The impact of tetrahydrocannabinol on central pain modulation in chronic pain: a randomized clinical comparative study of offset analgesia and conditioned pain modulation in fibromyalgia
Yara Agbaria 1 2 3 4, Raz Preger 4, Valerie Aloush 1, Jacob N Ablin 1, Haggai Sharon # 5 6 7 8, Giris Jacob # 9 10 11
- 1School of Medicine, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
- 2J. Recanati Autonomic Research Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
- 3Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
- 4Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
- 5School of Medicine, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. haggaisharon@gmail.com.
- 6Institute of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. haggaisharon@gmail.com.
- 7Sagol Brain Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. haggaisharon@gmail.com.
- 8Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. haggaisharon@gmail.com.
- 9School of Medicine, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel. jacob.giris@gmail.com.
- 10J. Recanati Autonomic Research Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. jacob.giris@gmail.com.
- 11Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. jacob.giris@gmail.com.
Affiliationer
Background: Tetrahydrocannabinol (THC) has shown efficacy in alleviating chronic pain, particularly in disorders characterized by central sensitization. Offset analgesia (OA) and conditioned pain modulation (CPM) are key biomarkers used to evaluate central pain modulation. This study aimed to compare the effects of THC on OA and CPM in fibromyalgia syndrome (FMS), a prototypical condition of central sensitization.
Methods: In a randomized, double-blind, placebo-controlled crossover design, 23 FMS patients participated in two experimental sessions. Each session included the McGill Pain Questionnaire, visual analogue scale (VAS) assessments, and evaluations of OA and CPM, conducted both before and after sublingual administration of either THC (0.2 mg/kg) or placebo.
Results: THC significantly reduced spontaneous pain ratings on the McGill scale compared to both baseline and placebo (P = 0.01 and P = 0.02, respectively). THC also significantly enhanced OA relative to baseline and placebo (P = 0.04 and P = 0.008), while no effect was observed on CPM (P = 0.27). Notably, baseline OA magnitude significantly predicted THC-induced pain relief (R² = 0.404, P = 0.003), whereas CPM did not show a significant association (P = 0.121).
Conclusions: This is the first study to evaluate THC’s distinct effects on central pain modulation using both OA and CPM. THC selectively enhanced OA without influencing CPM, highlighting differential neural mechanisms underlying these paradigms. Furthermore, OA predicted treatment response, suggesting its potential as a biomarker for personalized cannabinoid-based therapies in FMS and other central sensitization disorders.
Trial registration: The study was prospectively registered on ClinicalTrials.gov (ID: NCT05644054) at 1.1.2023. Further details can be found at: https://clinicaltrials.gov/study/NCT05644054?locStr=Israel&country=Israel&cond=fibromyalgi215a%20&intr=THC&aggFilters=status:not%20rec&rank=1.
Supplementary Information: The online version contains supplementary material available at 10.1186/s42238-025-00348-x.
Keywords: Central sensitization; Conditioned pain modulation; Fibromyalgia; Offset analgesia; Pain relief; Tetrahydrocannabinol.
