Santillo (2014) reported that AEPEA inhibits human monoamine-oxidase type A in vitro in a competitive and reversible manner similar to amphetamine, whereas DEPEA has much weaker effects in this regard.

Here, we examined the neurochemical and cardiovascular effects of -ethylphenethylamine (AEPEA), N -methyl- -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.

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 (0.13.0 mgkg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity.

AEPEA (110 mgkg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (110 mgkg, s.c.) increased BP, HR, and activity.

Our results show that -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 -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.

Introduction Nutritional supplements often contain ingredients that are not listed on the product labels, including analogs of phenethylamine (PEA) that display structural similarity to amphetamine ( Eichner, 2014; Pawar and Grundel, 2017 ).

We recently showed that the supplement additive -methylphenethylamine (BMPEA), a positional isomer of amphetamine (i.e., -methylphenethylamine), increases blood pressure (BP) in rats and may therefore produce adverse effects in humans ( Schindler et al., 2019 ).

Another PEA analog previously found in dietary supplements is N, -diethylphenethylamine (DEPEA; see Fig.

DEPEA has been detected in powdered material confiscated for drug trafficking ( Lee et al., 2013 ) and in supplement products destined for human consumption ( ElSohly and Gul, 2014; Cohen et al., 2014; Wahlstrom et al., 2014; ElSohly et al., 2015 ).

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

Urine toxicology testing has also confirmed the presence of DEPEA in users of some dietary supplements ( Wjtowicz et al., 2015 ).

For example, in urine samples obtained through routine toxicological testing, DEPEA was detected in samples from individuals who used a dietary supplement suspected of containing added DEPEA ( Uralets et al., 2014 ).

In addition to DEPEA, -ethylphenethylamine (AEPEA) was also found in some of the same samples, potentially the result of N -dealkylation of DEPEA via hepatic metabolism.

Both DEPEA and AEPEA have been found in urine samples collected by the World Anti-Doping Agency, demonstrating exposure to these substances among athletes ( World Anti-Doping Agency, 2012, 2013 ).

In a survey of German athletes who were asked about their supplement use, some respondents specifically reported seeking products containing DEPEA ( Dreher et al., 2018 ).

Since DEPEA and related analogs are not listed as ingredients on the labels of supplement products, the FDA considers them adulterants and requires companies selling the products to remove them from the market ( Pawar and Grundel, 2017 ).

However, PEA analogs may still be present in those supplements not tested by the FDA.

Despite the apparent widespread use of DEPEA and similar compounds, very little is known about their biologic effects.

Oberlender and Nichols (1991) reported that AEPEA partially generalizes to the discriminative stimulus effects of amphetamine.

In that study, rats were trained to respond on one lever when injected with amphetamine and another lever when injected with saline.

When the trained rats received a noncontingent injection of AEPEA, they responded on the amphetamine-associated lever, suggesting that AEPEA and amphetamine might share common effects.

Amphetamine Effects On The Body