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Indole‐ and indazole‐based synthetic cannabinoid receptor agonists (SCRAs), featuring valine or tert‐leucine substituents, are commonly abused new psychoactive substances (NPS). A major metabolic pathway for these SCRAs is hydrolysis of the terminal amide or methylester functionalities. Although these hydrolysis products were already detected as main ingredients in some “legal highs,” these metabolites are often poorly characterized. Here, we report a systematic investigation of the activity of 7 common hydrolysis metabolites of 15 SCRAs featuring scaffolds based on L‐valine or L‐tert‐leucine in direct comparison to their parent compounds. An activity‐based cannabinoid receptor 1 (CB₁) bio‐assay was used for activity profiling of SCRAs and their metabolites in a stable HEK293T cell system. The recruitment of β‐arrestin2 to the activated CB₁ (each fused to one part of a split Nanoluciferase) was …