A Pharmacological Basis for Some Bad LSD “Trips”?

AI Summary

LSD produces two temporal phases: an early serotonergic psychedelic phase and a later dopaminergic paranoid phase.
13-hydroxy-LSD is 380 times more potent at human dopamine D4 receptors than LSD, with an EC50 of 36 pM in vitro.
Whether sufficient unconjugated 13-hydroxy-LSD forms in vivo to activate central D4 receptors remains unknown and requires further study.

TL;DR (AI Generated)

PURPOSE: To test the hypothesis that the later "paranoid" phase of LSD intoxication is due to the formation of a metabolite of LSD.

RESULTS: Synthesis and in vitro receptor testing of 13- and 14-hydroxy-LSD at the human dopamine D4 receptor demonstrated that 13-hydroxy-LSD was 380 times more potent as a dopamine D4 agonist than LSD, with a 36 pM (36 × 10-12 M) potency (EC50), whereas LSD itself had a 14 nM (14 × 10-9 M) EC50.

CONCLUSION: 13-Hydroxy-LSD is an exceptionally potent dopamine D4 agonist in vitro, raising the possibility that this minor LSD metabolite could contribute to the delayed dopaminergic phase of LSD pharmacology.

Basic summary

Psychedelic Med (New Rochelle). 2026 Nov 12:28314425261505140. doi: 10.1177/28314425261505140. Online ahead of print.

ABSTRACT

BACKGROUND: In 1984, early clinical researcher Daniel Freedman noted that the clinical effects of LSD occurred in two temporal phases: an early psychedelic phase, followed later by a paranoid phase. Freedman drew parallels between this later phase and amphetamine psychosis in humans. Later, Mittman and Geyer¹ showed that behavior acutely induced by LSD in rats also occurred in two temporal phases: an initial suppression of behavioral responding, followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. Following that, Marona-Lewicka and colleagues^2-4 found through a series of two-lever drug discrimination experiments in rats that testing 30 min after administration of LSD generated an interoceptive cue that was mediated by serotonin 5-HT_2A receptor activation. However, when testing was delayed until 90 min after LSD administration, a time-dependent cue was generated that was mediated by dopamine D₄ receptor activation, as determined using highly selective receptor antagonists.

PURPOSE: To test the hypothesis that the later “paranoid” phase of LSD intoxication is due to the formation of a metabolite of LSD. In particular, 13- and 14-hydroxy-LSD have been identified as minor metabolites in several animal species and in man.

RESULTS: Synthesis and in vitro receptor testing of 13- and 14-hydroxy-LSD at the human dopamine D₄ receptor demonstrated that 13-hydroxy-LSD was 380 times more potent as a dopamine D₄ agonist than LSD, with a 36 pM (36 × 10^-12 M) potency (EC50), whereas LSD itself had a 14 nM (14 × 10^-9 M) EC50. Thus, 13-hydroxy-LSD may be the most potent dopamine D₄ agonist yet discovered.

CONCLUSION: 13-Hydroxy-LSD is an exceptionally potent dopamine D₄ agonist in vitro, raising the possibility that this minor LSD metabolite could contribute to the delayed dopaminergic phase of LSD pharmacology. Whether sufficient unconjugated 13-hydroxy-LSD is formed in vivo to produce meaningful central D₄ receptor activation remains unknown. Determining its formation, disposition, broader receptor pharmacology, and behavioral effects will be necessary to test this hypothesis directly. Additionally, the native function of the dopamine D₄ receptor remains largely unknown. These experiments argue that the importance of the D₄ receptor deserves more intense study.

PMID:43034301 | PMC:PMC13768275 | DOI:10.1177/28314425261505140

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