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Cannabinoids for the treatment of dementia

This article has been updated. “Cannabinoids for the treatment of dementia” in volume 2021, CD012820.

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine the efficacy and safety of cannabinoids for the treatment of dementia.

Background

Description of the condition

Dementia is a common chronic condition mainly affecting older adults and characterised by a progressive decline in cognitive and functional ability. The most common forms of dementia include Alzheimer’s disease (AD) (60% to 70% of cases), vascular dementia (VaD), dementia with Lewy bodies (DLB), dementia in Parkinson’s disease (PDD) and frontotemporal dementia (FTD). The boundaries between different subtypes of dementia are indistinct and mixed forms often co‐exist (WHO 2013).

It has been estimated that there were 47 million people worldwide living with dementia in 2016, and the number was projected to increase to more than 131 million in 2050 due to population ageing (ADI 2016). This disabling condition brings with it a significant burden to the individuals and their carers, as well as a large financial burden for the health system (Standfield 2017), thus driving the need to identify effective therapeutic interventions.

Medical treatments for dementia are limited. Licensed medications are available only for dementia due to AD and PDD and these have only modest benefits for cognitive symptoms. At least half of patients with dementia will also experience behavioural and psychological symptoms (BPSD) such as agitation, aggression, psychosis and circadian rhythm disturbances. These symptoms lead to significant caregiver stress (Rabins 1982), are distressing for the patient, and often precipitate placement in residential or nursing homes (Steele 1990). Antipsychotic drugs are widely used to treat BPSD but have only modest efficacy (Ballard 2006; Schneider 2006). Use of these drugs in dementia is also associated with serious side effects including an increased risk of cerebrovascular adverse events and death (FDA 2005; MHRA 2004; Schneider 2005). A range of pharmacological and non‐pharmacological interventions is used for BPSD, but there are still continuing problems with their lack of efficacy, safety and feasibility. Accordingly, there is a need for new, safe and more effective treatments for dementia and its associated symptoms.

Description of the intervention

The cannabinoids are one potential agent under investigation for the treatment of dementia. Multiple studies conducted among patients have indicated that they have positive attitudes towards medical cannabis (Banwell 2016; Gazibara 2017). There are three general classes of cannabinoids, including herbal cannabinoids (phytocannabinoids) that are derived from the cannabis plant (Cannabis sativa), endogenous cannabinoids that are produced in bodies of humans and animals, and synthetic cannabinoids that are produced in a laboratory. Cannabis, also known as marijuana, is preparation of the Cannabis plant. It is one of the most popular recreational drugs; an estimated 183 million annual users globally used cannabis in 2015, which roughly corresponds to 3.8 per cent of the global population (UNODC 2017). The use of cannabis is illegal in most countries. Although the general public may perceive cannabis as the least harmful illicit drug, there has been a noticeable increase in the number of patients seeking treatment for disorders related to cannabis use over the past decade (UNODC 2017).

Some countries have recently legalised medicinal‐grade cannabis for chronically ill patients. Nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, and Tourette syndrome are some indications for its legal use. Anxiety, drowsiness, euphoria, dry mouth, psychosis, dizziness and diarrhoea are known adverse effects (Whiting 2015).

The first cannabinoids to be identified were the main psychoactive compound delta‐9‐tetrahydrocannabinol (THC) and the non‐psychoactive compound cannabidiol (CBD), although there are thought to be numerous other cannabinoids, some of which may modulate the response to THC (Iversen 2000). Research for medical use of cannabinoids has resulted in development and marketing of synthetic cannabinoids dronabinol and nabilone. Dronabinol may be taken orally, or via local/topical, transdermal, sublingual or inhaled mode of administration. Nabilone is taken orally as a capsule. Daily dosage and route of administration depends on indication (Howard 2013). Nabilone and dronabinol are used as interventions for reducing vomiting associated with chemotherapy. A combination of cannabidiol and THC (Sativex) has been approved in several countries for treating spasticity in multiple sclerosis and it is being studies for cancer pain. The cannabidiol drug (Epidiolex) has been studied for use in epilepsy. Many ongoing studies are exploring therapeutic targets for both cannabinoid receptor agonists and antagonists (Kaur 2016).

Cannabinoids exert their effect by acting at two specific cannabinoid receptors, CB1 and CB2, in the endogenous cannabinoid system (Howlett 2002; Matsuda 1990). CB1 receptors are found throughout the central nervous system, particularly in the hippocampus, basal ganglia and cerebellum. In contrast, CB2 receptors are expressed in peripheral tissues, especially on white blood cells, and are much less widespread in the central nervous system (see Campbell 2007 for a review). Several studies have identified CB2 receptors on brainstem neurons (Van Sickle 2005) and cerebellar neurons (Onaivi 2006), but their role is not yet understood.

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How the intervention might work

Several neurobiological effects of cannabinoids have been demonstrated which could be relevant in the treatment of dementia. The main function of the endogenous cannabinoid system (ECS) is thought to be the regulation of synaptic transmission (Baker 2003) and this process can be disordered in many neurological conditions including dementia. The ECS consists of endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and enzymes responsible for synthesis and degradation of endocannabinoids (Lu 2016). The best characterised endogenous cannabinoids are anandamide (arachidonoyl ethanolamide) and 2‐arachidonoyl glycerol (2‐AG); there are also less characterised additional endogenous substances such as virodhamine and 2‐arachidonoyl glycerol ether that also belong to the repertoire of endocannabinoids. Endocannabinoids exert their actions mainly by acting on cannabinoid receptors CB1 and CB2 (Gowran 2011); other receptors such as Peroxisome Proliferator Activated Receptors (PPARs) and Transient Receptor Potential (TRP) channels also mediate certain endocannabinoid actions, especially of the acylethanolamides. Relevant enzymes are fatty acid amino hydrolase (FAAH) involved in degradation of anandamide, monoacylglycerol lipase (MGL) and alpha/beta domain hydrolases 6 and 12 (ABHD6 and 12) involved in degradation of 2‐AG (Lu 2016).

CB1 receptors are found mainly in the central and peripheral nervous system where they usually mediate inhibition of ongoing release of different neurotransmitters (Szabo 2005). Activation of CB1 affects cognition and memory, alters the control of motor function, and induces signs of analgesia (Pertwee 2010). They regulate processes such as excessive glutamate production and subsequent oxidative stress, which can damage neurons and lead to neurodegeneration (Grundy 2002).

They are also found in peripheral tissues where they have a role in energy balance and metabolism (Silvestri 2013). CB2 receptors modulate immune cell migration and cytokine release, as they are located mostly in the immune cells (Pertwee 2005), while in the central nervous system, they are mainly located in the microglia (Cabral 2009), and in some neurons (Brusco 2008, Onaivi 2008), where they are connected with facilitation of neuronal survivor (Viscomi 2009).

There is also some evidence that CB2 receptors may be involved in neuroprotection by reducing neuroinflammation (Ehrhart 2005). Neurodegeneration is a feature common to the various types of dementia and the neuroprotective effects of cannabinoids may therefore be beneficial in slowing the progression of these diseases.

Some authors have reported a significant reduction in the CB1 levels in cortical areas and neurons distant from senile plaques (Solas 2013), while others indicate that there are changes in the expression, distribution and availability of CB1 in AD (Ahmad 2014; Mulder 2011). According to Solas and colleagues, there is a significant increase of CB2 levels in the brains of people with AD, mainly on the microglia around the senile plaques (Solas 2013). Besides, CB1 and CB2, cannabinoids can bind to other types of receptors, such as GPR55, peroxisome proliferator‐activated receptors PPARα and PPARγ, and transient receptor potential vannilloid‐1 (TRPV1) channels (Maccarrone 2010; Pertwee 2010).

Cannabinoids may have more specific effects in Alzheimer’s disease pathology, as they can reduce excitotoxicity, mitochondrial dysfunction, oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles (Ahmed 2015; Aso 2014). Several studies have shown the protective effect of cannabinoids against amyloid‐β peptide and tau phosphorylation (reviewed in: Aso 2014), which are the neuropathological hallmarks of AD.

THC diminishes acetylcholinesterase‐induced amyloid beta‐peptide aggregation, the key pathological marker of AD (Ahmed 2015; Eubanks 2006). It has also been reported that THC competitively inhibits the enzyme acetylcholinesterase (AChE) ‐ a similar action to the anti‐dementia drugs like donepezil (Ahmed 2015). Another study investigated the effects of cannabinoids in rats injected with amyloid beta‐peptide to model AD. Intracerebroventricular administration of a synthetic cannabinoid (WIN55,212‐2) to these rats led to a prevention of their cognitive deficit and decreased neurotoxicity (Janefjord 2014; Ramirez 2005). These studies suggest that cannabinoids could interrupt the disease process as well as treat symptoms in AD. Endocannabinoids (AEA, 2‐AG, noladin ether) seem to increase the viability of neurons after exposure to toxic Aβ species (Chen 2011; Harvey 2012). Similar effect was reported with exogenous cannabinoids such as CBD (Janefjord 2014), ACEA (Aso 2012), JWH‐015, JWH‐133 and HU‐210 (Ramirez 2005). Several studies demonstrated positive results in prevention of memory deficits in Aβ‐injected rats and mice for exogenous cannabinoids (Aso 2013; Martin‐Moreno 2012; Wu 2013).

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These studies indicate that the disease‐modifying action of cannabinoids is most likely. However, there are also known symptomatic effects of cannabinoids which may be of benefit in dementia. The most common neuropsychiatric symptoms (NPS) in dementia, including depression, anxiety, agitation, aggression, wandering, pacing, sleep disorders, psychosis, and eating disorders, are associated with more rapid dementia progression and higher healthcare costs (Beeri 2002; Tschanz 2013). To this day, no drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of the NPS associated with AD dementia (Ahmed 2015), while in the European Union and Australia, only the antipsychotic risperidone is indicated for the short‐term management of severe aggression in patients with AD, with unsuccessful non‐pharmacological methods (Panza 2015). A recent review indicated that findings from six studies showed significant benefits from synthetic cannabinoids dronabinol or nabilone on agitation and aggression; however conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies (Liu 2015). In another randomised controlled trial (van den Elsen 2015), oral THC 4.5 mg daily showed no benefit in the treatment of neuropsychiatric symptoms, but it was well‐tolerated, which allows further study on whether higher doses would be more efficient. An open‐label pilot study evaluated the effect of dronabinol in the treatment of NPS in dementia and showed that it significantly improved nocturnal motor activity and behaviour (Walther 2006). A recent retrospective systematic chart review suggested that administration of dronabinol improved sleep duration, food consumption and agitation (Woodward 2014).

Why it is important to do this review

Because of the increasing number of elderly people, the number of new cases of dementias is projected to rise. There is a growing need to offer effective and safe interventions to people with dementias. Since firm evidence of efficacy and safety of cannabinoids in this vulnerable patient group is lacking, a systematic review can help inform decisions of healthcare workers, researchers, politicians and other public health decision makers.

Objectives

To determine the efficacy and safety of cannabinoids for the treatment of dementia.

Can CBD Help with Dementia?

CBD, which stands for cannabidiol, has become a pretty popular product in recent years. Cannabidiol is just one of the many compounds found in cannabis. While it’s not a miracle drug, there are many benefits that could potentially be had from using the compound according to scientific research. You may have heard about how CBD could help relieve pain and improve your sleep. However, did you know that CBD can help with dementia?

What is Dementia?

Dementia, according to a review called Medical Cannabis for the Treatment of Dementia: A Review of Clinical Effectiveness and Guidelines is simply a set of “symptoms and signs associated with a progressive deterioration of cognitive functions that affects daily activities”. According to the World Alzheimer Report 2018, 50 million people were living with dementia. Unfortunately, it doesn’t seem to be going anywhere anytime soon. The number of people that will be living with dementia in 2050 was predicted to be 152 million.

Types of Dementia

There are actually multiple types of dementia. Alzheimer’s, the most common form, accounts for two-thirds of all dementia. However, other cases, according to the review are vascular dementia, mixed dementia, Lewy body dementia, frontotemporal dementia, and young-onset dementia.

Signs and Symptoms of Dementia

There are a variety of signs and symptoms associated with the disease, it’s really not just memory loss.

According to the review, signs and symptoms include:

  • difficulties with thinking
  • problem-solving or language
  • changes in mood, perception, personality, or behavior

Neuropsychiatric symptoms, which are common to all forms of dementia include:

  • Agitation
  • Aggression
  • Wandering
  • Apathy
  • Sleep disorders
  • Depression
  • Anxiety
  • Psychosis
  • Eating disorders

Can CBD Help with Dementia?

Although some have posited that CBD reverses dementia, unfortunately, dementia currently has no cure nor can the progression of the disease be altered. However, CBD may help ease some of the uncomfortable signs and symptoms associated with the disease. The review says that the way in which CBD helps dementia is not crystal clear but what they do know is that CBD interacts with the neurotransmitters that are responsible for or involved in the manifestation of neuropsychiatric symptoms.

Alzheimer’s Disease and CBD Treatment

According to Dementia Care Central, fortunately, CBD has been shown to either reduce or remove the impact of inflammation. The inflammation is responsible for a lot of the negative effects of Alzheimer’s. The inflammatory response occurs when the brain’s immune cells are not able to clear disorienting blockages. Oxygen is released and starts building up. According to the article, “Important brain functions such as memory are decreased as more oxygen is released in the brain’s cells. Memory loss and other brain deterioration indirectly leads to increased oxygen in the brain”. CBD acts as an antioxidant and counteracts the effects of oxygen stress on the brain.

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A 2011 study by Australian researchers Tim Karl and Carl Group concluded, according to Dementia Care Central, that that CBD promotes the growth and development of brain cells, reducing the decline of memory and other brain functions.

Therefore CBD seems as if it can reduce inflammation, oxygen buildup, and brain cell decline.

CBD for Vascular Dementia

Vascular Dementia is a form of dementia characterized by experiencing thought processes such as reasoning, planning, judgment, memory as a result of brain damage caused by an impairment of blood flow to the brain. CBD may help increase blood flow to the brain. According to Dementia Care Central, “Activating the CB2 receptors with CBD has increased brain cell activity and helped reduce brain cell damage commonly associated with vascular dementia.”

CBD for Lewy Body Dementia

Dementia with Lewy Bodies refers to a disease characterized by an abnormal amount of alpha-synuclein otherwise known as Lewy bodies deposited in the brain. According to the Alzheimer’s Association, these deposits, though microscopic, damage the brain cells. Dementia with Lewy bodies results in a decline in thinking, reasoning and independent function. Fortunately, CBD can be helpful. According to Dementia Care Central, “CBD can be an effective anti-inflammatory agent, reduce motor symptoms (tremor, rigidity, bradykinesia) and maintain circadian (sleep) rhythms”. It was also noted that it doesn’t block acetylcholine which this disease preys on. Acetylcholine is essential for memory and learning. The fact that CBD doesn’t block acetylcholine is great. Traditionally, patients suffering from this disease are given a cholinesterase inhibitor drug which prevents the breakdown of acetylcholine.

CBD for Frontotemporal Dementia / Pick’s Disease

According to Dementia Care Central, Pick’s Disease is a “progressive nerve cell loss in the brain’s frontal lobes (the areas behind one’s forehead) or its temporal lobes (the regions behind one’s ears)”. This disease leads to depression or psychosis and usually requires antipsychotic drugs for treatment. Unfortunately, antipsychotic drugs may increase the risk of death. On the bright side, CBD does not do that and may actually improve your sleep, reduce anxiety, attack inflammation, and reduce motor symptoms such as tremor, rigidity, and bradykinesia.

CBD Dementia Counterclaims & CBD Oil for Dementia

However, not everyone is fully convinced of CBD’s role in treating dementia. According to Alzheimer’s Society, the studies done have been small and low quality and so that makes it harder to come to a conclusion. The article also expresses concern about the concentration of CBD oil for dementia used in the studies and its long term effects. The article said, “these studies have used high concentrations of CBD oil that may not be available to buy. These studies have also been short term so we still don’t know what the long term effects of using CBD oil might be.” That said, it is not certain what is the best CBD dosage for dementia.

As for right now, CBD has been labeled as safe to try. According to the World Health Organization (WHO), “In humans, CBD exhibits no effects indicative of any abuse or

dependence potential….” Just be on the lookout for product mislabelling especially if you have drug tests coming up.

CBD and Dementia Conclusion

CBD to treat dementia appears to be a good addition to the plethora of medication used to treat the varying forms of dementia. Of course, more research is always a good thing and so hopefully scientists continue to research and find out more about how CBD works against dementia.

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