Dexmedetomidine for Treatment of Delayed Peak Symptoms of Cannabis Withdrawal Syndrome: A Case Report

Abstract

Background: Cannabis withdrawal syndrome (CWS) is characterized by irritability, sleep disorders, and physical discomfort that typically peaks within 7 days of cessation. Case: A patient with a 30-year history of heavy cannabis developed prolonged symptoms of CWS that peaked at greater than 40 days after cessation, who was successfully managed with dexmedetomidine. Discussion: This case report documents an unusual case of significantly delayed CWS peak in symptoms, as well as the novel use of dexmedetomidine for inpatient management of CWS.

Introduction

We report a case of a 44-year-old Caucasian male who developed prolonged symptoms of cannabis withdrawal syndrome (CWS), peaking over 40 days after cessation with acute psychosis requiring hospitalization.

Case Presentation

The patient was a 44-year-old Caucasian male who presented to the emergency department (ED) with symptoms of acute encephalopathy, consisting of confabulation, visual hallucinations, and insomnia. The patient had a 30-year history of heavy cannabis use (smoking) and had abruptly stopped “cold-turkey” 42 days prior to presentation whereupon his symptoms had begun, and progressively worsened. He had discontinued smoking cannabis to obtain employment, which required a urine drug screen. Since cessation of cannabis, he reported sleeping approximately 2 hours per night and had been struggling with insomnia. He also reported for the past 4 days leading up to his presentation in the ED, he had a nonspecific, generalized headache without neck stiffness. His home medications purportedly included alprazolam, amlodipine, baclofen, diphenhydramine, duloxetine, lamotrigine, lisinopril, methylphenidate, and nortriptyline. Of note, his wife stated that he had used alprazolam and lorazepam in the past, but denied recent use. The patient denied additional over-the-counter products, supplements, or other drugs of abuse. A reliable medication reconciliation was unable to be obtained due to his altered mental status. His past medical history was significant for the following: cannabis use, hypertension, panic attacks, and a possible diagnosis of attention deficit hyperactive disorder.

While in the ED, the patient was alert and oriented, but was experiencing visual hallucinations of red ribbons on the ceiling. His wife stated she had never known the patient to experience such hallucinations, and that he had no psychiatric history consistent with visual hallucinations. The patient exhibited normal ambulation, but showed some altered precision dexterity with his fingers due to bilateral tremors. In addition, the patient experienced visual accommodative dysfunction. His physical examination was otherwise negative, and vital signs were stable.

The patient’s workup included a cranial computer tomography scan, which was negative for acute findings, lumbar puncture to rule out bacterial meningitis, urinalysis negative for a genitourinary infection, normal thyroid stimulating hormone, negative alcohol level, quantitative urine drug screen positive only for cannabis, and all values within normal limits on basic metabolic panel and complete blood count. The urine drug screen was notably negative for benzodiazepines, which was consistent with the wife’s report of no recent benzodiazepine use by the patient. This made benzodiazepine withdrawal an unlikely differential diagnosis. The patient’s ultimate diagnosis was psychosis due to CWS (see Table 1), which was made by the hospitalist after consultation with telepsychiatry.

Table 1.

Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) Diagnostic Criteria for Cannabis Withdrawal.

A. Cessation of cannabis use that has been heavy and prolonged (ie, usually daily or almost daily use over a period of at least a few months)

B. Three (or more) of the following signs and symptoms develop within approximately 1 week after Criterion A: • Irritability, anger or aggression • Nervousness or anxiety • Sleep difficulty (eg, insomnia, disturbing dreams) • Decreased appetite or weight loss • Restlessness • Depressed mood • At least one of the following physical symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache

C. The signs or symptoms of Criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning

D. The signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance

During the first 2 days in the ED, the patient received several medication trials, including diphenhydramine 50 mg PO, haloperidol lactate 5 mg IM, hydroxyzine 50 mg PO, lorazepam 1 mg IV, lorazepam 2 mg PO and IV, midazolam 2 mg IV, olanzapine 10 mg IM, and quetiapine 100 mg PO, to mitigate symptoms of CWS. His inadequate response to various medication trials led the health care team to initiate dexmedetomidine 0.2 mcg/kg/h on day 2, titrated to a score of −2 to 0 (“light sedation” to “alert and calm”) on the Richmond Agitation-Sedation Scale (Table 2). He was admitted to the critical care unit (CCU) after the dexmedetomidine infusion was started. The dexmedetomidine infusion was gradually titrated to 1.5 mcg/kg/h over approximately 8 hours and held at that rate for ~14 hours, and then tapered over the next ~17 hours. In total, the patient received dexmedetomidine for approximately 41 hours. On day 3, while receiving the dexmedetomidine infusion in the CCU, he continued to endorse visual hallucinations of balloons and ribbons on the ceiling and circles, as well as new onset auditory hallucinations of people talking and dogs barking. The patient was aware he was experiencing both visual and auditory hallucinations at this time, but was unable to make them stop. Olanzapine 5 mg PO twice daily was initiated on day 3, and he was also given 4 doses of haloperidol 2 to 5 mg IV. On day 4, clonidine 0.2 mg PO 3 times daily was added, and 2 doses of lorazepam 1 mg PO were administered. It was at this time he denied both visual and auditory hallucinations, but suffered impaired short-term memory of the events leading up to his presentation in the ED.

Table 2.

Richmond Agitation-Sedation Scale.

Score	Term	Description
+4	Combative	Overtly combative or violent; immediate danger to staff
+3	Very agitated	Pulls on or removes tube(s) or catheter(s) or has aggressive behavior toward staff
+2	Agitated	Frequent nonpurposeful movement or patient-ventilator dyssynchrony
+1	Restless	Anxious or apprehensive but movements not aggressive or vigorous
0	Alert and calm	Spontaneously pays attention to caregiver
−1	Drowsy	Not fully alert, but has sustained (more than 10 seconds) awakening, with eye contact, to voice
−2	Light sedation	Briefly (less than 10 seconds) awakens with eye contact to voice
−3	Moderate sedation	Any movement (but no eye contact) to voice
−4	Deep sedation	No response to voice, but any movement to physical stimulation
−5	Unarousable	No response to voice or physical stimulation

When receiving dexmedetomidine at rates of 1.2 to 1.5 mcg/kg/h, the patient developed hypotension and bradycardia (systolic blood pressure as low as 85 mm Hg and heart rate as low as 51), but with mean arterial pressure consistently ≥ 65 mm Hg; this did not require intervention.

Notably, after admission, the patient’s wife obtained collateral information from a family member that the patient had experienced a similar episode in his 20s that necessitated an inpatient psychiatric hospitalization following cessation of cannabis. No additional information related to the episode in his 20s was able to be procured.

The patient continued to improve and was discharged in stable condition on day 15. Upon discharge, it was recommended he establish outpatient mental health services.

Discussion

Cannabis is the third most widely used recreational psychotropic in the world (following nicotine and alcohol), and is the number-one illicit substance of abuse in the United States, with currently 26 million users older than 12 years. The 2017 National Survey on Drug Use and Health reported 1.5% of the population older than 12 years met criteria for cannabis use disorder (CUD) within the past year.^1,2

As of February 2020, 11 states and Washington D.C. have legalized some form of recreational marijuana for individuals aged 21 years and older. ³ Those seeking employment, particularly with a national employer, may require a negative drug screen as part of the hiring process. The most common drug screen method uses a urine sample, which can detect infrequent cannabis use (<2 times/wk) for 1 to 3 days, moderate use (several times/wk) for 7 to 21 days, and heavy use for 30 days or longer, depending on individual patient factors. ⁴ Our patient’s urine drug screen obtained in the ED was positive for cannabinoids only. The fact that his drug screen was still positive for cannabinoids over 40 days after cessation is not altogether unsurprising, as cannabinoids are highly lipophilic and distribute to fat stores, thus are detectable for over 3 weeks in chronic cannabis smokers. ⁵

In 2013, the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) added CWS as a criterion of CUD (Table 1). ⁶ Symptoms of CWS may include anger, aggression, irritability, anxiety/nervousness, and restlessness. Less common symptoms include chills, depression, physical discomfort, shakiness, and sweating. ⁷ Cannabis is known to affect sleep, and disturbed sleep is considered a hallmark of withdrawal. ⁸ While only 3 of the above symptoms are required for a diagnosis of CWS, our patient met nearly all criteria upon presentation to the ED on day 1.

Budney et al. reviewed literature in 2004 and found that the onset of symptoms of CWS is typically within 1 to 2 days of cessation, with peak symptoms around day 6, and all symptoms subsiding within 1 to 2 weeks, with the exception of sleep disturbances (particularly unusual dreams), irritability, and physical tension. ⁹ Data published by Hesse et al. in 2013 describe typical withdrawal symptoms of cannabis cessation peaking by day 10. ¹⁰ In contrast, the patient described in this case report had symptoms peak over 40 days after cannabis cessation; with such severe CWS, he required hospitalization, physical restraint, and ultimately sedation in a CCU, making this an unusual, and previously undocumented delay in onset of symptoms.

Prior investigations on management of CWS and CUD have included cannabinoids,^11,12 lithium, antidepressants, anticonvulsants, and antipsychotics ¹³ with varying degrees of success.

Dexmedetomidine (Precedex; Abbott Labs, Abbott Park, IL) was approved in 1999 by the US Food and Drug Administration for short-term use as a sedative in critically ill adults. ¹⁴ It is a highly selective, centrally acting α₂-agonist that has shown utility in the management of withdrawal symptoms from alcohol and opioids. It is a unique sedative in that it has anxiolytic and analgesic properties without risk for respiratory depression seen with other sedating agents. Adverse effects may include hypotension, bradycardia, and nausea.^{15 -17} Interestingly, dexmedetomidine has also been used in at least 2 cases to quell symptoms of cannabis intoxication/delirium.^15,18 The dexmedetomidine infusion was effective in treating acute psychosis, but did cause hypotension and bradycardia (not requiring intervention) possibly related to the infusion rate. In this particular case report, after ~41 hours of treatment with dexmedetomidine, the medication was tapered to discontinuation with complete resolution of psychosis.

Could the patient’s improvement seen after initiation of dexmedetomidine be attributed in part to the medications administered on day 1 in the ED? While this is worthy of consideration, we find it unlikely. While those medications have pharmacokinetic profiles with half-lives ranging from 6 hours (midazolam and quetiapine) to 30 hours (olanzapine), each of them reaches a peak in less than 3 hours. Thus, it is worth noting that even after peak levels of those medications were reached, they were insufficient to manage symptoms. It was only after dexmedetomidine was initiated that his symptoms began to subside.

A limitation of this case report is the inability to quantify the patient’s cannabis use. While he did endorse “heavy” use via smoking marijuana, clarification on the amount of tetrahydrocannabinol (THC)/cannabidiol (CBD) present, and the specific products he was using were unable to be obtained. In addition, the health care team was unable to obtain a clear history of his prior to admit medication list, which can therefore not rule out the use of other psychoactive medications. The wife’s denial of recent benzodiazepine use was consistent with the results of the urine drug screen, which provided evidence against benzodiazepine withdrawal.

Conclusion

We present a case of a patient who, after over 30 years of heavy cannabis use, developed severe CWS symptoms, peaking over 40 days after abrupt cessation that required inpatient hospitalization. This case is the first published report of successful treatment of CWS with dexmedetomidine, a centrally acting α₂-agonist.