Methamphetamine Dependence
Conditions
Keywords
Entacapone, COMT val158met, Methamphetamine
Brief summary
Addiction to methamphetamine is a serious health problem. There are no medications that a doctor can give someone to help them stop using methamphetamine. Entacapone (Comtan©) is a medication that could help people addicted to methamphetamine. This study will see how entacapone works in healthy people who are given methamphetamine. We think that the study drug will be well tolerated, and that it will prevent some of the effects of methamphetamine that make it so addictive. We also want to see how differences in people's genes may cause differences in the ways the study drug and methamphetamine work for them. The study has six total visits. The first visit is for screening. Tests and procedures will make sure it is safe for subjects to participate. The second visit is a familiarization day. Subjects will receive methamphetamine, but no entacapone. This is done to make sure they can tolerate the drug and recognize its effects before being given a second drug on the same day. Subjects will take surveys and computer tests to see how the medications change mood, thinking, and liking the drug. The final four visits are the actual study days. Subjects will be randomly assigned (like the flip of a coin) to the different ways to get either 1) study medication or placebo (placebo contains no active study medication) and then 2) methamphetamine or placebo. Subjects will be in all four groups during the study, which means that each day a subject will get a different group.
Interventions
DRUGEntacapone
Entacapone 200 mg oral dose
DRUGMethamphetamine
Methamphetamine 20 mg oral dose
DRUGPlacebo
capsules compounded to be of similar appearance to the active drugs
Sponsors
Portland VA Medical Center
Oregon Health and Science University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* No history of pre-existing physical (including cardiovascular) illness * No history of drug abuse or dependence * Ability to read and write English * Have had at least one exposure to a stimulant (e.g. cocaine, methamphetamine, ecstasy, methylphenidate or any medication in the stimulant class) in their lifetime
Exclusion criteria
* Pregnant * Taking any psychotropic medication * Meeting DSM-IV criteria for active substance abuse or dependence * On any stimulant medication * History or current hypertension (BP \> 140/90 mm Hg) or systolic hypotension (SBP \< 90 mm Hg) * Subjects with resting pulse rate \> 90/min * Any active medical illness * Family history of abnormal heart rhythms, or sudden cardiac death * Subjects who anticipate they may require the emergent use of epinephrine (such as an Epi-Pen®) for the treatment of severe allergic reactions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Entacapone on Methamphetamine-induced Mood | Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint. | Profile of Mood States is a 65 item questionnaire using a Likert rating scale to assess transient, distinct moods. The questionnaire contains 65 words/statements that describe feelings people have. The test requires you to indicate for each word or statement how you have been feeling in the past week including today. A Total Mood Disturbance score is calculated by adding scores for Tension, Depression, Anger, Fatigue and Confusion and then subtracting the Vigour score. The Total Mood Disturbance scale ranges from -32 to 200 with lower scores indicative of people with more stable mood profiles. |
| Effect of Entacapone on Subjective Effects of Methamphetamine | Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint. | The subjective effects of the study drug were evaluated with the Addiction Research Center Inventory (ARCI-49), a 49 item questionnaire consisting of true/false items. True items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when answer is opposite to scoring direction. There are 5 subscales: Morphine Benzedrine group scale to measure euphoria (range: 0-16 with higher numbers indicating more euphoria), A Lysergic Acid Diethylamide group scale to estimate dysphoria and agitation (range: 0-14 with higher scores indicating more dysphoria), a Pentobarbital Chlorpromazine Alcohol group scale to measure sedation (range: 0-15 with higher scores indicating more sedation), and a Benzedrine group scale and an Amphetamine Scale to assess stimulant effects (range: 0-13 and 0-11, respectively, with higher scores indicating higher stimulant effects) . |
| Effect of Entacapone on Methamphetamine-induced Stimulation | Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint. | The Global Rating of Stimulation is a 1-item question I feel light-headed, restless, or speeded-up in which the participant is asked to circle one answer on a scale from 0-4, 0 is 'normal', 1 is 'slightly', 2 is 'moderately', 3 is 'very much', and 4 is 'extremely'. Whichever number they circled is their reported score. A higher score is indicative of a greater stimulating effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Function | Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint. | 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. |
Countries
United States
Participant flow
Recruitment details
Study staff screened 80 subjects over the phone between June 2014 to June 2016 at a clinical hospital in Portland, OR.
Pre-assignment details
51 subjects failed the pre-screen primarily due to history of substance use disorder, time commitment conflicts, or unwilling to take methamphetamine. 14 of 29 subjects completed first randomization. Of the 29, 6 declined to participate, 4 did not meet inclusion criteria, 1 was excluded due to an adverse event, and 6 dropped out.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Participants who completed all four study arms including:
1. Placebo followed by Placebo
2. Placebo followed by Methamphetamine (20 mg)
3. Entacapone (200 mg) followed by Placebo
4. Entacapone (200 mg) followed by Methamphetamine (20 mg) | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| First Intervention | Withdrawal by Subject | 1 |
| Open-Label Methamphetamine | Adverse Event | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 29.1 years STANDARD_DEVIATION 5.12 |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 13 | 0 / 13 | 0 / 12 | 0 / 13 |
| other Total, other adverse events | 1 / 19 | 0 / 13 | 0 / 13 | 0 / 12 | 0 / 13 |
| serious Total, serious adverse events | 0 / 19 | 0 / 13 | 0 / 13 | 0 / 12 | 0 / 13 |
Outcome results
Primary
Effect of Entacapone on Methamphetamine-induced Mood
Profile of Mood States is a 65 item questionnaire using a Likert rating scale to assess transient, distinct moods. The questionnaire contains 65 words/statements that describe feelings people have. The test requires you to indicate for each word or statement how you have been feeling in the past week including today. A Total Mood Disturbance score is calculated by adding scores for Tension, Depression, Anger, Fatigue and Confusion and then subtracting the Vigour score. The Total Mood Disturbance scale ranges from -32 to 200 with lower scores indicative of people with more stable mood profiles.
Time frame: Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.
Population: The analysis population includes only the 12 subjects that completed each intervention of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Effect of Entacapone on Methamphetamine-induced Mood | 12.500 units on a scale | Standard Deviation 8.187 |
| Placebo Followed by Placebo | Effect of Entacapone on Methamphetamine-induced Mood | 13.750 units on a scale | Standard Deviation 9.037 |
| Placebo Followed by Methamphetamine | Effect of Entacapone on Methamphetamine-induced Mood | 7.500 units on a scale | Standard Deviation 4.166 |
| Entacapone Followed by Placebo | Effect of Entacapone on Methamphetamine-induced Mood | 9.833 units on a scale | Standard Deviation 4.783 |
| Entacapone Followed by Methamphetamine | Effect of Entacapone on Methamphetamine-induced Mood | 8.750 units on a scale | Standard Deviation 4.309 |
Primary
Effect of Entacapone on Methamphetamine-induced Stimulation
The Global Rating of Stimulation is a 1-item question I feel light-headed, restless, or speeded-up in which the participant is asked to circle one answer on a scale from 0-4, 0 is 'normal', 1 is 'slightly', 2 is 'moderately', 3 is 'very much', and 4 is 'extremely'. Whichever number they circled is their reported score. A higher score is indicative of a greater stimulating effect.
Time frame: Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.
Population: The analysis population includes only the 12 subjects that completed each arm, or intervention, of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Effect of Entacapone on Methamphetamine-induced Stimulation | 0.1667 units on a scale | Standard Deviation 0.5586 |
| Placebo Followed by Placebo | Effect of Entacapone on Methamphetamine-induced Stimulation | 0.1667 units on a scale | Standard Deviation 0.5774 |
| Placebo Followed by Methamphetamine | Effect of Entacapone on Methamphetamine-induced Stimulation | 1.4167 units on a scale | Standard Deviation 1.1645 |
| Entacapone Followed by Placebo | Effect of Entacapone on Methamphetamine-induced Stimulation | 0.4167 units on a scale | Standard Deviation 0.9003 |
| Entacapone Followed by Methamphetamine | Effect of Entacapone on Methamphetamine-induced Stimulation | 1.3333 units on a scale | Standard Deviation 1.1547 |
Primary
Effect of Entacapone on Subjective Effects of Methamphetamine
The subjective effects of the study drug were evaluated with the Addiction Research Center Inventory (ARCI-49), a 49 item questionnaire consisting of true/false items. True items receive a score of 1 if answer is 'True', false items receive a score of 1 if answer is 'False'. No points are given when answer is opposite to scoring direction. There are 5 subscales: Morphine Benzedrine group scale to measure euphoria (range: 0-16 with higher numbers indicating more euphoria), A Lysergic Acid Diethylamide group scale to estimate dysphoria and agitation (range: 0-14 with higher scores indicating more dysphoria), a Pentobarbital Chlorpromazine Alcohol group scale to measure sedation (range: 0-15 with higher scores indicating more sedation), and a Benzedrine group scale and an Amphetamine Scale to assess stimulant effects (range: 0-13 and 0-11, respectively, with higher scores indicating higher stimulant effects) .
Time frame: Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.
Population: The analysis population includes only the 12 subjects that completed each arm, or intervention, of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline | Effect of Entacapone on Subjective Effects of Methamphetamine | Benzedrine | 4.9583 units on a scale | Standard Deviation 1.4869 |
| Baseline | Effect of Entacapone on Subjective Effects of Methamphetamine | Morphine Benzedrine | 1.9375 units on a scale | Standard Deviation 2.661 |
| Baseline | Effect of Entacapone on Subjective Effects of Methamphetamine | Amphetamine | 2.0000 units on a scale | Standard Deviation 1.8451 |
| Baseline | Effect of Entacapone on Subjective Effects of Methamphetamine | Lysergic Acid Diethylamide | 3.0625 units on a scale | Standard Deviation 1.1923 |
| Baseline | Effect of Entacapone on Subjective Effects of Methamphetamine | Pentobarbital Chlorpromazine Alcohol | 4.8125 units on a scale | Standard Deviation 2.5066 |
| Placebo Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Benzedrine | 5.1667 units on a scale | Standard Deviation 2.0817 |
| Placebo Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Pentobarbital Chlorpromazine Alcohol | 5.0000 units on a scale | Standard Deviation 2.9233 |
| Placebo Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Lysergic Acid Diethylamide | 3.25 units on a scale | Standard Deviation 1.1382 |
| Placebo Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Amphetamine | 2.1667 units on a scale | Standard Deviation 2.4802 |
| Placebo Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Morphine Benzedrine | 1.8333 units on a scale | Standard Deviation 2.8868 |
| Placebo Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Pentobarbital Chlorpromazine Alcohol | 1.5833 units on a scale | Standard Deviation 1.832 |
| Placebo Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Morphine Benzedrine | 7.9167 units on a scale | Standard Deviation 5.9308 |
| Placebo Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Lysergic Acid Diethylamide | 4.75 units on a scale | Standard Deviation 2.0944 |
| Placebo Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Benzedrine | 8.6667 units on a scale | Standard Deviation 3.6013 |
| Placebo Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Amphetamine | 5.9167 units on a scale | Standard Deviation 3.4499 |
| Entacapone Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Amphetamine | 2.5833 units on a scale | Standard Deviation 2.6097 |
| Entacapone Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Morphine Benzedrine | 2.5833 units on a scale | Standard Deviation 4.1 |
| Entacapone Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Benzedrine | 5.3333 units on a scale | Standard Deviation 2.1462 |
| Entacapone Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Pentobarbital Chlorpromazine Alcohol | 4.0833 units on a scale | Standard Deviation 2.811 |
| Entacapone Followed by Placebo | Effect of Entacapone on Subjective Effects of Methamphetamine | Lysergic Acid Diethylamide | 3.25 units on a scale | Standard Deviation 1.1382 |
| Entacapone Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Pentobarbital Chlorpromazine Alcohol | 2.0000 units on a scale | Standard Deviation 2.132 |
| Entacapone Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Benzedrine | 7.8333 units on a scale | Standard Deviation 3.7376 |
| Entacapone Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Morphine Benzedrine | 6.9167 units on a scale | Standard Deviation 6.2879 |
| Entacapone Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Amphetamine | 5.5833 units on a scale | Standard Deviation 4.0104 |
| Entacapone Followed by Methamphetamine | Effect of Entacapone on Subjective Effects of Methamphetamine | Lysergic Acid Diethylamide | 3.8333 units on a scale | Standard Deviation 1.3371 |
Secondary
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.
Time frame: Measurements acquired before drug ingestion (baseline) then hourly for 4 hours. The peak interaction effect of entacapone and methamphetamine occurs 1 hour after ingestion, therefore the reported values are from this timepoint.
Population: The analysis population includes only the 12 subjects that completed each arm, or intervention, of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baseline | Cognitive Function | Rapid Visual Information Processing Task | 38.813 number of correct answers | Standard Deviation 11.23 |
| Baseline | Cognitive Function | Digital Symbol Substitution Task | 73.167 number of correct answers | Standard Deviation 17.765 |
| Placebo Followed by Placebo | Cognitive Function | Rapid Visual Information Processing Task | 40.500 number of correct answers | Standard Deviation 13.215 |
| Placebo Followed by Placebo | Cognitive Function | Digital Symbol Substitution Task | 72.000 number of correct answers | Standard Deviation 20.662 |
| Placebo Followed by Methamphetamine | Cognitive Function | Rapid Visual Information Processing Task | 41.333 number of correct answers | Standard Deviation 11.073 |
| Placebo Followed by Methamphetamine | Cognitive Function | Digital Symbol Substitution Task | 71.167 number of correct answers | Standard Deviation 27.788 |
| Entacapone Followed by Placebo | Cognitive Function | Digital Symbol Substitution Task | 72.750 number of correct answers | Standard Deviation 14.973 |
| Entacapone Followed by Placebo | Cognitive Function | Rapid Visual Information Processing Task | 42.583 number of correct answers | Standard Deviation 10.423 |
| Entacapone Followed by Methamphetamine | Cognitive Function | Rapid Visual Information Processing Task | 40.083 number of correct answers | Standard Deviation 10.396 |
| Entacapone Followed by Methamphetamine | Cognitive Function | Digital Symbol Substitution Task | 72.750 number of correct answers | Standard Deviation 15.004 |