Introduction:
Alzheimer's disease (AD) is a neurodegenerative pathology and represents the most common type of dementia, characterized by a progressive loss of memory, visual-spatial and complex cognitive abilities, such as language and reasoning, which progressively lead to a total inability to carry out any type of daily activity. [1,2].

AD is ultimately fatal due to complications such as immobility, swallowing problems and malnutrition which greatly increase the risk of acute fatal conditions such as pneumonia and vascular changes [3].

Since one of the main risk factors for AD is aging and the human lifespan is constantly increasing, the number of Alzheimer's cases is expected to double in the following decades. Actually, more than 50 million people are affected by AD worldwide [4].

The progression of AD from initial brain changes to brain changes that cause memory problems and finally physical disability is called the Alzheimer's continuum [5]. The symptom continuum includes three major phases: a) the preclinical phase, b) the mild cognitive impairment phase, c) the dementia phase.

The Alzheimer's dementia stage is further divided into mild, moderate, and severe stages, which reflect the degree to which symptoms interfere with the ability to carry out activities of daily living [6,7,8,9]. The time people spend in each stage of the continuum is variable and individual as it is influenced by age, genetics, gender and other factors [10]. Although the rate of symptom progression can vary, the average life expectancy after diagnosis is between three and nine years [11,12].

AD can also be divided, based on the pathophysiological aspects, into a) Sporadic (or late-onset) and b) familial (or early onset). Both sporadic and familial AD develop a similar pathology consisting of parenchymal deposition of Beta-amyloid (Aβ) in plaques and intra-neuronal accumulation of hyperphosphorylated tau protein, leading to brain inflammation and oxidative stress that have a fundamental impact on the onset of the disease [13,14].

The scientific literature recognizes two distinctive etiopathological aspects of AD: a) the presence of extracellular deposits of Beta-Amyloid (Aβ) in Alzheimer's brains [15] and b) hyperphosphorylation of the tau protein associated with cytoskeletal microtubules [16].

The Endogenous Cannabinoid System (or Endocannabinoid System, ECS) is a complex molecular/biological system implicated in several physiological processes [17,18,19,20,21,22,23].

The ECS consists of two primary cannabinoid receptors (CB1 and CB2) and two primary neurotransmitters of endogenous cannabinoids, commonly called Endocannabinoids: N-arachidonoyl ethanolamine (AEA or anandamide) [24]  and 2-arachidonoyl glycerol (2-AG) [25].

In addition to endocannabinoids, other substances act as ligands for ECS receptors and are represented by phytocannabinoids and synthetic compounds derived from them. Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (Δ9-THC) are the most intensively studied phytocannabinoids.

∆9-THC (for simplicity THC) is the main psychoactive component of cannabis. THC has a similar affinity for both CB1 and CB2 receptors, although most of the psychoactive effects of THC are related to the activation of CB1 receptors [26]. Chronic and acute intoxication by marijuana, and consequently by THC, has often been associated with several adverse effects, such as a reduction in most cognitive functions, learning, memory, attention and executive functions [27], and in some vulnerable subjects, an increased risk of both psychotic symptoms and schizophrenia-like psychosis [28].

Unlike THC, CBD has no psychotropic properties [29]. CBD has a very low affinity with the CB1 and CB2 receptors. Numerous results have highlighted that CBD acts as an allosteric modulator both in the CB1 and CB2 receptors [30,31,32].

There are other potentially therapeutic phytocannabinoids, which have been tested in pre-clinical studies, represented by: ∆8-tetrahydrocannabinol [33], Cannabinol [34], Cannabigerol [35], Cannabichromene [36], ∆9-tetrahydrocannabivarin (∆ 9-THCV) [37] and Cannabidivarin (CBDV) [38].

From published data, alterations in the cannabinoid receptors and in the enzymes responsible for the degradation of endocannabinoids in AD emerge, even if some data is conflicting [39,40].

Materials and Methods:

A literature search was conducted on major databases to find useful studies for the purposes of this paper.

Discussion:
The recreational and pharmacological properties of marijuana have been known since ancient times. The first texts documenting the medical benefits of marijuana date back to a Chinese medical manual from 2700 BC. about. [41].

In recent decades, scientific literature has deepened research on the chemical properties of the active ingredients in marijuana extract, but recently attention has focused on understanding the biological mechanism involved in their multiple effects. Most of the accumulating evidence supporting the potential therapeutic utility of cannabinoids in AD has been obtained using cellular and animal models that mimic a variety of AD-related changes.

Information obtained from literature data suggests that cannabinoids and substances that act on degradation enzymes can have multiple effects on AD by acting as antioxidants and anti-inflammatories, modulating a notable number of factors that contribute to the pathogenesis of AD such as altered Aβ plaques metabolism and autophagy. Aso and Ferrer [42] classified the results obtained into six areas: a) Effects on Aβ plaques; b) Effects on TAU hyper-phosphorylation; c) Anti-inflammatory properties; d) Actions on mitochondria activity; e) Modulation of neuro-transmission; f) Other effects (for a summary, see Table 1).

Table 1: Six areas of effects

Although the data obtained so far are hopeful, the confirmation of the clinical efficacy of cannabinoids and the clarification of the underlying molecular mechanisms have yet to be fully identified [75], lacking efficacy data from randomized clinical trials.

To date, no cannabinoid compound has yet been approved for the treatment and/or management of AD symptoms. There are still few clinical studies completed evaluating the use of synthetic derivatives of THC (dronabinol and nabilone) and CBD.

In the literature, clinical studies using cannabinoids to treat consequences and comorbidities of AD, such as anxiety, agitation and depression are numerically scarce. Nabilone reduced the severity of agitation in a 72-year-old man with cognitive decline [76]. A randomized study reported that dronabinol was more effective than placebo in reducing agitation and was well tolerated with adverse events no different from placebo in patients with AD [77]. In addition, dronabinol was effective in 15 patients who refused food. Adverse reactions included euphoria, drowsiness, and fatigue, but did not require discontinuation of therapy [78]. Nabilone and dronabinol were found to be more potent THC analogs acting on CB1 and CB2 receptors and reducing general agitation in AD patients [79]. Another study examining the effectiveness of nabilone as a potential treatment for psychiatric symptoms of Alzheimer's disease similarly found an overall decrease in agitation and sometimes even aggression [80]. A study found that co-administration of CBD and THC is necessary to provide the beneficial elements of cannabis while attempting to reduce some of the side effects of THC in Alzheimer's patients. [81]. CBD is considered particularly beneficial in the treatment of Alzheimer's disease as it lacks psychoactive properties and does not risk further damage to cognitive decline in Alzheimer's patients [82]. Cannabis, it seems, can help restore the cognitive dysfunctions characteristic of AD [83]. Dronabinol administration reduced nocturnal activity and strengthened circadian rhythms [84].

Considerable clinical potential emerges in the use of cannabinoids in AD which is not yet supported by clinical evidence as the number of randomized clinical trials is almost absent and does not allow the real clinical efficacy to be determined. Indeed, cannabinoids were often used in conjunction with other pharmacological therapies, leading to poor methodological rigor in the studies themselves. In addition, the studies carried out were conducted on small sample sizes, undermining the real significance of the data reported. Furthermore, there is a lack of longitudinal studies that take into consideration any short and long-term side effects of cannabinoid therapy.

Acknowledgments:

This paper was entirely funded by the author, and no pharmaceutical companies were informed of or were involved in the paper. The author has no potential conflict of interests that are directly relevant to the contents of the paper.

Conclusions:

The authors took into consideration the in vitro and in vivo research on murine models of the use of cannabinoids for the etiological aspects of Alzheimer's disease. Finally, clinical studies on patients with Alzheimer's disease present in the literature were presented. Encouraging and positive aspects have certainly emerged in the possible and future therapeutic use of cannabinoids in the pathological evolution of Alzheimer's disease, but at present, the data in the literature is too scarce to be able to highlight real therapeutic effects. Furthermore, rigorous studies from a methodological point of view and with a larger sample size are therefore necessary to be able to evaluate the real risks and benefits of the therapeutic use of cannabinoids in Alzheimer's disease.