To the Editor: Nausea and anxiety are common side effects of modafinil. Palpitations are common at higher doses when increased dosing is not performed (1), but a lower dose of 400 mg without increase has been tolerated in cocaine-dependent subjects (2). We report the case of a possible interaction between modafinil and the consumption of free glutamate.
“Mr. B,” a 40-year-old African American man with a 16-year history of cocaine use, was participating in an inpatient research study. He had no significant medical history, was not receiving any medication, was abstinent from cocaine use for 6 days, and had unremarkable physical and laboratory examinations.
On days 1 and 2 of the study, he received modafinil, 400 mg, at 7:30 a.m. He reported mild anxiety (1 on a 0- to 3-point scale), mild nausea, and a strong but not fast heartbeat (pulse: 68–82; blood pressure:120–140/80–90), which began 30 to 60 minutes after dosing on both days. These symptoms resolved within 8 hours, and on day 2, at 9:00 p.m., he rated his anxiety and nausea as 0. From approximately 10:30 to 11:00 p.m. on day 2, he ate a large meal of take-out food, including substantial soy sauce and other free-glutamate containing foods, with a total free-glutamate content estimated at 3 to 7 grams of monosodium glutamate equivalent (3, 4) or approximately 10 times the typical Western daily consumption (4, 5). According to his own recollection as well as that of his wife, he had eaten similarly from the same restaurant at least three times during the past year without incident and had no known sensitivity to monosodium glutamate. Thirty minutes after he finished eating, he reported sleeplessness, chest tightness, nausea (moderate), anxiety (moderate), and a pounding but not fast heartbeat, and he appeared severely anxious and in significant distress to the staff. His vital signs were unremarkable (blood pressure:136/84; pulse 84). He was transferred to the emergency department for evaluation. All symptoms subsided within 2 hours, with no electrocardiogram changes or cardiac-enzyme elevation. The patient returned to the research unit with a diagnosis of palpitations. Modafinil, 200 mg daily, was started 30 hours later and increased to 400 mg without incident after 2 days.
In our patient, the symptoms reported on the second night included the side effects he experienced earlier in the day, and in retrospect, he described them as “the same but much more intense.” The timing, however, was consistent with the spike in plasma glutamate after a glutamate-rich meal (6) and not with modafinil pharmacokinetics (4). Although in preclinical models modafinil does not increase glutamate synthesis (7), it increases brain glutamate (8), suggesting that an interaction between modafinil and the consumption of free glutamate could have caused the incident reported in our case.
1.Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O’Brien CP:A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 2005; 30:205–211
2.Stegink LD, Filer LJ, Baker GL: Plasma amino acid concentrations in normal adults ingesting aspartame and monosodium L-glutamate as part of a soup/beverage meal. Metabolism 1987; 36:1073–1079
3.Ajinomoto Food Ingredients: http://www.ajiusafood.com (2007)
4.Rhodes J, Titherley AC, Norman JA, Wood R, Lord DW: A survey of the monosodium glutamate content of foods and an estimation of the dietary intake of monosodium glutamate. Food Addit Contam 1991; 8:663–672
5.Wong YN, Simcoe D, Hartman LN, Laughton WB, King SP, McCormick GC, Grebow PE: A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol 1999; 39:30–40
6.Beyreuther K, Biesalski HK, Fernstrom JD, Grimm P, Hammes WP, Heinemann U, Kempski O, Stehle P, Steinhart H, Walker R: Consensus meeting: monosodium glutamate—an update. Eur J Clin Nutr 2007; 61:304–313
7.Perez de la Mora M, Aguilar-Garcia A, Ramon-Frias T, Ramirez-Ramirez R, Mendez-Franco J, Rambert F, Fuxe K: Effects of the vigilance promoting drug modafinil on the synthesis of GABA and glutamate in slices of rat hypothalamus. Neurosci Lett 1999; 159:181–185
8.Ferraro L, Antonelli T, Tanganelli S, O’Connor WT, Perez de la Mora M, Mendez-Franco J, Rambert F, Fuxe K: The vigilance promoting drug modafinil increases extracellular glutamate levels in the medial preoptic area and the posterior hypothalamus of the conscious rat: prevention by local GABAA receptor blockade. Neuropsychopharmacology 1999; 20:346–356
Supported by the National Center for Research Resources (PTM; K12RR17594), the National Institute on Drug Abuse (RTM; R01DA011744), and the Connecticut Department of Mental Health and Addiction Services.
The authors report no competing interests.
This letter (doi: 10.1176/appi.ajp.2007.07040717) was accepted for publication in August 2007.