Future Directions for Clinical Psychedelic Research : The Relaxed Symptom Network

Evan Lewis-Healey, Ruben Laukkonen , Michiel van Elk

Pre-Print, May 2021

Abstract

Recent clinical trials have demonstrated that psilocybin may have strong antidepressant effects, and may be effective in the treatment of depressive disorders when embedded in a psychotherapeutic protocol (psychedelic-assisted psychotherapy; PAP). There are now dozens of registered and ongoing clinical trials that intend to test for the efficacy of psilocybin within a psychotherapeutic protocol. Despite promising results, the mechanism(s) that may be responsible for the antidepressant effects of PAP are still hotly contested. In this paper, we provide a broad overview of the recent clinical work conducted with psychedelics on depressive disorders, and summarise several theories of action of PAP. Extending on the state of the field, we argue that the ‘Network Theory of Mental Disorders’ is a useful tool for clinical research with psychedelics. We hypothesise that, if PAP is successful, the connections between symptoms in a network will weaken, thereby rendering the patient less vulnerable to developing or relapsing into depression. We argue that application of the Network Theory may (a) provide deeper insights into the effects of PAP on specific symptom interactions, both on an interindividual and intraindividual basis, (b) generate fruitful hypotheses for the clinical action of PAP, and (c) provide a pre-emptive tool for making the most of ‘intentions’ preceding and during psychedelic experiences. These findings we hope will ultimately improve responsiveness and reduce relapse in response to this promising therapy.

Keywords : Psychedelics, Network Theory, Psychopathology, Psychotherapy, Depression

Future Directions for Clinical Psychedelic Research: Application of the Network Theory

‘Classic’ psychedelics are defined as agonists, or partial agonists, at the 5-HT2A receptor (Nichols, 2016). This broad category of substances includes psilocybin (4-phosphoryloxy-N,N- dimethyltryptamine), lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT). Neuroimaging studies have revealed that ingestion of these substances significantly alters the functional organisation of the brain (Girn et al., 2020; Muthukumaraswamy et al., 2013; Carhart- Harris et al., 2012; Roseman et al., 2014; Petri et al., 2014). Moreover, these radical changes in the brain are accompanied by a significantly altered state of consciousness, comprising of changes in mood, perception, and cognition (e.g., Griffiths et al., 2006; Hasler et al., 2004; Liechti et al., 2017; Schmid et al., 2015). In addition to the distinct neurobiological and phenomenological effects of classic psychedelics, recent clinical trials have found extremely large effect sizes when using psilocybin (the psychoactive component in naturally-occurring psychedelic mushrooms) to treat depressive disorders (Grob et al., 2011; Ross et al., 2016; Griffiths et al., 2016; Carhart-Harris et al., 2016; 2018; Agin-Liebes et al., 2020; Davis et al., 2020). Moreover, at the time of writing, clinicaltrials.gov lists 99 registered trials that intend to use psychedelics to treat a variety of mental health disorders, including anorexia nervosa (e.g., NCT04661514), alcohol use disorder (e.g., NCT04410913), and obsessive-compulsive disorder (e.g., NCT03356483). As the field of psychedelic psychiatry develops, it is imperative for researchers and clinicians to deepen their understanding of the clinical action of psychedelics. We therefore aim to highlight how clinicians and researchers may achieve this through the integration of a contemporary practical and statistical tool in the field of clinical psychology, known as the Network Theory of Mental Disorders (Borsboom, 2017; hereby, the network theory), into future psychedelic research.

The network theory aims to reconceptualise mental health disorders as symptom networks, rather than as a latent construct (such as depression) causing a constellation of symptoms (see ‘The Network Theory…’ section for an overview). The symptoms within the networks are connected to each other in varying strengths, which determine an individual’s vulnerability to developing a specific mental health issue (Cramer et al., 2016). The primary hypothesis of this paper is that, if psychedelic-assisted psychotherapy (PAP) is successful, the connections between symptoms in a network will weaken, thereby rendering the patient less vulnerable to developing depression. Moreover, this testable hypothesis has important implications for how to maximise the potential of PAP to support the emergence of a network robust to depression and potentially other disorders.

Leading up to the presentation of the ‘Relaxed Symptom Network’ hypothesis, we begin with an overview of the growing evidence that examines the antidepressant potential of PAP. We specifically present evidence of psychedelics for depressive disorders as it is the most thoroughly researched in contemporary psychedelic psychiatry. However, while much of the literature focuses on the use of psilocybin, we acknowledge that there are transdiagnostic elements at play when it comes to PAP. Therefore, we argue that the application of the network theory may benefit clinical psychedelic research as a whole, but, for the sake of simplicity, we focus specifically on depressive disorders. Second, we present several recent theoretical papers that attempt to underpin how psilocybin, and other classic psychedelics, may exert their therapeutic effects. The aim of this section is to provide a broad overview into the psychological and neurobiological changes that may be responsible for a psychedelic’s antidepressant effects. Third, we provide an overview of the network theory of mental disorders, and outline our hypothesis regarding the action of PAP on the psychopathology network. Finally, we outline the concrete benefits that the network theory will provide when applied to clinical psychedelic research. The benefits of applying the network theory to psychedelic research include: a) gaining deeper insights into patients’ potential to relapse, b) answering questions regarding the efficacy of PAP to target specific symptoms within a network across patients, and c) identifying central symptoms in an individual patients’ network, allowing both patients and clinicians to specify an intention for an upcoming therapeutic psychedelic session.

What is Psychedelic-Assisted Psychotherapy?

Clinical psychedelic research has a tumultuous history, and has been marred by prohibition (Nutt & Carhart-Harris, 2021). However, contemporary academia is re-opening itself up to the study of psychedelics, both on the brain and on mental health (Nutt & Carhart-Harris, 2021). Psychedelic-assisted psychotherapy (PAP) is an intervention that is receiving considerable and growing clinical and scientific attention. Commonly, a PAP protocol lasts for six to ten weeks, and will involve one to three dosing sessions with a psychedelic (Payne et al., 2021). The most common psychedelic used in Western psychedelic science is psilocybin, which we will hereby refer to. Prior to the dosing session(s), the patient undergoes preparatory therapeutic support. Within this part of the protocol, the patient develops a relationship with the therapist(s) that is/are present for the dosing session. The patient is told what to expect, and often sets an ‘intention’ for the upcoming dosing session (Watts & Luoma, 2020). During the session, the patient ingests psilocybin (commonly 25-30mg as a high dose) in the presence of a therapist(s), who provides guidance and emotional support when needed. However, the patients are encouraged to approach the session introspectively – eye shades are provided, and a curated playlist of music is played in order to accompany or guide the psychedelic experience (Kaelen et al., 2018). Succeeding the psychedelic session, a number of integration sessions are provided, aiming to synthesise any insights from the experience, with the aim of integrating behavioural or cognitive changes that may lead to positive long-term mental health outcomes. While there has been some effort to standardise the therapeutic protocols associated with PAP (Watts & Luoma, 2020), further research is needed to verify the ideal way to deliver psychedelic therapy.

It is beyond the scope of this review to summarise all of the clinical research that has used PAP to treat depressive disorders. We invite the reader to seek out the following references, which each provide a meta-analysis of PAP for depressive disorders (Goldberg et al., 2020; Vargas et al., 2020; Romeo et al., 2020; Luoma et al., 2020; Galvão-Coelho et al., 2021). While the observed effect sizes within these meta-analyses are consistently larger in magnitude than those associated with the use of psychotherapy alone (Cuijpers et al., 2008; Cuijpers et al., 2010), antidepressants (Fournier et al., 2010), or pharmacotherapy and psychotherapy combined (Cuijpers et al., 2014), it should be highlighted that these effect sizes in clinical psychedelic trials may be overestimated due to low sample sizes, or due to a lack of robust placebo-controls. It is therefore of the utmost importance to replicate these findings in larger sample sizes with robust placebo-control measures. Furthermore, it is pertinent to highlight that all of the summarised studies use cross-sectional data to evaluate the effectiveness of PAP on depressive symptoms. While this is a conventional method, we argue that time-series data may be a more appropriate and informative style of sampling when evaluating the efficacy of PAP (see our recommendations below).

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