Emerging preclinical evidence supports a potential role for cannabidiol in the management of sickle cell disease.

Sickle cell disease (SCD) imposes a substantial global health burden, with acute and chronic pain representing a major component of morbidity. Standard pain management, largely opioid-based, carries significant risks and often provides inadequate long-term relief, highlighting an unmet need for alternative analgesics as well as disease modifiers. Medicinal cannabinoids have analgesic and anti-inflammatory properties; most clinical studies so far have used Δ9-tetrahydrocannabinol (THC)-containing products with conflicting outcomes. In contrast, purified cannabidiol (CBD) has a broader spectrum of action beyond the endocannabinoid system, lacks psychoactive effects and associated long-term risks, allows safe dose optimization and can be prescribed legally in many settings. Here, we review evidence for CBD's potential analgesic and disease-modifying properties for the management of SCD. Pain in SCD arises from local tissue inflammation and neuroinflammation, compounded by abnormal pain modulation and pro-nociceptive central nervous system alterations. CBD may attenuate the pathophysiological processes of SCD by modulating pro-inflammatory immune pathways, reducing oxidative stress and suppression of neurogenic inflammation. CBD also has a direct inhibitory effect on afferent nociceptive pathways. Furthermore, CBD has an important pain-modulating role by suppressing excitatory mechanisms in the dorsal root ganglia and central nervous system. Additionally, CBD may modulate pain-processing brain networks and attenuate opioid-induced reward-seeking behavior. Although human data are very limited, emerging preclinical findings and early reports on patients offer cautious optimism for CBD as a therapeutic option with potential disease-modifying properties in SCD. Clinically meaningful benefits may be expected in specific subgroups of patients, identifiable through well-designed clinical and mechanistic studies focused on pain processing and neuroinflammation.