Cannabis, Hyperalgesia, Pain, Tolerance
Conditions
Brief summary
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. These patients tend to seek products that are low in delta-9-tetrahydrocannabinol (THC; the primary psychoactive, and thus intoxicating, component of cannabis), and high in cannabidiol (CBD), a cannabinoid that purportedly has therapeutic benefit for pain but does not produce intoxicating effects. However, there are few well-controlled human laboratory studies assessing the efficacy of high-CBD cannabis 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. The proposed randomized, within-subjects, placebo-controlled 16-day crossover inpatient human laboratory pilot study (N = 16 healthy cannabis users; 8 men, 8 women) will address important gaps in our understanding of the potential therapeutic utility of cannabis for pain: 1) If repeated cannabis use can result in hyperalgesia; 2) If tolerance to the analgesic and abuse-related effects of cannabis develops and is reversible. Two distinct modalities of experimental pain will be assessed: The Cold Pressor Test (CPT) and Quantitative Sensory Testing Thermal Temporal Summation (QST-TTS), and participants will smoke cannabis 3x/day. Throughout the study, experimental pain and abuse-related effects will be assessed, as will sleep and subjective mood assessments. This protocol is currently suspended due to the NYSPI human subjects research pause and results cannot currently be analyzed and posted. Upon un-suspension, we will analyze the data and post results immediately.
Interventions
DRUGActive Cannabis
2.98% THC:4.91% CBD cannabis.
DRUGPlacebo Cannabis
\<0.01% THC:CBD cannabis.
Sponsors
Alkermes, Inc.
New York State Psychiatric Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
Participants are blind to what cannabis dose they are receiving on which day, though it is the same for all: Day 1: active cannabis (2.98% THC and 4.91% CBD) Day 2-8: placebo cannabis (\<0.01% THC, CBD) Day 9-15: active cannabis (2.98% THC and 4.91% CBD)
Intervention model description
This study comprises a 16-day inpatient stay. On the first full inpatient day (Day 1), participants will smoke one specified strength (Dose A; active cannabis, 2.98% THC and 4.91% CBD) of cannabis. Days 2-8 will comprise Phase 1, in which a second strength (Dose B; placebo cannabis, \<0.01% THC,CBD) of cannabis will be administered 3x/day. The next 7 days (Day 9-15) will be Phase 2, in which cannabis Dose A (active cannabis, 2.98% THC and 4.91% CBD) will be administered once again, at the same 3 daily time points.
Eligibility
Sex/Gender
ALL
Age
21 Years to 60 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cold Pressor Test (CPT) Latency | Up to 15 days | 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 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. Data points reported here represent Percent Change in Pain Tolerance from Day 1 (first timepoint, 15 minutes post-cannabis \[2.98% THC / 4.91% CBD\]) across study days (Day 2, 5, 8, 9, 12, and 15). Other timepoints are not reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cannabis Rating Form (CRF) Ratings | Up to 15 days | Participants rate the high experienced as a result of cannabis administration on a 100mm visual analog scale. Data points represent Percent Change from Day 1 (first timepoint, 15 minutes post-cannabis \[2.98% THC / 4.91% CBD\]) across study days (Day 2, 5, 8, 9, 12, and 15) Repeats at days 1, 2, 5, 8, 9, 12, and 15. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited between June 2021 and June 2023. Eligible participants were recruited from the New York, NY area and occurred through advertisements in local newspapers, online through Craigslist, RecruitMe, and by word of mouth.
Pre-assignment details
There were no significant events in the study post-enrollment and/or prior to participants beginning study procedures.
Participants by arm
| Arm | Count |
|---|---|
| Dose A - Dose B - Dose A On the first full inpatient day (Day 1), participants smoked one specified strength (Dose A; active cannabis, 2.98% THC, 4.91% CBD) of cannabis. Days 2-8 comprised Phase 1, in which a second strength (Dose B; placebo cannabis, \<0.01% THC, CBD) of cannabis was administered 3x/day. The next 7 days (Day 9-15) comprised Phase 2, in which cannabis Dose A (active cannabis, 2.98% THC, 4.91% CBD) was administered again, at the same 3 daily time points. All participants underwent this same allocation.
Cannabis: Investigates two strengths of cannabis. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Dose A - Dose B - Dose A |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment United States | 5 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 4 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
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 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. Data points reported here represent Percent Change in Pain Tolerance from Day 1 (first timepoint, 15 minutes post-cannabis \[2.98% THC / 4.91% CBD\]) across study days (Day 2, 5, 8, 9, 12, and 15). Other timepoints are not reported.
Time frame: Up to 15 days
Population: Data represents CPT Pain Tolerance for study completers (n=5) across the 15-day testing period. This is a repeated measures design, meaning that all 5 participants contributed to each timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CPT Pain Tolerance: Day 2 | Change in Cold Pressor Test (CPT) Latency | 21.40 percent change from Day 1 baseline | Standard Error 24.22 |
| CPT Pain Tolerance: Day 5 | Change in Cold Pressor Test (CPT) Latency | 10.94 percent change from Day 1 baseline | Standard Error 18.81 |
| CPT Pain Tolerance: Day 8 | Change in Cold Pressor Test (CPT) Latency | 2.07 percent change from Day 1 baseline | Standard Error 5.84 |
| CPT Pain Tolerance: Day 9 | Change in Cold Pressor Test (CPT) Latency | 15.17 percent change from Day 1 baseline | Standard Error 16.97 |
| CPT Pain Tolerance: Day 12 | Change in Cold Pressor Test (CPT) Latency | 20.06 percent change from Day 1 baseline | Standard Error 25.07 |
| CPT Pain Tolerance: Day 15 | Change in Cold Pressor Test (CPT) Latency | 30.16 percent change from Day 1 baseline | Standard Error 28.67 |
Secondary
Change in Cannabis Rating Form (CRF) Ratings
Participants rate the high experienced as a result of cannabis administration on a 100mm visual analog scale. Data points represent Percent Change from Day 1 (first timepoint, 15 minutes post-cannabis \[2.98% THC / 4.91% CBD\]) across study days (Day 2, 5, 8, 9, 12, and 15) Repeats at days 1, 2, 5, 8, 9, 12, and 15.
Time frame: Up to 15 days
Population: Data represents mean ratings for high on a 0-100mm visual analog scale, where 0 represents no high and 100 represents the maximum amount of high for study completers (n=5) across the 15-day testing period. This is a repeated measures design, meaning that all 5 participants contributed to each timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CPT Pain Tolerance: Day 2 | Change in Cannabis Rating Form (CRF) Ratings | 14.60 score on a scale | Standard Error 7.53 |
| CPT Pain Tolerance: Day 5 | Change in Cannabis Rating Form (CRF) Ratings | 9.6 score on a scale | Standard Error 7.756 |
| CPT Pain Tolerance: Day 8 | Change in Cannabis Rating Form (CRF) Ratings | 17.60 score on a scale | Standard Error 12.66 |
| CPT Pain Tolerance: Day 9 | Change in Cannabis Rating Form (CRF) Ratings | 11.20 score on a scale | Standard Error 8.16 |
| CPT Pain Tolerance: Day 12 | Change in Cannabis Rating Form (CRF) Ratings | 30.80 score on a scale | Standard Error 10.29 |
| CPT Pain Tolerance: Day 15 | Change in Cannabis Rating Form (CRF) Ratings | 42.00 score on a scale | Standard Error 18.2 |
| Day 15 Cannabis Rating Form: High | Change in Cannabis Rating Form (CRF) Ratings | 41.40 score on a scale | Standard Error 15.84 |