Cocaine and Zolmitriptan

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

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

Study Overview

• Status: Recruiting
• Conditions: Cocaine Use Disorder
• Intervention / Treatment: Drug: Placebo oral capsule; Drug: Cocaine; Drug: Zolmitriptan

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: William W Stoops, PhD; Phone Number: 859-257-5388; Email: william.stoops@uky.edu

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40507
      • Recruiting
      • University of Kentucky
      • Contact: William W Stoops, PhD; Phone Number: 859-257-5388; Email: william.stoops@uky.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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
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
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
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

Collaborators and Investigators

• Sponsor: William Stoops
• Collaborators: National Institute on Drug Abuse (NIDA)

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2021
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): July 31, 2024

Study Registration Dates

• First Submitted: August 13, 2021
• First Submitted That Met QC Criteria: August 18, 2021
• First Posted (Actual): August 24, 2021

Study Record Updates

• Last Update Posted (Estimated): December 4, 2023
• Last Update Submitted That Met QC Criteria: December 1, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Anesthetics, Local; Dopamine Uptake Inhibitors; Vasoconstrictor Agents; Zolmitriptan; Cocaine
• Other Study ID Numbers: BED In 42; R01DA052203 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No