WO2020115751A1

WO2020115751A1 - Cannabis-based compositions for the treatment of alzheimer's disease and dementia

Info

Publication number: WO2020115751A1
Application number: PCT/IL2019/051333
Authority: WO
Inventors: Lihi BAR-LEV SCHLEIDER; Sid TAUBENFELD
Original assignee: To Pharmaceuticals Llc
Priority date: 2018-12-06
Filing date: 2019-12-05
Publication date: 2020-06-11

Abstract

The invention relates to therapeutic products and methods applicable to the treatment of dementia, including Alzheimer's disease (AD), and in particular to the alleviation of symptoms of behavioral syndrome related to dementia and AD. The products and methods of the invention apply certain type of cannabis-based compositions with a high CBD content and minimal THC content, up to the proportion of 20:1, respectively, provided under specific dose regimens and modes of administration.

Description

CANNABIS-BASED COMPOSITIONS FOR THE TREATMENT OF

ALZHEIMER'S DISEASE AND DEMENTIA

TECHNOLOGICAL FIELD

The present invention generally relates to therapeutic products and methods applicable to the treatment of dementia and Alzheimer's disease (AD), and in particular to the alleviation of symptoms of the behavioral syndrome related to dementia and AD.

BACKGROUND

Clinical value of cannabis is well documented in the medical literature. Cannabinoids, the active ingredients of cannabis, are present in significantly higher concentrations in resin- producing pistillate inflorescences of cannabis plants. Various types of cannabis, such as C. Sativa, C. Indica and C. Ruder alis, may contain more than 100 different types of cannabinoids in distinct concentrations and proportions. The two predominant types, the tetrahydrocannabinol (THC) and cannabidiol (CBD), have been related to a number of clinically beneficial effects attributed to their analgesic, antiemetic, antioxidative, neuroprotective and anti-inflammatory activities in mammals and humans.

The mammalian endocannabinoid system is a signal transduction system acting predominantly in the brain, and also in the peripheral tissues. Several cannabinoid receptors have been identified so far, the most prominent being the cannabinoid receptors types 1 and 2 (CBi and CB2). The endocannabinoid system has been implicated in maintenance of pain, appetite, memory, immunity and inflammation, among others. This underlies the notion of high therapeutic potential of exogenous cannabinoids and cannabis-based medicines, and the likelihood of their broad clinical applications. However, a rationalized use of cannabinoids still imposes significant challenges due to lack of significant controlled clinical trials.

A number of oral formulations of cannabinoids are commercially available today by prescription for specific indications. Marinol capsules containing dronabinol, a synthetic D⁹- THC isoform, in oil - were approved in a number of countries as an antiemetic in cancer patients under chemotherapy and in patients with AIDS. Cesamet capsules with a synthetic THC analog were approved as a Marinol substitute. Additional formulations such as Namisol and Arvisol tablets with pure THC and pure CBD, respectively, are now under clinical trial for various indications. More recently, orphan cannabis-derived compositions such as Sativex have been approved for spasticity in multiple sclerosis and Epidolex - for rare forms of epilepsy. The invention is relevant to a group of age-related neurodegeneiative conditions collectively named dementia, generally described as a decline in memory or thinking skills severe enough to reduce a person's ability to perform everyday activities. With steadily rising life expectancy and the size of elderly population, the number of people suffering from dementia has been increasing accordingly.

More specifically, dementia is a condition in which there is a damage to a person's cognitive performance in terms of higher brain capabilities such as language, memory, perception, learning ability, understanding of reality and more. Dementia has been related to a wide range of behavioral symptoms, such as outbursts and various verbal behaviors inappropriate in content or intensity, and inexplicable violence unrelated to any medical, social or environmental problem, or a perceived need, which are prevalent in up to 90% of patients. This is apparent by their common occurrence in nursing wards. According to clinical studies behavioral disorders in dementia reduce the length of time patients stay at home and accelerate the process of hospitalization, and also shortened median survival.

Alzheimer's disease (AD) is a particular sub-type of dementia, or more precisely, is one of its major causes responsible for up to 60-80% of all cases. AD is recognized at the molecular level by a number of pathological markers, most prominent of which are the sinking of the peptide b-amyloid (Ab) and hyper-phosphorylation of tau, which eventually lead to neuronal cell death and damage to neural connectivity. Additional markers in AD include nerve

The most common and consistent syndrome found in patients with severe dementia or AD is agitated behavior characterized by a combination of violent behavior (physical or verbal), restlessness and inappropriate loudness and other behavioral disturbances. Since there is no treatment approved by the Food and Drag Administration (FDA) for this problem, due to lack of a better alternative patients are often prescribed antipsychotic medications. However, particularly in the context of dementia, these drags have limited effectiveness and can cause serious side effects, including death.

In patients with dementia and advanced dementia in particular, psychiatric medications have been related to significant risks of Parkinsonism, drowsiness, increased instances of felling, accelerated cognitive decline and increased mortality. In patients with milder forms of dementia they have been related to a decline in quality of life in terms of activeness, mood and social interaction. Alternatives, such as, carbamazepine, have not shown conclusive efficacy. Certain cannabis-based compositions have been previously suggested as potential solutions for maintenance and relief of a wide range of disorders, including neurodegeneration, mental disorders and trauma, and other conditions (US9675656, US8673368, WO07138322).

GENERAL DESCRIPTION

The presently disclosed invention seeks to provide a targeted therapeutic solution for particular symptoms of dementia, which are widely common in dementia in general and even more common in advanced dementia and AD, specifically behavioral disorders such as agitation, aggressiveness anxiety, sleep and circadian disorders, and related co-morbidities. In a more general sense, the invention aims at providing a relief to the overall burden of symptoms in dementia and other age-related neurodegenerative disorders.

At the core of the invention is certain type of cannabis-based compositions generally characterized as being enriched in CBD. The compositions of the invention have been found effective for treating or alleviating dementia, and particularly effective in terms of improvement of behavioral disorders (also the behavioral syndrome) as revealed in agitated behavior and often violent behavior (physical or verbal) to self and others, restlessness, inappropriate loudness, hoarding, resistance and negativism, and other symptoms. These findings were highly unexpected and reassuring in view of that the treatment options for this type of symptoms in dementia are limited and the existing options lead to severe side effects.

It should be noted that there have been occasional reports on use of certain type of cannabinoid compositions for treating symptoms of dementia. None of these reports, however, related in a consistent and standardized manner to the behavioral syndrome in dementia and AD Moreover, the exiting knowledge predominantly related to purified or synthetic THC as the only active (Walther et al. 2006. Psychopharmacology, 185, 524-528; Walther et al. 2011. J Clin Psychopharmacol, 31, 256-258; Fabre & McLendon 1981. J Clin Pharmacol 21, 3775- 3825), with certain studies reporting on a series of adverse events (Volicer et al. 1997. IntJ Geriatr Psychiatry, 12, 913-919), and one study reporting no improvement of neuropsychiatric symptoms in dementia (Van den Elsen et al. 2015. Neurology, 84, 2338-2346. Few studies reported on use of THC-rich cannabis plants by smoking (Kumar et al. 2001. Anaesthesia, 56, 1059-1068; Janse et al. 2004. Utrecht, the Netherlands, PHARMO Inst Drug Outcomes Res)

Therapeutic value of the compositions of the invention in dementia and the behavioral syndrome is now exemplified with oil extracts of certain type of CBD enriched cannabis strains. An exemplary member of this group is the strain referred to herein as 'AvidekeV first reported in US Plant Patent Application No.2014/259228 (Continuation Application No.2017/290286). More precisely, Avidekel herein encompasses a group of strains or cultivars produced from the original Avidekel strain selected due to its particularly CBD/THC content, starting from CBD:THC ratio of about 4: 1, and more recently reaching an unprecedented ratio of about 20: 1, respectively.

In terms of CBD/THC content, a typical Avidekel strain can comprise as high as 15-20% CBD or more (w/w), and THC as 1-4% or less than 1% (w/w). More specifically, Avidekel strain can be further defined as a cannabis strain comprising CBD up to at least 15%, 16%, 17%, 18%, 19%, 20% or more, and THC up to 4%, 3%, 2%, 1%, 0.5% or less (w/w).

According to the invention, erode plant material of Avidekel (female flowers) can be extracted in oil, e.g., olive oil or other vegetable or natural oil, using known in the art methods. The advantage of this procedure is that it preserves other plant components, such as terpenes, contributing to therapeutic effects and other properties of this product (flavor and smell). After the extraction step, the CBD/THC content is carefully monitored to achieve further enrichment of CBD, with final concentrations of CBD of at least about 30%, and THC - 1.5% (w/w) (see Example 1).

More precisely, such oil preparations of Avidekel can be defined as comprising CBD up to at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29, 30% or more, and THC up to 2%, 1.9%, 1.8%, 1.7%, 1.6%.1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1% or less (w/w).

In terms of CBD/THC amount, typically a single drop of Avidekel oil comprises about 12 mg CBD and 0.6 mg THC, and 21 drops of Avidekel oil, being the maximal dose used in this study - about 252 mg CBD and 12.6 mg THC (see Table 1).

It should be appreciated that a cannabis-derived material can include additional types of cannabinoids, although at much lesser concentrations and proportions, potentially contributing to the presently demonstrated therapeutic effects.

Safety and efficacy of the compositions of the invention have been evaluated in a double-blind, placebo controlled randomized clinical trial (Example 2). In this trial, the compositions of the invention have been tested as a combination therapy - together with other anti-psychotics for the treatment of the behavioral syndrome in dementia. It is likely that the same compositions can be further used as monotherapies, thus dispensing with the need for anti-psychotics and their side-effects in elderly patients.

Therapeutic validity of the compositions of the invention have been demonstrated using the gold standard Diagnostic and Statistical Manual of Mental Disorders, 5^th Edition (DSM-5), and further clinical questionnaires for the assessment of specific symptoms of behavioral disorders in dementia and AD, well-known and acknowledged in geriatric practice: BPSD Behavioral and Psychological Symptoms of Dementia

CGI-S-A/A Clinical Global Impression-Severity-Agitation/Aggressive

CMAI Cohen-Mansfield Agitation Inventory

GDS Geriatric Depression Scale

MMSE Mini-Mental State Examination

NPI-NH Neuropsychiatric Inventory

PAIN AD Pain Assessment In Advanced Dementia

Safety of the tested compositions has been assessed by evaluation of adverse events (AE) and serious adverse events (SAE), and blood and urine analyses for exposure to THC.

The success rate has been established using a number of high-fidelity statistical methods comparing between the treatment and control groups. A detailed description of this trial is provided further below (Example 2).

This clinical trial has further provided tools for establishing therapeutically effective doses and regimens for maximization of beneficial clinical outcomes and avoidance of side effects and cross-drug interaction. In other words, this study provided an exemplary framework for applying the compositions of the invention in a rationalized manner to achieve more effective and safe treatment of dementia and the behavioral syndrome in dementia in particular.

In terms of methods, the compositions of the invention can be administered via oral and/or topical routes, such methods are particularly advantageous in geriatric patients. Sublingual administration of the compositions of the invention has been presently demonstrated. Another advantageous route of administration is in the form of a transdermal patch, administered apart or together with the oral dosage forms.

As noted above, the compositions and methods of the invention can be applied as combination therapies with other drags, including those directed at the behavioral syndrome. Elderly patients are usually exposed to a large number of drags for specific age-related clinical conditions (e.g., cancer, heart disease, metabolic disorders, etc.) In terms of behavioral disorders, dementia patients are usually treated with one or more drags from the following groups:

Antipsychotic medications (typical and atypical antipsychotics),

Antidepressant medications (SSRIs, TCAs),

Mood stabilizers (lithium, valproate),

Benzodiazapines and other anxiolytics,

Anti-dementia drags (cholinesterase inhibitors, NMDA-R antagonists). Importantly, as combination therapies the compositions and methods of the invention can lead to a reduced intake of concurrent drugs, and thereby mitigate or reduce their adverse effects. Ultimately, the prospect is to apply them as monotherapies forthe behavioral syndrome.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Tetrahydrocannabinol ( THC) refers herein to a class of psychoactive cannabinoids characterized by high affinity to CB 1 and CB2 receptors, having a molecular formula C₂₁H₃₀O₂, an average mass of approximately 314.46 Da, and a general structure of Formula I.

Cannabidiol ( CBD ) refers to a class of non-psychoactive cannabinoids with a low affinity to CB1 and CB2 receptors, having a formula C₂₁H₃₀O₂, an average mass of approximately 314.46 Da, and a general structure of Formula P.

The terms THC and CBD herein further refer to isomers, derivatives, or precursors of these molecules, such as (-)-trans-D9-tetrahydrocannabinol (D9-THC), D8-THC, and D9-CBD, and further to THC and CBD derived from their respective 2-carboxylic acids (2-COOH), THC- A and CBD-A. In the broadest sense, the terms THC and CBD can refer to a synthetic or semi-synthetic or a natural cannabinoid (i.e. purified or extracted from a cannabis plant). THC responsible for the psychoactive ('high') effect of cannabis and is known to relieve pain. CBD has no psychoactive effects and moderates the euphoric effect of THC, it is known to reduce inflammation and nausea.

Cannabis-based and cannabis-derived, these terms herein are interchangeable and denote a composition or a constituent thereof purified or extracted from a cannabis plant using known technologies known in the art. These terms can further relate to a crude dry plant material. Regarding extracts, there are number of methods for producing a concentrated cannabis-derived material, e.g., filtration, maceration, infusion, percolation, decoction in various solvents, Soxhlet extraction, microwave- and ultrasound- assisted extractions and other methods. Certain oil extracts from the cannabis strain Avidekel are presently exemplified.

Therapeutic agent denotes here a broad range of agents from various groups, including antipsychotic medications (typical and atypical antipsychotics), antidepressant medications (e.g., SSRIs, TCAs), mood stabilizers (e.g., lithium, valproate), benzodiazapines and other anxiolytics, anti-dementia drugs (cholinesterase inhibitors, NMDA-R antagonists). This term herein further encompasses vitamins and minerals used as dietary supplements generally recognized as safe (GRAS).

The terms therapeutic dose or therapeutically effective dose, which herein are interchangeable, relate to doses of the compositions of the invention, in any dosage form, capable of producing an improvement/ reduction of at least one symptom of the behavioral syndrome in dementia according to clinically accepted criteria (e.g., Example 2). Such improvement can be further evaluated according to severity scales. Thus an improvement relates to a type and/or a number of symptoms, a severity, a frequency of symptom(s), specific groups of symptoms (partial symptoms), and/or overall manifestation of symptoms in a subject or a group evaluated by a physician or self-reporting and estimated as at least 5%, 10%, 15%, 20%, 25%, 50%, 75%, 100% reduction or a complete abolition of symptom(s).

Therapeutically effective amount (also pharmacologically, pharmaceutically or physiologically effective amount) herein denotes an amount of active agent needed to provide a desired level physiological response or improvement as above. The precise amount depends on numerous factors, e.g. type of an agent, activity of a composition, intended patient use (e.g. number of doses per day), patient's considerations, and others. An effective amount of an agent can be administered in one administration, or multiple administrations. The exact amount can be the result of empirical and/or individualized (case-by-case) determination. Approximately or about, these terms herein are interchangeable, denote up to ± 10% deviation from a respective measurement, or 9%, 8%, 7%, 6%, 5% or less a deviation thereof.

Thus in one of its main aspect the invention provides certain type of cannabis-based compositions for treating, alleviating or reducing dementia or at least one symptom of the behavioral syndrome related to dementia, characterized in that they comprise CBD:THC ratio of at least about 20: 1, respectively, or more in favor of CBD.

As has been noted, dementia is not a specific disease but rather denotes a group of symptoms associated with a decline in memory or other thinking skills. AD is responsible for a large proportion of dementia cases. Behavioral abnormalities are common and prominent characteristics of dementia. They include symptoms such as depression, anxiety psychosis, agitation, aggression, disinhibition, and sleep disturbances. Up to 90% of patients with dementia suffer from behavioral disorders.

The term 'behavioral syndrome' herein collectively referred to behavioral disorders in dementia. The meaning of this term in terms of specific clinical symptoms, severity and duration will be explained in detail further below. More importantly far this purpose, specific symptoms of the behavioral syndrome can be assessed by one or more clinical tools widely used and acknowledged in geriatric practice.

Thus in numerous embodiments the cannabis-based compositions of the invention can be used for alleviating or reducing at least one symptom of the behavioral syndrome assessed according to at least one of:

Behavioral and Psychological Symptoms of Dementia (BPSD),

Cohen-Mansfield Agitation Inventory (CMAI),

Neuropsychiatric Inventory (NPI-NH),

Clinical Global Importation Severity-Agitation/Aggression (GAI-S-A/A),

Geriatric Depression Scale (GDS),

Pain Assessment in Advanced Dementia (PAINAD),

Mini-Mental State Examination (MMSE).

In numerous embodiments the compositions of the invention can comprise as high as 15-20% CBD or more (w/w), and THC as 1-4% or less than 1% (w/w). More specifically, they can comprise CBD up to at least 15%, 16%, 17%, 18%, 19%, 20% or more, and THC up to 4%, 3%, 2%, 1%, 0.5% or less (w/w).

In certain embodiments the composition of the invention can comprise up to at least about 30% CBD (w/w). In further embodiments the compositions of the invention can comprise about 30% CBD and about 1.5 % THC (w/w). More specifically, they can comprise CBD up to at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29, 30% or more, and THC up to 2%, 1.9%,

I.8%, 1.7%, 1.6%.l, 5%, 1.4%, 1.3%, 1.2%, 1.1%, 1% or less (w/w).

In terms of amounts of actives, the compositions of the invention can comprise at least about 12 mg CBD and 0.6 mg THC up to at least about 1200 mg CBD and 600 mg THC. More specifically, they can comprise in a single dosage form starting from 5, 10, 15, 20,30, 40, 50, 60, 70, 80, 90, 100 mg CBD and 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 mg THC, and up to 150, 200, 250, 300, 350, 400, 450, 500, mg CBD and up to 2, 3, 4, 5, 6, 7, 8, 9, 10,

I I, 12, 13, 14, 15 mg THC, while keeping the desirable ratio of 20: 1 respectively.

The transdermal patches (see below) can comprises higher concentrations of actives.

In terms of formulations and dosage forms, the presently disclosed compositions can be adapted for oral, sublingual, topical or transdermal administration.

In certain embodiments the compositions of the invention are provided in a form of an oil extract of a cannabis strain. Oil extracts are particularly advantageous as they retain a range of lipophilic components, i.e., cannabinoids, terpenes, carotenes and others, in specific proportions and combinations, the sum total of which is responsible for the presently demonstrated effects. In addition, the oil extracts are easily applicable via oral, sublingual and topical routes. Certain type of olive oil extracts of cannabis has been presently exemplified.

Notwithstanding, the term ' oil extract of a cannabis strain' denotes herein various types of oils and various types of plant material from the relevant cannabis strains. With respect to the latter, the most applicable plant material with the highest concentration of actives is the inflorescences female cannabis plants, more precisely the resin-producing part of these flowers. It is possible however that other parts of cannabis (seeds, stem, etc.) can be applicable for the purpose of specific embodiments.

In the same way, othertypes of oils can be applicable for producing the cannabis extracts of the invention, vegetable oils in general (e.g., soybean, canola, com, cotton seed, sunflower, peanut, sesame, rice bran oils), and also essential oils (e.g., lemon, cinnamon, iemongrass, clary sage, lavender, tea tree, eucalyptus).

Still in other embodiments , the compositions of the invention can be provided in the form of a transdermal patch, or incorporated into various transdermal delivery systems by means of known in the art technologies, including first-, second- and more recent third- generation delivery systems. The terms 'transdermal patch' or ' transdermal delivery system' in this context refer to a variety of systems, including first-generation transdermal delivery systems known to be applicable for lipophilic drugs. First-generation transdermal delivery systems are systems where the drug is stored in a reservoir enclosed on one side with an impermeable backing and on the other side - with an adhesive contacting to the skin. This term encompasses systems wherein the drug is dissolved in a liquid or gel-based reservoir, and also systems where the drug is incorporated into a solid polymer matrix.

For example, the transdermal delivery system of the invention can be composed of four layers, including an impermeable backing membrane, a drug reservoir, a semi-permeable membrane that may serve as a rate-limiting barrier, and an adhesive layer. These particular systems can permit the use of liquid chemical enhancers, such as ethanol.

Further, transdermal delivery systems can have three layers, by eliminating the semi- permeable membrane, or just two layers, by incorporating the drug directly into the adhesive.

Another type of transdermal delivery systems employs second-generation delivery systems, i.e., those using chemical enhancers, non-cavitational ultrasound and iontophoresis.

The most recent type of transdermal delivery systems are third-generation delivery systems, i.e., target their effects to skin’s barrier layer of stratum comeum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound.

In numerous embodiments of the compositions of the invention can incorporated into delivery systems permitting controlled or suspended release of actives. These types of systems have been subject to intensive R&D, yielding first-, second- and third-generation delivery systems, including so-called 'smart' polymers and hydrogels to make systems that are triggered by changes in environmental factors, such as pH, temperature, or glucose.

Controlled drug delivery systems are applicable to oral and transdermal forms of the presently disclosed compositions.

Still, in numerous embodiments the compositions of the invention can be made of extracts of the cannabis strain designated herein as Avidekel. Such compositions using olive oil extracts of female flowers of Avidekel strain have been presently exemplified.

Further, in numerous embodiments the compositions of the invention can further comprise at least one additional therapeutic agent for treating dementia or the behavioral syndrome related to dementia. The importance of this combination therapy in dementia and in the behavioral syndrome in particular, and the relevant concurrent drugs or drug groups, have been mentioned above. Importantly, the compositions of the invention when given with other drugs in the same formulation or by a concurrent administration, can lead to the alleviation or reduction of at least one adverse effect or improving a dosing regimen of said concurrent drags. In other words, the compositions of the invention, in themselves safe and devoid of adverse reactions, are particularly advantageous in the form of combination therapies, particularly in elderly patients who due to slower metabolism, background diseases and cross-drag interaction, and other factors are more prone drag adverse events.

It is another important aspect of the invention to provide methods for treating, alleviating or reducing dementia or at least one symptom of the behavioral syndrome related to dementia in a subject in need thereof by administering to the subject a therapeutically effective amount of a cannabis-based composition comprising CBD:THC ratio of at least about 20:1, respectively.

As has been noted, the term 'dementia' does not denote a specific disease, but rather describes a group of symptoms associated with a decline in memory or other thinking skills. Alzheimer's disease (AD) is the most common type of dementia. Vascular dementia, which occurs after a stroke, is the second most common type. But there are many other conditions that can cause symptoms of dementia, including some that are reversible, such as thyroid problems and vitamin deficiencies. While symptoms of dementia can vary greatly, at least two of the following core mental functions must be significantly impaired to be considered dementia:

Memory,

Communication and language,

Ability to focus and pay attention,

Reasoning and judgment,

Visual perception.

Dementia encompasses herein mild-moderate, middle stage and late stage forms. This term further relates to people experiencing problems with short-term memory (problems coming up with the right word or name, trouble remembering names, challenges performing tasks, forgetting material that one has just read, losing or misplacing objects, increasing trouble with planning or organizing); and also patients with progressive symptoms (forgetfulness of events, feeling moody or withdrawn, confusion about time and place, the need for help choosing proper clothing, trouble controlling bladder and bowels in some individuals).

Particularly relevant in this context are patients experiencing changes in sleep patterns, becoming restless, wandering and becoming lost, with personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like hand-wringing. Dementia is caused by damage to brain cells lading to loss of neuronal communication. Different types of dementia are associated with particular types of brain cell damage in particular regions of the brain. In AD, the primary site of brain damage is hippocampus. Thus the term dementia further overlaps with the terms 'neurodegeneration' and 'neurodegenerative disease' in the sense of age-related damages to specific regions in the CNS.

More specifically, the compositions and methods of invention are applicable for treating, alleviating or reducing symptoms of behavioral syndrome in dementia. Today, there are a number of specifically tailored clinical tools for the diagnosis and follow up of the behavioral syndrome in dementia. The most notable have been implemented in the presently described clinical trial (Example 2), namely:

- Behavioral and Psychological Symptoms of Dementia (BPSD),

- Cohen-Mansfield Agitation Inventory (CMAI),

- Neuropsychiatric Inventory (NPI-NH),

- Clinical Global Importation Severity-Agitation/Aggression (GAI-S-A/A),

- Geriatric Depression Scale (GDS),

- Pain Assessment in Advanced Dementia (PAIN AD),

- Mini-Mental State Examination (MMSE).

A short version of the CMAI questionnaires is provided in Annex A, detailing the spectrum of symptoms included in the behavioral syndrome, their specific nature, duration and frequency.

Thus it is meant that the compositions and methods of the invention can alleviate or reduce each one of these symptoms, or any combination thereof, in terms of intensity, frequency and/or duration. To that end, the compositions of the invention should be provided in therapeutically effective doses and under therapeutically effective regimens, and by permissible administration routes.

In numerous embodiments the methods of the invention can apply the cannabis-based compositions of the invention in a daily dose in the range of at least about 36 mg CBD and 1.8 mg THC up to at least about 756 mg CBD and 37.8 mg THC or more. More specifically, the daily dose can be in the range of at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mg CBD and 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2 mg THC and up to about 200, 300, 400, 500, 600, 700, 800, 900, 1000 mg CBD and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 mg THC, while preserving the ratio 20: 1, respectively, The methods of the invention can apply said amounts as a single dose or as two or three doses per day, or more.

Importantly, according to the methods of the invention the therapeutically effective amount of the cannabis-based compositions can be personalized. In other words, the exact therapeutically effective amount is established for each patient by titration of the dose and monitoring of therapeutic effects. Examples of such personalized methods have been presently demonstrated (Table 1).

Further, in numerous embodiments the methods of the invention are applied as a combination therapy further comprising at least one additional therapeutic agent administered simultaneously or in succession with the cannabis based-composition. Advantages of such combination therapies in dementia have been previously discussed.

With respect to concurrent drags or therapeutic agents, at least four drags should be avoided: Astemizole, Cisapride, Pimozide and Terfenadine, due to potential cross-drag interaction and/or competition on metabolizing enzymes (CYP3A4 and CYP2C9).

In this context, the methods of the invention can be further applied for alleviating or reducing adverse effects or improving a dosing regimen of at least one concurrent drag.

In certain embodiments the methods of the invention can be applied a monotherapy for dementia or symptoms of the behavioral syndrome in dementia, thereby replacing other antipsychotic drags.

In terms of administrations routs, according to the methods of the invention the cannabis-compositions are administered via oral, sublingual, topical or transdermal routes. The oral dosage forms, and particularly those in the form of oil extracts, are particularly applicable for personalization and careful titration to achieve a therapeutically effective dose.

Particularly advantageous oral dosage forms are provided as oil extracts of the cannabis strain Avidekel. Methods using these particular preparations have been presently exemplified.

Generally, the methods of the invention apply cannabis-based compositions comprising up to at least about 30% CBD (w/w). In numerous embodiments the methods of the invention apply compositions comprising about 30% CBD and about 1.5 % THC (w/w). The compositions of the invention have been described in detail above.

It is another aspect of the invention to provide use of a cannabis-derived material for manufacture of a medicament for treating, alleviating or reducing dementia or at least one symptom of the behavioral syndrome related to dementia, said cannabis-derived material comprises CBD:THC ratio of at least about 20: 1, respectively. EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

EXAMPLE 1

INVESTIGATIONAL PRODUCT (IP)

1.1 Characterization of Avidekel oil

In general, there are a number of methods for producing cannabis oils, and oil from other medicinal plants. Present preparations use olive oil as a solvent for preservation of cannabinoids and other beneficial components such as terpenes to be available in higher concentrations. Cannabis oil can be taken orally by ingesting a small number of drops under the tongue several times a day.

An extract of Avidekel flowers is dissolved in olive oil. In terms of the two main cannabinoids, Avidekel oil usually comprises CBD and D9-THC in a ratio of about 20: 1 and at concentrations of about 30% and 1.5%, respectively. Fine tuning of CBD/THC content is achieved by a titration with pure CBD and/or olive oil to reach the required ratio of 20:1 (CBD:THC) and 30% CBD.

In other words, each drop of Avidekel oil (about 0.04 ml) contains about 12 mg CBD and 0.6 mg D⁹-THC.

In terms of other components, Avidekel oil comprises about 45% olive oil, 30% CBD, 1.5% THC, 0.5% CBG, <0.1% CBN, <1.5% CBC, <0.5% CBDV and other unidentified cannabinoids reaching up to 21%, and further certain percentages of terpenes, flavonoids, waxes and chlorophyll.

The IP is stored at room temperature.

1.2 Administration mode

IP is administered in the form of drops under the tongue twice a day. In the present examples IP is taken as add-on to the standard medications in patients with dementia.

1.3 Dosing and titration period

In order to reach the optimal dose for each patient, as the effective dose (number of drops) and the timing can vary between individuals, patients are subjected to a titration period that can last for up to 4 weeks. During that time the dose is balanced between maximum impact on symptoms and minimal side effects. The initial dose is one drop of Avidekel oil under the tongue three times a day (morning, noon and evening) for two days. The dose is increased gradually for each patient with in increments of one drop per two days, depending on clinical effects and patient's tolerability (Table 1). The titration is dropped when an adverse reaction occurs (see below), then the patient is tapered down to a pre-adverse reaction dose, or when the maximum dose is achieved.

The maximum dose is 21 drops per administration, i.e., (12.6 mg of D9-THC and 252 mg of CBD).

Patients in the control group receive placebo oil containing olive oil and chlorophyll.

The titration phase (usually 6 weeks) is followed treatment phase (10 weeks) using a personalized maximal dose (without side effects) achieved during the titration. The total treatment period (16 weeks) therefore accounts for a sub-optimal treatment during the titration, and an optimal treatment during the treatment period.

Table 1. Titration schedule demonstrating titration of one administration to maximal dose

* Titration is stopped upon one or more of the following:

- worsening of mental status,

- worsening of BPSD,

- feinting or lightheadedness as indicated by falling, worsening gait instability, or marked decline in motor function based on staff assessments,

- significant changes in blood pressure,

- significant changes in pulse,

- significant changes in blood sugar levels,

- significant changes in respiration rates. 1.4 Concomitant medications

Patients receiving one of the following: Astemizole, Cisapride, Pimozide or Terfenadine, are excluded from the study. In the present examples, IP is given as a combinations therapy with traditional medications. All changes in drugs consumption are carefully monitored. When properly titrated and controlled for adverse reactions, IP can be effective for reducing the dose of concomitant medications and their related side effects.

EXAMPLE 2

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 3.1 Objective

To evaluate the safety and efficacy of Avidekel oil for the treatment of subjects with agitation related to dementia and AD.

3.2 Working hypothesis

Administration of Avidekel oil to patients with dementia will lead to the reduction of the behavioral syndrome compared to the placebo.

3.3 Study endpoints

3.3.1 Primary efficacy endpoint

The proportion of subjects achieving a CMA1 > 4-point decrease at week 16 compared to baseline.

3.3.2 Secondary efficacy endpoints

- Assessment of the proportion of subjects achieving a CMAI > 4-point decrease during the treatment period at each time point,

- Time to 4 point reduction in CMAI in treatment vs. control,

- Mean change in CMAI score,

- Mean change in NPI-NH,

- Assessment of BPSD response to the treatment,

- Change in pain in PAIN AD,

- Change in GDS,

- Clinical literal assessment of subject in GAI-S-A/A.

3.3.3 Safety endpoints

- Incidence and severity of adverse events (AE) and serious AE (SAE). 3.4 Design

3.4.1 Duration

The study is composed of two phases: a) titration period during which a personalized maximal dose is determined (about 6 weeks) and b) treatment period when a patient is subjected to a stable treated with the personalized maximal dose as above (10 weeks), yielding the toal period of approximately 4 months.

3.4.2 Population

A total of approximately 60 subjects, 40 in the treatment and 20 in the control groups, assigned under randomization.

Inclusion criteria include: male and female >60 years of age with documented diagnosis of dementia (NCD) according to the DSM-V Criteria, a MMSE < 26 and clinically relevant BPSD, operationally defined as NPI-NH sub score of agitation ³ 3. Patients having a stable concomitant medication for the control of BPSD and for any other concurrent condition.

Exclusion criteria include: patients receiving Astemizole, Cisapride, Pimozide or Terfenadine. Patients with agitation/aggression attributable to concomitant medications or environmental conditions. Patients with severe heart disease, epilepsy or active mental disorder other than dementia/AD. Patients after surgery.

3.5 Procedures

Relevant variables are collected on each patient during 10 concurrent visits (see Table 2 below). During the enrollment stage the following information is obtained:

- Informed consent,

- Assessment as per inclusion and exclusion criteria,

- Demographic information,

Medical history and history of dementia.

Physical examination is performed in all concurrent visits, including evaluation of vital signs: temperature, pulse, blood pressure, height (only screening visit) and weight. The assessment of the behavioral syndrome is performed in the enrollment and concurrent visits by: i. Cohen-Mansfield Agitation Inventory (CMAI),

ii. Neuropsychiatric Inventory (NPI-NH),

iii. Clinical Global Impartation Severity- Agitation/Aggression (CGI-S-A/A), iv. Pain Assessment in Advanced Dementia (PAINAD),

v. Mood using Geriatric Depression Scale (GDS),

vi. Mini-Mental State Examination (MMSE). Adverse events (AE) are monitored all through the study in relation to cannabis and concomitant medications regarding the number and severity, and any changes in medications dosing regimen. Safety test include hematology and chemistry panels.

3.6 Statistics

Patients and control groups are compared by c² test or t-test for independent groups, as relevant for the variable type. An individual improvement of each of patient is evaluated by McNemar's test or paired sample t-tests according to the variable type. All tests are two-tailed and considered significant when p <0.05.

3.7 Criteria for endpoint evaluation

3.7.1 Efficacy outcome measures

Primary measures:

- The proportion of subjects achieving a Cohen-Mansfield Agitation Inventory (CMAI) > 4-point decrease at week 16.

Secondary measures:

- The proportion of subjects achieving agitation status improvement of CMAI > 4-point decrease score at weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline.

- Mean change in the CMAI score at weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline.

- Mean change in the 4-item agitation/aggression subscale of the NPI-NH.

- Change in measurement of verbal and physical agitation and aggression symptoms at Weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline..

- Mean change of the NPI-NH at weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline.

- Mean change in CGI-S-A/A at weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline.

- BPSD type response assessment by the NPI-NH at weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline.

Changes in recurring consumption of medications at weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline.

Mean change in the GDS score at weeks 6, 12 and 16 vs. baseline.

Change in PAIN AD score at weeks 2, 4, 6, 8, 10, 12, 14 and 16 vs. baseline. 3.7.2 Safety outcome measures

Clinical and laboratory results, including:

Adverse Events (AEs) - all study visits,

- Serious Adverse Events (SAEs) - entire study duration for the patient,

- Suspected Unexpected Serious Adverse Reaction (SUSARs) all visits,

- Vital signs- all visits.

Serum chemistry and hematology, weeks 2, 6, 10 and 14.

- Changes from baseline in BPSD by means of the CMAI, NPI-NH and CGI- S-A/A - all study visits and MMSE at weeks 6, 12 and 16.

3.8 Side effects

In general, the tolerance to cannabis is considered to be relatively good, with only mild side effects. In rare cases, subjects on cannabis reported: dizziness, dry mouth, nausea, sleepiness, psychoactive effects, headaches, confusion and disorientation, increased appetite, weakness, red / irritated eyes, decreased memory, decreased concentration, heart palpitations, restlessness, vomiting and fear.

Synopsis of the study protocol is provided in Table 3 below.

3.9 Preliminary findings

Evaluation of preliminary findings of this study has shown significant differences between the placebo and the treatment group, specifically reduced agitation and behavioral symptoms in patients subjected to the treatment with the composition of the invention (according to NPI-NH score, p<0.02).

Table 3. Protocol synopsis

ANNEX A.

Claims

CLAIMS:

1. A cannabis-based composition for use in treating, alleviating or reducing dementia or at least one symptom of the behavioral syndrome related to dementia, the composition comprising CBD:THC ratio of at least about 20: 1, respectively.

2. The composition of claim 1, wherein the at least one symptom of the behavioral syndrome related to dementia is assessed according to at least one of:

Behavioral and Psychological Symptoms of Dementia (BPSD),

Cohen-Mansfield Agitation Inventory (CMAI),

Neuropsychiatric Inventory (NPI-NH),

Clinical Global Impartation Severity-Agitation/Aggression (GAI-S-A/A),

Geriatric Depression Scale (GDS),

Pain Assessment in Advanced Dementia (PAIN AD),

Mini-Mental State Examination (MMSE).

3. The composition of claim 1 or 2 comprising up to at least about 30% CBD (w/w).

4. The composition of claim 1 or 2 comprising about 30% CBD and about 1.5 % THC

(w/w).

5. The composition of any one of claims 1-4 adapted for oral, sublingual, topical or transdermal administration.

6. The composition of claim 5 in a form of an oil extract of a cannabis strain.

7. The composition of claim 5 in a form of a transdermal patch.

8. The composition of claim 6, wherein the cannabis strain is Avidekel.

9. The composition of any one of the preceding claims, the composition comprising at least about 12 mg CBD and 0.6 mg THC up to at least about 1200 mg CBD and 600 mg THC.

10. The composition of any of the preceding claims, the composition further comprising at least one additional therapeutic agent for treating dementia or the behavioral syndrome related to dementia.

11. The composition of claim 1 or 10, wherein treating, alleviating or reducing dementia further comprises alleviating or reducing at least one adverse effect or improving a dosing regimen of at least one concurrent drag.

12. A method for treating, alleviating or reducing dementia or at least one symptom of the behavioral syndrome related to dementia in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of a cannabis-based composition comprising CBD:THC ratio of at least about 20: 1, respectively.

13. The method of claim 12, wherein the behavioral syndrome in said subject is assessed according to at least one of:

Behavioral and Psychological Symptoms of Dementia (BPSD),

Cohen-Mansfield Agitation Inventory (CMAI),

Neuropsychiatric Inventory (NPI-NH),

Clinical Global Impartation Severity-Agitation/Aggression (GAI-S-A/A),

Geriatric Depression Scale (GDS),

Pain Assessment in Advanced Dementia (PAINAD),

Mini-Mental State Examination (MMSE).

14. The method of claim 12 or 13, wherein the cannabis-based composition comprises up to at least about 30% CBD (w/w).

15. The method of claim 12 or 13, wherein the cannabis-based composition comprises about 30% CBD and about 1.5 % THC (w/w).

16. The method of any one of claims 12-15, wherein the cannabis-based composition is administered via oral, sublingual, topical or transdermal routes.

17. The method of any one of claims 12-16, wherein the cannabis-based composition is provided in a form of an oil extract of a cannabis strain.

18. The method of claim 17, wherein the cannabis strain is Avidekel.

19. The method of any one of claims 12-18, wherein the cannabis-based composition is administered in a daily dose in the range of at least about 36 mg CBD and 1.8 mg THC up to at least about 756 mg CBD and 37.8 mg THC or more.

20. The method of claim 19, wherein the daily dose is administered as a single dose or as two or three doses per day.

21. The method of any of claims 12-20 constituting a monotherapy for dementia or a symptom of the behavioral syndrome related to dementia.

22. The method of any of claims 12-20 constituting a combination therapy further comprising at least one additional therapeutic agent administered simultaneously or in succession with the cannabis based-composition.

23. The method of claim 22, wherein further comprises alleviating or reducing at least one adverse effect or improving a dosing regimen of at least one concurrent drag.

24. Use of a cannabis-derived material for manufacture of a medicament for treating, alleviating or reducing dementia or at least one symptom of the behavioral syndrome related to dementia, said cannabis-derived material comprises CBD:THC ratio of at least about 20:1, respectively.

25. Use according to claim 24, wherein the behavioral syndrome is assessed according to at least one of:

Behavioral and Psychological Symptoms of Dementia (BPSD),

Cohen-Mansfield Agitation Inventory (CMAI),

Neuropsychiatric Inventory (NPI-NH),

Clinical Global Impartation Severity-Agitation/Aggression (GAI-S-A/A),

Geriatric Depression Scale (GDS),

Pain Assessment in Advanced Dementia (PAIN AD),

Mini-Mental State Examination (MMSE).