Neurobiology and Pharmacokinets of Acute MDMA Administration
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 40 |
| Updated: | 3/22/2019 |
| Start Date: | February 10, 2004 |
| End Date: | July 18, 2012 |
Neurobiology and Pharmacokinetics of Acute MDMA Administration
Background:
- 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a synthetic
psychoactive drug that has shown a steep increase in recreational use and abuse by young
people in recent years. Research studies have reported that chronic MDMA users who also
consume other legal and illegal substance show memory deficits; however, because of the
combination of drugs often involved, it is difficult to determine MDMA s contribution to
these effects.
- Only a few studies have examined the immediate physical and behavioral effects of MDMA
given at dose levels commonly used in young adults. Researchers are interested in using
functional magnetic resonance imaging (fMRI) to examine changes in brain activity and
function in MDMA users compared with users of other drugs and non-drug-using
individuals.
Objectives:
- To evaluate the effects of MDMA on thinking and brain function.
Eligibility:
- Individuals between 18 and 30 years of age who are (1) current users of MDMA (2), current
drug users who do not use MDMA, or (3) healthy non-drug-using volunteers.
Design:
- Participants will complete one training session and three scanning sessions.
- Before the start of the study, participants will complete questionnaires about medical
and psychological history, and provide information about past or current drug use.
Researchers will introduce the tasks to be performed during the scanning session(s), and
will allow participants to practice the tests.
- Participants will provide urine, saliva, and hair samples for testing before the start
of the study, and multiple times during each scanning session.
- Participants who use MDMA and participants who use other drugs will stay overnight at
the clinical center prior to each scanning session. Participants who do not use drugs
can spend the night prior to scanning or arrive at the clinical center on the morning of
the scanning session.
- Participants who use MDMA will receive either MDMA or a placebo during the scanning
sessions, and will not be told which one they have received. Because of the nature of
MDMA, participants will be required to stay at the clinical center until the effects of
the drug have worn off, and will be required to return to the clinical center on the
following day for a follow-up examination.
- During the study, participants will be asked to do one or more tasks selected by the
researchers. The tasks will be performed on a computer in an MRI machine, and may
involve receiving monetary rewards for actions, memory and reaction-time tests, or other
tests that involve responding to instructions on the screen.
- 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a synthetic
psychoactive drug that has shown a steep increase in recreational use and abuse by young
people in recent years. Research studies have reported that chronic MDMA users who also
consume other legal and illegal substance show memory deficits; however, because of the
combination of drugs often involved, it is difficult to determine MDMA s contribution to
these effects.
- Only a few studies have examined the immediate physical and behavioral effects of MDMA
given at dose levels commonly used in young adults. Researchers are interested in using
functional magnetic resonance imaging (fMRI) to examine changes in brain activity and
function in MDMA users compared with users of other drugs and non-drug-using
individuals.
Objectives:
- To evaluate the effects of MDMA on thinking and brain function.
Eligibility:
- Individuals between 18 and 30 years of age who are (1) current users of MDMA (2), current
drug users who do not use MDMA, or (3) healthy non-drug-using volunteers.
Design:
- Participants will complete one training session and three scanning sessions.
- Before the start of the study, participants will complete questionnaires about medical
and psychological history, and provide information about past or current drug use.
Researchers will introduce the tasks to be performed during the scanning session(s), and
will allow participants to practice the tests.
- Participants will provide urine, saliva, and hair samples for testing before the start
of the study, and multiple times during each scanning session.
- Participants who use MDMA and participants who use other drugs will stay overnight at
the clinical center prior to each scanning session. Participants who do not use drugs
can spend the night prior to scanning or arrive at the clinical center on the morning of
the scanning session.
- Participants who use MDMA will receive either MDMA or a placebo during the scanning
sessions, and will not be told which one they have received. Because of the nature of
MDMA, participants will be required to stay at the clinical center until the effects of
the drug have worn off, and will be required to return to the clinical center on the
following day for a follow-up examination.
- During the study, participants will be asked to do one or more tasks selected by the
researchers. The tasks will be performed on a computer in an MRI machine, and may
involve receiving monetary rewards for actions, memory and reaction-time tests, or other
tests that involve responding to instructions on the screen.
Background: 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a
synthetic compound that has shown a steep increase in abuse by young people in recent years.
In animals, when high and multiple doses of MDMA were given, serotonergic toxicity was
observed. Clinically, the number of severe ecstasy related acute toxicities is low in
relation to the extent of recreational use. Data from some retrospective studies report
memory deficits in abstinent chronic users who often abuse MDMA with other illicit and licit
substances; therefore, it is difficult to determine MDMA s contribution to observed cognitive
deficits. There are few prospective controlled MDMA human administration studies that
describe its acute physiological and behavioral effects following doses commonly used in
young adults. We propose a functional magnetic resonance imaging (fMRI) study to examine
specific changes in brain activity and cognitive performance and to correlate these changes
with plasma MDMA concentrations.
Goals: The primary goals are identification of MDMA effects on human brain function and
elucidation of the relationship of effects to plasma MDMA concentrations. We propose a
within-subject design of changes in memory, attention, affect, semantic processing and
decision-making performance following placebo and two recreational MDMA doses with
simultaneous fMRI monitoring and plasma collections. Secondly, pharmacokinetic data will be
collected on the disposition of MDMA and metabolites in plasma, urine, oral fluid, sweat,
breath, and hair. These data are needed to accurately interpret drug concentrations in
alternative biological matrices in order for drug tests to function as a deterrent to drug
use in drug abuse treatment, law enforcement, military, and workplace drug testing programs.
Pharmacokinetic data will also enable drug tests to serve as valid diagnostic tools in
emergency medicine and public safety settings, as well as useful objective outcome measures
in treatment research.
Subject Population: Eighteen current MDMA users will complete the neurocognitive and
pharmacokinetics group. Thirty-six MDMA non-using controls will include 18 non-drug using
participants and 18 drug using (primarily cannabis) participants. Controls in each group will
be matched to MDMA users in the neurocognitive and pharmacokinetics group. All participants
must be between the ages of 18 and 40. The estimated target enrollment, based on ecstasy use
by race/ethnic group and Baltimore demographics, will be 41% female and 59% male, 83%
Caucasian, 14% African American, 3% Asian, and 2% Hispanic.
Experimental Design and Methods: A randomized, balanced, double blind, within-subject drug
administration study with placebo, low (1.0 mg/kg, approximately 70 mg) and high (1.6 mg/kg,
approximately 112 mg) doses of MDMA is proposed. The non-drug using and drug using control
groups will be matched to MDMA users in the neurocognitive and pharmacokinetics group for
sex, age, IQ, education level and intersession interval. The drug using control group will
control for cannabis and other drug usage in the MDMA group. The drug using control group is
necessary because many MDMA users also use other drugs, primarily cannabis. Control groups
allow for a between-subjects analysis for trait differences between the population groups, as
well as provide normative data for the cognitive tasks. Drug using control group participants
will stay on the clinical research unit overnight prior to each of the three sessions;
non-drug using control group participants will arrive the morning of each session.
Participants from the MDMA group will complete three separate stays, each lasting
approximately 26 hours, within one year. While under the influence of MDMA, qualified
participants will perform memory, attention, semantic processing, affect and decision-making
tasks before, during, and after fMRI scanning. Physiological, behavioral and biochemical
measures of all MDMA users will be monitored throughout the study to determine onset,
magnitude and duration of pharmacodynamic effects. Blood, urine, oral fluid, sweat, breath,
and hair specimens will be collected from MDMA users for analysis of MDMA and metabolite
concentrations by GC/MS and/or LC/MS/MS to determine the disposition and pharmacokinetics of
MDMA.
Risks and Benefits: A main potential risk of this study is associated with acute
cardiovascular responses to MDMA administration; however, these doses have proven safe and
well tolerated in previous human studies conducted within the US and abroad. In addition,
impaired cognitive function has been reported following long-term MDMA use in some but not
all studies. A potential benefit of the proposed study is to understand how MDMA affects
human brain function at doses employed by recreational users. Additionally, advances will be
made in understanding MDMA pharmacokinetics.
synthetic compound that has shown a steep increase in abuse by young people in recent years.
In animals, when high and multiple doses of MDMA were given, serotonergic toxicity was
observed. Clinically, the number of severe ecstasy related acute toxicities is low in
relation to the extent of recreational use. Data from some retrospective studies report
memory deficits in abstinent chronic users who often abuse MDMA with other illicit and licit
substances; therefore, it is difficult to determine MDMA s contribution to observed cognitive
deficits. There are few prospective controlled MDMA human administration studies that
describe its acute physiological and behavioral effects following doses commonly used in
young adults. We propose a functional magnetic resonance imaging (fMRI) study to examine
specific changes in brain activity and cognitive performance and to correlate these changes
with plasma MDMA concentrations.
Goals: The primary goals are identification of MDMA effects on human brain function and
elucidation of the relationship of effects to plasma MDMA concentrations. We propose a
within-subject design of changes in memory, attention, affect, semantic processing and
decision-making performance following placebo and two recreational MDMA doses with
simultaneous fMRI monitoring and plasma collections. Secondly, pharmacokinetic data will be
collected on the disposition of MDMA and metabolites in plasma, urine, oral fluid, sweat,
breath, and hair. These data are needed to accurately interpret drug concentrations in
alternative biological matrices in order for drug tests to function as a deterrent to drug
use in drug abuse treatment, law enforcement, military, and workplace drug testing programs.
Pharmacokinetic data will also enable drug tests to serve as valid diagnostic tools in
emergency medicine and public safety settings, as well as useful objective outcome measures
in treatment research.
Subject Population: Eighteen current MDMA users will complete the neurocognitive and
pharmacokinetics group. Thirty-six MDMA non-using controls will include 18 non-drug using
participants and 18 drug using (primarily cannabis) participants. Controls in each group will
be matched to MDMA users in the neurocognitive and pharmacokinetics group. All participants
must be between the ages of 18 and 40. The estimated target enrollment, based on ecstasy use
by race/ethnic group and Baltimore demographics, will be 41% female and 59% male, 83%
Caucasian, 14% African American, 3% Asian, and 2% Hispanic.
Experimental Design and Methods: A randomized, balanced, double blind, within-subject drug
administration study with placebo, low (1.0 mg/kg, approximately 70 mg) and high (1.6 mg/kg,
approximately 112 mg) doses of MDMA is proposed. The non-drug using and drug using control
groups will be matched to MDMA users in the neurocognitive and pharmacokinetics group for
sex, age, IQ, education level and intersession interval. The drug using control group will
control for cannabis and other drug usage in the MDMA group. The drug using control group is
necessary because many MDMA users also use other drugs, primarily cannabis. Control groups
allow for a between-subjects analysis for trait differences between the population groups, as
well as provide normative data for the cognitive tasks. Drug using control group participants
will stay on the clinical research unit overnight prior to each of the three sessions;
non-drug using control group participants will arrive the morning of each session.
Participants from the MDMA group will complete three separate stays, each lasting
approximately 26 hours, within one year. While under the influence of MDMA, qualified
participants will perform memory, attention, semantic processing, affect and decision-making
tasks before, during, and after fMRI scanning. Physiological, behavioral and biochemical
measures of all MDMA users will be monitored throughout the study to determine onset,
magnitude and duration of pharmacodynamic effects. Blood, urine, oral fluid, sweat, breath,
and hair specimens will be collected from MDMA users for analysis of MDMA and metabolite
concentrations by GC/MS and/or LC/MS/MS to determine the disposition and pharmacokinetics of
MDMA.
Risks and Benefits: A main potential risk of this study is associated with acute
cardiovascular responses to MDMA administration; however, these doses have proven safe and
well tolerated in previous human studies conducted within the US and abroad. In addition,
impaired cognitive function has been reported following long-term MDMA use in some but not
all studies. A potential benefit of the proposed study is to understand how MDMA affects
human brain function at doses employed by recreational users. Additionally, advances will be
made in understanding MDMA pharmacokinetics.
- INCLUSION CRITERIA: Participants must:
1. Be between the ages of 18 and 40.
2. If MDMA group, have consumed at least five tablets of ecstasy in their lifetime
with no clinically significant adverse medical or psychiatric reactions from
using the drug or other stimulants and must have used at least once within the
past 30 days (Drug Use Survey), with no current intention to stop MDMA use.
History of ecstasy consumption is supported by a minimum of one positive urine
amphetamines or hair MDMA drug test within the past 90 days. Urine drug tests at
scanning visits must not be positive for drugs, other than amphetamines and
cannabis. Scanning visits can be rescheduled once due to a positive urine test
for other drugs.
3. If control group, have no history of MDMA use (Drug Use Survey) and have negative
urine test for amphetamines. If in the non-drug using group, must have a negative
urine test for non-therapeutic psychoactive drugs at screening and scanning
visits. Lifetime cannabis use for these participants cannot exceed ten times,
with no use in the past two years (Timeline Follow-Back Method (146)). At
screening, drug using controls may test positive for other drugs, other than
amphetamines. At scanning, drug using controls may be positive for cannabis only.
Scanning visits can be rescheduled once due to a positive urine test for other
drugs.
4. Be without current clinically significant medical problems that would preclude
safe study participation.
5. If female, must use a reliable method of birth control or abstain from sexual
intercourse. Female participants will be counseled that a urine pregnancy test
cannot detect pregnancies within 7 to 14 days of conception.
6. Have an 8th grade reading and comprehension level.
Additional requirements for participants undergoing neurocognitive testing:
7. Have an IQ ? 85 determined by the Wechsler Abbreviated Scale of Intelligence
(WASI) (The Psychological Corporation, 1999).
8. Be right handed (Edinburgh Handedness Inventory (147)).
9. Speak English as their first language.
EXCLUSION CRITERIA: Participants must NOT:
1. Have known major medical or axis I psychiatric diagnosis other than substance abuse
(Structured Clinical Interview (SCID) for the Diagnostic & Statistical Manual of
Mental Disorders IV (DSM-IV) criteria). Participants with a history of psychotropic
medicine use will be evaluated by the MRP on a case-by-case basis to uncover the
precise diagnosis for the use of the drug. Individuals who have substance dependence
other than nicotine or cannabis, based on DSM IV criteria, will be excluded from the
study. Prospective participants will be excluded if they smoke more than two packs of
cigarettes per day.
2. If MDMA user, be currently using (within 30 days of MDMA administration) one of the
following inhibitors of CYP2D6 or CYP3A4 or inducers of CYP3A4:
CYP2D6 inhibiting drugs
Antidepressants: paroxetine, fluoxetine, sertraline, fluvoxamine, nefazodone,
venlafaxine, clomipramine, amitriptyline, citalopram, bupropion
Antipsychotics: haloperidol, perphenazine, thioridazine, levomepromazine, pimozide,
fluphenazine
Antiarrythmics: quinidine
Protease inhibitors: ritonavir
CYP3A4 inhibiting drugs
Antidepressants: nefazodone, fluvoxamine, fluoxetine, sertraline, paroxetine,
venlafaxine, norfluoxetine
Azole antifungals: ketoconazole, itraconazole, fluconazole
Protease inhibitors: ritonavir, nelfinavir, amprenavir
Nonnucleoside reverse transcriptase inhibitors: efavirenz, delavirdine
Histamine H2 -receptor antagonists: cimetidine
Macrolide antibiotics: clarithromycin, erythromycin
Calcium channel blockers: diltiazem
In addition, participants will be advised to limit their consumption of grapefruit
juice.
CYP3A4 inducing drugs
Antibacterials: rifampin
Antidepressants: St. John s wart
Anticonvulsants: carbamazepine, phenobarbital, phenytoin
Adrenocortical steroids: dexamethasone
If potential participants need to continue taking these drugs as part of a physician
prescribed treatment regimen, they will be excluded for safety purposes. Potential
participants will be advised that there should be a minimum 30-day abstention from the
use of these listed compounds prior to MDMA administration.
3. If MDMA user, SBP greater than 135 and DBP greater than 85 taken after at least 5
minutes rest, tachycardic (resting HR greater than 100 bpm), or hypercholesterolemic
(total cholesterol greater than 250 mg/dL) if above the age of 30.
4. If MDMA user, have hemoglobin levels less than 12.5-g/100 mL if male and less than
12-g/100 mL if female.
5. If MDMA user, have clinically significant abnormal resting 12-lead ECG.
6. If female, be pregnant or nursing.
7. Have liver function tests greater than 3 times upper limit of normal range.
8. Be unable to comply with task demands.
9. Have a history of neurological illnesses including but not limited to stroke, central
nervous system tumor, encephalitis or other CNS infection, multiple sclerosis or other
demyelinating diseases, epilepsy, movement disorders, or migraine headaches severe
enough to require treatment.
10. If non-drug using control, have a hair test positive for non-therapeutic psychoactive
drugs.
11. If drug using control, have hair test results that are inconsistent with self-reported
drug use.
Additional exclusion criteria for participants undergoing neurocognitive testing:
12.
13.
14.
the A or B subscale.
15.
confirmatory test for syphilis.
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