Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics
Deborah Rudin, Matthias E. Liechti, Dino Luethi
Experimental Neurology June 4, 2021 DOI: 10.1016/j.expneurol.2021.113778 via OpenAlex
Summary
New psychoactive stimulants and psychedelics affect monoaminergic systems through different mechanisms: stimulants interact with monoamine transporters, while psychedelics act mainly as agonists at serotonin 5-HT2A receptors. Both types have been linked to neurological and cognitive impairments. In vitro and rodent studies suggest mechanisms such as cytotoxicity, mitochondrial dysfunction, and oxidative stress may contribute to neurotoxicity from stimulants, and serotonin 5-HT2A receptor-mediated toxicity and apoptosis pathways may contribute to neurotoxicity from psychedelics. It remains unclear how well these preclinical findings translate to humans.
Study at a glance
| Characteristics | Review Peer reviewed |
|---|---|
| Topics | MDMA Serotonin |
| Keywords | Neurotoxicity Pharmacology Monoaminergic |
| Citations | 48 |
| Key finding | Stimulant and psychedelic new psychoactive substances can cause neurotoxicity through mechanisms including oxidative stress, mitochondrial dysfunction, and serotonin 5-HT2A receptor-mediated toxicity, but translation to humans is uncertain. |
Abstract
New psychoactive stimulants and psychedelics continue to play an important role on the illicit new psychoactive substance (NPS) market. Designer stimulants and psychedelics both affect monoaminergic systems, although by different mechanisms. Stimulant NPS primarily interact with monoamine transporters, either as inhibitors or as substrates. Psychedelic NPS most potently interact with serotonergic receptors and mediate their mind-altering effects mainly through agonism at serotonin 5-hydroxytryptamine-2A (5-HT2A) receptors. Rarely, designer stimulants and psychedelics are associated with potentially severe adverse effects. However, due to the high number of emerging NPS, it is not possible to investigate the toxicity of each individual substance in detail. The brain is an organ particularly sensitive to substance-induced toxicity due to its high metabolic activity. In fact, stimulant and psychedelic NPS have been linked to neurological and cognitive impairments. Furthermore, studies using in vitro cell models or rodents indicate a variety of mechanisms that could potentially lead to neurotoxic damage in NPS users. Cytotoxicity, mitochondrial dysfunction, and oxidative stress may potentially contribute to neurotoxicity of stimulant NPS in addition to altered neurochemistry. Serotonin 5-HT2A receptor-mediated toxicity, oxidative stress, and activation of mitochondrial apoptosis pathways could contribute to neurotoxicity of some psychedelic NPS. However, it remains unclear how well the current preclinical data of NPS-induced neurotoxicity translate to humans.