ANZCTR - Registration

Registration number

ACTRN12622001535763

Ethics application status

Approved

Date submitted

21/11/2022

Date registered

12/12/2022

Date last updated

9/10/2023

Date data sharing statement initially provided

12/12/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

A study of the psychological, cognitive and physiological effects of Psychedelic Medicines (ASSESS)

Scientific title

A study of the psychological, cognitive and physiological effects of Psychedelic Medicines on healthy individuals (ASSESS)

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

ASSESS

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Mental Health

Condition category

Condition code

Mental Health

Depression

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Participants will undergo a single drug exposure session with either psilocybin or Methylenedioxymethamphetamine (MDMA). This may occur individually or in small groups of 2-6 individuals within a session, all of whom will receive the same substance. The selection of group size will be based on participant and study staff availability. The selection of which substance each participant will receive will be based on participant preference. Since between substance comparisons are not primary aims, this non-random allocation will not pose any issue for the validity of the study. It will, however, improve participant tolerance of the substance, as receiving the substance of their preference is likely to lead to a more acceptable experience. Dosing sessions will be supported all times by two therapists (one male and one female) for the duration of the experience, in comfortable surroundings. The dosing session will last approximately 8 hours, during which time participants will sit in comfortable chairs with access to blindfolds and music if they would like. In the MDMA sessions, participants will be more likely to engage in a group discussion, while in the psilocybin session they will be more likely to use the blindfolds and listen to music. However, this will be up to participant preference. Prior to the dosing session, participants will undergo a preparatory session with one of the therapists who will supervise the dosing session, in order to orient participants to the experiences they will have in the session. This preparatory session will last between 45 minutes and 1.5 hours, and will involve a semi-structured conversation with considerable time for answering participant questions.

Some participants may return for a second series of sessions, where they will receive the drug they did not receive in the first session. For example, if they were administered MDMA initially, the second session will involve psilocybin. The selection of these participants will be based on participant choice and study staff and resource availability. This second session will take place at least 3 months following the first session.

For the psilocybin arm of the study, a single dose of 25 mg of psilocybin will be provided for a person weighing under 90 kg. A single dose of 30 mg of psilocybin will be provided for a person weighing between 90 kg and 115 kg. A single dose of 35 mg of psilocybin will be provided for a person weighing over 115 kg.

For the MDMA arm of the study, a single dose of 80 mg of MDMA will be provided, followed by an optional half-dose of 40 mg between 1 and 4 hours after the initial dose.

Both the MDMA and psilocybin will be orally administered in capsule form under the supervision of study personnel.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Depression rating scale score (measured by the Depression and Anxiety Stress Scale).

Timepoint [1]

The primary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 3 months after the initial dosing session.

Primary outcome [2]

The personality dimension of 'openness to experience' as measured by the IPIP-NEO-60.

Timepoint [2]

The primary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 3 months after the initial dosing session.

Primary outcome [3]

Trust in others, as measured by the The General Trust Scale

Timepoint [3]

The primary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 3 months after the initial dosing session.

Secondary outcome [1]

The first secondary outcome will be the electroencephalographic (EEG) measure known as the N100 (a negative voltage deflection occurring 100ms after stimulus presentation) in a latent inhibition task.

Timepoint [1]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 3 months after the initial dosing session.

Secondary outcome [2]

Cognitive flexibility, as measured by accuracy at learning the new rule set in the Penn Conditional Exclusion Test.

Timepoint [2]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [3]

Neural markers of working memory, as reflected by EEG measures of theta and gamma activity in the 3back task

Timepoint [3]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [4]

Neural response to the presentation of negative emotional face expressions, as measured by the amplitude of the EEG measures N170 and P3 and theta activity following angry and fearful emotional faces.

Timepoint [4]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 3 months after the initial dosing session.

Secondary outcome [5]

Tolerability, as measured by self-report measures designed for this study to assess side effects and the quality of the experience. We will also assess these measures in the context of the number of participants in the group, to determine whether group size affects feasibility.

Timepoint [5]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [6]

Therapist competency questionnaire to assess whether exposure to the psychedelics increases self-reported feelings of competency to be a psychedelic assisted psychotherapist.

Timepoint [6]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [7]

The mystical experiences questionnaire.

Timepoint [7]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [8]

Feelings of connectedness to one's self and others, as measured by the The Watts Connectedness Scale.

Timepoint [8]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [9]

Cognitive performance in the latent inhibition task

Timepoint [9]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [10]

Cognitive performance in the Go Nogo task.

Timepoint [10]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [11]

Reaction times in the Emotional Stroop task

Timepoint [11]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [12]

Cognitive performance in the Penn Conditional Exclusion test

Timepoint [12]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [13]

Cognitive performance in the 3back task

Timepoint [13]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Secondary outcome [14]

Anxiety rating scale score (measured by the Depression and Anxiety Stress Scale).

Timepoint [14]

The secondary timepoints will be a single baseline assessment within 5 to 16 days prior to the psychedelic exposure session, and a single post-psychedelic exposure assessment, within 5 to 16 days after the psychedelic exposure session. An exploratory analysis will also assess this measure at a follow-up timepoint, 3 months after the dosing session for all participants.

If participants take part in the cross-over component of the study, the same timepoints as with the initial dosing session will be assessed before and after the cross-over dosing session, which will take place a minimum of 6 months after the initial dosing session.

Eligibility

Key inclusion criteria

Participants will be healthy individuals who have undergone training in psychedelic assisted psychotherapy. Participants can be included if they are between the ages of 21 and 70, and voluntarily consent to participate after demonstrating competence to consent following discussion with one of the study researchers. Additional inclusion criteria will be:
- Participants must be able to swallow capsules.
- If of childbearing potential, agree to practice an effective means of birth control throughout the duration of the study.
- Participants must have an identified support person and agree to be accompanied home by that person following dosing be in the presence of that person until the next day.
- Agree to not operate a vehicle for at least 48 hours after initial drug administration. Participants must have transportation available after the Experimental Session and through the following day. Participants will also be warned that the substances will be potentially detectable in roadside drug tests for a number of days after ingestion.
- Must provide a contact (relative, spouse, close friend, or other caregiver) who is willing and able to be reached by the investigator in the event of an emergency or if the participant is unreachable.
- Must agree to inform the investigator within 48 hours if any medical conditions occur or medical procedures are planned.
- Are proficient in speaking and reading English.
- Have completed a Certificate in Psychedelic-Assisted Therapies course.

Minimum age

21 Years

Maximum age

70 Years

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

- Participants who are not able to give adequate informed consent.
- Participants will be excluded if they are pregnant or lactating, have a history of neurological or mental illness or substance abuse or dependence. Participants will also be excluded if taking medication or drugs known to alter brain activity or have a history of seizures.
- Have any of the following cardiovascular conditions: uncontrolled hypertension, coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, cardiac ischemia, congestive heart failure, myocardial infarction, tachycardia, artificial heart valve, a clinically significant screening ECG abnormality, or any other significant cardiovascular condition.
- Participants who are older than 40 years with a positive family history (in a first degree relative) of coronary heart disease and/or presenting substantive risk factors for cardiovascular disease as determined judged by a study doctor.
- Have a history of ventricular arrhythmia at any time, other than occasional premature ventricular contractions (PVCs) in the absence of ischemic heart disease.
- Have Wolff-Parkinson-White syndrome or any other accessory pathway that has not been successfully eliminated by ablation.
- Moderate to severe previous or current head injury/Traumatic Brain Injury (TBI).
- Have a history of stroke or Transient Ischemic Attack (TIA).
- Have moderate to severe hepatic impairment.
- Have epilepsy.
- Have insulin-dependent diabetes.
- Nicotine dependence that would disallow an individual to be nicotine free for the 7-10 hours during the dosing period.
- Current or previous diagnosis of schizophrenia spectrum or other psychotic disorders, including major depressive disorder with psychotic features, or Bipolar I or Bipolar II Disorder.
- Or an immediate family member with a diagnosed psychotic disorder or meeting the DSM-5 criteria for any of these disorders.
- Current or previous diagnosis of alcohol or drug use disorder, or meeting the DSM-5 criteria for either of these disorders.
- History of serious suicide attempts requiring hospitalisation, or any participant presenting current serious suicide risk, as determined through meeting criteria on the Columbia Suicide Severity Rating Scale (C-SSRS) (participants will be excluded if they meet criteria on this scale).
- Significant history of mania.
- Any other psychiatric condition judged to be incompatible with safe exposure to psilocybin, e.g. borderline personality disorder.
- Positive pregnancy test at screening or during the study, women who are planning a pregnancy and/or women who are nursing/breastfeeding. Any person with female reproductive organs and of childbearing potential will undertake a pregnancy test as part of the study prior to any dosing of MDMA or psilocybin.
- Participants who do not agree to use an acceptable contraceptive method throughout their participation in study.
- Use of contraindicated medication (outlined further below).
- Previous experience with MDMA or psilocybin in the past three months.
- Current or previous diagnosis of antisocial personality disorder, or meeting the DSM-5 criteria for this disorder, or any other significant personality disorder as determined by the Standardized Assessment of Personality: Abbreviated Scale (SAPAS; Moran et al., 2003).
- Participants who weigh less than 48kg.

Study design

Statistical methods / analysis

For the psychological variables, meta-analysis of the effects of psychedelic assisted therapy on depression within placebo-controlled trials show a Hedge’s g of 1.21 (Luoma, Chwyl, Bathje, Davis, & Lancelotta, 2020). However, these studies included multiple psychedelic sessions, along with psychotherapy, in individuals with diagnosed depression. Our sample will only undergo a single session of psychedelic exposure, without psychotherapy, and our participants are healthy, so any changes in psychological symptoms will be smaller (with less scope for change given their symptoms will be in the healthy range to begin with). Meta-analysis including only healthy individuals exposed to psilocybin provided a standardized mean difference effect size of 0.671 for improvement in depression symptoms (Galvão-Coelho et al., 2021). In addition to depressive symptoms, we are including measures such as personality and trust, which may be altered by exposure to psychedelics, but to a lesser extent than depressive symptoms. As such, assuming a conservative effect size provides a Cohen’s d of 0.45. Aiming for a p-value threshold of 0.5 with 80% power would require 41 participants, so recruiting 50 participants in each group will provide sufficient power to detect these moderate effects accounting for 10% attrition and any data collection issues (such as partial responses or outlying scores that require exclusion).

The self-report measures will be analysed as exploratory comparisons using robust repeated measures ANOVAs with the WRS2 package in R, which are as sensitive as traditional parametric t-tests, but robust against violations of the assumptions of traditional statistical methods (such as normality) (Mair & Wilcox, 2020) .

With regards to the EEG measures, while there is no directly comparable research available from which to extrapolate potential effect sizes, effect sizes in previous research that has examined the effects of acute exposure to psychedelics across a range of neural activity measures reported large effect sizes (Cohen’s d > 0.70) in measures obtained using some EEG tasks (Duerler et al., 2021; Muthukumaraswamy et al., 2013; Timmermann et al., 2018). Similarly large effect sizes have been obtained in clinical populations and in comparisons of healthy aging with measures of latent inhibition and 1/f metrics that assess excitation / inhibition balances (Kathmann, von Recum, Haag, & Engel, 2000; Schneider et al., 2018; Voytek et al., 2015). Additionally, effect sizes in cross-sectional studies comparing heavy MDMA users to healthy controls in EEG measures of the oddball task produce only medium effect sizes (d ~=0.6) (Croft, Klugman, Baldeweg, & Gruzelier, 2001; Tuchtenhagen et al., 2000). As such, we expect that non-acute effects of a single session psychedelic exposure are likely to be similarly medium sized for facial emotion processing, the Go Nogo task, and our other measures also. As such, we will power our core study to detect medium effect sizes (d = 0.6). Primary comparisons will be performed using paired samples t-test designs with two tailed statistical testing, comparing pre- to post MDMA exposure in a separate analysis to the pre- and post-psilocybin exposure. With this study design, recruiting 30 participants to the EEG component, and accounting for 10% attrition or technical issues in data collection (N = 27) provides sufficient statistical power to detect an effect size d = 0.57 with a power value of 0.80 at an alpha of 0.05.

EEG analyses will be performed automatically on the processed EEG data, time-locked to the stimuli presentation from each task, including all electrodes and time windows (without any specific electrode or time window selection that excludes any of the data), using randomisation statistics provided by the randomisation graphical user interface (RAGU) software (Habermann, Weusmann, Stein, & Koenig, 2018). This analysis approach applies randomisation statistics to robustly test for differences in the neural response strength using the global field potential, and for differences in the distribution of neural activity using global dissimilarity maps. This approach uses all electrodes and timepoints in its analysis, so prevents any potential experimenter bias from selection of electrodes or timepoints for analysis, while still robustly controlling for multiple comparisons using variations on traditional randomisation statistical approaches (the global duration statistic and global count statistic).

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

1/08/2023

Actual

26/09/2023

Date of last participant enrolment

Anticipated

12/01/2026

Actual

Date of last data collection

Anticipated

30/04/2026

Actual

Sample size

Target

100

Accrual to date

4

Final

Recruitment in Australia

Recruitment state(s)

NSW,VIC

Recruitment postcode(s) [1]

3127 - Surrey Hills

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Monarch Mental Health Group

Country [1]

Australia

Funding source category [2]

University

Name [2]

Australian National University

Country [2]

Australia

Funding source category [3]

Charities/Societies/Foundations

Name [3]

Mind Medicine Australia

Country [3]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Monarch Mental Health Group

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

ACT Health

Ethics committee address [1]

PO Box 11, Woden, ACT, 2606.

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

12/10/2022

Approval date [1]

13/01/2023

Ethics approval number [1]

Summary

Brief summary

The primary objective of this project is to investigate psychological, cognitive and physiological changes associated with a single session of psychedelic drug exposure with psilocybin or 3,4-methylenedioxymethamphetamine (MDMA) in a group setting. Specifically, the study aims to use measures of psychological experience, cognitive function and electroencephalography (EEG) before and after psychedelic exposure. 

Secondary aims are (1) to assess changes in neural activity during acute substance exposure, (2) to determine whether tolerability is similar to previous studies, (3) to determine whether any pre-post differences we detect with the primary sample are replicated in a smaller sample who enter into a cross-over arm, taking the substance they did not take in the first instance, and (4) whether exposure to psychedelic drugs impacts self-assessed therapist competency. 

As both psilocybin and MDMA are becoming more commonly used to treat psychiatric illnesses, this study is important to improve our understanding of the mechanisms of action of these drugs. In addition, this study will contribute to enhancing the delivery of psychedelic therapies by identifying whether psychedelic dosing in a group setting is associated with improved outcomes, and whether exposure to psychedelic medicines enhances clinical self-rated competency. As such, this study will have the potential to be highly beneficial in improving our understanding of these drugs, and how to apply them, as they transition towards broad scale implementation as therapies for psychiatric conditions.

Trial website

Public notes

Contacts

Principal investigator

Name

Dr Neil Bailey

Address

Monarch Mental Health Group, Shop 2, 629 Canterbury Road, Surrey Hills Vic 3127.

Country

Australia

Phone

+61 1300 867 888

Email

[email protected]

Contact person for public queries

Name

Samantha Webb

Address

Monarch Mental Health Group, Shop 2, 629 Canterbury Road, Surrey Hills Vic 3127.

Country

Australia

Phone

+61 1300 867 888

Email

[email protected]

Contact person for scientific queries

Name

Neil Bailey

Address

Monarch Mental Health Group, Shop 2, 629 Canterbury Road, Surrey Hills Vic 3127.

Country

Australia

Phone

+61 1300 867 888

Email

[email protected]

Trial Review

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