Safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and effects of intravenous (IV) and intramuscular (IM) dosing of SPL028 (deuterated DMT fumarate [a serotonergic psychedelic]) in healthy volunteers and participants with major depressive disorder (MDD)

Plain English Summary

Background and study aims
This is a study investigating a modified version of N, N-dimethyltryptamine (DMT) – DMT is a psychedelic substance that occurs naturally in many plants and animals. Psychedelic substances, also known as hallucinogens, act on the brain causing temporary changes to perception, sensations, and emotions, which can be intense. DMT is best known for being the main psychedelic substance in ayahuasca (a hallucinogenic brew that has been used for centuries in religious ceremonies in some South American countries). DMT is a Class A illegal drug – we have a special licence to be able to give this modified version of DMT to participants in this study. The modified version of DMT being investigated in this study is called SPL028 (also known as the ‘study drug’).
The modification that has been made to the DMT molecule is predicted to cause SPL028 to have a longer duration of effect compared to standard DMT; other than the predicted longer duration of effect, SPL028 is very similar to standard DMT. We’re testing the study drug as an experimental treatment for Major Depressive Disorder (MDD) in combination with therapy sessions. In Part A of this study, we’re investigating how safe and tolerated SPL028 is in healthy volunteers.

The main aims of this study are:
• To assess the safety and tolerability of the study drug, given as a slow injection into a vein in the arm or given as a quick injection into a muscle. The safety and tolerability will be compared between these different ways of giving the study drug.
• To see how the body absorbs and removes the study drug.
• To assess the effect of the study drug on the body, mood, feelings, thoughts and beliefs.

Who can participate?
To take part in Cohorts 1 and 2 of this study, you must:
• Be 25 to 65 years of age.
• Have a body mass index (BMI) between 18 and 33.9 – your BMI may be too high if you’re overweight or if you’re very muscular; you can ask us to explain how we work out your BMI.
• Have suitable veins (so we can easily inject the study drug and/or take blood samples).
• Be registered with a General Practitioner (GP).
• Be willing to be contacted by email, telephone and video call, and have internet access.
• Have not taken any monoamine oxidase inhibitors for at least 3 months before the Screening visit.
• Agree to follow the contraception requirements of the study.
• Be willing to follow the study lifestyle restrictions .
• Have had at least two previous ‘breakthrough’ experiences with serotonergic psychedelic drugs, including but not limited to: DMT, ayahausca, LSD, LSA (morning glory seeds), amphetamine-class drugs, mescaline, peyote, san pedro, ibogaine and psilocybin (including mushroom species containing psilocybin). A breakthrough experience is an immersive and intense experience, in which almost all connection to the real world is lost.
• Match all the other characteristics required to enter this study.

To take part in Cohorts 3, 4 and 5 of this study, you must:
• Be 25 to 65 years of age.
• Have a body mass index (BMI) between 18 and 33.9 – your BMI may be too high if you’re overweight or if you’re very muscular; you can ask us to explain how we work out your BMI.
• Have suitable veins (so we can easily inject the study drug and/or take blood samples).
• Be registered with a General Practitioner (GP).
• Be willing to be contacted by email, telephone and video call, and have internet access.
• Have not taken any monoamine oxidase inhibitors for at least 3 months before the Screening visit. Have not taken any monoamine oxidase inhibitors for at least 3 months before the Screening visit.
• Agree to follow the contraception requirements of the study.
• Be willing to follow the study lifestyle restrictions.
• Have had a maximum of 2 previous experiences with serotonergic psychedelic drugs with no ‘breakthrough’ experiences, including but not limited to: DMT, ayahausca, LSD, LSA (morning glory seeds), amphetamine-class drugs, mescaline, peyote, san pedro, ibogaine and psilocybin (including mushroom species containing psilocybin). A breakthrough experience is an immersive and intense experience, in which almost all connection to the real world is lost.
• Match all the other characteristics required to enter this study.

What does the study involve?
Cohorts 1&2:
Your maximum length of participation in this study will be approximately 15 weeks and you will be given two doses of the study medication. You will be required to attend study visits on 3 occasions in total, consisting of a Screening visit and 2 inpatient periods (2-night periods), and 2 video calls.
You will attend the clinic on the day prior to the day of dosing (Day -1) of each Treatment Period and stay until Day 2 of each Treatment Period (2-night period). You will be administered study medication on Day 1 of each Treatment Period. On Day 2, you will be discharged from the clinic following completion of safety assessments and a session to discuss your experience with the therapist team. You will be contacted on Day 15 (±2 days) of each Treatment Period by video call for an Integration session with the therapist team and completion of safety assessments (which may be separate telephone or video calls). Alternatively, you may be asked to come to the clinic to complete one or both of the Follow-up visits in person, instead of by video call. In addition, you will be required to self-complete multiple other questionnaires regarding your attitudes, moods and relationships. There will be a 3 to 6 week period between Treatment Periods; all assessments performed in the Treatment Periods will be the same.

We’ll give you information about a psychedelic participant advocacy network and community run psychedelic Integration groups that you may wish to attend after your End-of-Study video call. The clinic visits will take place at the MAC Clinical Research Unit (CRU) located in Manchester. You will visit the same CRU for all study visits.

Cohorts 3-5:
Your maximum length of participation in this study will be approximately 8 weeks and you will be given one dose of the study medication. You will be required to attend study visits on 3 occasions in total, consisting of a Screening visit, 1 inpatient period (2-night period) and 1 video call. Following your Screening visit, you will attend the clinic on the day prior to the day of dosing (Day -1) and stay until Day 2 (2-night period). You will be administered study medication on Day 1. On Day 2, you will be discharged from the clinic following completion of safety assessments and a session to discuss your experience with the therapist team. You will be contacted on Day 15 (±2 days) by video call for an Integration session with the therapist team and completion of safety assessments (which may be separate telephone or video calls). Alternatively, you may be asked to come to the clinic to complete the Follow-up visit in person, instead of by video call. In addition, you will be required to self-complete multiple other questionnaires regarding your attitudes, moods and relationships. We’ll give you information about a psychedelic participant advocacy network and community run psychedelic Integration groups that you may wish to attend after your End-of-Study video call. The clinic visits will take place at the MAC Clinical Research Unit (CRU) located in Manchester. You will visit the same CRU for all study visits.

What are the possible risks and benefits of participating?
The dose of SPL028 you’ll receive is likely to cause a psychedelic experience or ‘trip’, which could last a maximum of 4 hours, although it will likely be much shorter than this (expected to last about 1 hour following IV infusion in your arm and about 2 hours following IM injection into a muscle). Typically, standard DMT causes an experience that lasts a maximum of 30 minutes. Due to a small modification of the DMT molecule, this may be longer for SPL028. Administration by injection into a muscle may also extend the duration of effect.

You may experience: visual imagery or hallucinations (seeing colourful patterns, or seeing or hearing things that aren’t real), a sense of being detached from your thoughts or feelings, changes in your sense of time and space, out-of-body experiences, disorientation or confusion, anxiety, intense emotions such as happiness or grief. Sometimes people experience unpleasant images and sounds and may also ‘relive’ painful memories or traumas. You’ll have the support and guidance of expert therapists to help you interpret and deal with any experiences you may have during your trip. If you become very upset or agitated after your dose, the study doctor may give you a licensed medicine to help you relax.

Before you take part in the study, we’ll explain what you should expect from a psychedelic trip and how to respond to it (while on the ward and once you’ve gone home), and you’ll have an interview with a psychiatrist to make sure you’re suitable to take part. We’ll monitor you closely during and after your dose – the therapist team and a nurse will be with you, and a psychiatrist will be available if needed. If you are being dosed by IV infusion, we’ll stop the infusion of study medicine early if you ask us to, or if we think it’s necessary. We will not be able to stop dosing early when you are being given the study medicine by injection into a muscle. Before and after your dose, the study therapist team will talk to you about your experience.
If you were to have a challenging experience or negative reaction to SPL028 during or after the session, our research team will be able to help you. Challenging experiences can be triggered by psychedelic drugs, such as DMT, and are usually temporary and resolve with reassurance and support. The chances are that we won’t need to use any medication at all, and any psychedelic effects will be short-lived and resolve of their own accord. Your experience with SPL028 might make you feel differently about yourself and your life, so we’ll advise you not to make any life changing decisions for 6 weeks following the session.
As with any new medicine, we don’t yet know all its side effects. In any clinical trial, there is a risk of an unexpected, serious reaction to the study drug, which could be potentially life-threatening.

In clinical studies of DMT, some people had physical effects, such as increased blood pressure and heart rate, feeling sick, and headaches. We’ll monitor your heart rate and blood pressure during the study. In the unlikely event that your heart rate or rhythm or your blood pressure changes significantly, the study doctor will take the appropriate steps to reverse this side effect. If deemed necessary, you may be referred to the hospital emergency department and/or a cardiologist for further investigations and/or treatments.

You will be closely monitored throughout the study, and questions about suicidal thoughts and feelings will be frequently asked throughout the study using a rating scale. If your mental health were to deteriorate significantly during any point of the study and we had serious concerns about your safety, then we would be obliged to involve local mental health services to determine how best to manage your condition.
The study drug’s effect on the body may change when the drug is taken in combination with another drug, which can result in either a decrease or increase in the effects of either, or both, drugs. This could have potential side effects. The study team will carefully evaluate any prescription or non-prescription medications that you are taking at your Screening visit. For further details on medications that are not allowed during this study.

So called ‘flashbacks’, or a sense of re-experiencing psychedelic drug effects when no drug has been taken has been described in scientific literature with recreational use of drugs such as DMT. If this occurs it is usually not a problem but please do let the research team know, who can support or guide you.
A very rarely reported side effect of taking psychedelics as recreational drugs is something called hallucinogen-induced persistent perceptual disorder (HPPD). People who report symptoms of HPPD may see haloes around objects, light trails and alterations in the colour and shape of objects. This effect is seen very rarely following recreational use of psychedelic drugs and has not been reported when psychedelic drugs have been taken in scientific and clinical studies.

As with any new medicine, the study drug might affect an unborn child. You must not take part in the study if you are pregnant or want to become pregnant at the time of the study. Please tell us straight away if you think you or your partner might be pregnant. We would want to keep in touch with you until the end of the pregnancy, to find out if the study drug had affected your unborn child – we’d ask your permission to do that.
The study drug may affect your concentration or judgement, so you shouldn’t drive or operate machinery for 24 hours after your dose (if you leave MAC for any reason, before the scheduled time).

You will be carefully monitored during your time on the study, although this does not mean these side effects could not occur. It is important that you report to your study doctor all symptoms and side effects that you may experience, as soon as they appear, whether or not you think they are related to the study medication. You will always be closely looked after throughout the study.

Although all possible precautions are taken to prevent serious side effects, if such a side effect occurs, you may need to be admitted into hospital. Depending on the type of side effect, a medical specialist may be asked to take over your care. If you’re ill while you’re on the ward, we’ll give you any immediate treatment you need. If you’re ill after leaving the ward, call us as soon as you can. We might need to see you again, but if you weren’t well enough to travel, you’d need help from a local doctor or hospital. One of our doctors is always available on the telephone to discuss medical problems with you or with other doctors.

We’ll give you a medical alert card with some information about the study and contact numbers of MAC doctors. When you’ve left the ward, carry the card with you at all times until your End-of-Study video call. If you visit other healthcare professionals (such as a doctor, nurse or dentist), show them the card. Bring your medical alert card with you whenever you visit the ward. We will also provide you with an out of hours emergency contact number for a member of staff.
This drug will not be available for use after you have completed the study. It is not anticipated that there will be any benefit to you, but you are contributing to the scientific knowledge which may lead to the expansion of treatment options for people with MDD.

DMT is a Class A illegal drug, as is SPL028 (modified DMT) – we have a special licence to be able to give SPL028 to volunteers in this study.
The Sponsor, and/or others working with the Sponsor, will own the results of this study. The results might have commercial or intellectual property value and might be used to apply for patents. You won’t receive any financial benefit that might come from the study.

Where is the study run from?
The study is run from a commercial clinical research centre in Manchester (UK)

When is the study starting and how long is it expected to run for?
June 2022 to December 2023

Who is funding the study?
The study is funded by a company called Cybin UK Ltd, based in England (UK)

Who is the main contact?
Ellen James, ellen@cybin.com

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• England
• United Kingdom

Study participating centre

Sponsor information

Funders

Funder type

Industry

Results and Publications

Study outputs

Additional files

ISRCTN42293056 CT028_001 MAC150 CSR_Synopsis_V1.0_02Dec2024_redacted.pdf

Editorial Notes

16/12/2024: A file containing results was uploaded to the record.
15/07/2024: Trial's existence confirmed by Wales Research Ethics Committee 1.