Pharmacogenetics of Naltrexone for Stimulant Abuse

Using Pharmacogenetics to Better Evaluate Naltrexone for Treating Stimulant Abuse

This investigation will be the first study assessing genetic modulation of naltrexone's NTX effects upon the abuse liability of a stimulant drug (methamphetamine). The study team will assess the ability of oral NTX to block the reinforcing and positive subjective effects of intranasal (IN) methamphetamine (30mg/70kg). This investigation could identify an important Gene x Pharmacological interaction, contributing to the personalization of stimulant abuse pharmacotherapy.

Study Overview

• Status: Completed
• Conditions: Substance Use Disorders; Methamphetamine Abuse
• Intervention / Treatment: Drug: Intranasal Methamphetamine

Detailed Description

A recent meta-analysis concluded that the OPRM1 A118G SNP (rs1799971) significantly moderates the treatment efficacy of Naltrexone (NTX) in treating alcohol abuse, increasing the treatment efficacy by over 2-fold among G-allele carriers (AG/GG). The proposed application would be the first to investigate the moderating effect of this genotype in the efficacy of NTX to treat stimulant abuse. More specifically, the study team proposes to investigate the interaction between NTX and intranasal (IN) methamphetamine (30mg/70kg). Participants who meet DSM criteria for mild-to-severe stimulant use disorder (N=up to 70) will complete 4 testing sessions where drug effects are tested following pretreatment with NTX (0, 50 mg). Naltrexone pretreatment effects upon the abuse liability of IN methamphetamine will be assessed using self-report measurements of positive subjective effects and drug self-administration. Medication effects on these validated predictors of abuse potential will be compared between A118G A allele homozygotes (AA) and G-allele carriers (AG/GG; an anticipated 25% of the total sample), in order to assess genetic moderation of treatment outcome.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • New York State Psychiatric Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 50 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female age 21 to 50 years
2. DSM-5 criteria for mild-to-severe stimulant use disorder, along with intravenous, intranasal or smoked use of amphetamine-type stimulants in amounts equal to or greater than administered in the current study.
3. Able to give written informed consent to participate.
4. Females must be either post-menopausal, surgically sterilized, or using an acceptable method of contraception (double-barrier method like a condom with a spermicidal lubricant) to participate in this study.
5. Racially Caucasian or of European descent.

Exclusion Criteria:

1. Currently seeking treatment for a substance use disorder.
2. DSM-5 criteria for moderate-to-severe substance use disorders (except those involving cocaine, amphetamines and nicotine).
3. Psychiatric condition that may affect the participants' ability to provide informed consent (e.g., psychotic disorder), or make participation hazardous for the participant or study staff (e.g., severe depression/suicidality, or risk of violence).
4. Uncontrolled neurological, cardiovascular, and hepatic diseases, active tuberculosis, or any other disorder that might make administration of study medications hazardous.
5. Gastrointestinal or renal disease that would significantly impair absorption, metabolism or excretion of study drug, or require medication or medical treatment.
6. Current treatment with a psychotropic medication that in the physician's judgement would interfere with the study endpoints.
7. History of allergy, adverse reaction, or sensitivity to amphetamines.

8. Medical conditions that may make study participation hazardous:

   • History of seizures or cardiac risk conditions (unstable angina, cardiac arrhythmias, chest pain, strong palpitations (subjectively defined as the feeling that the heart is beating too hard, too fast, skipping a beat, or fluttering).
   • Elevated liver function tests (i.e., AST and ALT > 3 times the upper limit of normal).
   • Impaired renal function (creatinine > 1.2).
   • Hypertension (>140/90).
   • Asthmatic symptoms within the past 3 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Naltrexone 0 mg; This aim assess the effects of pretreatment with 0 mg of naltrexone on laboratory measures of the abuse potential of methamphetamine (30mg/70 kg).	Drug: Intranasal Methamphetamine; Intranasal Methamphetamine HCL administered at a dose of 30mg per 70 kg of the participants' body weight)
EXPERIMENTAL: Naltrexone 50 mg; This aim assess the effects of pretreatment with 50 mg of naltrexone on laboratory measures of the abuse potential of methamphetamine (30mg/70 kg).	Drug: Intranasal Methamphetamine; Intranasal Methamphetamine HCL administered at a dose of 30mg per 70 kg of the participants' body weight)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Methamphetamine Self-Administration	To assess the reinforcing effects of methamphetamine, participants complete a drug self-administration procedure. The outcome measure for this procedure is the number of operant responses (clicks on a mouse) participant are willing to make in order to receive drug (methamphetamine).	1 day.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Positive Subjective Effects of Methamphetamine.	Participant ratings of methamphetamine "Liking," on a 100 mm visual analog scale. Participants are asked to indicate on a 100 mm line the extent to which they agree with the description of the drug provided. The 0 mm end of the line indicates "Not at All," while the 100 mm indicates "Extremely."	1 day

Collaborators and Investigators

• Sponsor: New York State Psychiatric Institute
• Investigators: Principal Investigator: Jermaine Jones, PhD, NYSPI

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 15, 2016
• Primary Completion (ACTUAL): July 15, 2019
• Study Completion (ACTUAL): July 30, 2020

Study Registration Dates

• First Submitted: July 20, 2017
• First Submitted That Met QC Criteria: July 20, 2017
• First Posted (ACTUAL): July 21, 2017

Study Record Updates

• Last Update Posted (ACTUAL): November 24, 2020
• Last Update Submitted That Met QC Criteria: November 8, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Sympathomimetics; Adrenergic Uptake Inhibitors; Methamphetamine
• Other Study ID Numbers: #7347

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No