Converging lines of evidence from pharmacologic, electrophysiologic, and behavioral research in animals strongly suggest that activation of cortical 5-hydroxytryptamine-2A receptors is the most critical step in initiating a cascade of biological events that accounts for serotonergic hallucinogen (SH) psychoactive properties. Psilocybin produces hyperfrontality with divergent prefrontal–subcortical activation in such a way as to increase cognitive and affective processing in the context of reduced gating and reduced focus on external stimulus processing. In contrast to all other drugs of abuse, SHs are not considered to be capable of producing sufficient reinforcing effects to cause dependence (addiction) syndromes. Given that SHs increase extracellular glutamate levels and activity in the prefrontal– limbic circuitry, it is possible that a normalization in functional connectivity in this network through a glutamate-dependent neuroplastic adaptation could produce an anti-addictive effect. KEYWORDS : • Serotonergic hallucinogens • Addiction • Treatment • Pharmacotherapy