Cocaine and Zolmitriptan

Early Phase 1

Completed

• Conditions: Cocaine Use Disorder
• Interventions: Drug: Cocaine; Drug: Placebo oral capsule; Drug: Zolmitriptan

• Registration Number: NCT05019430
• Lead Sponsor: William Stoops

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-08-13
• Study First Submitted QC: 2021-08-18
• Study First Posted: 2021-08-24
• Study Start: 2021-10-15
• Primary Completion: 2025-01-09
• Study Completion: 2025-01-09
• Results First Submitted: 2025-06-27
• Status Verified: 2025-07
• Results First Submitted QC: 2025-07-16
• Last Update Submitted: 2025-07-16
• Results First Posted: 2025-08-05
• Last Update Posted: 2025-08-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo oral capsule	Subjects will be maintained on oral placebo. Cocaine will be administered acutely during placebo maintenance. Placebo will be administered acutely during placebo maintenance.
Zolmitriptan Dose 2	Zolmitriptan	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.
Placebo	Cocaine	Subjects will be maintained on oral placebo. Cocaine will be administered acutely during placebo maintenance. Placebo will be administered acutely during placebo maintenance.
Zolmitriptan Dose 1	Cocaine	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.
Zolmitriptan Dose 2	Cocaine	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.
Zolmitriptan Dose 3	Cocaine	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.
Zolmitriptan Dose 3	Zolmitriptan	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.

Primary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (1)

University of Kentucky; 🇺🇸 Lexington, Kentucky, United States