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Psychopharmacology

, Volume 98, Issue 4, pp 495–499 | Cite as

Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis

  • Bernard Sadzot
  • Jay M. Baraban
  • Richard A. Glennon
  • Robert A. Lyon
  • Sigrun Leonhardt
  • Chung-Ren Jan
  • Milt Titeler
Original Investigations

Abstract

It has been shown that the hallucinogenic potencies of LSD, the phenylisopropylamines, such as DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) and DOI (4-iodo-2,5-dimethoxyphenylisopropylamine), and the indoleaklylamines, such as DMT (dimethyltryptamine) and 5-OMe-DMT (5-methoxy-dimethyltryptamine), strongly correlate with their in vitro 5-HT2 receptor binding affinities in rat cortical homogenates. In order to ascertain if this correlation applies to human 5-HT2 receptors as well, we examined the affinities of 13 psychoactive compounds at 3H-ketanserin-labelled 5-HT2 receptors in human cortical samples. Both radioligand binding and autoradiographical procedures were used. As in rat brain d-LSD was the most potent displacer of 3H-ketanserin specific binding with a Ki of 0.9 nM. The phenylisopropylamine DOI also displayed high affinity (Ki of 6 nM). Stereospecific interactions were found with DOB; (-_ DOB had a Ki of 17 nM while (+) DOB had a Ki of 55 nM. The behaviorally active compound DOM (4-methyl-2,5-phenylisopropylamine) had an affinity of 162 nM while its behaviorally less active congener iso-DOM had an affinity of 6299 nM. The indolealkylamines 5-OMe-DMT and DMT competed with moderate affinities (207 and 462 nM, respectively). In general, Hill coefficients were significantly less than unity which is consistent with an agonist interaction with 5-HT2 receptors. MDMA, a substituted amphetamine analog was inactive with a Ki of greater than 10 μM. A strong correlation was found for the hallucinogen affinities and human hallucinogenic potencies (r=0.97). Also, human and rat brain 5-HT2 receptor affinities were strongly correlated (r=0.99). These results strongly support the hypothesis that the hallucinogenic effects of these drugs in humans are mediated in whole or in part via 5-HT2 receptors. Furthermore, these studies imply that treatment with 5-HT2 receptor antagonists may be effective in reversing the hallucinogenic effects caused by the ingestion, of LSD and LSD-like drugs.

Key words

Hallucinogen DOB DOI 5-HT2 receptor LSD 

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Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Bernard Sadzot
    • 1
  • Jay M. Baraban
    • 1
  • Richard A. Glennon
    • 3
  • Robert A. Lyon
    • 4
  • Sigrun Leonhardt
    • 2
  • Chung-Ren Jan
    • 2
  • Milt Titeler
    • 2
  1. 1.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Pharmacology and ToxicologyAlbany Medical CollegeAlbanyUSA
  3. 3.Department of Medicinal Chemistry, Medical College of VirginiaVirginia Commonwealth UniversityRichmondUSA
  4. 4.Miami Valley LaboratoriesThe Procter & Gamble CompanyCincinnatiUSA

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