Methamphetamine Isomer Pharmacology in Humans

The Low-Down on Methamphetamine Isomers: Prevalence and Pharmacology in Humans

This study is being done to understand the metabolism and impairment profile of methamphetamine (meth). Meth exists as two chemical structures that are mirror images of each other: R-meth and S-meth. S-meth is a strong central nervous system stimulant and used to treat attention deficit disorder (ADD). R-meth is not a strong central nervous system stimulant and is available over-the-counter in nasal decongestant sprays.17 healthy participants will be enrolled for 3 study visits and on study for up to 12 weeks.

Study Overview

• Status: Not yet recruiting
• Conditions: Methamphetamine
• Intervention / Treatment: Drug: S-(+)-methamphetamine; Drug: R-(-)-methamphetamine; Drug: 1:1 racemic mixture of two isomers

Detailed Description

Double-blind crossover study design. Healthy volunteers will attend three study drug administration visits, at least 7 days apart, in which methamphetamine isomer pharmacology will be assessed following intravenous administration of (1) S-(+)-methamphetamine, (2) R(-)-methamphetamine, or (3) a (1:1) racemic mixture of R-(-)- and S-(+)-methamphetamine. The order of these interventions will be counterbalanced across participants. Serial blood samples will be drawn during each dosing visit and compared with concurrent dried blood spots from a finger stick, oral fluid collections, and pooled urine specimens.

Primary Objective

• Characterize the pharmacokinetics of acute S-(+)-methamphetamine administration.
• Characterize the pharmacokinetics of acute R-(-)-methamphetamine administration.
• Characterize the pharmacokinetics of acute racemic (1:1) R-(-)- and S-(+)-methamphetamine administration.

Secondary Objectives

• Assess for evidence of stereo-selective metabolic pathways.
• Assess for evidence of subjective, cognitive, or physiological effects from acute R-(-)-methamphetamine administration.
• Assess for evidence of more than additive effects when administering racemic methamphetamine.

Correlative Objectives

• Compare biological methamphetamine and metabolite concentrations in surveyed biological matrices (i.e., plasma, whole blood, oral fluid, dried capillary blood spots, and urine) over time.
• Compare cognitive and subjective effects of acute S-(+)-methamphetamine, R-(-)-methamphetamine, and racemic methamphetamine administration.

• Study Type: Interventional
• Enrollment (Estimated): 17
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Heather Barkholtz, PhD; Phone Number: 608-890-1967; Email: hbarkholtz@wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Good mental health as determined by self-reported responses to the Psychopathology Screener
• Absence of any major cardiac, neurologic, psychiatric, oncologic, endocrine, metabolic, renal, or hepatic disease as determined by self-reported responses to the Medical History Screener
• English-speaking (able to provide consent and complete questionnaires)
• Written Informed Consent

Exclusion Criteria:

• Any serious prior adverse response to sympathomimetic agents or amphetamine analogs
• History of or current substance use disorder as determined by self-reported responses to the Internalizing, Externalizing, and Substance Use Disorder Screener
• Pregnancy or lactation (pregnancy test, if needed)
• Use of medications that may impact cognition or metabolism (e.g., mood stabilizers, sedatives)
• Dependent on prohibited concomitant therapy that cannot be withheld for 48 hours prior to and during study visits.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: S-Meth, R-Meth, Racemic Isomer; First visit: Administer S-Meth, then at least 7 days later Second visit: Administer R-Meth, then at least 7 days later Third visit: Administer (1:1) racemic methamphetamine	Drug: S-(+)-methamphetamine; 15 mg; Other Names: S-Meth; Drug: R-(-)-methamphetamine; 15 mg; Other Names: R-Meth; Drug: 1:1 racemic mixture of two isomers; 15 mg R-Meth + 15 mg S-Meth
Experimental: R-Meth, Racemic Isomer, S-Meth; First visit: Administer R-Meth, then at least 7 days later Second visit: Administer (1:1) racemic methamphetamine, then at least 7 days later Third visit: Administer S-Meth	Drug: S-(+)-methamphetamine; 15 mg; Other Names: S-Meth; Drug: R-(-)-methamphetamine; 15 mg; Other Names: R-Meth; Drug: 1:1 racemic mixture of two isomers; 15 mg R-Meth + 15 mg S-Meth
Experimental: Racemic Isomer, S-Meth, R-Meth; First visit: Administer (1:1) racemic methamphetamine, then at least 7 days later Second visit: Administer S-Meth, then at least 7 days later Third visit: Administer R-Meth	Drug: S-(+)-methamphetamine; 15 mg; Other Names: S-Meth; Drug: R-(-)-methamphetamine; 15 mg; Other Names: R-Meth; Drug: 1:1 racemic mixture of two isomers; 15 mg R-Meth + 15 mg S-Meth

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak concentration (Cmax)	The pharmacokinetic analysis relies on observed drug and metabolite concentration measurements over time and across biological matrices (plasma, whole blood, dried capillary spots, oral fluid, urine) included in this study.	pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48 hours
Area under the concentration versus time curve (AUC)	The pharmacokinetic analysis relies on observed drug and metabolite concentration measurements over time and across biological matrices (plasma, whole blood, dried capillary spots, oral fluid, urine) included in this study.	pre-dose, 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive Effects: Divided Attention Task (DAT)	The DAT requires participants track a moving stimulus on a computer screen while simultaneously monitoring numbers located in the corners of the screen. Participants must respond to target numbers as they appear, and the task quantifies mean distance of the mouse cursor from the center of the target stimulus.	Visit 1 (baseline), Visit 2 (week 1), Visit 3 (week 2)
Cognitive Effects: Digital Symbol Substitution Task (DSST)	The DSST asks participants to recreate patterns of various shapes presented on a computer screen using the keyboard. The total number of correct patterns are recorded within 90 seconds.	Visit 1 (baseline), Visit 2 (week 1), Visit 3 (week 2)
Cognitive Effects: Paced Serial Addition Task (PASAT)	The PASAT has participants view a string of single-digit numbers and calculate the sum of the two most recently presented numbers. The total number of correct trials out of 90 will be recorded.	Visit 1 (baseline), Visit 2 (week 1), Visit 3 (week 2)
Subjective Effects: Drug Effect Questionnaire (DEQ)	Subjective current general effects will be measured by asking the participant to rate if they feel the drug effect, if they like/dislike the drug effect, if they feel high, and if they would like more of the drug. Effects will be measured on a scale from "not at all" anchored at 0 to "extremely" at 100.	Visit 1 (baseline), Visit 2 (week 1), Visit 3 (week 2)
Subjective Effects: Number of Participants Who Answer 'True' for Amphetamine-specific questions	Participants will be asked 11 amphetamine-specific questions including feelings of pleasantness, excitability, memory, emptiness, body tingling, weird feeling, patience, and mental sharpness. Results are measured as either "true" (experiencing the specific state) or "false" (not experiencing the specific state). Number of participants who answered 'True' is reported here	Visit 1 (baseline), Visit 2 (week 1), Visit 3 (week 2)

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: U.S. Department of Justice
• Investigators: Principal Investigator: Heather K Barkholtz, PhD, University of Wisconsin, Madison; Principal Investigator: David Leinweber, MD, University of Wisconsin, Madison

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: December 9, 2024
• First Submitted That Met QC Criteria: December 18, 2024
• First Posted (Actual): December 24, 2024

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: pharmacology; meth; isomers
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Membrane Transport Modulators; Adrenergic Agents; Central Nervous System Stimulants; Dopamine Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Dopamine Agents; Adrenergic Uptake Inhibitors; Sympathomimetics; Methamphetamine
• Other Study ID Numbers: 2024-1164; A523000 (Other Identifier: UW Madison); Protocol Version 2/12/25 (Other Identifier: UW Madison)

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
• product manufactured in and exported from the U.S.: No