The Mephedrone Conundrum

by mtaffe

The recently emerged recreational drug called mephedrone (4-methylmethcathinone; 4-MMC) has been popular since at least 2008 (particularly in the UK) and the scientific literature is just starting to catch up. In a prior post I reviewed the Kehr et al (2011) paper which reported that 4-MMC had relatively greater effect on serotonin accumulation in the nucleus accumbens of rats than it does on dopamine accumulation. This profile is more consistent with that found for 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) than for d-methamphetamine. This thereby supported subjective human user comments to the effect that 4-MMC was similar to Ecstasy. Nevertheless, there have been many hints that 4-MMC has enhanced abuse liability. This starts from user comments but was reinforced by survey data in which cocaine-experienced individuals report intranasal 4-MMC to be “as good as” or even superior to cocaine (Winstock et al, 2011). A prior post outlines more survey data on 4-MMC subjective effects.

ResearchBlogging.orgBaumann and colleagues have published a more comprehensive neurochemical study of the effects of 4-MMC in which they contrast this drug with d-methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) and methylone (3,4-methylenedioxymethcathinone, typically referred to as beta-keto-MDMA or bk-MDMA) in Sprague-Dawley rats. Using a cumulative dosing paradigm in which two doses are administered in a single microdialysis session they show here that, much as with the prior report from Kehr et al (2011), the relative increase in dopamine (DA) was smaller than the relative increase in serotonin (5-HT). This profile was shown similar to that produced by MDMA and the reverse of that observed for MA, which produced approximately 18 fold increases in DA but only 9 fold increases in 5-HT. Interestingly, the 4-MMC compound produced slightly higher increases in 5-HT compared with MDMA but approximately similar increases in DA. This was consistent with in vitro pharmacological data in rat synaptosomes showing equal potency at releasing DA but a slightly greater potency for 4-MMC in releasing 5-HT.

The Baumann paper also examined locomotor stimulation, thermoregulatory and neurotoxic endpoints, which I’m not going to cover since I wanted to focus on the Ecstasy versus stimulant-like character in the post today.

Another recent paper presented a very tantalizing small bit of data on the intravenous self-administration of MDMA. Hadlock and colleagues (2011) included a
comparison of the initial acqusition of the self-administration of 4-MMC in contrast with MA in Sprague-Dawley rats. The investigators examined 0.24 mg per infusion of 4-MMC versus MA in different groups, this amounts to 0.48 to 0.72 mg/kg/infusion given the rats were about 333 gm to 500 gms. Animals were run in 4 hour sessions under ambient temperature conditions of 29 degrees Celsius. [These are longer than average sessions and much higher temperatures for this sort of study, see this and this for context.] Figure 4 from the paper, above, shows about 25 infusions for mephedrone and about 9 infusions for methamphetamine after 7 sessions. Therefore they obtained a cumulative dose in a 4 hour session of anywhere from 2-3 mg/kg of mephedrone and 0.72-1.08 mg/kg of methamphetamine.

The lay interpretation of these graphs may be “OMG, mephedrone is self-administered more compulsively than is methamphetamine! Abuse liability is therefore greater.

My initial read is that this is a potency issue. They take more drug because it is less potent, not more potent, and they need more of it to experience the same high (which is traditionally attributed to relative DA effect, particularly in the nucleus accumbens). This is reflected in the Baumann paper in three ways. First, MA was a more potent releaser of DA in the in vitro pharmacological experiment. Second, MA caused a little over a 3-fold greater effect on DA overflow in nucleus accumbens compared with 4-MMC. Finally, 4-MMC increased serotonin in nucleus accumbens perhaps 50% more than did MA which is likely to have a protective effect against self-administration, possibly due to inhibition of the DA release in vivo.

Given this difference in neurochemical potency of the available per-infusion dose used by the Hadlock study, the escalation of intake over successive sessions could be interpreted as similar to what was shown for different training doses (0.05, 1.0, 2.0 mg/kg/inf) for methamphetamine ( Kitamura et al 2006).

This brings the story around to the emerging case literature. Winder and colleagues (2012) present a comprehensive review of the drug history of a patient who finally came to medical services for 4-MMC dependence.

Upon initial presentation to our hospital, the patient was observed
to be a young, gaunt Caucasian male who was visibly tremulous and frightened and who complained of intermittent anxiety and paranoia. He reported previous episodes of mood instability, some directly related to his substance use, and had been on multiple trials of antidepressants in the past with no effect. He had no history of
suicidal ideation or gestures. He denied any trauma exposure in his military or civilian life. Substance abuse had been a persistent problem for him since age 14

In terms of this 33 year old’s more proximal drug history:

His lifestyle revolved primarily around obtaining and using drugs with concurrent use of opiates and methamphetamine being his preferred regimen immediately prior to his involvement with bath salts.

One of the more fascinating aspects of this Case is that the individual contrasted “bath salts” products which apparently contained either 4-MMC or methylenedioxypyrovalerone (MDPV) and selected the 4-MMC as preferred for reasons of cost and possibly the initial euphoria:

…products containing MDPV conferred realistic hallucinations
(auditory and visual) and a more attenuated, subtle high as prominent features while products containing mephedrone were notable for their stimulant effects…each
compound he sampled shared these features to some degree, the variation in effect between jars was reliable. Further, the jars containing MDPV were more expensive ($45) than those of mephedrone ($26)…effects of MDPV lasted longer and were more enjoyable, Mr. H could not sustain the higher cost…gravitated towards brands containing mephedrone, which provided a more intense initial euphoria which he preferred despite a more severe withdrawal syndrome.

The Case goes on to detail consistent use over a 2 month period with considerable paranoia, disordered thinking and hallucinations as a result. The continued use resulted in severe withdrawal symptoms upon ceasing 4-MMC and these were alleviated only by further 4-MMC or MA use.

Repeated attempts were made, to no avail, to mitigate the withdrawal symptoms with dextroamphetamine/amphetamine, benzodiazepines, and “speedballs” composed of a concoction of an opiate and cocaine. In the end, it was only methamphetamine that relieved his withdrawal symptoms to any significant degree.

The Case closes on a positive note by indicating the subject remained in cessation therapy and was drug free at the time of writing the Report.

In closing, this drug is as yet still incompletely understood in terms of available scientific studies. It is convincingly a stimulant, with many of the same liabilities for compulsive use that attend classic representative drugs such as methamphetamine and cocaine. Yet the neurochemical data suggest a drug with considerable similarity to MDMA which has not been observed to have anywhere near the liability for compulsive use (and ultimately dependence) in both human users and rodent models (see De la Garza et al, 2007 for review). Additional studies can potentially identify whether human experiences like this one in the Case report by Winder and colleagues are likely to be rare or common and why a drug with reduced DA effect (neurochemically) and reduced DA/5-HT ratio of effects is self-administered at higher rates than is MA under similar study conditions.

[Disclaimer: The Taffe laboratory has presented data on the effects of 4-MMC in rat models at several scientific meetings over the past 2 years. We are actively engaged in research on these topics.]
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Baumann, M., Ayestas, M., Partilla, J., Sink, J., Shulgin, A., Daley, P., Brandt, S., Rothman, R., Ruoho, A., & Cozzi, N. (2011). The Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue Neuropsychopharmacology, 37 (5), 1192-1203 DOI: 10.1038/npp.2011.304

Hadlock GC, Webb KM, McFadden LM, Chu PW, Ellis JD, Allen SC, Andrenyak DM, Vieira-Brock PL, German CL, Conrad KM, Hoonakker AJ, Gibb JW, Wilkins DG, Hanson GR, & Fleckenstein AE (2011). 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. The Journal of pharmacology and experimental therapeutics, 339 (2), 530-6 PMID: 21810934

Kehr, J., Ichinose, F., Yoshitake, S., Goiny, M., Sievertsson, T., Nyberg, F., & Yoshitake, T. (2011). Mephedrone, compared to MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and serotonin levels in nucleus accumbens of awake rats British Journal of Pharmacology DOI: 10.1111/j.1476-5381.2011.01499.x

Winder, G., Stern, N., & Hosanagar, A. (2012). Are “Bath Salts” the next generation of stimulant abuse? Journal of Substance Abuse Treatment DOI: 10.1016/j.jsat.2012.02.003

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