2026 ECNP Congress

PS02-2205

Monoamine oxidase inhibition preferentially elevates trace amines over classical monoamines in rodent brain: a meta-analysis

Talah Khoury — R. Nejati Bervanlou, D. Grinchii, E. Dremencov · Institute of Molecular Physiology and Genetics, Centre of Biosciences- Slovak Academy of Sciences, Bratislava, Slovak Republic

2026 ECNP Congress

Introduction

Trace amines (β-phenylethylamine [PEA], tyramine, and tryptamine) are metabolised by monoamine oxidase (MAO), while dopamine, noradrenaline, and serotonin are partly buffered by vesicular storage and reuptake mechanisms. This difference predicts that MAO inhibition produces larger proportional increases in trace amines than in classical monoamines, a pattern observed in early rodent work [1]. MAO inhibitors (MAOIs) are established antidepressants, yet whether this amine-class imbalance forms part of their pharmacological profile has never been quantitatively examined.

Aims

To quantify and compare the fold-change in trace amine and classical monoamine brain concentrations following MAOI administration in rodents, and to determine whether the differential response varies by inhibitor selectivity class.

Methods

A systematic review and random-effects meta-analysis was conducted following a preregistered protocol (osf.io/qg93a). PubMed, Europe PMC, and LENS.org were searched for in vivo rodent studies reporting quantitative brain amine concentrations after MAOI versus vehicle treatment. Records were deduplicated and screened in two stages. Eligible studies used rat and mouse models. Studies providing complete mean, standard error of the mean (SEM), and sample size for both groups entered the quantitative model (k = 14 effect sizes from 3 studies, reflecting multiple amine-MAOI combinations per study; [2,3,5]); studies reporting means only contributed to narrative synthesis. Subgroup analyses by inhibitor selectivity class were prespecified. Effect sizes were log-transformed fold-changes with delta-method variance estimates. Random-effects models used restricted maximum likelihood (REML) estimation (metafor v4.8, R v4.5.3). Non-independence of effect sizes within studies is a recognised limitation of the current model.

Results

Trace amines showed a pooled fold-increase of 8.53× (95% CI 3.16–23.02, p < 0.0001); classical monoamines increased by 1.21× (95% CI 1.13–1.30, p < 0.0001). The trace amine model showed high heterogeneity (I² = 99.60%); the classical monoamine model showed no detectable heterogeneity (I² = 0%, Q-test p = 0.43; interpretation limited by small k). In subgroup analyses, the MAO-B selective subgroup was underpowered (k = 2) and could not be assessed reliably for trace amines; exploratory estimates suggest elevation (2.84×, 95% CI 0.94–8.61, p = 0.065); classical amines showed a significant increase (1.15×, 95% CI 1.03–1.29, p = 0.017). Non-selective inhibitors raised trace amines 11.69× (95% CI 3.67–37.27, p < 0.0001) and classical amines 1.25× (95% CI 1.15–1.37, p < 0.0001). Across all included studies, narrative synthesis showed trace amine fold-changes of 1.6× to 100× [3,4,5] and classical monoamine fold-changes of 1.1× to 1.8× [2,3,4], consistent in direction with the quantitative model.

Conclusions

Preliminary findings come from an ongoing meta-analysis; the final dataset will be larger. MAO inhibition raised trace amine concentrations substantially more than classical monoamines across rodent brain regions, most robustly under non-selective inhibition. The evidence base remains limited: only three studies with full variance data, non-independence of effect sizes within studies, high heterogeneity in the trace amine model, and no human data. Directional consistency across studies was nonetheless observed. Whether the amine-class imbalance contributes to the clinical pharmacology of MAOI antidepressants, and whether it suffices to engage TAAR1 in vivo, are questions the full analysis and future human studies should address. Supported by grant VEGA-2/0045/24.

References

References

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  2. Juorio, A.V., Greenshaw, A.J., Wishart, T.B., 1988. Reciprocal changes in striatal dopamine and β-phenylethylamine induced by reserpine in the presence of monoamine oxidase inhibitors. Naunyn Schmiedeberg’s Arch. Pharmacol. 338 (6), 644–648.
  3. Karoum, F., 1987. N-propargylbenzylamine, a major metabolite of pargyline, is a potent inhibitor of monoamine oxidase type B in rats in vivo: a comparison with deprenyl. Br. J. Pharmacol. 90 (2), 335–345.
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  5. Tabakoff, B., Moses, F., Philips, S.R., Boulton, A.A., 1977. Effects of tranylcypromine and pargyline on brain tryptamine. Experientia 33 (3), 380–381.