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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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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 MAOA 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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Acknowledgements

Supported by National Institute on Drug Abuse Awards R01 DA002925 and F32 DA025412, and the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding data were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Dr. Bryan Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. For experimental details, please refer to the PDSP web site: http://pdsp.med.unc.edu/.

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Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, La Jolla, CA, USA

    Adam L. Halberstadt & Mark A. Geyer

  2. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy—RHPH, Purdue University, West Lafayette, IN, USA

    David E. Nichols

  3. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0804, USA

    Adam L. Halberstadt

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  1. Adam L. Halberstadt
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Correspondence to Adam L. Halberstadt.

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Supported by National Institute on Drug Abuse Awards R01 DA002925 and F32 DA025412 and the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center.

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Halberstadt, A.L., Nichols, D.E. & Geyer, M.A. 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. Psychopharmacology 221, 709–718 (2012). https://doi.org/10.1007/s00213-011-2616-6

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