AMB-FUBINACA is a potent indazole synthetic cannabinoid that reflects the continued evolution of chemical structures of cannabinoid receptor agonists (Figure 1). Recent in vitro pharmacologic studies of the actions of AMB-FUBINACA at the cannabinoid receptor 1 indicate that it is 85 times as potent as Δ9-THC and 50 times as potent as JWH-018, which was found in the early outbreaks of “K2” synthetic cannabinoid products.5-8 The potency of AMB-FUBINACA is consistent with strong CNS depressant effects that would account for the “zombielike” behavior of the users that was reported in this mass intoxication. Descriptions found on online drug forums (e.g., Reddit) regarding AMB-FUBINACA use terms such as “out of this world potent” with regard to its effects, which are described as being subjectively similar to those of Δ9-THC.28

Despite the potential for overdose, increasingly potent synthetic cannabinoids may have become popular with drug dealers and users because of their low cost and potential for dilution into large volumes of product. A recent Internet query for purchase of AMB-FUBINACA powder showed prices of $1.95 to $3.80 per gram ($1,950 to $3,800 per kilogram). As shown in Table 1, the mean concentration of AMB-FUBINACA found in the packet recovered from the scene described in this report was 16.0 mg per gram. To obtain a 16-mg-per-gram product, a manufacturer could mix 1 kg of AMB-FUBINACA with 66.7 kg of plant material and produce approximately 15,625 packets, each containing 4 g of the product, with an online price averaging $35 per packet.

The absence of the parent compound, AMB-FUBINACA, in the biologic samples that were analyzed is typical for short-acting, potent psychoactive substances. For most esterified drugs, such as AMB-FUBINACA, hydrolysis occurs rapidly after intake, and the corresponding acid metabolites are detectable in biologic samples; the parent compound, however, may be detectable only at low levels.29 For example, the only other serum value reported in the literature for any esterified indazole synthetic cannabinoid parent compound (5F-AMB, 0.19 ng per milliliter) is far below the range we observed for metabolites in biologic samples obtained in this outbreak.30

The concentration of AMB-FUBINACA metabolite observed in serum samples in this case series is similar to the range observed in samples from patients with intoxication caused by a different indazole synthetic cannabinoid (ADB-PINACA) that caused severe delirium in an outbreak in Georgia in 2013.17 The severe behavioral alteration observed in the patients in New York City and reported by the press is consistent with the potent cannabinoid activity of AMB-FUBINACA; intoxication with this agent is unusual in that extreme CNS depression is not accompanied by the tachycardia, arrhythmia, seizures, hyperthermia, cardiotoxicity, and acute kidney injury that are usually found in association with potent or high doses of synthetic cannabinoid. In both the New York and the Georgia outbreaks, there may have been selection bias toward more severe cases because most of the samples analyzed were obtained from hospitals that received the most heavily intoxicated patients.

The cause of a cluster of serious intoxications by a new drug is usually not familiar to the medical community until it is first described in a case series. Identification of the responsible agent requires collaboration among clinical laboratories, health professionals, law enforcement agencies, and synthetic organic chemists so that timely information about the causative agent can be disseminated. The analysis of new psychoactive substances requires more than the typical targeted drug panels used in emergency departments and relies on more sophisticated analytic platforms that have the ability to rapidly identify previously unreported compounds. The clinical history provided by medical professionals aids in toxicologic analysis by eliminating well-characterized agents such as cocaine, heroin, and methamphetamine. The law enforcement agencies involved during an outbreak may be able to provide products and paraphernalia collected during mass intoxications for analysis. This may be especially important when very low concentrations of the drug or its metabolites are present in biologic samples. Finally, the ability to predict and rapidly generate reference standards for new drugs and their metabolites allows for the identification of previously unknown new psychoactive substances for which commercial reference standards are not available for many months after identification of the compound.31 The collaborations in the current AMB-FUBINACA outbreak allowed for characterization of the responsible synthetic cannabinoid in only 17 days. As the number and complexity of new psychoactive substances increases, this type of coordination among multiple agencies is important for the timely resolution of future outbreaks.