Serotonin Transporter Blockade Reduces the Psychedelic-Like Effects of 4-Methoxy- N -methyl- N -isopropyltryptamine and Related Analogs
Grant C. Glatfelter, Serena S. Schalk, Donna Walther, Alexander D. Maitland, Nicholas R. Gonzalez, John S. Partilla, Nicholas A. Anas, Andrew R Chadeayne, Marilyn Naeem, David R. Manke, John D. Mccorvy, Michael H. Baumann
ACS Chemical Neuroscience May 27, 2026 DOI: 10.1021/acschemneuro.6c00083 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | C57BL/6J mice |
| Interventions | 4-MeO-MiPT 4-HO-MiPT 4-MeO-DiPT 4-HO-DiPT 4-MeO-McPT 4-HO-McPT fluoxetine |
| Dose | 0.03–30 mg/kg for 4-HO-MiPT and 4-MeO-MiPT; 10 mg/kg for fluoxetine |
| Topics | Serotonin 5-MeO-DMT |
| Keywords | Serotonin transporter Tryptamine Partial agonist Blockade Reuptake inhibitor Pharmacology Intrinsic activity 5-HT Receptor Fluoxetine In vivo In vitro Serotonin antagonists |
| Key findings | 4-MeO-MiPT and its analogs with potent SERT inhibition show reduced psychedelic-like effects in mice compared to their 4-hydroxy counterparts, indicating that SERT blockade attenuates 5-HT2A-mediated responses. |
Abstract
High Resolution Image Download MS PowerPoint Slide Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT 2A ), but the compounds are generally nonselective. 4-Methoxy- N -methyl- N -isopropyltryptamine (4-MeO-MiPT) is a 5-HT 2A agonist which also blocks the 5-HT transporter (SERT) and has blunted visual and other psychedelic effects in humans. Here, we compared the pharmacology of 4-MeO-MiPT, its 4-hydroxy derivative (4-HO-MiPT), and related analogs with N- alkyl or 4-alkoxy variations. We hypothesized that compounds with more potent SERT uptake inhibition would display reduced 5-HT 2A -mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro target profiling revealed potent and efficacious 5-HT receptor activities for most of the compounds, including 5-HT 2A receptor agonism (EC 50 = 10–118 nM, E max = 72–97% 5-HT). Importantly, 4-MeO-MiPT and its N, N -diisopropyl (4-MeO-DiPT) and N -methyl- N -cyclopropyl (4-MeO-McPT) analogs displayed more potent uptake inhibition at SERT (IC 50 = 17–107 nM) than their 4-OH counterparts (IC 50 = 280–423 nM). Studies administering the drugs subcutaneously to C57BL/6J mice revealed that 4-HO- and 4-MeO-MiPT (0.03–30 mg/kg) had similar potencies for inducing HTRs (ED 50 = 0.75 vs 0.97 mg/kg), but 4-MeO-MiPT had reduced efficacy ( E max = 77 vs 34 HTRs/30 min). A similar trend for decreased HTRs was observed for 4-MeO-DiPT and 4-MeO-McPT. Pretreatment with the SERT inhibitor fluoxetine (10 mg/kg) prior to 4-HO-MiPT, 4-HO-DiPT, or 4-HO-McPT reduced the maximal number of HTRs to levels observed for their respective 4-MeO analogs. Overall, our data indicate that 4-MeO-MiPT interacts with 5-HT 2A and other 5-HT receptors, but the drug also inhibits SERT to reduce the efficacy of psychedelic-like effects in mice. Therefore, 4-MeO-MiPT and other dual 5-HT 2A /SERT ligands may be therapeutically relevant compounds with reduced potential for traditional acute psychedelic effects.