The neurotensin (NT) system is an endogenous regulator of central dopaminergic neurotransmission and peptide neurotensin receptor 1 (NTR1) agonists have shown efficacy in animal models of schizophrenia and addiction. Several decades of effort to identify small molecule NTR1 agonists in Gq protein-based assays have led to very few drug candidates. Through the MLPCN effort and lead optimization, we have identified an allosteric, small molecule NTR1 ligand that is biased and fully effective at promoting NTR1/β-arrestin interactions with or without the endogenous ligand. This ligand, SBI-553, increases the availability of NT-NTR1 binding sites, increases NT-NTR1 affinity, and promotes β-arrestin-associated cellular responses while antagonizing NTR1 G protein signaling. However, SBI-553 does not compete for the NT-NTR1 at the orthostatic site. In vivo, SBI-553 attenuates cocaine and/or opiate self-administration and psychostimulant-induced hyperlocomotion without the dose-limiting side effects characteristic of conventional unbiased NTR1 agonism. These pharmacological effects are dependent on β-arrestin2 in dopamine D2 receptor-expressing spiny projection neurons (SPN) or MSNs. These data support an allosteric model for G protein-coupled receptor signaling and demonstrate the ability of an exogenous compound to confer functional selectivity/biased signaling onto an endogenous ligand.