AzTrials
AzTrials

Methamphetamine-dependencePhase 4MATAARNCT03973489

Effects of Genotype on Resting State Connectivity During Methamphetamine Administration

A Phase 4 study testing Magnetic resonance imaging (MRI) and Methamphetamine Hydrochloride Tablets in people with Methamphetamine-dependence, run by Oregon Health and Science University at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for
Methamphetamine-dependence
What is being tested?
Magnetic resonance imaging (MRI) and Methamphetamine Hydrochloride Tablets
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
69 participants
Where
2 sitesUnited States
Study dates
16 Aug 2019to 31 Mar 2023
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Criteria for Inclusion:

[All groups]

  • 18 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

Criteria for Exclusion:

[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

[Healthy volunteer group]

  • History of any severe substance use disorders within the last 5 years except tobacco use disorder
  • Positive urine drug screen at any point in the study (except for marijuana or for verified medical reasons)

Trial locations and contacts

2 sites in 1 country.

United States2 sites
  • Portland VA Medical Center

    Portland, Oregon, 97204

  • Oregon Health and Science University

    Portland, Oregon, 97239

Other trials in United States

About this study

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. Determine the influence of CV vs. WT genotype on RSFC and craving in individuals with chronic MUD and healthy controls.
  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.
Read the detailed description

This proposal will determine the effect of a common variant (CV) synonymous single nucleotide polymorphism (SNP) of the gene for the human trace amine associated receptor 1 (TAAR1) on the neural and behavioral response of subjects with methamphetamine (MA) use disorder (MUD) and healthy control subjects to acute MA administration. The SNP (rs8192620 on human Genome Reference Consortium Human Build 38 patch release 7 chromosome 6 at 132,645,140 bp in htaar1, allelic frequency 22%) results from a change of adenine to guanine in a valine codon occurring at amino acid position 288 (V288V). MA is a potent agonist at the TAAR1 receptor, in addition to its actions at the dopamine transporter and the vesicular monoamine transporter. In rodents, a decrease in TAAR1 expression or non-functional TAAR1 receptor is associated with an increase in striatal dopamine (DA) signaling.

The scientific premise of this project is based on 1) preliminary findings that support a model that the CV alters RSFC of the striatum, a dopaminergic terminal region, and associated behavior in chronic MUD, 2) published reports that delineate the effect of TAAR1 on DA signaling and 3) preclinical evidence that TAAR1 influences sensitivity to rewarding and aversive effects of MA.

Furthermore, this proposal will address questions that have important implications for understanding and treating patients with MUD, as the TAAR1 receptor is implicated in MA self-administration. As an allele of the murine TAAR1 gene associated with an inactive receptor leads to increased MA intake in homozygotes, it is critically important to study the feasibility of exploiting human variant htaar1.

The investigators propose a model based on this premise that makes testable predictions about the interaction of the CV with chronic and acute MA administration in MUD. The investigators' preliminary data show that the CV causes over-expression of TAAR1 in cell culture. Stimulation of the TAAR1 receptor decreases dopaminergic signaling in mesocorticolimbic and corticostriatal networks. The investigators propose that this effect in conjunction with chronic MA use causes neuroadaptations that result in the increased striato- and corticolimbic RSFC as well as increased drug craving observed in MUD subjects with the CV. The investigators can indirectly test the hypothesis of decreased DA release due to ever-expression via MA administration. The effect of acute MA administration on RSFC in humans is not known but acute administration of S-amphetamine and methylphenidate reduce RSFC in salience attribution and default mode networks presumably via increased DA release. Stimulation of over-expressed TAAR1 should blunt this effect in CV carrying individuals compared to WT. There are no published reports on neural effects of the interaction between either chronic or acute MA administration and htaar1 genotype in humans, therefore this proposal represents a unique opportunity to determine whether the RSFC response to acute MA administration in humans is mediated by genotype.

Being tested
Magnetic resonance imaging (MRI), Methamphetamine Hydrochloride Tablets, Placebo oral tablet
Keywords
Methamphetamine

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Magnetic resonance imaging (MRI)Behavioural

    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.

  • Methamphetamine Hydrochloride TabletsDrug

    Also called Desoxyn

    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.

  • Placebo oral tabletDrug

    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.

Study groups in NCT03973489
Study groupRoleWhat they receive
Wild Type (WT) MUD GroupExperimentalWild Type (WT) Group: individuals who are WT for the TAAR1 gene
Receives: Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet
Common Variant (CV) MUD GroupExperimentalCommon 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
Receives: Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet
Wild Type (WT) Healthy Control GroupExperimentalWild Type (WT) Group: individuals who are WT for the TAAR1 gene
Receives: Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet
Common Variant (CV) Healthy Control GroupExperimentalCommon Variant (CV) Group: individuals who are hetero-or homozygous for the V288V SNP on the TAAR1 gene
Receives: Behavioral: Magnetic resonance imaging (MRI); Drug: Methamphetamine Hydrochloride Tablets; Drug: Placebo oral tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 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)

  2. 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.

    Measured: 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)

  3. 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.

    Measured: 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)

  4. 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.

    Measured: 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)
  1. Methamphetamine Concentration in Saliva (ng/ml)

    Saliva samples were acquired to test concentration of methamphetamine levels

    Measured: 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)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2019
  2. Study start16 Aug 2019
  3. Primary completion31 Mar 2023
  4. Study completion31 Mar 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Diagnosis
Allocation
Randomised
Intervention model
Crossover
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
69 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03973489
Sponsor's protocol ID
17932
Acronym
MATAAR
Status last verified
Nov 2024
First submitted
31 May 2019
Last updated
15 Nov 2024
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Magnetic resonance imaging (MRI) and Methamphetamine Hydrochloride Tablets in people with Methamphetamine-dependence, run by Oregon Health and Science University at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Nov 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Functional Connectivity During Resting State Magnetic Resonance Imaging (MRI) (time frame: 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)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Nov 2024.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in