Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis.
B Sadzot, J M Baraban, Richard A Glennon, R A Lyon, Sigrun Leonhardt, C R Jan, M Titeler
Psychopharmacology 1989 DOI: 10.1007/bf00441948 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro receptor binding study Peer reviewed |
|---|---|
| Population | Human cortical tissue samples (postmortem brain cortex) |
| Measures | 3H-ketanserin radioligand binding, autoradiography, Ki values, Hill coefficients |
| Topics | LSD |
| Key points | Binding affinities of 13 psychoactive compounds at human cortical 5-HT2 receptors correlated strongly with their known human hallucinogenic potencies (r = 0.97), and human and rat 5-HT2 receptor affinities were closely correlated (r = 0.99). The authors argue these results support the hypothesis that hallucinogenic effects of LSD and related drugs in humans are mediated in whole or in part via 5-HT2 receptors. |
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 indolealkylamines, 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 microM. 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.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
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- Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions. Current Drug Metabolism October 1, 2010
- Pivotal mental states Journal of Psychopharmacology April 1, 2021
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Cites 7
- Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences December 17, 1984
- 3H-DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) labels a guanyl nucleotide-sensitive state of cortical 5-HT2 receptors. Molecular Pharmacology February 1, 1987
- Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharmacology 1988
- Indolealkylamine analogs share 5-HT2 binding characteristics with phenylalkylamine hallucinogens. European Journal of Pharmacology 1988
- Effect of hallucinogens on spontaneous and sensory-evoked locus coeruleus unit activity in the rat: reversal by selective 5-HT2 antagonists. Brain Research October 1, 1986
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