Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors

Abstract

RATIONALE The hallucinogenic tea known as ayahuasca is made from a combination of psychoactive plants that contribute the active components N,N-dimethyltryptamine (DMT) and 5-methoxy-DMT (5-MeO-DMT), as well as the monoamine oxidase (MAO) inhibitors (MAOIs) harmine and harmaline for oral activity. OBJECTIVE The present study examined the effects of 5-MeO-DMT in combination with MAOIs in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration. Interaction studies using the serotonin (5-HT)1A antagonist WAY-100635 (1.0 mg/kg) and the 5-HT2A antagonist MDL 11,939 (1.0 mg/kg) were also performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in MAOI-treated animals. RESULTS 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) decreased locomotor activity and investigatory behavior. In rats pretreated with a behaviorally inactive dose of harmaline (0.1 mg/kg), 1.0 mg/kg 5-MeO-DMT had biphasic effects on locomotor activity, initially reducing locomotion and then increasing activity as time progressed. The ability of harmaline to shift 5-MeO-DMT to a biphasic locomotor pattern was shared by the selective MAOA inhibitor clorgyline, whereas the selective MAOB inhibitor (−)-deprenyl was ineffective. The late hyperactivity induced by the combination of 1.0 mg/kg 5-MeO-DMT and 0.3 mg/kg clorgyline was blocked by pretreatment with MDL 11,939. Pretreatment with WAY-100635 failed to attenuate either the early hypoactivity or the late hyperactivity. CONCLUSIONS The ability of harmaline to modify the behavioral effects of 5-MeO-DMT is mediated by inhibition of MAOA. Further, 5-HT2A receptors are responsible for the late hyperactivity induced by 5-MeO-DMT in the presence of MAOA inhibitors.

Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status

“…2 and 3) of 5-MeO-DMT and largely enhances the systemic and cerebral exposure to 5-MeO-DMT (Figs. 3 and 6) as well as hyperserotonergic effects (unpublished data) and behavioral changes (Halberstadt et al, 2008;Winter et al, 2011).…”

Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes

“…The psychoactive effects of five of the compounds have not been reported. Further pharmacological characterization of these compounds would need to be conducted in order to further understand their behavioral outcomes, in particular related to metabolism by monoamine oxidases (Halberstadt et al 2008; Reimann and Schneider 1993) and their pharmacokinetic profiles (Shen et al 2011), which could be critical. As noted above, psychoactivity can also be influenced by a number of other receptors such as DA receptors, trace amine-associated receptors, cannabinoid receptors, the sigma-1 receptor, and the kappa opioid receptor.…”

Nonlinear Pharmacokinetics of 5-Methoxy-N,N-dimethyltryptamine in Mice

“…5-HT 1A and 5-HT 2 receptors have been shown to determine the complex pharmacological and toxicological actions of 5-MeO-DMT in the central nervous system (Winter et al, 2000;Krebs-Thomson et al, 2006;Halberstadt et al, 2008). Understanding brain 5-MeO-DMT concentrations would be helpful.…”