Raynaud Syndrome Associated with Medication for Attention-Deficit/Hyperactivity Disorder: A Systematic Review (Besag, Vasey, 2025)

Besag FMC; Vasey MJ; Roy S; Cortese S; 

CNS drugs [CNS Drugs] 2025 Mar; Vol. 39 (3), pp. 213-241. Date of Electronic Publication: 2025 Jan 29.

Available online at this link

Background: Raynaud syndrome (RS) is a peripheral vasculopathy characterised be impaired acral perfusion typically manifesting as skin discolouration with pallor, cyanosis and/or erythema, and increased sensitivity to cold. RS may be primary or secondary to systemic disease, lifestyle and environmental factors or medication. RS has been reported with medication to treat ADHD, but we found no recent comprehensive overview of the literature. The aim of this review is to evaluate the evidence in the published literature for Raynaud syndrome associated with medication for ADHD.

Methods: We systematically searched PubMed and Embase from inception to 12 June 2024 for articles published in English describing cases of RS in individuals treated with stimulant medication, atomoxetine, guanfacine or clonidine. Identified cases were assessed against the Naranjo Adverse Drug Reaction Scale criteria to determine the probability of a causal relationship with the medication.

Results: The initial search identified 197 articles. A total of 61 cases were identified from 15 case reports, 5 case series, 1 retrospective case-control study, and 1 retrospective cohort study. No randomised, controlled studies were identified. Implicated medications included methylphenidate, (dex)amfetamine and, more rarely, atomoxetine. Most cases were mild and resolved within weeks of discontinuation, dose reduction or switch to an alternative medication. A few cases associated with systemic disease were reported, leading to ulceration, gangrene and the need for amputation or revascularisation in some individuals. Assessment of 28 cases using the Naranjo criteria suggested a 'possible' causative role of ADHD medication in 13 cases, a 'probable' role in 13 cases and a 'definite' role in two cases.

Conclusions: Due to the uncontrolled nature of all but one of the available studies, a causal relationship between medication for ADHD and RS could not be determined reliably. However, in view of the possibility of severe sequelae, albeit in rare cases, routine monitoring for signs of RS is recommended in individuals treated with CNS stimulants or atomoxetine, especially when initiating treatment or increasing the dose. Large database studies in which individuals act as their own controls should be conducted to clarify any association between treatment with these medications and RS, controlling for confounding factors.
Competing Interests: Declarations. Funding: No funding was received in relation to the preparation of this manuscript. Conflicts of Interest: S.C., NIHR Research Professor (NIHR303122) is funded by the NIHR for this research project. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care. S.C. is also supported by NIHR grants NIHR203684, NIHR203035, NIHR130077, NIHR128472, RP-PG-0618-20003 and by grant 101095568-HORIZONHLTH- 2022-DISEASE-07-03 from the European Research Executive Agency. S.C. has declared reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, and from Healthcare Convention for educational activity on ADHD, and has received honoraria from Medice. S.C. is an Editorial Board member of CNS Drugs. S.C. was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. The other authors declare that they have no conflicts of interest. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent to Publish: Not applicable. Availability of Data and Material: Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Code Availability: Not applicable. Authors Contributions: The authors contributed equally to the drafting of the review text. The primary literature search and article screening was conducted by F.B. and M.V. S.R. and M.V. conducted the Naranjo assessment with mediation provided by F.B. All authors read and approved the final manuscript and agree to be accountable for the work presented.