Phentermine and other monoamine-oxidase inhibitors may increase plasma serotonin when given with fenfluramines.

Phentermine has been used in the USA to treat obesity sinc, at least 1961 and was widely used after 1992 in combinatio. with fenfIuramine_ A swdy in 1997 suggested that thi combination could be associated with hean-valve diseas similar to that seen in the carcinoid syndrome or in patients who had taken ergotamine, as well as with pulmo hypertension, previously descn"bed.' It was suggested that these findings, were' due to an increase in circulating! serotonin. Subsequently, the US Food and Drug! Administration found heart-valve lesions among patients I taking a fenfluramine without phentermine. ' Given the paucity of data on' phentermine's actions, we detennined whether phentermine could modify the metabolism of other monoamines besides the norepinephrine released from sympathetic neurons. In rats, phentermine, like d-amphetamine, releases dopamine into: brain synapses! We tested the ability of a low dose (15 mg' by mouth) to affect plasma dopamine in human beings. Nine young, non-obese male volunteers gave blood, just 'before, I and 1, 2, or 4 h after receiving the drug. Plasma dopamine concentrations, assayed by radioimmunoassay', rose with' phentermine' (p<0'05; ANOVA;,Wllcoxon's test); however a' greater increase was noted in serotin levelswithin the blood platelets as assayed by EIlSA and confirmed by high performance liquid 'chromatography, (r=0-496; p<O-OOI). The increase in' platelet s~tonin' could reflect increased release of serotonm from" 'enterochromaffin cells, or inhI"bitionof its met:iboIism by monoamine oxidase (MAO)_ That the increase resuItedfrom MAO inhibition and not from increased serotonin release was shown by the finding that plasma seroto~ concen~tionfell slightly. That phenterri1ine inhI"bits theMAO which qJtabolises serotonin was well known in the early 1970s,' but apparently this in(onnation never made its way onto the drug's label. There is evidence that free plasma serotonin can damage vascular tissue' and that its concentration is normally kept low by the action of the tWo high-capacity' systems that remove it from the circulation-uptake into platelets and MAO. If the fenfluramine and phentermine regimen did produce pulmonary hypertension and cardiac valve lesions then they might have been obviated had the phetermine label within the US mentioned that the drug is an MAO inhI"bitor. Such a mention would also' warn physicians against combining phentermine with fIuoxetine, fIenf1uramine, or other SSRIs.