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Cited by 57Psychedelics and Drug StudiesNeurotransmitter Receptor Influence on BehaviorAlkaloids: synthesis and pharmacology

Behavioral effects of α,α,β,β-tetradeutero-5-MeO-DMT in rats: comparison with 5-MeO-DMT administered in combination with a monoamine oxidase inhibitor

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Halberstadt, Adam L., Nichols, David E., Geyer, Mark A.·2012·Psychopharmacology
DOI 10.1007/s00213-011-2616-6PMC PMC3796951
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Abstract

Rationale Ayahuasca is a psychoactive tea prepared from a combination of plants that contain a hallucinogenic tryptamine and monoamine oxidase inhibitors (MAOIs). Behavioral pattern monitor (BPM) experiments demonstrated that the combination of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and a behaviorally inactive dose of an MAO(A) inhibitor such as harmaline or clorgyline induces biphasic effects on locomotor activity in rats, initially reducing locomotion and then increasing activity as time progresses.Objectives The present study investigated whether the biphasic locomotor profile induced by the combination of 5-MeO-DMT and an MAOI is a consequence of a reduction in the rate of 5-MeO-DMT metabolism. This hypothesis was tested using a deuterated derivative of 5-MeO-DMT (α,α,β,β-tetradeutero-5-MeO-DMT) that is resistant to metabolism by MAO.Results Confirming our previous findings, 1.0 mg/kg 5-MeO-DMT (s.c.) had biphasic effects on locomotor activity in rats pretreated with a behaviorally inactive dose of the nonselective MAOI pargyline (10 mg/kg). Administration of 5-MeO-DMT alone, even at doses greater than 1.0 mg/kg, produced only reductions in locomotor activity. Although low doses of α,α,β,β-tetradeutero-5-MeO-DMT (0.3 and 1.0 mg/kg, s.c.) produced only hypoactivity in the BPM, a dose of 3.0 mg/kg induced a biphasic locomotor profile similar to that produced by the combination of 5-MeO-DMT and an MAOI. Receptor binding studies demonstrated that deuterium substitution had little effect on the affinity of 5-MeO-DMT for a wide variety of neurotransmitter binding sites.Conclusions The finding with α,α,β,β-tetradeutero-5-MeO-DMT indicates that the hyperactivity induced by 5-MeO-DMT after MAO inhibition is a consequence of reduced metabolism of 5-MeO-DMT, leading to prolonged occupation of central serotonin receptors. These results demonstrate that deuterated tryptamines may be useful in behavioral and pharmacological studies to mimic the effects of tryptamine/MAOI combinations.

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  • 5-MeO-DMT has considerably higher affinity at 5HT1-like sites compared to 5HT2-like sites in vitro, and 5HT1A and 5HT2A/B antagonists are equally effective in blocking its behavioral effects in rats.

    “Indeed, 5-MeO-DMT (15) has considerably higher affinity at 5HT1-like sites compared to 5HT2-like sites in vitro [56], and 5HT1A and 5HT2A/B antagonists are equally effective in blocking its behavioral effects in rats [133].”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [56]

    The citation to this paper is attached to the claim that 5-HT1A and 5-HT2A/B antagonists are equally effective at blocking behavioral effects in rats. The Discussion instead reports that 5-MeO-DMT-induced hyperactivity with an MAO inhibitor was blocked by a selective 5-HT2A antagonist but unaffected by a selective 5-HT1A antagonist; the supplied passage does not address 5-HT2B antagonism. (LLM, conf=0.90)

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  • 5-MeO-DMT has similar affinity at 5HT2A receptors (Ki = 200 nM), under binding conditions where LSD had a Ki of only 1 nM, and had >100-fold selectivity for 5HT1A/B/C receptors relative to 5HT2A receptors in vitro.

    “5-MeO-DMT (15) has similar affinity at 5HT2A receptors (Ki = 200 nM), under binding conditions where LSD (1) had a Ki of only 1 nM [47], and had >100-fold selectivity for 5HT1A/B/C receptors relative to 5HT2A receptors in vitro [56].”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [56]

    The Results (Radioligand binding experiments; page unavailable) report binding across serotonin receptors, and the Discussion describes relatively low 5-HT2A affinity of about 0.9 μM. The available passages do not establish greater than 100-fold selectivity for 5-HT1A/B/C over 5-HT2A; the 200 nM and LSD comparison is attached to a different citation in the citing sentence. (LLM, conf=0.78)

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  • Despite 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 [56]

  • Deuterium substitution of 5-MeO-DMT, which results in reduced metabolism, increased its behavioral effects in rats to a profile similar to that evoked by ordinary 5-MeO-DMT in conjunction with MAO-A inhibition.

    “Finally, deuterium substitution of 5-MeO-DMT (15), which results in reduced metabolism, increased its behavioral effects in rats to a profile similar to that evoked by ordinary 5-MeO-DMT (15) in conjunction with MAO-A inhibition [56].”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [56]

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Research works printed but not linked: 2

  1. Geyer MA 1990 Approaches to the characterization of drug effects on locomotor activity in rodents Adler MW Cowan A Modern methods in pharmacology: testing and evaluation of drugs of abuse Wiley-Liss New York 81 99
  2. Glennon RA Rosecrans JA Young R 1982 The use of the drug discrimination paradigm fpr studying hallucinogenic agents. A review Colpaert FC Slangen JL Drug Discrimination: Applications in CNS Pharmacology Elsevier Amsterdam 69 96

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Authors
Halberstadt, A. L., Nichols, D. E., & Geyer, M. A.
Affiliations
  • University of California San Diego (US)
  • Purdue University West Lafayette (US)
Corresponding author
Halberstadt, Adam L.
ORCID
Venue
Psychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2012-01-06
Volume
221
Issue
4
Pages
709-718
ISSN
  • 0033-3158 (ISSN-L)
  • 1432-2072
DOI
10.1007/s00213-011-2616-6
PMC
PMC3796951
OpenAlex
W1996279456
Cited by
57
References
70
Citations by year
2026: 10 · 2025: 10 · 2024: 10 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 1 · 2016: 4 · 2014: 3 · 2012: 2
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Psychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Drug Abuse (F32DA025412, R01DA002925)
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 › Pharmacology › Alkaloids: synthesis and pharmacology
Keywords
5-MeO-DMT, monoamine oxidase inhibitors, pargyline, ayahuasca, drug metabolism, serotonin receptors, deuteration, receptor binding affinity, rats
MeSH terms
Animals, Behavior, Animal, Bufotenin, Deuterium, Dose-Response Relationship, Drug, Drug Therapy, Combination, Male, Methoxydimethyltryptamines, Monoamine Oxidase Inhibitors, Motor Activity, Pargyline, Receptors, Serotonin, Rats, Sprague-Dawley, Rats

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