methamphetamine demonstrated signs of methamphetamine toxicity with tachycardia, hypertension, and atrial and ventricular ectopy ... One smaller animal (animal 8, 30 kg, at 1.0 mg⁄ kg methamphetamine) had a supraventricular tachycardia (SVT) shortly (7 minutes) after methamphetamine administration requiring cardioversion. One animal (animal 11, 78 kg, at 1.5 mg⁄ kg methamphetamine) had
apparent seizure-like activity shortly (4 minutes) after methamphetamine administration that resolved spontaneously.

Effects of the ECD (Electronic control device, i.e.TASER) stimulus:
Smaller animals (n = 8, ≤ 32 kg, mean = 29.4 kg) had supraventricular dysrhythmias immediately after the
ECD exposures (including SVTs and frequent premature atrial contractions). Larger animals (n = 8, 68 kg, mean = 72.4 kg) had only sinus tachycardia after the ECD exposures.

Note the bimodal size distribution, the authors accidentally ordered too-small animals in their first cohort but decided to go ahead with the study. This ended up being fortuitous as it identified possible age-related differences (interestingly the authors just focus on the size question, I'd like to know more about sheep development and whether these smaller animals were juveniles, adolescents, young adults or whatever). Unfortunately, however, that pushes the study right into trying to make something out of individual differences2.

One of the smaller animals had frequent episodes of ventricular ectopy after two ECD exposures, including runs of delayed-onset (2-5 minutes after the exposure), nonsustained, six- to eight-beat unifocal and multifocal ventricular tachycardias that spontaneously resolved. This animal had significant ventricular ectopy after the methamphetamine administration and prior to the exposures as well.

Now tachycardia (elevated heart rate) and hypertension (increased blood pressure) I more or less grasp but not being a cardiac physiologist I had to resort to the Googles for a couple of these.
Ventricular ectopy:
Ventricular ectopy leading to ventricular tachycardia (VT), which, in turn, can degenerate into ventricular fibrillation, is one of the common mechanisms for sudden cardiac death.

Supraventricular tachycardia:
..the heart rate is sped up by an abnormal electrical impulse starting in the atria.

-The heart beats so fast that the heart muscle cannot relax between contractions.

-When the chambers don't relax, they cannot contract strongly or fill with enough blood to satisfy the body's needs.

-Because of the ineffective contractions of the heart, the brain does not receive enough blood and oxygen. You can become light-headed, dizzy, or feel like fainting (syncope).

Sinus Tachycardia:
..is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult.
cardioversion:
..is a medical procedure by which an abnormally fast heart rate or cardiac arrhythmia is converted to a normal rhythm, using electricity or drugs.

For some reason the authors don't make much of a stab at inferential statistics to deal with the main quantitative measures of heart rate, blood pressure, etc. The MA group (N=4) means are presented for each of the doses and stimulus-duration conditions, as are the stats for a nonparametric comparison with the c... Read more »

Dawes DM, Ho JD, Cole JB, Reardon RF, Lundin EJ, Terwey KS, Falvey DG, & Miner JR. (2010) Effect of an electronic control device exposure on a methamphetamine-intoxicated animal model. Academic emergency medicine : official journal of the Society for Academic Emergency Medicine, 17(4), 436-43. PMID: 20370784  

  • April 14, 2010
  • 09:49 AM
  • 822 views

Impaired or improved driving in abstinent Ecstasy users?

by DrugMonkey in DrugMonkey

A recent paper set out to examine automobile driving skills in people who had previously used Ecstasy (presumptively 3,4-methylenedioxymethamphetamine; MDMA) but were currently not using. Dastrup and colleagues (2010) used a driving simulator task in which the job was to maintain a set distance behind a lead vehicle (LV) displayed on the computer screen. The job was to stay abut two car lengths (given as 18 meters) behind the LV while accelerating to 55mph. My Google U conversion calculation makes 55 mph out to be about 25 meters / sec. I would therefore estimate the closing time between the cars as about 0.4-0.5 seconds, depending on car length and how much space you assume between these lengths. Thereafter the LV changed speed as depicted in the Figure 2 from the paper.
The horizontal line sits at the 55 mph point and you can see that the speed of the LV varies up to about 59 mph and down to about 51 mph with the maximum change taking place over about 18-20 seconds. . As with most of the literature on cognitive function in abstinent MDMA users the biggest challenge (and limitation) is that Ecstasy consumers also tend to use a wide range of other recreational drugs, many of which might have lasting effects on their own. Consistent with the better studies on the topic, this study used
four groups of drivers: abstinent MDMA users, abstinent THC users, abstinent alcohol users, and non-drug using controls

Another problem with human user studies in general is that nobody has been exposed to exactly the same amount or variety of recreational drugs. So the researchers have to devise somewhat reasonable criteria to minimize contributions from other drugs while accepting that "pure" populations are essentially impossible to find. Additional criteria and limits for the groups were given as:
MDMA poly substance users: These individuals used MDMA ≥5 times in the last three years, and may have used THC 10 times. They may have occasionally used drugs other thanMDMAand THC, but <30 times in their lifetime. The amount of any other drug use could not exceed that in which MDMA was used. For example, someone who used MDMA 10 times, but used THC 20 times, or
cocaine 30 times was excluded.
THC poly substance users: These individuals used THC ≥10 times in the last three years, but never used MDMA. Other drug use was
<30 times in their lifetime and did not exceed the number of times
they used THC.
Alcohol users: These individuals never used MDMA. They may have tried THC or other drugs, but only a few times (<6 times) in their lifetime. Alcohol use in this group was ≥6 alcoholic drinks per week. To control for tobacco use, we attempted to recruit equal number of participants who used alcohol and tobacco (<20 cigarettes per week) and who used alcohol but not tobacco (<1 cigarette per week).
Non-drug users: These individuals were similar to the alcohol users with respect to MDMA, THC or other drug use. The last time they used any drug (except alcohol or nicotine) was ≥12 months prior
to the study. The alcohol use in this group was ≤5 alcoholic drinks
per week.

If experience is any guide, some readers will want to kvetch about the impurity of the study populations. This is an inescapable feature of human subjects investigations (the design, not the kvetching). Where possible we'd like to follow up findings with controlled studies in laboratory animals performing much simpler behavioral tasks that share some critical feature such as velocity tracking or responding quickly and accurately to stop/go signals. That way the drug exposure would be both known and identical within a group. In my view, the combination of human and nonhuman studies gives us the quickest way to determine if a given substance to which humans are exposed leads to acute or lasting behavioral problems.

There were several key parameters of the subjects' driving performance measured including coherence (are they tracking the speed changes of the LV), average following distance, delay (how long after the LV changes does the subject require to adjust speed) and gain (under/overshooting the changes of the LV- i.e. slowing too much or speeding up too much). Examples are given in Figure 3 which depicts three individuals' performance on the task relative to the LV speed.

The only group results that were significantly different were in the delay and following distance parameters. MDMA (2.36 sec) and THC (2.2 sec) groups responded more quickly than did the ALC (3.1 sec) and control (3.4 sec) groups to changes in the LV speed. The MDMA users selected a much shorter following distance (91 ft) than did the THC (140 ft), ALC (121 ft) and control (155 ft) groups. In both cases the differences were present even when statistically adjusting for age- and sex-related differences in performance of the task.

So how to interpret theses findings? Well, responding more quickly to speed changes seems like a good thing when it comes to driving. Following more closely than you are supposed to seems like a bad thing. So are abstinent MDMA and THC users better drivers? Or is the MDMA group impaired relative to all other groups?

One way to think about the tradeoff is as stated in the Discussion of the paper:

While all participants traveled approximately 55mph (80 ft/s), the MDMA drivers showed a mean 1.04 second shorter delay than non-drug using comparison drivers (leaving 83 more feet to respond) but drove 64 feet closer to the LV. Although abstinent MDMA users drove closer to the LV, they compensated for the risk of driving close by reacting quickly to the LV velocity changes.

To make a similar comparison, the THC group had 96 more feet in which to respond but only drove, on average, 15 feet closer, than did the control subjects. Remember, these are not people who are acutely intoxicated. There are only about three obvious hypotheses once we conditionally credit the group effects as specific to the groupings. First, that the populations who self-select into these drug use conditions start off with altered risk-tolerance and attentiveness to driving. Second, it could be that the users are made that way via brain changes induced by their drug taking- some sort of toxicity. As it happens one reasonably well-populated and productive areas of research on human drug users focuses on both pre-existing and drug-induced traits of impulsivity and risk tolerance. Third, it could be that drug experienced individuals intentionally compensate for any real or perceived performance deficits they've noticed in their own driving by altering their attentiveness, riskiness or both.

The more attentive / risk tolerant nature of the abstinent MDMA users' driving phenotype in this study is interesting to consider in the light of recent political efforts to ban cell phone use when driving. Those discussions have pointed to a few studies showing the detrimental effect of such distraction on one's ability to react to changing circumstances. Drivers are also poor at cell phone use showing that the issue here has to do with the limits of your (39/40 of you anyway) brain allocating attention to multiple tasks.

The point is, of course, that real world driving is a more demanding situation than is posed by the simulator used in this study of abstinent drug users. The next step will be to examine performance in a more multi-tasking type of situation. It may be that that MDMA and THC groups still perform faster...or perhaps they are already at the limit and additional cognitive demands overcome whatever compensations they have made.

__
Dastrup, E., Lees, M., Bechara, A., Dawson, J., & Rizzo, M. (2010). Risky car following in abstinent users of MDMA Accident Analysis & Prevention, 42 (3), 867-873 DOI: 10.1016/j.aap.2009.04.015

Driving simulator user group wiki. ... Read more »

Dastrup, E., Lees, M., Bechara, A., Dawson, J., & Rizzo, M. (2010) Risky car following in abstinent users of MDMA. Accident Analysis , 42(3), 867-873. DOI: 10.1016/j.aap.2009.04.015  

  • March 15, 2010
  • 09:52 PM
  • 1,014 views

Discriminating Cathinone Analogs

by DrugMonkey in DrugMonkey

sourceMy Google news alert for MDMA, Ecstasy and the like has been turning up references to a cathinone analog called variously 4-methylmethcathinone (4-MMC), mephedrone (2-methylamino-1-p-tolylpropan-1-one), Meow-Meow, MMCAT and a few other things. There has been one fatality attributed* to 4-MMC that I can find and a few bits of seized-drug analysis confirming that the stuff is indeed being used. A quick scan over at PubMed finds little reported on the effects of this compound in animal models or in humans. I did, however, run across an article on other cathinone analog drugs that caught my attention.

The newpaper reports on 4-MMC coming out of the UK, for the most part, are experiencing the usual difficulty in characterizing the subjective properties of an analog of a stimulant class of drugs. This not dissimilar to the case of MDMA and relatives such as MDA, MDEA/MDE which are structurally similar to amphetamine and methamphetamine but convey subtly different subjective properties. This gives me an opportunity to talk about an animal model used quite a bit in drug abuse studies: The drug-discrimination assay. Since the news reporting


Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs. Dal Cason TA, Young R, Glennon RA. Pharmacol Biochem Behav. 1997 Dec;58(4):1109-16. (DOI) In this case, for example, the rats were trained to discriminate 1.0 d-amphetamine (d-AMP) from saline. The drug (or saline vehicle) was administered by intraperitoneal injection and then the animal was placed in the operant chamber and allowed to respond on two levers to produce a delivery of sweetened powdered milk. When d-AMP was administered before the session one lever produced reward and this became the drug-associated lever for that animal (left/right was balanced across the group). Presses on the other lever were rewarded under saline conditions.

The critical step in this assay is that responses on the levers in the first 2.5 minutes of the session did not produce any consequences. Animals were considered trained when they made over 80% of their responses during this test interval on the drug-appropriate lever after receiving 1.0 d-AMP and less than 20% on the drug-appropriate lever after receiving saline. Once trained, animals are challenged with either different doses of the training drug or different drugs entirely. The procedure is interpreted as giving an indication of how similar the subjective properties of a drug is to the training drug and how potent that drug is relative to the training drug.

In this paper, the authors investigated the subjective properties of several cathinone analog compounds including N-Monoethylcathinone (N-Et CAT), N-mono-n-propylcathinone (N-Pr CAT), and N,N-dimethylcathinone (Di Me CAT), 3,4-Methylenedioxycathinone (MDC) and 3,4-Methylenedioxymethcathinone (MDMC). I have taken the liberty of graphing the data provided in tabular form in the paper.

As you can see in the graph, as you decrease the dose of the training drug, the rats are less and less likely to "report" that they have been given the active training drug. This is a classic feature of the assay. In terms of the cathinone analogs under investigation, four of them would substitute for the training drug if you pushed the dose high enough. Notice that in all cases the necessary dose was higher on a mg/kg basis than the training dose of d-AMP. One compound (MDC) did not fully substitute for d-AMP; part of the reason for this is that beyond the graphed dose range, the animals were behaviorally disrupted- i.e., they didn't make more than 5 total responses (on either lever) in the initial test interval.

So cathinone analogs are producing subjective properties similar to amphetamine in many cases, all well and good. At this point you are screaming that sure, this procedure just asks the animal to report if it is intoxicated on a drug or not. Unfortunately I don't have the time or inclination to go through the arguments step by step so I'll refer you back to the drug-discrimination database for the moment.

I did want to highlight two papers from Goodwin and Baker (here, here) that took the modestly unusual step of training rats to discriminate d-AMP and MDMA from saline using a three-lever setup. The take home here is that by using this procedure you can get the rats to report d-AMP classic stimulant-like effects differently from serotonin-mediated classic hallucinogen effects. The data confirm in a rat model that MDMA does indeed share stimulant and hallucinogen-like properties**. (Man, I wish more people would use this three-lever procedure.)

Returning the Dal Cason paper, we see that they also conducted another study in which the rats were initially trained to discriminate 1.5 mg/kg MDMA from saline and then tested on the methylenedioxycathinone and methylenedioxymethcathinone compounds. In this case 77% MDMA-like responding was produced at only 2 mg/kg of MDC and the 93% considered full substitution at 2.25 mg/kg. In contrast MDC did not substitute fully for d-AMP, producing the most d-AMP-like responding of 58% at 2.75 mg/kg. The MDMC compound produced full substitution for MDMA at 2 mg/kg (98% MDMA-appropriate) and nearly full substitution (77%) at 1.75 mg/kg. This drug produced full substitution for d-AMP at 3 mg/kg and 69% drug-appropriate responding at 2.75 mg/kg. Although this between-groups procedure is not as elegant as the three-lever paradigm, still we have some evidence here for how subjective properties of several cathinone analogs shake out in a behaving animal.

I'm hoping a lab or two is busily working on 4-MMC so we can start getting some data on the behavioral pharmacological properties of this drug which appears to be gaining popularity in the UK at the moment.
__
*in combination with cannabis. Cue designer drug fans complaining how it can't be the entactogen/stimulant, it must be the known danger of...um, uh-oh.

**I can't help undercutting my attempt to get you to believe in drug-discrimination by pointing out this paper (also from the Glennon group) showing that MDMA-trained rats will report cocaine as MDMA-like but cocaine-trained rats do not fully generalize to MDMA. If it were easy it wouldn't be interesting...

DALCASON, T., YOUNG, R., & GLENNON, R. (1997). Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs Pharmacology Biochemistry and Behavior, 58 (4), 1109-1116 DOI: 10.1016/S0091-3057(97)00323-7... Read more »

DALCASON, T., YOUNG, R., & GLENNON, R. (1997) Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs. Pharmacology Biochemistry and Behavior, 58(4), 1109-1116. DOI: 10.1016/S0091-3057(97)00323-7  

  • January 28, 2010
  • 06:13 PM
  • 976 views

Cannabis Hyperemesis

by DrugMonkey in DrugMonkey

Most of my readers are aware of the growing head of steam being perked up by the medical marijuana movement (and that I think it is a Trojan Horse for recreational consumption). I have also described how perceptions of the harms associated with cannabis are associated with population level use. This suggests to me that it is important to identify adverse health consequences of cannabis smoking ranging from oral health complications to paradoxical potentiation of Ecstasy-induced hyperthermia, to a dependence syndrome in some users that shares some features with nicotine dependence.

I have a new and fascinating consequence of cannabis smoking for your consideration today, Dear Reader. There is an odd syndrome of cyclical vomiting that has resulted in a series of Case Reports. One theme that runs through these is the apparently mysterious presentation at the hospital, since most of the expected causes of severe episodic vomiting were painstakingly ruled out. Allen and colleagues (2004) reported a series of 14 consenting (of 19 approached) individuals from South Australia, 9 of whom could not be excluded for obvious confounds. The remaining 9 cases all had suffered from a cyclical pattern of sustained episodes of vomiting which remitted and then returned weeks or months later. They also comment on a case one of the authors had published in 1996 of a similar case attributed to "psychogenic vomiting".

Roche and Foster (2005) identified a case of a 21 yr old New Zealand man who was admitted to hospital seven times over a two year period with severe vomiting. All of the usual suspects were excluded in medical tests and workups.

Sontineni and colleagues (2009) report a single case of a 21 yr old male from Omaha Nebraska in the United States who suffered from 2-3 hr bouts of uncontrolled vomiting several times per day during a symptomatic episode.

Donnino and colleagues (2009) report on three cases from the Boston area of the United States. In this case all three were males (22, 23, 51 yo) and were found to have visited the Emergency Department many times over approximately 2 year intervals with episodes of severe emesis. The striking thing about this case report is the description of extensive medical workup undergone trying to determine or rule out various causes for the vomiting. E.g.,
a 51-year-old man who presented to the ED with nausea, vomiting, and abdominal pain. The patient had experienced similar episodes over the previous 2 years (2006 -2008), involving 10 ED visits and four hospital admissions, during which he underwent a total of two EGDs, one colonoscopy, several abdominal
ultrasound examinations, and four abdominal CT scans, with no clear cause for his symptoms identified.

Not cheap!

There were two striking similarities across all these cases. The first is that patients had discovered on their own that taking a hot bath or shower alleviated their symptoms. So afflicted individuals were taking multiple hot showers or baths per day to obtain symptom relief.

The second similarity is, as you will have guessed, they were all cannabis users. The cannabis use predated the cyclic hyperemesis, typically by many months to a few years. Cannabis use was also fairly heavy with the afflicted individuals smoking multiple times per day. In those cases where individuals were able/willing to stop using cannabis, the cyclic vomiting remitted. In at least three cases (from Allen et al) individuals were unable or unwilling and the cyclic hyperemesis continued.

It will not escape your attention that one of the supposed medical indications for cannabis smoking is the prevention of nausea and emesis, particularly in those undergoing chemotherapy for cancer. Anti-emesis is an expected property of cannabis ingestion. Cyclical hyperemesis is not. The symptom relief provided by hot showers or baths only fuels additional curiosity. Consequently, there are very intriguing scientific questions arising from these Case Reports. Very intriguing indeed.

Overall this is a fascinating tale and clearly, given the timeline of the publications (this is not an exhaustive list), an association that is only beginning to be recognized. Presumably it is not a highly common syndrome because the cases are often relatively young and there have been plenty of chronic cannabis smokers around for decades. If it were a common feature of chronic cannabis you might expect it would have been identified earlier. Nevertheless, even if this is rare, if we continue to enact polices which will increase the amount of cannabis smoking or the number of chronic smokers this syndrome might be expected to rise.

__
Literature Cited
Allen, J. (2004). Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse Gut, 53 (11), 1566-1570 DOI: 10.1136/gut.2003.036350

Donnino MW, Cocchi MN, Miller J, & Fisher J (2009). Cannabinoid hyperemesis: A case series. The Journal of emergency medicine PMID: 19765941

Roche E, & Foster PN (2005). Cannabinoid hyperemesis: not just a problem in Adelaide Hills. Gut, 54 (5) PMID: 15831930

Sontineni SP, Chaudhary S, Sontineni V, & Lanspa SJ (2009). Cannabinoid hyperemesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World journal of gastroenterology : WJG, 15 (10), 1264-6 PMID: 19291829... Read more »

Allen, J. (2004) Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut, 53(11), 1566-1570. DOI: 10.1136/gut.2003.036350  

Donnino MW, Cocchi MN, Miller J, & Fisher J. (2009) Cannabinoid hyperemesis: A case series. The Journal of emergency medicine. PMID: 19765941  

Roche E, & Foster PN. (2005) Cannabinoid hyperemesis: not just a problem in Adelaide Hills. Gut, 54(5), 731. PMID: 15831930  

Sontineni SP, Chaudhary S, Sontineni V, & Lanspa SJ. (2009) Cannabinoid hyperemesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World journal of gastroenterology : WJG, 15(10), 1264-6. PMID: 19291829  

  • January 15, 2010
  • 04:44 PM
  • 1,175 views

Is it a substance use disorder or is he a substance abuser?

by DrugMonkey in DrugMonkey

This is awesome. I've been waiting for the paper to show up ever since I saw the poster presentation at a meeting last year. Or maybe I just saw a related type of poster because I seem to recall the analysis being particularly critical of general medical doctors? At any rate, this is a pretty important finding because it speaks to the stigma that surrounds certain types of medical problems. This stigma might have serious implications for judicial decision making when crimes are involved, personal health care recommendations / efforts from physicians, etc. The paper is in the queue at the International Journal of Drug Policy.

Does it matter how we refer to individuals with substance-related conditions? A randomized study of two commonly used terms
John F. Kelly and Cassandra M. Westerhof, International Journal of Drug Policy, In Press, Corrected Proof, Available online 14 December 2009, [DOI]


I was alerted to the publication by the description here at Science Daily.
The investigators randomly distributed surveys to more than 700 mental health professionals attending two 2008 conferences focused on mental health and addiction. The surveys began with a paragraph describing the current situation of "Mr. Williams," who is having trouble adhering to a court-ordered treatment program requiring abstinence from alcohol and other drugs. On half of the surveys, he is referred to as a "substance abuser;" on the others, he is described as having "a substance use disorder," with the rest of the narrative being exactly the same. The survey consisted of 32 statements about Mr. Williams' situation, and participants were asked to indicate how much they agreed or disagreed with those statements. Subjects were mental health care providers recruited at two substance abuse related conferences in the fall of 2008. The 516 responding subjects completed a series of Likert-scale (1-6; strongly disagree to strongly agree) evaluations of statements such as the following.
His problem is caused by a reckless lifestyle
Mr. Williams is responsible for causing his problem
Mr. Williams' problem is God's will
He should be given some kind of jail sentence as a "wake up" call
Mr. Williams should be referred to a spiritual or natural healer
I believe he will do something violent to others
The judge should increase the severity of the consequences for any further alcohol or drug use
His problem is caused by the way in which he was raised
Mr. Williams could have avoided using alcohol and drugs

The investigators then performed an exploratory factor analysis- a statistical procedure in which the idea is to find groups of statements for which the answers tended to be correlated. From this they extracted three principal statement-grouping factors characterized as "perpetrator-punishment", "social threat", and "victim-treatment". The major focus of the study was on the independent manipulation of whether the narrative described the subject as "a substance abuser" or a person "with a substance use disorder". No group differences were found for social threat ("I would be willing to have Mr.Williams as a neighbor") or victim-treatment ("Mr. Williams' problem is caused by a chemical imbalance in the brain") type of statements. However, the characterization of "a substance abuser" or "with a substance use disorder" did influence rsponses on the perpetrator-punishment statements ("In order to help Mr.Williams stay on track, the judge should initiate disciplinary action").

those assigned the "substance abuser" term .. were significantly more in agreement with the notion that the character was personally culpable for his condition and more likely to agree that punitive measures be taken

The authors describe the statements which cluster in this perpetrator-punishment group as follows.
Overall, items associated with this subscale appear to convey internal causal attribution and personal culpability, a moral vs. medical solution, suggesting the character has volitional control and might be viewed as a "perpetrator"who is willfully engaging in the behavior and thus more deserving of punishment.

So the take home here is that we should endeavor to focus our descriptors on actions and diagnoses rather than on terms which imply essential characteristics of a person.

The authors do caution that their effect size was pretty small and the connection to real-world decision making unclear. But I buy their argument that since these were substance-abuse experience mental healthcare professionals, one might expect this to be the floor of the effect. Those such as legislators, judges and even doctors who do not specialize in substance abuse might be predicted to be even more influenced by the way they perceive substance use. If perceiving it as a volitional or moral failing, they are likely to be more punitive and select less therapeutic options, I would argue.

__
Kelly, J., & Westerhoff, C. (2009). Does it matter how we refer to individuals with substance-related conditions? A randomized study of two commonly used terms☆ International Journal of Drug Policy DOI: 10.1016/j.drugpo.2009.10.010

Massachusetts General Hospital (2010, January 14). Words used to describe substance-use patients can alter attitudes, contribute to stigma. ScienceDaily. Retrieved January 14, 2010, from http://www.sciencedaily.com/releases/2010/01/100113122310.htm... Read more »

Kelly, J., & Westerhoff, C. (2009) Does it matter how we refer to individuals with substance-related conditions? A randomized study of two commonly used terms☆. International Journal of Drug Policy. DOI: 10.1016/j.drugpo.2009.10.010  

  • December 23, 2009
  • 04:53 AM
  • 727 views

In which I serve up a big fattie for my self-perceived critics

by DrugMonkey in DrugMonkey

There is an interesting paper that I just ran across which will possibly please a certain segment of my audience. You see, it provides a bit of a test of the hypothesis frequently bandied by my commenters that anti-drug messages backfire. That if you tell adolescents all sorts of bad things are going to happen to them if they try an illicit drug once, and it doesn't happen, somehow you are actually encouraging them to try the drug again. This general area is an occasional interest of mine and you can read a few thoughts here, here, here, here and here. The paper itself is this one.

Skenderian JJ, Siegel JT, Crano WD, Alvaro EE, Lac A. Expectancy change and adolescents' intentions to use marijuana. Psychol Addict Behav. 2008;22(4):563-569. [Free PubMed Central version]

This paper describes a secondary analysis of data collected under the National Survey of Parents and Youth which focuses on the efficacy of an anti-drug media campaign. This means that it is, necessarily, correlational in nature, not a prospective experiment*. The purpose of this secondary study was laid out as:
There are many possible reasons for [poor effect of anti-drug messages] including the possibility that the typical campaign often is designed to develop expectancies regarding marijuana use outcomes that may not be experienced by the initiate. Changes in expectancies regarding marijuana, and the effects of such changes on initiates' intentions to continue use, are the focus of this investigation.

In short, if we deliver lies-to-children to adolescents, do we end up encouraging cannabis use? The sample:
...consisted of 1,344 adolescents who ranged in age from 12 to 18 years in the 1st year of the research (M = 14.15, SD = 1.52). ... All demographic characteristics were weighted to be nationally representative.

For the purposes of this paper, the sample from the parent survey was limited to those who had never tried cannabis at the time of the first interview. The experimental data were derived from interviews with the subjects, conducted at a one-year interval. Questions of interest included Intentions:
"How likely is it that you will use marijuana, even once or twice, over the next 12 months?"
"How likely is it that you will use marijuana nearly every month for the next 12 months?"

as well as questions about Expectancy:
"How likely is it that the following would happen to you if you used marijuana nearly every month over the next 12 months:" ( followed by the expectation outcome "Damage my brain." ..."Lose my friends' respect" ... "Have a good time with my friends." .."Be more creative and imaginative" .."Be acting against my moral beliefs." .. "Mess up my life," "Do worse in school," .."Lose my ambition.")

The meat of the statistical analysis focused on the changes in both Intention and Expectancy from the first to the second interview. Some 14.5% of the sample had tried cannabis at that point, a group of additional focus. The bottom line result was that changes in intention were correlated with changes in expectancy and that moreover this correlation was stronger in the subgroup which had tried cannabis. Table 3 has the best summary but note that they've done a weird transformation so that all correlations are positive. The shorthand is that perceiving cannabis as less detrimental was correlated with greater intention to use, no matter which of he eight expectancy questions you look at.

Now, before you get all het up over the obvious, go read the Discussion section. This is a correlational study, not an experiment. Nevertheless, the focus here is on change in attitudes between those that actually changed their behavior (started smoking cannabis) and those that did not. Is it because the initiators changed their perception of risk and therefore chose to smoke or because they smoked and found their prior expectation of harm to require adjustment? Doesn't really matter in some sense, does it? It seems to me that getting that knowledge about risks as accurate as possible conveyed to the adolescents would minimize any change in expectancy, since there would be less room for experience to modify these expectancies.

I do think the authors go a bit off the rails with their "implications". They acknowledge the essence in their Discussion
Attention should be focused on whether users attained user status prior to a change in expectancies or rather if a change in expectancies resulted in changes to user status.
but then go right on to end on the strong claim that:
Our results do indicate that the best chance for reducing future use might be to persuade adolescents that if they do initiate use, the harms they will experience at some point may prove worse than anticipated, or the expected benefits may not prove as positive. At a minimum, the results warn against overstating marijuana harms in prevention.


yeah, not really sure we know that yet folks.

I'll finish up with the observation that I was alerted to this by a NIDA NewsScan dated September 11, 2009 (which strangely just showed up in my email box). Oh yes and we should review the Acknowledgments statement from the study:
This research was supported by National Institute on Drug Abuse Grant 5R01DA020879-02.

See, my legalize-eet friends? Is this a crack in the great right-wing prohibitionist conspiracy? Or is this bug, you know, actually a feature....
__
*he says, fruitlessly hoping to head off the usual idiotic correlation != causation triumphalism

Skenderian, J., Siegel, J., Crano, W., Alvaro, E., & Lac, A. (2008). Expectancy change and adolescents' intentions to use marijuana. Psychology of Addictive Behaviors, 22 (4), 563-569 DOI: 10.1037/a0013020... Read more »

Skenderian, J., Siegel, J., Crano, W., Alvaro, E., & Lac, A. (2008) Expectancy change and adolescents' intentions to use marijuana. Psychology of Addictive Behaviors, 22(4), 563-569. DOI: 10.1037/a0013020  

  • October 7, 2009
  • 10:29 AM
  • 1,373 views

Longitudinal analysis of street Ecstasy content

by DrugMonkey in DrugMonkey

A topic that arises every now and again, particularly when I am discussing Ecstasy-related medical emergency and death, is the nature of the psychoactive ingredients in Ecstasy tablets. For definitional purposes, I consider 3,4-methylenedioxymethamphetamine (MDMA) to be what is considered by the vast majority of consumers to be canonical "Ecstasy".

It is reasonably well-established in the peer reviewed literature and the ecstasydata.org harm reduction effort that some fraction of Ecstasy that is distributed contains non-MDMA psychoactive compounds either in addition to, or replacement for, MDMA. There are, however, some nagging questions because the published data are spotty. One topic of interest to me is that of selection bias. Tablet analyses are published either from samples turned in by Ecstasy consumers or those obtained by law enforcement seizures. In the former case there is a reasonable case to be made that perhaps Ecstasy found to result in suspicious subjective effects on the user are submitted to harm reduction sites preferentially. In the case of law enforcement seizure, well, the ones that got caught are by definition not on the street for sale. And you can make up a whole list of other caveats about why the published analyses might not accurately reflect the picture of what is actually being consumed.

A recent paper doesn't nail down every complaint but at least it compares samples submitted willingly and unwillingly by the consumer.

Vogels, N., Brunt, T., Rigter, S., van Dijk, P., Vervaeke, H., & Niesink, R. (2009). Content of ecstasy in the Netherlands: 1993-2008 Addiction Epub ahead of print Oct 5 2009; DOI: 10.1111/j.1360-0443.2009.02707.x Read the rest of this post... | Read the comments on this post...... Read more »

Vogels, N., Brunt, T., Rigter, S., van Dijk, P., Vervaeke, H., & Niesink, R. (2009) Content of ecstasy in the Netherlands: 1993-2008. Addiction. DOI: 10.1111/j.1360-0443.2009.02707.x  

  • October 6, 2009
  • 06:40 AM
  • 1,180 views

Vaccination against cocaine: Incremental advance

by DrugMonkey in DrugMonkey

I last broached the topic of immunization against drug use some time ago and I concentrated more on the ethical implications of vaccinating. I was being ever so slightly disingenuous because the current state of progress is not such that we need to consider such questions as:
Would you recommend it broad-spectrum for all children much like MMR?
Would you recommend parents be permitted to subject their drug abusing teen against his or her will?
Allow the courts to mandate inoculation?
Suppose it were made a condition of employment?

A recent paper by Martell and colleagues provides a nice opportunity to review the promise and limitations of immunopharmacotherapy for drugs of abuse. The rationale for such studies is pretty easy to grasp, although at present the result fall short of the lasting immunity you associate with childhood vaccines and even the seasonal flu shot. Drugs of abuse are molecules that do not generate any immune response because they are too small. The starting rationale is that if you create a drug mimic and attach it to something that will attract the attention of the immune system you might be able to generate antibodies that recognize the target drug. Read the rest of this post... | Read the comments on this post...... Read more »

Bonese KF, Wainer BH, Fitch FW, Rothberg RM, & Schuster CR. (1974) Changes in heroin self-administration by a rhesus monkey after morphine immunisation. Nature, 252(5485), 708-10. PMID: 4474602  

Killian A, Bonese K, Rothberg RM, Wainer BH, & Schuster CR. (1978) Effects of passive immunization against morphine on heroin self-administration. Pharmacology, biochemistry, and behavior, 9(3), 347-52. PMID: 101989  

Carrera, M., Ashley, J., Parsons, L., Wirsching, P., Koob, G., & Janda, K. (1995) Suppression of psychoactive effects of cocaine by active immunization. Nature, 378(6558), 727-730. DOI: 10.1038/378727a0  

Bridget A. Martell, MD, MA, Frank M. Orson, MD, James Poling, PhD, Ellen Mitchell, RN, Roger D. Rossen, MD, Tracie Gardner, PhD, & Thomas R. Kosten, MD. (2009) Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained Patients: A Randomized, Double-blind, Placebo-Controlled Efficacy Trial. ARCH GEN PSYCHIATRY, 66(10), 1116-1123. info:/

  • September 9, 2009
  • 03:36 PM
  • 1,291 views

Diagnostic Criteria for MDMA abuse and dependence

by DrugMonkey in DrugMonkey

A recent paper on the test / re-test reliability of diagnostic criteria for MDMA abuse and dependence is fascinating. Foremost because the nature of substance abuse is always a fun topic for discussion when you are dealing with a compound which the users argue so strenuously is perfectly benign. Even more so because the advocacy position tends to put a finer point on the argument about just how to draw lines between ordered and disordered behavior within what is very likely a continuous distribution. The paper also shows some of the limitations of trying to fit drugs which have very distinct subjective experience profiles, use patterns and even dependence modes/risks into a single (albeit reasonably flexible) diagnostic strategy.

In their paper Test-re-test reliability of DSM-IV adopted criteria for 3,4-methylenedioxymethamphetamine (MDMA) abuse and dependence: a cross-national study, Cottler and colleagues are primarily focused on whether diagnostic criteria for MDMA abuse and dependence (there are distinct diagnoses for some substances of abuse within the Diagnostic and Statistical Manual of Mental Disorders, but not for MDMA which falls under the general abuse criteria) are reliable. As you might imagine, it is a pretty important part of medical diagnosis that a given clinical test gives the same answer when repeated for the same individual in close temporal proximity. It is no great leap of genius to see that reliability is even more important when the diagnostic instrument consists of asking people about their affect and behaviors. Particularly when the behaviors are illegal and socially stigmatized.
Read the rest of this post... | Read the comments on this post...... Read more »

Cottler, L., Leung, K., & Abdallah, A. (2009) Test-re-test reliability of DSM-IV adopted criteria for 3,4-methylenedioxymethamphetamine (MDMA) abuse and dependence: a cross-national study. Addiction, 104(10), 1679-1690. DOI: 10.1111/j.1360-0443.2009.02649.x  

  • August 25, 2009
  • 04:59 PM
  • 1,277 views

Noncaloric sweeteners might not be the solution either

by bikemonkey in DrugMonkey

The American Heart Associations recommendation to cut down on dietary sugar is all over the news. Discussion of this by Isis the Scientist triggered a comment from Callinectes :

Someone reading this may therefore assume diet drinks with Aspartame, Splenda, etc. may be okay because it's 0 calories and added "sugar". Can anyone comment authoritatively on this? The way I see it, it's still just empty calories and not very good for you when consumed regularly on a weekly or (heaven forbid) daily basis.

To which Isis responded:

One might argue that diet drinks still activate the "Hedonistic food pathways" in the brain (centers in the ventral tegmental area and nucleus accumbens) that lead us to associate reward with food intake, causing us to take in more energy-dense food... That said, I don't know of any multi-variate studies comparing risk between sugar drinks, diet drinks,... let's be clear that Aspartame and Splenda are zero calorie sweeteners, meaning they would technically not contribute to the AHA's recommended daily intake.

I am reminded of what I think of as a reasonably provocative series of observation from Susan Swithers and Terry Davidson at Purdue. Read the rest of this post... | Read the comments on this post...... Read more »

Swithers, S., & Davidson, T. (2008) A role for sweet taste: Calorie predictive relations in energy regulation by rats. Behavioral Neuroscience, 122(1), 161-173. DOI: 10.1037/0735-7044.122.1.161  

Swithers SE, Baker CR, & Davidson TL. (2009) General and persistent effects of high-intensity sweeteners on body weight gain and caloric compensation in rats. Behavioral neuroscience, 123(4), 772-80. PMID: 19634935  

join us!

Do you write about peer-reviewed research in your blog? Use ResearchBlogging.org to make it easy for your readers — and others from around the world — to find your serious posts about academic research.

If you don't have a blog, you can still use our site to learn about fascinating developments in cutting-edge research from around the world.

Register Now

News

Editor's Selections: Tectonic Aneurysms, Energy Drinks, And Invisible Aliens

Editor's Selections: Atomic force microscopy, and hijacking dendritic cells

Editor's Selections: Science of Superheroes, The Problem with Mobile Apps, and Imaging the Brain's Acidity

Research Blogging is powered by SMG Technology.

To learn more, visit seedmediagroup.com.