Pharmacokinetic and Pharmacodynamic Interaction of the Ayahuasca Constituents Harmine and Dimethyltryptamine (DMT) in the Rat Brain

Co-administration of harmine with N,N-dimethyltryptamine (DMT) in rats inhibited the formation of the DMT metabolite indole-3-acetic acid in the brain and increased cerebral availability of DMT, confirming harmine's role in making oral DMT bioavailable. However, no significant occupancy by DMT at serotonin 5-HT2A receptors was detected ex vivo, despite brain DMT concentrations reaching 11.3 µM at moderate doses. Low doses of DMT and/or harmine did not strongly influence brain glucose metabolism measured with [18F]FDG-PET. The results call for further experiments on dose-dependent effects of harmine/DMT on receptor occupancy and cerebral metabolism.

Study at a glance

Abstract

RationaleThe psychedelic effects of the traditional Amazonian botanical decoction known as ayahuasca are attributed to the effects of N,N-dimethyltryptamine (DMT) at brain serotonin 5-HT2A receptors. To make oral DMT bioavailable, ayahuasca additionally contains reversible monoamine oxidase A (MAO-A) inhibitors, namely β-carboline alkaloids such as harmine. However, there is lacking biochemical evidence to substantiate this pharmacokinetic potentiation in the brain. ObjectivesTherefore, we measured the pharmacokinetic profile of harmine and DMT in the rat brain. Additionally, we investigated the pharmacodynamic properties of DMT and/or harmine. MethodsWe first measured brain concentrations of harmine and DMT after treatment with harmine and/or DMT at low doses (1 mg/kg each) or harmine plus DMT at moderate doses (3 mg/kg each). In the same groups of rats, we also measured ex vivo the effects of these treatments on the availability of serotonin 5-HT2A receptors in frontal cortex. Finally, we explored influences of DMT and/or harmine in the lower dose group on brain glucose metabolism with [18F]FDG-PET. ResultsResults confirmed that co-administration of harmine inhibited the formation of the DMT metabolite indole-3-acetic acid (3-IAA) in the brain, while increasing the cerebral availability of DMT. However, we were unable to detect any significant occupancy by DMT at 5-HT2A receptors measured ex vivo, despite brain DMT concentrations as high as 11.3 µM at moderate doses. We did not observe strong influences of low dose DMT and/or harmine on [18F]FDG-PET. ConclusionsThe present preliminary results call for further experiments to establish the dose-dependent effects of harmine/DMT on receptor occupancy and on cerebral metabolism.