by Melissa Free, MD; Hena Choi, BA; and Ritika Baweja, MD

Drs. Free and Baweja are with Department of Psychiatry and Behavioral Health, Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania. Ms. Choi is with Penn State College of Medicine in Hershey, Pennsylvania.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2024;21(4–6):11–13.

Abstract

Stimulants are the first-line pharmacological treatment for attention deficit hyperactivity disorder (ADHD). We present the unique case of a patient who developed a chewing compulsion when taking mixed amphetamine salts (MAS). A 32-year-old female patient with a past medical history of gastroesophageal reflux disease (GERD), gastroparesis, and migraines was seen for initial psychiatric assessment due to concerns for irritability. She was diagnosed with post-traumatic stress disorder (PTSD); generalized anxiety disorder; ADHD, inattentive type; and unspecified bipolar disorder. Lamotrigine was started and titrated to 25mg twice per day, with improved mood stability. MAS immediate-release (IR) was started at 2.5mg and titrated to 5mg daily for ADHD. She then experienced an uncontrollable urge to chew, finding relief when chewing on a child’s teething necklace, which provided satisfaction and a reduction in anxiety. She denied jaw tightness or teeth grinding. The dose of MAS IR was reduced to 2.5mg daily with improvement in symptoms and later increased again to 5mg daily, which she was then able to tolerate. Stereotyped biting behaviors have been observed in rats with the use of amphetamines, and the onset of compulsive behavior has emerged in children with the use of dextroamphetamine. However, this is the first known case of compulsive chewing or biting movements reported in humans with MAS use. This case highlights the need to assess patients for adverse events, such as compulsive biting and chewing movements or other oral facial stereotypies, after commencement of stimulants, including MAS.

Keywords: Attention deficit hyperactivity disorder, ADHD, mixed amphetamine salts, stimulant, biting, chewing, compulsion, stereotypy

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by developmentally inappropriate levels of hyperactivity, impulsivity, or inattention that impair functioning and/or development, with onset of symptoms occurring before the age of 12 years.1 ADHD was historically believed to be a disorder outgrown by adulthood.2 We now have evidence that suggests ADHD symptoms can persist into adulthood, affecting a pooled estimate of 5.29 percent of children and adolescents and 2.58 percent of adults globally.3–5 ADHD, if left untreated, can lead to significantly poorer long-term outcomes in multiple domains, such as nonmedicinal drug use/addictive behavior, academics, antisocial behavior, social function, occupation, self-esteem, driving, services used (e.g., justice system, emergency health care, financial assistance), and obesity.6 

Stimulants are the first-line pharmacological treatment for the management of ADHD. Commonly reported side effects of stimulants are nausea, loss of appetite, abdominal pain, nervousness, and insomnia. Side effects such as perseverative/compulsive behaviors and movement disorders have been reported in the literature to a limited degree.7,8 There are no previously reported cases of biting in humans associated with the use of amphetamine salts. We present the unique case of a patient who developed a biting and chewing compulsion when taking mixed amphetamine salts (MAS).

Case Presentation

A 32-year-old White female patient with a past medical history of gastroesophageal reflux disease (GERD), gastroparesis, and migraines presented for initial psychiatric assessment due to concerns for irritability. She was previously treated by her primary care physician for reported post-traumatic stress disorder (PTSD), anxiety, depression, and ADHD with MAS extended-release (XR) 10mg daily, buspirone 7.5mg twice daily as needed for anxiety, and lorazepam 0.5mg as needed for anxiety. Upon evaluation, she was diagnosed with PTSD; generalized anxiety disorder; ADHD, inattentive type; and unspecified bipolar disorder due to a history of mood episodes with predominant agitation, rage, and impulsive decisions that were amplified with antidepressant use and a family history of bipolar disorder. 

Lamotrigine was started and titrated to 25mg twice daily, at which point the patient achieved good mood stability. MAS immediate-release (IR) was started at 2.5mg daily for ADHD, monitoring for destabilization of mood, then was titrated to 5mg daily. Following titration, the patient experienced the urge to bite or chew on something within 1 to 2 hours after taking the medication. This urge persisted for approximately 1 to 2 hours. There were times that she had to clench her jaw tightly in an attempt to achieve relief from the uncomfortable urge, to no avail. She tried to chew gum, which did not provide relief, followed by a hard child’s teething necklace, which provided satisfaction when chewed. Not engaging in chewing led to increased anxiety. She denied jaw tightness or teeth grinding. The dose of MAS IR was reduced to 2.5mg daily the following day, which led to an improvement in symptoms. She again went up to 5mg daily of MAS IR to see if her initial urge to chew and bite were a side effect or a coincidental finding. She experienced the urge again; however, she continued the medication daily at the same time each morning, and the side effect attenuated and was no longer present with one week of consistent use. During this time, no other changes were made to the remainder of her medication regimen.

Discussion and Conclusion 

In the current literature, there are a limited number of publications related to stereotyped movements or obsessive-compulsive behaviors in humans associated with the use of stimulants. The rat model has been used in research involving stimulants to elucidate a better understanding for psychostimulant-induced behavioral changes. The mechanism of action of amphetamine is complex and includes the release of dopamine across multiple central nervous system (CNS) regions, including dorsal and ventral striatum, substantia nigra, and the cortex.9 Repetitive and compulsive behaviors, such as licking, sniffing and gnawing, have been induced from stimulation of striatal dopamine neurons. Injection of amphetamine in the ventrolateral sector of rat striatum has led to oral stereotypies, particularly intense biting behaviors.10 Notably, rats injected with varying doses of d-amphetamine demonstrated more sniffing and repetitive behaviors overall, whereas those treated with methylphenidate displayed predominantly gnawing behavior.11 This information suggests there might be different mechanisms explaining each psychostimulant-induced behavior, rather than purely dose-related side effects universal to all psychostimulants.

Studies and case reports have begun to describe the phenomenon of stereotyped movements and obsessive-compulsive behaviors in humans with various psychostimulants. Methylphenidate has led to lip and tongue biting behavior and induced obsessive-compulsive behavior in a patient with no prior history of psychiatric disorders.12 In a double-blind study of 45 hyperactive boys, Borcherding et al8 found that 34 children exhibited stereotyped orofacial movements, compulsive hand motions, repetitive eye blinking or head jerking, perseverative grunting, or tremor following stimulant therapy. Interestingly, two boys in this study (one using dextroamphetamine and the other using both dextroamphetamine and methylphenidate independently) experienced an increase in movements that dissipated 24 to 48 hours after initial dose or dose increase. Additionally, there appeared to be a population of boys who were more prone to develop stereotyped movements on both forms of stimulants. Compulsive behaviors were observed more frequently with dextroamphetamine (56%), compared to methylphenidate (22%), among the 23 participants who experienced such behaviors. Particularly, amphetamine had a tendency to increase cleaning and checking behaviors resembling childhood-onset obsessive-compulsive disorder (OCD).8,13 No reports in the literature described a compulsive urge to bite or chew as our patient described, but a theme of compulsive behavior and stereotypical movements induced by methylphenidate, dextroamphetamine, and now MAS has been identified. 

Dose-related obsessive-compulsive behaviors or stereotypies have not been clearly identified with methylphenidate or dextroamphetamine use in humans, but our case does attempt to elucidate dose-related side effects with MAS. Pharmacokinetic studies have shown that a single dose of MAS XR 20mg daily is bioequivalent to two 10mg doses of MAS IR administered four hours apart. Time to peak plasma concentration is approximately seven hours for the XR formulation, compared to three hours for the IR formulation.14 In our case, the patient had previously tolerated MAS XR at a higher dose of 10mg daily. However, her intense urge to bite occurred at MAS IR 5mg daily, which implied that she had previously tolerated an overall higher maximum plasma concentration of d- and l-amphetamine but had difficulty with a more rapid increase in plasma concentration. The time to side effect onset and duration of side effect burden correlated with the time peak plasma concentration of the MAS IR. Based on the pharmacokinetics, we would expect the side effects to lessen as the medication is metabolized and eliminated, with MAS having a half-life between approximately 9.77 to 13.8 hours.15 Additionally, the patient’s side effect did dissipate over time with consistent daily use of MAS IR 5mg, which can be explained by reaching a steady-state concentration. Reaching steady state would occur after approximately five half-lives, or 2 to 3 days of consistent dosing of MAS IR. Once in steady state, there might be less fluctuation in the plasma concentration, providing a possible explanation for resolution of the side effect over time.16

Lastly, adding to the complexity of side effect management when treating for a condition is the challenge of treating comorbid disorders, such as ADHD and bipolar disorder in this case. A meta-analysis published in 2021 showed that between 10 to 20 percent of adults with bipolar disorder have comorbid ADHD.17 Evidence has shown that treating ADHD with stimulants without accompanying mood stabilizers can contribute to mood instability or manic/hypomanic switch.18,19 As demonstrated in this case, best practice in comorbid bipolar disorder and ADHD is to first achieve mood stabilization. Once achieved, treatment of residual ADHD symptoms with a stimulant is reasonable while monitoring for possible manic/hypomanic switch.20

In summary, orofacial stereotypies and compulsions can occur with stimulant use, though these are less common side effects with unclear mechanisms. This case highlights the need to assess patients for adverse events, such as compulsive chewing movements or other oral facial stereotypies, after commencement of stimulants, including MAS. Additionally, development of side effects such as compulsions or stereotypies might dissipate with time or change in dose, but this can be unpredictable. Dose changes and repeat medication trials should be tailored to each patient and their level of safety and tolerability. Lastly, this case highlights the comorbidity of ADHD and bipolar disorder, as well as the need to cautiously monitor for mood instability while treating both conditions. 

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