A qualitative and quantitative account of patient’s experiences of ketamine and its antidepressant properties

Rachael L. Sumner, Emme Chacko, Rebecca McMillan, Meg J. Spriggs, Christie Anderson, James Chen, Amelia French, SungHun Jung, Akshaya Rajan, Gemma Malpas, John Hay, Rhys Ponton, Suresh D. Muthukumaraswamy and Frederick Sundram

Journal of Psychopharmacology, 2021, 1-16

Doi : 10.1177/0269881121998321

Abstract

Background : Ketamine is central to one of the most rapidly growing areas of neuroscientific research into novel treatments for depression. Limited research has indicated that the psychedelic properties of ketamine may play a role in its antidepressant effects.

Aim : The aim of the current study was to explore the psychedelic experiences and sustained impact of ketamine in major depressive disorder.

Methods : In the current study, ketamine (0.44 mg/kg) was administered to 32 volunteers with major depressive disorder in a crossover design with the active-placebo remifentanil, in a magnetic resonance imaging (MRI) environment. The 11-dimension altered states of consciousness questionnaire and individual qualitative interviews were used to capture the acute psychedelic experience. The Montgomery-Asberg Depression Rating Scale and further interviewing explored lasting effects. The second qualitative interview took place ⩾3 weeks post-ketamine.

Results : Greater antidepressant response (reduction in Montgomery-Asberg Depression Rating Scale at 24 h) correlated with the 11-dimension altered states of consciousness dimensions: spirituality, experience of unity, and insight. The first qualitative interview revealed that all participants experienced perceptual changes. Additional themes emerged including loss of control and emotional and mood changes. The final interview showed evidence of a psychedelic afterglow, and changes to perspective on life, people, and problems, as well as changes to how participants felt about their depression and treatments.

Conclusions : The current study provides preliminary evidence for a role of the psychedelic experience and afterglow in ketamine’s antidepressant properties. Reflexive thematic analysis provided a wealth of information on participants’ experience of the study and demonstrated the psychedelic properties of ketamine are not fully captured by commonly used questionnaires.

Keywords : Ketamine, depression, qualitative research, thematic analysis, psychedelic

 

Introduction

Ketamine has been dominant in the growing field of research into rapid-acting antidepressants. This is partly because ketamine is an established, safe and widely used medication in surgery and pain management (Kohrs and Durieux, 1998). Its potential as an antidepressant was first reported by Berman et al. (2000), and has gained considerable momentum since a larger replication by Zarate et al. (2006) demonstrated significant antidepressant effects within 3 h of treatment in 70% of a group of participants with treatment resistant depression, that lasted for around 1 week. Ketamine is often discussed alongside the classic serotonergic psychedelic psilocybin due to their rapid action as antidepressants and the psychedelic nature of their acute effects (Majić et al., 2015; Vollenweider and Kometer, 2010). Therefore, an area of research interest has been whether the psychedelic effects of these drugs and the content of the acute experiences are related to their antidepressant properties (Mathai et al., 2020). A second area of interest has been determining the nature of the lasting changes in perspective or perception of oneself or one’s depression after taking just a single dose of these drugs, both in consideration of and beyond alleviation of the symptoms of depression (Griffiths et al., 2016; Majić et al., 2015; Roseman
et al., 2018; Watts et al., 2017).

There is less research in this area for ketamine compared to psilocybin, despite there having been considerably more studies investigating the antidepressant effects of ketamine (see Schenberg (2018)). Compared to ketamine, classic serotonergic psychedelics (like psilocybin) have highly distinct pharmacological, phenomenological, and therapeutic profiles (see Vollenweider and Kometer (2010) for a brief review). It is not the purpose of the current study to provide a critical comparison of ketamine and classic psychedelics, however it is the case the there is real need for unique research to be conducted evaluating ketamine because of these differences.

Existing research investigating the relationship between the acute experience of ketamine and its antidepressant properties typically explores the dissociative, hallucinogenic, and psychotomimetic effects of doses around 0.5 mg/kg. However, describing sub-anesthetic ketamine using each of these terms in isolation is insufficient (Bowdle et al., 1998). Psychotomimesis describes alterations in perception and thought (e.g. paranoia and delirium) brought on by drugs such as ketamine but also phencyclidine hydrochloride (PCP) and, lysergic acid diethylamide (LSD) among others, particularly in relation to pathological psychosis (Krystal et al., 1994). The related construct of dissociation refers to the disruption of perception primarily in terms of connection with one’s senses and body. Hallucinogen implies ketamine always or exclusively causes hallucination. Instead the term psychedelic1 is preferred to describe ketamine, to allow and explore fluidity in people’s experiences of the above properties of ketamine in varying quantities, and where the alteration of consciousness crosses and transcends multiple sensory and perceptual domains, often giving way to a rich experience. During the acute experience of ketamine, symptoms such as hallucinations or dissociations may manifest themselves as emotionally or spiritually important or meaningful, occurring alongside higher level or transcendent experiences, such as a dissolution of the ego (Jansen, 2004; Krupitsky and Grinenko, 1997). Such experiences are widely referred to as “peak experiences”, which is a term introduced by Maslow (1961) and developed in the psychedelic field by Pahnke (1966; 1969) to refer to the most intense point of the psychedelic state and specifically encompass “mystical” experiences (e.g. a sense of unity, transcendence of time and space). Empirical research on classic psychedelics demonstrate that it is these more meaningful and insightful experiences that are often associated with therapeutic effects (Carhart-Harris et al., 2018b; Haijen et al., 2018; Watts et al., 2017; Watts and Luoma, 2020).

The psychedelic afterglow refers to a persistent “elevated and energetic mood with a relative freedom from concerns of the past and from guilt and anxiety,” as well as enhanced willingness “to enter into close interpersonal relationships” (Pahnke, 1966). The psychedelic afterglow of ketamine (Jansen, 2004; Krupitsky and Grinenko, 1997; Majić et al., 2015), may be emergent in people undergoing ketamine infusions to alleviate major depressive disorder (MDD). While the afterglow of ketamine has been reported in the context of ketamine-assisted psychotherapy (KAP) (Dore et al., 2019; Krupitsky and Grinenko, 1997), how these experiences emerge unprompted, intrinsically to the ketamine experience
has not been explored.

Further motivating thorough and unique investigation into the acute and lasting experience of different psychedelics, ketamine and classic psychedelics have differing and apparent domain specific effects on memory and cognition (Healy, 2021; Krystal et al., 1994; Morgan and Curran, 2006; Passie et al., 2005).
Ketamine is known to cause dose-dependent negative impacts on memory encoding (Honey et al., 2005) and working memory manipulation (Adler et al., 1998; Morgan and Curran, 2006). However, people who have had ketamine still report a detailed psychedelic experience (Bowdle et al., 1998; Krupitsky and Grinenko, 1997). Ketamine’s effects on memory may impact how people report their psychedelic experience, and therefore uniquely interact with psychedelic related therapeutic outcomes in depression.

A recent meta-analysis (Mathai et al., 2020) reported that of eight included studies, only three demonstrated a relationship between the acute psychedelic effects of ketamine and the antidepressant
response (Luckenbaugh et al., 2014; Phillips et al., 2019; Sos et al., 2013). However, limitations identified included the common use of the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS) (Mathai et al., 2020). These scales test only symptoms of dissociation and psychotomimesis respectively. In contrast the Altered States of Consciousness (ASC) questionnaire provides a more detailed interrogation of the phenomenology of the psychedelic experience, importantly targeting mystical experiences (Dittrich, 1998; Studerus et al., 2010). The single study included in the meta-analysis that used the ASC found no relationship with the antidepressant response, though it only had 10 participants (Mathai et al., 2020; Vidal et al., 2018).

In combination with quantitative questionnaires, qualitative research can be useful to allow participants to explore and explain meaningful experiences and changes that scales are not sensitive to. The aim of the current study was to understand participant’s memory of their experience of the ketamine infusion in terms of changes to mood and perception that may be intrinsic to the antidepressant properties of the drug. This was investigated in both the acute stages of the ketamine infusion, and also in the longerterm
changes that were sustained for the week-long therapeutic window of ketamine’s antidepressant effects and beyond. In particular, ketamine was considered in terms of how the qualitative changes compare with classic serotonergic psychedelic drugs such as psilocybin. This aim was investigated with a combination of qualitative and quantitative techniques. Qualitative interviews were carried out both directly after the infusion, and as part of the debrief at the conclusion of the study approximately 3–8 weeks post ketamine. In addition, quantitative data were collected on the acute effects of ketamine using the 11-dimensional altered state of consciousness (11D-ASC) questionnaire (Dittrich, 1998; Studerus et al., 2010). Also, in a broader sense, the aim was to investigate the impact of rapid but short-lived alleviation of each participant’s symptoms (if it occurred), as well as the impact of participation in the trial more generally on participants’ perceptions of their depression and of receiving future treatment. This was incorporated into the same interview as part of the debrief and included only qualitative questioning.

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