Hallucinogens

Roth and colleagues open by arguing that the term "hallucinogen" is a historical misnomer and that the category has been used too broadly. The paper restricts its focus to classical serotonergic psychedelics — substances pharmacologically similar to mescaline, psilocybin (psilocin in vivo), and LSD — and emphasises that the now-prevailing mechanistic hypothesis implicates agonist or partial agonist action at serotonin 5-HT2A receptors as the principal central nervous system (CNS) mechanism. The review sets out to synthesise decades of behavioural, pharmacological, molecular, anatomical, imaging, and clinical work to (1) characterise the psychopharmacology and safety profile of classical hallucinogens, (2) collate evidence for 5-HT2A receptor mediation and downstream signalling, (3) localise likely neuroanatomical substrates of action (notably prefrontal cortex and thalamocortical circuits), and (4) summarise clinical and cognitive neuroscience implications including tentative therapeutic applications and avenues for future research.

Definitions, taxonomy, and historical context are introduced early. The review limits the term "hallucinogen" to tryptamine- and phenethylamine-type compounds plus ergolines that act principally via 5-HT2A receptor agonism. It summarises ethnobotanical and ritual uses through history (e.g. peyote, psilocybin mushrooms, ayahuasca) and notes resurgence of controlled human research after a long hiatus due to regulatory restrictions. Toxicity and dependence liability are addressed: classical hallucinogens are described as physiologically safe at typical doses with no clear evidence of organ toxicity or classical dependence/addiction. Animal self-administration models generally do not support reinforcing properties for these drugs. Psychologically mediated harms are emphasised: "bad trips," precipitation of psychosis in vulnerable individuals, and hallucinogen-persisting perception disorder (HPPD) are reported as low-incidence but clinically important risks. Flashbacks/HPPD incidence is difficult to quantify owing to heterogeneous definitions, and no reliable treatment for persistent perceptual effects is identified. Chemical classes, routes, doses, and pharmacokinetics are summarised. The paper distinguishes simple tryptamines (DMT, 5-MeO-DMT, psilocybin/psilocin), ergolines (LSD), and phenethylamines (mescaline and substituted amphetamines such as DOI, DOB). Representative human dose ranges and durations are given when available: DMT smoked or i.v. (free-base ~60–100 mg smoked; i.v. 0.2–0.4 mg/kg produces rapid onset and effects resolving within ~20–30 min), psilocybin oral effective doses ∼6–20 mg (psilocin is the active species), LSD p.o. active from ~0.025 mg upward with typical doses 0.05–0.2 mg and effects lasting 8–12 hr, and mescaline oral doses in the hundreds of milligrams with 10–12 hr duration. A major theme is the central role of the 5-HT2A receptor. Converging evidence from drug discrimination in rodents, head-twitch responses, antagonist correlation analyses, tolerance studies, and human antagonist challenge studies supports 5-HT2A agonism as necessary for the characteristic effects. Behavioural pharmacology in rats shows block of discriminative and head-twitch effects by selective 5-HT2A antagonists (for example M100907), and human studies demonstrated that 5-HT2A-preferring antagonists such as ketanserin or ritanserin substantially attenuate or abolish psilocybin-induced altered states measured with validated scales (APZ‑OAV). Risperidone (5-HT2/D2 antagonist) also blocked psilocybin effects, whereas pure D2 blockade with haloperidol had little impact on core visual phenomena, indicating primary 5-HT2A mediation in humans. Mechanistic details of 5-HT2A signalling are reviewed and the authors emphasise ‘‘functional selectivity’’ or agonist-directed trafficking: different ligands variably engage canonical Gq/PLC–IP3–DAG signalling versus PLA2/arachidonic acid (AA) release and may recruit other pathways such as phospholipase D (PLD). Empirical observations include poor correlation between behavioural potency and efficacy in stimulating PLC-mediated PI hydrolysis; several hallucinogens show comparatively greater potency for PLA2/AA mobilisation. Rapid tolerance (tachyphylaxis) to repeated dosing is linked to 5-HT2A downregulation. Species differences and receptor structure–function relationships are discussed. A single amino acid difference (Ser242 in human versus Ala242 in rat 5-HT2A TM V) alters ligand affinities and complicates direct extrapolation from rodent receptor data to humans. The review cautions about interpreting some animal data owing to these differences. Neuroanatomical localisation is synthesised from autoradiography, in situ hybridisation, immunocytochemistry, and PET: high densities of 5-HT2A receptors are found in neocortex (layers II–III and V), particularly prefrontal regions, with additional expression noted in thalamic sensory and nonspecific nuclei, reticular thalamic nucleus, locus coeruleus (LC), and ventral tegmental area (VTA). Electron microscopy and immunostaining studies show predominant postsynaptic localisation on pyramidal apical dendrites and variable detection on dendritic spines and interneurons; a minority of presynaptic labelling is reported. The authors highlight the functional relevance of prefrontal pyramidal cells and thalamocortical afferents. Functional consequences in the prefrontal cortex are developed at length. Electrophysiological and microdialysis studies indicate that 5-HT2A activation increases cortical excitability and enhances glutamatergic transmission: hallucinogen administration elevates extracellular glutamate in cortex and augments both spontaneous and electrically evoked excitatory postsynaptic currents in layer V pyramidal neurons. The review outlines competing mechanistic proposals for how 5-HT2A agonism increases cortical glutamate: direct presynaptic 5-HT2A heteroreceptors on thalamocortical terminals, indirect retrograde signalling from postsynaptic cells (e.g. via PLA2/AA-mediated K+ channel modulation), and interactions with NMDA receptor function. Group II mGlu2/3 receptor agonists suppress DOI-induced glutamate release and associated behaviours, indicating a presynaptic modulatory locus for part of the effect. The authors present a systems model in which altered thalamic gating, increased cortical excitability, and disrupted cortico-striato-thalamo-cortical loops reduce signal-to-noise and permit underconstrained perceptual phenomena. In vivo imaging and metabolic studies are summarised. PET studies with [18F]FDG after psilocybin show bilateral increases in prefrontal cortical glucose utilisation (frontomedial/frontolateral cortex and anterior cingulate) with increases of around 24–25% in some regions; these metabolic changes correlate with subjective measures of altered consciousness. Other imaging reports note relative hypometabolism in thalamus in some studies and increased right anterior cingulate metabolism of roughly 10% associated with particular psychological effects. Molecular and genomic consequences are reviewed: acute 5-HT2A stimulation induces immediate-early genes (c-fos, egr-1/egr-2, arc) and other transcripts implicated in synaptic plasticity. Microarray work in rodent prefrontal cortex after LSD identified small but reproducible transcriptional changes (e.g. arc, krox-20, Nor1), many of which are PSP- or synaptic-plasticity-related; several of these changes are 5-HT2A-dependent as shown using selective antagonists or receptor knockouts. Interactions with other receptors are considered. The 5-HT2C subtype may modulate overall intoxication and mood effects and could be necessary in addition to 5-HT2A activation; lisuride (an ergoline) is discussed as a nonhallucinogenic comparator that has differing 5-HT2C/2A pharmacology. The 5-HT1A autoreceptor agonism of tryptamines (e.g. DMT, psilocin, LSD) can suppress raphe firing and modulate cortical 5-HT tone; 5-HT1A antagonism (pindolol) potentiated DMT in human studies. Dopaminergic interactions are highlighted as a plausible potentiator of LSD’s unusually high in vivo potency: LSD has appreciable affinity for D2 and D1 receptors and may show time-dependent D2-mediated discriminative cues in animals, whereas phenethylamines lack such dopamine receptor affinity. Clinical and translational findings are aggregated. Human experimental work with DMT (i.v. 0.2–0.4 mg/kg), psilocybin (∼0.25 mg/kg p.o. in several studies), mescaline (500 mg p.o. in early studies), and LSD historical trials are reviewed. Psilocybin’s subjective and cognitive effects (altered mood, perception, ego boundaries, increases in indirect semantic priming, impairment in specific working-memory and attentional tasks) are reliably attenuated by 5-HT2A antagonists. Small clinical literatures and anecdotal reports are summarised regarding potential therapeutic applications: LSD-assisted care for terminal patients, historical but methodologically weak trials in alcoholism, and limited case reports or small-series suggestions for benefit in obsessive-compulsive disorder. The authors stress that the early clinical literature is generally of poor methodological quality by modern standards and that contemporary trials are few but emerging. Finally, the review emphasises the value of serotonergic hallucinogens as tools for cognitive neuroscience: their capacity to perturb thalamocortical and prefrontal circuits, modulate working memory and semantic network dynamics, and produce controlled altered states makes them useful probes of conscious processing, attention, and cortical integration.

Roth and colleagues conclude that modern neuroscience tools have reframed classical hallucinogens as relatively specific 5-HT2A receptor–targeting molecules that alter neuronal excitability, synaptic signalling, and gene expression in circuits central to perception and cognition. They propose that 5-HT2A agonism, interacting with glutamatergic systems and with modulatory influences from 5-HT1A, 5-HT2C, and dopaminergic receptors, can account for many of the neurophysiological and phenomenological features of the psychedelic state. The authors advocate for renewed, carefully controlled research — including comparative work across chemical classes, more electrophysiology with LSD and tryptamines (not only DOI), studies of thalamic function, and clinical trials using modern methods — while noting that legal restrictions have constrained progress. They suggest that serotonergic hallucinogens are both promising research tools for cognitive neuroscience and potential candidates for selected therapeutic applications, but emphasise that definitive clinical utility remains to be established through rigorous contemporary trials.