First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder

This open-label study (n=14) with MDMA-assisted psychotherapy (2 sessions;187.5mg) found it well-tolerated and safe to use. The average consumption of alcohol nine months later was 18.7 units, versus 130.6 units before the detox (start of the study).

Abstract

“Background: 3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study. We present data from the Bristol Imperial MDMA in Alcoholism (BIMA) study. This is the first MDMA addiction study, an open-label safety and tolerability proof-of-concept study investigating the potential role for MDMA therapy in treating patients with alcohol use disorder (AUD).

Aims: This study aimed to assess if MDMA-assisted psychotherapy can be delivered safely and can be tolerated by patients with AUD post detoxification. Outcomes regarding drinking behaviour, quality of life and psychosocial functioning were evaluated.

Methods: Fourteen patients with AUD completed a community alcohol detoxification and received an eight-week course of recovery-based therapy. Participants received two sessions with MDMA (187.5mg each session). Psychological support was provided before, during and after each session. Safety and tolerability were assessed alongside psychological and physiological outcome measures. Alcohol use behaviour, mental well-being and functioning data were collected for nine months after alcohol detoxification.

Results: MDMA treatment was well tolerated by all participants. No unexpected adverse events were observed. Psychosocial functioning improved across the cohort. Regarding alcohol use, at nine months post detox, the average units of alcohol consumption by participants was 18.7 units per week compared to 130.6 units per week before the detox. This compares favourably to a previous observational study (the ‘Outcomes’ study) by the same team with a similar population of people with AUD.

Conclusions: This study provides preliminary support for the safety and tolerability of a novel intervention for AUD post detox. Further trials to examine better the therapeutic potential of this approach are now indicated.”

Authors: Ben Sessa, Laurie Higbed, Steve O’Brien, Claire Durant, Chloe Sakal, Daniel Titheradge, Tim M. Williams, Anna Rose-Morris, Elsa Brew-Girard, Sam Burrows, Chantelle Wiseman, Sue Wilson, James Rickard & David J. Nutt

Summary

Introduction

Alcohol use disorder

A growing number of people consume alcohol in a harmful manner, and approximately 24% of adults in England consume alcohol harmfully. Those with alcohol use disorder often have a past history of psychological trauma and commonly present with high levels of depression, social anxiety and social exclusion.

The Bristol Imperial MDMA in Alcoholism (BIMA) study is the first to explore the potential role for MDMA therapy in treating patients with alcohol use disorder.

Fourteen patients with alcohol use disorder completed a community alcohol detoxification and received an eight-week course of recovery-based therapy. They received two sessions with MDMA (187.5 mg each session).

MDMA treatment was well tolerated by all participants and improved psychosocial functioning. Alcohol consumption decreased to 18.7 units per week compared to 130.6 units per week before the detox.

This approach is indicated.

Traditional treatments for AUD include medical and psychosocial interventions. Benzodiazepines are commonly prescribed as part of alcohol detoxification programmes, and mindfulness techniques have been increasingly explored as a potential approach to assist recovery.

MDMA is a phenethylamine that elevates mood, increases sociability and feelings of closeness to others, and facilitates imagination and memory. It has been used to treat alcohol addiction and co-morbid psychological disorders, and is now being developed for use in medicine.

Potential risks associated with MDMA as an adjunct to psychotherapy

Clinical MDMA may cause anxiety, neurocognitive effects, and a transient reduction in verbal and visual memory, but healthy volunteers without any previous experience with ecstasy did not express a wish to use it outside of the clinical setting.

MDMA increases blood pressure, heart rate and body temperature, causes jaw tightness, bruxism, reduced appetite, poor concentration and impaired balance, but no long-term neurotoxicity has been reported when pure MDMA is administered in a controlled clinical setting.

Methods

Approvals and drug source

This trial was sponsored by Imperial College London and approved by the National Research Ethics Committee and the Medicines and Healthcare products Regulatory Agency. MDMA was obtained from Sterling Pharmaceuticals.

Study design

A feasibility study was conducted in 14 patients with AUD who had recently undergone detoxification. The study measured the effects of MDMA-assisted therapy on drinking behaviour, mental well-being, psychosocial functioning, quality of life and concomitant drug use.

Patients with a primary diagnosis of AUD were recruited from the North Somerset Substance Misuse Service (Addaction). They received an eight-week course of recovery-based therapy comprising 10 psychotherapy sessions, comprising two dosing sessions with open-label MDMA.

Inclusion criteria

Informed consent, primary diagnosis of alcohol use disorder, successful alcohol detoxification, between 18 and 65 years old, proficient in speaking and reading English, and agreement to comply with protocol requirements are required.

Exclusion criteria

Lack of capacity, history of psychotic disorder, bipolar affective disorder type 1 or personality disorder, serious suicide risk, and abnormal clinical findings may render a subject unsuitable for study. Regular users of ecstasy (material represented as containing MDMA) and other drugs must not take part in the study. Female participants of childbearing age must use an effective form of birth control for at least six days after administration of MDMA.

Patients with AUD were screened using the DSM-IV SCID interview, underwent detoxification, and were then entered into an eight-week course of psychotherapy. This comprised weekly 60-minute outpatient non-drug psychotherapy sessions delivered by two clinicians trained in delivering MDMA-assisted psychotherapy by the USA-based organisation MAPS.

Participants were dosed with MDMA twice during the eight-week course, and their mood, suicidal risk factors and quality of sleep were assessed daily for six days. They were then seen again at three, six and nine months for longer-term follow-up data collection.

Data analysis

All data were recorded on paper case report forms and then digitized into MS Excel spreadsheets. No hypothesis testing was performed as this was a nonrandomised, controlled, open-label study.

Results

Demographics

Thirty-six participants were screened, 14 were enrolled (8 males and 6 females), and the average age of first alcohol use was 13 years old.

Severity of AUD criteria at screening and baseline

All eligible participants scored above the diagnostic threshold on the DSM-5 SCID questionnaire for AUD, and 100% of eligible participants had successfully completed detoxification.

Physiological and tolerability effects during MDMA sessions

Of the 14 participants, 12 received both sessions of MDMA-assisted psychotherapy. Temperature, blood pressure and heart rate were measured before and after the medicine was administered.

All physiological parameters remained within normal limits for all participants, except for one participant who experienced a transient abnormal rise in blood pressure after taking the initial dose of 125 mg MDMA. No medical interventions were required in respect of these or any other physiological events during MDMA sessions.

The subjective effects of MDMA were measured hourly throughout the MDMA sessions. There was no significant difference between observers’ and participants’ drug effects scores, and all drug effects returned to baseline by the end of the MDMA session day.

Changes in drinking behaviour

We collected data on alcohol consumption during and after MDMA therapy. At the nine-month follow-up end point, 11 participants were drinking fewer than 14 units of alcohol per week, and three participants had relapsed to drinking more than 14 units per week.

Seven-day follow-up after MDMA sessions

Medical literature and the popular press report that ecstasy users experience a ‘come-down’ effect and a drop in mood after using the drug recreationally. Our study revealed that participants sustained a positive mood for seven days.

Other mental health measures and quality of life measures

After the eight-week MDMA therapy course, anxiety and depression scores decreased, followed by a transient rise, a further reduction, and a moderate rise at nine months.

Discussion

MDMA may improve self-awareness and reduce the denial of harmful alcohol use, especially in patients with pre-existing histories of trauma. It can also help patients with AUD to ‘make themselves present in the moment’, which is a core concept of mindfulness.

The same study team carried out a non-interventional observational study following 14 participants through their treatment-as-usual post-alcohol detox, which found that the BIMA participants had a higher success rate in terms of alcohol consumption over nine months compared to current best treatments available locally.

Limitations

The BIMA study had a relatively small sample size and was an open-label, non-placebo-controlled study. Although efforts were made to test objectively for alcohol use, all data were nonetheless reliant primarily on retrospective self-report.

Conclusion

MDMA-assisted psychotherapy may be safe and effective in the treatment of patients with alcohol use disorder, and may also improve symptoms of other conditions that are frequently co-morbid with harmful use of substances.

Notes

The participants in the study underwent a 7-10 days detox, followed by 8 weeks (10 sessions) of psychotherapy where in weeks 3 and 6, an additional session with MDMA was given (125mg + 62,5mg booster). The normal therapy sessions lasted one-hour, the ones with MDMA 6-8 hours.

The primary measures of the study were the completion of the therapy program, participants accepting the booster dose, and adverse events. Secondary measures were the changes in drinking behavior, mental well-being, psychosocial functioning, quality of life, and drug use after therapy.

The participants in the study were all diagnosed with alcohol use disorder (AUD) and were motivated to seek help and participated in detoxification. A majority used medications (e.g. SSRIs) which were gradually reduced and stopped before the therapy sessions.

After the initial eight weeks, the participants did a follow-up at three, six, and nine months (after the start of the study).

The study was completed by 13 participants. One participant dropped out after the first MDMA-assisted session due to personal circumstances. Another patient didn’t receive the first booster because of forgetting to take her hypertension medications. There were no other significant or unexpected physiological/adverse events.

The units of alcohol (8g) drank changed from 130.6 a week to between 16.9 and 38.0 in the months after therapy. At the end-point (9 months after detox), 11 participants drank fewer than 14 units per week, 9 of them were totally abstinent. Three participants relapsed to drinking more than 14 units per week.

Interestingly, this study found no negative effects on mood that is experienced by part of the recreational users. This bodes well for using MDMA in a clinic and helps alleviate some fears around relapses or negative moods a few days later.

The participants experienced lower anxiety and depression scores after the therapy sessions, which held up to the end-point. Note: at the six month data collection, only six results were measured.

In the discussion, the paper is compared to a group of participants in another study (Sessa et al., 2020) that also underwent detoxification but received no therapy after the detoxification. Within three months, 8 out of the 12 participants in that study had relapsed to drinking (75% instead of 21%, or 75% vs 36% at 6 months).

The current study is compared to that study, but the graph included in the paper does give the suggestion that the other study also included therapy.

This paper opens the door for future studies of MDMA-assisted psychotherapy for alcohol use disorder (AUD) or addiction in general. Although double-blind studies are needed, one hopes that the expected approval of MDMA for PTSD, will help fast-track the research and (if results warrant it) approval of this therapeutic model.

“A logical next step would be to carry out a placebo-controlled randomised controlled trial in which the level of therapist contact is consistent between conditions. This would enable any between-group differences in clinical outcomes to be attributed to MDMA rather than to the psychological support provided.“

This study was also reported on in The Times.