Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: a systematic review

Abstract Introduction Neuropsychiatric symptoms are an integral component of the natural history of dementia, occurring from prodromal to advanced stages of the disease process and causing increased burden and morbidity. Clinical presentations are pleomorphic and clinical management often requires combinations of pharmacological and non-pharmacological interventions. However, limited efficacy and a non-negligible incidence of adverse psychotropic drug events emphasize the need for novel therapeutic options. Objectives To review the evidence supporting use of medical cannabinoids for treatment of neuropsychiatric symptoms (NPS) of dementia. Methods We conducted a systematic review of the medical literature to examine scientific publications reporting use of medical cannabinoids for treatment of NPS. Medical Subject Headings (MeSH) were used to search for relevant publications and only papers reporting original clinical information were included. A secondary search was performed within selected publications to capture relevant citations that were not retrieved by the systematic review. The papers selected were categorized according to the level of evidence generated by the studies in relation to this clinical application, i.e. (1) controlled clinical trials; (2) open-label or observational studies; and (3) case reports. Results Fifteen publications with original clinical data were retrieved: five controlled clinical trials, three open-label/observational studies, and seven case reports. Most studies indicated that use of medical cannabinoids engendered favorable outcomes for treatment of NPS related to moderate and advanced stages of dementia, particularly agitation, aggressive behavior, sleep disorder, and sexual disinhibition. Conclusion Medical cannabinoids constitute a promising pharmacological approach to treatment of NPS with preliminary evidence of benefit in at least moderate to severe dementia. Controlled trials with longitudinal designs and larger samples are required to examine the long-term efficacy of these drugs in different types and stages of dementia, in addition to their adverse events and risk of interactions with other drugs. Many pharmacological details are yet to be determined, such as dosing, treatment duration, and concentrations of active compounds (e.g., cannabidiol [CBD]/ Δ9-tetrahydrocannabinol [THC] ratio) in commercial preparations of medical cannabinoids.

Parkinsonism. In AD, for instance, NPS can be observed from the pre-dementia phase through all stages of dementia, with increasing incidence and magnitude as the disease progresses. 4,5 At prodromal and preclinical stages of AD, the occurrence of NPS is associated with increased risk of conversion to dementia and subsequent cognitive and functional deterioration. 6 In most etiologies, NPS tend to become more prevalent with progression of the neurodegenerative processes, in which case symptoms and abnormal behaviors may illustrate the damage to specific brain areas. 2,3 Relevant and persistent behavioral abnormalities have been related to increased morbidity and higher mortality risk. As a general rule, the occurrence of persistent symptoms often accounts for debilitating outcomes and predicts more severe global deterioration. 2 Also, NPS invariably increase caregiver burden, being associated with early nursing home placement and hastening the decision to institutionalize. 7 Effective treatment of NPS is still a challenge in clinical practice. At earlier stages of dementia in AD and related disorders, regular use of cholinesterase inhibitors and meantime in therapeutic doses is recommended as the first step in the pharmacological management of mild behavioral changes. However, in the presence of severe and disruptive behaviors such as psychosis and agitation, which often occur in advanced stages of dementia, other psychotropic drugs must be considered, including antipsychotics, antidepressants, benzodiazepines, and anticonvulsants. Nonetheless, studies of psychopharmacological interventions for treatment of NPS have so far yielded at best modest evidence of efficacy, which must be counterbalanced by relevant safety concerns. Special attention must be given to increased risk of cerebrovascular events and all-cause mortality, especially when these medications are used for extended periods. [8][9][10] On the other hand, non-pharmacological strategies, although more acceptable and safer, may not be efficacious (or even inapplicable) in certain types of NPS, particularly the most severe. Nonetheless, it is widely accepted that these interventions must accompany and if possible precede introduction of psychotropic drugs for clinical management of NPS, with recognizable benefits for general state of health. 11 In this context, new therapeutic options to treat NPS are needed and eagerly awaited by the clinical and scientific community.
The endocannabinoid system (eCB) plays important homeostatic roles, modulating multiple physiological functions through signaling from widespread receptors (CB1 and CB2) present in the peripheral and central nervous systems. Systemically, the eCB is relevant to cardiovascular, immunological, and reproductive functions. 12 In the brain, with signaling predominantly through CB1 receptors, it impacts on distinct neurobehavioral functions that range from cognition (learning and memory) to behavior (mood regulation, emotional control, appetite, feeding, and addictive behavior), in addition to sensitivity to pain and mechanisms of neuroprotection. 13 Expression of CB1 receptors in the basal ganglia regulates locomotor activity, 14 whereas their expression in the cortex and hippocampus is predominantly related to cognitivebehavioral effects as well as to psychotropic and antiepileptic properties. The ubiquitous expression of cannabinoid receptors in the brain also illustrates their potential to interact with other neurotransmitter systems, such as those mediated by acetylcholine, or "cognitive decline" or Alzheimer* or "vascular dementia" or "frontotemporal dementia" or "semantic dementia" or aphasia or "language dementia" or "Lewy bodies" or "dementia in psychiatric diseases") and ("behavioral and psychological symptoms of dementia" or BPSD or "neuropsychiatric symptoms" or agitation or aggression or delusions or hallucinations or depression or anxiety or irritability or apathy or "sleep disorders" or insomnia or "appetite disorder" or disinhibition or cognition or cognitive). We also performed a manual

Controlled clinical trials
In a placebo-controlled study with a crossover design, Volicer et al. 17  Treatment with dronabinol substantially improved anorexia and weight gain, and also reduced the severity of behavioral disorders, e.g., agitation and euphoria.
Somnolence and tiredness were the most commonly Herrmann et al. 21 conducted a randomized, doubleblind, crossover trial with nabilone, a THC-analogue, synthetic cannabinoid that is used therapeutically for its antiemetic, orexigenic, and analgesic properties.
Thirty-eight patients with moderate and severe AD (mean age 87.0 years) and treatment-resistant agitation were given 1.0-2.0 mg of nabilone daily for 14 weeks. The first part of the intervention consisted of a 1-week placebo phase followed by 6 weeks of nabilone treatment. The second part of the study again started with a placebo intervention for 1 week, followed by 6 additional weeks of treatment with the active drug. Nabilone treatment was associated with a significant decrease in agitation, besides important reduction in related caregiver burden. Sedation constituted the most common emerging adverse event, which deserves particular consideration.

Open-label and observational studies
In an open-label pilot study, Walther et al. 22 examined the effects of dronabinol for six patients, aged 81.5 years (five with AD and one with VD at advanced stages of dementia) who suffered from behavioral and day-night rhythm disturbances. Patients received 2.5 mg of dronabinol daily for 2 weeks. Nighttime behavior was assessed using actigraphy. With this treatment, agitation and nocturnal motor activity decreased from baseline in all patients. Furthermore, irritability, anxiety and appetite disorders also improved.
However, delusions, hallucinations, and apathy did not change during dronabinol therapy. The drug was well tolerated, with no reported adverse events during the study. In an observational study, Broers et al. 24  tearing clothes) in most patients, who appeared to be calmer, more relaxed, less irritable, and smiling more.

Case reports
Favorable outcomes from the experience with medical cannabinoids were also described in case reports. Passmore 16 Table 1.
The studies were also summarized according to the level of evidence supporting the effects of the various cannabinoid drugs for treatment of NPS ( and in general, the statistical significance related to outcomes of studies varied widely.

Discussion
In spite of the enthusiasm of many clinicians including agitation and nighttime behaviors, 25,29 as well as in agitation and aggression with nabilone. 16,26 Notably, in patients with severe FTD, nabilone was effective for control of agitation and aggression, 26 with reduced disinhibition and sexual disorders. 27 Favorable results were also observed in patients with FTD suffering from agitation and anxiety who were given CBD (medical marijuana). 30 Conversely, in two controlled trials (level of evidence According to Murillo-Rodriguez, 31  Likewise, according to a review conducted by Crippa et al. 44 in patients with Parkinson's disease, CBD was well tolerated when prescribed for treatment of non-motor symptoms.

Methodological aspects and limitations
RCTs with adequate sample sizes, reputed as the Case studies also varied widely, from 7 to 78 days. Disclosure No conflicts of interest concerning the publication of this article.