Pharmacology of Hallucinations: Several Mechanisms for One Single Symptom?

Hallucinations are defined as perceptions in the absence of an external stimulus and occur across a range of psychiatric and neurological states, most characteristically in schizophrenia. Rolland and colleagues note that hallucinations may also be pharmacologically induced by three broad drug classes: psychostimulants (e.g. cocaine, amphetamine), dissociative anaesthetics (e.g. PCP, ketamine) and classical psychedelics (e.g. LSD, psilocybin). Each class maps onto a different principal receptor mechanism—dopamine D2 receptor (D2R) hyperactivation for psychostimulants, NMDA receptor (NMDAR) blockade for dissociative anaesthetics, and 5HT2A receptor (5HT2AR) stimulation for psychedelics—which raises the question whether the clinical and neurobiological phenomenon called “hallucination” is homogeneous or instead comprises distinct forms with different substrates. This paper presents a narrative synthesis of the literature addressing those competing and complementary models. Rolland and colleagues set out to summarise the three pharmacological models, examine pairwise and fully integrated interactions among D2Rs, NMDARs and 5HT2ARs, and confront these mechanistic accounts with clinical phenomenology and neuroimaging findings. The aim is to evaluate whether a unified circuit-level explanation can accommodate observed clinical differences or whether each receptor system confers a characteristic hallucinatory profile.

The extracted text indicates that the article is a narrative review synthesising experimental, clinical and imaging literature on pharmacological mechanisms of hallucinations. The authors do not report a formal systematic search strategy, selection criteria, or quantitative meta-analytic methods in the provided extraction; therefore the review appears to be qualitative and integrative rather than a systematic review with prespecified methods. Structure of the review is organised around: (1) descriptions of the three main pharmacological models (dopaminergic, glutamatergic/NMDA, and serotonergic/5HT2A), (2) examinations of pairwise interactions between these systems (D2R–NMDAR, D2R–5HT2AR, NMDAR–5HT2AR), and (3) proposals for integrated, circuit-level frameworks (notably cortico-striato-thalamo-cortical filtering disruptions). Where available, the authors draw on human pharmacological challenge studies, animal models, genetic findings and neuroimaging data to compare phenomenology and cognitive correlates across models. The extracted text does not provide details on inclusion dates, databases searched, or explicit risk-of-bias assessment.

Rolland and colleagues present three principal pharmacological models and then review evidence about their overlap and distinctiveness. Dopamine (D2R) model: The classic pharmacological account links positive symptoms of schizophrenia—predominantly auditory verbal hallucinations—to excessive dopaminergic transmission in the striatum and the therapeutic efficacy of antipsychotics to D2R antagonism. Imaging work supports increased striatal dopaminergic activity during positive symptoms. The authors describe hypotheses that psychosis more broadly may reflect striatal dopaminergic hyperfunction (including drug-induced psychosis and dopaminergic agonist–related psychosis in Parkinson’s disease) and note theories invoking D2High receptor supersensitivity as a unifying mechanism. Psychostimulant-induced psychosis is presented as clinically consonant with this dopaminergic account, often accompanied by motor agitation and excitement. Glutamate (NMDAR) model: Dissociative anaesthetics such as PCP and ketamine produce schizophrenia-like syndromes including hallucinations, negative symptoms and dissociation; these effects are attributed to antagonism of NMDARs. The review highlights genetic links between schizophrenia susceptibility and glutamatergic/NMDAR function, reports that NMDAR modulators can affect positive and negative symptoms, and notes that NMDAR hypofunction is regarded by many researchers as a central hypothesis for schizophrenia pathophysiology. Importantly, NMDAR blockade can induce psychosis-like states without clear dopaminergic increases in the striatum, and these states often exhibit mixed positive and negative symptoms that differ phenomenologically from pure dopaminergic psychoses. Serotonin (5HT2AR) model: Classical psychedelics primarily stimulate 5HT2ARs on cortical neurons and produce a constellation of effects dominated by visual hallucinations, synesthesia and profound alterations in consciousness (including so-called mystical experiences). The authors emphasise phenomenological differences from schizophrenia: visual hallucinations and preserved insight or “pseudohallucinations” are more typical with psychedelics, whereas auditory hallucinations and loss of insight predominate in schizophrenia. Some evidence links 5HT2ARs to schizophrenia—upregulated 5HT2AR expression in young, untreated patients and antagonism of 5HT2AR by many second-generation antipsychotics—but the therapeutic relevance of 5HT2AR blockade for positive symptoms remains uncertain. Interactions between systems: The review considers evidence for reciprocal and hierarchical interactions. - D2R–NMDAR: Rivalrous accounts have been proposed, with some asserting dopamine as central and explaining NMDAR-antagonist effects via downstream dopamine mechanisms (e.g. D2High affinity). Others counter that NMDAR antagonists produce effects without striatal dopamine increases and that few antipsychotics reverse some PCP-induced deficits in animal models, supporting NMDAR blockade as an independent path to psychosis. Preclinical data also indicate bidirectional regulation—prefrontal glutamatergic activity can reduce striatal dopaminergic tone, and D2R activation can downregulate NMDARs in striatal neurons—suggesting reciprocal modulation rather than exclusivity. - D2R–5HT2AR: Reintroduction of 5HT2AR into schizophrenia models stems partly from the pharmacology of second-generation antipsychotics, which combine D2R and 5HT2AR antagonism. The authors review mixed findings: LSD shows biphasic effects in animals, with an early 5HT2AR-mediated phase and a later D2R-associated phase in some paradigms, and heteromeric 5HT2AR–D2R complexes have been identified in mouse striatum. However, human pharmacology shows that haloperidol (a D2 antagonist) does not block psilocybin's psychotomimetic effects whereas ketanserin (a 5HT2AR antagonist) does, arguing that psychedelic effects can be independent of D2R modulation. - NMDAR–5HT2AR: Several cognitive impairments seen in schizophrenia (for example, inhibition of return) are reproduced by both NMDAR antagonists and 5HT2AR agonists, but other deficits (e.g. mismatch negativity, alterations in prepulse inhibition) are more specifically linked to NMDAR antagonism. Mechanistic links include potentiation of serotonergic activation by NMDAR antagonists, and crucially a proposed requirement for functional complexes between 5HT2AR and metabotropic glutamate receptor mGlu2 for psychedelic actions. Agonists at mGlu2/3 can reverse behavioural effects of NMDAR antagonists and show antipsychotic properties in humans, which supports the idea of a common pharmacological process—involving mGlu2/3 hypoactivation—that might bridge 5HT2AR agonism and NMDAR hypofunction. Integrated circuit model: Drawing together these strands, the authors describe an integrated framework centred on disruptions of filtering in cortico‑striato‑thalamo‑cortical loops. In this account, D2Rs and NMDARs act within the limbic striatum while prefrontal 5HT2ARs modulate striatal activity via cortical pyramidal neurons; dysfunction at any of these nodes could impair sensory and cognitive gating and produce psychotic symptoms. Experimental rodent data indicate interdependence of the three systems for some psychosis-like behaviours. Nonetheless, the integrated model does not fully account for the nuanced clinical differences observed across drug classes and disease states. Phenomenological correlations: The review emphasises that psychedelics disproportionately produce visual phenomena, synesthesia and preserved insight, often linked to occipitoparietal cortical activity; NMDAR antagonists produce mixed positive/negative symptoms and robust cognitive deficits; dopaminergic drugs tend to produce excitement and motor agitation alongside hallucinations. Neuroimaging reports are noted where psychedelic and NMDAR‑antagonist effects both disrupt prefrontal–posterior cingulate networks, but occipitoparietal associations appear more specific to psychedelic-induced visual phenomena.

Rolland and colleagues interpret the literature as supporting both shared and unique mechanisms for hallucinations. They stress that hallucinations seldom occur in isolation—typically they coexist with delusions, disordered thought and altered insight—and question whether hallucinations can be cleanly separated from the broader construct of psychosis. Drawing on dopaminergic theory, some researchers view delusions and hallucinations as inseparable manifestations of striatal dopaminergic overactivity, whereas others emphasise distinctions in phenomenology and underlying circuitry. The authors highlight the clinical contrast between psychedelic-induced “pseudohallucinations”, which often retain insight and provoke less anxiety, and psychostimulant- or NMDAR antagonist–induced hallucinations, which more commonly feature loss of insight and negative symptoms. They propose a possible threshold model in which psychedelics produce pseudohallucinations at lower intensities but can produce vivid hallucinations with loss of insight at higher doses; alternatively, pseudohallucinations may be relatively specific to 5HT2AR activation. The visual dominance of psychedelic phenomena, the occurrence of synesthesia and the subjective experience of “oceanic boundlessness” are presented as evidence that 5HT2AR activation disrupts visual and multisensory integration in ways that differ from NMDAR blockade or dopaminergic hyperactivity. Neurobiological integration is possible, the review argues, because the three receptor systems can interact and converge on shared circuit-level processes—chiefly filtering disruptions in cortico‑striato‑thalamo‑cortical loops—but each system also appears to confer characteristic cognitive and perceptual effects. The authors acknowledge limitations of existing evidence: some animal and pharmacological findings are difficult to reconcile, imaging data are still sparse and heterogeneous, and the integrated model has trouble explaining subtle clinical differences. They call for further experimental work to determine whether certain phenomenological patterns (for example pseudohallucinations or occipitoparietal visual activations) are specific to particular receptor mechanisms or are dose-dependent manifestations of a common disrupted filter.