EDWARD MULLEN, ALEX GUERIN, EMILY KARANGES, AMELIA LOPATECKI, ORLI SCHWARTZ, SHALINI ARUNOGIRI, COLLEEN LOO , ANDREW CHANEN, ENRICO CEMENTON, ASWIN RATHEESH, CHRIS DAVEY, GILLINDER BEDI

AN OPEN-LABEL PILOT STUDY OF SUBANAESTHETIC KETAMINE FOR STIMULANT USE DISORDER - METHAMPHETAMINE TYPE IN YOUTH

• Most AOD use starts in adolescence (AIHW, 2017)

• Peak onset of SUD 18-20 years old (Dennis & Scott, 2007)

• Methamphetamine use highest in 20-29 age group (AIHW, 2019)

• Outcomes improved by early treatment (Dennis et al, 2005)

AOD USE IN YOUTH

3Chan 2019

KETAMINE AS NOVEL TREATMENT FOR SUD

Ketamine• Non-competitive antagonist at NMDA receptor• Increased glutamate transmission in prefrontal regions• May normalize glutamatergic dysregulation in SUDs (Mclennan 2000)• Ultra-rapid remission of depression and suicidal ideation using sub-

anesthetic dosages (Han 2016)• May improve ability to learn new behaviours in the treatment of SUDs

(Naughton 2014)

4

KETAMINE IN SUBSTANCE USE DISORDERS

• Rodents: Reverses hypo-dopaminergic state in amphetamine withdrawal in rats (Belujon 2016)

• Humans: • Non-treatment-seeking cocaine users reduced cravings, cocaine self-

administration by two-thirds, increased motivation to quit (Dakwar 2014)• Reduced drinking days and alcohol consumed in problematic drinkers

(Das 2019)• Increased abstinence from opiates at 1-2 years (Krupintksy 2002) and

reduced opiate withdrawal symptoms (Jovaisa 2006)

5

MASKOT

MethAmphetamine use in young people: Sub-anaesthetic Ketamine Open-label Trial (MASKOT)N=20, youth (15-25) with moderate to severe Substance use disorder –methamphetamine type (SUD-MA).Recruited through online and at AOD services.

6

AIMS

Primary Aim: Confirm the safety and tolerability of S/C ketamine administration in youth (15-25) with SUD-MA.Secondary Aims: Test the preliminary efficacy of two SC doses of ketamine (initial dose 0.75 mg/kg) separated by at least 7 days (and up to 10) to reduce methamphetamine use and methamphetamine craving.Exploratory Aims: To explore mechanisms of clinical response to ketamine treatment in young people with SUD-MA and assess potential predictors of treatment response including cognitive function, cognitive control, and impulsivity.

7

MASKOT INTERVENTION – DAY 1 AND 7

Dose Level

S/C

Ketamine

Dose

Titration Procedure

Level 0 0.6mg/kg • Dose reduction from Level 1 if not tolerated.Level 1 0.75mg/kg • Starting Dose for all participants.

Level 2 0.9mg/kg • Dose escalation from Level 1 if initial dose is tolerated.

8

Participants also receiving counselling at AOD service/headspace centre.

Baseline assessment (Day -7 to Day -1)• Interview • Urine drug screening test,

breathalyzer, CO breath test

• Questionnaires

Informed Consent• Participants AND• Parent/Guardian for those under 18

years

Confirm eligibility

1st treatment visit (5 hours; Day 0)• Vital signs • Urine drug screening test,

breathalyzer, CO breath test

• Questionnaires • Treatment administration

• Pregnancy test (if applicable)

• 4 hours of monitoring

48 hours after 1st treatment (15 minutes)• Questionnaires (over the phone and

electronically)

2nd treatment visit (5 hours; Day 7)• Vital signs • Urine drug screening test,

breathalyzer, CO breath test

• Questionnaires • Treatment administration

• Pregnancy test (if applicable)

• 4 hours of monitoring

MASKOT PARTICIPATION FLOW CHART

48 hours after 2nd treatment (15 minutes)• Questionnaires (over the phone and

electronically)

MASKOT Participation Flow Chart v1.1 21st October 2020 9

End of Study follow-up (1.5 hours; Day 42)• Interview • Urine drug screening test,

breathalyzer, CO breath test

• Questionnaires

Week 3 (Day 21) and Week 4 (Day 28 ) follow-ups (1.5 hours)

• Interview • Urine drug screening test,breathalyzer, CO breath test

• Questionnaires

Treatment phase (Day 0 to Day 14)

End treatment phase (2 hours; Day 14)• Clinical Blood test • Urine drug screening test,

breathalyzer, CO breath test

• Questionnaires • Vital signs

• Optional: cognitive assessments

Follow-up phase (Day 14 to Day 42)

Screening assessment (Day -21 to Day -8)• Medical and psychiatric

review• Urine drug screening test,

breathalyzer, CO breath test

• Interview • Clinical Blood Test

• Questionnaires • Pregnancy test (if applicable)

• Physical Exam & Vital signs • Optional: cognitiveassessments

STUDY ENDPOINTS

Primary Endpoints at 6 weeksSafety: change in ketamine use (Timeline Follow-Back) and craving at week 6 and LFTs at week 2.Tolerability: number of withdrawn participants due to adverse effects.Secondary EndpointsChange in past week days and quantity of methamphetamine use and cravings from baseline to weeks 2, 3, 4, and 6.Methamphetamine abstinence and relapse.Change in use of other substances.

10

SAFETY AND ETHICAL CONSIDERATIONS

• Good safety data from depression studies • Ketamine dosage is low• Potential drug of abuse – needs further assessment of

safety in this population

11

PROGRESS TO DATE

COVID!Staffing – Project Manager, Study DoctorHREC – Awaiting approvalDatabase developmentRecruitment and Communication StrategyNew projected dates: Jan 2021- Dec 2021

12

SUBSTANCE USE RESEARCH GROUP AND EARLY INTERVENTION CLINIC & INVESTIGATORSDr Gill BediDr Eddie MullenAlex GuerinDr Emily KarangesAmelia LopateckiDr Enrico CementonDr Aswin RatheeshProf Andrew ChanenProf Coleen LooProf Chris Davey

13

THANK YOU

INCLUSION CRITERIA

15-25 years old ;

Current stimulant use disorder – methamphetamine type, moderate or severe,

Current methamphetamine use, indicated by positive urine toxicology (qualitative)

Seeking treatment to reduce methamphetamine use;

Engaged with a regular treating doctor (general practitioner, GP, or psychiatrist;

Ability to provide informed consent (both adequate IQ and English fluency; 15 to 17 year olds will provide consent themselves, as will a parent/guardian).

History of psychosis or bipolar disorder

Acute suicidality, based on clinical judgement by the study doctor or other qualified clinician, or severe depression (>15 on the Quick Inventory of Depressive Symptomatology; QIDS);

If female, pregnancy or current breastfeeding, or, if sexually active, no effective contraception;

Abnormal liver or thyroid function as indicated by clinically significant findings on blood tests;

If prescribed antidepressants, the participant must have been on a stable dose for >2 weeks;

Current treatment with antipsychotic medication, mood stabiliser, or ADHD medication;

Any unstable medical or neurological condition, or medical contraindication to ketamine use, e.g. uncontrolled hypertension;

Current or past DSM-5 diagnosis with ketamine use disorder, moderate or severe; and

Current DSM-5 diagnosis with other substance use disorders, moderate or severe, except tobacco, caffeine, or cannabis.

EXCLUSION CRITERIA

EDWARD MULLEN, ALEX GUERIN, EMILY KARANGES, AMELIA LOPATECKI, ORLI SCHWARTZ, SHALINI ARUNOGIRI, COLLEEN LOO , ANDREW CHANEN, ENRICO CEMENTON, ASWIN RATHEESH, CHRIS DAVEY, GILLINDER BEDI�AOD use in youthSlide Number 3Ketamine as novel treatment for SUDKetamine in substance use disordersmaskotAIMSMASKOT intervention – Day 1 and 7Slide Number 9Study endpointsSafety and ethical considerationsProgress to dateSubstance use research group and early intervention clinic & investigatorsSlide Number 14Inclusion criteria�