Abstract
Chief Complaint and Presenting Problem
O. was a 16-year-old adolescent boy with a history of depression, polysubstance use disorders (alcohol, cannabis, tobacco, benzodiazepine, inhalant, and dextromethorphan), and multiple psychiatric admissions for ingestion of illicit substances that culminated in an admission to an inpatient rehabilitation center.
History of Present Illness
O. experienced the onset of depressive symptoms, including low mood, poor energy, anhedonia, poor concentration, and sleep onset insomnia, when his parents divorced when he was 13 years old. Although he denied suicidal ideation, he admitted to a history of impulsive self-injurious behavior, punching himself in the head. He had had three psychotherapy sessions with a psychologist but did not continue because of his father’s disapproval, as he believed O. was not “crazy” and would get better on his own. At the age of 16, 3 months prior to O.’s first hospitalization, he began to withdraw from the family. He slowly started becoming verbally aggressive, screaming that he hated his parents, and ultimately physically attacked them by pushing and shoving them to the ground. Parents disciplined him by giving time-out and grounding him by taking video games away. It was around this time that O. began drinking alcohol, vaping nicotine, and smoking cannabis.
Shortly thereafter, O. began secretly drinking alcohol found in his father’s house. While at home with mother, he stole beer from convenience stores and attended class while intoxicated with alcohol. He obtained cannabis from another classmate and began smoking before class daily for 2 months. For this reason, he was suspended from school and subsequently admitted to a psychiatric facility for the first time.
During this admission, O. was diagnosed with bipolar II disorder for which he was treated with quetiapine 300 mg at bedtime. While in the hospital, O. also impulsively consumed hand sanitizer for inebriation. Not long after discharge, O. consumed rubbing alcohol from household cleaning items, resulting in prolonged inebriation, but this event did not lead to inpatient admission as no one else discovered it. However, O.’s mother found a bottle of butane in his room and realized he had been inhaling this for its euphoric effects. Mother did not know how often he consumed this, but O. reported it was only once. O. had also been obtaining alprazolam from the street from adult friends but said he only used it several times. Mother was unable to corroborate because she did not see his alprazolam use firsthand.
Due to mother’s concerns for O.’s substance abuse, which interfered with his school and family life, she petitioned for an involuntary assessment that resulted in a second hospitalization with a recommendation for inpatient rehabilitation. O. was discharged to home while awaiting rehab bed availability. However, upon discharge, O. became nonadherent with the quetiapine after developing headaches. A few weeks later, O.’s mother received a call from him reporting that he had overdosed on dextromethorphan (via cough-syrup ingestion) and butane (via air duster inhalation). Mother called 911 and O. was taken to the hospital, which led to his third involuntary psychiatric hospitalization.
Upon transfer to the child and adolescent psychiatry unit after medical clearance, O. appeared intoxicated. He was easily distracted, disorganized, paranoid, and fixated on having “brain damage” because of intoxication. O. adamantly denied that this was a suicide attempt but rather an accidental overdose during recreational substance use. He was inconsistent in his reports of recent alcohol use but adamantly denied intoxication at least during the past few weeks prior to admission. He also reported ongoing symptoms of depression that had not been medically treated and therefore was started on escitalopram 10 mg daily for depression and guanfacine 1 mg at bedtime for impulsivity. Prior to discharge, O. reported a desire to stop using substances.
Shortly after discharge, O. impulsively ran into a pharmacy, while at a pit stop on a family car ride and grabbed a 3 fluid ounce (89 mL) bottle of Delsym (dextromethorphan); he ingested the entire bottle. Upon arrival home, mother found O. intoxicated, and this led to a fourth involuntary admission to a psychiatric unit. On admission, O. reported that he drank the entire bottle to become intoxicated but again adamantly denied suicidality. Aside from this event, he denied all other substance use at that time. However, he described constant cravings for different drugs.
Between O.’s third and fourth psychiatric hospitalizations, his outpatient psychiatrist had discontinued escitalopram and guanfacine but restarted quetiapine to optimize for bipolar II and insomnia. Nevertheless, the hypomanic episodes did not last for more than 1 day, and what seemed to predominate was depression. Therefore, all three of these medications were restarted and continued, respectively, during this admission, and a few days prior to discharge, naltrexone was initiated to target cravings and impulsivity related to substance use.
At the end of his last hospital stay, O. appeared to be ambivalent in wanting to reduce or stop substance use. While accepting that there were significantly negative health, social, and academic effects of using substances, he also reported an ongoing urge to use anything to achieve inebriation. O. was discharged home roughly 3 weeks prior to the court-ordered admission for inpatient rehabilitation for polysubstance use disorders. At the time of discharge from O.’s fourth and last known psychiatric hospitalization, his final medication regimen was escitalopram 10 mg daily, quetiapine 300 mg at bedtime, guanfacine 2 mg at bedtime, and naltrexone 25 mg daily. A follow-up phone call to the parent confirmed that O. was adherent to his discharge medications and was able to start his inpatient rehabilitation program successfully without any worsening in symptoms, intoxication, or hospitalization.
Past Psychiatric History
Prior to his first hospitalization, O. had no known previous psychiatric history. However, he had experienced long-lasting untreated depression with associated self-injurious behaviors. O. had a total of four psychiatric hospitalizations, all during the second half of the calendar year when he began using substances.
Developmental History
O. was the product of a 39-week pregnancy during which mother had eczema that only responded to oral steroids at 7 months. Mother does not remember the name or dose of steroids. She reports that there was no in utero substance exposure. O. was delivered via C-section due to cephalopelvic disproportion. Birth weight was 3.9 kg.
Mother reports that O. met all developmental milestones on time.
Educational History
O. was enrolled in a private school in the 11th grade. O. had been on the honor roll, receiving all A’s and B’s before the onset of illness. He was in advanced placement classes and obtained a high score on his SAT. He was not involved in any extracurricular activities. O. had experienced one school suspension for alcohol and cannabis intoxication.
Social History
O. was born and raised in South America and moved to the United States at the age of seven. He grasped the English language quickly and adapted well to a new environment. In the United States, both parents began working, which left O. partially unsupervised at times. Parents divorced when O. was 13 years old, after which they obtained joint custody; O. split his time living with mother and father. Differences in parenting style were reported, in that father tended to be more lenient and mother more strict. O. had a 14-year-old younger sister with whom he had a good relationship.
O.’s family did not identify with a specific religion nor attend a house of worship, but they regularly prayed together and taught family morals. O. enjoyed playing video games online with his friends as well as riding his bicycle.
Family History
Mother and maternal grandmother had a history of depression, but there were no reported suicide attempts in the family. There was no significant family history of substance use disorders or significant medical conditions.
Medical History
O. was born with idiopathic clubfoot (talipes equinus), for which he had a surgical repair after arrival in the United States. Mother denied any other medical history. There was no reported history of seizures, loss of consciousness, or traumatic brain injury. O. had never been prescribed nonpsychiatric medications.
Mental Status Exam
On the initial mental status examination, O. was casually dressed, appeared at his stated age with appropriate grooming and hygiene, and displayed no dysmorphic features. His sensorium was intact and was oriented to time, place, and person. At first, he was distractible, made poor eye contact, and speech was somewhat pressured and incoherent. After resolution of acute intoxication, his speech was clear and coherent with normal prosody. The trigger that O. described as leading to the substance use was “boredom,” poor sleep, and lack of motivation to do other things.
O. became calm and cooperative although intermittently guarded. He appeared frustrated with constricted affect. He at first displayed disorganized thought processes with preoccupation with “brain damage,” but in subsequent days, he displayed linear and organized thought processes with largely unremarkable thought content. He denied any perceptual disturbances and did not appear to be responding to internal stimuli. O. denied suicidal or homicidal ideation. He exhibited poor insight and judgment regarding his substance use.
Formulation
In summary, O. was a 16-year-old adolescent boy with no prior psychiatric history referred for his first hospitalization after several months of increasing and impulsive alcohol and cannabis consumption. He then rapidly began to experiment with several other substances, including butane, dextromethorphan, hand sanitizer, isopropyl alcohol, and alprazolam.
Predisposing factors included male sex, adolescence, and impulsivity; although no family history of substance use was reported, mother and maternal grandmother had a history of depression. Persistent depression, parental divorce, negative mental health stigma from father, somewhat conflicting parenting styles in that father tended to be more lenient and mother more strict, as well as continual parental conflict were precipitating factors to substance use. There was no known history of bullying or trauma. There did not appear to be significant perpetuating factors such as psychosocial stress or poor social influences. Protective factors included strong social support from parents, adherence to pharmacological treatment, and engagement in hobbies and interests in a healthy manner.
Multiaxial Diagnoses
Alcohol use disorder Cannabis use disorder Tobacco use disorder Inhalant use disorder Sedative–hypnotic or anxiolytic use disorder Other psychoactive substance use disorder
Treatment Course
O. was started on quetiapine 300 mg at bedtime during his first psychiatric admission for suspicion of bipolar II disorder. His second psychiatric admission, shortly thereafter for a court-ordered involuntary assessment of substance use, resulted in recommendation for inpatient rehab. No medication changes were made at that time. During O.’s third hospitalization, escitalopram 10 mg daily was initiated for mood symptoms and guanfacine 2 mg at bedtime for impulsivity. Quetiapine was discontinued. O. tolerated medications well, and there were no concerns for manic or hypomanic symptoms with this regimen. This lowered the treatment team’s suspicion for bipolar II disorder and suggested the possibility that this diagnosis had been made without ruling out the effects of ongoing substance use. However, O.’s outpatient psychiatrist discontinued both escitalopram and guanfacine and restarted quetiapine at the previous dose.
During O.’s fourth hospitalization, escitalopram and guanfacine were restarted and quetiapine continued. During O.’s last few days of hospitalization, the decision was made to start naltrexone 25 mg daily to target cravings and impulsivity related to substance use. Guanfacine 1 mg was briefly given during the day but subsequently discontinued prior to discharge due to daytime somnolence. No other adverse effects of medications were noted. On this medication regimen, O. reported that he felt fewer cravings to use substances. O. remained hospitalized until his court-ordered treatment date to minimize the risk of another impulsive intoxication. As the court mandated, O. was placed in a residential rehabilitation program 3 weeks after his hospital discharge.
Discussion
This case illustrates the importance of providing rapid and effective treatment for substance use disorders and suggests alternative options in medication management. It also highlights the complexity of managing impulsive substance use in adolescence.
Commonly abused substances in adolescents include alcohol, cannabis, and tobacco (Moor et al., 2020). According to national datasets, rates of substance use increase rapidly in adolescence, peak during the transition to young adulthood, but decline the remainder of adulthood (Griffin and Botvin, 2010). From a neurobiological perspective, this may be explained by an immature regulatory prefrontal cortex that matures last in young adulthood (Halladay et al., 2020). Thus, O.’s developmental stage might be considered a significant risk factor in addition to other psychosocial stressors for his worsening substance use.
Research shows that early-life onset of substance use is associated with higher levels of abuse later in life (Halladay et al., 2020), leading to important negative physical and psychological outcomes (Newcomb and Locke, 2005). O. had a rapid decline in school function once he began drinking alcohol. Shortly afterward, he began experimenting with cannabis and more rarely used substances. This led to his expulsion from school, increased family discordance, and repeated hospital admissions. The degree of involvement with substances is often dictated by a combination of negative social influences and developmental or genetic predispositions (Griffin and Botvin, 2010). Harsh disciplinary practices, poor parental supervision, and high family conflicts increase the risk of substance use (Lochman and van den Steenhoven, 2002). Inversely, youth who are actively involved in community institutions such as school clubs, community service, or religious activities are less likely to engage in substance use (Griffin and Botvin, 2010). O. did not have after-school activities and appeared to have suboptimal parental supervision.
This illustrates the need for early interventions, either programs in school or in the community, that have been found to reduce the severity and persistence of substance use and its associated consequences (Griffin and Botvin, 2010, Halladay et al., 2020). O. apparently did not utilize such resources either during onset of his depressive symptoms at age 13 or during very fast progressing substance use and related problems, resulting in multiple psychiatric admissions.
During hospital admissions, O. was started on various psychotropic medications to target mood symptoms and impulsivity since he tolerated them well; however, there was a disconnect with the outpatient psychiatrist in the follow-up plan. Additionally, naltrexone was added primarily to address O.’s cravings in the context of highly impulsive drug-seeking behavior. Naltrexone is approved by the U.S. Food and Drug Administration (FDA) in adults for alcohol and opioid dependence (Singh and Saadabadi, 2023) and is being studied in patients with other substance use disorders (Trivedi et al., 2021). In children and adolescents, naltrexone is used off-label for other impulse-control-related conditions including substance use (Stancil et al., 2021). It has also been found to be effective in reducing self-injurious behavior, agitation, and irritability (Elchaar et al., 2006), all of which were relevant in O.’s case.
Another goal of introducing naltrexone to O.’s treatment was to help with better symptom control at home until he could start his planned inpatient rehabilitation program. Oral naltrexone is readily absorbed in the gastrointestinal tract (Singh and Saadabadi, 2023). Its long-acting properties are due to its liver metabolism to the primary active metabolite, 6-β-naltrexol, which has an elimination half-life of 13 hours (Singh and Saadabadi, 2023; Treatment C for SA, 2009). Peak blood levels are reached within the first hour of dosing and reach therapeutic effectiveness rapidly following the initiation of oral dosing (Treatment C for SA, 2009). We speculate naltrexone might have helped O. to control impulsive substance use until starting inpatient rehabilitation.
The progression of alcohol use disorder is thought to be mediated by hypothalamic–pituitary–adrenal (HPA) axis dysregulation that interplays with decreased prefrontal inhibitory control of the dopaminergic reward system (Blaine et al., 2016). However, this pathway is not unique to alcohol use. In fact, during abstinence from substances in general, exposure to drug-related cues stimulates this neuroendocrine axis, resulting in cravings that promote relapse (Goeders, 2007). Furthermore, naltrexone has been found to suppress the HPA axis via its opioid-antagonist modulation (King et al., 2002). These effects have been long studied in the context of alcohol consumption and have been linked to its effect of suppressing alcohol consumption (King et al., 2002). Dysfunction in the HPA axis has been described in depression; however, it is important to keep in mind that treatment with naltrexone does not reduce the risk of depression and suicidal ideation (Dean et al., 2006; Molero et al., 2018; Na et al., 2022) Moreover, it is recommended to monitor for depressive symptoms and suicidal ideation during treatment with naltrexone (Dean et al., 2006). To reduce risk, O.’s medications for mood symptoms were restarted even before starting naltrexone.
For O., naltrexone was not only initiated with these mechanisms in mind but also for the prospect of a future augmentation strategy with acamprosate. Acamprosate is an N-methyl-D-aspartate (NMDA) receptor antagonist FDA-approved for maintenance of abstinence from alcohol use disorder. Studies have found that acamprosate and naltrexone in combination with cognitive-behavioral therapy is superior to either medication alone for alcohol abstinence (Feeney et al., 2006). This could lead to better control of alcohol use disorder (Feeney et al., 2006). Acamprosate has also been studied for the treatment of other drug addictions whose mechanisms involve NMDA receptor antagonism (Tomek et al., 2013). Relevant to O.’s use of substances, butane (Brosnan et al., 2017) and dextromethorphan both antagonize the NMDA receptor (Brosnan et al., 2017; Oh et al., 2023).
In addition to NMDA receptor antagonism, dextromethorphan and butane also have distinct receptor modulation. Dextromethorphan, commonly found in cough syrup, also acts on sigma-1, nicotinic, serotonin, and norepinephrine receptors (Oh et al., 2023). Hence, dextromethorphan abuse can be associated with serotonin syndrome if the individual is on serotonergic antidepressants (Oh et al., 2023) like O. Therefore, assessment of risk versus benefit of initiating pharmacotherapy must be carefully assessed.
Like alcohol, butane also potentiates (Gamma-aminobutyric acid) GABAA receptor function (Brosnan et al., 2017). Its euphoric effect is thought to be mediated by nonspecific neuronal membrane effects (Brosnan et al., 2017). It can be easily obtained in lighter refill cans, antiperspirants, and air dusters (Sen and Erdivanli, 2015). Risks of use may include cardiac arrest, as seen in multiple cases (Sen and Erdivanli, 2015). Luckily, O. did not suffer any major medical complications from inhaling air duster, but he did have transient psychotic symptoms in the context of acute intoxication.
Cannabis has a more unique mechanism, as it acts on cannabinoid receptor types 1 and 2 (CB1 and CB2, respectively) (Sheikh and Dua, 2023). Responses can range from analgesia and anti-emesis to euphoria or even paranoia (Sheikh and Dua, 2023). As states in the United States. continue to legalize medical and recreational cannabis use, its perceived harmfulness has decreased while adolescent use has increased (Ladegard et al., 2020). Additionally, adolescents who initiate cannabis use earlier and who use at higher frequencies demonstrate poorer illness and treatment outcomes (Bagot et al., 2015). O. had a benign perspective of cannabis and did not appreciate its negative consequences. His daily cannabis use was associated with the use of other substances that lead to poor outcomes, demonstrated by repeated hospitalizations with similar presentations. Although there are no FDA-approved medications, there is a phase 2a clinical trial studying a prospective medication for cannabis use disorder, currently known as AEFO117 (NIDA, 2020). This medication reportedly counteracts the intoxicating effects of Tetrahydrocannabinol by blocking the cannabinoid receptor CB1, without inducing precipitated cannabis withdrawal (Haney et al., 2023). Other available treatments for cannabis use disorder include cognitive-behavioral therapy, contingency management, and motivational enhancement therapy (NIDA, 2020).
In conclusion, substance use disorders can have a strong negative impact on health outcomes in adolescents. Naltrexone, together with a combination of other pharmacologic and nonpharmacologic treatments, may be useful for adolescents with substance use disorders. Controlled studies are needed to understand more about effective and safe use of this promising off-label treatment option in adolescents.
Footnotes
Disclosures
B.J.C. is on the scientific advisory board of the Tourette Association of America (TAA), medical advisory board of Galen Mental Health, and received honoraria from the American Academy of Child and Adolescent Psychiatry, Partners Healthcare, Harvard Medical School/Psychiatry Academy, grant support from Florida, Children’s Medical Services, and research support from Emalex, National Institute of Mental Health, and Zynerba. She is on the national advisory board of Skyland Trail and was former cochair of the medical advisory, board of the TAA, a nonpaid position. D.O., J.R., and Y.B. have no disclosures.