A Pharmacological Basis for Some Bad LSD “Trips”?

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 Geyer 1 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 D 4 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 D 4 receptor demonstrated that 13-hydroxy-LSD was 380 times more potent as a dopamine D 4 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 D 4 agonist yet discovered.

Conclusion: 13-Hydroxy-LSD is an exceptionally potent dopamine D 4 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 D 4 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 D 4 receptor remains largely unknown. These experiments argue that the importance of the D 4 receptor deserves more intense study.