Naltrexone-induced psychosis in a patient with alcohol use disorder

Naltrexone is a competitive antagonist of μ, δ, and κ opioid receptors, which are used for the targeted treatment of alcohol use disorders (AUD). Naltrexone-related psychotic symptoms are an uncommon side effect. We report a case of a patient with AUD who experienced auditory hallucinations after receiving naltrexone.

A 45-year-old divorced woman presented to the emergency room with auditory hallucinations, visual hallucinations of bugs, persecutory delusions, restlessness, hand tremor and cold sweating. She had unipolar depression in her 20s but never exhibited manic symptoms. She persistently drank various alcoholic beverages (e.g., whiskey, beer, and wine) over the last 10 years after becoming unemployed. During the COVID-19 pandemic, she became afraid of going outside, mostly stayed at home, and engaged in excessive drinking. Laboratory data revealed unremarkable findings except for mildly elevated concentrations of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase. During her most recent drinking session, which occurred several hours prior to hospital admission, she drank two bottles of sake (approximately 60 drinks). A psychiatric admission was arranged because of suspected alcohol-related psychosis and alcohol withdrawal symptoms.

She underwent inpatient detoxification, during which lorazepam (12 mg per day) and sulpiride (400 mg per day) were administered. The medications were tapered gradually over 2 weeks, and her psychosis subsided after detoxification. She agreed to receive naltrexone for maintenance treatment. One hour after receiving her first dose of naltrexone (25 mg), she experienced auditory hallucinations (voices) and dysphoria. These symptoms persisted for 4 hours and then subsided. Because auditory hallucinations are not a common side effect of naltrexone, the patient agreed to retake it, after which she reported similar experiences and symptoms that subsided without other medical prescriptions. Follow-up lab data and computed tomography of the brain revealed no notable findings. She was prescribed normal doses of mirtazapine and estazolam and a low dose of quetiapine after discharge. No further psychotic symptoms were reported.

Naltrexone has been used to treat the psychotic symptoms of patients with schizophrenia, but supporting evidence for this treatment is unavailable.¹ Naltrexone-induced psychotic symptoms are uncommon. A 24-year-old female patient with schizophrenia experienced visual hallucinations after receiving 50 mg of naltrexone daily for 2 to 3 days to achieve an anti-obesity effect. Her visual hallucinations disappeared 3 to 4 days after she stopped taking naltrexone.² Another 44-year-old female patient without schizophrenia reported auditory hallucinations, visual hallucinations, and persecutory delusions after receiving 50 mg of naltrexone daily for 3 days for alcohol dependence. Her psychotic symptoms resolved 2 days after she discontinued naltrexone.³ In our patient, psychotic symptoms were noted after she received 25 mg of naltrexone, and her symptoms subsided after 4 h. In these three cases, they were young to middle-aged female patients. Our patient and another schizophrenic patient had pre-existing psychosis, while the third patient with AUD did not have psychosis before treatment. The mechanisms through which naltrexone causes hallucinations remain unclear and require further research.

Dopamine release in the medial frontal cortex and nucleus accumbens can be differentially modulated.⁴ Although naltrexone reduces the dopamine level in the nucleus accumbens, resulting in a reduction in alcohol intake,⁵ the antagonist effect of the κ opioid receptor on naltrexone may disinhibit dopamine release in the medial prefrontal cortex and induce psychosis.⁴ Naltrexone-induced psychotic symptoms have not been reported in patients with opioid use disorder probably because of the rare occurrence rate, and more people have received treatment for AUD than for opioid use disorder.

Because our patient started receiving naltrexone during hospitalization, we were able to perform a differential diagnosis and observe her conditions closely. If she had started naltrexone as an outpatient, the side effects could have led to undesirable results. The prescription of naltrexone after alcohol detoxification is helpful for differentiating drug-induced psychosis from delirium caused by alcohol withdrawal. When naltrexone-induced psychosis is suspected, naltrexone must be discontinued instead of prescribing additional doses of antipsychotic agents.

References

• ¹
  Clark SD, Van Snellenberg JX, Lawson JM, Abi-Dargham A. Opioid antagonists are associated with a reduction in the symptoms of schizophrenia: a meta-analysis of controlled trials. Neuropsychopharmacology. 2020;45:1860-9.
• ²
  Lee DB, Woo YS, Bahk WM. Naltrexone-associated Visual hallucinations: a case report. Clin Psychopharmacol Neurosci. 2019;17:329-31.
• ³
  Amraoui A, Burgos V, Baron P, Alexandre JY. [Acute delirium psychosis induced by naltrexone chlorhydrate]. Presse Med. 1999;28:1361-2.
• ⁴
  Margolis EB, Lock H, Chefer VI, Shippenberg TS, Hjelmstad GO, Fields HL. Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex. Proc Natl Acad Sci U S A. 2006;103:2938-42.
• ⁵
  Anton RF. Naltrexone for the management of alcohol dependence. N Engl J Med. 2008;359:715-21.

Publication Dates

• Publication in this collection
  12 May 2023
• Date of issue
  Mar-Apr 2023

History

• Received
  22 Oct 2022
• Accepted
  18 Dec 2022