[DRAFT] The Endocannabinoid System – Ch 6: Dementia & The ECS

Introduction

Dementia is a group of diseases characterized by progressive and debilitating symptoms including cognitive decline, memory loss, and changes in perception and personality. According to the World Health Organization, there were around 50 million persons worldwide suffering from dementia in 2017, and this number is increasing with the global aging of the population in most countries. The most common types of dementia are Alzheimer’s disease (50–70%) and vascular dementia (20–30%) which have different aetiologies and disease courses. Common to all dementia types is the suite of neuropsychiatric symptoms (NPS) including agitation, aggression, wandering, apathy, sleep disorders, depression, anxiety, psychosis, and eating disorders. It is estimated that up to 90% of people living with dementia will experience at least one of these symptoms in their disease course.

First-line treatment for NPS in dementia involves a range of non-pharmacological interventions, despite a limited and disparate evidence base. These interventions are based upon identifying unmet physical and emotional needs that may be triggering the NPS and may include assessment for inadequately treated pain and unpleasant environmental factors. Second-line treatment of NPS involves the use of pharmacological interventions, usually in addition to the non-pharmacological strategies. Pharmacological intervention is usually warranted when a person becomes a risk to either themselves or others and non-pharmacological interventions have been unsuccessful. The most common class of medications used to treat NPS in dementia is atypical antipsychotics (e.g. risperidone, olanzapine, and quetiapine), although not all countries approve the use of these medications to treat NPS in dementia.

Given the limited range, questionable effectiveness and side-effect profile of current therapeutic options for treating NPS of dementia, research into alternative therapies are a priority for this growing and vulnerable population. In recent years, research has focused on developing novel therapeutic agents to treat a range of NPS in dementia. Following the identification of two main cannabinoid receptors (CB1, predominantly in the central nervous system, and CB2, predominantly in the immune system), cannabinoids have been investigated for their safety and efficacy in treating NPS of dementia.

Dysregulation of endocannabinoid production and/or receptor expression has been reported under different pathophysiological conditions, including nociception, emotional disorders, energy imbalance, neurodegenerative diseases, cancer, diabetes, metabolic disorders, and cardiovascular disease among others. There is evidence to suggest that cannabinoids can reduce neurodegeneration, and neuroinflammation and have neuroprotective effects through the activation of the CB1 and CB2 receptors. The CB1 receptors are present in great density in the cerebral cortex, hippocampus, basal ganglia, and cerebellum. The CB2 receptor activation has been associated with reduced production of pro-inflammatory compounds and the removal of amyloid-beta (Aβ) plaques among humans. Alzheimer`s disease is characterized by progressive neurodegeneration due to the formation of β‐amyloid plaques, neurofibrillary tangles, gliosis, and neuroinflammatory response. All these effects lead to loss of cognitive function. There is also evidence to suggest that cannabinoid receptor agonists, including WIN55,212-2 and arachidonyl-2-chloroethylamide, may reduce aggressive behaviors.

Literature

A review was published by the University of South Australia to identify, describe and critically appraise studies investigating cannabinoid use in treating NPS in dementia. The cannabinoids used in the included studies were dronabinol (dose range = 2.5–7.03 mg/day), delta-9 tetrahydrocannabinol (THC; Namisol®; dose range = 1.5–15 mg/day) or nabilone (dose range = 0.5–2.0 mg/day) and were all administered orally. The mean age ranged from 72.7 to 81.5 years, with the proportion of males included ranging from 30 to 100%. Dronabinol (three studies) and THC (one study) was associated with significant improvements in a range of neuropsychiatric scores. The most common adverse drug event (ADE) reported was sedation. The researchers concluded that while the efficacy of cannabinoids was not proven in a robust randomized control trial, observational studies showed promising results, especially for patients whose symptoms were refractory. In addition, the safety profile is favorable as most of the ADEs reported were mild.

A collaboration between The National Institute on Alcohol Abuse and Alcoholism and the Rutgers New Jersey Medical School in the US made an extensive review of the role of the Endocannabinoid System modulation in the neuroprotection during the oxidative stress seen in neurodegenerative diseases. Notably, the non‐psychoactive, marijuana‐derived cannabinoid, cannabidiol (CBD) has been shown to exert potent neuroprotective effects against neuroinflammation. CBD was shown to prevent hydrogen peroxide‐induced oxidative damage in neuronal cultures, effectively decreased ROS production, caspase‐3 activation, and attenuated ER stress‐induced apoptosis via mechanisms that do not depend on CB1, CB2, TRPV1, or PPARγ signaling, suggesting a unique cannabinoid receptor-independent neuroprotective mechanism most likely related to the direct antioxidant and anti-inflammatory effect of this compound. Thus, the non‐psychoactive phytocannabinoid, CBD has been demonstrated to be neuroprotective in vitro and in vivo in Alzheimer`s disease models.

A review by the health system MetroHealth and Diamond Healthcare in the US examined the cannabinoids for the treatment of behavioral and psychological symptoms of dementia. Behaviors that were improved with the use of cannabinoids included agitation, aggression, impulsivity, nocturnal restlessness, wandering, and poor sleep. It was unclear from these studies whether any particular type of BPSD (behavioral and psychological symptoms of dementia) responded better to the treatment with the cannabinoids. Moreover, seven of the eight studies indicated that symptoms of BPSD improved with the use of cannabinoids. Only one study found that there was no benefit to using THC when compared with a placebo in the treatment of BPSD over a 12-week period at a maximum dose of 3 mg a day. Four of the eight studies did not report any significant adverse effects with the use of cannabinoids. The authors concluded that cannabinoids appear to show promise in the treatment of BPSD with some benefit in ameliorating symptoms while having a limited adverse effect profile. However, current data on the use of cannabinoids in the treatment of BPSD should be considered as preliminary.

A pilot study completed by the University of Geneva in Switzerland aimed to demonstrate the feasibility of the administration of a THC/CBD-based oil medication in patients with severe dementia and BPSD and/ or rigidity living in one nursing home in Geneva. This prospective observational pilot study of 10 patients received a cannabinoid-based medication with an average age of 79.5 years. Ten female demented patients with severe behavior problems received oral medication with on average 7.6 mg THC/13.2 mg CBD daily after 2 weeks, 8.8 mg THC/17.6 mg CBD after 1 month, and 9.0 mg THC/18.0 mg CBD after 2 months. The introduction of the medication was according to protocol with the principle of “start low, go slow,” stop when sufficient effect, and stop the medication when no effects or side effects. The medication was given three times daily. The nurses used medication with a natural cannabis extract, with a THC/CBD ratio of 1:2. Other studies used pure, often synthetic, THC medications; the researchers hypothesized that a natural cannabis extract might be better tolerated and/or that CBD adds to the overall positive effects on behavior. As a result, half of the patients decreased or stopped other psychotropic medications. The staff appreciated the decrease in rigidity, making daily care and transfers easier, the improved direct contact with the patients, the improvement in behavior, and the decrease in constipation with fewer opioids. There was no withholding of the medication for reasons of side effects, and the effects persisted after 2 months. An oral cannabis extract with THC/ CBD, in higher dosages than in other studies, was well tolerated and greatly improved behavior problems, rigidity, and daily care in severely demented patients. The cannabis oil has to be given with some oil-rich food; after having tried out different food options, the nurses found that putting the drops on a small piece of chocolate cake was the best administration option.

Limitations

The major limitations of these studies included a small number of participants and a short study duration. Moreover, in spite of the numerous promising results with cannabinoids in preclinical models of Alzheimer`s disease, suitable clinical studies are still lacking in patients suffering from Alzheimer`s disease. Clinical studies conducted so far have focused on the symptom-relieving effects of cannabinoids (dronabinol, CBD), however, they did not investigate the effect of cannabinoids on the progression of this devastating disease.

Conclusions

Dementia is increasing worldwide. No effective medication is currently available for the treatment of the underlying disease and accompanying behavioral symptoms. Currently, the options for treating BPSD include pharmacological and non-pharmacological therapies. Psychotropic medications are often used to reduce the frequency and severity of BPSD, but in the majority of patients, they provide only modest symptom control and important side effects.

While the efficacy of cannabinoids was not proven in a robust RCT, observational studies showed promising responses, especially for refractory patients. In addition, the safety profile presented was favorable, as the majority of ADEs reported were mild. Positive data from additional well-controlled and sufficiently larger studies with longer treatment time duration and specific endpoints that include the evaluation of cannabinoid effects on BPSD are necessary before cannabinoids could be labeled as definitive agents for the treatment of BPSD. Furthermore, former studies often used pure THC, since this was considered the “active” ingredient of cannabis. Basic research suggests that the interest in cannabinoids in Alzheimer’s disease, and other forms of dementia, goes well beyond THC only. Therefore, future studies should consider cannabinoid-based medication to focus more on standardized extracts of natural cannabis with different cannabinoids.

Moreover, targeting the ECS in order to modulate redox state‐dependent cell death, and to decrease consequent or preceding inflammatory response holds therapeutic potential in a multitude of oxidative stress‐related acute or chronic neurodegenerative disorders from stroke and traumatic brain injury to Alzheimer`s and Parkinson`s diseases, and multiple sclerosis, just to name a few. Since oxidative/nitrative stress and NO production by active astrocytes and microglial cells in neurofibrillary tangles are the hallmarks of Alzheimer`s disease even in early phases, therapies targeting ROS production might hold great therapeutic potential in slowing the progression of the disease. For the moment, it appears that targeting CB2 signaling with selective agonists in various neuroinflammatory/neurodegenerative diseases may represent a promising therapeutic avenue to attenuate inflammation and interrelated oxidative/nitrative stress if the impending target validation studies and studies with novel ligands are successful. Certain cannabis-based natural constituents, such as cannabidiol, may also have therapeutic potential to treat certain human diseases associated with oxidative stress and inflammation.

Broers, B., Patà, Z., Mina, A., Wampfler, J., de Saussure, C., & Pautex, S. (2019). Prescription of a THC/CBD-Based Medication to Patients with Dementia: A Pilot Study in Geneva. Medical Cannabis and Cannabinoids, 1–4. doi:10.1159/000498924 

Hillen, J. B., Soulsby, N., Alderman, C., & Caughey, G. E. (2019). Safety and effectiveness of cannabinoids for the treatment of neuropsychiatric symptoms in dementia: a systematic review. Therapeutic Advances in Drug Safety. https://doi.org/10.1177/2042098619846993

Paloczi, J., Varga, Z. V., Hasko, G., & Pacher, P. (2018). Neuroprotection in Oxidative Stress-Related Neurodegenerative Diseases: Role of Endocannabinoid System Modulation. Antioxidants & Redox Signaling, 29(1), 75–108. doi:10.1089/ars.2017.7144 

Tampi, R. R., Young, J. J., & Tampi, D. J. (2018). Cannabinoids for the treatment of behavioral and psychological symptoms of dementia. Neurodegenerative Disease Management. doi:10.2217/nmt-2018-0019