Amphetamine-like Neurochemical and Cardiovascular Effects of α-Ethylphenethylamine Analogs Found in Dietary Supplements

Abstract

Dietary supplements often contain additives not listed on the label, including α-ethyl homologs of amphetamine such as N,α-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of α-ethylphenethylamine (AEPEA), N-methyl-α-ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1-3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1-10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1-10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that α-ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential. SIGNIFICANCE STATEMENT: The α-ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.

Fig. 1.

Chemical structures of AEPEA, MEPEA, and DEPEA as compared with amphetamine and methamphetamine.

Fig. 2.

Effects of amphetamine and PEA analogs on inhibition of uptake and stimulation of efflux (i.e., release) at DAT (upper panels) or NET (lower panels) in rat brain synaptosomes. For uptake assays, synaptosomes were incubated with different concentrations of test drugs in the presence of 5 nM [³H]dopamine ([³H]DA) or [³H]norepinephrine ([³H]NE). Data are means ± S.D., expressed as a percentage of transmitter uptake for N = 3 experiments performed in triplicate. For release assays, synaptosomes were preloaded with 9 nM [³H]MPP⁺ and then incubated with different concentrations of test drugs to evoke release via reverse transport. Data are means ± S.D., expressed as a percentage of [³H]MPP⁺ release for three experiments performed in triplicate.

Fig. 3.

Effects of GBR12909 (GBR) or desipramine (DMI) on drug-induced release of [³H]MPP⁺ at DAT (upper panels) or NET (lower panels). For substrate reversal assays, synaptosomes were preloaded with 9 nM [³H]MPP⁺, and then test drugs were incubated with or without GBR12909 (1 nM) for DAT assays or desipramine (8 nM) for the NET assays. Data are means ± S.D. expressed as a percentage of [³H]MPP⁺ release for three experiments performed in triplicate.

Fig. 4.

Time course effects of AEPEA administration on BP, HR, motor activity, and core body temperature. Male rats bearing biotelemetry transponders received subcutaneous injection of 1, 3, or 10 mg/kg AEPEA or its saline vehicle and were returned to their home cages. Five minutes later, cages were placed atop telemetric receivers. Data were collected in 10-minute epochs for 3 hours. Data are expressed as means ± S.E.M. for five rats per group.

Fig. 5.

Dose-effect functions for amphetamine (Amph) and PEA analogs on BP, HR, motor activity, and core body temperature. Data represent mean values across the full 3-hour session. Solid symbols indicate significant differences from the respective saline group. Data are means ± S.E.M. for five rats per group.