Part A:- Evaluate the safety of increasing doses of a single dose continuous DMT infusion over 90 minutes in healthy smokers - Characterize the pharmacokinetics of a single dose DMT administered continuously over 90 minutes in healthy smokers -…
ID
Source
Brief title
Condition
- Other condition
- Mood disorders and disturbances NEC
Synonym
Health condition
Substance use disorders: Tobacco and Nicotine Addiction
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A:
- Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit.
- Concomitant medication throughout the study at every study visit.
- Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic
blood pressure (mmHg)) as per assessment schedule.
- Clinical laboratory tests (Hematology, blood chemistry and urinalysis) as per
assessment schedule.
- ECG parameters (Heart Rate (HR) (bpm), PR, QRS, QT, QTcB, QTcF) as per
assessment schedule.
- Occurrence of psychotic symptoms as measured with the BPRS.
- Occurrence of central serotonergic toxicity as measured with the Hunter
criteria.
- Occurrence of suicidal thoughts and ideations (CSSRS).
- Plasma concentrations of DMT.
- PK parameters: AUCinf, AUClast, CL, Cmax, t1/2, tmax, Vz, Vss.
- Dose-normalized PK parameters: AUCinf, AUClast, Cmax.
- Neurocart test battery
• Saccadic eye movements:
o saccadic reaction time (second),
o saccadic peak velocity (degrees/second), and
o saccadic inaccuracy (%);
• Smooth pursuit eye movements:
o percentage of time the eyes of the subjects are in smooth pursuit of the
target (%);
• Body sway:
o antero-posterior sway (mm);
• Adaptive tracking:
o average performance (%);
• Visual Analog Scales (VAS) according to Bond and Lader to assess:
o mood (mm),
o alertness (mm), and
o calmness (mm).
• VAS Bowdle to assess:
o subjective psychedelic effects (mm).
• VAS Drug Rating to assess:
o positive or negative drug effect (mm).
- Changes in subjective psychedelic. experience rating scales that include the
HRS, MEQ and 5D-ASC administered retrospectively.
- Changes in intensity score (from the Real-time Intensity Scale) from baseline
to the end of infusion.
- Serum ACTH, cortisol and prolactin.
- DMT plasma concentrations.
- Changes in intensity score from baseline to the end of infusion.
- Changes in subjective psychedelic experience rating scales that include the
HRS, MEQ and 5D-ASC administered retrospectively.
Part B:
- Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit.
- Concomitant medication throughout the study at every study visit.
- Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic
blood pressure (mmHg)) as per assessment schedule.
- Clinical laboratory tests (Hematology, blood chemistry and urinalysis) as per
assessment schedule.
- ECG parameters (Heart Rate (HR) (bpm), PR, QRS, QT, QTcB, QTcF) as per
assessment schedule.
- Occurrence of psychotic symptoms as measured with the BPRS.
- Occurrence of central serotonergic toxicity as measured with the Hunter
criteria.
- Occurrence of suicidal thoughts and ideations (CSSRS).
Part C:
- Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit.
- Concomitant medication throughout the study at every study visit.
- Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic
blood pressure (mmHg)) as per assessment schedule.
- Clinical laboratory tests (Hematology, blood chemistry and urinalysis) as per
assessment schedule.
- ECG parameters (Heart Rate (HR) (bpm), PR, QRS, QT, QTcB, QTcF) as per
assessment schedule.
- Occurrence of psychotic symptoms as measured with the BPRS.
- Occurrence of central serotonergic toxicity as measured with the Hunter
criteria.
- Occurrence of suicidal thoughts and ideations (CSSRS).
- Neurocart test battery
• Saccadic eye movements:
o saccadic reaction time (second),
o saccadic peak velocity (degrees/second), and
o saccadic inaccuracy (%);
• Smooth pursuit eye movements:
o percentage of time the eyes of the subjects are in smooth pursuit of the
target (%);
• Adaptive tracking:
o average performance (%);
- Visual Analog Scales (VAS) according to Bond and Lader to assess:
• mood (mm),
• alertness (mm), and
• calmness (mm).
- VAS Bowdle to assess:
• subjective psychedelic effects (mm).
- VAS Drug Rating to assess:
• positive or negative drug effect (mm) and
• any drug effects (mm).
- Changes in subjective psychedelic. Experience rating scales that include the
HRS, MEQ and 5D-ASC administered retrospectively.
- Changes in intensity score (from the Real-time Intensity Scale) from
baseline to the end of infusion.
- Serum ACTH, cortisol and prolactin.
- PK parameters: AUCinf, AUClast, CL, Cmax, t1/2, tmax, Vz, Vss.
- Dose-normalized PK parameters: AUCinf, AUClast, Cmax.
Secondary outcome
NA only exploratory
Background summary
Over the last three decades, there has been a resurgence of interest in the
potential application of central nervous system active compounds that induce
psychedelic, dissociative, and entactogenic effects in various mental and
addiction-related disorders. N,N-dimethyltryptamine (DMT) is a naturally
occurring psychoactive compound. DMT is a potent agonist at the 5-HT2A
receptor, through which (not unlike other serotonergic psychedelics), it exerts
many of its subjective, visual, and potentially therapeutic effects.When
administered intravenously as a bolus injection, CNS effects of DMT peak within
2-5 minutes and dissipate rapidly, with effects returning to baseline (or close
to) following roughly 30 minutes post administration. However, one drawback of
IV administration of DMT is its high, and up until now largely unexplained,
variability in PK in humans. Several strategies are being developed to decrease
this variability, one of which is deuteration of the DMT molecule, which
entails the selective replacement of protium hydrogen (1H) isotope atoms with
deuterium hydrogen (2H) isotope atoms. This deuteration is anticipated to
improve the pharmacokinetic profile of DMT whilst maintaining pharmacodynamic
effects. Therefore, Cybin IRL limited has developed CYB004, in which 10 protium
hydrogen atoms are substituted with 10 deuterium atoms. Preclinical data shows
that CYB004 exhibited a similar in vitro and in vivo pharmacology as DMT, but
an increased exposure and delayed metabolism in dogs after intravenous (IV)
administration. Consequently, CYB004 could have higher potential for clinical
application when compared to DMT.
As nicotine addiction is associated with a high mortality rate and efficacious
pharmacological treatment is lacking, smoking cessation following DMT and
therefore potentially also CYB004 administration is a potentially promising
clinical research area. Observational studies, anecdotal reports, and
ceremonial use of 5-HT2A receptor agonists such psilocybin and ayahuasca were
associated with reduced smoking behaviour. Since DMT and CYB004 are also 5-HT2A
agonists, there is potential for clinical interest in both compounds as a novel
smoking cessation therapies. In addition, both DMT and CYB004 may have clinical
benefits in other psychiatric disorders including mood and anxiety disorders.
However, prior to exploring the clinical efficacy of DMT and CYB004 in nicotine
users or other populations, it is crucial to establish their safety profile
and, pharmacokinetic-pharmacodynamic (PK-PD) relationship at increasing doses,
as well as the most optimal infusion scheme to induce sustained psychedelic
effects in smoking and non-smoking subjects.
Study objective
Part A:
- Evaluate the safety of increasing doses of a single dose continuous DMT
infusion over 90 minutes in healthy smokers
- Characterize the pharmacokinetics of a single dose DMT administered
continuously over 90 minutes in healthy smokers
- Characterize the pharmacodynamics of a single dose DMT administered
continuously over 90 minutes in healthy smokers
- Establish the minimum DMT dose required to produce moderate subjective
psychedelic effect
Part B:
- Confirm the safety of increasing doses of DMT administered IV over 60 minutes
(5 minute bolus followed by a 55 minute continuous infusion) in healthy
non-smokers.
Part C:
• Cohort 1:
o Evaluate the safety of increasing doses of deuterated DMT (CYB004)
administered IV over maximally 60 minutes (bolus of maximally 10 minutes
followed by a continuous infusion of maximally 55 minutes) in healthy
non-smokers.
o Characterize the pharmacokinetics (PK), pharmacodynamics (PD) and PK-PD
relationship of increasing doses of CYB004 administered IV over maximally 60
minutes (bolus of maximally 10 minutes followed by a continuous infusion of
maximally 55 minutes) in healthy non-smokers.
• Cohort 2 (optional):
o If needed optimize the CYB004 infusion scheme (i.e. duration of
administration and/or total dose) of a relevant safe dose identified in cohort
1 in healthy non-smokers
Study design
Part A:
Adaptive ascending single-dose, double-blind, randomized, placebo-controlled
design.
Part B:
Open label, fixed order, 2-way crossover rising dose design.
Part C:
Cohort 1: randomized, double-blind, 3-way crossover rising dose, interspersed
placebo-controlled design
Cohort 2: optional cohort to optimize the infusion scheme. Randomized,
double-blind, 3-way crossover rising dose, interspersed placebo-controlled
design
Intervention
Part A
0.12 mg/kg DMT or placebo (0.9% saline)
18.2 mg DMT or placebo (0.9% saline)
36.4 mg DMT or placebo (0.9% saline)
72.8 mg DMT or placebo (0.9% saline)
Part B
Two doses of DMT
Part C
Cohort 1 and 2: Placebo or two doses of CYB004
Study burden and risks
The principal mitigations for potential risks of the study drug are:
- The selection of dose levels that were previously shown to be safe and
tolerable in subjects.
- Thorough preparation of the study subjects regarding the trial and selection
of subjects that have had a prior experience with hallucinogenic drugs as this
is deemed to reduce the risk of negative psychological reactions.
- Selection of subjects that have no prior history of psychiatric illness or
family history of psychiatric illness, as this will reduce the chances of
subjects developing psychiatric complaints due to the study drug significantly.
- Prespecified safety monitoring procedures.
- The trial facility, where close monitoring can be performed and rapid
institution of appropriate care can be given. Potential risks can be monitored
clinically and/or with laboratory tests and have been considered when
determining the stopping rules for this clinical trial.
In addition to the potential risks associated with study drug administration,
there is minimal risk associated with trial procedures including insertion of a
canula for withdrawing blood (limited to < 500 mL) and non-invasive procedures
including vital sign assessments, electrocardiograms (ECGs) and PD assessments.
Overall, the benefit-risk profile is considered appropriate for this trial
One spencer Dock North Wall quay .
Dublin D01X9R7
IE
One spencer Dock North Wall quay .
Dublin D01X9R7
IE
Listed location countries
Age
Inclusion criteria
1. Healthy male and female volunteers.
2. Aged 21 - 60 years inclusive.
3. Part A: Regular use of nicotine (5-10 cigarettes daily).
Part B and C: non-smokers, defined as individuals who have never smoked
tobacco or used nicotine or tobacco containing products, or individuals with no
use of nicotine or tobacco containing products in the past 2 months.
4. Self-report of at least one prior hallucinogen drug experience that included
a meaningful altered state of consciousness (a state in which the subject
experienced phenomena that altered his psychological functioning, such as loss
of ego boundaries, impaired control of actions and cognition, disembodiment,
changed meaning of percepts, visual alterations and audio-visual synesthesia)
the past 5 years. Hallucinogenic substances can include psilocybin, LSD, DMT,
ayahuasca, mescaline, ibogaine, 2C-drugs (such as 2CB, 2CI and 2CE) and/or
ketamine.
5. Participant has a body mass index (BMI) between 18.0 and 30.0 kg/m2
inclusive (BMI=weight/height2).
6. Subject must be healthy based on physical examination, medical history,
vital signs, and 12-lead ECG. Minor abnormalities in ECG, which are not
considered to be of clinical significance by the investigator, are acceptable.
7. Subjects must be healthy based on clinical laboratory tests performed at
screening. If the results of the serum chemistry panel, hematology, or
urinalysis are outside the normal reference ranges, the subject may be included
only if the investigator judges the abnormalities to be not clinically
significant. This determination must be recorded in the subject's source
documents and initialed by the sub investigator.*
8. Agree to refrain from using any psychoactive drugs, including alcoholic
beverages within 24 hours of each drug administration.
Exclusion criteria
1. Subject has a history of or current liver or renal insufficiency;
significant cardiac, vascular, pulmonary, gastrointestinal, endocrine,
neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances,
any inflammatory illness or any other illness, which are considered to be of
clinical significance by the investigator.
2. Clinically relevant abnormal history, physical finding,12-lead safety
ECG12-lead safety ECG (e.g. PQ/PR interval > 210ms, presence of Left Bundle
Branch Block (LBBB), AV Block (second degree or higher), or a permanent
pacemaker or implantable cardioverter defibrillator [ICD]), or laboratory value
at screening that could interfere with the objectives of the trial or the
safety of the volunteer.
3. Subject has a history of or current hypertension (systolic blood pressure
>140 mmHg or diastolic blood pressure >90 mmHg).
4. Presence or history of cardiovascular disease, including acute coronary
syndrome or angina, ischemic disease, ventricular arrhythmias or cardiac
transplantation as determined by self-report during review of medical history.
5. Subject has a history of chronic or frequent migraines.
6. Females of childbearing potential with positive urine pregnancy at screening
or the day of the first treatment.
7. Subject has a history of drug or alcohol use disorder according to DSM-IV or
DSM 5 within the past five years.
8. Subject has a positive test result(s) for alcohol and/or drugs of abuse
(including: opiates (including methadone), cocaine, amphetamines,
methamphetamines, cannabinoids, barbiturates, and benzodiazepines) at screening
or admission to the clinical unit.*
9. Current or history of any clinically relevant psychiatric disorder as
classified according to DSM-IV or DSM 5 (e.g. psychotic disorder e.g.
schizophrenia/schizo-affective disorder, bipolar disorder Type I or Type II,
personality disorder, major depressive disorder/persistent depressive disorder,
obsessive-compulsive disorder, panic disorder, anorexia nervosa, bulimia
nervosa, generalized anxiety disorder (GAD), post-traumatic stress disorder
(PTSD) or autism spectrum disorder (ASD).
10. Family history of a relevant psychiatric disorder in first-degree
relatives. Psychiatric history in second degree relatives will be discussed on
a case to case basis.
11. Persistent psychological effects following the previous use of psilocybin,
LSD, DMT, ayahuasca, mescaline, ibogaine, 2C-drugs (such as 2CB, 2CI and 2CE)
and/or ketamine. Such effects might include but are not limited to anxiety,
depressed mood, paranoid ideation and/or hallucinations (including hallucinogen
persisting perception disorder - HPPD) or recurrent flash-backs related to use.
12. Risk of suicide, as judged by an Investigator, based upon available source
information -including the C-SSRS or family history of suicide -indicating
current suicidal ideation or a history of active suicidal ideation or suicide
attempts
13. Positive SARS-CoV-2 rapid antigen test analysis prior to first dosing.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-005207-12-NL |
| CCMO | NL79463.056.22 |