Impact of Repeatedly-Administered THC-cannabis on Experimental Pain and Abuse Liability in Humans

Chronic pain is a significant public health concern in the U.S., for which prescription opioids have historically been the standard treatment. This has resulted in striking rates of opioid use disorders and fatal overdoses. Identifying non-opioid medications for the management of chronic pain with minimal abuse liability is a public health necessity, and cannabinoids are a promising drug class for this purpose. More than 80% of medicinal cannabis users report pain as their primary medical indication, and they report experiencing minimal psychoactive effects. However, there are few well-controlled human laboratory studies assessing cannabis' efficacy for pain in the context of abuse, and even less is known regarding the effects of daily repeated use of cannabis on pain and its relationship to abuse liability. Carefully controlled research is needed.

The proposed randomized, within-subjects, placebo-controlled 16-day crossover inpatient human laboratory study (N = 20 healthy cannabis users; 10 men, 10 women) will address three important gaps in our understanding of the potential therapeutic utility of cannabis for pain: 1) Does tolerance develop to repeated, daily smoked cannabis administration on measures of experimental pain and abuse liability; 2) If so, is tolerance reversed during the 7 days of abstinence from active-THC cannabis; 3) Does abrupt abstinence from active cannabis increase experimental pain sensitivity, i.e. hyperalgesia, relative to baseline, and do these effects parallel measures of cannabis withdrawal such as disrupted mood and sleep?

Two distinct modalities of experimental pain will be assessed: The Cold Pressor Test (CPT) and Quantitative Sensory Testing Thermal Temporal Summation (QST-TTS). Throughout the study, experimental pain and abuse-related effects will be assessed, as will sleep and subjective mood assessments.

Study Overview

• Status: Suspended
• Conditions: Pain; Cannabis; Hyperalgesia; Tolerance
• Intervention / Treatment: Drug: Placebo Cannabis; Drug: Active Cannabis

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • New York State Psychiatric Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Males/non-pregnant females, 21-60 years old
• Current cannabis user
• Able to perform all study procedures

Exclusion Criteria:

• Use of other illicit drugs
• If medical history, physical and psychiatric examination, or laboratory tests performed during the screening process reveal any significant illness that the study physician deems contraindicated for study participation
• Insensitivity to the cold-water stimulus of the Cold Pressor Test or the heat stimulus of Quantitative Sensory Testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose A: Standardization Phase; On the first full inpatient day (Day 1), participants smoke one specified strength (Dose A; 75% of two 6.58% cannabis cigarettes) of cannabis at three timepoints.	Drug: Active Cannabis; 6.58% THC + <0.01% CBD cannabis (in one cigarette)
Placebo Comparator: Dose B: Placebo Phase; On Days 2-8, participants smoke a second strength (Dose B; 75% of two < 0.01%THC:CBD cannabis cigarettes) of cannabis will be administered 3x/day.	Drug: Placebo Cannabis; <0.01% THC:CBD cannabis.
Experimental: Dose A: Active Phase; On Days 9-15, cannabis Dose A will be administered again (75% of two 6.58% cannabis cigarettes) at three timepoints each day.	Drug: Active Cannabis; 6.58% THC + <0.01% CBD cannabis (in one cigarette)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Cold Pressor Test (CPT) latency	The CPT apparatus consists of two refrigerated circulators, filled with warm (36.5-37.5°C). participants will complete the CPT 30 minutes before the 1000h cannabis administration (baseline), and 0, 15, 30, 45, 60, and 90 minutes post-cannabis administration. and cold (3.5 - 4.5°C) water. Participants will insert their non-dominant hand into the warm water and remove it after 3 minutes; skin temperature of the thumb pad will be measured. Participants will then insert their hand in the cold water and will be instructed to report when they first experience pain (pain threshold) and remove their hand when the cold water can no longer be tolerated (pain tolerance). Maximum immersion time will be 3 minutes. Repeats on days 1, 2, 5, 8, 9, 12, and 15.	Up to 15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quantitative Sensory Testing-Thermal Temporal Summation (QST-TTS) ratings	The QST-TTS apparatus is a thermal testing analyzer with a 30 x 30 mm Peltier thermode, which will use repetitive nociceptive heat stimulation of a fixed frequency and intensity. At the beginning of the procedure, a research assistant (same gender as the participant) will read a script describing the procedure to the participant. Tonic noxious heat stimulation will be applied to the palm using a ramp-and-hold method, in which the baseline temperature will be set at 32.0°C, and will increase at a rate of 1°C/s up to 46.5°C, remaining constant for 120 sec. During the total duration of stimulation (135 seconds), participants will continuously rate the magnitude of perceived pain using a visual analog scale. participants will complete the CPT 30 minutes before the 1000h cannabis administration (baseline), and 0, 15, 30, 45, 60, and 90 minutes post-cannabis administration. Repeats on days 1, 2, 5, 8, 9, 12, and 15.	Up to 15 days
Change in Cannabis Rating Form (CRF) ratings	Participants rate the strength, liking, desire to take again, good drug effect and bad. 7x on each of drug effect of cannabis on a 100mm visual analog scale. Repeats on days 1, 2, 5, 8, 9, 12, and 15.	Up to 15 days

Collaborators and Investigators

• Sponsor: New York State Psychiatric Institute
• Collaborators: National Institute on Drug Abuse (NIDA)

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2021
• Primary Completion (Actual): August 31, 2024
• Study Completion (Estimated): October 31, 2026

Study Registration Dates

• First Submitted: October 16, 2020
• First Submitted That Met QC Criteria: October 16, 2020
• First Posted (Actual): October 22, 2020

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 6, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Sensation Disorders; Somatosensory Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Marijuana Abuse; Hyperalgesia
• Other Study ID Numbers: 8058; R21DA050752 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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