# 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

## TL;DR

This study finds that tetrahydrocannabinol (THC) reduces chronic pain in fibromyalgia patients by enhancing a specific pain modulation mechanism called offset analgesia.

## Contribution

The study is the first to compare THC's effects on offset analgesia and conditioned pain modulation in fibromyalgia.

## Key findings

- THC significantly reduced spontaneous pain in fibromyalgia patients compared to placebo.
- THC enhanced offset analgesia but had no effect on conditioned pain modulation.
- Baseline offset analgesia predicted THC-induced pain relief, suggesting its role as a biomarker.

## Abstract

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.

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.

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).

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.

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.

The online version contains supplementary material available at 10.1186/s42238-025-00348-x.