Cocaine and Zolmitriptan

Study Overview
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Brief Summary
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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

Official Title
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Behavioral Effects of Drugs (Inpatient): 42 (Cocaine and Zolmitriptan)

Conditions
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Cocaine Use Disorder

Intervention / Treatment
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* Drug: Cocaine
* Drug: Placebo oral capsule
* Drug: Zolmitriptan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will be maintained on oral placebo. Cocaine will be administered acutely during placebo maintenance. Placebo will be administered acutely during placebo maintenance. | Drug: Cocaine<br>* The pharmacodynamic effects of cocaine will be determined during maintenance on placebo and zolmitriptan.<br>Drug: Placebo oral capsule<br>* The pharmacodynamic effects of placebo will be determined.<br>|
| Experimental: Zolmitriptan Dose 1<br>Subjects will be maintained on oral zolmitriptan dose 1. Cocaine will be administered acutely during zolmitriptan dose 1 maintenance. Placebo will be administered acutely during zolmitriptan dose 1 maintenance. | Drug: Cocaine<br>* The pharmacodynamic effects of cocaine will be determined during maintenance on placebo and zolmitriptan.<br>|
| Experimental: Zolmitriptan Dose 2<br>Subjects will be maintained on oral zolmitriptan dose 2. Cocaine will be administered acutely during zolmitriptan dose 2 maintenance. Placebo will be administered acutely during zolmitriptan dose 2 maintenance. | Drug: Cocaine<br>* The pharmacodynamic effects of cocaine will be determined during maintenance on placebo and zolmitriptan.<br>Drug: Zolmitriptan<br>* The pharmacodynamic effects of zolmitriptan maintenance will be determined.<br>|
| Experimental: Zolmitriptan Dose 3<br>Subjects will be maintained on oral zolmitriptan dose 3. Cocaine will be administered acutely during zolmitriptan dose 3 maintenance. Placebo will be administered acutely during zolmitriptan dose 3 maintenance. | Drug: Cocaine<br>* The pharmacodynamic effects of cocaine will be determined during maintenance on placebo and zolmitriptan.<br>Drug: Zolmitriptan<br>* The pharmacodynamic effects of zolmitriptan maintenance will be determined.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reinforcing Effects of Cocaine Following Placebo Maintenance. | Number of cocaine doses earned by subjects on a progressive ratio schedule of reinforcement. | Following at least 3 days of maintenance on placebo during inpatient admission | 
| Reinforcing Effects of Cocaine Following Zolmitriptan Dose 1 Maintenance. | Number of cocaine doses earned by subjects on a progressive ratio schedule of reinforcement. | Following at least 3 days of maintenance on zolmitriptan dose 1 during inpatient admission. | 
| Reinforcing Effects of Cocaine Following Zolmitriptan Dose 2 Maintenance. | Number of cocaine doses earned by subjects on a progressive ratio schedule of reinforcement. | Following at least 3 days of maintenance on zolmitriptan dose 2 during inpatient admission. | 
| Reinforcing Effects of Cocaine Following Zolmitriptan Dose 3 Maintenance. | Number of cocaine doses earned by subjects on a progressive ratio schedule of reinforcement. | Following at least 3 days of maintenance on zolmitriptan dose 3 during inpatient admission. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjective Rating Scale-Sedative | Subjects will complete the adjective rating scale during 12 sessions while they are admitted to our inpatient unit. Responses to 16 items are summed (total score=0-64; Higher values=more sedation) to calculate scores on a sedative subscale. | 12 times over approximately 1 month inpatient admission | 
| Adjective Rating Scale-Stimulant | Subjects will complete the adjective rating scale during 12 sessions while they are admitted to our inpatient unit. Responses to 16 items are summed (total score=0-64; Higher values=more sedation) to calculate scores on a stimulant subscale. | 12 times over approximately 1 month inpatient admission | 
| Drug Effect Questionnaire | Subjects will complete the drug effect questionnaire during 12 sessions while they are admitted to our inpatient unit. The items (total scores=0-100; Higher scores=greater drug effect) on this scale categorize the constellation of drug effects endorsed by subjects. | 12 times over approximately 1 month inpatient admission | 
| Heart rate | Beats per minute. Measured daily during inpatient admission. | Daily over approximately four week inpatient admissions | 
| Blood pressure | mmHg. Measured daily during inpatient admission. | Daily over approximately 1 month inpatient admission. | 
| Temperature | Degrees fahrenheit. Measured daily during inpatient admission. | Daily over approximately 1 month inpatient admission | 
| Side Effects | Subjects will complete a side effects questionnaire daily while they reside on the inpatient unit. Side Effects questions will query subjects about common effects of centrally active medications. | Daily over approximately 1 month inpatient admission | 
| Delay Discounting Task | Subjects will complete the delay discounting task during 12 sessions while they are admitted to our inpatient unit. Responses will be used to calculate discounting slope (i.e., K). | 12 times over approximately 1 month inpatient admission | 
| n-back Task | Subjects will complete the n-back task during 12 sessions while they are admitted to our inpatient unit. Percentage of correct responses will be the outcome. | 12 times over approximately 1 month inpatient admission | 
| Stop-Signal Task Reaction Time | Subjects will complete the stop-signal task during 12 sessions while they are admitted to our inpatient unit. Reaction time in milliseconds and proportion of inhibitory failures will be the outcome variables. | 12 times over approximately 1 month inpatient admission | 
| Stop-Signal Task Inhibitory Failures | Subjects will complete the stop-signal task during 12 sessions while they are admitted to our inpatient unit. Proportion of inhibitory failures will be the outcome variable. | 12 times over approximately 1 month inpatient admission |