A Case Report of Treatment-Resistant Agitation in Dementia With Lewy Bodies: Medical Marijuana as an Alternative to Antipsychotics

Introduction

Dementia currently affects ∼8% of Americans aged 70 years and older. ¹ Dementia with Lewy bodies (DLB) is increasingly identified as a common cause of neurodegenerative dementia, accounting for 4.2% of all cases of dementia in the community and 7.5% of cases in secondary care. ²

Clinical diagnosis of DLB is supported by dementia with at least two of four core clinical features: visual hallucinations, cognitive fluctuations, rapid eye movement sleep behavior disorder, and parkinsonism.^3,4 Less-specific supporting clinical features include repeated falls, a common early symptom of this disease. ⁵ Diagnosis of DLB is also supported by episodes of syncope, autonomic dysfunction, ⁶ hypersomnia, ⁷ hyposmia, ⁸ anxiety, depression, and delusions. ⁹ Auditory, tactile, and olfactory hallucinations are also seen in addition to the more common visual hallucinations. ¹⁰

DLB is progressive and terminal. ¹¹ No disease-modifying treatments exist, although some medications may provide symptomatic relief. Cholinesterase inhibitors such as rivastigmine and donepezil can improve cognition, psychotic symptoms, and parkinsonism in patients with DLB.^12,13 Memantine has also been shown to mildly improve global impression scores, but not cognition or neuropsychiatric symptoms. ¹⁴ Memantine is generally well tolerated, but may cause worsening agitation, delusions, or hallucinations.^15,16 Low-dose atypical antipsychotics may be considered in the management of severe psychosis, but special attention should be given due to the increased risk of adverse effects, including worsening confusion, extrapyramidal symptoms, and increased mortality in patients with DLB.^17–19

Cannabinoids are the subject of ongoing research in the treatment of the neuropsychiatric symptoms of dementia. Recent studies and meta-analysis have shown that cannabinoids, including low-dose oral delta-9-tetrahydrocannabinol (THC), are well tolerated and effective in treating neuropsychiatric symptoms of dementia, including agitation and aggression.^20,21 In addition, cannabinoids may slow the progression of neurodegenerative dementias due to their neuroprotective effects.^22–24 Although the efficacy of this class of drugs is not yet fully characterized, cannabinoids represent a promising adjunct to antipsychotic medications in the treatment of agitation and aggression in this patient population due to their comparatively benign side effect profile.

In this study, we present the case of an 85-year-old man with DLB who presented with acute agitation, aggression, and hallucinations refractory to initial antipsychotic therapy yet highly responsive to medical THC tincture.

Case Description

This is the case of an 85-year-old man with a past medical history of DLB, hypertension, asthma, and postoperative hypothyroidism who was admitted to the hospital in April of 2021 for hallucinations and increasingly violent behavior toward his wife and daughter.

The patient was initially seen in an emergency department visit for insomnia with hallucinations and discharged on melatonin and diphenhydramine with follow-up in primary care clinic the next day. Other home medications consisted of Advair 250–50 μg twice daily, albuterol inhaler as needed, hydrochlorothiazide 12.5 mg daily, losartan 50 mg daily, levothyroxine 100 μg daily, memantine 10 mg twice daily, and risperidone 0.25 mg twice daily. In the primary care follow-up visit the next day, obtaining medical history was complicated by multiple verbal outbursts toward his family while attempting to discuss hallucinations, delusions, and similar verbal aggression at home. It was later disclosed by his spouse that these delusions were of her engaging in extramarital affairs with male physicians.

During their departure from the clinic building, the patient hit his daughter in the chest and attempted to push his wife down the stairs. Clinic staff called an ambulance to transport the patient to the hospital as the patient was exhibiting behavior that threatened the safety of his wife and daughter. The patient was given 5 mg haloperidol and 2 mg lorazepam en route. On presentation to the ED, his vitals were within normal limits with a temperature of 97.8°F, blood pressure of 122/62 mm Hg, pulse of 69 beats per minutes, and oxygen saturation of 99%.

The patient was sedated but otherwise normal on the original physical examination. A complete blood count and basic metabolic panel were normal and urinalysis did not show a urinary tract infection. The patient was admitted for observation and restarted on 0.25 mg risperidone twice daily and provided a one-to-one sitter. He was continued on his home antihypertensive, hypothyroidism, and asthma medications.

The following morning, the patient was calm and his alertness had improved, although he still exhibited unintelligible speech. The next evening, the patient was found wandering the halls and attempting to enter other patients' rooms. He was not cooperative with verbal redirection, continued to speak incoherently, and became combative with nursing staff. Patient was given lorazepam 2 mg but continued to leave his room. Given the patient's agitation and nonverbal status, it was impossible to distinguish between delirium and baseline agitation with a confusion assessment scale. The patient received haloperidol 2 mg and became less agitated and combative. The sitter was able to redirect the patient to remain in his room for the rest of the night, but he continued to attempt to leave his bed. The Palliative Medicine team was consulted for further recommendations on the management of his agitation.

Risperidone was increased to 0.5 mg twice daily on hospital day two. Palliative Medicine recommended adding trazodone 25 mg at night for insomnia. After discussion with family, medical marijuana was ordered in the form of a tincture of THC 5 mg and cannabinol (CBD) 5 mg three times daily. The tincture was scheduled for delivery from a local dispensary within several days. On hospital day three, patient continued to wander the halls and was combative with hospital staff despite the increase in risperidone. He required multiple doses of lorazepam and haloperidol before becoming redirectable and returning to his room.

On hospital day four, the decision was made to discontinue risperidone due to inefficacy and development of upper arm rigidity concerning for extrapyramidal side effect development. Quetiapine 25 mg at night was started that evening. Overnight, the patient again became agitated, pulled out his IV lines, and required more lorazepam to control his behavior. On day four, the family became amenable to placement at a long-term care facility. Quetiapine was increased to 50 mg nightly while waiting for the medical marijuana tincture to arrive.

The marijuana tincture arrived and was started on hospital day seven in addition to his quetiapine 50 mg nightly. Within 24 hours, the patient's agitation had improved and rigidity had resolved. On day eight, the patient had no events overnight and exhibited improved cooperativity. For the next several days, the patient had no further episodes of aggression or wandering. Although he was still incoherent, he became more communicative. The nursing staff noted several minor episodes of agitation and pacing in the patient's room that resolved when the patient was given the scheduled marijuana tincture.

The patient remained hospitalized for five more days to arrange long-term care. Request for skilled nursing facility was denied by insurance due to lack of need for inpatient physical therapy. The Palliative Medicine team arranged for outpatient follow-up and continuation of the marijuana tincture at THC 5 mg/CBD 5 mg three times daily scheduled as well as quetiapine 50 mg nightly. Home health, physical therapy, and occupational therapy were arranged and the patient was discharged to home.

The patient followed up with his primary care physician five days posthospitalization and continued to report a favorable response to the THC/CBD tincture. One week later, the patient's wife called the Palliative Medicine team to report that he exhibited agitation when she would leave the house. The Palliative Medicine team recommended that she increase the tincture dosage to THC 10 mg/CBD 10 mg twice daily. He followed up in clinic with Palliative Medicine three days later and had no further signs of aggression after the increased dose. One month later in follow-up with Palliative Medicine, the patient's wife noted a continued improvement in sleep and no adverse effects of the increased dose.

Discussion

DLB with agitation and aggressive symptoms is particularly challenging to treat. Antipsychotics can acutely calm a patient, but unfortunately can exacerbate confusion, leading to a cycle of worsening agitation and caregiver burden. First-generation antipsychotics work by inhibiting dopamine receptors, but the exact mechanism is not fully understood. Of greatest concern with antipsychotic use is the risk of extrapyramidal symptoms, such as tardive dyskinesia, drug-induced parkinsonism, acute dystonia, and akathisia. In addition, there is an increased risk of mortality with antipsychotic use in dementia patients.^17–19 Because of this, it is prudent to consider alternative options for patients.

The cannabis plant has been used for years as a medicinal agent for a variety of symptoms, including pain, nausea, loss of appetite, anxiety, seizures, and muscle spasms. The major psychotropic component in the cannabis plant is THC, whereas the major nonpsychoactive ingredient is CBD, although there are many other phytocannabinoids being studied. THC is a partial agonist of the endocannabinoid receptors CB1 and CB2 affecting an endogenous homeostatic system involved in pleasure, memory, thinking, movement, coordination, and sensory and time perception.

The CB1 receptor distributed throughout the brain and spinal cord is thought to modulate the psychoactive effects of THC. In contrast, CBD does not appear to bind CB1 receptors, thought to result in the relative lack of psychoactive effects when used in isolate from THC. Although the exact mechanism of action is not known, it is theorized that CBD acts on the peripheral nervous system and plays a part in mediation of both THC and endocannabinoid metabolism. ²⁵ There are a wide variety of intake modalities and formulations of medical marijuana, including smoking the raw marijuana flower, vaporization of marijuana oil, by mouth as a tincture or other edible product, compounded topical creams, rectal suppositories, and oral sprays.

Oral intake has an onset of action of one to two hours due to first-pass metabolism, whereas inhalation has an almost immediate onset. It should be noted that accurate dosing of medical marijuana is difficult due to the lack of regulation of products sold in dispensaries. The clinical relevance of other phytocannabinoids is also not yet fully understood, and many formulations of medical marijuana do not quantify their inclusion.^20,21

Common side effects of medical marijuana include tachycardia and hypotension. For this reason, medical marijuana is not recommended for patients with cardiovascular conditions that could be exacerbated by these effects. Other side effects include dry mouth and facial flushing. There is a risk of acute intoxication with THC, but the amount at which this occurs can vary greatly depending on method of intake, patient tolerance, and body composition.^21,25 As with many psychoactive drugs, it is prudent to begin at low doses and titrate slowly.

Acute intoxication can present with paranoia, increased anxiety, panic attacks, acute psychosis, impaired decision making, and greater risk taking and impulsivity. ²⁶ Medical marijuana should not be recommended for patients with known psychotic disorders such as schizophrenia.^21,26 Nevertheless, medical marijuana is a promising therapeutic addition to first-line medical treatments for agitation in dementia.

Cost is a significant barrier to obtaining medical marijuana. Insurance companies do not cover medical marijuana because it is not federally legalized or approved by the Food and Drug Administration (FDA). It is classified as a Schedule 1 drug by the Drug Enforcement Administration (DEA), indicating that it is not approved for medical or recreational use. A one-month supply of tincture at a dispensary in Texas ranges from $105 to $200 depending on the potency of the THC-CBD combination. ²⁷

For a patient to obtain medical marijuana, a physician must submit a recommendation asserting that a patient will benefit from its use. There is much variety state by state in how this process is handled and what licensure is required, the details of which are beyond the scope of this study. In addition, there are a limited number of physicians willing and knowledgeable enough about medical marijuana to provide such a recommendation. The availability of physicians and high-cost burden can serve as a barrier to accessing this potentially beneficial therapy.

Beyond the complex treatment resistance in this patient, this case highlights the significant caregiver burden associated with caring for patients with dementia with agitation. At baseline, caregivers of patients with dementia are significantly more stressed than caregivers of patients without dementia, which oftentimes leads to institutionalization of the patient. The wife of this patient strongly considered long-term placement for her husband, but she reconsidered following resolution of his aggression. It is pertinent to recognize that prompt treatment of agitation in DLB is crucial to improving the quality of life of both patient and caregiver. New environments unfortunately increase the risk of delirium in dementia patients. Maintaining the home living situation and family unit is the preferred outcome for many caregivers and in this case was feasible with adequate support.

This complex case presented the nuances of caring for an agitated patient with DLB and highlights the benefits of integration of medical marijuana into a therapeutic plan. Limitations to medical marijuana include cost, risk of acute intoxication, and barriers to accessing providers approved to prescribe. However, the benefits can be dramatic and life-altering, as was the case with this patient. Further research is needed on medical marijuana to support FDA and DEA approval and expansion of state-specific approvals to meet the needs of patients with complex symptoms adversely affecting their quality of life.