Although the rare Alice in Wonderland syndrome (AIWS) is a neurologic condition, most often associated with migraine and epileptic seizures among others, emerging research suggests it may also be linked to certain medications prescribed for neurologic, psychiatric, and other disorders.

AIWS involves distortions in how the brain perceives the body and its surroundings, including seeing objects as much larger or smaller than they really are, as well as experiencing altered time perception and sensations of levitation.

Among 87 cases of AIWS identified from a global World Health Organization (WHO) database, the strongest signal of a drug association was found with the anti-inflammatory medication montelukast.

In adults, sertraline, topiramate, and aripiprazole demonstrated strong disproportionality signals, whereas methylphenidate showed a strong signal in pediatric cases. Although 64% of cases were considered serious, recovery was documented in approximately 80% of patients.

Lead study author Diane A Merino, MD, Department of Pharmacology and Pharmacovigilance, Université Côte d’Azur, Nice University Hospital, Nice, France, noted that although the study could not show causality, she hopes it can provide some insight to other researchers, as well as to clinicians in areas such as neurology, psychiatry, emergency medicine, and pediatrics.

“When people are taking these medications and having these symptoms, they should be carefully assessed,” Merino told Medscape Medical News.

The findings were published online on December 21 in Psychiatry Research.

Synthesizing the Literature

AIWS was named in 1955 by Psychiatrist John Todd after Lewis Carroll’s novel, in which main character Alice experiences dramatic shifts in size, becoming alternately too tall or too small.

Notably, patients with AIWS typically retain insight, recognizing that distortions in size, time, or body perception are not real — a feature that helps distinguish the condition from psychosis, where insight is often impaired.

Although a 2023 study showed that only about 200 cases of AIWS have ever been reported, its core symptoms are likely underrecognized and may overlap with other conditions, particularly migraine with aura, the investigators noted.

Initially linked to migraine and epileptic seizures, AIWS has since been associated with a wider range of triggers, including infections, tumors, and both illicit and prescription medications.

For the current study, the investigators examined reports of medication-associated AIWS in the WHO’s global pharmacovigilance database, VigiBase, with particular attention to differences by age.

“We aimed to synthesize the literature and collect the greatest number of cases” to look for possible associations with certain medications, said Merino.

After scanning data up to December 2024, the researchers identified 87 cases of AIWS, which occurred in 26 pediatric patients (mean age, 7 years; 58% boys) and 45 adult patients (mean age, 41 years; 78% women). The US accounted for the largest share of reported cases (37%), followed by the United Kingdom (11.5%) and Spain (9%).

The study used “disproportionality analysis” for reports of AIWS and used information component (IC) to express disproportionality signals.

Need for Greater Clinical Awareness

In terms of absolute number of reports, COVID vaccines accounted for the largest share of AIWS reports (19.5%), followed by montelukast (11.5%) and aripiprazole (9.2%). However, when signal strength was considered, montelukast showed the strongest association with AIWS across adult and pediatric patients (IC, 4.2), whereas COVID vaccines did not demonstrate a significant signal (IC, 0.6).

In pediatric cases, montelukast showed the strongest AIWS signal (IC, 3.2), followed by methylphenidate (IC, 2.3). Among adults, strong signals were identified for sertraline (IC, 3.4), topiramate (IC, 3.1), montelukast (IC, 2.7), and aripiprazole (IC, 2.1).

Among the 64.4% of AIWS cases classified as serious, 17.2% involved adverse drug reactions that led to hospitalization, and 2.3% were life-threatening. Among the 54 reports that included outcome information, 79.6% of patients were reported to have recovered or to be recovering from AIWS.

The investigators noted that the associations between AIWS and montelukast, aripiprazole, sertraline, and topiramate were consistent with prior case reports, and advised clinicians to consider AIWS when visual distortions occur during treatment with these medications.

“While typically reversible, AIWS warrants clinical awareness and careful risk-benefit assessment,” they wrote.

However, the researchers emphasized that the study did not establish causality and that additional population-based studies are needed to confirm these findings.

Recognize and Inquire

Commenting on the study for Medscape Medical News, Hope O’Brien, MD — adjunct associate professor of neurology at Morehouse School of Medicine, Atlanta, and medical director of the Headache Center of Hope, Cincinnati — described the research as a “thoughtful analysis” and noted that 80% of patients recovered after the suspected medication was withdrawn.

“Importantly, the authors were framing the findings as hypothesis generating, rather than causal — which is crucial given the inherent limitations of spontaneous-reporting databases. This is an exploratory study,” said O’Brien, who was not involved in the research.

“However, the consistency of signals across age groups and drug classes suggest that certain medications may act as potential triggers for Alice in Wonderland Syndrome in susceptible individuals,” she added.

O’Brien emphasized that “the key message is recognition and inquiry,” urging clinicians to specifically ask about potential AIWS symptoms when patients are taking these medications.

She noted that patients often do not volunteer these symptoms unless asked directly, underscoring the need for clinicians to raise the issue when visual distortions are suspected and to consider alternative medications if AIWS symptoms emerge.

She added that involving a patient’s family is also important, as the symptoms — while typically transient and reversible — can be distressing and, in some cases, lead to severe consequences requiring hospitalization.

Although AIWS is rare, O’Brien noted that as a headache specialist, she has seen patients with symptoms of AIWS, especially in those with migraine with aura.

Overall, the primary implication from the study is improved awareness so that AIWS “is recognized, documented, and then managed appropriately when it does occur,” O’Brien concluded.

The investigators and O’Brien reported no relevant financial relationships.