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J Sleep Med > Volume 20(1); 2023 > Article
Shin, Kim, Park, Park, and Cho: Pathological Gambling Disorder Associated With Modafinil Therapy in a Patient With Type 1 Narcolepsy


We report the case of a 22-year-old man with type 1 narcolepsy who experienced pathological gambling after modafinil therapy. The patient was administered with modafinil, which improved excessive daytime sleepiness (EDS). However, he experienced heart palpitations and nervousness, eventually developing gambling addiction. After six months of modafinil therapy, he engaged in various online gambling activities, leading to significant financial loss and stress. Consequently, modafinil was replaced with pitolisant, which is a potent and selective antagonist/inverse agonist of histamine H3 receptor. One month after modafinil discontinuation, EDS symptoms were well controlled with pitolisant and gambling urge was resolved. Modafinil is prescribed as a first-line therapy for treating EDS symptoms in patients with narcolepsy. However, it may cause psychiatric side effects via the dopaminergic system. Alternatively, pitolisant could be used to avoid modafinil’s psychiatric side effects in patients with narcolepsy.


Narcolepsy is a central hypersomnolence disorder characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations [1]. Type 1 narcolepsy (NT1) is diagnosed if cataplexy is present or the hypocretin level in the cerebrospinal fluid is ≤110 pg/mL; if these latter two findings are absent then type 2 narcolepsy (NT2) is diagnosed. NT1 incidence is rare (around 20–50 cases per 100,000 people), and it is caused by the complete destruction of hypocretin neurons. In comparison, the pathophysiology of NT2 is not yet fully understood because it is a heterogeneous disease. Narcolepsy is currently incurable, and its symptoms are mainly treated with medication. Modafinil, pitolisant, and solriamfetol are administered for EDS, while sodium oxybate and pitolisant are used for cases involving both EDS and cataplexy.
Modafinil is one of the first-line therapies for EDS in narcolepsy, usually administered at a dose of 100–400 mg once daily because it has a long half-life. It has been widely used since its approval by the United States Food and Drug Administration and the European Medicines Agency. Modafinil promotes wakefulness but does not treat cataplexy. Additionally, it has the advantage of a lower potential for abuse. However, it has side effects such as anxiety, headache, nausea, and insomnia [2]. Herein, we report a case of a patient with NT1 treated with modafinil and subsequently developed pathological gambling, which improved after replacing modafinil with pitolisant.


A 22-year-old man with NT1 who had uncontrolled EDS and gambling addiction symptoms was referred to the Pusan National University Yangsan Hospital. The patient, who had experienced EDS and cataplexy since the age of 12, presented with severe EDS with an Epworth Sleepiness Scale (ESS) score of 15 and reported experiencing cataplexy one to five times daily. Physical examination of the patient showed the following data: height, 178 cm; weight, 108 kg; and body mass index, 34.1 kg/m2.
Nocturnal polysomnography showed that the patient’s total sleep time was 390.5 minutes, and the sleep efficiency was 94.5%. The apnea-hypopnea index was 8.8 per hour, and the lowest oxygen saturation was 84%, indicating mild obstructive sleep apnea. Additionally, the rapid eye movement (REM) latency was 1.0 minutes, the respiratory arousal index was 1.7 per hour, the spontaneous arousal index was 24.6 per hour and the total arousal index was 26.7 per hour. The next day, the patient underwent a multiple sleep latency test. The results showed an average sleep latency of 0.9 minutes and four sleep-onset REM periods, indicating a diagnosis of narcolepsy.
At age 15, the patient was first diagnosed with NT1 at another hospital and commenced methylphenidate therapy for EDS; however, the symptoms were poorly controlled. At the age of 18, he switched to modafinil. While taking modafinil 200 mg daily, EDS improved somewhat, as evidenced by a decrease in the ESS score to 9. However, this improvement was accompanied by symptoms of palpitations, nervousness, and sensitivity.
The patient began online gambling activities on internet gambling sites, including coin flipping, baccarat, and roulette, 6 months after starting modafinil therapy. The amount of money spent on gambling, which used to be approximately US $100–200 a month, worsened in the previous year. When severe, approximately US $30,000 were lost in a month. The total cumulative loss amounted to US $70,000. The patient tried to relieve the stress and depression of everyday life through gambling. However, he lost more money, secretly transferred money from his parents’ account to make up for it, and continued gambling. After the patient’s parents discovered the patient’s gambling habits, the patient continued to gamble by borrowing money from financial institutions, but even that soon led to repeated failures. The patient tried to quit gambling but failed repeatedly. Even at school, he could not focus on his studies without gambling; consequently, his academic performance suffered. These symptoms met the criteria for severe gambling disorder diagnosed by The Diagnostic and Statistical Manual of Mental Disorders-V [3]. The patient had no history of gambling before taking modafinil or other significant psychiatric or medical history.
Brain magnetic resonance imaging showed no abnormalities or other factors that could have contributed to the pathological gambling. The authors, therefore, suspected modafinil as the cause and replaced it with pitolisant, a drug with a lower potential to cause adverse effects on impulse control.
Over 1 month, the modafinil dose was gradually reduced to 100 mg daily and replaced with pitolisant starting at 8.9 mg daily. One month later, modafinil was discontinued, and only pitolisant at a dose of 35.6 mg daily was administered.
One month after completely discontinuing modafinil, the patient reported that his EDS symptoms were well controlled with pitolisant, and he no longer had any urge to gamble.


Narcolepsy remains an incurable disorder, and treatment aims to alleviate symptoms such as EDS and cataplexy. In South Korea, modafinil and its enantiomer, armodafinil, are covered by insurance and prescribed for EDS or narcolepsy. While methylphenidate has been prescribed conventionally, pitolisant has been recently introduced and prescribed. Sodium oxybate, which is widely used in the United States and Europe, is unavailable in Korea.
Modafinil is a wakefulness-promoting agent; however, its exact mechanism of action is unclear. It is thought to reduce drowsiness by inhibiting dopamine removal through the inhibition of its transporters [4]. This is consistent with the results of preclinical tests where modafinil administration had no stimulant effects in rats with a deficiency of dopamine transporters or without D1 and D2 receptors. Modafinil increases dopamine concentrations in the cerebral cortex and caudate, which may lead to psychiatric side effects such as hallucinations, delusions, and perception disorders [2]. While unclear, previous research suggests that dopamine-related pathology may contribute to pathological gambling and other addictions [5]. Therefore, modafinil may also be associated with pathological gambling through the dopaminergic system.
There have been few reports of pathological gambling related to modafinil administration in patients with narcolepsy. George et al. [6] reported a case of a 46-year-old woman who was diagnosed with NT2 and developed compulsive gambling for 5 years after modafinil therapy at a dose of 200 mg daily. The symptoms improved within 1 month of switching to methylphenidate. Additionally, a 39-year-old man with narcolepsy had a ten-fold increase in slot machine use after modafinil therapy at a dose of 300 mg daily. The compulsive gambling symptoms improved after clomipramine administration and modafinil discontinuation [7].
Zack and Poulos [8] reported that modafinil has a bidirectional effect on patients with pathological gambling and suggested that modafinil increases gambling urges for patients with low impulsivity but decreases gambling urges for those with high impulsivity. In our case, the patient was not examined for impulsivity. Nonetheless, given that there was no history of gambling or other addictions, it can be assumed that modafinil increased gambling urges in this patient with low impulsivity.
Dopaminergic drugs are often reported to cause pathological gambling, and the latter is also mentioned as an adverse effect of levodopa and dopamine agonists, which are commonly used for treating Parkinson’s disease. D3 receptors in the mesolimbic pathway, nucleus accumbens, and olfactory tubercle are involved in motivation or reward behaviors. Hence, pathological gambling may occur when dopamine agonists excessively stimulate dopamine receptors, including D3.
Pitolisant is an effective medication for both EDS and cataplexy in patients with NT1 and NT2. It is an oral medication that acts as a potent and selective antagonist/inverse agonist of the histamine H3 receptor. The H3 histamine receptor acts as a presynaptic autoreceptor that inhibits feedback regulating histamine synthesis and release in the central nervous system. As a result, Pitolisant increases histamine synthesis and release in the hypothalamus [9]. Increased histamine concentrations in the hypothalamus are thought to contribute to regulating arousal and treating EDS and cataplexy. Comparative studies and meta-analyses have shown that pitolisant is not inferior to modafinil as a treatment for EDS [10]. Furthermore, pitolisant also has the advantage of simultaneously improving cataplexy, unlike modafinil. However, long-term, randomized controlled trials are needed to confirm whether pitolisant is an effective first-line therapy for narcolepsy.
The dose for pitolisant is mainly 4.5 mg and 18 mg worldwide, while 4.45 mg and 17.8 mg in the United States and South Korea. To treat narcolepsy symptoms, such as EDS and cataplexy, the starting dose is 8.9 mg once daily for the first week and then gradually increased to 17.8 mg once daily in the second week up to 35.6 mg once daily in the third week while monitoring the response. According to retrospective chart reviews, the common side effects of pitolisant include abdominal pain (15.4%), increased appetite (14.1%), weight gain (14.1%), headache (12.8%), insomnia (11.5%), and anxiety (9%). The patient, in this case, did not report any side effects after pitolisant administration.
According to a recent meta-analysis on the effects of drugs on patients with narcolepsy, solriamfetol showed a better ability to improve EDS than other drugs. However, it is not yet available in South Korea. Furthermore, it may be inappropriate to use solriamfetol as a replacement to avoid the side effects of modafinil because solriamfetol has a similar mechanism of dopamine and norepinephrine reuptake inhibitors, which may be related to dopamine.
Currently, the treatment for narcolepsy is lifelong medication therapy. If a patient develops pathologic gambling while taking modafinil, the drug may have an adverse effect related to dopamine. Therefore, it may be worth considering switching to a different medication. Pitolisant, which has a completely different mechanism of action, can be a good alternative in situations where other brain stimulants, such as sodium oxybate, cannot be used.


Ethics Statement
The patient provided informed consent.
Conflicts of Interest
Jae Wook Cho, a contributing editor of the Journal of Sleep Medicine, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.
Author Contributions
Conceptualization: Dong-Hyeon Shin, Jae Wook Cho. Data curation: Dong-Hyeon Shin, Sang Jun Park, Min-Gyu Park, Hyun-Woo Kim. Funding acquisition: Jae Wook Cho. Methodology: Jae Wook Cho. Supervision: Hyun-Woo Kim, Jae Wook Cho. Writing—original draft: Dong-Hyeon Shin, Jae Wook Cho. Writing—review & editing: Dong-Hyeon Shin, Jae Wook Cho.
Funding Statement
This research was supported by a grant from the Korean Health Technology R&D Project through the Korean Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI21C0852).


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