Psychiatry’s next top model: cause for a re-think on drug models of psychosis and other psychiatric disorders

This survey study (2013) compared five drugs on their ability to model a variety of psychiatric conditions. It found, among other results, that psilocybin was the best model for positive psychotic symptoms.

Abstract

“Despite the widespread application of drug modelling in psychiatric research, the relative value of different models has never been formally compared in the same analysis. Here we compared the effects of five drugs (cannabis, psilocybin, amphetamine, ketamine and alcohol) in relation to psychiatric symptoms in a two-part subjective analysis. In the first part, mental health professionals associated statements referring to specific experiences, for example ‘I don’t bother to get out of bed’, to one or more psychiatric symptom clusters, for example depression and negative psychotic symptoms. This measured the specificity of an experience for a particular disorder. In the second part, individuals with personal experience with each of the above-listed drugs were asked how reliably each drug produced the experiences listed in part 1, both acutely and sub-acutely. Part 1 failed to find any experiences that were specific for negative or cognitive psychotic symptoms over depression. The best model of positive symptoms was psilocybin and the best models overall were the acute alcohol and amphetamine models of mania. These results challenge current assumptions about drug models and motivate further research on this understudied area.”

Authors: Robin L. Carhart-Harris, Stefan Brugger, David J. Nutt & James M. Stone

Summary

Introduction

Drug models of mental illness are useful in psychiatry because they help to inform hypotheses on the biology of pathological states and provide a valuable testing ground for novel medications. However, few studies have compared the relative merits and shortcomings of different drug models.

Serotonergic psychedelics have been considered candidate drug models of psychosis, but have fallen out of favour in recent years as focus has shifted more on to their therapeutic potential. Ketamine is currently arguably the most popular drug model of psychosis in humans.

Certain drugs can induce spiritual-type experiences that are indistinguishable from spontaneously occurring spiritual experiences. However, clinicians sometimes identify such phenomena as pathological.

A comparison of different drug models of mental states is fraught with difficulty. It is important to evaluate how closely the features of the model resemble the symptoms of a specific disorder, and how reliably these features occur in the model.

In a two-part subjective analysis, mental health professionals compared the effects of five drugs on psychiatric symptoms. Individuals with personal experience with each of the drugs were asked how reliably each drug produced the experiences listed in part 1.

In this two-part study, we used novel methodologies to determine the reliability with which a drug can produce an endogenous state. We sought to address the question of what are the best drug models of psychiatric illness.

Basic design

We devised a subjective pilot study in two parts, in which mental health professionals rated how closely 58 first-person statements resembled particular mental states or symptom clusters.

In the second part of the study, drug users with personal experience with five different drugs were asked to say whether and how often they experienced certain phenomena while under the acute influence of a drug.

We asked 63 mental health professionals to complete the survey and 224 experienced drug users to complete the survey. The survey asked about previous experience with alcohol, high-potency cannabis, amphetamine, psilocybin-containing magic mushrooms and ketamine.

Survey format and procedure

In part 1 of the survey, respondents were presented with 58 first-person statements referring to experiences or symptoms a psychiatric patient might describe. They were instructed to ascribe each statement to up to eight different disorders or symptom clusters, including spiritual-type experiences.

Seventeen statements were selected from part 1 based on how specifically they were associated with a particular symptom cluster. However, to ensure we included items that covered a range of clinical phenomena, some items with lower % association values but relevance to a disorder that generally has low % association values were chosen.

The 17 first-person statements that were most closely associated with mania were calculated by summing the number of ascriptions to mania over the total number of ascriptions to any mental state (35) + 61. The frequency with which respondents experienced each effect was then expressed as a percentage. At least one well-loaded spliff/joint, three pints of beer or cider, three large glasses of wine, 12 fresh liberty cap magic mushrooms, 500 mg amphetamine, and 60 mg ketamine are required.

Data analysis for the part 2 survey

We quantified a drug’s ability to induce mania-related symptoms by measuring the percentage of part 2 respondents who selected ‘always/often’ for statements associated with a particular symptom cluster.

Part 1 results

Figure 1 displays the statements that had the greatest degree of association with each symptom cluster. None of the statements had a significant unique association with negative psychotic symptoms or cognitive symptoms of psychosis, because of a high co-association between four symptom clusters.

Part 2 results

None of the classic drug models of psychosis produced positive psychotic symptoms with any reliability. The best model was acute psilocybin, but it had a low reliability of just 13%.

Drug models of the spiritual experience were found to be sub-acute psilocybin, acute ketamine and psilocybin. These drugs were closely associated with the statement ‘I feel a profound inner peace’.

Discussion

This novel analysis found that none of the four classic drug models of psychosis produced positive psychotic symptoms with any reliability, and that only 13% of psilocybin users claimed to always or often experience positive psychotic symptoms after this drug.

There are many possible reasons for this discrepancy, including experienced drug users being more resilient to psychotomimetic effects, and people experiencing psychotic effects being less likely to take these drugs recreationally and frequent the websites on which this survey was advertised.

A key question when evaluating a drug’s ability to model psychosis is whether the drug is supposed to model auditory-verbal hallucinations or anxious states engendering false inferences. Auditory hallucinations are thought of as transients in a mechanistic sense, and may be merely epiphenomena of prolonged states. This hypothesis is consistent with the psychotogenic potential of cannabis, a drug commonly used over long periods.

The popular ketamine model of psychosis is often questioned for its construct validity as it models both positive and negative symptoms of psychosis. However, the mental health professionals who responded to the first survey were more likely to attribute these experiences to depression.

The results do not imply that negative symptoms do not exist in schizophrenia, nor that they are seriously disabling. However, it is not possible to make any claims about the validity of currently proposed drug models of negative symptoms.

The present study found that acute alcohol produced symptoms of mania with the highest exclusivity for any symptom cluster (70% specificity for mania). Sub-acute alcohol and amphetamine were also good models of depression, with 24% of respondents reporting this during the alcohol hangover.

The present survey included first-person statements relevant to the spiritual experience, and found that 53% of respondents always or often experience ‘I felt a profound inner peace’ in the acute psilocybin state and 48% said they experience it in the sub-acute period following psilocybin use.

This study has some important limitations, including the fact that data were derived from web-based surveys, and that respondents may have held biases. It also implies that we should be cautious about making general inferences about a drug’s pharmacology based on a set of subjective reports.

We could have collected more data by asking respondents about their ages and drug use frequency, but the advantages were balanced against the disadvantages.

The results of this study suggest that acute alcohol and amphetamine models of mania are the best drug models of psychiatric disorders, while sub-acute psilocybin appears to be the best model of non-pathological spiritual-type experiences.

This pilot study is hoped to motivate a larger controlled study involving administration of a range of psychotomimetic drugs to healthy individuals.