It was the MDPV that killed him

New Case Report from the Maryland Office of the Chief Medical Examiner

Kesha K, Boggs CL, Ripple MG, Allan CH, Levine B, Jufer-Phipps R, Doyon S, Chi P, Fowler DR. Methylenedioxypyrovalerone (“Bath Salts”),Related Death: Case Report and Review of the Literature. J Forensic Sci. 2013 Jul 3. doi: 10.1111/1556-4029.12202. [Epub ahead of print][PubMed, Publisher]

The subject was a 39 year old man with a history of depression, back pain and drug/alcohol abuse. He was found in public talking to himself, delusional. Once admitted to the hospital, he became agitated, tachycardic and hyperthermic (107 degF noted). Although the decedent was positive for diphenhydramine, promethazine, diazepam and nordiazepam the conclusion was….

Based on the investigative, autopsy, and toxicology findings in this case, the cause of death was methylenedioxypyrovalerone intoxication and the manner of death was accident. It is also important to note that his bizarre behavior with life-threatening hyperthermia is consistent with an MDPV-induced excited delirium state in this individual.

Yep.

The peripheral blood level was 1.0 mg/L of MDPV. We’re just starting to see reports so we’ll just have to wait and collect various blood levels that are associated with medical emergency and death to try to get an idea of the danger zone. Of course, there will be no such thing as an absolute threshold, as individual susceptibility and the circumstances will vary.

Effects of MDPV ("Bath Salts") interact with the ambient temperature

A new paper from the Fantegrossi laboratory examines the behavioral and physiological effects of the substituted cathinone drug, and “bath salts” constituent, 3,4-methylenedioxypyrovalerone (MDPV) [ Search PubMed ] which is the compound which has dominated the US media reports of averse consequences of bath salts intoxication. To the extent that verification of the drug has been provided in such reports, of course. Additional confirmation can be found here, here.

The current issue of Neuropsychopharmacology has a bath salts image on the cover and contains an article from Baumann and colleagues on MDPV pharmacology (I discussed it here) and this paper from Fantegrossi and colleagues.

William E Fantegrossi, Brenda M Gannon, Sarah M Zimmerman and Kenner C Rice In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity. Neuropsychopharmacology (2013) 38, 563–573; doi:10.1038/npp.2012.233; published online 5 December 2012 [ ArticleLink(free); PDF ]

This is a behavioral pharmacology study in male NIH Swiss mice which first uses drug discrimination techniques to show that when mice are trained to discriminate 0.3 mg/kg i.p. MDPV from saline the subsequent dose response curves for 0.01 to 0.3 mg/kg of MDPV, METH and MDMA are nearly identical. This article has been made freely available so I won’t belabor this part of the study.

What I wanted to focus on was the radiotelemetry studies of body temperature and locomotion. For reasons related to this classic paper on MDMA from Malberg and Seiden, most investigations of the effects of stimulant drugs in rodents should include some consideration of the role of ambient temperature. Fantegrossi and colleagues examined the effects of 0.3-30 mg/kg i.p. MDPV at both 20°C and 28°C. They showed, first of all, that MDPV produces no change in body temperature when administered at 20°C, but induces temperature elevations in a dose-dependent manner when animals are evaluated at 28°C. Even more interesting is what is shown in Figure 4 which I’ve included here. You can see that the locomotor stimulant effect (total activity counts over 6 hrs; left panel) of MDPV also is more pronounced at the higher ambient temperature with a peak differential observed after the 10 mg/kg i.p. dose (timecourse for this dose shown in right panel). There were also some other interesting phenomenological differences observed with the high ambient temperature condition.

At the highest tested dose of MDPV (30 mg/kg), significant focused stereotypy was observed at 28 1C, but not at 20 1C. Furthermore, four (of six) mice treated with 30 mg/kg MDPV at the high ambient temperature engaged in skin-picking and self-biting, which drew blood, and, in accordance with our IACUC approval, were removed from the study and euthanized. No signs of self-injurious behavior were observed at any dose of MDPV administered at 20 1C.

Repetitive, stereotyped behavior is common with locomotor stimulants and can be observed following high doses of amphetamine, methamphetamine and cocaine among other compounds. So this is probably an expected effect. What was interesting here was the dependency on ambient temperature. Off the top of my head, I can’t remember either the stimulant drug sterotypy literature (which focuses on charcterizing the repetitive behaviors) or the locomotor studies (where the “inverted U” dose effect function often reflects the emergence of stereotyped behavior after high doses) focusing too heavily on the ambient temperature issue. No doubt I could stand to go back and review some papers with a closer eye on the ambient temperature.

This study, however, points a finger at environmental issues when trying to figure out the degree to which the drug MDPV might cause sensational media-friendly outcomes in some users. Studies such as the present one may indicate that factors as subtle as how hot it is the day a person takes a given drug can change the experience from relatively benign into something much more severe. Thus, a dose of a drug which has been taken before by the same user may have highly unpredictable effects just based on this one difference in the situation.

ADDITIONAL READING

Watterson et al 2012 demonstrated intravenous self-administration in rats.
Huang et al, 2012 showed locomotor effects of MDPV on activity wheels in rats.
Fuwa et al 2007 shows dopamine responses with microdialysis and locomotor effects [in Japanese, but the Abstract is in English and the figures are easily interpreted]
Meltzer et al 2006 present monoamine pharmacology on a series of pyrovalerone compounds

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Fantegrossi WE, Gannon BM, Zimmerman SM, & Rice KC (2012). In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology PMID: 23212455

Gaining clarity on the pharmacology of the bath salt MDPV

There are two new pharmacological investigations on the substituted cathinone drugs that have been discussed here on occasion.

Each of

Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW.Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products. Neuropsychopharmacology. 2012 Oct 17. doi: 10.1038/npp.2012.204.

and

Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME.Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2012 Aug 17. doi: 10.1111/j.1476-5381.2012.02145.x.

report very similar findings for MDPV, the cathinone that appears most frequently in US newspaper reports.

As a very general rule, the amphetamine class stimulants do a couple of things to enhance the neuron-to-neuron chemical communication that occurs in the brain. The most common and significant effects tend to involve the transporter mechanisms that remove dopamine, norepinephrine and / or serotonin from the synapse, the gap between two neurons. These transporter molecules are an integral part of terminating a signalling event which has been caused by the release of one of these three monoamines from one of the neurons in question. Interfere with the operation of these transporters and a drug can potentiate the magnitude or duration of a given signalling event (i.e., release of one of the dopamine (DA), norepinephrine (NE) or serotonin neurotransmitters).

The amphetamine class stimulants have these properties. As does cocaine. As do therapeutic drugs such as methylphenidate (Ritalin) and Prozac. The term selective serotonin re-uptake inhibitor, SSRI, for Prozac-class antidepressant drugs refers to the transporter, obviously, and also indicates a key thing with the term “selective”. Drugs which have the ability to interact with one of the monoamine transporters tend to interact with the other ones as well. Substantial differences in effect can be associated with differences in the relative ability a specific molecule has to attach to the DAT versus the NET versus the SERotonin transporter (SERT). As one clear example, methamphetamine and MDMA differ in their relative ability to inhibit the SERT….this property of MDMA is associated with many of it’s stimulant-atypical properties relative to other amphetamine-class drugs.

The new studies both show that MDPV blocks all three transporters with much more potent effects at the DAT and NET relative to SERT. As Baumann and colleagues note, MDPV is 50 and 10 times more potent than cocaine (not an amphetamine, we’ll come to this) at DAT and NET respectively. Simmler and colleagues similarly indicate that MDPV is much more potent at DAT than cocaine or methamphetamine which did not qualitatively differ from each other.

So to this point, MDPV looks like a high-potency traditional stimulant. Most effective at the DAT, fairly effective at the NET and with less ability to block the SERT.

Cocaine and the amphetamines diverge at this point because the amphetamines act as a substrate at the transporters. Instead of only interfering and blocking them from doing anything, the amphetamines actually substitute for the neurotransmitter in question and are taken up into the cell. In so doing, they also cause an exchange to happen whereby the transporter moves some neurotransmitter from inside the cell back into the synapse. This transporter mediated efflux contributes to any “regular” release of neurotransmitter mediated through the merging of intracellular sacs (called vesicles) with the cell membrane.

The two papers agree in finding that MDPV has no ability to cause transporter-mediated efflux of dopamine and is therefore best categorized neuropharmacologically as a “pure” blocker (like cocaine) rather than an amphetamine-like transporter substrate.

The Simmler paper adds an in vitro model of blood/brain barrier penetration…in very simple terms the degree to which a molecule is fat-liking versus water-liking can alter the speed at which it can cross cell membranes and get into the brain. This paper used an in vitro preparation of human capillary endothelial cells (that form the blood-brain barrier) to show that MDPV is likely to cross the blood-brain barrier very rapidly, consistent with high lipophilicity predicted from its structure.

The upshot of the two papers is that MDPV shows pharmacological properties consistent with classical stimulants. It shows relatively high selectivity for DAT over SERT and high potency relative to drugs such as methamphetamine or cocaine. In vivo neurochemistry in the Baumann paper confirm that MDPV has potent effects on dopamine levels in the nucleus accumbens, a hallmark of drugs (beyond the stimulants even) which have substantial risk for compulsive use. The only somewhat discordant note for the structure-activity nerds is that MDPV looks so much like the rest of the amphetamines and cathinones that it will be interesting to discover why it doesn’t act as a transporter substrate (Simmler et al included a number of other cathinones and showed that many of them do act as transporter substrates.)

Together these papers suggest that MDPV has high abuse liability with a use pattern characterized by frequent re-dosing much like one sees with cocaine. This is consistent with many self-reports that are emerging from people who use MDPV and therefore, despite the relatively brief time on the “market”, we can predict a cocaine-like dependence problem to emerge for MDPV in the near future.