Visual Hallucinations with Methylphenidate and Acetaminophen in Combination

To The Editor:

Stimulants, such as methylphenidate (MPH), are used as first-line treatment for children with attention-deficit/hyperactivity disorder (ADHD), and their safety and efficacy are well established in this age group. They result in few, generally mild, adverse effects, including decreased appetite, sleep disturbance, and abdominal pain (Wilens et al. 2003). Tactile, visual, and auditory hallucinations have been reported in patients with ADHD during treatment with MPH at therapeutic doses (Gross-Tsur et al. 2004; Porfirio et al. 2011). These are described as rare, usually of acute onset, brief, and resolving within a few days after discontinuation of the medication (Ross 2006).

Acetaminophen is the most widely used analgesic and antipyretic medicine. Similarly, there are reports on psychotic symptoms developed during acetaminophen use (Servis and Connolly 1997; Carnovale et al. 2013). Here, we describe a pediatric patient who had visual hallucinations during the concurrent use of acetaminophen and MPH.

Case Report

A 6-year-old boy was brought to our outpatient clinic by his mother, with complaints of hyperactivity, temper tantrums, and aggressive and oppositional behaviors. He also had poor listening ability, and inattention problems. These symptoms were evident both at school and at home. His developmental history and intellectual capacity were within normal limits. He had no history of depressive, manic, and psychotic symptoms. His family history was negative for mood disorders and psychosis. According to the psychiatric assessment, he was diagnosed with ADHD and oppositional defiant disorder. Treatment with immediate release-MPH (IR-MPH) (5 mg b.i.d.) was commenced. Four weeks later, his mother reported partial improvement in his symptoms, and we decided to discontinue IR-MPH and start OROS-MPH at a dose of 18 mg/day. During the 3rd week of OROS-MPH treatment, the patient's mother reported significant improvement in his behaviors, and the only side effect was poor appetite.

Two months after the initiation of OROS-MPH, the patient's mother reported that he had developed new symptoms, including a high level of anxiety, fearfulness, and unwillingness to leave his parents and to stay alone. He described experiencing visual hallucinations, which included seeing adults walking around his bedroom. He refused to enter his room and sleep in his own bed. During these hallucinations, he was aware of the time, place, and people around him. His mother told us that those symptoms had begun 1week earlier, when he also started acetaminophen suspension (120 mg/day) after a flu-like illness. Because there were no such symptoms during OROS-MPH monotherapy, we decided to cease acetaminophen. The hallucinations resolved upon discontinuation of acetaminophen, and within a week the patient returned to sleep in his room. OROS-MPH was continued because of its positive effect on his behavioral and attentional problems. There was no recurrence of hallucinations on OROS-MPH treatment during a follow-up period of 6 months.

Discussion

There are some reports of hallucinations associated with MPH (Gross-Tsur et al. 2004; Porfirio et al. 2011), and with acetaminophen (Servis and Connolly 1997; Carnovale et al. 2013). However, there is no report on hallucinations with the combination of both. In our case, visual hallucinations developed during OROS-MPH and acetaminophen administered in combination, began shortly after starting acetaminophen, and resolved promptly after acetaminophen cessation. OROS-MPH monotherapy did not cause any hallucinations during the 6 month follow-up period. We can assume that OROS-MPH was not the causative agent alone. However, we did not re-challange with acetaminophen because of ethical considerations. Therefore, it remains unclear whether the causative agent was acetaminophen itself or combination of MPH and acetaminophen

The prevalence of hallucinations as a side effect of stimulants is not frequent, but not rare (Wilens et al. 2003; Ross 2006). Although the mechanism is unclear, the occurrence of hallucinations with MPH might be explained by the increased synaptic dopamine concentrations in the brain. In the literature, there are several cases of psychotic symptoms, including auditory and visual hallucinations, and paranoid delusions related to the administration of acetaminophen (Servis and Connolly 1997). It inhibits prostaglandin synthesis, and prostaglandin reduces the level of dopamine, which is suggested as a possible explanation for acetaminophen-induced psychosis. In our reported case, we speculate that acetaminophen and MPH in combination caused excessive levels of dopamine in the brain. The combination of MPH and acetaminophen might increase its blood levels as well, thus increasing the propensity for side effects. However, in our case, at this point the mechanism of acetaminophen–MPH combination-related hallucinations remains unclear.

MPH is established as an effective and safe treatment for ADHD. However, at therapeutic doses, it can cause psychotic symptoms in a small proportion of children under treatment. Clinicians should be aware of this rare adverse effect, especially when MPH is combined with other drugs.