Definitions/Description

• Classic psychedelics are defined as agonists or partial agonists at the serotonin 2A receptor (5-HT2A), with examples including psilocybin (the psychoactive compound in psychedelic mushrooms), lysergic acid diethylamide (LSD), and dimethyltryptamine (DMT). Their subjective effects include altered states of consciousness characterized by intensified perception, shifts in thought and affect, and changes in the sense of self and reality. These effects are primarily mediated through cortical 5-HT2A receptor activation, particularly in layer V pyramidal neurons which modulate both local excitatory activity and projections to subcortical structures. Classic psychedelics typically have “off-target” affinities for other serotonergic receptors, with LSD being one of the few classic psychedelics that also has direct affinity for dopaminergic receptors.
• Entactogens (like methylenedioxymethamphetamine, or MDMA) are distinguished from classical psychedelics by mechanism (serotonin release and more widespread monoaminergic affinity vs. 5-HT2A and selective serotonergic agonism) and subjective profile (prosocial, fear-memory access, without hallucinations).
• Dissociatives (like ketamine) are compared but not fully grouped with classic psychedelics, acknowledging apparent mechanistic differentiation (primary mechanism of NMDA antagonism with no direct serotonergic affinity) as well as some potential down-stream mechanistic overlap (in that both psychedelics and dissociatives may both evoke glutamatergic shifts and mTOR or TrkB signaling).
• At the systems level, psychedelics disrupt the balance of cortical-subcortical interactions and alter intrinsic brain network dynamics. This is thought to underlie both their therapeutic potential and acute subjective effects.