Differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice

Abstract

The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a β-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time-and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.

Fecal microbial transplant abates tolerance to methylone-induced hyperthermia

“…Similarly, in the present study, taxonomic comparisons at the Phylum level indicated that for both MN and MHT animals the greatest effects were also on Firmicutes and Bacteroidetes . As noted by Angoa-Perez et al, [33], this effect on Firmicutes and Bacteroidetes is expected as these two phyla are dominant in rodents [33]. The specific identity of the microbe(s) involved in the present temperature changes is unknown due to insufficient resolving power of 16S rRNA gene alone; however, the concordance of changes in the relative abundance of Gammaproteobacter and Alphaproteobacter following FMT implicates members of these two phyla as potential contributors to the establishment of methylone tolerance.…”

“…Similarly, in the present study, taxonomic comparisons at the Phylum level indicated that for both MN and MHT animals the greatest effects were also on Firmicutes and Bacteroidetes. As noted by Angoa-Perez et al, [33], this effect on Firmicutes and Bacteroidetes is expected as these two phyla are dominant in rodents [33]. There are a number of critical considerations to be made in the interpretation of these data.…”

“…In that same study, antibiotic treatment not only prevented the Proteus mirabilis enrichment but also attenuated MDMA-induced hyperthermia. Angoa-Perez et al, [33] examined the effects of synthetic cathinones on the diversity and taxonomic structure of the gut microbiome. Those authors found that the two phyla most altered by the synthetic cathinones were Firmicutes and Bacteriodetes .…”

New psychoactive substances: a review and updates

“…Synthetic cathinones are similar in structure to amphetamine type stimulants and are chemically referred to as β-ketone analogues because of the carbonyl (=O) group in β carbon. 38 , 39 The common pharmacophore group responsible for the psychoactive effect observed in synthetic stimulants is phenethylamine, 32 and its derivatives are reported to represent at least 37% of the NPS available on the illicit drug market. 40 …”

Potential Contribution of the Intestinal Microbiome to Phenethylamine-Induced Hyperthermia

“…Given that recent studies indicated a link between the microbiome-gut-brain axis and the regulation of body temperature [Rosenbaum et al, 2015;Li et al, 2019], and that phenethylamines can alter the composition of the gut microbiome [Ridge et al, 2019;Angoa-Pérez et al, 2020], we examine here the potential cellular mechanisms that may link the microbiome-gut-brain axis to PIH.…”