Terpenes for use in modulation of a physiological or psychological function

Abstract

Provided is a composition comprising at least one terpene for use in modulation of a physiological or psychological function via at least one selected from the group consisting of agonism of a cannabinoid type 2 receptor (CB2R), antagonism of a cannabinoid type 2 receptor (CB2R), modulation of agonism of a CB2R, modulation of antagonism of a CB2R and combinations thereof; and methods of use thereof.

Description

TERPENES FOR USE IN MODULATION OF A PHYSIOLOGICAL OR PSYCHOLOGICAL FUNCTIONCross-Reference to Related Applications

[0001] The present application gains priority from U.S Provisional Patent Application Serial No. 63 / 614,638 filed December 25, 2023, which is incorporated by reference as if fully set-forth herein.Field of the Invention

[0002] The present invention relates to the field of medical treatment, and more specifically to use of terpenes for modulation of a physiological or psychological function via modulation of activity of a cannabinoid type 2 receptor.Background of the invention

[0003] The cannabinoid type 2 (CB2) receptor is identified peripherally in the circulating immune cells, the spleen and on macrophage-derived cells including osteocytes, osteoclasts and hepatic cells. Unlike the widespread expression of CBi receptors in the central nervous system (CNS), the expression of CB2 receptors, under normal physiological conditions, is restricted to the brainstem and hippocampal pyramidal neurons. However, CB2 expression is highly inducible on the reactive microglia in the CNS following inflammation or injury.

[0004] Activation and deactivation of the activity of a CB2 receptor therefore affects a wide range of physiological or psychological functions and conditions in the body of a subject, such as pain, immune system related function, inflammation, fibrosis, sclerosis, bone structure, autoimmune diseases, cardiovascular function, gastrointestinal function, liver function, kidney function, neurodegenerative, psychiatric, skin disorders, lung function, cancer or addiction in a human subject.Summary of the invention

[0005] According to an aspect of some embodiments of the present invention, there is provided a composition comprising at least one terpene for use in modulation of a physiologicalor psychological function via at least one selected from the group consisting of agonism of a cannabinoid type 2 receptor (CB2R), antagonism of a cannabinoid type 2 receptor (CB2R), modulation of agonism of a CB2R, modulation of antagonism of a CB2R and combinations thereof.

[0006] According to an aspect of some embodiments of the present invention, there is provided a method of modulating a physiological or psychological function in a subject via at least one selected from the group consisting of agonism of a cannabinoid type 2 receptor (CB2R), antagonism of a cannabinoid type 2 receptor (CB2R), modulation of agonism of a CB2R, modulation of antagonism of a CB2R and combinations thereof, the method comprising administering to the subject at least one terpene.Brief description of the figures

[0007] Some embodiments of the invention are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments of the invention may be practiced.

[0008] In the Figures:

[0009] FIGs. 1A to IE and 2A to 2H are dose response curves of CB2 receptor activated GIRK currents by terpenes. Each graph depicts the response to 4-7 terpene concentrations (each data point represents the mean±SEM from 4-8 oocytes. Responses were normalized to the response evoked by 10 pM THC at the same oocyte;

[0010] FIGs. 3A to 3E are dose response curves of CB2 receptor activated GIRK currents following co-application of THC and terpenes at natural THC / terpenes w / w ratio. Black symbols and lines represent activation of the receptor by THC alone. Red symbols and lines represent activation of the receptor by co-application of THC and terpene. The w / w ratio between THC and terpene was kept 10:1 throughout (each data point represents mean ± SEM from 6-14 oocytes).Detailed Description of the invention

[0011] The present invention relates to use of terpenes for modulation of a physiological or psychological function related to activation of a cannabinoid type 2 receptor (CB2R).

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0013] The terminology used in the description of the invention herein is for describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0014] As used herein, the term “modulating” with regard to a physiological or psychological function refers to changing, controlling, affecting, managing or influencing a type or magnitude of a physiological or psychological function, and includes increasing or decreasing a magnitude, a frequency and / or a severity of the physiological or psychological function. “Modulating” may be applied to an abnormal physiological or psychological function for treating a condition or a symptom thereof arising from such abnormal function, or to a normal healthy physiological or psychological function in order to provide a desired change in the function. Modulation of a physiological or psychological function may be achieved, for example by modulation of activation of a receptor involved in modulation of the physiological or psychological function, such as by increasing or decreasing activation of the receptor by an agonist or antagonist or of a ligand to the receptor, including, but not limited to CB2R or an agonist, antagonist or modulator of CB2R; or by increasing or decreasing the availability of the agonist or antagonist, such as increase or inhibition of agonist / antagonist production, degradation, re-uptake and combination thereof. Alternatively, modulation may be achieved by increasing or decreasing binding of the agonist or antagonist to the receptor. Alternatively, modulation may be achieved by increasing or decreasing the distribution and activate state of the CB2R. Modulation may be additive or synergistic and may involve allosteric or orthosteric interaction of the agonist or antagonist with the receptor.

[0015] As used herein, the term “agonist” is intended to encompass both a full and a partial agonist i.e. an agent which fully or partially activates a receptor to which it binds. The agonist or partial agonist may be a natural or synthetic cannabinoid agonist. According to some embodiments, the agonist is a phytocannabinoid or endocannabinoid.

[0016] As used herein, the term "treating" includes ameliorating, mitigating, and reducing the instances of a disease or condition, or the symptoms of a disease or condition.

[0017] As used herein, the term "administering" includes any mode of administration, such as oral, subcutaneous, sublingual, transmucosal, parenteral, intravenous, intra-arterial, buccal, topical, vaginal, rectal, ophthalmic, otic, nasal, inhaled, intramuscular, intraosseous, intrathecal, dermal and transdermal, or combinations thereof. "Administering" can also include providing a different compound that when ingested or delivered as above will necessarily transform into the compound that is desired to be administered, this type of “different compound” is often being referred to as a “Prodrug”. "Administering" can also include prescribing or filling a prescription for a dosage form comprising a particular compound. "Administering" can also include providing directions to carry out a method involving a particular compound or a dosage form comprising the compound or compounds.

[0018] As used herein, the term "therapeutically effective amount" means the amount of an active substance that, when administered to a subject for treating a disease, disorder, or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease, disorder, or condition. The therapeutically effective amount will vary depending on the chemical identity and formulation form of the active substance, the disease or condition and its severity, and the age, weight, and other relevant characteristics of the patient to be treated. Determining the therapeutically effective amount of a given active substance is within the ordinary skill of the art and typically requires no more than routine experimentation.

[0019] Unless otherwise indicated, all numbers expressing quantities, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0020] As used herein, when a numerical value is preceded by the term "about", the term "about" is intended to indicate + / - 10% of that value.

[0021] As used herein, the terms “comprising”, “including”, "having" and grammatical variants thereof are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof. These terms encompass the terms "consisting of" and "consisting essentially of". As used herein, the terms “water content” and “moisture content” are used interchangeably.

[0022] Unless indicated otherwise, percent is weight percent and ratio is weight / weight ratio.

[0023] The particulars shown herein are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

[0024] The present invention will now be described by reference to more detailed embodiments. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0025] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0026] According to an aspect of some embodiments of the present invention, there is provided a composition comprising at least one terpene for use in modulation of a physiological or psychological function via at least one selected from the group consisting of agonism of a cannabinoid type 2 receptor (CB2R), antagonism of a cannabinoid type 2 receptor (CB2R), modulation of agonism of a CB2R, modulation of antagonism of a CB2R and combinations thereof.

[0027] According to some such embodiments, the at least one terpene is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof.

[0028] According to some such embodiments, the at least one terpene is selected from the group consisting of alpha pinene, beta pinene, beta caryophyllene, bisabolol, humulene, nerolidol, limonene, terpineol, geraniol, humulene, myrcene, ocimene, terpinolene, borneol, linalool, sabinene, eucalyptol and combinations thereof. According to some embodiments, the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene, seven terpenes, eight terpenes, nine terpenes, ten terpenes, eleven terpenes, twelve terpenes, thirteen terpenes of fourteen terpenes.

[0029] According to some embodiments, modulation of agonism of the CB2R and / or modulation of antagonism of the CB2R comprises modulation of an interaction between the CB2R and an agonist or an antagonist of the CB2R.

[0030] According to some embodiments, the composition further comprises at least one CB2R agonist or at least one CB2R antagonist, at a total terpene to total agonist or antagonist weight / weight ratio in the range between about 0.05:1 and 1:1, such as about 0.05:1, about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1 or about 1:1.

[0031] According to some embodiments, the composition is for co-administration with at least one CB2R agonist or at least one CB2R antagonist, at a total terpene to total agonist or antagonist weight / weight ratio in the range between 0.05:1 and 1:1.

[0032] According to some such embodiments, the terpene for co-administration is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof. According to some embodiments, the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene, seven terpenes or eight terpenes.

[0033] According to some embodiments, the agonist is selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabidivarin (THCV), tetrahydrocannabidivarinic acid (THCVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerolic acid (CBGA) and combinations thereof.

[0034] According to some embodiments, the agonist is present at a dosage of from about 1 to about 100 mg, such as about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg.

[0035] According to a preferred embodiment, the agonist comprises tetrahydrocannabinol (THC).

[0036] According to some embodiments, the THC is present at a dosage of from about 1 to about 100 mg, such as about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg.

[0037] According to some embodiments, the terpene is for administration to a subject at a dosage resulting in a concentration of up to about lOmM of said terpene in the plasma and or serum of the subject, such as about 0.5pM, about IpM, about 2pM, about 3pM, about 4pM, about 5pM, about 6pM, about 7pM, about 8pM, about 9pM, or about lOpM, about 0.5mM, about ImM, about 2mM, about 3mM, about 4mM, about 5mM, about 6mM, about 7mM, about 8mM, about 9mM, or about lOmM.

[0038] According to some embodiments, the agonism or modulation of the CB2 receptor results in increased activation, such as an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300% increase in activation as compared to that obtained with THC in the absence of a terpene. According to some embodiments, the agonism or modulation of the CB2 receptor is decreased activation, such as partial activation, partial or total deactivation, such as a deactivation of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0039] According to some embodiments, the modulation of a physiological or psychological function comprises modulation of a pathological function. According to some such embodiments, the modulation of the physiological or psychological function provides treating of a condition relating to the pathological or psychological function, or a symptom thereof. Hence according to some embodiments, there is provided a terpene for use in treating a condition related to activation of CB2R receptor.

[0040] According to some embodiments, the agonist is selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabidivarin (THCV), tetrahydrocannabidivarinic acid (THCVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerolic acid (CBGA) and combinations thereof. According to a preferred embodiment, the agonist comprises tetrahydrocannabinol (THC).

[0041] According to some embodiments, the at least one terpene is for administration together with tetrahydrocannabinol (THC) at a terpene to THC weight / weight ratio in the range between about 0.05:1 and about 1:1, wherein the modulation of the CB2R receptor is via modulation of an interaction of the THC with the CB2R. According to some embodiments, administration of the terpene together with THC provides a synergistic effect as compared to administration of either the terpene or THC alone.

[0042] According to some embodiments, administration of the terpene together with THC provides an additive effect, wherein the combined effect is similar to the sum of the individual effects of the terpene in the absence of THC and THC in the absence of terpene.

[0043] According to some embodiments, the terpene to THC weight / weight ratio is about 0.05:1, about 0.06:1, about 0.07:1, about 0.08:1, about 0.09:1, about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, or about 1:1. According to some embodiments, the terpene to THC weight / weight ratio is in the range of from about 0.05:1 to about 0.5:1.

[0044] According to some embodiments, the THC is provided in a form suitable for sublingual, oral, buccal, nasal, dermal, transdermal, or inhaled administration.

[0045] According to some embodiments, the terpene is for administration together with THC at a dosage of from about 1 to about 100 mg THC, such as about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg.

[0046] According to some embodiments, modulation of the interaction between the CB2R and the agonist or antagonist of the CB2R is selected from the group consisting of an allosteric interaction, an orthosteric interaction, and a combination thereof.

[0047] According to some embodiments, the terpene is for co-administration together with THC in a single dosage form.

[0048] According to some embodiments, the terpene is for administration in a separate dosage form from said THC, wherein the administration is performed independently, sequentially, simultaneously or concomitantly. According to some such embodiments, the separate dosage forms may be dosage forms configured for administration by different delivery routes, or dosage forms configured for separate administration by a same delivery route.

[0049] According to some embodiments, the terpene is for administration within 2 hours of administration of the THC.

[0050] According to some embodiments, the terpene is for administration prior to administration of the THC. According to some such embodiments, the terpene is for administration substantially immediately prior to administration of the THC. According to some embodiments, the terpene is for administration about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours prior to administration of the THC.

[0051] According to some embodiments, the terpene is for administration subsequent to administration of the THC. According to some embodiments, the terpene is for administration substantially immediately subsequent to administration of the THC. According to some embodiments, the terpene is for administration about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours subsequent to administration of the THC.

[0052] According to some embodiments, the THC is provided in a form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.

[0053] According to some embodiments, the terpene is provided in a form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.

[0054] According to some embodiments, the terpene is for administration together with a CB2R agonist other than tetrahydrocannabinol (THC) at a terpene to CB2R agonist weight / weight ratio in the range between about 0.05:1 and about 1:1, wherein the modulation of activation of the CB2R is via modulation of an interaction of the non-THC CB2R agonist with the CB2R.

[0055] According to some embodiments, the physiological or psychological function is a pathological physiological or a psychological function comprising abnormal CB2R activity

[0056] According to some embodiments, the pathological physiological or psychological function is a condition selected from the group consisting of pain, immune system related function, inflammation, fibrosis, sclerosis, bone structure, autoimmune diseases, cardiovascular function, gastrointestinal function, liver function, kidney function, neurodegenerative, psychiatric, skin disorders, lung function, cancer, addiction and combinations thereof in a human subject.

[0057] According to an aspect of some embodiments of the present invention, there is provided a method of modulating a physiological or psychological function in a subject via at least one selected from the group consisting of agonism of a cannabinoid type 2 receptor (CB2R); antagonism of a cannabinoid type 2 receptor (CB2R), modulation of agonism of a CB2R; modulation of antagonism of a CB2R; and combinations thereof, the method comprising administering to the subject at least one terpene.

[0058] According to some such embodiments, the at least one terpene is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof.

[0059] According to some such embodiments, the at least one terpene is selected from the group consisting of alpha pinene, beta pinene, beta caryophyllene, bisabolol, humulene, nerolidol, limonene, terpineol, geraniol, humulene, myrcene, ocimene, terpinolene, borneol, linalool, sabinene, eucalyptol and combinations thereof. According to some embodiments, the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene, seven terpenes, eight terpenes, nine terpenes, ten terpenes, eleven terpenes, twelve terpenes, thirteen terpenes of fourteen terpenes.

[0060] According to some embodiments, modulation of agonism of the CB2R, and / or modulation of antagonism of the CB2R, comprises modulation of an interaction between the CB2R and an agonist or an antagonist of the CB2R.

[0061] According to some embodiments, the method further comprises administration of at least one CB2R agonist or at least one CB2R antagonist, at a total terpene to total agonist or antagonist weight / weight ratio in the range between about 0.05: 1 and 1:1, such as about 0.05 : 1 , about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1 or about 1:1. According to some such embodiments, the terpene for co-administration is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof. According to some embodiments, the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene, seven terpenes or eight terpenes.

[0062] According to some embodiments, the agonist is selected from the group consisting of cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), tetrahydrocannabidivarin (THCV), tetrahydrocannabidivarinic acid (THCVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabigerol (CBG), cannabigerolic acid (CBGA) and combinations thereof.

[0063] According to some embodiments, the agonist is present at a dosage of from about 1 to about 100 mg, such as about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg.

[0064] According to a preferred embodiment, the agonist comprises tetrahydrocannabinol (THC).

[0065] According to some embodiments of the method, the THC is administered at a dosage of from about 1 to about 100 mg THC, such as about Img, about 5mg, about lOmg, about 15 mg, about 20mg, about 25 mg, about 30mg, about 35 mg, about 40mg, about 45 mg, about 50mg, about 55 mg, about 60mg, about 65 mg, about 70mg, about 75 mg, about 80mg, about 85 mg, about 90mg, about 95 mg or about lOOmg.

[0066] According to some embodiments of the method, the terpene is administered at a dosage resulting in a concentration of up to about lOmM of said terpene in the plasma and or serum of said subject, such as about 0.5pM, about IpM, about 2pM, about 3pM, about 4pM, about 5pM, about 6pM, about 7pM, about 8pM, about 9pM, or about lOpM, about 0.5mM, about ImM, about 2mM, about 3mM, about 4mM, about 5mM, about 6mM, about 7mM, about 8mM, about 9mM, or about lOmM.

[0067] According to some such embodiments, the at least one terpene comprises one terpene, two terpenes, three terpenes, four terpenes, five terpenes, six terpene or seven terpenes.

[0068] According to some embodiments of the method, the terpene is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof.

[0069] According to some embodiments, the terpene is selected from the group consisting of alpha pinene, beta pinene, beta caryophyllene, bisabolol, humulene, nerolidol, limonene, terpineol, geraniol, humulene, myrcene, ocimene, terpinolene, borneol, linalool, sabinene, eucalyptol and combinations thereof. According to some such embodiments, the modulation of the CB2 receptor comprises an agonistic or antagonistic interaction with the receptor.

[0070] According to some embodiments of the method, the modulation of the CB2 receptor results in increased activation, such as an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 300% increase in activation as compared to that obtained with THC in the absence of a terpene. According to some embodiments, the modulation of the CB2 receptor results in decreased activation, such as partial or total deactivation, such as a deactivation of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%.

[0071] According to some embodiments of the method, the modulation of a physiological or psychological function comprises modulation of a pathological function. According to some such embodiments, the modulation of the physiological or psychological function provides treating of a condition relating to the pathological or psychological function, or a symptom thereof. Hence according to some embodiments, there is provided a terpene for use in treating a condition related to activation of a cannabinoid type 2 receptor (CB2R).

[0072] According to some embodiments, the method further comprises administering tetrahydrocannabinol (THC) at a terpene to THC weight / weight ratio in the range between 0.05:1 and 1:1, wherein modulation of the CB2 receptor is via modulation of an interaction of the THC with the CB2 receptor. According to some such embodiments, administration of the terpene together with THC provides a synergistic effect as compared to administration of either the terpene or THC alone. According to some such embodiments of the method, the terpene is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof.

[0073] According to some embodiments of the method, the terpene to THC weight / weight ratio is about 0.05:1, about 0.06:1, about 0.07:1, about 0.08:1, about 0.09:1, about 0.1:1, about0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, or about 1:1. According to some embodiments, the terpene to THC weight / weight ratio is in the range of from about 0.05:1 to about 0.5:1.

[0074] According to some embodiments of the method, the THC is administered sublingually.

[0075] According to some embodiments of the method, modulation of the interaction between the CB2R and the agonist or antagonist of the CB2R is selected from the group consisting of an allosteric modulation, an orthosteric modulation and a combination thereof.

[0076] According to some embodiments of the method, the terpene and the THC are administered in a single dosage form.

[0077] According to some embodiments of the method, the terpene and the THC are administered in separate dosage forms, wherein the administration is performed independently, sequentially, simultaneously or concomitantly. According to some such embodiments, the separate dosage forms are administered by different delivery routes, or in dosage forms by a same delivery route.

[0078] According to some embodiments of the method, the terpene is administered within 2 hours of administration of the THC.

[0079] According to some embodiments of the method, the terpene is administered prior to administration of the THC. According to some such embodiments, the terpene is administered substantially immediately prior to administration of the THC. According to some embodiments, the terpene is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours prior to administration of the THC.

[0080] According to some embodiments of the method, the terpene is administered subsequent to administration of the THC. According to some such embodiments, the terpene is administered substantially immediately subsequent to administration of the THC. According to some embodiments, the terpene is administered about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour or about 2 hours subsequent to administration of the THC.

[0081] According to some embodiments of the method, the THC is administered in the form of a solid, a vapor, an aerosol or a liquid form.

[0082] According to some embodiments of the method, the terpene is administered in a form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.

[0083] According to some embodiments, the method further comprises administering a CB2 agonist other than Tetrahydrocannabinol (THC) at a terpene to CB2 agonist weight / weight ratio in the range between about 0.05:1 and about 1:1, wherein the modulation of activation of the CB2 receptor is via modulation of an interaction of the THC with the CB2 receptor.

[0084] According to some embodiments of the method, the physiological or psychological function is a pathological physiological or a psychological function comprising abnormal CB2R activity.

[0085] According to some embodiments of the method, the physiological or psychological function is a condition selected from the group consisting of pain, immune system related function, inflammation, fibrosis, sclerosis, bone structure, autoimmune diseases, cardiovascular function, gastrointestinal function, liver function, kidney function, neurodegenerative, psychiatric, skin disorders, lung function, cancer, addiction in and combinations thereof in a human subject.Examples

[0086] Materials and MethodsMaterials

[0087] THC was extracted from a THC-rich cannabis chemovar, using an authorized EU- GMP (European Good Manufactory Practice) extraction process at Bazelet manufacturing plant (Or Akiva, Israel) and verified by a validated High Performance Liquid Chromatography (HPLC) analysis (HPLC Waters PDA 2996, equipped with a pump, autosampler, column-oven, and a Photodiode Array detector (PDA) detector).

[0088] Purified terpenes were purchased from Vigon International Inc. (Pennsylvania, USA. a-pinene (natural, 98.2%), P-pinene (natural, 94%) limonene-D (natural, 99%), myrcene (natural, 95.5%), ocimene (Trans, natural, 69.3%) sabinene (natural, 76.67%), terpinolene (natural, 92.6%), borneol (natural, 59.9%), eucalyptol (natural, 100%), geraniol natural (97%), linalool (racemic mixture, 100%), terpineol (natural, 98%), P-caryophyllene (natural, 88.4%), humulene (natural, 91.6%), bisabolol (natural, 98.5%) and nerolidol (natural, 99%).

[0089] Solution preparations were made based on the method disclosed in Raz et al (Biochem Pharamacol. 2023) for studying THC and terpenes activity at CB1. Herein, CB2 receptors were expressed on isolated female adult X. laevis oocytes. CB2 responses were evaluated by measurement of K+ current levels. See detailed description in Raz et al (Biochem. Pharamacol. 2023).

[0090] For all experiments, 10 pM was taken as the highest THC concentration, as dictated by solubility limit. The response to 10 p M THC was measured as a reference value, and all recording were normalized to this value. Terpene concentrations used varied according to their solubilities, CB2 responses to 7 terpene concentrations of between 10 nM and 5 mM were measured for terpenes of higher solubility: borneol, eucalyptol, geraniol, linalool, and terpineol. Responses to 4 terpene concentrations of between 10 nM and 10 pM were measured for terpenes of lower solubility: a-pinene, P-pinene, limonene, myrcene, ocimene, sabinene, terpinolene, bisabolol and nerolidol. Responses to 4 terpene concentrations of between 10 nM and 300 nM were measured for terpenes of very low solubility: P-caryophyllene and humulene.

[0091] The responses evoked in a specific oocyte by either THC and\or terpenes measurements, were normalized to the reference value of 10 pM THC at this specific oocyte.Statistical analysis

[0092] Statistical analysis was made based on the method disclosed in Raz et al (Biochem. Pharamacol. 2023),Results

[0093] The effects of terpenes on CB2 receptor activation and on THC-induced CB2 receptor activation were assessed. Sixteen cannabis terpenes were studied, including: a-pinene, P-pinene, limonene, myrcene, ocimene, sabinene and terpinolene (monoterpenes, hydrocarbons consisting of two isoprene units, having the molecular formula of C10H16), borneol, eucalyptol, geraniol, linalool and terpineol, (monoterpenoids, oxygen-containing monoterpenes, C10H18O), P-caryophyllene and humulene (sesquiterpenes, hydrocarbons consisting of three isoprene units, C15H24), bisabolol and nerolidol (sesquiterpenoids, oxygen-containing sesquiterpenes, C15H26O).

[0094] Terpene-derived CB2 activations are presented in FIGs. 1A to IE (for borneol, eucalyptol, geraniol, linalool and terpineol, respectively); and 2 A to 2H (for sabinene, terpinolene, beta-caryophyllene, bisabolol, ocimene, limonene, myrcene and nerolidol, respectively), depicting DR curves of the various terpenes. The responses to each of the terpenein each experiment was normalized to the response evoked by 10 pM THC in the same oocyte, taken to be 1. As seen, CB2 receptor activity is detected for all terpenes. The response to the highest terpene concentration used ranged between 15% and 56% of the response amplitude obtained by the reference 10 pM THC.

[0095] To study terpene effects on the THC-activated CB1 receptor response, the CB1 receptor activation by THC alone was compared to its activation by the same THC concentrations, each supplemented with terpene at a weight / weight ratio of 1 / 10. Results are presented in FIGs. 3A to 3E for alpha-pinene, bisabolol, beta-caryophyllene, linalool and limonene, respectively.

Claims

CLAIMS1. A composition comprising at least one terpene for use in modulation of a physiological or psychological function via at least one selected from the group consisting of agonism of a cannabinoid type 2 receptor (CB2R), antagonism of CB2R, modulation of agonism of a CB2R, modulation of antagonism of a CB2R and combinations thereof.

2. The composition for use of claim 1, wherein said physiological or psychological function is a pathological physiological or a psychological function comprising abnormal CB2R activity.

3. The composition for use of claim 2, wherein said pathological physiological or psychological function is a condition selected from the group consisting of pain, immune system related function, inflammation, fibrosis, sclerosis, bone structure, autoimmune diseases, cardiovascular function, gastrointestinal function, liver function, kidney function, neurodegenerative, psychiatric, skin disorders, lung function, cancer, addiction and combinations thereof.

4. The composition for use of any one of claims 1 to 3, wherein said modulation of agonism of said CB2R and / or said modulation of antagonism of said CB2R comprises modulation of an interaction between said CB2R and an agonist or an antagonist of said CB2R.

5. The composition for use of any one of claims 1 to 4, further comprising at least one CB2R agonist or at least one CB2R antagonist, at a total terpene to total agonist or antagonist weight / weight ratio in the range between 0.05:1 and 1:1.

6. The composition for use of any one of claims 1 to 4, for co-administration with at least one CB2R agonist or at least one CB2R antagonist, at a total terpene to total agonist or antagonist weight / weight ratio in the range between 0.05:1 and 1:1.

7. The composition for use of claim 5 or claim 6, wherein said agonist comprises tetrahydrocannabinol (THC).

8. The composition for use of claim 7, wherein said THC is present at a dosage of from about 1 to about 100 mg.

9. The composition for use according to any one of claims 1 to 8, for administration to a subject at a dosage resulting in a concentration of up to about 10 mM of said terpene in the plasma and or serum of said subject.

10. The composition for use according to any one of claims 1 to 9, wherein said terpene is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof.

11. The composition for use according to any one of claims 1 to 9, wherein said terpene is selected from the group consisting of alpha pinene, beta pinene, beta caryophyllene, bisabolol, humulene, nerolidol, limonene, terpineol, geraniol, humulene, myrcene, ocimene, terpinolene, borneol, linalool, sabinene, eucalyptol and combinations thereof.

12. The composition for use according to any one of claims 7 to 11, for co-administration with said THC in a single dosage form.

13. The composition for use according to any one of claims 7 to 11, for administration in a separate dosage form from said THC.

14. The composition for use according to claim 13, wherein said terpene is for administration prior to administration of said THC.

15. The composition for use according to claim 13, wherein said terpene is for administration subsequent to administration of said THC.

16. The composition for use according to claim 13, wherein said terpene is for administration within 2 hours of administration of said THC.

17. The composition for use according to any one of claims 1 to 16, wherein said terpene is provided in the form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.

18. The composition for use according to any one of claims 7 to 17, wherein said THC is provided in a form suitable for sublingual, oral, buccal, nasal, dermal, transdermal, or inhaled administration.

19. The composition for use according to any one of claims 1 to 18, wherein said THC is provided in a form selected from the group consisting of a solid, a vapor, an aerosol and a liquid.

20. The composition for use of claim 4, wherein said modulation of said interaction between said CB2R and said agonist or said antagonist of said CB2R is selected from the group consisting of an allosteric modulation, an orthosteric modulation and a combination thereof.

21. A method of modulating a physiological or psychological function in a subject via at least one selected from the group consisting of agonism of a cannabinoid type 2 receptor (CB2R), antagonism of CB2R, modulation of agonism of a CB2R, modulation of antagonism of a CB2R and combinations thereof, the method comprising administering to the subject at least one terpene.

22. The method of claim 21, wherein said modulation of agonism of said CB2R and / or said modulation of antagonism of said CB2R comprises modulation of an interaction between said CB2R and an agonist or an antagonist of said CB2R.

23. The method of claim 21, further comprising administering at least one CB2R agonist or at least one CB2R antagonist, at a total terpene to total agonist or antagonist weight / weight ratio in the range between 0.05:1 and 1:1.

24. The method of claim 22, wherein said agonist comprises tetrahydrocannabinol (THC).

25. The method of claim 24, wherein said THC is administered at a dosage of from about 1 to about 100 mg THC.

26. The method of claim 21, wherein said terpene is administered at a dosage resulting in a concentration of up to about lOmM of said terpene in the plasma and or serum of said subject.

27. The method of claim 21, wherein said terpene is selected from the group consisting of alpha pinene, beta pinene, linalool, limonene, bisabolol, beta caryophyllene, ocimene, borneol, terpineol and combinations thereof.

28. The method of claim 21, wherein said terpene is selected from the group consisting of alpha pinene, beta pinene, beta caryophyllene, bisabolol, humulene, nerolidol, limonene, terpineol, geraniol, humulene, myrcene, ocimene, terpinolene, borneol, linalool, sabinene, eucalyptol and combinations thereof.

29. The method of claim 24, wherein said terpene and said THC are administered in a single dosage form.

30. The method of claim 24, wherein said terpene and said THC are administered in separate dosage forms.

31. The method of claim 30, wherein said terpene is administered prior to administration of said THC.

32. The method of claim 30, wherein said terpene is administered subsequent to administration of said THC.

33. The method of claim 30, wherein said terpene is administered within 2 hours of administration of said THC.

34. The method of claim 21, wherein said terpene is administered in the form of a vapor or an aerosol.

35. The method of claim 24, wherein said THC is administered sublingually.

36. The method of claim 21, wherein said terpene is administered in a liquid form.

37. The method of claim 22, wherein said modulation of said interaction between said CB2R and said agonist or said antagonist of said CB2R is selected from the group consisting of an allosteric modulation, an orthosteric modulation and a combination thereof.

38. The method of claim 21, wherein said physiological or psychological function is a pathological physiological or a psychological function comprising abnormal CB2R activity.

39. The method of Claim 38, wherein said pathological physiological or psychological function is a condition selected from the group consisting of pain, immune system related function, inflammation, fibrosis, sclerosis, bone structure, autoimmune diseases, cardiovascular function, gastrointestinal function, liver function, kidney function, neurodegenerative, psychiatric, skin disorders, lung function, cancer, addiction and combinations thereof.

Images