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

This randomized, double-blind, active placebo-controlled, crossover study (n=32) investigated the antidepressant efficacy of ketamine (31mg/70kg) by using quantitative and qualitative assessments of its long-term effects and acute psychedelic experience. Rapid improvements in depressive symptoms correlated with higher scores on the spirituality, experience of unity, and insight subscales of the altered states of consciousness questionnaire (11D-ASC), but were not sustained beyond two weeks. The authors classified subjective themes of the acute experience (e.g. change in perception, emotion, loss of control, questioning of existence or self) which highlight the psychedelic qualities of ketamine, and identify six additional themes of their long-term perspective (change in perspective, change in mood, change in emotion, time, expectations, attitude to future treatments) alluding to differences between treatment responders and non-responders that are not readily captured by the standardized symptom scores.

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.”

Authors: Rachael L. Summers, 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, Frederick Sundram

Summary

Introduction

Ketamine has been dominant in the growing field of research into rapid-acting antidepressants, partly because it is an established, safe and widely used medication in surgery and pain management. Its potential as an antidepressant was first reported by Berman et al. (2000), and has gained considerable momentum since.

There is less research in this area for ketamine compared to psilocybin, and there is a real need for unique research to be conducted evaluating ketamine because of its differences.

Ketamine is central to research into depression treatments.

Ketamine was administered to 32 volunteers with major depressive disorder in a crossover design with the active-placebo remifentanil. The results indicated that the psychedelic properties of ketamine may play a role in its antidepressant effects.

All participants experienced perceptual changes, loss of control, and emotional and mood changes, as well as changes to perspective on life, people, and problems.

Reflexive thematic analysis provided information on participants’ experience of ketamine.

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, the term psychedelic1 is preferred to describe ketamine, to allow for fluidity in people’s experiences. Ketamine induces hallucinations and dissociations that may be emotionally or spiritually meaningful, occurring alongside higher level or transcendent experiences, such as a dissolution of the ego. These experiences are often associated with therapeutic effects.

Ketamine may cause negative effects on memory and cognition, but people still report a detailed psychedelic experience. This may be because of ketamine’s effects on memory and cognition, and therefore how people report their psychedelic experience.

A recent meta-analysis found that three studies demonstrated a relationship between the acute psychedelic effects of ketamine and the antidepressant response, though limitations included the common use of the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS).

In a study of ketamine and depression, qualitative techniques were used to explore participant’s memory of their experience of the ketamine infusion. This was done in combination with quantitative questionnaires and included questions about the acute effects of ketamine and the impact of participation in the study.

Study design

This study was a double-blind, active placebo-controlled crossover trial of ketamine in MDD. The study was part of a larger imaging trial. 32 participants volunteered for the study. 30 completed the study, 2 only completed the ketamine study day, and all procedures were approved by the Health and Disabilities Ethics Committee of New Zealand.

The purpose of using remifentanil as an active placebo was to improve blinding to the profound psychoactive effects of ketamine. Remifentanil offered several advantages over other options such as midazolam, such as no known antidepressant/anxiolytic properties.

11D-ASC

Ketamine was administered to assess the acute psychoactive effect. The 11D-ASC questionnaire was used to assess participants’ experiences and was used to establish a relationship between ketamine and the antidepressant response.

Qualitative interviews

The methods are reported according to the COREQ checklist for qualitative research, and the interview schedule was initially broad to allow participants to describe their experiences. A more structured interview schedule was developed after the first three interviews.

Two types of qualitative interviews were carried out: the acute effects of ketamine and the active placebo remifentanil were probed, and the participants’ experiences were transcribed.

The second interview specifically explored the longer-term effects of ketamine and took place between 3 – 8 weeks post infusion. It included questions such as: Has the ketamine you received changed the way you feel about problems?

Qualitative analysis was carried out utilizing a reflexive thematic analysis approach to explore people’s experiences of ketamine. Themes were coded in the transcripts using an iterative process of identifying and reviewing data-driven and theory-driven themes at the semantic level.

The transcripts were entered into NVivo 12 Pro and thematic analysis was divided between authors CA, JC, AF, SJ, AR, and RS. Consensus was achieved between raters on final coding and the entire data-set was reviewed by RS to ensure consistency.

Montgomery-Asberg depression rating scale results

The MADRS results show that ketamine significantly reduced MADRS score relative to the active placebo by 3 h postdose, and remained significant at 1 day and 7 days postdose.

Remifentanil and ketamine reduced MADRS, though to a significantly lesser extent. There was no significant difference to baseline by 7 days.

11D-ASC

There was a significant relationship between percentage change in MADRS at 24 h and participant’s experience of unity, spirituality, and insight during the ketamine infusion.

Ketamine produced a marked psychedelic response, whereas the active placebo, remifentanil, produced a much smaller response.

Acute qualitative interview

Thirty-one participants took part in the acute interview, and reported experiencing a change in perception, dreamlike experiences, feelings of detachment, hallucinations and pseudo-hallucinations, emotional changes, losing control, and physiological symptoms that did not fit in the previous themes.

18/31 participants felt a distortion of their body, some said their hands were on backwards for a while, others said their head felt voluminous.

26/31 participants spoke of a distortion of space, while 13 spoke of a more grounded sense of change in space, such as the sensation of moving or falling backward.

Thirty of 31 participants described a distortion of time, including losing track of time entirely and even the concept of time itself.

15/31 participants described their experience as being dreamlike, as if they were asleep, or experiencing déjà vu. Four of these participants spoke of thinking about a specific person in their life.

Eighteen of 31 participants spoke of feelings of detachment, including some reference to not feeling connected to their body either entirely or almost entirely.

MRI scanners make sounds that pulse, beep, and move around the head of the person being scanned. Some participants experienced hallucinations, including auditory hallucinations.

Eleven of 31 participants reported hallucinations of taste and smell that could not be attributed to the equipment.

11/31 participants experienced visual hallucinations, including black and white birds flying at them while they were falling and speaking some weird language.

Twenty-six of 31 participants reported visual distortions, most of which were a distortion of the small cross they were asked to look at while in the MRI.

14/31 participants experienced auditory distortions while in the MRI scanner. The sounds were distorted and rhythmic, and made the participants feel relaxed.

Participants described feeling high during the experience, for some this was similar to previous experiences taking drugs recreationally or while in hospital.

12/31 participants reported negative feelings. Several expressed significant anxiety at the intensity of the experience, and some expressed concern about “messing up” the study results.

Most participants reported some kind of loss of control, which was commonly reported as a short feeling of being overwhelmed by ketamine initially and then an ability to go with it, or control it afterwards.

Several participants spoke of questioning their existence or their self, and four participants said they thought they might have died.

Final qualitative interview

Six major themes were identified from the final qualitative interview, including changes in perspective, change in mood, and emotional changes. These changes were often closely linked to the interview schedule.

The study affected how participants felt about ketamine as a future treatment option, and about engaging in treatments more generally.

Others have reduced their focus on how they are being judged or thought of by other people.

Some participants reported being more mindful of what others may be thinking or feeling.

F.2 Life. Most people who experienced relief from their depression spoke of increased hope, motivation, feelings of well-being and optimism.

The experience was wonderful and I wish I could tap back into it, but I don’t feel good at the moment.

Participants spoke of a change in their feelings towards problems, including an increased ability to cope with them, a reframing of what problems were, and a shift in how they viewed their own role in problems.

I wish I could say it had changed how I felt about problems, but having a one off experience like that hasn’t really changed anything.

Twelve out of 29 participants commented on how ketamine changed how they felt about their depression. This included a change in the way they perceived their own brain and the way they experienced reality.

Most participants identified a change in their mood, and nine out of 23 directly followed this with a statement on how the change in mood improved their motivation.

13/29 participants reported a change in how they feel emotions, with some reporting a reduction in negative emotion and some reporting an increase in positive emotion.

I used to put myself in the other persons shoes when I watched a sad movie, but now I just say that’s really sad.

I felt more excited about stuff, I wasn’t as edgy and grey as I used to be, and I was able to cope with my feelings.

Twenty-seven out of 29 participants reported experiencing some change in their perspective of people, life and problems, or their mood and emotions. Twenty-four reported experiencing a lasting change of at least 3 weeks.

The most common short-term change experienced was mood. Long-term changes included perspective on life and emotions, and two participants reported a worsening in their mood since before the study.

Twenty-seven of 29 participants had expectations about the study and 17 had some expectations about how the drug would make them feel.

Ten out of 27 participants said they had no expectations going into the study, and several who had set expectations expressed trying not to.

Twenty-one of 27 participants said the study met their expectations, 15 said it met at least some of their expectations, and five said it exceeded their expectations. Four non-responders indicated that the study met their expectations.

Twenty-eight of 29 participants spoke of future treatments, and twenty-two indicated increased hope in future treatments, especially if ketamine became available in future. However, one participant felt frustrated with their depression and increased frustration with trying to find another therapy.

Discussion

Ketamine has been increasingly researched as an antidepressant in the last decade, but to date studies have only used quantitative measures. In the current study, participants used a combination of a quantitative questionnaire (11D-ASC) and qualitative interviewing to capture the psychedelic state and explore the association with the antidepressant response. Six major themes emerged from the final interview.

ketamine infusion

The results of the current study indicate that the peak psychedelic experience, as well as spiritual experiences, experience of unity, and insight, are significantly correlated with the antidepressant response to ketamine. Importantly, these experiences are not captured by the commonly used CADSS or BPRS questionnaires.

The current study found that participants who experienced mystical experiences and emotional breakthrough also reported improvements in wellbeing following psilocybin induced psychedelic experiences. Furthermore, these experiences were explicitly linked to releases from the challenges of participant’s depression.

The qualitative analysis of acute interviews showed that responders had more detailed accounts of the psychedelic experience of ketamine than non-responders. These trends support the 11DASC results that showed some aspects of the dissociative and psychedelic experiences of ketamine are correlated with antidepressant response.

Set and Setting

Ketamine’s acute psychedelic experience may be difficult to reliably associate with the antidepressant response because participants in clinical trials largely experience ketamine passively and alone. The set and setting of the psychedelic experience is important to the experience’s long-term outcome.

Ketamine-assisted psychotherapy (KAP) has been used in the treatment of depression, anxiety, and post-traumatic stress disorder (PTSD). The study indicates that willingness to “let go” may be a positive prognostic factor for psilocybin, and may also be achievable with ketamine.

Lasting experience of ketamine

The MADRS results showed that 70% of participants experienced at least a 50% reduction in global score 24 h post-dose, and that the effect of ketamine lasted for at least 1 week. Participants also reported enduring effects of ketamine beyond the therapeutic window of ketamine’s antidepressant properties.

From a clinical point of view, the interviews captured more fundamental shifts in thinking, pointing to potential mechanisms by which ketamine may exert its antidepressant effects. Participants seemed to be able to engage and connect with people and life in general again, and experience less self-referential thinking.

Ketamine treatment may be combined with psychological/ psychotherapy-based treatments not only in the acute psychedelic phase as in KAP, but also in the days/weeks post-treatment. This may help sustain and imbed the positive shifts in thinking that occur in the initial week/s following ketamine treatment.

The personal impact of participation

The interviews captured how managing expectations is an important consideration for clinical trials that recruit patient populations. Ketamine frequently changed how participants viewed their depression, and many saw it as more temporary or changeable after responding to ketamine.

The ethical importance of considering these impacts is substantial from an ethical perspective, especially as ketamine was not available to the participants involved in the trial as a treatment afterward.

The current study found that participants had met expectations and had increased hope after the study. This is likely because the study team explained the purpose of the study and the lack of availability of ketamine poststudy to participants.

Comparing ketamine with other psychedelics

This article has focused on ketamine’s psychedelic properties and its use as an antidepressant. It raises interesting questions about the mechanisms that underlie the psychedelic peak and afterglow.

LSD, psilocybin, ayahuasca, and MDMA have been shown to have promising therapeutic effects across a number of psychological conditions. It has been proposed that the efficacy of classic psychedelics is due to the modulation of 5-HT2A opening a window of plasticity and facilitating long-term change and benefit.

Ketamine is a non-competitive N-methyl-D-aspartate (NDMA) receptor antagonist that acts on NMDA receptors and hyperpolaraization activated cyclic nucleotide gated potassium channel 1 (HCN1), and has similar downstream glutamatergic action to LSD, psilocybin, ayahuasca, MDMA, and other psychedelic drugs. The pharmacological justification for REBUS is heavily serotonin-centered, but there is growing evidence that the acute experience of ketamine may have therapeutic benefits. Ketamine may also increase sensitivity to prediction error, which may be related to improvements in depression.

Strengths and limitations

The current study uses qualitative techniques to explore the early and lasting effects of ketamine’s antidepressant and psychedelic properties. However, the correlations with the antidepressant response are only low-to-medium and require replication with a greater sample size.

The current study administered ketamine to participants while they were in an MRI setting, which interfered with elements of the acute psychedelic experience, but may have lasting effects on the therapeutic outcome.

The current study reveals a potential major strength of ketamine as a psychedelic treatment: important psychedelic effects occurred when the set and setting of the acute experience were not emphasized. This raises two important questions: could ketamine be made more effective by placing it inside a therapeutic model?

The current study largely fits around the neuroimaging protocol, and it is hoped that this study provides strong motivation for future research.

Conclusion

Ketamine administered in humans for depression produces hallmarks of a psychedelic experience. The afterglow and residual effects of ketamine therapy may positively affect people receiving ketamine therapy for depression.

Notes

Ketamine has a therapeutically versatile and dose-dependent pharmacological profile of effects that may have led to controversy over classifying ketamine as a psychedelic. The MRI environment influenced the nature of many of the experiences, particularly in the first theme: change in perception.

Ketamine did not produce challenging experiences in the pure sense of the term, but perhaps the lack of psychological preparation was the reason.