Safety, tolerability, pharmacokinetics, pharmacodynamics and exploratory efficacy of intravenous dosing of SPL026 drug product (N, N-dimethyltryptamine fumarate; DMT Fumarate [A Serotonergic Psychedelic]) alone or in combination with selective serotonin reuptake inhibitors in patients with major depressive disorder

Plain English Summary

Background and study aims
The purpose of this study is to test a drug called SPL026 (the ‘study drug’) that is being developed for the treatment of MDD.
Major depressive disorder, known as ‘depression’, is a common mental illness affecting about 280 million people worldwide. Depression affects people in different ways and causes a wide range of symptoms, such as feelings of unhappiness and hopelessness, losing interest in things they used to enjoy, and anxiety. The symptoms can also be physical, including feeling constantly tired, problems with sleep, and aches and pains. There are existing treatments for depression, but they don’t work well in some patients and more treatment options are needed. DMT (the study medicine, also known as SPL026) is being developed as an experimental new treatment for depression in combination with therapy sessions. It acts at sites in the brain (called serotonin receptors) that are associated with mood and mental health. Previous research on a similar psychedelic medicine (psilocybin), which works on the same sites in the brain as DMT, suggests that psilocybin may be an effective treatment for depression, when used alongside talking therapy. So, psychedelic medicines like psilocybin and DMT offer a different treatment method to traditional medicines. We hope DMT, when given alongside therapy sessions, will be an effective treatment for depression, and will therefore give patients with depression more treatment options.

It is important for you to know that when you receive DMT, you’ll likely have a psychedelic experience or ‘trip’. During your Screening visit and before you’re dosed, we’ll explain what to expect from a psychedelic experience and how to respond to it. We’ll also show you where you’ll stay on the ward and receive your dose, and you’ll meet the staff who’ll look after you during the study.
The study drug is ‘investigational’, which means that it has not yet been approved for marketing by the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK, or the Food and Drug Administration (FDA) in the USA.
The main aims and questions 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, to patients already taking a single SSRI antidepressant, compared to patients not taking an SSRI antidepressant.
• To see how the body absorbs and removes the study drug when taken alone and in combination with a single SSRI antidepressant.
• To assess the effect of the study drug on the body, mood, feelings, thoughts and beliefs when taken alone and in combination with a single SSRI antidepressant.

Who can participate?
We plan to enrol up to 24 patients with mild to severe MDD, who will be divided into the two following groups:
1. Patients with mild to severe MDD who are currently taking an SSRI antidepressant that is ineffective in fully relieving depression. Patients in this cohort must be on a stable dose, with no intention of making any changes, for at least 6 weeks before Screening. This group of patients will be known as the ‘Test Cohort’. This cohort will comprise of up to 18 patients.
2. Patients with mild to severe MDD who have not received any medication for their depression for at least 6 months before dosing, with the exception of monoamine oxidase inhibitor class antidepressants, which can have been taken up to 3 months before Screening. This group of patients will be known as the ‘Control Cohort’. This cohort will comprise of up to 6 patients. In the Test Cohort, 2 patients will be dosed first; the rest of the group will then be dosed at least 48 hours later if thought safe to do so by the research team after checking how the first 2 patients responded to the medication.

What does the study involve?
During this study, you will be given a single dose of DMT (27.5 mg). The study medication will be administered by intravenous (IV) infusion, allowing the controlled administration of the study medication directly into your bloodstream using a plastic cannula that will be fitted in a vein in your arm. In this study, DMT will be administered during a 10-minute IV infusion. If required, the infusion can be stopped at any time for safety reasons. In order to ensure your safety, the study medication will be administered alongside psychological support from a therapist team (which will include a psychiatrist and/or up to 2 therapists). The research team and your therapist team will be specially trained to prepare and support you through this experience. Therapists will be professionally qualified and work to an ethical guideline, against which they will be monitored throughout the trial. Your therapist team will be with you at all times and will be able to help you if you get anxious or distressed during the psychedelic experience. You will be given the study drug in a calm private room. A bespoke soundtrack will be played in the room, and you will be encouraged to wear eyeshades and headphones. The psychedelic effects are only temporary (typically lasting for 20 minutes) and you will be assessed for safety before being discharged from the research unit on Day 2.

What are the possible risks and benefits of participating?
In this study, we plan to test a single dose of 27.5 mg DMT, given by slow injection into a vein in the arm over 10 minutes, alone or in combination with a single SSRI antidepressant. This dose level has been based on results from a previous study investigating a single dose of DMT in 32 healthy volunteers. In that study, 24 healthy volunteers (who’ve never taken a psychedelic substance before) received up to 21.5 mg DMT given by a slow, 2-part injection into a vein over 10 minutes. There were no important side effects, but some people had headaches, or a mild, short-lived burning sensation at the site on their arm where they received their injection (the sensation lasted about 10 minutes – the duration of the injection). At least 100 volunteers in other studies have received doses of up to 0.25 mg/kg DMT (17 mg DMT for a 70 kg person), by injection into a vein over a few seconds. Those studies were in people who’d previously taken psychedelic substances. The doses of DMT tested were considered safe. DMT has been taken by people for centuries either by smoking or inhaling it, or as a hallucinogenic brew (ayahuasca), which is used in spiritual ceremonies in some South American countries.

The dose of DMT we will test in this study (27.5 mg) is higher than that tested in previous studies (21.5 mg), but we don’t expect it to give higher blood levels than those in previous studies, because we’ll give your dose by a single, continuous slow injection over 10 minutes. The dose of DMT you’ll receive is likely to cause a psychedelic experience or ‘trip’, which is expected to last about 20 minutes. 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. In published research into psychedelic treatments for depression, difficult emotions and upsetting content experienced during the ‘trip’ are considered therapeutically beneficial, as they can lead to important insights. 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. We’ll stop the injection of study medicine if you ask us to, or if we think it’s necessary. 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 DMT 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 DMT 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 medicine, 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.
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 medicine 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. Pleasetell 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 medicine had affected your unborn child – we’d ask your permission to do that. The study medicine 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 usas 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.

We don’t know if you’ll get any long-lasting medical benefit from taking DMT in this trial. It’s important for you to know that you can’t carry on taking DMT after the study, even if you do get some benefit from it. You may benefit from regular conversations with the study psychiatrist and therapist team. Our screening tests might be of benefit if we find an important medical problem, but they could reveal something you’d prefer not to know about. If you take part, you’ll be helping medical research.
DMT is a Class A illegal drug – we have a special licence to be able to give it 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?
Cybin UK Ltd.

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

Who is funding the study?
Cybin IRL Ltd., based in Ireland.

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

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• England
• United Kingdom

Study participating centres

Sponsor information

Funders

Funder type

Industry

Results and Publications

Study outputs

Additional files

ISRCTN10974027 Synopsis CT026_004 CSR v1 - 20 Mar 2024_redacted.pdf

Editorial Notes

10/06/2024: A file of unpublished results was added.
03/04/2024: Trial's existence confirmed by MHRA