This review (2014) examines the commonalities and differences across hallucinations occurring in schizophrenia and in response to psychostimulants, psychedelics, and dissociative anesthetics. They identify three principal pharmacological mechanisms 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, each of which explains different aspects of clinically observed hallucinations amongst patients with schizophrenia.

Abstract

“Introduction: 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.

Methods/Results: 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.

Discussion: 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.”

Authors: Benjamin Rolland, Renaud Jardri, Ali Amad, Pierre Thomas, Olivier Cottencin & Régis Bordet

Summary

Introduction

Hallucinations may occur in diverse psychiatric and neurological pathologies, and may be triggered by at least three different kinds of drugs: psychostimulants, dissociative anesthetics, and psychedelics.

The pharmacological hypotheses underlying the symptoms of schizophrenia are different depending on the situation considered. Dopamine D2R hyperstimulation, glutamate NMDA receptor blockade, and serotoninergic 5HT2A receptor stimulation are possible mechanisms.

The Three Main Pharmacological Models of Hallucinations

Schizophrenic hallucinations are mainly auditory verbal, but early-onset forms have visual and multisensory hallucinations. Antipsychotic drugs have the most blatant therapeutic effects on positive symptoms, and this effect is due to an antagonistic action on D2Rs, which is shared by all antipsychotic molecules.

It has been hypothesized that all forms of D2R overstimulation in striatum could trigger psychosis, even beyond the scope of schizophrenia. This hypothesis is supported by the clinical picture of psychosis induced by psychostimulant drugs and by the use of dopaminergic receptors agonists in Parkinson’s disease.

A new class of anesthetic drugs was synthesized at the end of the 1950s, and it was observed that these drugs could induce schizophrenia-like symptoms. It was later demonstrated that PCP exhibits antagonistic effects on NMDARs, and a new pharmacological model of hallucinations and other schizophrenic symptoms was introduced.

Other nonschizophrenic NMDAR-related psychoses have been reported, without any relation with the dopaminergic system. These states include hallucinations, which is in contrast to what happens with the use of dopaminergic drugs.

Psychedelics induce phenomenologically complex pictures, which may mix visual hallucinations, synesthesia, and peculiar altered states of consciousness with mystical feelings. This process triggers a breakdown of cognitive integrity and results in the subsequent occurrence of aberrant feelings and perceptions.

LSD induces serotoninergic-based psychosis, whereas schizophrenia-like psychosis induces dopaminergic-based psychosis. Pseudohallucinations are common, although insight into hallucinations in schizophrenia is poor.

Despite the numerous clinical differences, some arguments suggest that 5HT2ARs play a role in schizophrenia. Furthermore, many second-generation antipsychotics have an antagonistic action on the 5HT2AR, which highlights the role of 5HT2ARs in schizophrenia.

Confrontations between Models and Attempts for Integration

Scientists have questioned whether three different cerebral receptors are part of the same global neural circuitry, or whether they belong to pathways that induce hallucinations separately, with each having specific clinical expressions.

The “all-dopamine” hypothesis states that dopamine is central to the pathophysiology of schizophrenia, and that activation of D2Rs is indispensable to induce any form of psychosis and consequently any form of hallucinations. However, many symptoms induced by NMDAR antagonists have not been linked with an increase of dopamine transmission.

Activation of D2Rs and blockade of NMDARs may have opposite effects in the striatum, which may explain why both D2R activation and NMDAR blockade induce hallucinations in a similar manner. However, recent studies question the potential influences of D2Rs on ketamine-induced abnormalities in the striatum.

The role of 5HT2ARs in schizophrenia has been reintroduced, and second-generation antipsychotics are both D2R and 5HT2AR antagonists. However, the blockade of 5HT2ARs may not underlie the antipsychotic effects of these drugs, and first generation antipsychotics exhibit the same level of efficacy on positive symptoms.

Several studies have investigated the D2R-related theory of positive symptoms in schizophrenia and the activity of psychedelics. However, it remains unclear whether D2Rs are involved in psychedelic-induced hallucinations if 5HT2ARs are not involved in psychedelic-induced hallucinations.

NDMAR antagonists induce negative symptoms and have been used in drug-induced experimental models of schizophrenia. However, some cognitive functions are impaired in schizophrenia and are only reported when administering NDMAR antagonists.

There are several theories for integrating NMDAR and 5HT2AR into a common neurobiological framework for psychosis. These theories include mechanisms in series, in which NMDAR dysfunction leads to the enhanced activation of 5HT2ARs, or a final common pathway.

Recently, different types of interconnections between glutamatergic and serotoninergic neurotransmission systems have been proposed to explain psychosis. These interconnections may be responsible for the antipsychotic effects of NMDAR antagonists and 5HT2AR agonists.

Three different neurotransmission systems have been shown to be involved in psychosis. These three systems are interdependent in inducing psychosis-like behavioral abnormalities in rodents, and may constitute unspecific vulnerability points in the cortico-striato-thalamo-cortical loops.

A scheme was proposed to explain psychosis by integrating the different neurotransmission systems, but it struggles to explain the clinical dissimilarities.

Discussion

Hallucinations are often clinically associated with a collection of other symptoms, including delusions, thought disorders, and loss of insight. It has been contested whether hallucinations and delusions are separate clinical entities or intrinsically linked in their occurrence with other psychotic symptoms.

There are many definitions of psychosis, and even for hallucinations that occur in the general population, the state of consciousness is often clinically altered in some way. Therefore, it appears difficult to affirm that hallucinations exist outside the scope of psychosis.

Pseudohallucinations are misperceptions without anxiety and insightfulness that the misperceptions are not real. They are frequent with psychedelics, but may be a threshold effect, and there may be a dose-effect mechanism that underlies all types of hallucinogenic drugs.

HT2AR-induced symptoms appear to have a strong visual component, which is also observed in Parkinson’s disease and schizophrenic-related disorders. Psilocybin-induced visual hallucinations and synesthesia may be related to occipitoparietal cortex activity, which has not been observed in VH induced by NMDAR antagonists or in VH of schizophrenia or first psychosis episode.

Psychedelics induce nonperceptive symptoms that are very specific. These feelings consist of a merging with the external world and are thought to be derived from a cognitive reconstruction following preliminary visual disruptions.

All hallucinogenic drugs act by modulating the stimuli filtering and integrator system, but each pharmacological system also specifically acts on other cerebral processes, which could confer quite a specific phenomenological pattern to the disruption of one system compared to the other.