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J Anal Toxicol. 2016 April; 40(3): 240–242.
Published online 2016 January 27. doi:  10.1093/jat/bkw004
PMCID: PMC4885926

Reply to ‘Sudden Cardiac Death Following Use of the Synthetic Cannabinoid MDMB-CHMICA’

In a letter to the editor, Westin et al. described a case of sudden cardiac arrest after the consumption of a brown powder containing MDMB-CHMICA (methyl-(S)-2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate) (1). In this case, 1.4 ng/mL MDMB-CHMICA was detected in the serum sample obtained 2 h postconsumption and the intake of this synthetic cannabinoid was assumed as the most probable cause of death by the authors. MDMB-CHMICA seems to be an extremely potent drug mediating its effects via agonist activity at the CB1 receptor of the endocannabinoid system (2). Since December 2014, numerous nonfatal and fatal intoxication cases involving this compound have been reported (3). Given the high prevalence and the limited data published in the scientific literature so far we would like to add some more data on MDMB-CHMICA serum concentrations encountered in forensic case work. It has to be noted that the semisystematic nomenclature used by producers and retailers of synthetic drugs may lead to confusion regarding the exact chemical structures. MDMB-CHMICA is often offered on the Internet under the name ‘MMB-CHMINACA’, which falsely implies an indazole core structure. Since its first appearance as a pure powder in an online shop selling research chemicals in September 2014, we have encountered this compound as an additive in 81 different brands of herbal mixtures during product monitoring activities in the frame of the EU-projects ‘Spice II Plus’ (JUST/2011/DPIP/AG/3597) and ‘Spice profiling’ (JUST/2013/ISEC/DRUGS/AG/6421). In our routine forensic analysis, we use a validated method currently detecting 94 synthetic cannabinoids in serum. Samples undergo a liquid–liquid extraction with hexane/ethyl acetate followed by analysis with a QTRAP® 4000 tandem mass spectrometer (Sciex, Darmstadt, Germany) in scheduled MRM mode with at least two ion transitions for each analyte. In the period of September 2014 to August 2015, we detected MDMB-CHMICA in 140 serum samples with this method (total number of samples analyzed for synthetic cannabinoids in this period: 1,046). In 30 of the cases, only trace amounts (<0.10 ng/mL) of MDMB-CHMICA were detected. The MDMB-CHMICA concentrations in the other 110 samples ranged from 0.10 to 91 ng/mL (median: 0.67 ng/mL, mean: 3.5 ng/mL). Among these were seven cases involving uptake of MDMB-CHMICA, for which comprehensive toxicological screening analyses were carried out (Table I). In five of the serum samples, no additional synthetic cannabinoids or other drugs were detected. In two of the samples, a second synthetic cannabinoid was detected in the serum sample (Figure 1). The highest concentration of MDMB-CHMICA (91 ng/mL) was determined in the serum sample of a 32-year-old man (Case #1), who was arrested because of selling herbal blends containing synthetic cannabinoids. In this case, 3,4-methylenedioxymethamphetamine (MDMA) (150 ng/mL) and 3,4-methylenedioxyamphetamine (MDA) (16 ng/mL) were also detected in the serum sample. The lowest concentration (<0.1 ng/mL) was detected in the serum sample of a 15-year-old boy who was offered a cigarette for smoking. After smoking, he started to vomit and became unresponsive. He was transferred to a pediatric clinic.

Table I.
Patients' Characteristics, Time Post Ingestion (p.i.) Reported Symptoms, Synthetic Cannabinoid(s) Detected in Serum Samples and Results of Further Toxicological Analysis
Figure 1.
Chemical structures of MDMB-CHMICA, AB-CHMINACA and 5F-PB-22.

On the basis of the presented cases (Table I), it is evident that MDMB-CHMICA is indeed a highly problematic substance with a distinct toxicity profile and a high potency. However, severity of intoxication symptoms cannot be correlated directly with serum concentrations. In particular, there were several cases with serum concentrations in the range of the concentration reported by Westin et al. showing no signs of severe toxicity. Several facts could be taken into account as an explanation for this observation. Compared with THC, synthetic cannabinoids show additional and more severe side effects (4, 5), which can most likely be attributed to the full agonist activity at the CB1 receptor confirmed for many synthetic cannabinoids with indole core structures (2, 6). Most of the synthetic cannabinoids seem to have strong effects on the cardiovascular system (5). Consequently, it is important to consider pre-existing conditions of this system for an accurate interpretation regarding the cause of death. Furthermore, a frequent use of synthetic cannabinoids probably leads to tolerance (Case #1), which is often reported by ‘Spice’ users (5). In accordance with our data, high serum concentrations can be expected in frequent users without necessarily leading to adverse effects. Cross tolerance may be observed (7), and change of active ingredients potentially leads to higher toxicity in such users due to specific toxicity mechanisms (e.g., organ toxicity). In case of postmortem toxicology, it is inevitable to take postmortem redistribution of the substance into account when interpreting serum concentrations. It is known that postmortem blood/serum concentrations of cannabinoids and other highly lipophilic drugs may decline significantly during the postmortem interval due to diffusion of the compounds into other tissues (8). Additionally, further aspects such as the formation of pharmacologically active metabolites (as shown for, e.g., JWH-018 and AM-2201 (912)) and the plasma–blood ratio, which is probably well above 1.0 due to high plasma protein binding, have to be taken into consideration.

Therefore, each case has to be discussed individually taking into account all available information. Focusing too closely on measured blood concentrations may lead to wrong conclusions, particularly in postmortem investigations.

Funding

This publication has been produced with the financial support of the ‘Drug Prevention and Information Programme’ (JUST/2011/DPIP/AG/3597) and the ‘Prevention of and Fight against Crime’ (JUST/2013/ISEC/DRUGS/AG/6421) of the European Union, the German Federal Ministry of Health and the City of Frankfurt/Main, Germany. The contents of the paper are the sole responsibility of the authors and can in no way be taken to reflect the views of the European Commission.

Conflict of interest

The authors declare that no conflict of interest exists.

References

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2. Angerer V., Moosmann B., Franz F., Auwärter V. (2015) 5F-Cumyl-PINACA in ‘e-liquids for electronic cigarettes—a new type of synthetic cannabinoid in a trendy product. In 53rd Annual Meeting of the International Association of Forensic Toxicologists (TIAFT), Firenze, Italy, 09.08.–04.09.2015 https://www.uniklinik-freiburg.de/fileadmin/mediapool/08_institute/rechtsmedizin/pdf/Poster_2015/Angerer_V_-_5F-cumyl-PINACA_in_e-liquids_for_electronic_cigarettes_-_2015.pdf (accessed Dec 04, 2015).
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