Evaluation of Phentermine and Fenfluramine, Alone and in Combination, in Normal, Healthy Volunteers

Abstract

Recent clinical reports indicate that combined administration of phentermine and fenfluramine may have useful effects in the treatment of drug abuse. The present study was designed to evaluate the subjective and mood-altering effects of these drugs, alone and in combination, in normal healthy volunteers. Seven male and five female volunteers participated in an eight-session, double-blind study in which each subject received each of the following drug conditions: d-amphetamine (10 and 20 mg), phentermine (30 mg), fenfluramine (40 and 80 mg), phentermine (30 mg) with fenfluramine (40 mg), phentermine (30 mg) with fenfluramine (80 mg), and placebo. Sessions were conducted in a laboratory setting two or three days a week. Subjects completed standardized self-report questionnaires and psychomotor tests before and at regular intervals after each drug administration. Phentermine produced effects that were similar to those of d-amphetamine, whereas fenfluramine produced different and apparently aversive effects (e.g., it increased measures of anxiety and confusion). Phentermine reduced the apparently aversive effects of fenfluramine when the two drugs were given together. These results suggest that the combination of phentermine and fenfluramine would have a low potential for abuse.

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

“…It is well accepted that pharmacological treatments leading to increased synaptic 5-HT are not reinforcing. For example, increased serotonergic transmission decreases brain stimulation reward (Harrison and Markou, 2001), produces conditioned place aversions (Marona-Lewicka et al, 1996), and reduces the positive reward value of stimulants both in animals and humans (Brauer et al, 1996;Rea et al, 1998). Thus, in the presence of GBR-type compounds, illicit stimulants such as methamphetamine become very effective 5-HTreleasing agents that lack positive reinforcing qualities.…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Of note, not all studies were able to show a superior effect of the phen-fen combination on body weight relative to treatment with phentermine or fenfluramine alone (Weintraub et al, 1984;Li et al, 2003). However, there are some indications that the phen-fen combination has a lower abuse potential relative to treatment with phentermine alone (Brauer et al, 1996). In 1996, it is estimated that phen-fen was prescribed to more than 18 million people in the United States (Connolly et al, 1997), and it was in the same year when the FDA approved the use of dexfenfluramine, the d-isomer of fenfluramine, as a chronic treatment of obesity (Colman, 2005) (Fig.…”

Relationship between the Serotonergic Activity and Reinforcing Effects of a Series of Amphetamine Analogs

“…The depletion of 5-HT by medial forebrain bundle lesion with 5,7-dihydroxy-tryptamine seemed to increase the reinforcing efficacy of cocaine in rats (Loh and Roberts, 1990), whereas manipulations that increase CNS 5-HT function can decrease cocaine self-administration (Smith et al, 1986;Carroll et al, 1990;Howell and Byrd, 1995). Studies using coadministered phentermine and fenfluramine as a prototypical DA/5-HT releasing agents demonstrated that compounds that increase both extracellular DA and 5-HT in rat nucleus accumbens are not self-administered by rodents (Glatz et al, 2002), do not induce conditioned place preference in rats (Rea et al, 1998), and have low potential for abuse in human subjects (Brauer et al, 1996). Reinforcing efficacy among a series of cocaine analogs was shown to be negatively related to the SERT potency relative to DAT (Roberts et al, 1999).…”