Pharmacology of Hallucinations: Several Mechanisms for One Single Symptom?

Abstract

Hallucinations are complex misperceptions, that principally occur in schizophrenia or after intoxication induced by three main classes of drugs: psychostimulants, psychedelics, and dissociative anesthetics. There are at least three different pharmacological ways to induce hallucinations: (1) activation of dopamine D2 receptors (D2Rs) with psychostimulants, (2) activation of serotonin 5HT2A receptors (HT2ARs) with psychedelics, and (3) blockage of glutamate NMDA receptors (NMDARs) with dissociative anesthetics. In schizophrenia, the relative importance of NMDAR and D2R in the occurrence of hallucinations is still debated. Slight clinical differences are observed for each etiology. Thus, we investigated whether the concept of hallucination is homogenous, both clinically and neurobiologically. A narrative review of the literature is proposed to synthesize how the main contributors in the field have approached and tried to solve these outstanding questions. While some authors prefer one explanatory mechanism, others have proposed more integrated theories based on the different pharmacological psychosis models. In this review, such theories are discussed and faced with the clinical data. In addition, the nosological aspects of hallucinations and psychosis are addressed. We suggest that if there may be common neurobiological pathways between the different pharmacological systems that are responsible for the hallucinations, there may also be unique properties of each system, which explains the clinical differences observed.

The Pharmacology of Visual Hallucinations in Synucleinopathies

“…Glutamatergic synapses interact with dopaminergic and serotoninergic systems and play an important role in the genesis of auditory hallucinations (Sommer et al, 2018) and VH. In that respect, the hypofunction of NMDA receptors along with the overactivation of D2 and 5-HT receptor subtypes has been indicated to converge in producing VH and other psychotic symptoms (Rolland et al, 2014).…”

Asphyxia-activated corticocardiac signaling accelerates onset of cardiac arrest

“…Serotonin, whose release in the occipital cortex surged more than 20-fold within the first 2 min of asphyxia, plays diverse central functions via serotonin receptors. Activation of a subset of serotonin receptors, for instance, induces visual hallucinations with mystical feelings in humans (36). Internally generated visions and perceptions apparently occur during cardiac arrest in 10-20% of survivors (22,24,37).…”

Meta-analytic evidence for the plurality of mechanisms in transdiagnostic structural MRI studies of hallucination status

“…A significant issue in neuroimaging studies of hallucinations has been the lack of a clinical control group, thus confounding abnormalities specific to hallucination status with those of the broader phenotype. Equally challenging has been a tangled conceptual landscape, with numerous models proposed as cognitive or neurobiological accounts of auditory or visual hallucinations 5,26,[28][29][30][31][32][33][34][35][36][37][38][39][40][41] (Figure 1). Obtaining differentiating evidence is difficult as these models are not mutually exclusive, each drawing upon a similar repertoire of constituents, making it non-trivial to derive corresponding predictions 42 .…”