Pharmacological modelling of dissociation and psychosis: an evaluation of the Clinician Administered Dissociative States Scale and Psychotomimetic States Inventory during nitrous oxide (‘laughing gas’)-induced anomalous states

Abstract

Rationale A significant obstacle to an improved understanding of pathological dissociative and psychosis-like states is the lack of readily implemented pharmacological models of these experiences. Ketamine has dissociative and psychotomimetic effects but can be difficult to use outside of medical and clinical-research facilities. Alternatively, nitrous oxide (N2O) — like ketamine, a dissociative anaesthetic and NMDAR antagonist — has numerous properties that make it an attractive alternative for modelling dissociation and psychosis. However, development and testing of such pharmacological models relies on well-characterized measurement instruments. Objectives To examine the factor structures of the Clinician Administered Dissociative States Scale (CADSS) and Psychotomimetic States Inventory (PSI) administered during N2O inhalation in healthy volunteers. Methods Secondary analyses of data pooled from three previous N2O studies with healthy volunteers. Results Effect sizes for N2O-induced dissociation and psychotomimesis were comparable to effects reported in experimental studies with sub-anaesthetic ketamine in healthy volunteers. Although, like ketamine, a three-factor representation of N2O-induced dissociation was confirmed, and a more parsimonious two-factor model might be more appropriate. Bayesian exploratory factor analysis suggested that N2O-induced psychosis-like symptoms were adequately represented by two negative and two positive symptom factors. Hierarchical cluster analysis indicated minimal item overlap between the CADSS and PSI. Conclusion N2O and ketamine produce psychometrically similar dissociative states, although parallels in their psychosis-like effects remain to be determined. The CADSS and PSI tap largely non-overlapping experiences under N2O and we propose the use of both measures (or similar instruments) to comprehensively assess anomalous subjective states produced by dissociative NMDAR antagonists.

What is better for psychiatry: Titrated or fixed concentrations of nitrous oxide?

“…It is therefore significant that the dental titration technique has been safely used since the 1940's, in routine general dental practice ( 7 – 9 , 11 , 17 ) and since the 1980's in psychiatry ( 8 – 12 , 34 , 45 , 57 ). Concentrations used in dentistry are almost always lower ( 7 – 11 , 17 ) than those recommended in the most recent research ( 1 – 6 , 15 , 16 ).…”

“…Indeed, in some N 2 O-sensitive individuals 25% may also lie within the second half of Stage 1 ( 19 ). The difference is more relevant now, since the latest work, features the administration of relatively high concentrations of subanaesthetic N 2 O ( 1 – 6 , 13 , 15 , 16 , 19 ), not consistent with PAN ( 7 , 8 , 17 , 33 ).…”

“…However, like 50%, 25% is not tailored to each subject's needs. As a result, those sensitive to the actions of N 2 O, will be unnecessarily exposed to side-effects ( 7 , 8 ) including the undesirable psychomimetic states, found with ketamine ( 6 , 16 ). Inadvertently, by using different dosages, these authors have underlined the dose-dependent variability of the effects of N 2 O.…”

“…The main objection to using fixed concentrations, whether 25% or 50% is that the majority of individuals inhaling N 2 O will be subjected unnecessarily ( 7 ) to unwanted side-effects such as nausea, vomiting, sleepiness and headache ( 6 – 8 , 15 , 16 ). Indeed, in hypersensitive people sleepiness could be converted to anesthesia ( 7 , 8 ) as well as other undesirable psychomimetic effects, including delusions, anhedonia, mania and paranoia as well as distortions in perception, mental ineffectiveness and anhedonia ( 6 , 15 , 16 ). Likewise, at both the fixed 25% or 50% levels, many patients will not have received the optimal dosage.…”

The neurochemical bases of verbal suggestion and hypnosis

“…Glutamate is the brain's primary excitatory neurotransmitter and is involved in a wide range of cognitive functions including learning and memory (Olney & Farber, 1995;Riedel et al, 2003). The N-methyl-Daspartate (NMDA) receptor antagonists ketamine and nitrous oxide are known to induce pronounced dissociative states, such as depersonalization and derealization, as well as a range of psychotomimetic effects, including hallucinations and delusions (Piazza et al, 2022).…”