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, A.r. Chadeayne, Marilyn Naeem, David R. Manke, John D. Mccorvy, Michael H. Baumann
ACS Chemical Neuroscience May 27, 2026 Peer reviewed DOI: 10.1021/acschemneuro.6c00083 via OpenAlex
Summary
4-Methoxy-N-methyl-N-isopropyltryptamine (4-MeO-MiPT) is a serotonin 2A receptor agonist that also inhibits the serotonin transporter, leading to reduced psychedelic effects in mice. In studies with C57BL/6J mice, 4-MeO-MiPT and its analogs showed potent inhibition of serotonin uptake, with an IC50 range of 17-107 nM. Although 4-HO- and 4-MeO-MiPT had similar potencies for inducing head twitches, 4-MeO-MiPT exhibited lower efficacy. These findings suggest that 4-MeO-MiPT could have therapeutic applications with fewer traditional psychedelic effects.
Study at a glance
| Population | C57BL/6J mice |
|---|---|
| Key finding | 4-MeO-MiPT interacts with serotonin receptors and inhibits the serotonin transporter, reducing the efficacy of psychedelic-like effects in mice. |
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.