Wednesday, December 10, 2014

Case Report - Synthetic Cannabinoid NNEI Related Death

A case of death caused by abuse of a synthetic cannabinoid N-1-naphthalenyl-1-pentyl-1H-indole-3-carboxamide
Sasaki C, Saito T, Shinozuka T, Irie W, Murakami C, Maeda K, Nakamura N, Oishi M, Nakamura S, Kurihara K
Forensic Toxicology (2014) DOI 10.1007/S11419-014-0246-5

This case was reported out of the Department of Legal Medicine, Kitasato University School of Medicine; the Department of Emergency and Critical Care Medicine, Tokai University School of Medicine; and the Department of Pathophysiology, Yokohama College of Pharmacy in Japan. The report describes a death associated with the synthetic cannabinoid, N-1-naphthalenyl-1-pentyl-1H-indole-3-carboxamide.

This synthetic cannabinoid is also known as NNEI and is an indole carboxamide structural variant. NNEI is compared to other synthetic cannabinoid structures below.

A male (age was described as “in his twenties”) was found deceased on the floor in his bedroom. A package of “Fairy Evolution” herbal product was found in the vicinity. No medical history was known.

The Fairy Evolution herbal product was tested and NNEI was the only substance detected.

Exhaustive toxicological analyses were undertaken. Plasma, whole blood, urine, brain, heart, lung, liver, kidney, hair, and adipose tissue were analyzed. Femoral blood concentrations were 0.99 and 0.84 ng/mL (right and left vein respectively). NNEI was detected in all specimens analyzed, except urine. No other drugs or metabolites were detected in any biological specimens. Disposition of drug is discussed in the paper.

Pulmonary edema was detected at autopsy. The total weight of the lungs was 1,750 grams. Organs showed considerable congestion.

Arteriolar wall hypertrophy, slight interstitial fibrosis and contraction bands were detected in the heart.

Marked congestion and alveolar macrophage infiltrations were observed in the lungs.

Slight lymphocytic infiltrations were observed in liver.

Arteriolar hyalinization and severe splenic congestion was observed.

Corporal amylacea were observed in the corpus callosum in the brain.

No other remarkable findings were observed.

The authors determined cause of death to be associated NNEI and concluded that the acute circulatory disturbance to be induced by “NNEI poisoning”.  Manner of death was not disclosed in the paper, but my assumption is that it would be accidental or undetermined.

It is interesting to note that New Zealand preemptively banned NNEI from the market in 2012 due to the hypothesized formation of possible carcinogenic metabolites. It was hypothesized that the amide linkage could be hydrolyzed by carboxylesterases resulting in formation of 1-aminonaphthalene, a known carcinogenic substance. This was previously covered here. It has now been shown in in vitro experiments published by Thomsen et al. that carboxylesterase 1 (CES1) is the major hepatic and pulmonary enzyme that is responsible for the amide hydrolysis during metabolism of the indazole carboxamide synthetic cannabinoids AB-FUBINACA and AB-PINACA. As you can see from the structure representation above, AB-PINACA and NNEI share this same amide linkage. It is logical that NNEI would be metabolized via the same pathway.

Ultimately, I am ecstatic that we have seen a few papers published lately that describe case history + pathology/physical findings at autopsy + toxicology findings and analytical confirmation of substance.


  1. Very interesting post, and I have a couple questions if you'd be so kind.. First, in the paragraph on hydrolyzation, should one draw the conclusion that the carcinogen mentioned likely IS metabolized from NNE1? If so, are you saying it would also be metabolized in AB-FUBINACA and AB-PINACA?

    Secondly, in the toxicology report, as a near-laymen reading "No other drugs or metabolites were detected in any biological specimens", should I assume here and elsewhere that this means no unidentified spikes occur in the analysis? Or does this have the narrower interpretation that nothing was identified though the presence of other materials is not precluded? Thanks

  2. Thanks for the link to the article. I am a forensic pathologist and have been searching for microscopic findings on synthetic cannabinoid deaths. Most significant are the lung and brain findings on the few cases I have. Many corpora amylacea throughout the brain but more in the temporal lobes, almost looks like a neurodegenerative disease. The lungs are congested, but often there is frank hemorrhage on the users who die immediately after smoking. The heart does have interstitial fibrosis on histology. I usually have a history of synthetic cannabinoid use by family or friends but in 50% of the cases toxicology does not find the synthetic drug, even after working with a toxicologist, since the synthetics keep changing their compounds. Thanks again for this post.

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