Combined phentermine/fenfluramine administration enhances depletion of serotonin from central terminal fields

Abstract

Administration of phentermine (Phen) together with (+/-) fenfluramine (Fen) enhances the weight reduction that is observed with either drug alone; consequently, these anorectic agents are commonly prescribed together for weight reduction. Repeated administration of Fen is known to cause long-term depletion of axonal serotonin (5-HT) and loss of 5-HT transporters, and is therefore considered neurotoxic. We now report that combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg, and 20 mg/kg/3.125 mg/kg) can enhance the neurotoxic effect of Fen (3.125 mg/kg) and Phen (5 mg/kg and 20 mg/kg) on central 5-HT systems. Rats were repeatedly treated once each hour for a total of four injections with saline, Phen (5 mg/kg and 20 mg/kg), Fen (3.125 mg/kg and 12.5 mg/kg), or combined Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg), and sacrificed either 7 or 28 days after cessation of treatment. Combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused significantly greater reductions of 5-HT levels in the striatum, nucleus accumbens/olfactory tubercle, hypothalamus, amygdala, frontal parietal cortex, and hippocampus than either drug alone. Combined Phen/Fen at the higher drug-dose combination (20 mg/kg/3.125 mg/kg) was observed to reduce the density of 5-HT transporters in rat striatum at both 7 and 28 days after cessation of treatment. In addition, combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused greater weight loss than that observed with either compound alone. Collectively, the present data demonstrate that combined Phen/Fen administration enhances the neurotoxicity of Phen or Fen on 5-HT neurons.

Efficacy of administration of dexfenfluramine and phentermine, alone and in combination, on ingestive behavior and body weight in rats

“…Fenßuramine has been at the center of a decade-long dispute over potential neurotoxicity. When combined with PHEN, there either may (Lew et al 1997) or may not (Baumann et al 1996) be a potentiation of these e¤ects. We reported (Roth and Rowland 1997) no loss of paroxetine binding sites in frontal cortex by combining a low dose of DFEN (2 mg / kg) with PHEN (5 mg / kg).…”

Selective neurotoxins, chemical tools to probe the mind: The first Thirty years and beyond

“…are comparable to those of MDMA and MDA (Appel et al, 1989;Harvey and McMaster, 1975;Molliver and Molliver, 1990;Sanders-Bush et aI., 1975;Zaczek et al, 1990) and the extent of neurotoxicity apparently is enhanced by phentermine (PHEN) (Lew et al, 1997), which is the combination in the diet drug known as FEN-PHEN. The d-isomer of FEN is more potent than the/-isomer (Kleven and Seiden, 1989).…”

“…The d-isomer of FEN is more potent than the/-isomer (Kleven and Seiden, 1989). However, when PHEN is administered to rats in a single day at a dosage producing anorexia, neurotoxicity apparently does not occur (Lew et al, 1997).…”

Synergistic interactions between Fenfluramine and Phentermine

“…Animal studies clearly indicate a synergism between phentermine and dexfen¯uramine on the reduction of appetite and body weight in rats. 25,26 Animal studies have also demonstrated synergism between phentermine and fen¯ur-amine on reduction of brain serotonin levels, 51,52 and between dexfen¯uramine and phentermine on vasoconstriction of pulmonary arterial vessels. 39 Recent studies indicate the coadministration of phentermine increases the incidence of valve disease associated with fen¯uramine or dexfen¯uramine.…”