Journal of Neural Transmission

, 116:1591 | Cite as

Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter

  • Nicholas V. CozziEmail author
  • Anupama Gopalakrishnan
  • Lyndsey L. Anderson
  • Joel T. Feih
  • Alexander T. Shulgin
  • Paul F. Daley
  • Arnold E. Ruoho
Basic Neurosciences, Genetics and Immunology - Original Article


N,N-dimethyltryptamine (DMT) is a potent plant hallucinogen that has also been found in human tissues. When ingested, DMT and related N,N-dialkyltryptamines produce an intense hallucinogenic state. Behavioral effects are mediated through various neurochemical mechanisms including activity at sigma-1 and serotonin receptors, modification of monoamine uptake and release, and competition for metabolic enzymes. To further clarify the pharmacology of hallucinogenic tryptamines, we synthesized DMT, N-methyl-N-isopropyltryptamine (MIPT), N,N-dipropyltryptamine (DPT), and N,N-diisopropyltryptamine. We then tested the abilities of these N,N-dialkyltryptamines to inhibit [3H]5-HT uptake via the plasma membrane serotonin transporter (SERT) in human platelets and via the vesicle monoamine transporter (VMAT2) in Sf9 cells expressing the rat VMAT2. The tryptamines were also tested as inhibitors of [3H]paroxetine binding to the SERT and [3H]dihydrotetrabenazine binding to VMAT2. Our results show that DMT, MIPT, DPT, and DIPT inhibit [3H]5-HT transport at the SERT with K I values of 4.00 ± 0.70, 8.88 ± 4.7, 0.594 ± 0.12, and 2.32 ± 0.46 μM, respectively. At VMAT2, the tryptamines inhibited [3H]5-HT transport with K I values of 93 ± 6.8, 20 ± 4.3, 19 ± 2.3, and 19 ± 3.1 μM, respectively. On the other hand, the tryptamines were very poor inhibitors of [3H]paroxetine binding to SERT and of [3H]dihydrotetrabenazine binding to VMAT2, resulting in high binding-to-uptake ratios. High binding-to-uptake ratios support the hypothesis that the tryptamines are transporter substrates, not uptake blockers, at both SERT and VMAT2, and also indicate that there are separate substrate and inhibitor binding sites within these transporters. The transporters may allow the accumulation of tryptamines within neurons to reach relatively high levels for sigma-1 receptor activation and to function as releasable transmitters.


Biogenic amine Dihydrotetrabenazine Dimethyltryptamine DMT Dipropyltryptamine DPT Diisopropyltryptamine DIPT Methylisopropyltryptamine MIPT Psychedelic Paroxetine Serotonin Sigma-1 receptor Tetrabenazine 


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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Nicholas V. Cozzi
    • 1
    Email author
  • Anupama Gopalakrishnan
    • 1
  • Lyndsey L. Anderson
    • 1
  • Joel T. Feih
    • 1
  • Alexander T. Shulgin
    • 2
  • Paul F. Daley
    • 3
  • Arnold E. Ruoho
    • 1
  1. 1.Department of PharmacologyUniversity of Wisconsin School of Medicine and Public HealthWisconsinUSA
  2. 2.LafayetteUSA
  3. 3.Addiction Pharmacology Research LaboratoryCalifornia Pacific Medical Center Research InstituteSan FranciscoUSA

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