BACKGROUND AND AIMS: While the health hazards of synthetic cannabinoid receptor agonists (SCRAs) are often approximated using in vitro pharmacological parameters as surrogate, this approach fails to consider pharmacokinetic and pharmacodynamic complexity. This study aimed to develop a practical risk score for SCRAs prevalent in Germany between 2013 and 2021, based on prevalence data and differentiated data on intoxication cases in the same period of time.

DESIGN: The score integrates data from routine forensic serum/blood and urine analysis and clinical data from a prospective study involving emergency department patients after consumption of new psychoactive substances (NPS) (symptoms and quantification data).

SETTING: SCRA prevalence data were obtained from a database query of routine serum/blood and urine analyses conducted at the Institute of Forensic Medicine Freiburg (2013-2021). Intoxication case data were obtained from a prospective study of patients treated in German emergency departments and reported to the Poisons Information Center Freiburg.

PARTICIPANTS/CASES: During the study period, 9929 serum/blood and 45 464 urine samples were routinely analysed for SCRAs. Forty-eight non-fatal intoxications with clinical symptoms were included, with written consent provided by participants.

MEASUREMENTS: Twelve SCRAs were selected based on their prevalence. Quantification in serum/blood and urine samples was conducted with liquid chromatography tandem mass spectrometry. The human cannabinoid receptor 1 affinities and activities were assessed using a competitive radioligand binding assay with [H]CP-55940 and the functional [S]GTPγS assay.

FINDINGS: From 2013 to 2021, 1633 serum/blood and 8030 urine samples tested positive for one or more SCRAs (positive rate serum/blood: 16.5%; urine: 17.7%). The risk score comprises three parts: (1) SCRA prevalence in routine case samples relative to the occurrence of intoxication cases in a certain time-frame; (2) the Poison Severity Score; and (3) Toxicological Significance Score, to account for the extent to which each substance contributed to the observed clinical symptoms and consequently to the overall intoxication. The higher the risk score value, the greater the associated toxicological risk of an SCRA in the test set. Risk score values ranged from 9.9 (5F-PB-22) to 3.1 (5F-Cumyl-PEGACLONE). No inverse relationship was observed between the risk score ranking and the receptor affinity or activity values based on visual comparison of the respective plots.

CONCLUSIONS: In vitro potency of synthetic cannabinoid receptor agonists (SCRAs) does not clearly correlate with harm potential, and hence other properties of the SCRAs seem to be involved. The risk score introduced here provides a novel framework for assessing the potential hazards of emerging SCRAs by integrating routine forensic data with clinical intoxication case analyses.