Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes
Open accessAbstract
Rationale Synthetic hallucinogenic tryptamines, especially those originally described by Alexander Shulgin, continue to be abused in the USA. The range of subjective experiences produced by different tryptamines suggests that multiple neurochemical mechanisms are involved in their actions, in addition to the established role of agonist activity at serotonin 2A (5-HT₂A) receptors. Objectives This study evaluated the interaction of a series of synthetic tryptamines with biogenic amine neurotransmitter transporters and with serotonin (5-HT) receptor subtypes implicated in psychedelic effects. Methods Neurotransmitter transporter activity was determined in rat brain synaptosomes. Receptor activity was determined using calcium mobilization and DiscoveRx PathHunter assays in HEK293, Gα16-CHO, and CHOk1 cells transfected with human receptors. Results Twenty-one tryptamines were analyzed in transporter uptake and release assays, and 5-HT₂A, serotonin 1A (5-HT₁A), and 5-HT₂A β-arrestin functional assays. Eight of the compounds were found to have 5-HT-releasing activity. Thirteen compounds were found to be 5-HT uptake inhibitors or were inactive. All tryptamines were 5-HT₂A agonists with a range of potencies and efficacies, but only a few compounds were 5-HT1A agonists. Most tryptamines recruited β-arrestin through 5-HT₂A activation. Conclusions All psychoactive tryptamines are 5-HT₂A agonists, but 5-HT transporter (SERT) activity may contribute significantly to the pharmacology of certain compounds. The in vitro transporter data confirm structure-activity trends for releasers and uptake inhibitors whereby releasers tend to be structurally smaller compounds. Interestingly, two tertiary amines were found to be selective substrates at SERT, which dispels the notion that 5-HT-releasing activity is limited only to primary or secondary amines.
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The generally low affinity of DMT seen in [3H]-ketanserin displacement studies in vitro seems at odds with its much greater potency in functional assays, which showed a 38 nM EC50 for calcium mobilization in vitro.
“The generally low affinity of DMT (15) seen in [3H]-ketanserin displacement studies in vitro seems at odds with its much greater potency in functional assays, which showed a 38 nM EC50 for calcium mobilization in vitro [52].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [52]
The Discussion (page unavailable) includes DMT among the compounds active as 5-HT2A agonists in a calcium-mobilization assay. It does not give a 38 nM calcium-mobilization EC50 for DMT or report the claimed low affinity in [3H]-ketanserin displacement studies; searches for both details found no supporting passage. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDespite its relatively low affinity in vitro, 5-MeO-DMT had a comparably high EC50 of 4 nM at 5HT2A sites in a functional assay of intracellular calcium mobilization, confirming its higher potency at these sites compared to DMT.
“Despite its relatively low affinity in vitro [56], 5-MeO-DMT (15) had a comparably high EC50 of 4 nM at 5HT2A sites in a functional assay of intracellular calcium mobilization [52], confirming its higher potency at these sites compared to DMT (9).”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [52]
The Discussion (page unavailable) identifies 5-MeO-DMT as compound 7 and reports low-nanomolar 5-HT2A potency for methoxy compounds, greater than for unsubstituted compounds, in a calcium-mobilization assay. The Methods confirm that this assay generated EC50 values. The passages available from our copy do not give the specific 4 nM EC50; the low-affinity statement is attached to a different citation in the citing sentence. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe IC50 of DMT and its derivatives at 5HT2A sites did not seem to correlate with visual hallucination intensity in humans.
“Furthermore, the IC50 of DMT (9) and its derivatives at 5HT2A sites did not seem to correlate with visual hallucination intensity in humans [52].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [52]
The Introduction says that not all 5-HT2A agonists are psychedelics, and the Discussion reports receptor activity for tryptamines. Neither section assesses whether DMT derivatives’ 5-HT2A IC50 values correlate with the intensity of visual hallucinations in humans (searched for visual hallucinations, human intensity, and receptor-potency correlations). (LLM, conf=0.76)
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“Furthermore, the IC50 of DMT (9) and its derivatives at 5HT2A sites did not seem to correlate with visual hallucination intensity in humans [52].”
BackgroundResult
- Authors
- Blough, B. E., Landavazo, A., Decker, A. M., Partilla, J. S., Baumann, M. H., & Rothman, R. B.
- Affiliations
- RTI International (US)
- National Institutes of Health (US)
- Corresponding author
- Blough, Bruce E.
- Venue
- Psychopharmacology
- Published
- 2014-05-07
- Volume
- 231
- Issue
- 21
- Pages
- 4135-4144
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC4194234
- OpenAlex
- W2080760021
- Cited by
- 101
- References
- 5
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 17 · 2023: 11 · 2022: 12 · 2021: 8 · 2020: 7 · 2019: 3 · 2018: 8 · 2017: 4 · 2016: 4 · 2015: 4
- FWCI
- 4.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (R01DA012970)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
- Keywords
- hallucinogens, 5-HT2A receptor, serotonin transporter, 5-HT1A receptor, serotonin release, beta-arrestin, structure-activity relationship, tertiary amines
- MeSH terms
- beta-Arrestins, Animals, Brain, Hallucinogens, Humans, Receptors, Serotonin, Serotonin, Synaptosomes, Tryptamines, Selective Serotonin Reuptake Inhibitors, Arrestins, Dopamine Plasma Membrane Transport Proteins, Norepinephrine Plasma Membrane Transport Proteins, Serotonin Plasma Membrane Transport Proteins, Rats, HEK293 Cells
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