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The research aims to assess the effectiveness of cannabinoids in managing phantom limb pain in a rat model.

March 28, 2026Medical Cannabis and Cannabinoids0 citationsOpen Access

Targeting Phantom Limb Pain with Cannabinoids in a Rat Model

AEAnjalika EeswaraUniversity of Miami KPKristin PerrucciUniversity of Miami SJStanislava JergováUniversity of Miami

Key Points

The research aims to assess the effectiveness of cannabinoids in managing phantom limb pain in a rat model.
Chronic constriction injury to simulate pre-amputation pain
Formalin-induced inflammation to mimic localized pain
Administration of cannabinoids either preemptively or after pain onset
Assessment of pain behaviors over 72 days
Evaluation of spinal cytokine levels and glial reactivity
Preemptive THC or CBD/BCP reduced onset and severity of phantom limb pain
Delayed treatments with CBD/BCP and CBD/BCP/THC effectively mitigated pain
Pain reduction was linked to improved spinal GABAergic inhibition
All treatments decreased microglial and astrocyte reactivity
Cytokine levels shifted towards an anti-inflammatory state

Abstract

Introduction: Phantom limb pain (PLP) is a debilitating neuropathic condition arising after limb loss or nerve injury, with limited effective treatments. Cannabinoids, including cannabidiol (CBD), β-caryophyllene (BCP), and Δ⁹-tetrahydrocannabinol (THC), possess analgesic and anti-inflammatory properties. This study evaluated their combined efficacy as preventive or delayed interventions in a rodent model of PLP. Methods: To model phantom limb pain, a chronic constriction injury was used to mimic pre-amputation pain, followed by formalin-induced localized inflammation and complete sciatic nerve transection to simulate extremity amputation. Cannabinoid treatments (CBD/BCP/THC, CBD/BCP, or THC) or vehicle control were administered either preemptively on the day of axotomy (prevention paradigm) or after the emergence of pain behaviors (reversal paradigm). Progression of pain behaviors were assessed over a 72-day period, and modulation of spinal cytokine levels, glial reactivity, and GABAergic signaling were evaluated. Results: Preemptive THC or CBD/BCP reduced PLP onset and severity, while the full combination was less effective. In contrast, with delayed treatment, CBD/BCP and the CBD/BCP/THC combination were most effective in mitigating PLP. Pain reduction was correlated with restoration of spinal GABAergic inhibition. All cannabinoid treatments decreased microglial and astrocyte reactivity and shifted cytokines toward an anti-inflammatory state. Conclusion: Cannabinoid-based interventions demonstrate significant therapeutic promise for PLP, showing efficacy as both early and delayed treatments. Findings suggest that THC may exert greater therapeutic effects when administered pre-emptively, while CBD and BCP may offer greater therapeutic advantages in established pain states. These findings highlight the therapeutic potential of tailored cannabinoid interventions for neuropathic pain and underscore the importance of optimizing dosing strategies for maximal analgesic effect.

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