Effects of Genotype on Resting State Connectivity During Methamphetamine Administration

NCT03973489 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 17932
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 2

Brief Summary

Addiction to methamphetamine (MA) is a serious health problem in the United States. Right now, there are no medically approved treatments for MA dependence. More research is needed to understand how MA affects the brain and to eventually develop medical interventions for MA addiction. The purpose of the study is to learn more about how MA use affects the brain by investigating a receptor in the brain called trace amine-associated receptor 1 (TAAR1). The investigators are hoping to find out if individuals with certain versions of the brain receptor react differently when given MA. The TAAR1 receptor has two prevalent genetic variations due to a single nucleotide polymorphism. These are the wild type (WT) and a common variant (CV). Preliminary studies have shown that these variants produce different connectivity (resting state functional connectivity or RSFC) in the brains of individuals with MA use disorder (MUD), specifically that individuals with the CV genotype exhibit lower RSFC than WT. In this study, MA will be administered to individuals with MA use disorder and healthy controls in order to:

1. 1.Determine the influence of CV vs. WT genotype on RSFC and craving in individuals with chronic MUD and healthy controls.
2. 2.Determine the effect of acute methamphetamine or placebo administration on the interaction of CV vs WT genotype on RSFC, craving, cognitive control, attention and subjective experience in MUD and healthy controls.

Conditions

Methamphetamine-dependence

Keywords

Methamphetamine

Outcome Measures

Primary Outcomes (4)

• Functional Connectivity During Resting State Magnetic Resonance Imaging (MRI)

  Pearson correlation coefficient (r) was used to calculate cortico-striatal and intra-striatal functional connectivity during resting state. These r values were then converted into Fisher's Z-scores using the transformation: z = arctanh(r) = 0.5\*ln((1+r)/(1-r)). Fisher's Z-transformation linearizes Pearson correlations and allows for statistical analysis. The Z-scores represent the strength and direction of functional connectivity between brain regions. A Z-score of 0 represents the population mean for functional connectivity between brain regions. Larger Z-scores indicate stronger connectivity (potentially indicating greater activation or association), while smaller (negative) Z-scores indicate weaker connectivity, which could suggest reduced synchronization or disrupted brain function. Z-scores above or below ±1 standard deviation from the mean may indicate notable deviations from the expected connectivity patterns in the population.

  1 hour prior to and 1.5 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days)

• Euphoria Effects of Study Drug

  The Morphine Benzedrine group (MBG) scale is a subscale of the Addiction Research Center Inventory (ARCI-49), a 49 item questionnaire consisting of true/false items, which measures the euphoric effects of the study drug. The MBG scale ranges from 0-16 with higher numbers indicating more euphoria. The questionnaire was administered every hour for four hours following study drug administration and the highest score during this time is considered the post drug administration score.

  2.5 hours prior to and between 1-4 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days)

• Craving Assessed With the Stimulant Craving Questionnaire (STCQ)

  Current craving for methamphetamine was assessed using the Stimulant Craving Questionnaire (STCQ), which is a 10-item self-report measure that uses a seven-point scale, with answers ranging from 0 ("strongly disagree") to 6 ("strongly agree"). A composite score was computed by averaging the responses for all 10 items after reverse scoring items 4 and 7. Scores range from 0 to 6 with higher scores representing higher craving for methamphetamine.

  2 hours prior to and 3 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days)

• Cognitive Function

  Two computer tests were administered to measure how each medication intervention effects cognitive functioning. The tests administered included the Rapid Visual Information Processing Task (RVIPT), a 6 minute test of sustained attention in which participants are requested to detect target sequences of digits and the Digit Symbol Substitution Task (DSST), a 2 minute test of psychomotor speed and sustained attention consisting of digit-symbol pairs followed by a list of digits where the subject identifies the symbol that corresponds to each digit as fast as possible. The number of correct responses within the allowed time is measured. Higher scores on both tasks indicate better performance.

  2 hours prior to and 3 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days)

Secondary Outcomes (1)

• Methamphetamine Concentration in Saliva (ng/ml)

  2.5 hours prior to and 3 hours post study drug administration on visits 2 and visit 3 (randomized to placebo or methamphetamine; washout period between visit 2 and 3 was at least 3 days)

Study Arms (4)

Wild Type (WT) MUD Group

EXPERIMENTAL

Wild Type (WT) Group: individuals who are WT for the TAAR1 gene

Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet

Common Variant (CV) MUD Group

EXPERIMENTAL

Common Variant (CV) Group: individuals who are hetero-or homozygous for the valine codon occurring at amino acid position 288, designated V288V, SNP on the TAAR1 gene

Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet

Wild Type (WT) Healthy Control Group

EXPERIMENTAL

Wild Type (WT) Group: individuals who are WT for the TAAR1 gene

Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet

Common Variant (CV) Healthy Control Group

EXPERIMENTAL

Common Variant (CV) Group: individuals who are hetero-or homozygous for the V288V SNP on the TAAR1 gene

Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet

Interventions

Magnetic resonance imaging (MRI) BEHAVIORAL

On visits 2 and 3, subjects will undergo a baseline MRI scan approximately 1 hour after the start of each visit followed by drug administration (placebo or MA) and a second scan 1.5 hours after that.

Common Variant (CV) Healthy Control Group; Common Variant (CV) MUD Group; Wild Type (WT) Healthy Control Group; Wild Type (WT) MUD Group

Methamphetamine Hydrochloride Tablets DRUG

Study participants will receive an oral dose of methamphetamine hydrochloride on one of two scan days and an identical looking placebo in tablet form on the other scan day. Drug type will be randomized between the two visits. Participants will receive the following doses of methamphetamine hydrochloride in accordance with their weight: if weight is between 50-60 kg, 15 mg dose of methamphetamine hydrochloride will be administered. Similarly, for 60-80 kg, 20 mg dose; 80-100 kg, 25 mg dose; and 100+ kg, 30 mg dose.

Also known as: Desoxyn

Common Variant (CV) Healthy Control Group; Common Variant (CV) MUD Group; Wild Type (WT) Healthy Control Group; Wild Type (WT) MUD Group

Placebo oral tablet DRUG

Study participants will receive an oral dose of methamphetamine hydrochloride on one of two scan days and an identical looking placebo in tablet form on the other scan day. Drug type will be randomized between the two visits.

Common Variant (CV) Healthy Control Group; Common Variant (CV) MUD Group; Wild Type (WT) Healthy Control Group; Wild Type (WT) MUD Group

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• \[All groups\]
• to 55 years old
• Homozygous or heterozygous for the human TAAR1 (hTAAR1) V288V genotype or wild type for hTAAR1 (determined during screening visit "Visit 1")
• \[Meth use group\]
• Subjects must have a positive urine drug screen for methamphetamine during visit one
• Meets current criteria for methamphetamine use disorder
• Subjects should have been using at least 100mg of methamphetamine (not prescribed), 5 days per week for at least one year
• Abstinent from methamphetamine for 24 hours on days of scans
• \[Healthy volunteer group\]
• \- At least one exposure to a stimulant, either recreational or prescribed

You may not qualify if:

• \[All groups\]
• Allergies to stimulants or hypersensitivity to taking a stimulant in the past
• Diagnosis of a psychotic or mood disorder
• Self-reported claustrophobia
• Women who are pregnant or breast-feeding
• Intoxicated on study days
• Clinically significant neurological, cardiovascular, endocrine, renal, hepatic or systemic disease that could compromise safe participation or confound outcomes (including hepatitis C, HIV, severe anemia, or liver disease)
• History of glaucoma
• Metal in the body which is contraindicated for MRI or would compromise image quality
• Current prescription use of stimulants, anti-psychotic drugs or anti-Parkinson's drugs
• Use of monoamine oxidase inhibitors within 14 days
• Use of serotonin reuptake inhibiters, serotonin norepinephrine reuptake inhibiters, triptans, tricyclic antidepressants, Fentanyl, lithium, tramadol, tryptophan, buspirone , St. John's Wort, insulin, phenothiazines, guanethidine, acidifying/alkalinizing agents, CYP2D6 inhibitors, proton pump inhibitors
• \[Meth use group\]
• Positive urine drug screen at any point during the study (except for meth or marijuana)
• History of any severe substance use disorders within the last 5 years, except for methamphetamine use disorder or tobacco use disorder

Sponsors & Collaborators

• Oregon Health and Science University: lead
• Portland VA Medical Center: collaborator

Study Sites (2)

Portland VA Medical Center

Portland, Oregon, 97204, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

MeSH Terms

Interventions

Magnetic Resonance Spectroscopy; Methamphetamine

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques; Amphetamines; Phenethylamines; Ethylamines; Amines; Organic Chemicals

Results Point of Contact

• Title: William Hoffman
• Organization: VA Portland Health Care System

hoffmanw@ohsu.edu

503-220-8262

Study Officials

• William Hoffman, MD, PhD

  Oregon Health and Science University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Subjects will be grouped into either the CV or WT group. Neither they nor the researchers will know which group they are in. In addition, subjects will be randomly assigned to receive drug then placebo or placebo than drug. Neither researchers or subjects will know in which order they will receive drug.
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 31, 2019
• First Posted: June 4, 2019
• Study Start: August 16, 2019
• Primary Completion: March 31, 2023
• Study Completion: March 31, 2023
• Last Updated: November 15, 2024
• Results First Posted: November 15, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)