Monoamine neurotransmitter transporters (MAT) are a class of membrane proteins that fine-tune synaptic transmission by reuptaking monoamines after synaptic release, making them important molecular targets. Amphetamine-like substrates reverse the transport direction of MAT and trigger unrestrained neurotransmitter release in an exocytosis-independent manner, leading to several unwanted effects. Partial efficacy refers to a ligand's ability to induce less than maximal response with the protein of interest. While partial efficacy at G protein-coupled receptors (GPCRs) has been extensively described, the phenomenon has not been well characterized at MAT. Our research intends to uncover partial efficacy at MAT, addressing the critical issue of unrestrained neurotransmitter release and undesirable off-target effects associated with full efficacious substrates like amphetamine or fenfluramine. In the current study, we have systematically probed known classical chemical compounds ranging from tryptamine to piperazine in MAT-expressing HEK293 cells by combining radioactive uptake inhibition, transporter-mediated efflux assay, and transporter electrophysiology. Among the compounds tested at serotonin transporter (SERT), three out of seven were found to act as partial substrates. Notably, meta-Chlorophenylpiperazine (mCPP), 1-Phenylpiperazine(1-PPZ), and para-Trifluoromethyl-methcathinone (S-pTF-MCAT) robustly demonstrated partial efficacy, showing a previously underexplored molecular switch within modulation of neurotransmitter transport. These substrates induce efflux via SERT at a lower magnitude (mCPP: Emax=32%; 1-PPZ: Emax=30%; S-pTF-MCAT: Emax=70%) compared to the fully efficacious releasing agents. Thus, our findings provide structure-activity relationships of partial efficacy at MAT and suggest that drug-induced efflux could be chemically fine-tuned to maximize therapeutic response while reducing off-target effects, potentially offering a novel therapeutic strategy for treating neuropsychiatric diseases.