Supplementary Material for: Synthetic cannabinoid withdrawal: A systematic review of case reports

Abstract
Introduction: Synthetic cannabinoids are novel psychoactive substances with potential for abuse and severe withdrawal symptoms. Despite widespread use, research on withdrawal is limited. We conducted a systematic review of case reports describing SC withdrawal symptoms.
Methods: Literature searches were conducted across databases, including PubMed/Medline, Scopus, EMBASE, and PsycINFO, to identify case reports from inception to March 2025. Eligible studies involved human cases with confirmed SC use and clearly described withdrawal symptoms. Study quality was assessed using the CARE guidelines checklist.
Results: N=11 eligible case reports on SC withdrawal identified. Predominantly male (82%), mean age of 28.08 (SD 7.78). Most frequent withdrawal symptoms: psychosis (n=9), agitation/irritability (n=8), nausea/vomiting (n=6), seizures (n=5), tachycardia (n=4), and insomnia (n=3). Rarer effects like delirium, rhabdomyolysis, and auditory/visual hallucinations were also documented. Symptoms emerged within 24-48 hours (62%) and resolved within one week. Case report quality was variable, with an average of 8 out of 13 CARE checklist items reported.
Conclusion: SC withdrawal manifests with a broad spectrum of physiological and psychological symptoms that can rapidly escalate and require prompt medical management in certain cases. SC withdrawal symptoms are more severe and unpredictable compared to natural cannabinoids, particularly among daily and frequent users. The findings highlight SC withdrawal as an understudied yet clinically important syndrome, necessitating further research to elucidate neurobiological mechanisms and develop evidence-based treatment protocols.