A Report of Two Cases of Sexual Side Effects with OROS Methylphenidate

Case 1

A 15-year-old-boy was brought in for attention problems and forgetfulness. He was given a diagnosis of ADHD and borderline mental capacity. He was started on immediate release (IR) MPH (Ritalin) 10–30 mg/day in a divided dosage. Although he tolerated medication generally well, with some headache and nausea initially, his attention problems showed only mild improvement and he reported forgetting taking his medication. We then switched to OROS MPH 18 mg/day after 1 month. He tolerated medication generally well, but reported some emotional side effects (such as a sense of nervousness in the chest and occasional emotional numbing). His attention problems showed no further improvement during the next month, thus we aimed to increase OROS MPH to 36 mg/day. However, he refused increasing the dosage due to a reason that he had not reported previously. Upon questioning, he stated that he started to have erections up to ten times in a day after OROS MPH treatment. They were spontaneous, unrelated to sexual stimuli, painless, without ejaculations, and lasting 5–10 minutes. They were usually complete erections that started within a few hours after taking the medication and happened mostly during the day. He did not report increased sexual arousal or hypersexual behaviors. He denied the use of any substances. His sexual development was within normal limits, and he did not report similar erections before or during IR MPH treatment at all. He was concerned that his friends at school or other people would recognize his erections.

Afterward we negotiated an increase of his medication to 36 mg/day following 1 week of a medication-free period. During this period, he reported that he had erections for two times that were related to sexual stimuli or his sexual fantasies. However, his erections reemerged on the first day of OROS MPH 36 mg/day treatment with a longer duration compared with OROS MPH 18 mg/day. They persisted during the next 3 weeks of follow up. Erections did not happen on drug-free Sundays. He reported some headache and nausea during treatment with OROS MPH 36 mg/day. He also reported the same emotional side effects that occurred with OROS MPH 18 mg/day.

We concluded that this could be an OROS MPH-related side effect. Although his attention problems showed further improvement, we discontinued medication due to the socially and physically distressing nature of this side effect, and his erections disappeared during the following days.

Case 2

An 8-year-old boy with a weight of 21.5 kg was diagnosed with ADHD combined type with normal intellectual capacity. He was started on OROS MPH 18 mg/day. His symptoms showed much improvement in the ADHD scales. However, he reported loss of appetite, headache, abdominal pain, and sleep problems. He developed conjunctival injection after 10 days of treatment. While headache and abdominal pain almost completely disappeared after a week, sleep and appetite problems and the conjunctival injection persisted. He also started to display some hypersexual behaviors that he did not display before (such as touching his mother's or other women's genitalia, kissing young girls, and touching his penis frequently). The mother reported erections in the morning before he took his medication that lasted almost 1 hour. They were painless and resolved spontaneously or sometimes after urination. The mother and child did not report erections during the day after taking medication. The child was drug free on Sundays, and the mother reported that hypersexual behaviors almost disappeared during this day; the child did not have erections on the following morning. He did not have any new onset of symptoms suggestive of a manic or hypomanic episode.

Due to the sleep and appetite problems (he lost 1.5 kg within 2 months) and possible sexual side effects, we switched to IR MPH 10–20 mg/day. Morning erections and hypersexual behaviors decreased dramatically and his sleep and appetite problems improved mildly with IR MPH. However, his ADHD symptoms worsened, and the mother reported possible withdrawal symptoms (increased irritability and hyperactivity, getting tearful easily) after several hours of each dosage. We did not observe conjunctival injection with IR MPH. We then decided to switch OROS MPH 18 mg/day after 3 weeks. With OROS MPH 18 mg/day, the mother reported next-morning erections with an obvious increase in hypersexual behaviors during day after taking medication. Hypersexual behaviors almost disappeared on the drug-free day, and morning erections did not occur at the next morning. He was awaking between 8–9 a.m. and taking his medication between 9 and 10 a.m. The mother reported that erections usually started 20–30 minutes before awaking and lasted 30–40 minutes after awaking.

We instructed the mother to give OROS MPH 18 mg/day at 6 a.m. without totally awaking the child or letting the child go to sleep after taking medication. The child was able to sleep after taking medication, and the mother reported that erections did not occur during sleep or after awaking, but hypersexual behaviors during day continued. We did this trial for 4 days, and he did not have morning erections at all. However, his sleep and appetite problems persisted, and he developed conjunctival injection and a sense of pins and needles in his legs after 10 days of OROS MPH 18 mg/day. Routine pediatric and ophthalmologic examinations did not reveal any significant problems.

We decided to stop MPH treatment due to the side effects. The patient's morning erections and hypersexual behaviors disappeared during the next days of discontinuation.

Discussion

The three stages of the psychopharmacology of the human sexual response and their neurotransmitters involved are: Stage 1, libido, at which dopamine exerts a positive influence. Stage 2, arousal, correlates with erections in men. Both nitric oxide and acetylcholine facilitate sexual arousal, and dopamine may facilitate erection. Stage 3, orgasm, which is associated with ejaculation in men, is inhibited by serotonin and facilitated by norepinephrine (Stahl 2002).

Several researchers have found a significant association between stimulant abuse and increased sexual arousal or risky sexual behaviors that have been implicated as a contributing factor in the human immunodeficiency virus (HIV) epidemic among gay populations (Worth and Rawstorne 2005; Koblin et al. 2007; Volkow et al. 2007). However, psychopharmacological mechanisms of stimulant-related hypersexual behaviors or increased sexual arousal are not well documented. Several possible mechanisms mainly related to dopamine and norepineprine have been suggested. Stimulants may increase sexual libido via increasing dopamine in the mesolimbic–mesocortical system, which regulates sexual libido (Melis and Argiolas 1995; Stahl 2002) or they may facilitate penile erection via increasing dopamine, which activates paraventricular oxytocinergic neurons in the hypothalamus and induces penile erection (Argiolas and Melis 2005). Moreover, it has been known that dopamine-enhancing medications, such as anti-parkinsonian drugs, may increase sexual libido and facilitate penile erection (Argiolas and Melis 2005; Klos et al. 2005; Shapiroa et al. 2006). A common side effect for antipsychotic medications (dopamine receptor antagonists) is a reduction of sexual desire (Compton and Miller 2001). It is likely that while central noradrenergic effects of MPH may contribute to its sexual arousal effects, peripheral noradrenergic effects may facilitate ejeculation (Giuliano and Rampin 1999; Rampin 1999). Finally, it has been suggested that facilitation of risky sexual behaviors during intoxication with stimulants could result from impairment in self-control (disinhibition) (Volkow et al. 2007).

Despite all potential explanations, the psychopathological mechanisms of multiple erections, with or without hypersexual behaviors, related with MPH treatment in young subjects remain unclear and warrants further investigation. In our cases, the relationship between erections—with or without hypersexual behaviors—and OROS MPH treatment was clear enough to suggest a causality. Erections, with or without hypersexual behaviors, emerged with OROS MPH treatment and almost disappeared after discontinuation in repeated trials. However, the timing of erections with OROS MPH treatment was different in both cases. While case 1 developed erections during the day after taking medication, case 2 developed erections in the morning before taking medication. Emergence of morning erections before taking medication and disappearance with OROS MPH given at 6 a.m. in case 2 may suggest that erections could result from OROS MPH withdrawal. It may be important to note that erections did not occur with IR MPH withdrawal in this case. This may be consistent with the previous report of stuttering priapism associated with withdrawal from OROS MPH (Schwartz and Rushton 2004). These authors reported that approximately 5–10 painful erections occurred on the drug-free day, with occasional additional erections occurring during the weekday mornings as well.

However, there seem to be two common points for both cases. First, while erections, with or without hypersexual behaviors, were associated with OROS MPH treatment, IR MPH did not cause such side effects in both cases. It may be an interesting observation that although MPH has been used for many years, the reports of MPH-related erections and/or hypersexual behaviors are rare and have been published for the last few years. This may be related to the fact that such side effects may be more likely to happen with OROS MPH treatment, which has been in use more recently. Another common point could be that both subjects developed some unusual side effects (such as erections, hypersexual behaviors, nervousness, emotional numbing, conjunctival injection, and pins and needles in legs) along with few usual side effects. This may raise a question of whether sexual side effects of MPH are more likely to happen together with other unusual side effects.

In conclusion, clinicians should be aware of the possible sexual side effects of stimulant medications because this may be important for patient compliance. More research is warranted regarding psychopharmacological mechanisms of MPH-related hypersexual behaviors and erections.