Cocaine Use Disorder
Conditions
Brief summary
Cocaine potently inhibits the reuptake of serotonin (5-HT). Increased synaptic 5-HT resulting from this reuptake inhibition activates multiple 5-HT receptor subtypes. Some of these receptor subtypes have been implicated in the abuse-related effects of cocaine, including its primary reinforcing effects (i.e., cocaine taking behavior). 5-HT1b receptors, which are autoreceptors on 5-HT nerve endings that regulate 5-HT release and heteroreceptors that also mediate other neurotransmitter release, play a particularly important role in cocaine effects, likely because they are highly expressed in the mesocorticolimbic system. The 5-HT1b system displays profound dysregulation during both active cocaine use and abstinence. Initial preclinical research showed that selective 5-HT1b agonists enhanced the reinforcing and locomotor effects of cocaine during ongoing cocaine administration, but subsequent research showed that these agents robustly attenuated reinstatement of cocaine- and cue-primed cocaine seeking behavior. These findings have been replicated in rigorously conducted studies using multiple schedules of reinforcement and negative sucrose reinforcement controls across laboratories. Notably, though, these preclinical studies used compounds not approved for use in humans, hindering translation. Recently published data show that zolmitriptan, a commercially available selective 5-HT1b agonist migraine medication, also selectively attenuates the reinforcing and other abuse-related effects of cocaine, regardless of stage of use (i.e., ongoing or extinguished cocaine self-administration). Although a robust preclinical literature supports the premise that 5-HT1b activation reduces a number of cocaine-associated behaviors (e.g., self-administration, cocaine seeking), this area remains unstudied in humans. The overarching goal of this project is to advance these promising preclinical findings, specifically those with zolmitriptan, to a clinical population, thereby demonstrating that the 5-HT1b system plays a key role in the effects of cocaine in humans
Interventions
DRUGCocaine
The pharmacodynamic effects of cocaine will be determined during maintenance on placebo and zolmitriptan.
DRUGPlacebo oral capsule
The pharmacodynamic effects of placebo will be determined.
DRUGZolmitriptan
The pharmacodynamic effects of zolmitriptan maintenance will be determined.
Sponsors
National Institute on Drug Abuse (NIDA)
William Stoops
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Recent cocaine use
Exclusion criteria
* Abnormal screening outcome (e.g., ECG, blood chemistry result) that study physicians deem clinically significant * Current or past histories of substance use disorder that are deemed by the study physicians to interfere with study completion * History of serious physical disease, current physical disease, impaired cardiovascular functioning, chronic obstructive pulmonary disease, history of seizure or current or past histories of serious psychiatric disorder that in the opinion of the study physician would interfere with study participation will be excluded from participation * Females not currently using effective birth control * Contraindications to cocaine or zolmitriptan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reinforcing Effects of Cocaine | Over approximately four hours on each experimental session day, which generally occurred on Days 5-7, 13-15, 21-23 and 29-31 of inpatient admission. | Number of Times Subjects Choose Cocaine (Maximum of 5 Choices) Over Money |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Study This study used a within subjects design (i.e., all subjects were to receive all oral zolmitriptan maintenance conditions \[0, 2.5, 5 and 10 mg\] and intravenous cocaine doses \[0, 10 and 30 mg/70 kg\]). Ten subjects completed the full study. Two additional subjects were enrolled but discharged prior to completing the full study. Data from completed sessions for those subjects are included here. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 47 years STANDARD_DEVIATION 5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 11 | 0 / 11 |
| other Total, other adverse events | 10 / 10 | 10 / 10 | 11 / 11 | 11 / 11 |
| serious Total, serious adverse events | 1 / 10 | 0 / 10 | 0 / 11 | 0 / 11 |
Outcome results
Primary
Reinforcing Effects of Cocaine
Number of Times Subjects Choose Cocaine (Maximum of 5 Choices) Over Money
Time frame: Over approximately four hours on each experimental session day, which generally occurred on Days 5-7, 13-15, 21-23 and 29-31 of inpatient admission.
Population: Subjects completing the dose condition
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Condition 1 | Reinforcing Effects of Cocaine | 1.4 number of times subjects chose cocaine | Standard Deviation 1.96 |
| Dose Condition 2 | Reinforcing Effects of Cocaine | 4 number of times subjects chose cocaine | Standard Deviation 1.61 |
| Dose Condition 3 | Reinforcing Effects of Cocaine | 4.5 number of times subjects chose cocaine | Standard Deviation 1.51 |
| Dose Condition 4 | Reinforcing Effects of Cocaine | 0.7 number of times subjects chose cocaine | Standard Deviation 1.57 |
| Dose Condition 5 | Reinforcing Effects of Cocaine | 3.6 number of times subjects chose cocaine | Standard Deviation 2.06 |
| Dose Condition 6 | Reinforcing Effects of Cocaine | 4.5 number of times subjects chose cocaine | Standard Deviation 1.58 |
| Dose Condition 7 | Reinforcing Effects of Cocaine | 0.6 number of times subjects chose cocaine | Standard Deviation 1.57 |
| Dose Condition 8 | Reinforcing Effects of Cocaine | 3.5 number of times subjects chose cocaine | Standard Deviation 1.97 |
| Dose Condition 9 | Reinforcing Effects of Cocaine | 4.6 number of times subjects chose cocaine | Standard Deviation 0.67 |
| Dose Condition 10 | Reinforcing Effects of Cocaine | 0.7 number of times subjects chose cocaine | Standard Deviation 1.42 |
| Dose Condition 11 | Reinforcing Effects of Cocaine | 4.1 number of times subjects chose cocaine | Standard Deviation 1.45 |
| Dose Condition 12 | Reinforcing Effects of Cocaine | 4.2 number of times subjects chose cocaine | Standard Deviation 1.83 |