Is phentermine an inhibitor of monoamine oxidase? A critical appraisal

Abstract

Phentermine produces a spectrum of concentration-dependent biochemical effects. It interacts with NE transporters at 0.1 microM, DA transporters at about 1 microM, 5-HT transporters at 15 microM and MAO-A at about 100 microM. When administered at typical anorectic doses, phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting MAO-A. Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5-HT, since platelet MAO-B does not metabolize platelet 5-HT, and since amphetamine-type drugs are even weaker inhibitors of MAO-B than MAO-A. Clinical studies in humans have shown that amphetamine, which is a more potent inhibitor of MAO-A than phentermine, does not inhibit MAO-A at therapeutic doses. Neither phentermine alone, fluoxetine alone or their combined use have been associated with cardiac valvulopathy, and clinical experience has shown their combined use to be free of significant adverse effects. Viewed collectively, there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses.

Effects of VMAT2 inhibitors lobeline and GZ‐793A on methamphetamine‐induced changes in dopamine release, metabolism and synthesis in vivo

“…). However, as the relatively low dose of METH (0.5 mg/kg, SC) used in this study may not inhibit MAO (Rothman ), a more likely explanation is that the METH‐induced increase in extracellular DA reflects inhibition of VMAT2 uptake, perhaps via disruption of the amine‐proton gradient that maintains vesicular stores (Fleckenstein et al . ).…”

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

“…10 However, such a role of phentermine as an MAO inhibitor (MAOI) has been discounted based on a review of some basic and clinical biochemical findings. 11 Whilst such warnings undoubtedly generate concern among physicians and patients alike, neither report provides an unequivocal answer to the fundamental question of whether MAO inhibition is relevant to the actions of phentermine. The problem is compounded because until the recent study, 10 no published work from within the last two decades has examined the interaction between phentermine and MAO.…”

“…As phentermine is less potent still, we would argue that phentermine should not be classed as an MAOI, especially in view of its estimated plasma level in man of 0.7 mM following recommended doses. 11 MAO inhibition as a link with drug-associated cardiovascular disease One clear omission from the work described by Ulus et al 10 was a failure to consider the potency of the fenfluramines as MAOIs. This was surprising because fenfluramine and its isomers were attributed with weak MAO inhibitory properties (IC 50 % 1000 mM) 23 3 y prior to the earliest studies on phentermine and the results of these studies were later reinforced.…”