More than 600 new psychoactive substances (NPS) have been reported, yet information on their neuropharmacological and toxicological effects remains limited, hampering risk assessment. A review of in vitro neuronal modes of action created effect fingerprints for frequently reported NPS classes: cathinones, cannabinoids, hallucinogenic phenethylamines, arylcyclohexylamines, and piperazine derivatives. The fingerprints highlight main modes of action—such as inhibition or reversal of monoamine reuptake transporters for cathinones and activation of 5-HT2 receptors for hallucinogenic phenethylamines—and identify additional targets, including dopamine, adrenergic, GABAA, and acetylcholine receptors, by relating effect concentrations to estimated...
A new high-throughput fluorescent assay can detect how illicit drugs and new psychoactive substances (NPS) inhibit monoamine reuptake transporters (DAT, NET, SERT). The assay uses a fluorescent monoamine-mimicking substrate in human embryonic kidney cells expressing these transporters. It successfully discriminated between common drugs (cocaine, amphetamine, MDMA), several NPS (e.g., α-PVP, 2C-B, 25B-NBOMe), and the antidepressant fluoxetine. Most IC50 values matched those from traditional radiometric assays and estimated human brain concentrations, though phenethylamines showed higher IC50 values on SERT, possibly due to experimental differences. The fluorescent assay is simpler, works under physiological conditions, requires no special facilities, and allows kinetic measurements, making it a good alternative to radiometric methods.
The clinical outcome after MDMA intake ranges from mild entactogenic effects to life-threatening intoxication, and the most relevant mechanisms causing acute adverse effects remain unclear. Genetic factors, such as polymorphisms in CYP2D6 causing poor metabolism, and interactions from polydrug use, like co-exposure with selective serotonin reuptake inhibitors (SSRIs), modulate MDMA pharmacokinetics and dynamics. While SSRIs can increase MDMA plasma levels, they can reduce clinical effects like blood pressure and body temperature, possibly via pharmacodynamic interaction at the serotonin reuptake transporter. Pretreatment with inhibitors of dopamine or norepinephrine transporters, or antagonists like carvedilol, ketanserin, and haloperidol, can reduce multiple MDMA-induced effects. Investigating these drugs for treating MDMA intoxication is worthwhile.