Toxicodynamic insights of 2C and NBOMe drugs - Is there abuse potential?

Abstract

Drug use represents a prevalent and multifaceted societal problem, with profound implications for public health, social welfare, and economic stability. To circumvent strict international drug control regulations, there is a growing trend in the development and market introduction of novel psychoactive substances (NPS), encompassing a wide range of compounds with psychoactive properties. This includes, among other classes of drugs, the phenethylamines. Originally derived from natural sources, these drugs have garnered particular attention due to their psychedelic effects. They comprise a broad spectrum of compounds, including 2,5-dimethoxyphenylethylamine (2C) drugs and their corresponding N-(2,5-dimethoxybenzyl)phenethylamine (NBOMe). Psychedelics are conventionally perceived as having low addiction potential, although recent reports have raised concerns regarding this topic. These substances primarily interact with serotonin receptors, particularly the 5-HT_2A subtype, resulting in alterations in sensory perception, mood, and introspective experiences. In addition to their psychedelic properties, 2C and NBOMe drugs have been associated with a multitude of adverse effects, such as cardiovascular complications and neurotoxicity. This manuscript provides a comprehensive review of the psychedelic pathways underlying 2C and NBOMe designer drugs, focusing on their interactions with serotonergic and other neurotransmitter systems, shedding light on their potential for abuse.

Keywords: 2C drugs, NBOMe drugs; Abuse potential; New psychoactive substances; Psychedelic phenethylamines.

Graphical abstract

Fig. 1

Chemical structures of mescaline, 2C-B and 25B-NBOMe. The presence of different substituents (functional groups or halogens) at position-4 of the aromatic ring leads to the formation of distinct drugs (if the substituent is a methyl group the drug is known as 2C-D and 25D-NBOMe, respectively; if the substituent is an iodine, the drug is known as 2C-I and 25I-NBOMe, respectively).

Fig. 2

Mechanism of action of 2C and NBOMe drugs in serotoninergic neurons. (I) Serotonin (5-HT) is synthetized from L-Tryptophan by tryptophan hydroxylase 2 (TPH₂). When inside the presynaptic neuron, 5-HT is stored in neurotransmitter vesicles via the vesicular monoamine transporter (VMAT₂). (II) Once released, 5-HT can modulate postsynaptic neurotransmission by binding to Gα-coupled 5-HT_2A receptors, that can: (III) activate phospholipase C (PLC), originating the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃; leads to Ca²⁺ release from the endoplasmic reticulum) and diacylglycerol (DAG; stimulates protein kinase C (PKC) activity); (IV) activate phospholipase A2 (PLA₂), stimulating arachidonic acid (AA) release, through complex signaling mechanism involving Gα_i/o and G_12/13 proteins; and/or (V) couple to Ca²⁺ channels. (VI) The 5-HT transporter (SERT) reuptakes 5-HT back to the presynaptic neuron, where it can be restored into vesicles or degraded by monoamine oxidase (MAO) A to 5-hydroxyindole amino acid (5-HIIA). (VII) 2C and NBOMe drugs act as 5-HT_2A receptor agonists. The stimulation of these receptors mediates the characteristic psychedelic effects of these drugs.