Compositions comprising cannabigerol for use in the prevention and / or treatment of arrythmias

Abstract

The present application refers to a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in reducing: a) a frequency of calcium sparks in a cell, b) a number of calcium sparks per spark site in a cell, c) an intensity and / or a frequency of calcium waves in a cell, or d) any combination thereof. The present application also refers to said composition for use in the treatment and / or prevention of a cardiac arrhythmia.

Description

[0001] Compositions comprising cannabigerol for use in the prevention and / or treatment of arrythmias

[0002] This application claims the benefit of European Patent Application EP24383293.8 filed on 28 November 2024.

[0003] Technical Field

[0004] The present invention belongs to the field of medicine. In particular, it relates to compositions for the prevention and / or treatment of conditions characterised by abnormal cellular calcium handling. The compositions of the invention are particularly useful for the treatment of arrhythmias, in particular atrial fibrillation and ventricular fibrillation.

[0005] Background Art

[0006] An arrhythmia refers to a condition characterised by an abnormal heartbeat, where the heart may beat too slowly, too quickly, or irregularly. Atrial fibrillation (AFib), a type of arrhythmia, is a heart condition characterised by an abnormally fast rate and an irregular rhythm of contraction of the heart atrial chambers. In clinical practice, AFib is highly relevant as it is the most common arrythmia, affecting 2-3% of the general population, and is a common cause of stroke, heart failure, cardiovascular death, myocardial infarction, and dementia. Similarly, ventricular fibrillation (VFib) is a life-threatening arrhythmia characterised by an abnormal heartbeat rhythm and the quivering / fibrillation of the heart ventricles. VFib can cause cardiac arrest with loss of consciousness and no pulse, which is fatal, in the absence of prompt medical intervention. Even in the absence of life-threatening outcomes, arrhythmias, including AFib and VFib, decrease quality of life through symptoms and cause psychological distress.

[0007] Current treatments for arrythmias include lifestyle modifications to avoid arrhythmogenic stimuli, if possible, pharmacological treatment to control heartbeat rate and rhythm, and surgical interventions, which may optionally be carried out to implant medical devices, such as a pacemaker or a cardioverter defibrillator.

[0008] Thus, there remains a need for improved compositions that may be used in the prevention and / or treatment of arrythmias or related pathological conditions. Ideally, such compositions are safe, effective, have minimal side-effects and display minimal interactions with other pharmacological compounds.

[0009] Summary of Invention

[0010] Surprisingly, the inventors have found that treatment with cannabigerol, a minor phytocannabinoid, has the capacity to reverse and prevent arrhythmic cellular processes in ex vivo models of AFib and VFib, respectively. Particularly, in an ex vivo model of AFib, CBG reduces the AFib-associated overall frequency of Ca2+sparks in cells, as well as the number of Ca2+sparks per spark site. Furthermore, in ventricular cardiomyocytes, treatment with CBG reduced the density of Ca2+spark sites and the frequency of Ca2+sparks in cells. Importantly, in these cells, CBG treatment, initiated prior to the onset of a VFi b-mimicki ng pharmacological treatment, also prevented the VFib- associated increase in the density of Ca2+spark sites and in the frequency of Ca2+sparks.

[0011] Therefore, provided herein are methods and compositions related to treating and / or preventing arrhythmias or other diseases or physiological damages associated with dysregulated cellular calcium handling, particularly with an increase in rapid, transient calcium release events from intracellular stores, particularly with an increase in the parameters related to spontaneous calcium release events, such as an increase in the frequency of Ca2+sparks in a cell, an increase in the number of Ca2+sparks per spark site in a cell, an increase in the density of Ca2+spark sites in a cell, an increase in the amplitude of Ca2+waves in a cell, and / or an increase in the frequency of Ca2+waves in a cell.

[0012] Thus, a first aspect of the present invention relates to a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in reducing: a) a frequency of calcium sparks in a cell, b) a number of calcium sparks per spark site in a cell, c) an intensity and / or a frequency of calcium waves in a cell, or d) any combination thereof.

[0013] A second aspect of the present invention relates to a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the treatment and / or prevention of a disease or physiological damage, particularly a disease or physiological damage selected from the group consisting of: a cardiac arrhythmia, a pathological muscle contraction, and combinations thereof, in a subject in need thereof, more particularly a cardiac arrhythmia. This aspect may also be formulated as the use of said composition for the preparation of a medicament for the prevention and / or the treatment of said disease or physiological damage. The present disclosure also relates to a method for the prevention and / or the treatment of said disease or physiological damage, the method comprising administering a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue.

[0014] Furthermore, a third aspect of the present invention relates to a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the prevention and / or treatment of a disease or physiological damage associated with an increase in: a) a frequency of calcium sparks in a cell, b) a number of calcium sparks per spark site in a cell, c) an intensity and / or a frequency of calcium waves in a cell, or d) any combination thereof.

[0015] Finally, in a fourth aspect, the invention provides a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the prevention and / or treatment of a disease or physiological damage, particularly a cardiac arrhythmia, wherein the treatment comprises the simultaneous, sequential or separate administration within a therapeutic interval of the composition of the invention as defined herein with one or more further pharmaceutically active agents.

[0016] Brief Description of Drawings

[0017] FIG. 1 A shows the different Ca2+spark sites as identified in confocal micrograph of a mouse atrial cardiomyocyte. The location of each spark site is indicated on the image with a different number shown in white text inside square white boxes. The scale bar is shown in the lower left corner of the image, and it corresponds to 10 pm. The cell perimeter is marked on the image with a white line.

[0018] FIG. 1 B shows a representative trace of Rhod-2 fluorescence, as a readout of intracellular cytosolic Ca2+concentration, recorded simultaneously at different Ca2+spark sites within a cell over a 10- second time-window. The intensity of the fluorescent signal is plotted on the y-axis, while time is plotted on the x-axis. Asterisks (*) indicate individual Ca2+spark events. Each line shows the recording at a different spark site.

[0019] FIG. 2A shows the frequency of Ca2+spark events in mouse atrial cardiomyocytes under physiological, control conditions (CTRL), in mouse atrial cardiomyocytes exposed to an AFib- mimicking pharmacological treatment (AFib), and in mouse atrial cardiomyocytes exposed to the AFib-mimicking pharmacological treatment and also treated with CBG (AFib- ^BG). The horizontal dotted line indicates the arrhythmogenic threshold for Ca2+spark frequency in this experimental model. The frequency of Ca2+spark events (events / min / pm2) is shown on the y-axis (mean + / - SEM).

[0020] FIG. 2B shows the number of Ca2+spark events per spark site in mouse atrial cardiomyocytes under physiological, control conditions (CTRL), in mouse atrial cardiomyocytes exposed to an AFib- mimicking pharmacological treatment (AFib), and in mouse atrial cardiomyocytes exposed to the AFib-mimicking pharmacological treatment and also treated with CBG (AFib- ^BG). The mean number of Ca2+spark events per spark site is shown on the y-axis (mean + / - SEM).

[0021] FIG. 3 shows the frequency of Ca2+wave events (normalised to the recording period) in mouse atrial cardiomyocytes under physiological, control conditions (CTRL), following exposure to an AFib- mimicking pharmacological treatment (AFib), and further following CBG treatment initiated subsequently to the AFib-mimicking treatment (AFib- ^BG). The frequency of Ca2+wave events (number of events observed per 10 second interval in a cell) is shown on the y-axis, while the time points are indicated in minutes below each bar. Time points indicate the time since start of the recording. For the data shown in the AFib panel, the AFib-mimicking treatment was initiated concomitantly with the start of the recording. For the data shown in the AFib- ^BG panel, CBG treatment, of cells that were already exposed to the AFib-mimicking treatment, was initiated concomitantly with the start of the recording. The horizontal dotted line indicates the arrhythmogenic threshold for Ca2+wave frequency in this experimental model. FIG. 4 shows the peak Rhod-2 fluorescence intensity of cardiac myocytes transiently exposed to 10 mM caffeine, which induces the quick release of calcium from intracellular stores into the cytosol, as a readout for total calcium content in the cells. Data are shown for mouse atrial cardiomyocytes under physiological, control conditions (CTRL), cells exposed to an AFib-mimicking pharmacological treatment (AFib), and cells exposed to the AFib-mimicking pharmacological treatment and also treated with CBG (AFib-CBG). Peak Rhod-2 fluorescence intensity is shown on the y-axis (mean + / - SEM).

[0022] FIGs. 5A, 5B and 5C show representative confocal micrographs of a mouse ventricular cardiomyocyte exposed to different conditions, where the locations of different Ca2+spark sites identified in the cell are indicated on the images with numbers shown in white text inside square white boxes. The different conditions represent: physiological, control conditions (CTRL = cells were observed in the absence of CBG or the ventricular fibrillation (VFib)-mimicking pharmacological treatment; FIG. 5A), CBG treatment (CBG; FIG. 5B), and a subsequent VFib-mimicking pharmacological treatment in the presence of CBG treatment (CBG+VFib; FIG. 5C). Scale bars are shown in the upper right corner of each image, and they correspond to 10 pm in each case. Cell perimeters are marked on the images with a white line.

[0023] FIG. 6A shows the density of Ca2+spark sites in mouse ventricular cardiomyocytes under physiological, control conditions (CTRL), in mouse ventricular cardiomyocytes treated with CBG (CBG), and in mouse ventricular cardiomyocytes treated with CBG and exposed to a VFib-mimicking pharmacological treatment, where the VFib-mimicking treatment was initiated subsequently to the CBG treatment (VFib-CBG). The density of Ca2+spark sites (sites / pm2) is shown on the y-axis (mean + / - SEM).

[0024] FIG. 6B shows the frequency of Ca2+spark events in mouse ventricular cardiomyocytes under physiological, control conditions (CTRL), in mouse ventricular cardiomyocytes treated with CBG (CBG), and in mouse ventricular cardiomyocytes treated with CBG and exposed to a VFib-mimicking pharmacological treatment, where the VFib-mimicking treatment was initiated subsequently to the CBG treatment (VFib- ^BG). The frequency of Ca2+spark events (events / min / pm2) is shown on the y-axis (mean + / - SEM). The individual values, that were used to calculate the mean shown on the graph, were the average values of six consecutive 10s scans (cells were imaged at steady-state in each condition) of a mouse ventricular myocyte under control (CTRL) conditions, followed by incubation with CBG, and finally upon exposure to the VFib-mimicking pharmacological cocktail in the presence of CBG (VFib- ^BG).

[0025] Detailed description of the invention

[0026] Before describing the present invention in detail, it is to be understood that this invention is not limited to particular administration modes, patient populations, and the like, as such may vary, as will be apparent from the accompanying description and figures. Definitions:

[0027] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0028] As used herein, the indefinite articles "a" and "an" are synonymous with "at least one" or "one or more." Unless indicated otherwise, definite articles used herein, such as "the" also include the plural of the noun.

[0029] “Substantially” or “essentially” means nearly totally or completely, for instance, 95% or greater of some given quantity.

[0030] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0031] “Treatment” or “treating” a condition, disorder, disease or damage includes a prophylactic treatment before the clinical onset of the condition or a therapeutic treatment after the clinical onset of the condition and may be achieved by arresting the development or reversing the symptoms associated with the condition. In the sense of the present invention, treatment encompasses curing, mitigating, treating or preventing a disease, for example arrhythmia, in a subject.

[0032] The term "weight ratio" (weightweight) refers to the relation of weights of the molecules or compounds indicated. As used herein, "wt percent" (w / w) of a compound refers to the amount of the single compound relative to the total weight of the composition or, if specifically mentioned, of another compound or compounds. Where the weight, “weight ratio” or “wt percent” is indicated in reference to a compound or a pharmaceutically acceptable or edible salt thereof, this should be understood as referring to the weight, “weight ratio” or “wt percent” for the compound itself. The skilled person understands that if a pharmaceutically acceptable or edible salt of the compound is used, the weight, “weight ratio” or “wt percent” should be adjusted accordingly.

[0033] For the purposes of the present invention, any ranges given include both the lower and the upper endpoints of the range.

[0034] The term "subject" or "patient" in the present application includes humans and non-human mammals, in particular humans.

[0035] Cannabiqerol and cannabiqerol analogues:

[0036] CBG (CAS number: 25654-31-3) is a non-psychotropic plant-derived cannabinoid compound, also known as a phytocannabinoid, having the formula:

[0037] CBG, as well as over 115 other phytocannabinoids, may be prepared from plants of the Cannabis family. CBG results from the non-enzymatic decarboxylation of cannabigerolic acid (CBGA), the form endogenously produced by plants, upon exposure of CBGA to heat. As CBGA serves as the common precursor for other phytocannabinoids, most notably tetrahydrocannabinolic acid (THCA), cannabidioloic acid (CBDA), and cannabichromenic acid (CBCA), levels of CBGA are naturally low in Cannabis plants, often accounting for only 1% or less of the plant’s total phytocannabinoid content.

[0038] CBG is commercially available, for example in pure form from Sigma-Aldrich, but also in formats suitable for human administration from various suppliers. Plant extracts containing CBG are also commercially available or are obtainable by methods well known in the art. CBG may be isolated and purified from plants belonging to the genus Cannabis using methods known in the art, for example, as disclosed in European patent EP3247371 B1.

[0039] In recent years, synthetic CBG analogues have been developed. A CBG analogue as used herein, refers to a compound that has a structure and pharmacological properties similar to those of CBG. As used herein, “synthetic” refers to a compound that is not naturally encountered in Cannabis plants. In terms of structure, in the case of an analogue, one or more atoms will be replaced with a different functional group in a CBG analogue compared to CBG. Examples of suitable synthetic CBG analogues for use with the present invention include: pharmaceutically acceptable esters of CBG, such as CBG-O-acetate, CBG quinone derivatives, such as VCE-003 and VCE-003.2, and CBG- dimethyl heptyl (CBG-DMH). In particular, CBG-O-acetate, VCE-003 (CAS number: 1639872-94-8) and VCE-003.2 are considered suitable synthetic CBG analogues for use with the present invention. CBG quinone derivatives may be synthesised by methods known in the art, for example as described in Diaz-Alonso et al. “VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease”, Scientific Reports, 2016, vol. 6, pp. 29789, or in Granja et al. “A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis”, 2012, vol. 7, issue 4, pp. 1002-1016. CBG-DMH may also be synthesised using methods known in the art, such as, for example, as disclosed in Szczesniak et al. “Nonpsychotropic Cannabinoids, Abnormal Cannabidiol and Canabigerol-Dimethyl Heptyl, Act at Novel Cannabinoid Receptors to Reduce Intraocular Pressure”, 2011 , vol. 27, issue 5, pp. 427-435. The CBG ester CBG-O-acetate is commercially available and may be synthesised using methods known in the art, for example, as disclosed in US patent US10954209B.

[0040] In a particular embodiment, the (synthetic) CBG analogues show at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, at least 100% at least 105%, at least 110%, at least 120%, at least 150%, at least 200%, at least 300% or at least 500% the activity of CBG in the context of the present invention, particularly wherein the activity of CBG in the context of the present invention is the treatment and / or prevention of any of the medical conditions defined in the first, second, third or fourth aspects of the invention.

[0041] Methods to determine the activity of CBG in the context of the present invention comprise measuring how much a certain amount or concentration of CBG reduces a) the frequency of calcium sparks in a cell, wherein such frequency is pathological, b) the number of calcium sparks per spark site in a cell, wherein such number is pathological, c) the intensity and / or a frequency of calcium waves in a cell, wherein the calcium waves are arrhythmogenic, or d) any combination thereof; wherein the cells are as defined in the first aspect, particularly are cardiomyocytes or skeletal muscle cells. Such methods are well known by an expert in the field and include those provided in the examples below.

[0042] Methods to compare the activity of a (synthetic) CBG analogue with that of CBG comprise measuring the activity of a specific amount or concentration of the (synthetic) CBG analogue and that of the same amount or concentration of CBG, as indicated in the two paragraphs above, and comparing the level of activity obtained with each of them, so to determine the % of activity of the (synthetic) CBG analogue with respect to that of CBG.

[0043] Typically, a low strength dosage of CBG is considered to be a dosage that corresponds to (0.2 x subject body weight in kg) mg CBG per day, a medium strength dosage of CBG is considered to be a dosage that corresponds to (0.6 x subject body weight in kg) mg CBG per day, and a high strength dosage of CBG is considered to be a dosage that corresponds to (1 .0 x subject body weight in kg) mg CBG per day.

[0044] The present invention includes all possible esters and salts of the compounds of the present invention, namely CBG or CBG analogues, which may be a single salt or any mixture of the salts in any ratio.

[0045] Arrhythmias:

[0046] In mammals, the rhythm and rate of heart beats varies in response to a variety of stimuli but several mechanisms exist to ensure that heartbeat rate and rhythm return to values within physiological limits upon removal of the stimulus. In adult humans, a “normal” resting heart rate is considered to be between 60 to 100 beats per minute. It is considered normal for the heart rate to transiently accelerate under specific circumstances (for example, in response to physical activity) or to slow down during sleep or rest periods.

[0047] An arrhythmia, also known as a cardiac arrhythmia, is a condition wherein the heartbeat rate and / or rhythm are abnormal during resting state. In a subject with an arrhythmia, the heart beat may be too fast (tachycardia; resting heart rate equal to or above 101 beats per minute), too slow (bradycardia; resting heart rate equal to or below 59 beats per minute) or irregular.

[0048] According to the National Heart, Lung and Blood Institute of the United States National Health Institute (NIH), There are several different types of arrhythmias, which are often categorised into the following four groups: premature (extra) beats, supraventricular arrhythmias, ventricular arrhythmias, and bradyarrhythmias. Supraventricular arrhythmias are tachycardias that start in the heart atria or atrioventricular (AV) node and include, but are not limited to: atrial fibrillation (AFib), atrial flutter, paroxysmal supraventricular tachycardia (PSVT), and Wolff-Parkinson-White (WPW) syndrome. Ventricular arrhythmias start in the heart ventricles and include, but are not limited to: ventricular tachycardia and ventricular fibrillation (VFib).

[0049] A variety of medications may cause or exacerbate arrhythmias, for example, as disclosed in Tisdale et al. “Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association”, 2020, Circulation, vol. 142, issue 15, pp: e214-e233.

[0050] Alternatively, arrhythmias can also be classified by the site of origin. When categorised in this manner, arrhythmias may fall under categories that include but are not limited to: atrial arrhythmias, junctional arrhythmias, and ventricular arrhythmias. Atrial arrhythmias include but not limited to: sinus bradycardia, sinus arrhythmia, sinus tachycardia, premature atrial contractions (PACs), wandering atrial pacemaker, atrial tachycardia, multifocal atrial tachycardia, supraventricular tachycardia (SVT), atrial flutter, atrial fibrillation (AFib), and AV nodal reentrant tachycardia. Junctional arrhythmias include, but are not limited to: junctional rhythm, junctional tachycardia, and premature junctional contraction. Ventricular arrhythmias include, but are not limited to: premature ventricular contractions (PVCs), accelerated idioventricular rhythm, monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, ventricular fibrillation, torsades de pointes, arrhythmogenic right ventricular dysplasia, and re-entry ventricular arrhythmia.

[0051] Depending on how often atrial fibrillation occurs and how it responds to treatment, different types of atrial fibrillation may be distinguished: paroxysmal atrial fibrillation (the atrial fibrillation event, i.e. abnormal heart rhythm, may last up to a week), persistent atrial fibrillation (atrial fibrillation event lasts longer than a week), long-term persistent atrial fibrillation (atrial fibrillation lasts longer than a year without significant improvement), and permanent atrial fibrillation (atrial fibrillation persists longterm and, if applicable, normal heart rhythm has not been restored in response to treatment). Often, especially without treatment, atrial fibrillation may progress from paroxysmal to persistent to longterm and finally permanent.

[0052] Ca2+-release events:

[0053] Calcium ions (Ca2+) are vital intracellular second messengers, playing a central role in cellular physiology. Proper Ca2+handling is essential for maintaining homeostasis and ensuring the correct functionality of excitable cells, such as neurons, muscle cells, and hormone / cytokine-secreting cells like pancreatic beta cells. Key processes that depend on precise Ca2+regulation include neurotransmitter release, muscle contraction, and insulin secretion. Beyond its roles in excitable and pancreatic endocrine cells, intracellular Ca2+is critical in universal cellular processes, including cell shape modulation, motility, gene expression, growth, and apoptosis.

[0054] Dysregulation of cellular calcium handling has been reported for and, in many cases, causally linked with the pathophysiological processes underlying the development of a wide variety of diseases, particularly diseases associated with the loss or dysfunction of excitable cells. For example, abnormal intracellular calcium dynamics in cardiac cells have been recognized as an important contributor in arrhythmias, including atrial arrhythmia and ventricular arrhythmia. More specifically, in cardiomyocytes, an increase in spontaneous Ca2+-release events from the sarcoplasmic reticulum has been shown to promote cellular arrhythmogenesis and thus contribute to the development of paroxysmal and persistent AFib, despite a similar sarcoplasmic reticulum Ca2+content in subjects with versus without a history of AFib.

[0055] Rapid spontaneous Ca2+-release events from the sarcoplasmic reticulum or the endoplasmic reticulum, in particular those caused by the opening of ryanodine receptors (RyR2) in a cluster of such receptors, induce local increases in cytosolic Ca2+concentration, independently of the bulk cytosolic Ca2+concentration, which manifest as intracellular Ca2+sparks (defined as rapid, local, non-propagating Ca2+-release events from the sarcoplasmic reticulum or from the endoplasmic reticulum, which typically lead to a transient increase in local cytosolic Ca2+concentration). The fusion of two or more Ca2+sparks occurring as a result of the simultaneous opening of adjacent RyR2 clusters may trigger calcium release from neighboring RyR2 clusters, initiating a “chain reaction” known as intracellular Ca2+waves (referring to rapid, propagating Ca2+-release events that may remain localised in a sub-cellular region or may spread over the whole cell). In this sense, “rapid” Ca2+release refers to events wherein Ca2+release from intracellular stores at a Ca2+spark site occurs within a time window of 500 milliseconds or less, particularly 200 milliseconds or less, more particularly 100 milliseconds or less. Similarly, a “transient” increase in local cytosolic Ca2+concentration refers to an increase in local cytosolic Ca2+concentration, wherein the duration of the increase in local cytosolic Ca2+concentration is 1 second or less, particularly 500 milliseconds or less, more particularly 200 milliseconds or less, even more particularly 100 milliseconds or less. In other words, a “transient” increase in local cytosolic Ca2+concentration refers to an increase in local cytosolic Ca2+concentration, wherein the local cytosolic Ca2+concentration returns to levels similar to bulk cytosolic Ca2+concentration 1 second or less, particularly 500 milliseconds or less, more particularly 200 milliseconds or less, even more particularly 100 milliseconds or less. Intracellular Ca2+waves may propagate at a speed of up to 1000 pm / second, particularly up to 500 pm / second, particularly up to 100 pm / second, more particularly up to 50 pm / second, wherein the speed of propagation of a Ca2+wave refers to the distance traveled by the calcium wavefront from its point of origin divided by the time it takes the wavefront to travel this distance.

[0056] A “spark site”, as used herein, refers to an intracellular location associated with a Ca2+spark event.

[0057] A “density of Ca2+spark sites”, as used herein, refers to the number of spark sites per unit of area (e.g. number of spark sites / pm2).

[0058] A “number of sparks per site”, as used herein, refers to the total number of events per spark site over a period of time.

[0059] A “frequency” or “density” of Ca2+sparks, as used herein, refers to the number of event (i.e. Ca2+sparks) per unit of time per unit of area, for example: number of events / second / pm2. The frequency of Ca2+sparks may vary as a result of differences in the number of spark sites, differences in the number of sparks per site, or a combination of these.

[0060] A “frequency” of Ca2+waves, as used herein, refers to the number of events (i.e. Ca2+waves) per unit of time per cell.

[0061] An “intensity” of Ca2+sparks and / or waves, as used herein, refers to the amplitude of the signal emitted by the calcium sensitive dye (peak fluorescence intensity - fluorescence intensity at baseline) normalised to the signal at baseline (fluorescence intensity at baseline), i.e. AF / Fo.

[0062] A “duration” of Ca2+sparks and / or waves, as used herein, refers to the duration of the detectable increase in local Ca2+concentration associated with an individual Ca2+spark or wave, measured as the duration of the Ca2+spark at half maximal amplitude, also known as half-duration, half-maximum (FDHM).

[0063] Physiological values are considered to be the steady-state values observed in cells from subjects with a normal, non-pathological (i.e. in the absence of a cardiovascular pathological condition) heartbeat rate and rhythm, under resting, physiological conditions, in the absence of treatments or external stimuli, whether pharmacological or otherwise, that may affect cellular calcium handling, or heartbeat rate or rhythm. In this sense, a steady-state resting heartbeat rate in adult humans is considered to be between 60 to 100 beats per minute. Physiological levels may refer, but are not limited to a physiological frequency of Ca2+sparks, a physiological number of Ca2+sparks per spark site, a physiological intensity and / or frequency of Ca2+waves, and / or a physiological density of Ca2+spark sites. A reduction in a parameter refers to a reduction in comparison with the value observed for the respective parameter in the absence of CBG. Said parameter is selected from a list that includes, but is not limited to, a frequency of Ca2+sparks in a cell, a number of Ca2+sparks per spark site in a cell, an intensity and / or frequency of Ca2+waves in a cell, and / or a density of Ca2+spark sites in a cell.

[0064] An increase in the frequency or number of Ca2+sparks and / or waves that exceeds physiological levels by 2.5-fold or more is considered arrhythmogenic.

[0065] A local cytosolic Ca2+concentration refers to the average cytosolic Ca2+concentration measured over an area corresponding to 4 m2of a cell area imaged. Ca2+spark events are known to lead to a rapid, transient increase in local cytosolic Ca2+concentration in the vicinity of the spark site. An increase in a local cytosolic Ca2+concentration is deemed to occur when the local cytosolic Ca2+concentration is higher than a local cytosolic Ca2+concentration in an adjacent 4 m2area. The increase in local cytosolic Ca2+concentration associated with a Ca2+spark can be analyzed manually using commercial software (such as Leica LAS-AF or LAS-X) and may be deemed significant based on threshold values (i.e. the increase is a least 2-fold higher than the local cytosolic Ca2+concentration in an adjacent 4 pm2area, or the increase is at least three times the noise of the signal at baseline). Methods to measure local cytosolic Ca2+concentration are known in the art, for example, such as those described in Hove-Madsen et al. “Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes”, Circulation, 2004, vol. 110, issue 11 , pp. 1358-1363. Similarly, variations in cellular Ca2+-release events, such as Ca2+sparks and Ca2+waves, can be analysed through Ca2+-imaging techniques using methods known in the art, for example, such as those described in Hove-Madsen et al. “Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes”, Circulation, 2004, vol. 110, issue 11 , pp. 1358-1363. Methods for calcium image analysis that may be employed to quantify calcium release events and their properties in the context of the present invention are known in the art, for example, as disclosed in Tarifa et al. “Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes”, JACC Basic Transl Sci, 2022, vol. 8, issue 1 , pp. 1-15, or in Bray et al. “Multidimensional Detection and Analysis of Ca2+ Sparks in Cardiac Myocytes”, Biophysical Journal, 2007, vol. 92, issue 12, pp. 4433-4443.

[0066] As mentioned above, a first aspect of the present invention relates to a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in reducing: a) a frequency of calcium sparks in a cell, b) a number of calcium sparks per spark site in a cell, c) an intensity and / or a frequency of calcium waves in a cell, or d) any combination thereof. In a particular embodiment of the first aspect, the frequency of Ca2+sparks is a pathological frequency of Ca2+sparks. In a more particular embodiment, the pathological frequency of Ca2+sparks is at least 2.5-fold higher than the physiological frequency of Ca2+sparks. In a particular embodiment of the first aspect, the number of Ca2+sparks per spark site is a pathological number of Ca2+sparks per spark site. In a more particular embodiment, the pathological number of Ca2+sparks per spark site is at least 2.5-fold higher than the physiological number of Ca2+sparks per spark site. In a particular embodiment of the first aspect, the frequency and / or intensity of Ca2+waves is a pathological frequency and / or intensity of Ca2+waves. In a more particular embodiment, the pathological frequency and / or intensity of Ca2+waves is a frequency that is at least 2.5-fold higher than the physiological frequency and / or intensity of Ca2+waves. In another particular embodiment of the first aspect, the frequency and / or intensity of Ca2+waves is an arrhythmogenic frequency and / or intensity of Ca2+waves. In a more particular embodiment, the arrhythmogenic frequency and / or intensity of Ca2+waves is a frequency that is at least 2.5-fold higher than the physiological frequency and / or intensity of Ca2+waves.

[0067] In a particular embodiment of the first aspect, the frequency of Ca2+sparks is reduced by more than 10%, particularly by more than 12%, particularly by more than 14%, particularly by more than 16%, particularly by more than 18%, particularly by more than 20%, particularly by more than 25%, particularly by more than 30%, particularly by more than 35%, particularly by more than 40%, particularly by more than 45%, particularly by more than 50%, particularly by more than 50%, particularly by more than 60%, particularly by more than 65%, particularly by more than 70%, particularly by more than 75%, particularly by more than 80%, particularly by more than 85%, particularly by more than 90%, particularly by more than 95% compared to the frequency of Ca2+sparks observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In a more particular embodiment, the frequency of Ca2+sparks is reduced by more than 20% compared to the frequency of Ca2+sparks observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In a yet more particular, the frequency of Ca2+sparks is reduced by more than 30% compared to the frequency of Ca2+sparks observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In an even more particular embodiment, the frequency of Ca2+sparks is reduced by more than 40% compared to the frequency of Ca2+sparks observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue.

[0068] In another particular embodiment of the first aspect, the frequency of Ca2+sparks is reduced such that it is less than 2-fold higher than a physiological frequency of Ca2+sparks. In a yet another particular embodiment of the first aspect, the frequency of Ca2+sparks is reduced such that it is less than 50% higher than a physiological frequency of Ca2+sparks. In a further particular embodiment of the first aspect, the frequency of Ca2+sparks is reduced such that it is less than 20% higher than a physiological frequency of Ca2+sparks. In a yet further particular embodiment of the first aspect, the frequency of Ca2+sparks is reduced such that it is not significantly different from or it is lower than a physiological frequency of Ca2+sparks.

[0069] In a particular embodiment of the first aspect, the number of Ca2+sparks per spark site is reduced by more than 10%, particularly by more than 12%, particularly by more than 14%, particularly by more than 16%, particularly by more than 18%, particularly by more than 20%, particularly by more than 25%, particularly by more than 30%, particularly by more than 35%, particularly by more than 40%, particularly by more than 45%, particularly by more than 50%, particularly by more than 50%, particularly by more than 60%, particularly by more than 65%, particularly by more than 70%, particularly by more than 75%, particularly by more than 80%, particularly by more than 85%, particularly by more than 90%, particularly by more than 95% compared to the number of Ca2+sparks per spark site observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In a more particular embodiment, the number of Ca2+sparks per spark site is reduced by more than 20% compared to the number of Ca2+sparks per spark site observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In a yet more particular embodiment, the number of Ca2+sparks per spark site is reduced by more than 30% compared to the number of Ca2+sparks per spark site observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In an even more particular embodiment, the number of Ca2+sparks per spark site is reduced by more than 40% compared to the number of Ca2+sparks per spark site observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue.

[0070] In another particular embodiment of the first aspect, the number of Ca2+sparks per spark site is reduced such that it is less than 2-fold higher than a physiological number of Ca2+sparks per spark site. In a yet another particular embodiment of the first aspect, the number of Ca2+sparks per spark site is reduced such that it is less than 50% higher than a physiological number of Ca2+sparks per spark site. In a further particular embodiment of the first aspect, the number of Ca2+sparks per spark site is reduced such that it is less than 20% higher than a physiological number of Ca2+sparks per spark site. In a yet further particular embodiment of the first aspect, the number of Ca2+sparks per spark site is reduced such that it is not significantly different from or it is lower than a physiological number of Ca2+sparks per spark site.

[0071] In a particular embodiment of the first aspect, the intensity and / or number of Ca2+waves is reduced by more than 10%, particularly by more than 12%, particularly by more than 14%, particularly by more than 16%, particularly by more than 18%, particularly by more than 20%, particularly by more than 25%, particularly by more than 30%, particularly by more than 35%, particularly by more than 40%, particularly by more than 45%, particularly by more than 50%, particularly by more than 50%, particularly by more than 60%, particularly by more than 65%, particularly by more than 70%, particularly by more than 75%, particularly by more than 80%, particularly by more than 85%, particularly by more than 90%, particularly by more than 95% compared to the intensity and / or number of Ca2+waves observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In a more particular embodiment, the intensity and / or number of Ca2+waves is reduced by more than 20% compared to the intensity and / or number of Ca2+waves observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In a yet more particular embodiment, the intensity and / or number of Ca2+waves is reduced by more than 30% compared to the intensity and / or number of Ca2+waves observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue. In an even more particular embodiment, the intensity and / or number of Ca2+waves is reduced by more than 40% compared to the intensity and / or number of Ca2+waves observed prior to administration of cannabigerol and / or of the synthetic cannabigerol analogue.

[0072] In another particular embodiment of the first aspect, the intensity and / or number of Ca2+waves is reduced such that it is less than 2-fold higher than a physiological intensity and / or number of Ca2+waves. In a yet another particular embodiment of the first aspect, the intensity and / or number of Ca2+waves is reduced such that it is less than 50% higher than a physiological intensity and / or number of Ca2+waves. In a further particular embodiment of the first aspect, the intensity and / or number of Ca2+waves is reduced such that it is less than 20% higher than a physiological intensity and / or number of Ca2+waves. In a yet further particular embodiment of the first aspect, the intensity and / or number of Ca2+waves is reduced such that it is not significantly different from or it is lower than a physiological intensity and / or number of Ca2+waves.

[0073] In a particular embodiment of the first aspect, a Ca2+spark is an event of calcium release from a cell’s endoplasmic reticulum or a cell’s sarcoplasmic reticulum, wherein the event is spontaneous and non-propagable. In a more particular embodiment, the event is associated with an increase in a local cytosolic Ca2+concentration. In a yet more particular embodiment, the local cytosolic Ca2+concentration is the average cytosolic Ca2+concentration measured over an area corresponding to 4 m2of a micrograph and the increase in the local cytosolic Ca2+concentration is an increase of at least 3-fold, particularly 4-fold, particularly 5-fold, particularly 6-fold, particularly 7-fold, particularly 8- fold, particularly 9-fold, particularly 10-fold, compared to a local cytosolic Ca2+concentration measured in an adjacent 4 m2area.

[0074] In another particular embodiment of the first aspect, the a) pathological frequency of calcium sparks in the cell, b) the pathological number of calcium sparks per spark site in the cell, and / or c) the arrhythmogenic calcium waves in the cell, is / are associated with or caused by the activation of the adenosine A2A receptor, inhibition of phosphodiesterase 1 (PDE -1), or both in the corresponding cell. More particularly, it is associated with or caused by the activation of the adenosine A2A receptor together with the inhibition of adenosine A3 receptors, the inhibition of phosphodiesterase 1 (PDE - 1), or any combination thereof. In more particular embodiment of the second and / or third aspects, the disease or physiological damage is associated with or caused by any activation and / or inhibition referred in the present paragraph, in the cells as defined herein in the first aspect, particularly in cardiomyocytes, (skeletal) muscle cells, or both, yet more particularly in cardiomyocytes.

[0075] In a particular embodiment of the first aspect, the cell is a muscle cell. In a more particular embodiment of the first aspect, the muscle cell is a cardiomyocyte, a skeletal muscle cell, a smooth muscle cell, a striated muscle cell or any combination thereof. In another particular embodiment of the first aspect, the muscle cell is a striated muscle cell. In another particular embodiment of the first aspect, the muscle cell is a skeletal muscle cell. In an even more particular embodiment, the muscle cell is a cardiomyocyte. In a further more particular embodiment, the cardiomyocyte is an atrial cardiomyocyte or a ventricular cardiomyocyte. In an alternative even more particular embodiment, the muscle cell is a smooth muscle cell, particularly an arterial smooth muscle cell.

[0076] In a particular embodiment of the first aspect, the cell is a neuronal cell type. In a more particular embodiment of the first aspect, the neuronal cell type is a motor neuron. In another more particular embodiment of the first aspect, the neuronal cell type is a sensory neuron. In yet another more particular embodiment of the first aspect, the neuronal cell type is a neuron of the central nervous system, more particularly a glutamatergic neuron, a cholinergic neuron, a GABAergic neuron, a dopaminergic neuron, a serotonergic neuron, or any combination thereof.

[0077] As mentioned above, a second aspect of the present invention relates to a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the treatment and / or prevention of a disease or physiological damage. In this sense, physiological damage, refers to damage occurring in a bodily tissue or a cell that is not caused by a pathological condition, particularly damage that occurs in response to immediate physical stress. For example, physiological damage is deemed to occur in skeletal muscles in response to strenuous physical activity and / or physical exercise.

[0078] Furthermore, a third of the present invention relates to a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the prevention and / or treatment of a disease or physiological damage associated with an increase in: a) a frequency of calcium sparks in a cell, b) a number of calcium sparks per spark site in a cell, c) an intensity and / or a frequency of calcium waves in a cell, or d) any combination thereof. In a more particular embodiment, such increases are pathological, particularly the disease or physiological damage of the third aspect is associated with or caused by an increase in a) the frequency of calcium sparks in the cell wherein the frequency of calcium sparks is pathological, b) the number of calcium sparks per spark site in the cell, wherein the number of calcium sparks per spark site in the cell is pathological, c) the intensity and / or a frequency of calcium waves in a cell wherein the calcium waves are arrhythmogenic. In a more particular embodiment, such (pathological) increase(s) cause(s) the disease of the third aspect. In another particular embodiment of the third aspect, the disease or physiological damage is associated with or caused by arrhythmogenic calcium waves in a cell, particularly by an increase in the intensity and / or a frequency of arrhythmogenic calcium waves in a cell. In another particular embodiment, the cell referred in the third aspect is the cell as defined in the first aspect.

[0079] In a particular embodiment of the second and / or third aspects, the disease or physiological damage is selected from the group consisting of: a cardiac arrhythmia, a pathological muscle contraction, a physiological muscle damage, and combinations thereof. In a particular embodiment, the muscle contraction is in a striated muscle. In another particular embodiment, the muscle contraction is in a skeletal muscle. In another particular embodiment, the physiological muscle damage is in a striated muscle. In another particular embodiment, the physiological muscle damage is in a skeletal muscle. In a more particular embodiment of the second and / or third aspects, the disease or physiological damage is selected from the group consisting of: a cardiac arrhythmia, a pathological skeletal muscle contraction, a physiological skeletal muscle damage, and combinations thereof. In a more particular embodiment, the disease or physiological damage consists or comprises of a cardiac arrhythmia. In a yet more particular embodiment, the cardiac arrhythmia comprises or consists of atrial fibrillation (AFib), catecholaminergic polymorphic ventricular tachycardia (CPVT), ventricular fibrillation (VFib), or a combination thereof. In an even more particular embodiment, the atrial fibrillation (AFib) is selected from a list consisting of: paroxysmal atrial fibrillation, persistent atrial fibrillation, long-term persistent atrial fibrillation, and permanent atrial fibrillation.

[0080] In another more particular embodiment of the second and / or third aspects, the cardiac arrhythmia is at least partially caused by treatment with a medication. In an even more particular embodiment, the cardiac arrhythmia is a drug-induced cardiac arrhythmia. In a yet even more particular embodiment, the drug-induced cardiac arrhythmia is selected from a group consisting of: bradyarrhythmia, atrial tachycardia, atrioventricular node reentrant tachycardia, monomorphic ventricular tachycardia, Brugada syndrome, and torsades de pointes.

[0081] In an additional more particular embodiment of the second and / or third aspects, the cardiac arrhythmia is associated with or caused by an imbalance in circulating electrolytes, particularly an imbalance in circulating levels of an electrolyte selected from: calcium, sodium, phosphorous, magnesium, potassium, chlorine, and any combination thereof. In a yet more particular embodiment, the cardiac arrhythmia is associated with or caused by a higher concentration of phosphorous. In another yet more particular embodiment, the cardiac arrhythmia is associated with or caused by a lower circulating magnesium concentration. In this sense, “circulating levels of an electrolyte” refers to the concentration of the respective electrolyte in a subject’s serum, and an “imbalance” refers to an electrolyte concentration in serum that is outside the range which is medically deemed to be the physiological range observed in age-matched and sex-matched healthy adult subjects. For example, serum magnesium in healthy adult humans ranges from 0.7 to 1.3 mmol / L, serum phosphorus concentrations in healthy adult humans are typically between 1.12 to 1.45 mmol / L, steady-state serum sodium levels in healthy adult humans are typically maintained in a narrow range between 135 to 145 milliequivalents per liter (mEq / L), serum potassium concentrations in heathy adult humans are between 3.5 - 5.3 mmol / L, serum calcium concentrations in heathy adult humans are between 2.2 to 2.7 mmol / L (4.3 to 5.3 mEq / L), and serum chlorine concentrations in heathy adult humans are between 96-106 mmol / L.

[0082] In another particular embodiment of the second and / or third aspects, the disease or physiological damage is associated with or caused by the activation of the adenosine A2A receptor, inhibition of phosphodiesterase 1 (PDE -1), or both. More particularly, it is associated with or caused by the activation of the adenosine A2A receptor together with the inhibition of adenosine A3 receptors, the inhibition of phosphodiesterase 1 (PDE -1), or any combination thereof. In more particular embodiment of the second and / or third aspects, the disease or physiological damage is associated with or caused by any activation and / or inhibition referred in the present paragraph, in the cells as defined in the first aspect, particularly in cardiomyocytes, (skeletal) muscle cells, or both, yet more particularly in cardiomyocytes.

[0083] In an additional particular embodiment of the second and / or third aspects, the disease or physiological damage comprises or consists of exercise-induced muscle damage.

[0084] In a yet another particular embodiment of the second and / or third aspects, the disease or physiological damage is selected from the group consisting of: amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), schizophrenia, seizures, epilepsy, or a combination thereof.

[0085] In a particular embodiment, the term “associated with”, as used herein in the context of a disease or condition, encompasses the term “caused by”, particularly is substituted by “caused by”.

[0086] As mentioned above, in a fourth aspect, the invention provides a composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the prevention and / or treatment of a disease or physiological damage, wherein the treatment comprises the simultaneous, sequential or separate administration within a therapeutic interval of the composition of the invention as defined herein with one or more further pharmaceutically active agents.

[0087] In a particular embodiment of the fourth aspect, the disease or physiological damage is a cardiac arrhythmia. In a more particular embodiment, the cardiac arrhythmia is atrial fibrillation.

[0088] In another particular embodiment of the fourth aspect, the one or more further pharmaceutically active agents comprises an antiarrhythmic agent. In a further particular embodiment, the one or more further pharmaceutically active agents is selected from a group consisting of: beta blockers, statins, a2A-adrenergic receptor agonists, angiotensin II type 1 receptor (AT1 R) antagonists, angiotensinconverting enzyme (ACE) inhibitors, amiodarone, dofetilide, and combinations thereof.

[0089] All the embodiments disclosed in relation to one aspect of the invention are also embodiments of all other aspects of the invention. For example, all embodiments disclosed in relation to the first aspect of the invention are also embodiments of the second, third and fourth aspects of the invention. Particularly, the cell referred in any embodiment of the second, third or fourth aspect, is a cell as defined in the first aspect, particularly is the cell of the first aspect.

[0090] Further embodiments that relate to all aspects of the invention are disclosed below: In a particular embodiment, the composition is administered to a subject, wherein the subject is a mammal, particularly a human.

[0091] In another particular embodiment, the composition is administered to a subject that is deemed to be at risk of developing or has been diagnosed with renal failure.

[0092] In a particular embodiment, the composition is administered to a subject that has been diagnosed with hyperphosphatemia. In another particular embodiment, the composition is administered to a subject that has been diagnosed with hypomagnesemia.

[0093] In a particular embodiment, the therapeutically effective amount of cannabigerol and / or of the synthetic cannabigerol analogue in the composition is at least 0.1 pmol, particularly at least 0.3 pmol, particularly at least 0.5 pmol, particularly at least 1 pmol, particularly at least 1.5 pmol, particularly at least 2 mol, particularly at least 3 pmol, particularly at least 5 pmol, particularly at least 7 mol, particularly at least 10 pmol, particularly at least 15 pmoles, particularly at least 20 pmoles, particularly at least 25 pmoles, particularly at least 30 pmoles, particularly at least 35 pmoles, particularly at least 40 pmoles, particularly at least 45 pmoles, particularly at least 50 pmoles, particularly at least 55 pmoles, particularly at least 60 pmoles, particularly at least 65 pmoles, particularly at least 70 pmoles, particularly at least 75 pmoles, particularly at least 80 pmoles, particularly at least 85 pmoles, particularly at least 90 pmoles, particularly at least 95 pmoles, particularly at least 100 pmol, particularly at least 200 pmol, particularly at least 300 pmol, wherein the therapeutically effective amount present in the composition is the sum of the amounts of cannabigerol and of the synthetic cannabigerol analogue.

[0094] In another particular embodiment, the therapeutically effective amount of cannabigerol and / or of the synthetic cannabigerol analogue in the composition is of no more than 0.1 pmol, particularly of no more than 0.3 pmol, particularly of no more than 0.5 pmol, particularly of no more than 1 mol, particularly of no more than 1 .5 pmol, particularly of no more than 2 mol, particularly of no more than 3 pmol, particularly of no more than 5 pmol, particularly of no more than 7 mol, particularly of no more than 10 pmol, particularly of no more than 15 pmoles, particularly of no more than 20 pmoles, particularly of no more than 25 pmoles, particularly of no more than 30 pmoles, particularly of no more than 35 pmoles, particularly of no more than 40 pmoles, particularly of no more than 45 pmoles, particularly of no more than 50 pmoles, particularly of no more than 55 pmoles, particularly of no more than 60 pmoles, particularly of no more than 65 pmoles, particularly of no more than 70 pmoles, particularly of no more than 75 pmoles, particularly of no more than 80 pmoles, particularly of no more than 85 pmoles, particularly of no more than 90 pmoles, particularly of no more than 95 pmoles, particularly of no more than 100 pmol, particularly of no more than 200 pmol, particularly of no more than 300 pmol, wherein the therapeutically effective amount present in the composition is the sum of the amounts of cannabigerol and of the synthetic cannabigerol analogue.

[0095] In a particular embodiment, the composition is administered to a subject at a dose per day of between 5 to 3000 pmoles, particularly between 7 to 2500 pmoles, particularly between 10 to 2000 pmoles, particularly between 12 and 1700 pmoles, particularly between 15 to 1500 pmoles, particularly between 20 to 1400 pmoles, particularly between 30 to 1300 pmoles, particularly between 35 to 1200 pmoles, particularly between 40 to 1100 pmoles, particularly between 45 to 1000 pmoles, particularly between 50 to 900 pmoles, particularly between 55 to 800 pmoles, particularly between 60 to 700 pmoles, particularly between 65 to 600 pmoles, particularly between 70 to 500 pmoles, particularly between 75 to 450 pmoles.

[0096] In another particular embodiment, the composition is administered to a subject at a dose per day of between 0.1 to 3000 pmoles, particularly between 0.3 to 2500 pmoles, particularly between 0.5 to 2000 pmoles, particularly between 1 to 1700 pmoles, particularly between 1.5 to 1500 pmoles, particularly between 2 to 1400 pmoles, particularly between 3 to 1300 pmoles, particularly between 5 to 1200 pmoles, particularly between 7 to 1100 pmoles, particularly between 8 to 1000 pmoles, particularly between 9 to 900 pmoles, particularly between 10 to 800 pmoles, particularly between 12 to 700 pmoles, particularly between 15 to 600 pmoles, particularly between 20 to 500 pmoles, particularly between 50 to 250 pmoles, particularly between 100 to 200 pmoles.

[0097] In another particular embodiment, the composition is administered to a subject at a dose per day of between 15 to 100 pmoles, particularly between 20 to 95 pmoles, particularly between 25 to 90 pmoles, particularly between 30 to 85 pmoles, particularly between 35 to 80 pmoles, particularly between 40 to 75 pmoles, particularly between 45 to 70 pmoles, particularly between 50 to 65 pmoles.

[0098] In a particular embodiment, the composition is administered to a subject at a dose per day of between 0.1 to 100 pmoles, particularly between 0.1 to 95 pmoles, particularly between 0.1 to 90 pmoles, particularly between 0.1 to 85 pmoles, particularly between 0.1 to 80 pmoles, particularly between 0.1 to 75 pmoles, particularly between 0.1 to 70 pmoles, particularly between 0.1 to 65 pmoles, particularly between 0.1 to 50 pmoles, particularly between 0.1 to 40 pmoles, particularly between 0.1 to 35 pmoles, particularly between 0.1 to 30 pmoles, particularly between 0.1 to 25 pmoles, particularly between 0.1 to 20 pmoles, particularly between 0.1 to 15 pmoles, particularly between 0.1 to 10 pmoles, particularly between 0.1 to 8 pmoles, particularly between 0.1 to 5 pmoles, particularly between 0.1 to 3 pmoles, particularly between 0.1 to 1 pmol.

[0099] In a particular embodiment, the composition is administered to a subject at a dose per day of between 0.3 to 100 pmoles, particularly between 0.3 to 95 pmoles, particularly between 0.3 to 90 pmoles, particularly between 0.3 to 85 pmoles, particularly between 0.3 to 80 pmoles, particularly between 0.3 to 75 pmoles, particularly between 0.3 to 70 pmoles, particularly between 0.3 to 65 pmoles, particularly between 0.3 to 50 pmoles, particularly between 0.3 to 40 pmoles, particularly between 0.3 to 35 pmoles, particularly between 0.3 to 30 pmoles, particularly between 0.3 to 25 pmoles, particularly between 0.3 to 20 pmoles, particularly between 0.3 to 15 pmoles, particularly between 0.3 to 10 pmoles, particularly between 0.3 to 8 pmoles, particularly between 0.3 to 5 pmoles, particularly between 0.3 to 3 pmoles, particularly between 0.3 to 1 pmol.

[0100] In a particular embodiment, the composition is administered to a subject at a dose per day of between 1 to 100 pmoles, particularly between 1 to 95 pmoles, particularly between 1 to 90 pmoles, particularly between 1 to 85 pmoles, particularly between 1 to 80 pmoles, particularly between 1 to 75 pmoles, particularly between 1 to 70 pmoles, particularly between 1 to 65 pmoles, particularly between 1 to 50 pmoles, particularly between 1 to 40 pmoles, particularly between 1 to 35 pmoles, particularly between 1 to 30 pmoles, particularly between 1 to 25 pmoles, particularly between 1 to 20 pmoles, particularly between 1 to 15 pmoles, particularly between 1 to 10 pmoles, particularly between 1 to 8 pmoles, particularly between 1 to 5 pmoles, particularly between 1 to 3 pmoles.

[0101] In a particular embodiment, the composition is administered to a subject at a dose per day of between 1.5 to 100 pmoles, particularly between 1.5 to 95 pmoles, particularly between 1.5 to 90 pmoles, particularly between 1.5 to 85 pmoles, particularly between 1.5 to 80 pmoles, particularly between 1 .5 to 75 pmoles, particularly between 1 .5 to 70 pmoles, particularly between 1 .5 to 65 pmoles, particularly between 1.5 to 50 pmoles, particularly between 1.5 to 40 pmoles, particularly between 1.5 to 35 pmoles, particularly between 1.5 to 30 pmoles, particularly between 1.5 to 25 pmoles, particularly between 1.5 to 20 pmoles, particularly between 1.5 to 15 pmoles.

[0102] In a particular embodiment, the composition is administered to a subject at a dose per day of between 5 to 100 pmoles, particularly between 5 to 95 pmoles, particularly between 5 to 90 pmoles, particularly between 5 to 85 pmoles, particularly between 5 to 80 pmoles, particularly between 5 to 75 pmoles, particularly between 5 to 70 pmoles, particularly between 5 to 65 pmoles, particularly between 5 to 50 pmoles, particularly between 5 to 40 pmoles, particularly between 5 to 35 pmoles, particularly between 5 to 30 pmoles, particularly between 5 to 25 pmoles, particularly between 5 to 20 pmoles, particularly between 5 to 15 pmoles.

[0103] In a particular embodiment, the composition is administered to a subject at a dose per day of between 15 to 100 pmoles, particularly between 15 to 95 pmoles, particularly between 15 to 90 pmoles, particularly between 15 to 85 pmoles, particularly between 15 to 80 pmoles, particularly between 15 to 75 pmoles, particularly between 15 to 70 pmoles, particularly between 15 to 65 pmoles, particularly between 15 to 50 pmoles, particularly between 15 to 40 pmoles, particularly between 15 to 35 pmoles, particularly between 15 to 30 pmoles, particularly between 15 to 25 pmoles, particularly between 15 to 20 pmoles.

[0104] In a further particular embodiment, the composition is administered to a subject at a dose per day of between 500 to 2500 pmoles, particularly between 800 to 2250 pmoles, particularly between 900 to 2000 pmoles, particularly between 1000 to 1700 pmoles, particularly between 1100 to 1400 pmoles, particularly between 1200 to 1300 pmoles. In a further particular embodiment, the composition is administered to a subject at a dose per day of between 50 to 2500 pmoles, particularly between 70 to 2250 pmoles, particularly between 100 to 2000 pmoles, particularly between 125 to 1700 pmoles, particularly between 150 to 1500 pmoles, particularly between 165 to 1400 pmoles, particularly between 180 to 1300 pmoles, particularly between 195 to 1200 pmoles, particularly between 210 to 1100 pmoles, particularly between 225 to 1000 pmoles, particularly between 240 to 900 pmoles, particularly between 255 to 800 pmoles, particularly between 270 to 700 pmoles, particularly between 285 to 600 pmoles, particularly between 300 to 500 pmoles, particularly between 315 to 450 pmoles.

[0105] In another particular embodiment, the composition is administered to a subject at a dose per day of at least 0.1 pmoles, at least 0.2 pmoles, at least 0.3 pmoles, at least 0.5 pmoles , at least 0.75 pmoles, at least 1 pmol, at least 1 .5 pmoles, at least 2 pmoles, at least 3 pmoles, at least 4 pmoles, at least 5 pmoles, at least 7 p moles, at least 10 p moles, at least 12 p moles, at least 15 pmoles, at least 17 pmoles, at least 20 pmoles, at least 25 pmoles, at least 30 pmoles, at least 40 pmoles, at least 50 pmoles, at least 60 pmoles, at least 75 pmoles, at least 90 pmoles, at least 100 pmoles, at least 120 pmoles, at least 150 pmoles, at least 200 pmoles, at least 300 pmoles, at least 400 pmoles, at least 500 pmoles, at least 700 pmoles, at least 1000 pmoles, at least 1250 pmoles, at least 1500 pmoles, at least 1700 pmoles, at least 2000 pmoles, at least 2250 pmoles, at least 2500 pmoles, or at least 3000 pmoles.

[0106] In another particular embodiment, the composition is administered to a subject at a dose per day of no more than 0.1 pmoles, no more than 0.2 pmoles, no more than 0.3 pmoles, no more than 0.5 pmoles, no more than 0.75 pmoles, no more than 1 pmol, no more than 1.5 pmoles, no more than 2 pmoles, no more than 3 pmoles, no more than 4 pmoles, no more than 5 pmoles, no more than 7 pmoles, no more than 10 pmoles, no more than 12 pmoles, no more than 15 pmoles, no more than 17 pmoles, no more than 20 pmoles, no more than 25 pmoles, no more than 30 pmoles, no more than 40 pmoles, no more than 50 pmoles, no more than 60 pmoles, at no more than 75 pmoles, no more than 90 pmoles, no more than 100 pmoles, no more than 120 pmoles, no more than 150 pmoles, no more than 200 pmoles, no more than 300 pmoles, no more than 400 pmoles, no more than 500 pmoles, no more than 700 pmoles, no more than 1000 pmoles, no more than 1250 pmoles, no more than 1500 pmoles, no more than 1700 pmoles, no more than 2000 pmoles, no more than 2250 pmoles, no more than 2500 pmoles, or no more than 3000 pmoles.

[0107] In another particular embodiment, the composition is administered to a subject at a dose per day of around 0.1 pmoles, 0.2 pmoles, 0.3 pmoles, 0.5 pmoles , 0.75 pmoles, 1 pmol, 1.5 pmoles, 2 pmoles, 3 pmoles, 4 pmoles, 5 pmoles, 7 pmoles. 10 pmoles, 12 pmoles, 15 pmoles, 17 pmoles, 20 pmoles, 25 pmoles, 30 pmoles, 40 pmoles, 50 pmoles, 60 pmoles, 75 pmoles, 90 pmoles, 100 pmoles, 120 pmoles, 150 pmoles, 200 pmoles, 300 pmoles, 400 pmoles, 500 pmoles, 700 pmoles, 1000 pmoles, 1250 pmoles, 1500 pmoles, 1700 pmoles, 2000 pmoles, 2250 pmoles, 2500 pmoles, or 3000 pmoles. In a particular embodiment, the moles specified in the previous embodiments are of CBG and / or CBG analogue comprised in the composition, wherein the dose indicated corresponds to the sum of the amount of CBG and of the CBG analogue.

[0108] In another particular embodiment, the dose per day of CBG and / or of CBG analogue administered to a subject with the composition is as indicated in any of the embodiments above, wherein the dose indicated corresponds to the sum of the amount of CBG and of the CBG analogue. As well understood by a skilled person, in case the composition does not comprise a CBG analogue, the indicated dose in the previous embodiments is that of CBG (administered with the composition), and vis-versa.

[0109] In a particular embodiment, cannabigerol is present in a plant extract. In a more particular embodiment, the plant extract comprising cannabigerol is an aqueous extract. In another more particular embodiment, the plant extract comprising cannabigerol is a plant extract obtained through extraction with alcohol solvents. In yet another more particular embodiment, the plant extract comprising CBG is a plant extract obtained through extraction with organic solvents.

[0110] In a particular embodiment, the composition does not comprise cannabigerolic acid (CBGA).

[0111] In another particular embodiment, the CBG analogue is not cannabigerolic acid (CBGA).

[0112] In a further particular embodiment, the CBG analogue is selected from a list consisting of: CBG-O- acetate, VCE-003 and VCE-003.2.

[0113] In a particular embodiment, the composition is administered to a subject that has normal blood pressure. In another particular embodiment, the subject has a resting systolic blood pressure of 120 mmHg or lower and a resting diastolic blood pressure of 80 mmHg or lower. In yet another particular embodiment, the subject does not have hypertension. In a particular embodiment, the subject has been diagnosed with hypertension, but the subject has resting systolic blood pressure of 139 mmHg or lower and a resting diastolic blood pressure of 89 mmHg or lower at the time of administration of CBG and / or of a synthetic analogue of CBG. In a more particular embodiment, the subject has been diagnosed with hypertension, but the subject has a resting systolic blood pressure of 90 to 120 mmHg and a resting diastolic blood pressure of 60 to 80 mmHg at the time of administration of CBG, and / or of a synthetic analogue of CBG. In a further particular embodiment, the subject has received antihypertensive medication in the 7 days preceding. Hypertension is commonly understood to refer to a condition characterised by persistently elevated blood pressure. In adult humans between 18 to 79 years old, a subject is considered to have hypertension if resting systolic blood pressure of 140 mmHg or higher and a resting diastolic blood pressure of 90 mmHg or higher. Conversely, in adult humans between 18 to 79 years old, normal resting systolic blood pressure is considered to be between 90 to 120 mmHg and normal resting diastolic blood pressure is considered to be between 60 to 80 mmHg. In humans who are 80-years old or older, due to arterial stiffening with age, blood pressure is considered normal if the resting systolic blood pressure is lower than 150 mmHg and the resting diastolic blood pressure is lower than 90 mmHg.

[0114] In a more particular embodiment, the composition is administered to a subject that has previously received a treatment for arrhythmia but has not responded to said treatment. In a yet more particular embodiment, the treatment that the subject has previously received for arrhythmia is a pharmacological treatment.

[0115] In a particular embodiment, the concentration in % (w / w) of cannabigerol and / or of the synthetic cannabigerol analogue in the composition, is at least 5%, particularly at least 6%, particularly at least 7%, particularly at least 8%, particularly at least 9%, relative to the weight of the total composition.

[0116] In another particular embodiment, the concentration in % (w / w) of cannabigerol and / or of the synthetic cannabigerol analogue in the composition, is at least 10% relative to the weight of the total composition.

[0117] In yet another particular embodiment, the concentration in % (w / w) of cannabigerol and / or of the synthetic cannabigerol analogue in the composition, is at least 11 %, particularly at least 12%, particularly at least 13%, particularly at least 14%, particularly at least 15%, particularly at least 16%, particularly at least 17%, particularly at least 18%, particularly at least 19%, particularly at least 20%, relative to the weight of the total composition. In more particular embodiment, the concentration in % (w / w) of cannabigerol and / or of the synthetic cannabigerol analogue in the composition, is at least 16% relative to the weight of the total composition.

[0118] In a particular embodiment, cannabigerol and / or the synthetic cannabigerol analogue represent 95% (w / w) or more of the total phytocannabinoid content of the composition.

[0119] In another particular embodiment, the composition comprises cannabigerol and / or the synthetic cannabigerol analogue as the only phytocannabinoids.

[0120] In a particular embodiment, the concentration in % (w / w) of phytocannabinoid tetrahydrocannabinol, or of a salt or ester thereof, in the composition, is less than 10% relative to the weight of the total composition. In a more particular embodiment, the concentration in % (w / w) of phytocannabinoid tetrahydrocannabinol, or of a salt or ester thereof, in the composition, is less than 5% relative to the weight of the total composition. In a yet more particular embodiment, the concentration in % (w / w) of phytocannabinoid tetrahydrocannabinol, or of a salt or ester thereof, in the composition, is less than 3% relative to the weight of the total composition. In an even more particular embodiment, the composition does not comprise the phytocannabinoid tetrahydrocannabinol, or a salt or ester thereof.

[0121] In a particular embodiment, the concentration in % (w / w) of cannabidiol, or of a salt or ester thereof, in the composition, is less than 10% relative to the weight of the total composition. In a more particular embodiment, the concentration in % (w / w) of cannabidiol, or of a salt or ester thereof, in the composition, is less than 5% relative to the weight of the total composition. In an even more particular embodiment, the concentration in % (w / w) of cannabidiol, or of a salt or ester thereof, in the composition, is less than 3% relative to the weight of the total composition. In a yet more particular embodiment, the composition does not comprise cannabidiol, or a salt or ester thereof.

[0122] In a particular embodiment, the composition is for oral administration. In a more particular embodiment, the composition is for sublingual administration. In an alternative particular embodiment, the composition is for parenteral administration. In a more particular embodiment, the composition is for intravenous, subcutaneous, intradermal or intramuscular administration. In another more particular embodiment, the composition is for administration by inhalation.

[0123] In a particular embodiment, the composition is formulated in a liquid dosage form. In a more particular embodiment, the composition is formulated as a non-aqueous liquid dosage form. In a yet more particular embodiment, the composition is formulated as an oil dosage form. In an alternative more particular embodiment, the composition is formulated as an oil-in-water emulsion or as a water- in-oil emulsion.

[0124] In a particular embodiment, the composition is a pharmaceutical composition. In a more particular embodiment, the composition comprises, in addition to cannabigerol and / or the synthetic cannabigerol analogue, one or more pharmaceutically acceptable excipients or carriers.

[0125] In a yet more particular embodiment, the composition consists of cannabigerol and / or the synthetic cannabigerol analogue and of pharmaceutically-acceptable excipients and / or carriers. In a another yet more particular embodiment, the composition consists of cannabigerol and of pharmaceutically- acceptable excipients and / or carriers. In an alternative yet more particular embodiment, the composition consists of the synthetic cannabigerol analogue and of pharmaceutically-acceptable excipients and / or carriers.

[0126] In another particular embodiment, the composition consists essentially of cannabigerol and / or the synthetic cannabigerol analogue. In a more particular embodiment, the composition consists essentially of cannabigerol. In an alternative more particular embodiment, the composition consists essentially of the synthetic cannabigerol analogue.

[0127] In another particular embodiment, the composition is an edible composition. In another particular embodiment, the composition consists of CBG and edible excipients or carriers.

[0128] The term "pharmaceutical composition" refers to a composition used for improving or maintaining the health of a subject and which comprises pharmaceutically acceptable excipients or carriers. The pharmaceutical compositions of the present invention are suitable for administration in mammals, including humans.

[0129] ‘Active agents” or “active ingredients” according to the present invention include cannabigerol (CBG) and cannabigerol analogues, as detailed above. The expression "therapeutically effective amount" as used herein, refers to the amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the disease being addressed. The particular dose of compound to be administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.

[0130] The expression "pharmaceutically acceptable excipients or carriers" refers to pharmaceutically acceptable materials, compositions, or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0131] As described in detail below, the pharmaceutical compositions described herein may be specially formulated for administration by any suitable route in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; or (3) sublingually.

[0132] In some embodiments, the composition / s comprises additional agents. For example, the composition / s may comprise a nutritional agent, such as an antioxidant. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0133] The formulations of the compounds described herein may be presented in “unit dosage form” or “single dosage form”, also known as “unit dose”, and may be prepared by any methods well known in the art of pharmacy. In this sense, “unit dose” refers to a pharmaceutical product presented in a specific form for use, and which is to be administered to, or to be taken by a mammal, including a human. A unit dose comprises a combination of at least one pharmaceutically active ingredient and inactive ingredients (excipients), wherein the pharmaceutically active ingredient is apportioned into a specific dose. The amount of active ingredient, which can be combined with a carrier material to produce a unit dose, will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient, which can be combined with a carrier material to produce a unit dose, will generally be that amount of the active ingredient which produces a therapeutic effect.

[0134] In certain embodiments, a formulation described herein comprises an excipient, including, but not limited to, cyclodextrins, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and an agent of the invention. In some embodiments, an aforementioned formulation renders orally bioavailable an agent of the invention. Methods of preparing these formulations or compositions may include the step of bringing into association a compound of the invention with the carrier and, optionally, one or more accessory ingredients.

[0135] Liquid dosage forms for oral administration of the formulations or compositions provided herein include pharmaceutically acceptable emulsions, microemulsions, oils, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0136] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0137] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0138] Formulations provided herein suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the invention as an active ingredient. A compound of the invention may also be administered as a bolus, electuary, or paste.

[0139] In solid dosage forms of the invention for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically- acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0140] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0141] The tablets, and other solid dosage forms of the pharmaceutical compositions described herein, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. Compositions described herein may also be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0142] Pharmaceutical composition / s provided herein suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0143] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, coconut oils, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0144] The term "pharmaceutically acceptable or edible salt" refers to a relatively non-toxic addition salt of a compound of the present disclosure. For example, see Berge et al. "Pharmaceutical Salts", 1997, J Pharm Sci, volume 66, issue 1 , pp 1-19.

[0145] “Pharmaceutically acceptable or edible salt” includes, but is not limited to, amino acid salts, salts prepared with inorganic acids, such as chloride, sulfate, phosphate, diphosphate, bromide, and nitrate salts, or salts prepared from the corresponding inorganic acid form of any of the preceding, e.g., hydrochloride, etc., or salts prepared with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts. Similarly salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted ammonium).

[0146] An “edible composition” or a “food composition”, as used herein, are used interchangeably and refer to any solid, semi-solid, or liquid composition, also a drinkable liquid, which is suitable for human consumption. Food compositions are meant to also encompass the raw materials used for their elaboration, as well as dietary supplements. The term “dietary supplement” refers to a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantity in a subject’s diet. The term “edible” as used herein refers to a substance that can be ingested by animals, including humans, without significant deleterious health consequences. In the sense of the present invention an edible composition may comprise cannabigerol, or an edible salt thereof, or a cannabigerlol analogue, or an edible salt thereof.

[0147] The compositions of the invention can additionally incorporate one or more further pharmaceutically active agents which reinforce or complement the beneficial effects of CBG for use according to the present invention. As used herein, the term "pharmaceutically active agent" refers to an agent that has pharmacological activity and is used for curing, mitigating, treating or preventing a disease in a subject, in particular a human, more particularly for the prevention and / or treatment of an arrhythmia or of another condition associated with abnormal calcium handling, such as a condition characterised by increased frequency of Ca2+sparks, increased number of Ca2+sparks per spark site, increased intensity and / or number of Ca2+waves, such as, for example, a pathological muscle contraction.

[0148] The pharmaceutical compositions of the present invention can be prepared according to methods well known in the state of the art. The appropriate excipients and / or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared.

[0149] Any one of the particular embodiments, disclosed herein for aspects 1 and / or 2, can be optionally combined with any one or several of the other particular embodiments herein disclosed for aspects 1 and / or 2.

[0150] Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”.

[0151] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0152] Clause 1- A composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in reducing: a) a frequency of calcium sparks in a cell, b) a number of calcium sparks per spark site in a cell, c) an intensity and / or a frequency of calcium waves in a cell, or d) any combination thereof.

[0153] Clause 2- The composition for use according to clause 1 , wherein: a) the frequency of calcium sparks in the cell is pathological, b) the number of calcium sparks per spark site in the cell is pathological, and / or c) the calcium waves in the cell are arrhythmogenic calcium waves.

[0154] Clause 3- The composition for use according to any one of clauses 1-2, wherein the cell is a muscle cell, particularly a cardiomyocyte, more particularly an atrial cardiomyocyte or a ventricular cardiomyocyte, most particularly an atrial cardiomyocyte.

[0155] Clause 4- The composition for use according to any one of clauses 1-3, wherein the composition is administered to a subject deemed at risk of developing or diagnosed with a cardiac arrhythmia.

[0156] Clause 5- A composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the treatment and / or prevention of a cardiac arrhythmia.

[0157] Clause 6- The composition for use according to any one of clauses 4-5, wherein the cardiac arrythmia comprises or consists of atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia (CPVT), ventricular fibrillation, or a combination thereof.

[0158] Clause 7- The composition for use according to clause 6, wherein the cardiac arrythmia comprises or consists of atrial fibrillation.

[0159] Clause 8- The composition for use according to any one of the preceding clauses, wherein the therapeutically effective amount of cannabigerol and / or of the synthetic cannabigerol analogue is at least 15 pmoles per unit dose.

[0160] Clause 9- The composition for use according to any one of the preceding clauses, wherein the composition is administered to a subject in need of thereof at a dose per day of between 15 to 1500 pmoles, preferably between 20 to 1400 pmoles, more preferably between 30 to 1300 pmoles, even more preferably between 35 to 1200 moles, even more preferably between 40 to 1100 moles, most preferably between 45 to 1000 pmoles.

[0161] Clause 10- The composition for use according to any one of the preceding clauses, wherein the concentration of cannabigerol and / or of the synthetic cannabigerol analogue is at least 10% (w / w) relative to the weight of the total composition.

[0162] Clause 11- The composition for use according to any one of the preceding clauses, wherein the composition comprises less than 10% (w / w), relative to the weight of the total composition, of phytocannabinoid tetrahydrocannabinol, or of a salt or ester thereof.

[0163] Clause 12- The composition for use according to clause 11 , which does not comprise the compound phytocannabinoid tetrahydrocannabinol, or of the salt or ester thereof.

[0164] Clause 13- The composition for use according to any one of the preceding clauses, wherein the composition comprises less than 10% (w / w), relative to the weight of the total composition, of cannabidiol, or of a salt or ester thereof.

[0165] Clause 14- The composition for use according to clause 13, which does not comprise the compound cannabidiol, or the salt or ester thereof.

[0166] Clause 15- The composition for use according to any one of the preceding clauses, wherein the composition is a pharmaceutical composition, and wherein the composition comprises, in addition to cannabigerol and / or the synthetic cannabigerol analogue, one or more pharmaceutically acceptable excipients or carriers.

[0167] Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.

[0168] Examples

[0169] METHODS

[0170] Cardiomyocyte isolation. Cardiomyocytes were isolated using a procedure similar to that described in Lozano-Velasco et al. “Pitx2 impairs calcium handling in a dose-dependent manner by modulating Wnt signalling”, Cardiovasc Research, 2016, vol. 109, issue 1 , pp. 55-66. Briefly, isolated mouse hearts were Langendorff perfused and digested with an enzymatic solution (collagenase, proteinase, and BSA) of Ca2+-free Tyrode for 8 min. Afterwards, atrial chambers were dissected into small pieces, washed twice in stop solution by gentle agitation, and transferred into an enzymatic solution for 8 min again. This process was repeated several times until an adequate number of square- edged, rod-shaped cardiomyocytes were released. Subsequently, cells were pooled, centrifuged for 5 min at 500x g, and resuspended in the appropriate electrophysiological solution (pH = 7.4) containing: 136 mM NaCI, 4 mM KCI, 0.33 mM NaH2PO4, 4 mM NaHCO3, 2 mM CaCI2, 1.6 mM MgCI2, 10 mM HEPES, 5 mM glucose, and 5 mM pyruvic acid.

[0171] Mice were sacrificed using cervical dislocation after general anaesthesia with intraperitoneal administration of ketamine (75 mg / kg) and medetomidine (1 mg / kg). The study was approved by the Bioethical Committee at Hospital de Sant Pau (AF-RISK_2015) and authorized by Generalitat de Catalunya. The study conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

[0172] Ex vivo modelling of AFib. Atrial fibrillation (AFib) was mimicked ex vivo by treating isolated mouse atrial cardiomyocytes with a pharmacological cocktail comprising 200 nM CGS21680 (Merck, catalog # 0141 ; a selective adenosine A2A receptor agonist), 1 pM ITI-264 (MedChemExpress, calalog # Hy-12501 A; a selective inhibitor of PDE-1 , phosphodiesterase 1), and 1 pM mrs1191 (Thermofisher, catalog # M227; a selective inhibitor of adenosine A3 receptors, which was included in order to eliminate any potential interference caused by non-selective activation of adenosine A3 receptors by 200 nM CGS21680). Calcium imaging and pharmacological treatments were performed after myocytes were loaded with the fluorescent calcium indicator. Experiments were performed in an experimental solution (pH = 7.4) containing: 136 mM NaCI, 4 mM KCI, 0.33 mM NaH2PO4, 4 mM NaHCO3, 2 mM CaCI2, 1.6 mM MgCI2, 10 mM HEPES, 5 mM glucose, and 5 mM pyruvic acid. Myocytes were exposed to the AFib-mimicking solution for 10 minutes.

[0173] Ex vivo modelling of VFib. To mimic ventricular fibrillation (VFib) ex vivo, isolated mouse ventricular cardiomyocytes were treated with the same pharmacological cocktail described above for ex vivo modelling of AFib.

[0174] CBG treatment. To assess the effects of CBG on calcium handling, cells were treated with 3 pM CBG. For these experiments, CBG (purity >99%) isolated from Cannabis sativa L. plants was obtained from Phytoplant (ref: EX2408130001). CBG was added from a 10 mM stock solution to the experimental solution to achieve a concentration of 3 pM CBG. Myocytes were incubated with CBG for 5 minutes, when added before solutions mimicking AFib or VFib. When added after, the effect of the CBG treatment was monitored for at least 10 minutes until the recorded signal reached a new steady-state. Control experiments without CBG were performed over the same time interval to verify that the experimental protocol did not affect measurements.

[0175] Confocal calcium ion imaging. Freshly isolated primary mouse atrial myocytes were used to visualize intracellular calcium using methods similar to those previously described for mouse atrial myocytes in Nolla-Colomer et al. “P2-adrenergic stimulation potentiates spontaneous calcium release by increasing signal mass and co-activation of ryanodine receptor clusters”, Acta Physiol, 2022, vol. 234, issue 4, pp. e13736. Briefly, myocytes were loaded with 5 pM of the Rhod-2 AM calciumsensitive dye (Thermofisher, catalog # R1245-MP), in cell culture media, for 40 minutes, followed by washing in in cell culture media without the calcium sensitive dye, for at least 30 mins, according to the manufacturer’s instructions. Intracellular calcium was then visualized within less than three hours of the completion of the Rhod-2 dye loading protocol by recording Rhod-2 fluorescence with a resonance-scanning confocal microscope (Leica SP5 AOBS) and a 63x glycerol-immersion objective. Rhod-2 was excited with a HeNe laser (1 mW) at 543 nm. The laser power was set to 20% of the maximum and attenuated to 10%. Fluorescence emission was collected between 600 and 750 nm with the Leica Hybrid detector. Experiments were performed at room temperature, under atmospheric carbon dioxide and oxygen conditions. The digital zoom factor was increased to 6X and the image dimension was reduced to 64 x 256 pixels to obtain a good compromise between temporal and spatial resolution, i.e. a sample interval of 5.6 ms and a pixel size of 0.1 x 0.1 pm.

[0176] Detection and characterization of calcium sparks. The properties, spatial distribution, and frequency of the calcium sparks were analyzed using methods described in Tarifa et al. “Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes”, JACC Basic Transl Sci, 2022, vol. 8, issue 1 , pp. 1-15. Briefly, atrial myocytes were loaded with a calcium-sensitive dye, as described above, and images (140 x 512 pixels) were recorded at a frame rate of 90 Hz. Calcium sparks were detected using a custom-made image processing and analysis pipeline for live-cell imaging data (SparkSimple, described in Tarifa et al. “Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes”, JACC Basic Transl Sci, 2022, vol. 8, issue 1 , pp. 1-15). This tool identifies calcium spark candidates, their properties, and spatiotemporal distribution, followed by filtering delimiting the calcium spark dimensions and the minimal temporal and spatial distance between sparks. Subsequently, accepted sparks occurring repeatedly in the same place were pooled into a single spark site, allowing determination of the site density and the spark frequency per site. To determine the impact of the signal-to-noise ratio on spark detection, we used a mathematical myocyte model (see the following text) to generate synthetic sparks and determine the impact of signal noise on spark detection and properties. The algorithm successfully detected sparks with signal-to-noise ratios (signal / [max noise - min noise] / 2) higher than 2.62 ± 0.15. To fine-tune the filtering parameters of the algorithm, all sparks identified by the program were inspected manually and accepted or rejected as valid sparks using a validation subroutine within the detection program developed for this purpose. The spark amplitude (amp) had an asymmetric distribution because small-amplitude events, including sparks above or below the confocal plane, were discarded by the filter settings. Similarly, potential events with very fast decay (tau) could not be distinguished from noise and were eliminated by the detection filter.

[0177] Data analysis and statistical methods. Data were analyzed using IBM SPSS Statistics for Windows (version 26.0). Unless otherwise stated, values were averaged for each subject, and results are expressed as mean + / - SEM. Statistical significance was evaluated using chi-square test for categorical data. For normally distributed data (normality was evaluated using Shapiro-Wilk’s test and Q-Q plot), the Student’s t-test was used for paired or unpaired comparisons. For data that did not have a normal distribution, the Wilcoxon rank-sum test was used. Bonferroni post-hoc test was done for pairwise comparison of differences between groups. A value of P < 0.05 was considered statistically significant.

[0178] Example 1 : CBG reverses arrhythmogenic calcium release in an ex vivo model of AFib

[0179] To assess the effects of CBG on calcium handling under AFib conditions, the incidence of Ca2+sparks and Ca2+waves were analysed in isolated mouse atrial cardiomyocytes under different experimental conditions, namely: basal, physiological conditions (CTRL), AFib-mimicking conditions (AFib), and AFib-mimicking conditions followed by exposure to 3 pM CBG (AFib- ^BG). Ca2+sparks were recorded for individual spark sites (FIG. 1). As shown in FIG. 2, compared to CTRL cells, AFib cells displayed an increased frequency of Ca2+sparks (FIG. 2A; expressed as Ca2+spark events / min / pm2) and an increased number of Ca2+sparks per spark site (FIG. 2B; expressed as Ca2+spark events / spark site). Subsequent treatment of the cells with 3 pM CBG (AFib- ^BG) completely abrogated the AFib-associated increases in the frequency of Ca2+sparks (FIG. 2A) and number of Ca2+sparks per spark site (FIG. 2B).

[0180] Similar experiments were performed to analyse Ca2+waves. As shown in FIG. 3, the frequency of Ca2+waves in isolated mouse atrial cardiomyocytes (expressed as number of Ca2+wave events per 10-second time window) remained low under control, physiological conditions (CTRL panel; FIG. 3 bottom / left) over a 10-min recording time window, while exposure to the AFib-mimicking pharmacological cocktail (AFib panel; FIG. 3 middle) increased Ca2+wave frequency by 3-fold over the same time period. Subsequent treatment with CBG (AFib- ^BG panel; FIG. 3 top / right) attenuated the AFib-associated increase in Ca2+wave frequency, decreasing said frequency below the arrhythmogenic threshold by 8 minutes after the start of the CBG treatment, and reversing the Ca2+wave frequency back down to control levels by 12 minutes.

[0181] Importantly, the observed effect of CBG on reversing the AFib-associated abnormal calcium handling was not due to a reduction in the calcium available for release, as the amount of calcium stored in the sarcoplasmic reticulum (SR) was similar in all conditions. As shown in FIG. 4, peak Rhod-2 fluorescence values were comparable across all conditions when the calcium stored in the SR was released by transient exposure to 10 mM caffeine. As this experimental manipulation is known to cause rapid opening of the SR calcium channels, the peak Rhod-2 fluorescence following caffeine exposure serves as a measure of the calcium released from the SR into the cytosol and, thus, of the SR calcium content.

[0182] Example 2: CBG prevents arrhythmogenic calcium release in an ex vivo model of VFib

[0183] To assess the effects of CBG on calcium handling in the context of VFib, Ca2+spark sites and Ca2+sparks were analysed in isolated mouse ventricular cardiomyocytes under different experimental conditions, namely: basal, physiological conditions (CTRL), treatment with 3 pM CBG (CBG), and treatment with 3 pM CBG followed by exposure to VFib-mimicking conditions (VFib- ^BG). Ca2+ sparks were recorded for individual spark sites (FIG. 5). As shown in FIG. 6, compared to CTRL cells, CBG treatment decreased the density of Ca2+spark sites (FIG. 6A; expressed as Ca2+spark sites / pm2), as well as the frequency of Ca2+sparks (FIG. 6B; expressed as Ca2+spark events / min / m2). Upon subsequent exposure of the CBG-treated cells to a VFib-mimicking pharmacological cocktail (VFibCBG), CBG prevented VFib-associated abnormalities in calcium handling. Specifically, CBG treatment prevented an increase in the density of Ca2+spark sites (FIG. 6A) and in the frequency of Ca2+sparks (FIG. 6B) under VFib-mimicking conditions.

[0184] Example 3- CBG effect at low doses

[0185] Additional experiments with lower doses of CBG have been performed with cells preincubated with the phytocannabinoid prior to the application of the arrhythmogenic stimulus. Under these conditions, the arrhythmogenic stimulus did not induce any spontaneous events in atrial myocytes of 4 patients exposed to lower CBG concentrations, such as 300 nM CBG or 1000 nM CBG. Moreover, even at lower CBG concentrations, including 100 nM of CBG, the arrhythmogenic stimulus did not induce any spontaneous event in atrial myocytes of 2 patients.

[0186] These results support that these lower CBG concentrations also prevent the induction of spontaneous arrhythmogenic events (induced by calcium waves).

[0187] Citation List

[0188] Patent Literature:

[0189] US patent US10954209B

[0190] European patent EP3247371 B1

[0191] Non-Patent Literature:

[0192] Berge et al. "Pharmaceutical Salts", 1997, J Pharm Sci, volume 66, issue 1 , pp. 1-19

[0193] Bray et al. “Multidimensional Detection and Analysis of Ca2+ Sparks in Cardiac Myocytes”, Biophysical Journal, 2007, vol. 92, issue 12, pp. 4433-4443

[0194] Diaz-Alonso et al. “VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease”, Scientific Reports, 2016, vol. 6, pp. 29789

[0195] Granja et al. “A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis”, 2012, vol. 7, issue 4, pp. 1002-1016

[0196] Hove-Madsen et al. “Atrial fibrillation is associated with increased spontaneous calcium release from the sarcoplasmic reticulum in human atrial myocytes”, Circulation, 2004, vol. 110, issue 11 , pp. 1358-1363

[0197] Lozano-Velasco et al. “Pitx2 impairs calcium handling in a dose-dependent manner by modulating Wnt signalling”, Cardiovasc Research, 2016, vol. 109, issue 1 , pp. 55-66

[0198] Nolla-Colomer et al. “P2-adrenergic stimulation potentiates spontaneous calcium release by increasing signal mass and co-activation of ryanodine receptor clusters”, Acta Physiol, 2022, vol. 234, issue 4, pp. e13736

[0199] Szczesniak et al. “Nonpsychotropic Cannabinoids, Abnormal Cannabidiol and Canabigerol-Dimethyl Heptyl, Act at Novel Cannabinoid Receptors to Reduce Intraocular Pressure”, 2011, vol. 27, issue 5, pp. 427-435 Tarifa et al. “Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes”, JACC Basic Transl Sci, 2022, vol. 8, issue 1 , pp. 1- 15

[0200] Tisdale et al. “Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association”, 2020, Circulation, vol. 142, issue 15, pp: e214-e233

Claims

Claims1- A composition comprising a therapeutically effective amount of cannabigerol and / or of a synthetic cannabigerol analogue for use in the treatment and / or prevention of a disease or physiological damage selected from the group consisting of a cardiac arrhythmia, a pathological skeletal muscle contraction, a physiological skeletal muscle damage, and combinations thereof.2- The composition for use according to claim 1 , wherein the disease or physiological damage is a cardiac arrhythmia.3- The composition for use according to any one of claims 1-2, wherein the cardiac arrythmia comprises or consists of atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia (CPVT), ventricular fibrillation, or a combination thereof.4- The composition for use according to claim 3, wherein the cardiac arrythmia comprises or consists of atrial fibrillation.5- The composition for use according to any one of the preceding claims, wherein the therapeutically effective amount of cannabigerol and / or of the synthetic cannabigerol analogue is at least 15 pmoles per unit dose.6- The composition for use according to any one of the preceding claims, wherein the composition is administered to a subject in need of thereof at a dose per day of between 15 to 1500 pmoles, preferably between 20 to 1400 pmoles, more preferably between 30 to 1300 pmoles, even more preferably between 35 to 1200 pmoles, even more preferably between 40 to 1100 pmoles, most preferably between 45 to 1000 pmoles.7- The composition for use according to any one of the preceding claims, wherein the concentration of cannabigerol and / or of the synthetic cannabigerol analogue is at least 10% (w / w) relative to the weight of the total composition.8- The composition for use according to any one of the preceding claims, wherein the composition comprises less than 10% (w / w), relative to the weight of the total composition, of phytocannabinoid tetrahydrocannabinol, or of a salt or ester thereof.9- The composition for use according to claim 8, which does not comprise the compound phytocannabinoid tetrahydrocannabinol, or of the salt or ester thereof.10- The composition for use according to any one of the preceding claims, wherein the composition comprises less than 10% (w / w), relative to the weight of the total composition, of cannabidiol, or of a salt or ester thereof.11- The composition for use according to claim 10, which does not comprise the compound cannabidiol, or the salt or ester thereof.12- The composition for use according to any one of the preceding claims, wherein the composition is a pharmaceutical composition, and wherein the composition comprises, in addition to cannabigerol and / or the synthetic cannabigerol analogue, one or more pharmaceutically acceptable excipients or carriers.13- The composition for use according to anyone of the preceding claims, wherein the synthetic cannabigerol analogue is a pharmaceutically acceptable ester of CBG, or a pharmaceutically acceptable CBG quinone derivative.14- The composition for use according to claim 13 wherein the ester of CBG is CBG-O- acetate.15- The composition for use according to any one of claims 13-14 wherein the CBG quinone derivative is VCE-003, VCE-003.2, or CBG-dimethyl heptyl (CBG-DMH).

Images