cbd oil for 85 years old alzheimer’s

Older adults and medical marijuana: Reduced stigma and increased use

As a primary care doctor who has incorporated medical cannabis into his practice, it is notable how many silver-haired patients are coming in to discuss the pros and cons of a trial of medical cannabis. These patients range from people in their 60s with kidney failure who can no longer take certain pain medications but still need to manage chronic pain, to patients in their 90s, who are looking for a good night’s sleep and are leery of the side effects of traditional sleep medications. Some of them — typically “children of the 60s” — are quite comfortable with the idea of using medical marijuana; others bring it up quietly, as if they are asking permission to break the law.

According to a recent study in the Journal of the American Medical Association, cannabis use among older adults (defined as 65 and older) in the US has been steadily increasing. In this study, the prevalence of past-year use increased from 2.4% to 4.2% from 2015 to 2018. This study is consistent with other research, as well as with reports from physicians who recommend cannabis in their daily practices.

What might be behind this trend?

A confluence of factors seems to be responsible, including the decrease in stigma associated with cannabis use and the increased interest in the use of medical marijuana by older patients. Stigma is a complicated issue, but most would agree that the stigma associated with cannabis use is lessening, especially for medical cannabis. In a recent poll, 94% of Americans voiced support for legal access to medical marijuana, and most states have approved some form of legal access.

One marker for the decrease in stigma is the recent statement by the 38 million-member AARP, in which they declared their support for the medical use of marijuana for older adults in states that have legalized it, in close consultation with their medical providers, where they can discuss the most up-to-date clinical evidence, weighing the balance of benefits and harms.

What conditions are older adults using cannabis for?

Studies show that older adults commonly use medical cannabis for the same conditions younger patients do: pain, insomnia, neuropathy, and anxiety.

What are the risks for older people using medical cannabis?

This is new territory, as either there haven’t been large numbers of older adults who report using medical cannabis, or if they have been using it they have kept it quiet, due to its illegality and due to the stigma. Medical cannabis is typically well tolerated among older adults; however, as with all medications, there is no such thing as a free lunch, meaning that there are always side effects and downsides to consider.

Cardiac health and cannabis use

Cannabis is known to increase heart rate and can increase blood pressure, though there doesn’t seem to be much if any quality evidence directly linking cannabis use with coronary events, according to a recent review by the Journal of the American College of Cardiology. Still, the authors of this review do recommend screening people with coronary disease for cannabis use. The scenario that I would be most concerned about is an older patient, with underlying coronary disease, taking a very high dosage of cannabis (perhaps by mistake via edibles) and then having an anxiety attack, which could trigger a coronary syndrome or an arrhythmia.

Medication interactions

Older people tend to have comorbid health conditions and may be taking multiple medications. Cannabis has about 600 chemicals in it, and in theory, the two main active ingredients in cannabis, THC and CBD, could either increase or decrease the blood levels of other drugs you are taking, by affecting the enzymes in your liver that help metabolize your medications. CBD, in particular, is at risk for increasing the other drugs in your system by “competitively inhibiting” (or, in plain English, using at the same time) the molecules that you need to break down and clear these medications from your body.

People should be particularly cautious using cannabis with anti-seizure medications and with blood thinners, as these medications tend to have serious side effects and not as much room for error, and it is important that you always communicate with your medical providers about your cannabis use. Disclosing marijuana use is particularly important if you plan to have surgery, as the drugs used for anesthesia and post-surgical pain management may need to be adjusted.

Changes in thinking, both pro and con

The psychoactivity, or the high that cannabis causes, is another potential concern for older adults, especially those at risk for confusion and dementia. These days, with the ability to buy cannabis in medical dispensaries, there is more control over the types or strains of cannabis that one can buy and consume, and it is easier to avoid the high by controlling the dose and by keeping the THC content low. Strains that are low in THC (the chemical that causes the high) and higher in CBD, which is non-intoxicating, may be preferable to avoid the psychoactive experience of marijuana. Still, if an older person has experienced delirium, or any psychiatric conditions, they and their doctors should proceed with caution.

Interestingly, there is some research that cognitive functioning can actually improve when patients use medical cannabis, due to, among other things, improved sleep and pain control. It seems plausible that older patients might be using lower doses of pain and sleep medications, which can affect thinking, and they are combatting the negative effects of chronic pain and insomnia, which also have an effect on cognitive functioning. However, as with most things cannabis-related, this too needs further study to confirm and clarify.

What’s the bottom line?

Cannabis use among the elderly is growing as there is more public acceptance and reduced stigma. Medical cannabis is increasingly viewed as an effective option for managing insomnia and chronic pain. It’s key to have an informed discussion with your doctor to weigh the safety risks, especially if you have cardiac issues, are taking multiple medications, or have cognitive changes due to aging. Educate yourself (and your doctor) as much as possible about cannabis before starting to use it. Most of the adverse effects associated with cannabis usage are dose-related, so it is important to know the strength of the marijuana you are taking and to “start low and go slow”: start with the lowest effective dose and take your time working your way up to a dose that alleviates your symptoms with a minimum of side effects.

Disclaimer:

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Comments

I have enjoyed reading your blog on the use of CBD for insomnia and chronic pain which I suffer from. I have been taking Ambien and Tramadol for almost 4 years in order to sleep more than 4 hours. I also had a pacemaker put in to increase my slow heart rate which means I also take eliquis twice daily. I would dearly love to get off the Ambien and Tramadol and was wondering if CBD would be a viable option. Also, would adding THC help? I discussed this with my family physician in passing but have not pursued it. I am currently 68 which makes me one of those children of the 60’s. I also live in NC where medical marijuana has not been legalized. Your thoughts would be appreciated.

Not mentioned here: adverse effects of smoking cannabis (chronic bronchitis) and the potential for addiction to cannabis in a small percentage of users.

Thank you for your helpful comments. While chronic bronchitis is a real concern very heavy cannabis smokers, most elderly people don’t use inhalational methods of consumption (and certainly aren’t encouraged to do so by their providers!), so chronic bronchitis is not a commonly seen issue. While the possibility of dependence on and, less commonly, addiction to cannabis is a real concern as well, this is something that is discussed by the provider with the patient as it is being recommended (as is the case with most medicines which have side effects as they are prescribed). For context, it is important to note that the risk of addiction to cannabis is significantly less compared to the rates seen in the opiates and benzodiazepines or other sedative/hypnotics that they are quite often replacing.

Medical Cannabis for Older Patients—Treatment Protocol and Initial Results

Older adults may benefit from cannabis treatment for various symptoms such as chronic pain, sleep difficulties, and others, that are not adequately controlled with evidence-based therapies. However, currently, there is a dearth of evidence about the efficacy and safety of cannabis treatment for these patients. This article aims to present a pragmatic treatment protocol for medical cannabis in older adults. We followed consecutive patients above 65 years of age prospectively who were treated with medical cannabis from April 2017 to October 2018. The outcomes included treatment adherence, global assessment of efficacy and adverse events after six months of treatment. During the study period, 184 patients began cannabis treatment, 63.6% were female, and the mean age was 81.2 ± 7.5 years (median age-82). After six months of treatment, 58.1% were still using cannabis. Of these patients, 33.6% reported adverse events, the most common of which were dizziness (12.1%) and sleepiness and fatigue (11.2%). Of the respondents, 84.8% reported some degree of improvement in their general condition. Special caution is warranted in older adults due to polypharmacy, pharmacokinetic changes, nervous system impairment, and increased cardiovascular risk. Medical cannabis should still be considered carefully and individually for each patient after a risk-benefit analysis and followed by frequent monitoring for efficacy and adverse events.

1. Introduction

The recent interest and use of medical cannabis (MC) are growing substantially in many countries. The regulations on its use vary among countries, affecting medical practice and experience [1]. Current public opinion is that cannabis has the therapeutic potential to treat and cure a long list of diseases, but there is a large gap between that opinion and the current evidence in the medical literature [2]. Another common opinion is that MC is mainly used by young adults. However, the use of MC by older adults is increasing [3], and studies show variable prevalence, ranging from approximately 7% to more than one-third, depending on the country [4,5]. Recreational use of cannabis by older adults is also increasing substantially, especially in the United States [6].

Relief of suffering and promotion of functional status and quality of life are major goals of geriatric medicine. Chronic pain, Parkinson’s disease, depression, sleeping disorders, and malnutrition are all common among older adults [7,8,9,10,11,12]. Current medical treatments of these syndromes can have serious adverse events, frequently endangering patients’ health. For example, some non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal bleeding, renal impairment, and cardiovascular adverse events [13]. Sedative hypnotics can cause psychomotor impairment, dizziness, confusion, increased risk of falls, next-day somnolence, impairment of driving skills, orthostatic hypotension, and blood electrolyte impairment [14]. Opioid treatment causes constipation, nausea, vomiting, drowsiness, delirium, sedation, anticholinergic effects, falls, and respiratory depression, which is the most serious potential adverse effect [13]. Beyond individual factors, current concerns about opioid-related deaths have greatly influenced our thinking about pain management and medication treatment [15].

1.1. Efficacy and Indications for Medical Cannabis in Older Adults

The geriatric population may benefit from cannabis treatment for a variety of symptoms, such as chronic pain, sleep difficulties, tremor, spasticity, agitation, nausea, vomiting, and reduced appetite. Cannabis may also be useful in palliative care. However, currently, there is a dearth of evidence about the efficacy of cannabis in older adults for any of these symptoms. This has been emphasized in several reviews [16,17,18] and in large reports such as the report of the National Academies of Sciences in the United States [19] and the Information for Health Care Professionals in Canada [20].

1.2. Chronic Pain

Chronic pain is one of the most common indications for prescribing MC. The report by the National Academies of Sciences concludes that cannabis is effective for the treatment of chronic pain in adults [19]. Despite this conclusion and a large number of studies, including randomized controlled trials, the efficacy for cannabis as a chronic pain medication remains in dispute [21]. Pain relief is very often cited as a reason for MC use among older individuals. For example, 89.7% of the older patients in the Colorado MC registry listed pain as their primary or secondary condition [4]. All the large studies that evaluated cannabis for pain have included older adults in the inclusion criteria, but their number was small, or they were not analyzed separately for safety and efficacy [21,22].

1.3. Parkinson’s Disease

Parkinson’s disease (PD) is a common neurodegenerative disease found mostly among older adults, which is caused by dopaminergic neuron loss. It is mainly characterized by motor symptoms that include bradykinesia in combination with resting tremor or rigidity [23]. PD also has a distinct prodromal stage identified by non-motor symptoms, such as olfactory dysfunction, constipation, urinary dysfunction, depression, anxiety, and pain [24]. Two small-scaled randomized controlled trials failed to demonstrate the efficacy of cannabis in treating the motor symptoms of PD [25,26]. However, cannabis might improve quality of life in PD and relieve other non-motor symptoms [27].

1.4. Sleep Difficulties

Approximately 50% of people above age 65 complain about sleeping difficulties, and there is an increase in sleep disturbances in old age [28]. Care must be taken not to mistake geriatric sleep complaints for physiological aging, as these complaints are mainly attributable to medical, psychiatric and health-related burdens [29]. It should be noted that sleep disturbances are among the most frequent complaints of cannabis withdrawal, and are a major cause for continued use after attempts to quit [30]. Both pharmacological and non-pharmacological treatments are used to address sleep disorders among older individuals [31]. A meta-analysis evaluating the therapeutic effect of cannabis on sleeping disturbances has not reached a decisive conclusion. The effects of cannabis on the sleep–wake cycle are also unclear [32], though some research suggests that cannabis might aid in sleep disorders due to its anxiolytic effect [30].

1.5. Nausea and Vomiting

A Cochrane review concluded that “Cannabis-based medications may be useful for treating refractory chemotherapy-induced nausea and vomiting” [33]. A more recent review states that there is low-quality evidence that cannabinoids prevent nausea and vomiting as compared to other agents or a placebo [34]. The only study that addressed this issue in older adults was in 1982, and it found no difference between tetrahydrocannabinol (THC) and prochlorperazine in reducing nausea and vomiting [35].

1.6. Post-Traumatic Stress Disorder (PTSD)

The efficacy of cannabis treatment for PTSD in older individuals was not evaluated thus far in any study. Several studies evaluated the efficacy of cannabis treatment for PTSD in younger adults, but these studies also failed to demonstrate a clear effect of MC treatment for these patients [21].

1.7. Dementia

Dementia is a prevalent condition in older adults causing cognitive decline [36]. Small studies that used Dronabinol, oral synthetic Δ 9 -THC, or an extract of THC from plants, showed it improved neuropsychiatric symptoms, agitation, nocturnal motor activity, sleep duration, and meals consumption in dementia patients, while only a few serious adverse events were observed [37,38,39].

However, a study conducted with Namisol, an oral tablet containing ≥98% natural ∆ 9 -THC, showed it did not reduce neuropsychiatric symptoms, agitation, activities of daily living, or improved quality of life in dementia patients [40].

1.8. Palliative Treatment

A recent systematic review and meta-analysis were unable to make any recommendation about the use of cannabis in palliative care after evaluating studies that included mainly younger adults and a small number of older adults [41].

2. Special Considerations and Precautions

2.1. Pharmacokinetics, Pharmacodynamics, and Drug Interactions

It is well known that aging is associated with substantial changes in pharmacokinetics and pharmacodynamics. For instance, hepatic drug clearance, as well as renal elimination, are both decreased in older adults. Furthermore, aging is associated with increased body fat and decreased lean body mass [42], which increases the volume of distribution for lipophilic drugs, such as cannabis. Two small studies evaluated the pharmacokinetics and pharmacodynamics of older adults who received an oral drug containing pure THC. These phase I and phase II trials included 12 healthy older adults and 10 older adults with dementia, respectively, and found smaller pharmacodynamic effects of THC in both groups, although the pharmacokinetic data showed substantial inter-individual variation [43,44]. Interaction between cannabis products and other drugs is also largely unknown, as the current evidence from human studies is sparse [45]. Concomitant administration of cannabis with other drugs that influence the hepatic CYP family enzymes may greatly alter the metabolism of the cannabinoids [46]. This issue is especially important in the geriatric population, where polypharmacy is common [47].

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2.2. Nervous System Impairment

The common adverse effects experienced by patients due to cannabis use include dizziness, euphoria, drowsiness, confusion, and disorientation [16]. These effects are particularly important in the geriatric population, which may have conditions such as dementia, frequent falls, mobility problems, hearing, or vision impairments [48]. The long-term effect of adult cannabis use on cognition is unclear. Two systematic reviews showed evidence that long-term use of cannabis is associated with negative effects on some cognitive functions, but evidence of enduring negative effects was weak [49,50].

2.3. Cardiovascular Risks

The effects of cannabis on cardiovascular diseases are not yet well established. In recent years, however, there has been an increasing number of case series and reports concerning young, healthy recreational cannabis users who suffer from arrhythmias, myocardial infarction, and even sudden cardiac death [51]. Direct causality has not been proven, but the implication is that care must be taken concerning older adults since they have more cardiovascular comorbidities and risk factors.

The acute cardiovascular effects of cannabis, based on studies performed on younger individuals, include an increase in sympathetic activity that causes an increase in heart rate, cardiac output, and myocardial oxygen demand. Tolerance of the effects of cannabis on heart rate develops rather quickly in young people [52].

This article aims to present a novel medical cannabis treatment protocol in older adults and the initial results from its use. The protocol will be presented in the Discussion segment of the manuscript.

3. Methods

3.1. Patients and Methods

Israeli medical cannabis regulations include a number of indications and recommendations for its use [1]. We have adopted the general recommendations to suit the physiological and pathophysiological needs of the elderly. In 2017, NiaMedic established a specialized geriatric clinic to provide MC therapy within a comprehensive geriatric platform. We have followed 184 consecutive patients above 65 years of age prospectively who were treated with MC from April 2017 to October 2018. The patients were followed for at least six months since treatment initiation. The inclusion criteria were age of 65 years and above and any of the following indications for cannabis treatment: chronic cancer pain and non-cancer pain, Parkinson’s disease, sleep disorders, anorexia, post-traumatic stress disorder, spasticity, and palliative treatment. The exclusion criteria were severe cardiovascular diseases, such as heart failure or a recent major myocardial infarction, liver failure, psychotic comorbidities, and those with a history of addictions. The follow-up evaluation includes detailed questioning regarding adverse events, adherence to treatment, and its efficacy.

3.2. The Treatment Protocol

As previously mentioned, the regulations of cannabis and its products vary by country, which affects the clinical experience of physicians. In Israel, cannabis can be prescribed for the following conditions: nausea and vomiting due to chemotherapy treatment, cancer-associated pain; Crohn’s disease, ulcerative colitis; neuropathic pain; AIDS patients with Cachexia; multiple sclerosis, Parkinson’s disease, Tourette syndrome, epilepsy (both adult and pediatric population); palliative treatment; post-traumatic stress disorder [1]. The initially approved dosing is 20 grams of cannabis compound per month (0.6 grams per day), with a cannabis product that contains the lowest concentration of active ingredients, but without limitation to the ratio of the different cannabinoids. The only cannabinoid-based medicine that is approved at the time of this manuscript preparation is Nabiximols, and its use is infrequent. Thus, we provide here our approach that is based on the available literature, data analysis, and our clinical experience with treating older adults with herbal cannabis, which includes the cohort above and previously published data [53]. We offer many recommendations consistent with Minerbi et al. and MacCallum et al. [17,54].

3.3. Ethics

Our study collected all the relevant clinical data as a part of the routine medical practice. Thus, Soroka University Medical Center institutional review board (IRB) Committee approved the protocol and waived the request for informed consent (confirmation number 0036-18-SOR). All clinical investigations were conducted according to the principles expressed in the Declaration of Helsinki.

4. Results

We present here initial data from a cohort of patients who initiated MC therapy between April 2017 and October 2018. Most of our patients, 83.2% (n = 153) were 75 years of age or older, and 63.6% (n = 117) were females. The demographic characteristics, the comorbidities of the patients, and the indications for cannabis treatment are detailed in Table 1 . When we evaluated the patients after six months of MC treatment, we found that 58.1% were still using cannabis, 8.1% discontinued the treatment, 10.9% were lost to follow-up, and 17.9% did not complete six months of treatment by the time of the analysis. Of the 122 patients eligible to respond, 91.8% (n = 112) globally assessed the effect of cannabis on their general condition, with 84.8% of them reporting some degree of improvement ( Figure 1 ). Of the patients who were still treated with cannabis, 33.6% reported adverse events, the most common of which were dizziness (12.1%), sleepiness and fatigue (11.2%), dry mouth (5.6%), and psychoactive sensation (5.6%). Since well-established and evaluated protocols for treatment of older adults with cannabis do not exist, we have developed our own approach based on close follow-up of effects, adverse events, and slow titration.

Potential and Limits of Cannabinoids in Alzheimer’s Disease Therapy

This review was aimed at exploring the potentiality of drugging the endocannabinoid system as a therapeutic option for Alzheimer’s disease (AD). Recent discoveries have demonstrated how the modulation of cannabinoid receptor 1 (CB1) and receptor 2 (CB2) can exert neuroprotective effects without the recreational and pharmacological properties of Cannabis sativa. Thus, this review explores the potential of cannabinoids in AD, also highlighting their limitations in perspective to point out the need for further research on cannabinoids in AD therapy.

Abstract

Alzheimer’s disease (AD) is a detrimental brain disorder characterized by a gradual cognitive decline and neuronal deterioration. To date, the treatments available are effective only in the early stage of the disease. The AD etiology has not been completely revealed, and investigating new pathological mechanisms is essential for developing effective and safe drugs. The recreational and pharmacological properties of marijuana are known for centuries, but only recently the scientific community started to investigate the potential use of cannabinoids in AD therapy—sometimes with contradictory outcomes. Since the endocannabinoid system (ECS) is highly expressed in the hippocampus and cortex, cannabis use/abuse has often been associated with memory and learning dysfunction in vulnerable individuals. However, the latest findings in AD rodent models have shown promising effects of cannabinoids in reducing amyloid plaque deposition and stimulating hippocampal neurogenesis. Beneficial effects on several dementia-related symptoms have also been reported in clinical trials after cannabinoid treatments. Accordingly, future studies should address identifying the correct therapeutic dosage and timing of treatment from the perspective of using cannabinoids in AD therapy. The present paper aims to summarize the potential and limitations of cannabinoids as therapeutics for AD, focusing on recent pre-clinical and clinical evidence.

1. Introduction

Alzheimer’s disease (AD) is one of the principal conditions of disability among older people, which impairs a person’s ability to function in daily life. Currently, it is estimated that more than 50 million people are suffering from AD worldwide [1]. Furthermore, since one of the main risk factors of AD is aging, and the human lifespan is constantly increasing, the number of AD cases is projected to double in the following decades [1]. AD can be divided based on its pathophysiology in sporadic or late-onset AD and familial or early-onset AD. Sporadic AD, the preeminent form of AD (about 95% of all cases), is a multifactorial disease, where the etiopathogenesis is still not fully understood and is influenced by epigenetic and genetic variants combined with environmental and lifestyle factors. In contrast, familial AD is rare (<5%) and is caused by gene mutations of amyloid precursor protein (APP) and presenilin-1 and 2 (PSEN1 and PSEN2) [2]. Both sporadic and familial AD develop a similar pathology consisting of parenchymal deposition of amyloid-β (Aβ) in plaques and intraneuronal accumulation of hyperphosphorylated tau protein, leading to brain inflammation and oxidative stress that have a fundamental impact on the onset of the disease [3,4,5]. To date, there is no effective cure, and the treatments available can reduce only the symptoms in the initial phase of the disease. For that reason, it is of paramount importance to identify novel effective compounds for counteracting the AD course or even treat the disease [6,7]. Therefore, a better understanding of the etiopathological mechanisms involved in AD may provide novel effective, druggable targets for AD treatment.

The Endocannabinoidergic System (ECS) plays an essential role in brain memory and cognitive function in multiple ways, and most importantly, ECS is involved in synaptic responsiveness and plasticity [8]. The high presence of the primary ECS receptor, the cannabinoid receptor 1 (CB1) in the hippocampus and cortex, seems to be the main factor responsible for the psychotropic and cognitive effects linked to cannabis use. Controversial side effects have been observed after marijuana and synthetic cannabinoids exposition [9,10]. Learning and memory impairment has been reported in several studies, especially in young individuals [11,12]. Since brain development is completed only around the age of 25, cannabis use in adolescence may be associated with increased adverse effects on brain formation and function, particularly in areas sensitive to the pharmacological effects of cannabis. However, over recent decades the modulation of the ECS has emerged as a potentially attractive strategy for treating AD. Activation of both CB1 and cannabinoid receptor 2 (CB2) has revealed beneficial neuroprotective effects reducing β-amyloid deposition and tau phosphorylation. It should also be noted that low doses of Δ 9 -tetrahydrocannabinol (THC) showed several beneficial effects by inducing hippocampal neurogenesis and reducing Aβ toxicity (i.e., plaque deposition) in rodents, as well as in other dementia-related symptoms in both pre-clinical and clinical studies [13,14]. Furthermore, (i) the phytocannabinoid cannabidiol, (ii) the activation of the CB2 receptors, and (iii) the modulation of the endogenous cannabinoid levels all seem to be potentially attractive strategies for the absence of psychoactive effects, instead observed, after stimulation of the CB1 receptor [15,16,17]. Several synthetic selective CB1/CB2 agonists/antagonists and inhibitors of endogenous cannabinoid degradation have been generated and tested for their therapeutic effects in the last years. Thus, this review aims to summarize the most recent advances in cannabinoids research for AD, describing their limitations and potential as a therapeutic option.

2. Cannabinoids and Endocannabinoid Systems

The recreational and pharmacological properties of marijuana have been known since ancient times. The first texts documenting the medical benefits of marijuana dates back to a Chinese medical manual from approximately 2700 B.C. [18]. In recent decades, the scientific community has deepened its investigation of the chemical properties of the principal actives in marijuana extract, yet recently, the attention has been focused on understanding the biological mechanism involved in their multifaceted effects [19]. Marijuana (or Cannabis sativa) contains more than 500 distinct compounds, where 120 are classified as phytocannabinoids with different chemical structures and pharmacological properties [20]. The first compounds isolated from marijuana extract were cannabinol (CBN) and cannabidiol (CBD) in 1940 [21], followed years later in 1964 by the isolation of the main psychoactive component of marijuana (−)-trans-Δ 9 -tetrahydrocannabinol (Δ 9 -THC or THC) [22]. A milestone in the modern history of the therapeutic use of cannabis is associated with the identification of the endocannabinoid system in the early 1990s [23]. The isolation, cloning, and expression of the CB1 receptor were succeeded some years later with the characterization of the CB2 receptor [24]. Both these receptors are coupled to the Gi/o proteins signal transduction pathway. Over recent years, several other receptors have been associated as part of the endocannabinoidergic system and were able to modulate the effect of phyto- and synthetic cannabinoids and endogenous ligands, such as the orphan G protein-coupled receptors, GPR3, GPR6, GPR12, and GPR55, and the nuclear hormone peroxisome proliferator-activated receptors (PPARs) [25,26,27,28]. The CB1 receptor is expressed in both the peripheral and central nervous systems, where it is predominantly presynaptically located ( Figure 1 ). The brain distribution of CB1 is consistent with the known physiological effects of cannabinoids as impairment of short-term memory formation, altered motor activity, and anxiety [29]. High levels of CB1 receptors have been detected in the hippocampus, cortical regions, and the cerebellum. Only recently studies have reported the presence of CB1 receptors in astrocytes [30,31,32], where CB1 activation was associated with an increase in calcium uptake and release of glutamate. On the contrary, the CB2 receptor is, for the most part, expressed in the peripheral immune system cells and tissues. The presence in the brain of CB2 is very low compared to CB1 and has been detected in the ventral tegmental area and hippocampal neurons [33]. Nevertheless, CB2 seems to play a crucial role in macrophage/microglia functions [34,35]. The expression of CB2 drastically increases in activated microglia, and activation of CB2 decreases the production of proinflammatory molecules [36]. Another important event in revealing the brain cannabinoidergic system was the isolation of endogenous compounds, which were able to modulate the cannabinoid receptors. The most investigated and characterized are the arachidonic acid derivatives: N-arachidonoylethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG) [37,38]. A particularity of endocannabinoids is that they are produced postsynaptically on demand and are not stored in vesicles [39]. As described in Figure 1 that reported a schematic representation of the endocannabinoidergic system at the neuronal level, endocannabinoids are released in the synaptic cleft from the postsynaptic neurons. They interact with the cannabinoid receptors located on the presynaptic neurons, negatively modulating the GABA and glutamate release [40]. Anandamide and 2-AG have a very short half-life. After their secretion in the synaptic cleft, these compounds re-uptake and are hydrolytically inactivated by the integral membrane enzyme fatty acid amide hydrolase (FAAH) and the monoacylglycerol lipase, respectively (MAGL) [41,42]. Most remarkably, the release of anandamide and 2-AG in the brain affects memory, memory acquisition, and consolidation such as long-term potentiation [43].

Schematic representation of the endocannabinoidergic system in the brain. Putative localization of endocannabinoid receptors in the nervous and glia system. Enzymes involved in endocannabinoid biosynthesis and degradation are reported in both pre-and postsynaptic neurons. 2-AG (green) and AEA (blue) are synthesized from phospholipids on demand. Activation of presynaptic CB1 receptors negatively modulates cell calcium influx and the release of GABA and glutamate neurotransmitters in GABAergic and glutamatergic neurons, respectively. Instead, the stimulation of CB1 in astroglia positively modulates calcium influx and glutamate release. Activation of CB2 in microglia negatively affects the release of TNFα and ILs. AA: arachidonic acid; 2-AG: 2-acylglycerol; AEA: anandamide; PPARs: peroxisome proliferator-activated receptors; FAAH: Fatty acid amide hydrolase; MAGL: monoacylglycerol lipase; mGluR metabotropic glutamate receptors; ILs: interleukins; TNFα: tumor necrosis factor-α.

2.1. Phytocannabinoids and Modulation of Cannabinoid Receptor 1 (CB1)

The CB1 receptor is one of the most abundant G protein-coupled receptors present in the brain. In humans, it is mainly expressed in the hippocampus, cortex, basal ganglia, brainstem, and cerebellum [44]. The high presence of CB1 in the hippocampus and cortex correlates with the documented effect of cannabinoids on the learning and memory process. Although the pathophysiological role of CB1 in AD is still elusive, the lack of CB1 receptors has been associated with a faster decline of cognitive function and loss of neurons in the hippocampus in WT mice [45]. Lee and colleagues (2010) [46] demonstrated that CB1 receptor levels do not change in AD, and they suggested a role of CB1 in preserving cognitive function. Interestingly, CB1, together with the CB2 cannabinoid receptor, was found in Aβ plaques in post-mortem brain tissue from individuals with AD [47]. Several findings showed that acute activation of CB1, especially at a young age, negatively affects dose-dependently short-term memory performance [48,49]. An analogous consequence has also been reported for chronic users, through observation, a decrement in the capacity to learn and remember new information compared to non-marijuana users [50]. In contrast, there is no clear evidence that acute or chronic use of cannabis has a permanent impairment in long-term memory and working memory [51]. Even though undesired psychoactive effects have conditioned the medical research and have created skepticism in the therapeutic use of cannabis and its related chemicals, a consistent beneficial impact in memory impairment in AD-aged rodents and humans has been described for THC, cannabidiol, and other synthetic compounds. Findings that endorse the CB1 receptor as a potential therapeutic target for AD treatment and it needs and deserves further investigation.

2.2. THC

Δ 9 -THC or THC is the most abundant compound among the more than 500 components isolated from marijuana extract [52] and is the primary psychoactive component of cannabis. THC has a similar affinity for both CB1 and CB2 receptors, although most of the THC psychoactive effects are related to the activation of CB1 receptors [53].

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Chronic and acute intoxication by marijuana, and consequently to THC, has often been associated with several adverse effects, such as a reduction in most cognitive functions, learning, memory, attention, and executive function [54], and in some vulnerable subjects, an increased risk of both psychotic symptoms and schizophrenia-like psychoses [55]. In cannabis-dependent subjects, a deficit in striatal dopamine release was found [56], and a single-photon emission computed tomography analysis showed lower hippocampal perfusion among marijuana users than controls [57]. Furthermore, abnormalities in axonal connectivity and hippocampus and amygdala volumes have been found in long-term, heavy cannabis users [58,59]. The recreational consumption of cannabis has increased in the past few years, and particularly in those countries that have legalized the use as well as reduced the starting age for consumers. With the increased potency of cannabis in the last few years, vulnerable users being negatively impacted has ensued. There has been a continual increase in the THC content or potency of marijuana in recent decades, from approximately 4% in 1995 to 17% in 2017 [60]. This rise increases the chance of experiencing adverse effects linked to recreational consumption [61].

Conversely, the use of marijuana and THC have shown a strong therapeutic potential for the treatment of neuronal inflammation and neurodegenerative diseases such as AD. For the correct interpretation of the therapeutic potential of THC, it is vital to circumscribe and separate the THC or marijuana effects reported under a “non-medical” (recreational consumption), and list it under recreational consumption along with the pre-clinical findings and the effects reported in clinical trials under medical supervision. Essentially, the primary reported harmful effects of marijuana came from studies conducted in young adults or in adolescents, which is a critical period of development associated with a high vulnerability to the central effects of the drugs, whereas few studies have been conducted in adults. Only recently, a biphasic dose-response and an age-related effect started to be considered important discriminative factors to induce a beneficial impact of THC on the brain and cognition [62] ( Figure 2 ). THC showed a broad spectrum of effects that could be potentially beneficial in blocking or preventing AD. For example, THC has shown an anti- Aβ aggregation activity in an in vitro study. THC reduced the fluorescence intensity in the thioflavin test in a dose-dependent manner by direct interaction with the Aβ peptide [63], affecting Aβ fibril formation and aggregation [64]. THC stimulates the removal of intracellular Aβ and blocks the inflammatory response [65,66]. THC has been shown to inhibit the enzyme acetylcholinesterase (AChE) activity more effectively than the approved drugs for AD treatment—donepezil and tacrine [67]. In rat cortical neuron cultures, the toxicity induced by high levels of the excitatory neurotransmitter glutamate was inhibited by THC. The neuroprotection effects of THC were not reduced by cannabinoid receptor antagonist, indicating a therapeutic mechanism not mediated by cannabinoid receptors [68]. Administration of low doses of THC in rats was associated with enhanced neurogenesis in the brain, especially in the hippocampus, and an improvement of cognitive functions. The administration of ultralow doses of THC in mice protected the brain from LPS neuroinflammation-induced cognitive damage [69]. THC was effective in significantly reducing Aβ levels and neurodegeneration in 5XFAD transgenic mice by increasing the levels of neprilysin, the endopeptidase responsible for Aβ degradation [70]. In APP/PS1 mice treated with THC, astrogliosis, microgliosis, and inflammatory-related molecules were found reduced with effects that were even stronger in the combined treatment of THC and CBD [71]. Chronic treatment with THC and CBD improved memory impairment in APP/PS1 mice at advanced stages of the AD pathology. However, this treatment did not change the Aβ deposition and gliosis; phenomena instead observed when THC and CBD were administered at the early stages of the disease [72]. The therapeutic effects produced by THC and CBD in aged APP/PS1 mice were combined with an improvement of synaptic function. In particular, the treatment induced a reduction in metabotropic glutamate receptor 2/3 and increased the levels of GABA-A Rα1 compared with control mice [72]. In general, CB1 receptor agonists and THC induced the release of brain-derived neurotrophic factor BDNF in cells and several brain regions [73]. This phenomenon can be one of the main biological events linked to the THC neuroprotective effect. In this respect, Marsicano et al. [74] revealed that the CB1-induced BDNF expression participates in the therapeutic effect of CB1 receptor activity against neurotoxicity. These results have a high translational value considering that BDNF signaling regulates morphological and physiological synaptic plasticity. Most importantly, BDNF expression declines with aging and even more in pathological aging, and re-established BDNF physiological levels can be considered an essential way for rescuing synaptic plasticity in AD patients.

Schematic representation of the biphasic effects of THC.

On the clinical side, in patients with AD treated for six weeks with dronabinol (2.5 mg), a synthetic form of THC was observed as a positive effect on body weight and an improvement in disturbing behavior [14]. After two weeks of treatment, dronabinol (2.5 mg) reduced nighttime activity and agitation in patients in advanced stages of AD [75]. In another study, low-dose oral THC (1.5 mg)—in a 21-day-treatment—did not affect dementia-related neuropsychiatric symptoms. In contrast, it was tolerated in treated patients, and no relevant side effects were reported [76]. THC safety at low concentration and rapid absorption (with maximum plasma concentrations at two hours after treatment) was also reported in another clinical study on older dementia patients [77]. Efficacy and safety with a significant reduction in the Neuropsychiatric Inventory and Clinical Global Impression severity scale was also reported in patients treated with medical cannabis oil (MCO) containing THC [78]. The synthetic oral THC analog Nabilone significantly reduces agitation over six weeks of treatment in AD patients. Nabilone was also associated with significant improvements in overall neuropsychiatric symptoms and caregiver burden [79].

The clinical efficacy of THC on agitation and aggression in patients with AD remains inconclusive, though there may be a signal for a potential benefit of synthetic cannabinoids.

2.3. Cannabidiol

The other main phytocannabinoid in cannabis plants is cannabidiol (CBD), which comprises up to 40% of the total compounds extract. CBD, as opposed to THC, has no psychotropic properties, as also confirmed in a recent trial where healthy volunteers did not show any effects in the emotional state, cognitive performance, or attention after receiving CBD [80]. CBD has a very low affinity to the CB1 and CB2 receptors [53], and several findings proposed that CBD operated as a negative allosteric modulator/inverse agonist in both CB1 and CB2 receptors [81,82,83]. Furthermore, CBD acts as an inverse agonist for G protein-coupled orphan receptors such as GPR3, GPR6, and GPR12. Other studies reported that CBD could activate the Transient Receptor Potential Vanilloid (TRPV) channels, serotonin (5-HT1A), PPARs, N-methyl-D-aspartate (NMDA) receptor, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The potential employment of CBD in AD therapy is under debate, with still few studies available. However, several findings support the therapeutic potential of this compound in improving some symptoms associated with AD. Notably, in preclinical characterization, CBD exhibited neuroprotective, anti-inflammatory, anxiolytic, and anti-insomnia properties. In this context, the strong antioxidant effect of CBD was reported against glutamate toxicity in primary neuronal culture [68]. The neuroprotection and antioxidant properties of CBD were also observed on β-amyloid peptide-induced toxicity in cultured rat PC12 cells [84]. CBD modulates microglial cell function in vitro and prevents the learning of a spatial navigation task and TNF-α and IL-6 gene expression in β-amyloid-injected mice [71,85]. Tau hyperphosphorylation plays a crucial role in the pathogenesis of AD. In this regard, it has been demonstrated that CBD inhibits β-amyloid-induced tau protein hyperphosphorylation nitric oxide production [86,87]. In mesenchymal stem cells treated with CBD, a lower gene expression of some specific genes associated with AD were observed, including genes coding for the proteins responsible for tau phosphorylation and Aβ production as the β- and γ-secretase genes [88]. Likewise, CBD prevented the expression of proinflammatory glial molecules in the hippocampus of an in vivo model of Aβ-induced neuroinflammation. CBD prevented the expression of proinflammatory glial peptides in the hippocampus of mice Aβ-induced neuroinflammation [89]. Long-term oral CBD treatment improved the social recognition memory and pathophysiology of a double transgenic APP × PS1 mouse model for AD [90]; in the same mouse model, CBD treatment significantly up-regulated the autophagy pathway [91]. Furthermore, in a recent case study, CBD consumption significantly improved neuropsychiatric symptoms in AD patients [92].

2.4. Synthetic CB1 Modulators

Several synthetic cannabinoid compounds have been generated in the last decades with the aim to selectively investigate the physiological and pathophysiological role of the two primary endocannabinoid receptors CB1 and CB2. These synthetic compounds have been tested as a therapeutic tool in several pre-clinical models, including in vivo and in vitro AD models. To date, the only chemical modification of Δ 9 -THC that has reached the status to be an approved drug from the FDA is nabilone, under the name Cesamet, for the treatment of nausea and vomiting associated with cancer chemotherapy [93]. CP 55,940 was the first synthetic cannabinoid analog to be synthesized from a chronological perspective [94], followed by several others. Some of the most extensively studied selective CB1 or mixed CB1/CB2 agonists are WIN 55,212-2, HU 210, ACEA, and JWH-018. Regarding these compounds, in recent decades, numerous preclinical studies in rodents, despite sometimes controversial, have highlighted their positive effects on memory and learning processes and on other neurobiological mechanisms underlying AD. Systemic administration of CP 55,940, WIN 55,212-2, and ACEA affected working memory [95] and object recognition memory in rats [96,97]. A similar effect using CP 55,940 was also reported in mice [98]. The negative effects of synthetic cannabinoids (WIN 55,212-2 and CP 55,940) on learning and memory appear to be directly linked to the inhibition of acetylcholine release in the hippocampal region [99,100] and the inhibition of glutamatergic synaptic transmission in the prefrontal cortex [101,102]. Nonetheless, CB1 receptor modulation in the hippocampus is essential for the memory disruptive effects of cannabinoids but are not essential for the other common CNS actions [103]. Hippocampal slices exposure to synthetic cannabinoid agonists (WIN 55,212-2, HU 210) affects long-term potentiation (LTP) [104,105], and (HU 210; JWH-018) alter spontaneous firing, bursting, and synchronicity in hippocampal cells [106,107,108]. Acute administration in mice of JWH-018, known in the illegal market as Spice and ‘herbal blend’, impair cognitive function affecting hippocampal synaptic transmission and memory mechanisms [108]. A decrease in BDNF following JWH-018 treatment was observed in the hippocampus. As previously mentioned, the neurotrophic factor BDNF plays an important role in modulating the learning and memory process, promoting neurogenesis, synaptogenesis [109], and the alteration of BDNF levels after JWH-018 exposition, which may explain its negative effect on memory performance. Nevertheless, this effect on BDNF release observed with JWH-018 is in contradiction with the effect reported previously with THC administration, where an increased BDNF production was observed. Together with the negative effect on memory and learning processes, other findings strongly supported a beneficial therapeutic effect by CB1 receptors activation. Likewise, reported for the phytocannabinoid THC, neurogenesis in the hippocampus of aged rats could be induced using a low dose of WIN 55,212-2 [110]. A similar effect was also observed after chronic treatment with HU 210, which promoted neurogenesis in the dentate gyrus of adult rats [111]. The primary role of CB1 cannabinoid receptors in regulating neurogenesis in the adult brain was confirmed in CB1-knockout mice, which showed reductions in the number of BrdU-labeled cells to −50% of WT levels in the dentate gyrus and subventricular zone—suggesting that CB1 activation promotes neurogenesis. The involvement of CB1 in neurogenesis was further confirmed in CB1 knockout mice where it was observed defective adult neurogenesis [112]. Furthermore, the treatment of activated primary human astrocytes with WIN 55,212-2 significantly reduced in a dose-dependent manner the expression and release of cytokines [113]. HU 210 ameliorated the memory deficits of olfactory bulbectomized (OBX) rats [114]. In contrast with what was previously reported, chronic treatment with WIN 55,212-2 significantly normalizes this cognitive deficit in old Tg APP mice accompanied by a reduction in the inflammation and an increased Aβ clearance [115,116]. Chronic administration of the selective CB1 agonist ACEA at pre-symptomatic or early AD stages reduced the learning and memory deficits observed in the double APP/PS1 transgenic mice. In primary neuronal cell cultures, ACEA reduced the cytotoxic effect induced by Aβ42 oligomers and reduced Aβ-induced glycogen synthase kinase-3β activity in cortical neurons. Moreover, a defect in astroglial response and a decreased expression of the proinflammatory interferon-gamma were found in the surrounding area of Aβ plaques deposition in ACEA-treated mice when compared with non-AD mice [117]. The infusion of ACEA in the rat hippocampus prevented the neurotoxic Aβ-induced effect. ACEA prevented cognitive impairment and decreased the activation of microglia and astroglia in the dentate gyrus [118].

2.5. Modulation of Cannabinoid Receptor 2 (CB2)

The other side of the endocannabinoid system is mainly represented by the CB2 receptor—mostly considered as related to the periphery—as it was initially found to be highly expressed at the spleen level and hard to detect in the brain. Today, many confirmed CB2 expression in selective areas of the brain, despite its main localization in the microglia. In detail, Svizenska et al. [119], mapping the CB2 receptor distribution in the mammalian nervous system, found CB2 receptor in the anterior olfactory nucleus in the neurons of the piriform, orbital, visual, motor, and auditory cortex. However, CB2 receptors in physiological conditions are expressed very low in the brain while increasing in the expression in both neuronal and non-neuronal cells but only in pathological conditions. CB2 receptors may play a role in nociception [120,121], gastrointestinal function [122], neural progenitor cell proliferation and axon guidance [123,124], and synaptic transmission [125,126] among other functions.

Since CB1 receptors are primarily related to the unwanted psychotropic effects of marijuana-derived cannabinoids, the CB2 receptor becomes really attractive as a druggable target. The potential therapeutic use of CB2-agonist in AD is also reinforced by the findings that in the AD human brain, CNR2 (the gene encoding the CB2 receptor) was found to be increased compared to age-matched controls [127]. The anti-inflammatory effects of CB2 agonists have been widely described in different transgenic mouse models of AD and in in vitro AD-like models [128]. Additionally, it was demonstrated that in Aβ-treated mice, cannabinoid treatment prevented microglial activation and avoided induced cognitive impairment. In human postmortem AD brain tissues, cannabinoid CB2 receptors were found selectively overexpressed in neuritic plaque-associated glia [129]. A novel CB2 agonist (MDA7) promised improved cognitive performance in rats microinjected with Aβ into the hippocampus by favoring Aβ clearance [130]. CB2 receptors, as reported for CB1, are involved in neurogenesis. In fact, in CB2-deficient mice, the number of BrdU+ cells in the dentate gyrus was found reduced [15,123].

Evidence suggests that neuroinflammation may be pivotal in tangle formation [131]. Thus, another therapeutically CB2-mediated effect was also linked to the modulation of hyperphosphorylated tau, another benchmark of AD. In fact, chronic administration of JWH-133, a selective CB2 receptor agonist, was found effective in reducing tau hyperphosphorylation surrounding Aβ plaques in APP/PS1 mice [132]. Furthermore, mice overexpressing human tau (PK−/−/TauVLW) showed a marked reduction in neurofibrillary tangles with prolonged treatment with Sativex ® , an already approved medicine based on mixed Δ9-THC and CBD natural extracts [133]. Due to the multifactorial and sporadic nature of AD, multi-target drugs capable of acting on multiple targets simultaneously (comprising the CB2 receptor) are becoming an attractive therapeutic option in the field of AD. Recently, Scheiner et al. [134] synthesized dual-acting hybrid compounds combining the effects of a benzimidazole-based CB2 selective agonist with those of tacrine as a cholinesterase (ChE) inhibitor. These hybrids showed neuroprotection against glutamate-induced oxidative stress when tested in vitro while showing pronounced effects on short- and long-term memory, avoiding the hepatotoxicity side effect of tacrine [134]. Again, with a similar hybrid approach, Montanari et al. [135] identified a potent and selective hybrid CB2-ligand able to simultaneously restore the cholinergic system by inhibiting butyrylcholinesterase (BuChE), within addition neuroprotective activity against Aβ1-42 oligomers and immuno-modulatory effects, addressing microglia to the neuroprotective M2 phenotype [135]. Consequently, multi-target CB2 agonists can be useful in the development of neuroprotective and potential immunomodulating drugs for AD, acting via the endocannabinoid system.

2.6. Modulation of Endogenous Cannabinoid Anandamide and 2-AG

Modulating the levels of the endogenous cannabinoid compounds (i.e., anandamide and 2-AG by pharmacological blockade of their degradation) is a potential therapeutic approach for treating AD. The inhibition of the two main endocannabinoid hydrolase enzymes, FAAH and MAGL, augments the levels of endocannabinoid available for interaction with their receptors. Most importantly, it augments no relevant undesirable side effects in motility, catalepsy, body temperature, or cognition as reported for high doses of CB1 agonists [136,137,138]. Specifically, relevant expression changes of anandamide (2-AG) and their proteolytical enzymes (FAAH and MAGL) during normal aging and the neurodegenerative process have been observed in both humans and rodents [139,140].

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In humans, the analysis of frontal and temporal cortex tissues from post-mortem AD patients revealed significantly reduced levels of anandamide compared to the control subjects. Yet, no differences in 2-AG levels were observed [141]. Moreover, anandamide levels have been inversely correlated with Aβ42 but not with Aβ40, amyloid plaque deposit, or tau protein phosphorylation. In another study, on the contrary, in the frontal cortex from human AD patients and in aged-rat synaptic terminals, a higher anandamide availability and reduced FAAH synaptic activity were observed [142]. High levels of the anandamide hydrolase enzyme FAAH were instead found around the amyloid plaque deposition in astrocyte and microglia cells, supporting the ECS may play a modulatory role in the inflammatory response in the AD neuroinflammation process surrounding the plaques [129]. The hippocampal protein concentrations for the DAGLα and DAGLβ, 2-AG-biosynthesizing enzymes, were also found to be significantly increased in the advanced stage of AD (Braak stage VI) in microglia accumulating near senile plaques [143].

In rodents, an enhancement in the mRNA levels of the 2-AG-biosynthesizing enzyme DAGLα together with a higher level of 2-AG was also observed at hippocampal level after acute stereotaxic injection of amyloid proteins into the rat cortex [144]. In the same study, the β-amyloid-induced neuronal toxicity in the hippocampus was reversed by VDM-11, an inhibitor of endocannabinoid cellular reuptake. In WT mice, hippocampus 2-AG, but not anandamide levels, decreased during aging; this decrease seemed to be linked with a significant reduction in DAGLα expression at both protein and mRNA levels and by enhanced MAGL activity [140]. Still, there is a lack of information concerning the age-related changes in endocannabinoid levels, and more research is needed to clarify some controversial findings reported in the literature. However, re-establishing the physiological endocannabinoid tone may represent a preventive or even a potential treatment for AD.

In this context, the selective pharmacological inhibition of FAAH and MAGL or dual inhibition of FAAH/MAGL—with the following increase in anandamide and 2-AG—promotes a reduction in Aβ-protein deposition in an AD rodent’s model. Currently, several classes of reversible and irreversible covalent FAAH inhibitors have been developed, such as URB597, OL-135, PF-3845, AM3506, PF-04457845, JNJ-40355003, JNJ-42165279, JNJ-1661010, and BIA 10-2474, although the majority of studies have involved URB597. The irreversible covalent URB597 promoted the increase in endocannabinoid anandamide by inhibiting FAAH activity [145,146]. Furthermore, URB597 efficiently suppressed glutamate Aβ42-induced toxicity in primary hippocampal neurons and stimulated the mitochondrial membrane potential [147]. URB597 treatment is associated with the reduction in interleukin (IL)-1β, tumor necrosis factor-α (TNFα) expression, and restoration of long-term potentiation in aged rats [148]. Similar findings have been recently reported after treating monocytes/macrophages from AD patients with URB597, where a general reduction in proinflammatory cytokines was observed [149]. It is noteworthy to mention the inhibition of FAAH by OL-135 accelerated acquisition and extinction rates in a spatial memory task [150]. Many FAAH inhibitors (i.e., PF-04457845 and JNJ-42165279) have been characterized mainly for their analgesic and anxiolytic effects in rodents and humans [138,151]. In particular, PF-04457845, which is 25-fold higher for human FAAH inhibition than URB597, showed a high in vivo efficacy and long duration of action in a rat model of inflammatory pain with also a high oral bioavailability and high brain penetration. These results made this compound a strong candidate to be used in the clinical treatment of central nervous system disorders. So far, only a few clinical trials exist; however, the pharmacological effects of PF-04457845 have been evaluated in humans and were found to be very well tolerated in healthy subjects [152]. It should also be mentioned that the inhibition and the knockdown of FAAH suppressed prostaglandin E2 production and proinflammatory gene expression [153] supported even stronger FAAH inhibition as a therapeutic strategy for reducing AD-related neuroinflammation. The effects of selective inhibition of MAGL have also been characterized. The MAGL inhibitors synthesized can be classified into irreversible inhibitors (maleimides, disulfides, carbamates, ureas, and arylthicarmide) and reversible inhibitors (tetrahydrolipstatin-based derivatives, isothiazolines, natural terpenoids, and amide-based derivatives). Pharmacological and genetic inactivation of MAGL (in a mouse model of AD) attenuated eicosanoid levels, attenuated glial activation and associated neuroinflammation, lowered amyloid β levels, and reduced amyloid plaque burden [154]. Interestingly, a reduced prostaglandin production, rather than enhanced endocannabinoid signaling, seemed to be the underlying main pathophysiology mechanism involved. In this regard, MAGL has been shown that, with the hydrolyzes of 2-AG, it generates the primary arachidonic acid pool for neuroinflammatory prostaglandins [155]. Among different MAGL inhibitors, JZL184 was characterized first, and then after further structural modification, several new derivatives of JZL184 were generated [17]. In an AD mouse model where JZL184 was used as a treatment, a decrease in proinflammatory reactions of microglia, along with reduced total Aβ burden and its precursors, were found. Likewise, it reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice [156]. Inhibition of MAGL enzyme activity and subsequent increase in 2-AG correlated with decreased Aβ accumulation and expression of β-secretase (or BACE1), an enzyme involved in APP cleavage and Aβ generation. MAGL inhibition has been associated with several anti-AD effects: reducing neuroinflammation, improving synaptic plasticity, spatial learning, and memory in AD animals [8].

The compound JZL195 is a potent inhibitor of both FAAH and MAGL, with an IC50 of 2 and 4 nM, respectively [17]. Subcutaneous delivery of JZL195 enhanced the brain levels of anandamide and 2-AG in a concentration-dependent way and produced anti-allodynic effects in a mice model of chronic neuropathic pain [17,157]. The important role of the endocannabinoid system in the adult neurogenesis process was confirmed in FAAH-deficient mice [158]. In these mice, the hippocampal proliferation of multipotent neural progenitor cell counting was significantly higher when compared with control WT mice. A similar finding was also observed increasing the levels of anandamide by pharmacological inhibition of FAAH activity [159]. Additionally, in DAGL-KO mice, the adult neurogenesis in the hippocampus and the subventricular zone was compromised [160]. Although the molecular mechanisms responsible for the FAAH and MAGL effects against neuropathology of AD remain to be determined, the findings reported so far support that FAAH and MAGL would be promising therapeutic targets for preventing and treating AD. Therefore, the pharmacological inhibition of these two enzymes has appeared as a potentially appealing strategy to elevate endocannabinoidergic tone. Table 1 summarizes the principal AD-related beneficial and adverse effects of the prevalent cannabinoids described.

Table 1

Cannabinoids principal AD-related beneficial and adverse effects.

Compounds Endocannabinoid System Targets Beneficial Anti-AD Effects Adverse/Unwanted Effects
THC Mixed CB1 and CB2 agonist Inhibition of achetylcholinesterase [67]
Reduce Aβ levels [63]
Hippocampal neurogenesis [166]
Induce BDNF release [73,74]
Psychotic effects [55]
Reduce cognitive functions [54]
A deficit in dopamine release [56]
CBD Mixed CB1 and CB2 agonist No psycoactive effets [80]
Neuroprotection [84]
Reduce microglia activation [85]
Delay cognitive decline [167]
Hypotension at high doses [168]
Anxiogenic-like effect [169]
WIN 55,212-2
HU 210
CP 55,940
JWH-018
Mixed CB1 and CB2 agonist Increase Aβ clearance [116]
Promote neurogenesis [111]
Prevent cognitive impairment [113,114]
Defect in working memory [95,96,97]
Affects long-term potentiation [104,105]
Sedation [170]
ACEA Selective CB1 agonist Anti-inflammatory [117]
Prevent spatial memory impairment [118]
N.R.
JWH-133
AM-1241
MDA7
Selective CB2 agonist Increase Aβ clearance [116]
Improve cognitive performance [116]
Prevent microglial activation [128]
Reduce tau hyper-phosphorylation [132]
Immune suppression [171]
URB597
PF-04457845
JZL184
JZL195
Modulation of endogenous cannabinoid anandamide and 2-AG Suppress glutamate Aβ42-induced toxicity [147]
Reduce proinflammatory interleukin
expression [148,156]
Restore long-term potentiation [148]
Reduce amyloid plaque burden [154]
Cardiac diastolic stiffness [172]

Another potential of endocannabinoids as a therapeutic option for AD is their ability to modulate the mammalian target of the rapamycin (mTOR) signaling pathway [161,162]. The activation of mTOR is a trigger for Aβ generation; thus, its inhibition is an important therapeutic target for AD [163]. Of note, 2-AG treatment was able to prevent the activation of mTOR signaling pathway in the hippocampus in mice through a CB2-dependent mechanism [164]. Again, CB1 and mTOR are intimately linked and involved in regulating excitatory glutamatergic inputs and energy balance at the brain level [165]. Overall, despite this intriguing link between endocannabinoids and mTOR need to be further explored, these data further confirmed the endocannabinoid system as an attractive therapeutic strategy to be further deepened in AD.

3. The Orphan G Protein-Coupled Receptors (GPRs)

In addition to the two well-characterized G protein-coupled receptors CB1 and CB2, several orphan G protein-coupled receptors or GPRs have been described in the last years to be putative cannabinoid receptors, such as GPR3, GPR6, GPR12, GPR18, and GPR55 [173,174,175]. GPR3, GPR6, and GPR12 have a close phylogenetic affinity and conserve specific sequences with the cannabinoid receptors CB1 and CB2 [173]. Moreover, these receptors are highly expressed in several brain areas, where sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine have been identified as putative endogenous ligands of GPR3, GPR6, and GPR12 [176,177]. Recently, it has also been shown that CBD, the non-psychotropic phytocannabinoid, binds to GPR3, GPR6, and GPR12, acting as an inverse agonist [27]. Therefore, besides their physiological role is still unclear, they seem involved in several brain processes related to pain, memory, and emotion. Interestingly, GPR3 was found highly expressed in the AD postmortem brain and correlated with the entity of the AD pathology [178]. The activation of GPR3 directly affects Aβ-plaques deposition by stimulating Aβ production [179]. On the other hand, genetic deletion of GPR3 decreased the amyloid plaque deposition and improved cognitive impairment in preclinical AD mouse models [178]. An increased hippocampal expression was also observed for GPR6 in the 3 × Tg AD mouse model, where GPR6 modulates the neuroprotective effect of the complement protein C1q against Aβ [180]. GPR18 and GPR55 despite, GPR3, GPR6, and GPR12, have low homology with CB1 and CB2 [175]. GPR55 has opposite signaling pathways from CB1/CB2 since it is coupled to Gα12,13, and its activation is linked to an outflow of calcium from intracellular stores via phospholipase C [181]. Several cannabinoid compounds have been found to bind to GPR18 and GPR55 as anandamide, 2-AG; the bioactive lipid related to endogenous cannabinoids lysophosphatidylinositol (LPI); the phytocannabinoids THC and CBD; and the synthetic compounds CP 55,940, AM251 [181,182,183]. Both GPR18 and GPR55 form a receptor-receptor interaction with CB2 in microglia [184,185]. The physiological properties of this heteroreceptor are not still fully elucidated; however, some studies showed a negative cross-talk between GPR55 and CB2 [185,186]. GPR55 modulates neuroinflammation, and its activation has been reported to increase the release of interleukins (ILs) [187]. On the other hand, GPR55 antagonists effectively block microglial activation, similarly in GPR55 −/− knockout mice have observed a reduction in the release of the proinflammatory cytokines [188,189]. GPR55 −/− mice show a normal life span and no alteration in endocannabinoids and related lipids levels; however, a deficit in motor coordination was reported, supporting a role for GRP55 in motor function [190]. GPR55 is highly expressed in the hippocampus, which suggests a role in learning and memory processes. The pharmacological inhibition of GPR55 has been associated with an improvement in spatial learning and memory in rats [191]. In a recent study, GPR55 was found highly expressed in the hippocampus dentate gyrus, CA1, and CA3 of the 5xFAD AD mouse model [192]. These findings, taken together, support GPRs being potentially involved in AD pathology and can be considered promising novel pharmacological targets for AD treatment. In particular, despite just a few studies are available to date, and GPR antagonism might be associated with side effects mostly in motor function as for GPR55 deletion, the GPR modulation of inflammatory response could be a new therapeutic opportunity to counteract AD neuroinflammation.

4. Limits of Cannabinoids in Alzheimer’s Disease Therapy

To date, cannabis and cannabis-derived compounds have not been approved by the US Food and Drug Administration (FDA) to treat or manage Alzheimer’s, and only a few clinical trials to evaluate the use of THC (dronabinol and nabilone) or CBD have been completed or are ongoing. For example, nabilone, a synthetic cannabinoid currently approved for the treatment of chemotherapy-related nausea and vomiting, was found effective in reducing symptoms of agitation and aggression among AD patients [79]. However, to ensure patient safety, it becomes critically important to closely monitor side effects such as sedation and possibly cognitive decline.

Considering cannabinoids as a therapeutic option, identifying an effective dosage and treatment time is challenging. It is already well-known that molecular changes related to AD began several years before symptoms manifest. As a result, neuroprotective and immunomodulatory potential effects of cannabinoids should be administered before AD is exacerbated and prolonged in time. However, studies on the long-term effects of cannabinoids are not yet available. While studies on the long-term cognitive effects of heavy cannabis use suggest, cannabis negatively influences cognitive functions, such as episodic memory, attentional control, and motor inhibition [193,194]. For this reason, further studies to explore the short- and long-term effects of cannabinoids are urgently needed.

Unfortunately, studies investigating cannabinoid drug-drug interactions are still limited. Several investigations would be fundamental to underpinning this critical point, considering patients with dementia take multiple medications, and cannabinoids could be included as an additional therapeutic strategy to tackling the symptoms of dementia.

5. Final Remarks

Marijuana and cannabinoids have been associated with a wide range of beneficial pharmacological effects from one side and with harmful and adverse effects from the other. The mechanisms behind this opposed phenomenon are not fully understood. However, emerging data suggest that dosage and user age are crucial factors involved in multifaceted cannabinoids effects. Marijuana’s adverse effects are mainly related to interfering with cognitive and executive functions. Many western countries are legalizing the use of marijuana without giving any education and information to users about the risks associated with its abuse. An open market makes cannabis easily accessible, increases consumption, and consequently leads to adverse health repercussions in individuals in vulnerable categories such as adolescents and young adults.

On the contrary, increasing scientific evidence supports that the ECS is associated with neurodegenerative diseases, and modifying its tone could be a promising therapeutic tool for treating AD. In some cases, the same substances implicated in impairing learning and memory functions could be beneficial in counteracting neurodegenerative processes at low doses. Cannabinoids can reduce oxidative stress and excitotoxicity, amyloid plaques, and neurofibrillary tangles formation. AD neuroinflammatory processes can be suppressed by the immunomodulatory effect of the CB2 receptor controlling microglial activity. Another significant effect is on the availability of acetylcholine and prevention of acetylcholinesterase-induced Aβ aggregation. Most importantly, accumulated evidence indicates that cannabinoids induce neurogenesis in the hippocampus in adults. Likewise, the inhibition of endocannabinoid degradation can be a promising pharmacological strategy to counteract the aging process and have a beneficial impact on AD progression. The modulation of production and degradation of endocannabinoids can be other than efficacious, with low side effects, compared to synthetic CBs receptors agonist/antagonist compounds. Clinical studies reported several beneficial effects in AD-related symptoms after cannabinoid administration. After dronabinol consumption, patients in the late stages of dementia showed a reduction in nocturnal motor activity and agitation. Notably, CBD has shown relevant high safety and anti-AD properties by mediating mechanisms related to the non-canonical cannabinoid receptor, making it one of the most prominent candidates between the phytocannabinoid compounds to be further tested in clinical trials. Recently, spray cannabinoid-based drugs such as Sativex (containing a 1:1 ratio of THC:CBD) and Epidiolex (containing only CBD) have been approved for chronic pain conditions in the USA, Canada, and several European countries, which makes it easy to control the cannabinoid dose delivery if compared to smoke inhalation [195]. In addition, this mouth spray and oral delivery approach could be especially beneficial for individuals with AD.

6. Conclusions

The last in vitro and in vivo studies strongly supported the further investigation into the use of cannabinoids as a therapeutic approach to AD. Currently, only a few clinical trials have been performed. Therefore, a deeper investigation is necessary to evaluate the safety, pharmacokinetic, pharmacodynamic, and most importantly, the efficacy of cannabinoid-based drugs for treating AD.

Acknowledgments

Figure 1 was created with BioRender.com.

Author Contributions

Conceptualization, S.T. and G.A.; writing—original draft preparation, S.T. and G.A.; writing—review and editing, S.T., G.A. and D.U. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Stiftelsen För Gamla Tjänarinnor, and Demensfonden from Demensförbundet.