Combination therapy for amelioration of side effects of estrogen receptor inhibitor treatment

Abstract

The present invention provides a combination therapy useful in ameliorating the severe and debilitating side effects prevalent in patients receiving treatment with estrogen receptor inhibitors. The combination therapy includes the administration of 3,4,5-trimethoxyphenethylamine or a pharmaceutically acceptable salt or derivative thereof in conjunction with an estrogen receptor inhibiting agent.

Description

[0001] COMBINATION THERAPY FOR AMELIORATION OF SIDE EFFECTS OF ESTROGEN RECEPTOR INHIBITOR TREATMENT

[0002] FIELD OF INVENTION

[0003]

[0001] The present invention provides a combination therapy useful in ameliorating the severe and debilitating side effects prevalent in patients receiving treatment with hormonal therapy drugs, in particular estrogen receptor inhibitors. The combination therapy includes the administration of 3,4,5-trimethoxyphenethylamine or a pharmaceutically acceptable salt thereof, analogs thereof, and derivatives thereof to an individual, in conjunction with an estrogen receptor inhibiting agent.

[0004] BACKGROUND OF THE INVENTION

[0005]

[0002] Estrogen is a sex hormone that plays a key role in the development and regulation of the female reproductive system. In normal cells, estrogen binds either estrogen receptor alpha or beta (ERa or ER[3), leading to ligand-activated signaling. In the absence of estrogen, the estrogen receptors remain in an inactive form. However, in the presence of estrogen, the receptors undergo a conformational change and form a dimerization complex that is translocated to the nucleus. In ER-related diseases including cancer, estrogen stimulates cell growth and further development by enhancing expression of genes related to cell proliferation and survival.

[0006]

[0003] Accordingly, the predominant treatment strategy of ER-related diseases aims at inhibiting ERa activation by multiple inhibitors (endocrine therapy). These inhibitors, termed herein as estrogen receptor-modulating pharmaceutical agents are divided into three categories based on their mechanism of action: (i) Aromatase Inhibitors (AIs) that inhibit estradiol biosynthesis; (ii) Selective Estrogen Receptor Degraders (SERDs) that bind to ERa causing its degradation; and (iii) Selective Estrogen Receptor Modulators (SERMs) that function as antagonists by competing with estradiol for binding.

[0007]

[0004] There are several types of SERMs, the most prominent one being tamoxifen, which was listed by the World Health Organization as an essential drug for breast cancer treatment. Tamoxifen is also being used for the prevention of cancer in women at high risk of developing breast cancer which are estrogen-receptor positive (ER+). Tamoxifen is administered in doses of 10 or 20 mg of tamoxifen citrate per individual dose. Following surgery for tumor removal, breast cancer patients are required to complete daily tamoxifen treatment for at least 5 years. However, there is known to be poor adherence to tamoxifen treatment predominantly due to adverse effects which include hot flashes, pain, nausea, fatigue, constipation, loss of libido, weight gain, vaginal dryness, abnormal discharge and bleeding, and mental issues such as depression, irritability, and negative mood. Patients younger than 50 or that were pretreated with hormonal therapy are more likely to report severe adverse effects.

[0008]

[0005] The ER targeted by an estrogen receptor modulating pharmaceutical agent is a ligand-activated transcriptional regulatory protein that mediates induction of a variety of biological effects through its interaction with endogenous estrogens. The main classes of naturally occurring estrogens in women are estrone, estradiol, estriol and estetrol. In some embodiments the ER is one of two isoforms, ERa or ERP

[0009]

[0006] Mescaline (3,4,5-trimethoxyphenethylamine) is a ring- substituted amphetamine - a central nervous system (CNS)-activating compound belonging to the phenethylamine drug family, which includes a range of substances that possess stimulating and\or hallucinogenic properties. Mescaline is one of several hallucinogenic alkaloids derived from Lophophora williamsii (the Peyote plant) and is also found in several other cacti including the Echinopsis pachanoi (San Pedro), two plants that have been used in ritualistic and religious ceremonies for 8000 years mostly across north and south America. Similar to the other classic psychedelics, mescaline is a nonselective serotonin receptor agonist (Kovacic and Somanathan, Oxidative Medicine and Cellular Longevity 2:4, 181-190, 2009), specifically, 5HT2A / 2C- It is unclear how activating the 5-HT2A receptor leads to the quasipsycho tic and altered perception state characterizing psychedelia, but it likely involves excitation of noradrenergic neurons in the locus coeruleus and areas of the prefrontal cortex where hallucinogens exert their most prominent effects. In addition to serotonin receptor activity, mescaline also affects other neuroreceptors by acting on dopaminergic Dl / 2 / 3 and adrenergic alA / 2A receptors (Vamvakopoulou et al., Neuropharmacology 222, 109294, 2023). However, it is unclear whether mescaline possesses dopamine receptor agonist properties or initiates the release of dopamine. Various methods of extraction have been published.

[0007] Mescaline is rapidly absorbed from the gastrointestinal tract and onset of effect may be observed within 30 minutes of ingestion. The highest psychedelic effect may be achieved within 2 hours of ingestion, but the effect may last as long as 8 hours. The plasma half-life of mescaline is approximately 6 hours. Although mescaline has the lowest potency among naturally occurring hallucinogens (30 times less potent than psilocybin), a full dose (200-400 mgs) has a long duration of action. Higher dosage of mescaline is needed to produce the psychedelic effect not only due to weak potency of mescaline as a hallucinogen but also due to the polar nature of the mescaline molecule. Because of poor lipid solubility, mescaline does not easily pass the bloodbrain barrier. Although mescaline is metabolized by liver enzymes, approximately 87% of ingested dosage is excreted in urine within 24 hours while 92% is excreted within 48 hours. A small amount of mescaline is oxidatively deaminated into 3,4,5- trimethoxyphenyacetic acid. Another minor metabolite of mescaline in human is 3,4- dimethoxy-5-hydroxyphenyethylamine.

[0010]

[0008] There is an unmet need for pharmaceutical compositions suitable for treating diseases related to ER with a minimal side-effect profile which allows for adherence to treatment.

[0011] SUMMARY OF THE INVENTION

[0012]

[0009] The present invention relates to the amelioration of side effects associated with treatment with hormonal therapy drugs, in particular an estrogen-receptor modulating pharmaceutical agent. The present invention provides a combination therapy comprising: an estrogen receptor modulator in conjunction with 3,4,5- trimethoxyphenethylamine (mescaline). The invention is based in part on the surprising benefit of the combination therapy in reducing the severity of the side effects of the estrogen-receptor modulating pharmaceutical agent, whilst still maintaining its indicated therapeutic efficacy.

[0013]

[0010] The estrogen receptor modulator compounds for use in the combination therapy described herein are any pharmaceutical agent which effectively reduces the activity or levels of circulating estrogen, including but not limited to: aromatase inhibitors (e.g. letrozole, anastrozole and exemestane), selective estrogen receptor down-regulators (SERDs, e.g. fulvestrant) and selective estrogen receptor modulators (SERMs, e.g. tamoxifen and raloxifene), together with mescaline in a subpsychoactive dose.

[0014] [Oi l] According to one aspect, there is provided a method for treating a subject afflicted with an ER-related disease, the method comprising administering to the subject a combination therapy of an estrogen receptor modulating agent and mescaline, thereby treating the subject afflicted with an ER-related disease whilst ameliorating the side effects characterizing sole treatment with an estrogen receptor modulating pharmaceutical agent.

[0015]

[0012] In some embodiments, the patient population targeted for treatment with this invention’s combination therapy, is characterized by a diagnosis of any estrogen- related disease that requires treatment with an estrogen receptor modulating pharmaceutical agent. In some instances, the estrogen related disease is selected from the group consisting of: breast cancer, ovarian cancer, prostate cancer, colon cancer, and endometrial cancer. Each of these is considered a separate embodiment of the invention. In other embodiments the disease being treated with an estrogen receptor modulating pharmaceutical agent is selected from the group consisting of: polycystic ovary syndrome, endometriosis, uterine leiomyomas or fibroids, cardiovascular disease, autoimmune disease. Each of these is considered a separate embodiment of the invention. In a particular embodiment the estrogen related disease is estrogen receptor positive breast cancer.

[0016]

[0013] In some embodiments the patients receiving the combination therapy, i.e., with an anti-estrogen and mescaline are pre-menopausal women. In other embodiments patients receiving the combination therapy are post-menopausal women. In additional embodiments, the patients receiving the combination therapy are men with a hormonal abnormality. In some embodiments the patients are candidates for endocrine therapy as complementary to surgical procedures from the group consisting of oophorectomy, adrenalectomy, hypophysectomy. In some embodiments, said endocrine therapy comprises ovarian function suppression, selective estrogen receptor modulators (SERMs), selective estrogen receptor down-regulators (SERDs) and aromatase inhibitors.

[0014] In some embodiments, the estrogen receptor modulator is a selective estrogen degrader (SERD). In some embodiments the estrogen receptor modulator is a selective estrogen receptor modulator (SERM).

[0017]

[0015] In some embodiments, the estrogen receptor modulator is selected from the group consisting of tamoxifen, raloxifene and fulvestrant. In some embodiments, the aromatase inhibitors are letrozole, anastrozole and exemestane. Exemestane is used in women who have already received tamoxifen.

[0018]

[0016] In some embodiments, the present invention provides for a combination therapy, by administering mescaline, a salt of mescaline, analogs or derivatives thereof to a subject, and ameliorating side effects which are known to be associated with the consumption of an estrogen-receptor modulating pharmaceutical agent. According to some embodiments the derivative may be devoid of psychoactivity. According to some embodiments the derivative may have increased bioavailability. According to alternative embodiments the derivative may have improved pharmacokinetics with an increased half-life. According to yet other embodiments the derivative may have altered metabolism providing improved pharmacodynamics.

[0019]

[0017] The pharmaceutical composition disclosed herein is useful for ameliorating the side effects resulting from treatment with an estrogen receptor-modulating pharmaceutical agent in combination with mescaline or salts and derivatives thereof in sub-psychoactive doses. In accordance with these embodiments, there is provided a method of ameliorating the side effects resulting from treatment with an estrogen receptor-modulating pharmaceutical agent in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition of mescaline in a sub-psychoactive dose in combination with at least one estrogen receptor-modulating pharmaceutical agent.

[0020]

[0018] In some embodiments, a single dosage form contains both active agents of the combination therapy. In other embodiments, the individual agents may be administered separately.

[0021] BRIEF DESCRIPTION OF THE FIGURES

[0022] Figure 1. The molecular structure of mescaline sulfate. Figure 2. Tabulated summary of estrogen receptor modulating agents, their usages, patient population, side effects, effectiveness, adherence rate, and main reasons for non-adherence to treatment protocols.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024]

[0019] The present invention is directed to the use of mescaline, as well as salts thereof or derivatives thereof as adjunctive therapy that is capable of reducing or eliminating the side effects that may cause cessation or non-compliance with antiestrogen therapies.

[0025]

[0020] Figure 2 present a tabulated summary of estrogen receptor modulators, their usages, patient population, side effects, effectiveness, adherence rate, and main reasons for non-adherence to treatment protocols. The more common side effects of tamoxifen and other estrogen receptor modulators are hot flashes, night sweats, vaginal discharge, irregular periods in premenopausal women, general feeling of tiredness or weakness. The more common side effects of aromatase inhibitors are joint and muscle pain, hot flashes, night sweats, vaginal dryness or irritation and tiredness.

[0026]

[0021] In some embodiments, the composition comprising mescaline comprises or consists of dried plant matter. In alternative embodiments, the composition comprising mescaline comprises or consists of a plant extract.

[0027]

[0022] As used herein, the term “extract” includes the whole extract, a fraction thereof, a portion thereof, an isolated compound therefrom, or any combination thereof.

[0028]

[0023] In some embodiments, the extract is derived from a fresh plant material. In some embodiments, the plant material is first dried and then extracted. In some embodiments, the plant material is air-dried. In some embodiments, the plant material is further heat treated (e.g., hot drying) and then extracted.

[0029]

[0024] In some embodiments, the extraction comprises at least one of organic solvent extraction, carbon dioxide (dry ice) extraction, supercritical and subcritical carbon dioxide extraction, hydrocarbon extraction, rosin press, or a combination thereof. Each possibility represents a separate embodiment. In some embodiments, the extraction is a solvent-based extraction. In some embodiments, the solvent is a polar solvent. As used herein, a polar solvent includes, but is not limited to, ethanol and isopropyl alcohol. In some embodiments, the solvent is a non-polar solvent. In some embodiments, the extraction is a solvent-free extraction.

[0030]

[0025] In other embodiments, alternative methods of extraction or synthesis can be used. In one embodiment, the synthetic process begins with a solution of 3,4,5- trimethoxybenzaldehyde, nitromethane and cyclohexylamine combined with acetic acid, which is then heated and diluted to allow for the formation of a crystalline mass. Subsequent steps include filtration, washing with H2O and dehydration, following which is recrystallization by boiling MeOH. In other embodiments nitromethane can be used as solvent as well as reagent. In other embodiments, a refluxing suspension of LAH in Et2O can be used, adding P-nitro-3,4,5-trimethoxystyrene as a saturated Et2O solution by use of a modified Soxhlet extraction condenser. In other embodiments, a synthetic form of mescaline is manufactured in laboratory conditions using methods known in the art.

[0031]

[0026] In some embodiments, any alkaloid derivative or 3,4,5- trimethoxyphenethylamine analog with the same pharmacokinetic and physiological characteristics is used as a replacement for mescaline in the combination therapy. In other embodiments the analog may have improved pharmacokinetic or physiological characteristics.

[0032]

[0027] In some embodiments, the Echinopsis pachanoi derived substance used in the compositions and methods as described herein includes the compound of the invention. In one embodiment, the composition described herein comprises a purified or substantially purified (e.g., greater than 80% w / w, 85% w / w, 90% w / w, 95% w / w, or 97% w / w) compound of the invention. In some embodiments of the methods described herein, the purified or substantially purified (e.g., greater than 80% w / w, 85% w / w, 90% w / w, 95% w / w, or 97% w / w) compound of the invention is administered to a subject suffering from side effects induced by an estrogen receptor modulating pharmaceutical agent as described herein.

[0033] Delivery Routes and Administration Terms

[0034]

[0028] The compositions of the invention can be delivered by various routes of administration with enteral routes of delivery preferred.

[0029] The term "route of administration" in the present disclosure refers to the path or delivery route or location by which said combination therapy is taken into the body. Routes of administration refer to oral, gastrointestinal, intraoral (sublingual, buccal), transdermal, topical, intranasal, inhalation, nebulization, vaporization, ocular, vaginal, rectal, injection (intravenous, intramuscular, subcutaneous), transmucosal, among other routes of administration.

[0035]

[0030] The terms "gastrointestinal delivery" and gastrointestinal delivery systems" in the present disclosure refer to delivery systems designed to deliver said combination therapy, and other orally administered active ingredients to the intestinal mucosa for absorption into the bloodstream. The oral route is by far the most common route of mescaline administration.

[0036]

[0031] The terms "buccal delivery" and "buccal delivery systems" in the present disclosure refer to delivery systems designed to deliver said combination therapy, by intraoral delivery across the buccal mucosa (the epithelium lining of the cheeks, gums, and lips) into the bloodstream. Effective buccal delivery systems require a mucoadhesive agent to increase mucosal retention time and absorption.

[0037]

[0032] The terms "sublingual delivery" and "sublingual delivery systems" in the present disclosure refer to delivery systems designed to deliver combination therapy, by intraoral delivery across under the tongue into the bloodstream. Effective sublingual delivery systems require a mucoadhesive agent to increase mucosal retention time and absorption before salivary washout carries the active ingredients into the stomach.

[0038]

[0033] The terms "intranasal delivery" and "intranasal delivery systems" in the present disclosure refer to delivery systems designed to deliver combination therapy, across nasal mucosa into the bloodstream. Intranasal delivery includes direct nose-to- brain delivery systems along the olfactory and trigeminal that bypass the restrictive blood-brain barrier preventing most substances from entering the brain. Effective intranasal delivery systems require a mucoadhesive agent to increase mucosal retention time and absorption, and prevent ciliary motion carrying active ingredients into the stomach.

[0039] Pharmacology and Pharmacokinetic Terms

[0034] The term "dosage form" in the present disclosure refers to the physical form of a dose of a combination therapy, including any chemical compound used as a drug, or medication intended for administration or consumption. Dosage forms comprise pills, tablets, capsules, oral suspensions, tinctures, emulsions, liquid drinks, powders, gels, creams, lotions, liniments, sprays, suppositories, crystals, aerosols, vaporization, liquid injections, transdermal liquids or gels or patches, eye drops, eye gels, eye ointments, nasal sprays, nasal gels, nasal solutions, oral strips, mucoadhesive buccal or sublingual compositions, among many others in the present disclosure. The route of administration delivery is dependent on the dosage form of the substance.

[0040]

[0035] The term "effective dose" in the present disclosure refers to a dose or concentration of combination therapy, or bioactive substance that produces a biological response.

[0041]

[0036] The term "liquid dosage form" in the present disclosure refers to a solution, suspension, multiphase dispersion, syrup, gel, emulsion, nanoemulsion, liquid nanostructure, reconstituted powder, liquid preparation, liquid composition, liquid drug formulation, and liquid drug preparation.

[0042]

[0037] The term " bioactive substance" in the present disclosure refers to a substance or compound or molecules having an effect on, or causing a reaction, or triggers a response in living tissue or on a living organism, presenting therapeutic potential.

[0043]

[0038] Degradation poses a greater challenge for natural product drugs derived through extraction techniques from natural sources. During the extraction process, the bioactive compounds can degrade in different aqueous and ethanol solutions, as fluid solutions, dispersions, tinctures, emulsion, and powdered extractions. They can degrade in current delivery dose forms after manufacturing, during storage, and before use.

[0044]

[0039] Provided in this disclosure are compositions and methods of using mescaline in stable drug dosage form for amelioration of side effects of therapy with estrogen receptor inhibitors. In some embodiments, the pharmaceutical composition comprises mescaline or a salt thereof. In another embodiment, the mescaline is a mescaline salt selected from a group of pharmaceutically acceptable salts comprising: sulfate, hydrochloride, maleate, fumarate, acetate, citrate, hydrogen citrate, and dihydrogen citrate. In some exemplary embodiments, the pharmaceutical composition comprises mescaline sulfate.

[0045]

[0040] In some embodiments of this disclosure, the pharmaceutical compositions of the mescaline and the estrogen receptor inhibitor may be individual dosage forms that are administered separately. In other embodiments of the disclosure the mescaline and the estrogen receptor inhibitor may be administered in a single combined dosage form. The pharmaceutical compositions are intended for oral administration and may be selected from tablets, capsules, dragees, powders, suspensions of any other dosage form for oral administration.

[0046]

[0041] The formulations of the active agents may be selected from a group consisting of: nanoparticles, a lipid or polymer structure, an emulsion, or nanoemulsion, or microemulsion, or self-forming nanoemulsion, or self-forming microemulsion, a film system, a microparticle, a dendrimer system.

[0047]

[0042] In some embodiments of this disclosure, the excipients are selected from pharmaceutically acceptable carriers or diluents. In some embodiments the excipients are selected from the group consisting of an organic acid, an antioxidant, a lipid, a phospholipid, a polymer, a chelation agent, a preservative compound, a nanoparticle structure, a hydrogel, an organogel, a micelle, a reverse micelle, a nanoparticle lipid composition, a nanoemulsion, an emulsion.

[0048]

[0043] The term “therapeutically effective amount” as used herein refers to the amount that achieves the targeted biological activity following the administration of the desired dosage.

[0049]

[0044] In some embodiments, the present invention provides for combination therapy of mescaline with one of the following therapies: (a) Aromatase Inhibitors (AIs) that inhibit estradiol biosynthesis; (b) Selective Estrogen Receptor Degraders (SERDs) that bind to ERa causing its degradation; and (c) Selective Estrogen Receptor Modulators (SERMs) that function as antagonists by competing with estradiol for binding. Mescaline or a derivative thereof is used to reduce the unwanted side effects of the above types of therapies. The beneficial effect of mescaline or mescaline derivative may be mediated by its activity on various types of receptors including 5-HT2A / 2C, the dopaminergic D 1 / 2 / 3 and adrenergic alA / 2A.

[0045] In some embodiments, the pharmaceutical composition comprises from 0.1- 100s mg of mescaline or a salt thereof. In additional embodiments the dose of mescaline will be 1-40 mgs. In exemplary embodiments the dose of mescaline will be 2-20 mgs. In principle, the doses of mescaline being used will be below the threshold of psychoactivity, termed herein as a sub-psychoactive dose, which is generally a dose up to 100 mg.

[0050]

[0046] The mescaline may be selected from dried plant material or a selective extract from the plant material. As disclosed herein the dried plant material may have a slower onset of activity and a longer duration of activity. The isolated extract with at least partially purified mescaline has a rapid onset of activity and a shorter duration of action. Without wishing to be bound by any theory of mechanism of action it is postulated that the plant matter may contain additional activities that affect the pharmacokinetics of mescaline.

[0051]

[0047] According to the subject being treated the composition may be ingested once daily or several times daily if necessary. The period of treatment may be continuous or at intervals as required. The initial dose may be increased as necessary in order to achieve the reduction or elimination of side effect of the estrogen receptor modulator. The objective is to allow the subject to continue the therapy with the estrogen receptor pharmaceutical agent as prescribed. The combination therapy enhances patient compliance.

[0052]

[0048] In some embodiments, the pharmaceutical composition may comprise both the estrogen modulating agent and mescaline. For example, such a combination drug formulation may comprise 10-20 mgs of tamoxifen.

[0053]

[0049] In some embodiments, the pharmaceutical composition comprises from 2-20 mgs of mescaline or a salt thereof and 10-20 mgs of tamoxifen.

[0054]

[0050] In some embodiments, the present invention provides for a combination therapy, by administering mescaline, a salt of mescaline, analogs thereof, or derivatives thereof to a subject, and ameliorating side effects which are known to be associated with the consumption of an estrogen-receptor modulating pharmaceutical agent. According to some embodiments the derivative may be devoid of psychoactivity. According to some embodiments the derivative may have increased bioavailability. According to alternative embodiments the derivative may have improved pharmacokinetics with an increased half-life. According to yet other embodiments the derivative may have altered metabolism providing improved pharmacodynamic s .

[0055]

[0051] The following examples are presented in order to illustrate some embodiments of the invention more fully. They should, in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

[0056] EXAMPLES

[0057] Materials and Methods

[0058] Example 1: Dried plant matter

[0059]

[0052] Selective isolation of active compounds including 3,4,5- trimethoxyphenethylamine, or additional alkaloids, from the Echinopsis pachanoi plant is conducted using a preliminary step of separating the plant’s outer skin, then removing only the first 2-3 mm of the plant’s flesh where most of the chlorophyll and active ingredients are typically found. This plant material is dehydrated at 70°C until less than 10% moisture is achieved, then the dried plant material is powdered. The powdered matter may be encapsulated or used as a source for extraction.

[0060] Example 2: Extraction and purification of active compounds from Echinopsis pachanoi plant

[0061]

[0053] Dried plant matter of Example 1 is extracted as follows: Alkaline water prepared by adding 25 gr of calcium hydroxide (Ca(OH)2) to 250 ml of DDW in order to break down the plant cell and raise the molecule above its baseline pKa (9.56) to ensure its solubility in water. The procedure is performed batchwise, e.g., 100 gr of dry plant powder is added in small portions while mixing thoroughly over several minutes. The mixture is pressure cooked for 40 minutes in order to cause further chlorophyll saponification. 200 gr of ethyl acetate is mixed gently into the paste for 2 minutes, then allowed to rest for an additional 2 minutes. Free solvent is separated from plant biomass, filtered with Whatman filter paper, and collected to a separate container. This procedure is repeated for 5 more times but with 125 gr solvent portions. Crystallization of the freebase mescaline from the solvent is done by adding 200 pl of 98% sulfuric acid (H2SO4) (acid volume varies depending on plant alkaloidal content) while stirred with a magnetic stirrer at 300 rpm. Clear solution turns pearl silver after a few seconds, due to mescaline sulfate precipitation. Mixing is stopped after 5 minutes, then larger clusters start to appear and sink to the bottom. Separation of the solids is conducted by using Buchner funnel, followed by the evaporation of the crystalline precipitate at 90°C for 24h. Crystals are resolubilized with 200 ml of DDW, adjusted to pH 7 using 34% ammonia solution (NH3) and adding 1 g of powdered activated carbon, mixed, boiled and let rest for 12 h. This removes possible organic compounds and excess ammonia. After separation of the aqueous solution, assumed to contain mostly mescalin sulfate but also some other trace amounts of unwanted non-polar alkaloids and ammonium sulfate, the solution is slowly evaporated at 90°C to the point of saturation, where mescaline sulfate crystals start to precipitate. Solution is topped with 10 ml DDW to resolubilize precipitants, and throughout the time course of 24 h solution temperature is decreased down to 4°C. This causes mescaline sulfate to loss its aqueous solubility and recrystallize into large white crystals. Crystals that precipitate from this solution are clear, needle like shapes that range between 0.1 to 10 cm long. The slower the temperature drop is, the larger the crystals are. Crystals are collected, washed with ice cold DDW to remove polar pollutants, then with ice cold acetone to remove other possible non-polar compounds, then dehydrated and stored at dry place in room temperature. Purity was not measured by any analytical device, but it is assumed to be of relatively high degree due to the formation of perfectly shaped crystals which are not formed readily in the presence of contaminations.

[0062] Example 3: Evidence of mescaline amelioration of symptoms

[0063]

[0054] A volunteer undergoing tamoxifen therapy at a dose of 20 mg / day (manufacturer: Teva), complained of severe side effects from the drug after several days of treatment with the drug. After one month the volunteer began taking 2 capsules / day containing 0.4 g of the powdered dried plant matter for a duration of 4 days, then raised the dosage to 4 capsules / day for another 3 days.

[0064]

[0055] The following week the same volunteer took one capsule / day containing 20 mg of the selective plant extract, i.e., mescaline sulfate crystals, for 7 days.

[0065]

[0056] She reported a complete halt in tamoxifen side effects from which she had suffered initially, namely: cramps and pain in the uterus and ovaries, hot flashes, mood swings, lack of appetite, hair loss and lack of concentration. The physical improvement was as follows: in the first 4 days of capsules ingestion, consumption was 1 hour after tamoxifen capsules ingestion, the tamoxifen side effects disappeared for several hours and then returned. By increasing the amount from 2 capsules to 4, the symptoms completely disappeared for the duration of the day. Even further improvement reported with the single 20 mg capsule of the selective plant extract, showing a 24-hour coverage in the disappearance of side effects. Following these 14 days, the volunteer felt no more tamoxifen related side effects.

[0066] Example 4: Evidence of mescaline amelioration of symptoms after 3 months

[0057] After 3 months the same volunteer reported the recurrence of side effects and the appearance of new side effects: cramps and pain in the uterus and ovaries, hot flashes, severe pain in the head, especially in the forehead and cheeks. With the onset of these side effects, the volunteer consumed 2 capsules / day for 7 days: one of 0.4 g of dried plant matter and the other of 20 mg of the selective plant extract (containing mescaline sulfate). To obtain better absorption of the active substance, the volunteer consumed the capsules right before sleep so secretion of the un-metabolized molecule by urine was assumed to decrease. All described tamoxifen side effects have disappeared about an hour after capsules ingestion for a duration of 24-hours, and were completely gone after these described 7 days.

[0067] Example 5: Evidence of mescaline amelioration of symptoms after 6 months

[0058] The side effects of tamoxifen have completely disappeared for three consecutive months since their last appearance, the volunteer reports regular consumption of tamoxifen throughout these 3 months with no side effects and no impairment of quality of life.

[0068] Example 6: Evidence of mescaline amelioration of symptoms

[0069]

[0059] A volunteer undergoing letrozole therapy at a dose of 2.5 mg / day, after continuous therapy with the drug alone for one month, is given escalating doses of mescaline containing plant matter or extract. At the first week of treatment, the volunteer is given 1 capsule / day containing 1.0 g of the dried plant matter. At the second week the same volunteer receives a dose of 2 capsules / day containing 1.0 g of the dried plant matter. During the third week the same volunteer receives one capsule / day containing 20 mg of the selective plant extract, i.e., mescaline sulfate crystals. She reports that side effects are gradually eliminated.

[0060] A volunteer undergoing anastrozole therapy at a dose of 1 mg / day, after continuous therapy with the drug alone for one month, is given escalating doses of mescaline containing plant matter or extract. At the first week of treatment, the volunteer is given 1 capsule / day containing 1.5 g of the dried plant matter. At the second week the same volunteer receives a dose of 2 capsules / day containing 1.5 g of the dried plant matter. During the third week the same volunteer receives two capsule / day containing 20 mg of the selective plant extract, i.e., mescaline sulfate crystals. She reports that side effects are gradually eliminated.

[0070]

[0061] A volunteer undergoing fulvestrant therapy monthly at a dose of 500 mg, after continuous therapy with the drug alone for one month, is given escalating doses of mescaline containing plant matter or extract. At the first week of treatment, the volunteer is given 1 capsule / day containing 1.5 g of the dried plant matter. At the second week the same volunteer receives a dose of 2 capsules / day containing 1.5 g of the dried plant matter. During the third week the same volunteer receives two capsule / day containing 20 mg of the selective plant extract, i.e., mescaline sulfate crystals. She reports that side effects are gradually eliminated.

[0071]

[0062] A volunteer undergoing exemestane therapy at a dose of 25 mg / day, after continuous therapy with the drug alone for one month, is given escalating doses of mescaline containing plant matter or extract. At the first week of treatment, the volunteer is given 1 capsule / day containing 1.0 g of the dried plant matter. At the second week the same volunteer receives a dose of 2 capsules / day containing 1.0 g of the dried plant matter. During the third week the same volunteer receives two capsule / day containing 20 mg of the selective plant extract, i.e., mescaline sulfate crystals. She reports that side effects are gradually eliminated.

[0072]

[0063] A volunteer undergoing raloxifene therapy at a dose of 60 mg / day, after continuous therapy with the drug alone for one month, is given escalating doses of mescaline containing plant matter or extract. At the first week of treatment, the volunteer is given 1 capsule / day containing 1.0 g of the dried plant matter. At the second week the same volunteer receives a dose of 2 capsules / day containing 1.0 g of the dried plant matter. During the third week the same volunteer receives two capsule / day containing 20 mg of the selective plant extract, i.e., mescaline sulfate crystals. She reports that side effects are gradually eliminated. Example 7: General guidelines for dosing

[0073]

[0064] The treatment with mescaline and the estrogen receptor-modulating pharmaceutical agent (i.e., aromatase inhibitors, selective estrogen receptor downregulators and selective estrogen receptor modulators or a combination thereof) is initiated only upon the appearance of side effects associated with receiving the estrogen receptor-modulating pharmaceutical agent, that warrant the addition of mescaline to the therapeutic regimen.

[0074]

[0065] The treatment with mescaline is administered alone or in a combined dosage form.

[0075]

[0066] For example, a specific limited treatment period can be decided for mescaline. In another embodiment, the treatment regimen includes treatment with the therapeutic agent that reduces estrogen levels or activity, either the aromatase inhibitors, selective estrogen receptor down-regulators or selective estrogen receptor modulators in combination with the mescaline.

[0076]

[0067] The amount of a compound that will be effective in the treatment or prevention of a particular disorder or condition, will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the progression of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.

[0077]

[0068] Estrogen receptor-modulating pharmaceutical agent is administered according to current standard of care and as prescribed. However, the administration schedule of mescaline either as a dried plant matter or a selective plant extract will depend on several factors such as the severity of side-effects associated with the estrogen receptor modulator, the patient population, age, weight, etc. For example, for severe side effects the compositions containing the mescaline, either as a plant matter or plant extract, or a combination thereof, can be taken once-daily, twice-daily, or even thrice daily. Treatment of less severe side effects may necessitate a lower frequency of administration once-weekly or bi-weekly. In addition, the administration can be continuous, i.e., every day, or intermittently. The terms "intermittent" or "intermittently" as used herein means stopping and starting at either regular or irregular intervals. For example, intermittent administration can be administration one to six days per week or it may mean administration in cycles (e.g., daily administration as needed, then a rest period with no administration until side-effects resumes) or it may mean administration on alternate days. The different components of the combination can, independently of the other, follow different dosing schedules.

[0078]

[0069] The pharmaceutical composition disclosed herein is useful for ameliorating the side effects resulting from treatment with an estrogen receptor-modulating pharmaceutical agent in combination with mescaline or salts and derivatives thereof in sub-psychoactive doses. In accordance with these embodiments, there is provided a method of ameliorating the side effects resulting from treatment with an estrogen receptor-modulating pharmaceutical agent in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of mescaline in combination with at least one estrogen receptor-modulating pharmaceutical agent. The therapeutically effective amount of the mescaline composition to be administered depends on various factors including, but not limited to, the subject being treated (age and gender) and the severity of sideeffects associated with being treating with estrogen receptor-modulating pharmaceutical agent, etc., and can be determined by the judgment of the prescribing physician. Due to the variability observed among patients, dosages are a guideline only and the physician may adjust doses of the compounds to achieve the level of effective mescaline treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as, but not limited to, the age of the patient and the presence of other diseases or conditions.

[0079] Example 8: Protocol for clinical trials: Mescaline in combination with tamoxifen

[0070] Brief summary: A randomized double-blind early phase trial involving 20-30 women receiving tamoxifen is used to confirm the efficacy, safety of use, and dosage of mescaline in ameliorating tamoxifen side effects. Patients diagnosed with estrogen- receptor positive (ER+) breast cancer, who have taken tamoxifen daily for at least one month are eligible for the trial.

[0080]

[0071] Tamoxifen, at a current standard of care dose, i.e., 20 mg, is administered orally once daily. Mescaline at an escalating dose of 0.1-20 mgs is administered orally daily or several times daily if necessary. The period of mescaline treatment may be continuous or at intervals as required. Mescaline initial dose may be increased as necessary in order to achieve the reduction or elimination of tamoxifen side effects.

[0081]

[0072] Subjects should take their dose at approximately the same time each day. The assessment of side effects of the tamoxifen is recorded by the subjects themselves and reported to the medical staff during each visit scheduled for disease assessment. Any exceptional adverse reactions are reported immediately to the treating physician.

[0082]

[0073] Trial duration: Treatment is continued for at least 6 months or until subject refusal to continue, or termination of participation in the trial from other causes. Subjects who voluntarily stop the study, will be followed for a total of 24 months after discontinuation of study drug.

[0083]

[0074] Evaluation criteria: A questionnaire is applied to subjects to evaluate the effect of using mescaline in ameliorating tamoxifen side effects. The questionnaire includes: personal data; height (m); weight (kg); medical history; previous breast cancer treatment; tamoxifen use duration; tamoxifen side effects; mescaline use duration, and treatment adherence. Adherence is defined as a >80% dosage compliance during the previous month as quantified by pill count. Questionnaire items included yes / no questions on the occurrence of the following tamoxifen side effects: cramps and pain in the uterus and ovaries; hot flashes; mood swings; lack of appetite; lack of concentration; headache. Items also address side effect severity, which is rated on a Likert-type scale based on the Common Terminology Criteria for Adverse Events of the U.S. National Cancer Institute: 1 (mild), 2 (moderate), and 3 (severe) (National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) v5.0.).

[0084]

[0075] Subject inclusion criteria: Subjects must fulfill the following criteria before being included in the study: Female subjects diagnosed with breast cancer which is Estrogen-Receptor-positive (ER2 -positive), Age between 30 and 60 years (inclusive); Tamoxifen daily consumption of at least one month. Ability to provide written informed consent; Ability to swallow oral medications; Subjects must be accessible for treatment and follow-up by questionnaires.

[0085]

[0076] Subject exclusion criteria: Subjects are to be excluded from the study if they display any of the following criteria: Any subject with metastatic disease; Other clinically significant comorbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the subject's participation in the study; Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the protocol- specified treatment; Subjects unwilling or unable to comply with the study protocol; Subjects who are currently being treated with cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).

[0086] Example 9: Protocol for clinical trials: Mescaline in combination with letrozole

[0077] The protocol for clinical trial involving mescaline in combination with letrozole is performed according to example 8, only with the replacement of tamoxifen with letrozole and with the following adjustments:

[0087]

[0078] Brief summary: A randomized double-blind early phase trial involving 20-30 women is used to assess the efficacy, safety of use, and dosage of mescaline in ameliorating letrozole side effects. Patients, postmenopausal females who have taken letrozole daily for at least one month are eligible for the trial.

[0088]

[0079] Letrozole, at a current standard of care dose, i.e., 2.5 mg, is administered orally once daily. Mescaline at an escalating dose of 0.1-20 mgs is administered orally daily or several times daily if necessary. The period of mescaline treatment may be continuous or at intervals as required. Mescaline initial dose may be increased as necessary in order to achieve the reduction or elimination of letrozole side effects.

[0089] Example 10: Protocol for clinical trials: Mescaline in combination with anastrozole

[0090]

[0080] The protocol for clinical trial involving mescaline in combination with anastrozole is performed according to example 8, only with the replacement of tamoxifen with anastrozole and with the following adjustments:

[0091]

[0081] Brief summary: A randomized double-blind early phase trial involving 20-30 women is used to assess the efficacy, safety of use, and dosage of mescaline in ameliorating anastrozole side effects. Patients, postmenopausal females, diagnosed with breast cancer, who have taken anastrozole daily for at least one month are eligible for the trial.

[0092]

[0082] Anastrozole, at a current standard of care dose, i.e., 1 mg, is administered orally once daily. Mescaline at an escalating dose of 0.1-20 mgs is administered orally daily or several times daily if necessary. The period of mescaline treatment may be continuous or at intervals as required. Mescaline initial dose may be increased as necessary in order to achieve the reduction or elimination of anastrozole side effects.

[0093] Example 11: Protocol for clinical trials: Mescaline in combination with fulvestrant

[0083] The protocol for clinical trial involving mescaline in combination with fulvestrant is performed according to example 8, only with the replacement of tamoxifen with fulvestrant and with the following adjustments:

[0094]

[0084] Brief summary: A randomized double-blind early phase trial involving 20-30 women is assessing the efficacy, safety of use, and dosage of mescaline in ameliorating fulvestrant side effects. Patients, postmenopausal females, diagnosed with estrogen-receptor positive (ER+) breast cancer, who have taken fulvestrant for at least one month are eligible for the trial.

[0095]

[0085] Fulvestrant, at a current standard of care dose, i.e., 500 mg is administered intramuscularly once a month. Mescaline at an escalating dose of 0.1-20 mgs is administered orally daily or several times daily if necessary. The period of mescaline treatment may be continuous or at intervals as required. Mescaline initial dose may be increased as necessary in order to achieve the reduction or elimination of fulvestrant side effects.

[0096] Example 12: Protocol for clinical trials: Mescaline in combination with Exemestane

[0097]

[0086] The protocol for clinical trial involving mescaline in combination with exemestane is performed according to example 8, only with the replacement of tamoxifen with exemestane and with the following adjustments:

[0098]

[0087] Brief summary: A randomized double-blind early phase trial involving 20-30 women is assessing the efficacy, safety of use, and dosage of mescaline in ameliorating exemestane side effects. Patients, postmenopausal females, who have taken exemestane daily for at least one month are eligible for the trial.

[0099]

[0088] Exemestane, at a current standard of care dose, i.e., 25 mg is administered orally once daily. Mescaline at an escalating dose of 0.1-20 mgs is administered orally daily or several times daily if necessary. The period of mescaline treatment may be continuous or at intervals as required. Mescaline initial dose may be increased as necessary in order to achieve the reduction or elimination of exemestane side effects. Example 13: Protocol for clinical trials: Mescaline in combination with Raloxifene

[0089] The protocol for clinical trial involving mescaline in combination with raloxifene is performed according to example 8, only with the replacement of tamoxifen with raloxifene and with the following adjustments:

[0100]

[0090] Brief summary: A randomized double-blind early phase trial involving 20-30 women is used to assess the efficacy, safety of use, and dosage of mescaline in ameliorating raloxifene side effects. Patients, post-menopausal females, at high risk of developing estrogen receptor positive breast cancer, who have taken raloxifene daily for at least one month are eligible for the trial.

[0101]

[0091] Raloxifene, at a current standard of care dose, i.e., 60 mg, is administered orally once daily. Mescaline at an escalating dose of 0.1-20 mgs is administered orally daily or several times daily if necessary. The period of mescaline treatment may be continuous or at intervals as required. Mescaline initial dose may be increased as necessary in order to achieve the reduction or elimination of raloxifene side effects.

[0102]

[0092] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

Claims

CLAIMS1. A combination therapy for use in ameliorating the side effects resulting from treatment with an estrogen receptor-modulating pharmaceutical agent in a patient in need thereof, the method comprising administering to the patient a combination therapy comprising an estrogen receptor modulating pharmaceutical agent in conjunction with 3,4,5-trimethoxyphenethylamine (mescaline) in a subpsychoactive dose.

2. The combination therapy of claim 1 wherein the mescaline is provided in a composition selected from dried plant matter containing mescaline and a selective plant extract containing at least partially purified mescaline.

3. The combination therapy of claim 1 wherein the mescaline is a mescaline salt selected from the group consisting of: sulfate, hydrochloride, maleate, fumarate, acetate, citrate, hydrogen citrate, and dihydrogen citrate.

4. The combination therapy of claim 1, wherein the estrogen receptor-modulating pharmaceutical agent is selected from a group consisting of: aromatase inhibitors, selective estrogen receptor down-regulators and selective estrogen receptor modulators.

5. The combination therapy of claim 4 wherein the aromatase inhibitor is selected from letrozole, anastrozole, and exemestane.

6. The combination therapy of claim 4 wherein the selective estrogen receptor down regulator is fulvestrant.

7. The combination therapy of claim 4 wherein the selective estrogen receptor modulator is tamoxifen.

8. The combination therapy of claim 4 wherein the selective estrogen receptor modulator is raloxifene.

9. The combination therapy of claim 1, wherein the patient receiving the combination therapy is characterized by a diagnosis of an estrogen-related disease from the group consisting of: breast cancer, ovarian cancer, prostate cancer, colon cancer, endometrial cancer, polycystic ovary syndrome, endometriosis, uterine leiomyomas, or fibroids.

10. The combination therapy of claim 1 wherein the patient receiving the combination therapy is selected from the group consisting of: premenopausal women, postmenopausal women, men with hormonal abnormalities.

11. A pharmaceutical composition comprising a combination of an estrogen receptor modulator and 3,4,5-trimethoxyphenethylamine (mescaline) in a subpsychoactive dose.

12. The pharmaceutical composition of claim 11, wherein the daily dose of mescaline is up to 40 mg of mescaline sulfate.

13. The pharmaceutical composition according to claim 11, wherein the estrogen receptor modulator is selected from a group consisting of: aromatase inhibitors, selective estrogen receptor down-regulators and selective estrogen receptor modulators.

14. The pharmaceutical composition of claim 13 wherein the selective estrogen receptor modulator is tamoxifen.

15. The pharmaceutical composition of claim 11 wherein the composition comprises a synthetic form of mescaline.

16. The pharmaceutical composition of claim 11 wherein the composition comprises a plant extract containing mescaline.

17. The pharmaceutical composition of claim 16 wherein the composition comprising mescaline is extracted from plants selected from the group consisting of: Echinopsis pachanoi, Echinopsis peruviana, Echinopsis lageniformis, Lophophora williamsii, Acacia berlandieri.

18. The pharmaceutical composition of claim 16 wherein the dosage of the selective plant extract containing 3,4,5-trimethoxyphenethylamine (mescaline) ranges between 5 and 20 mg.

19. The pharmaceutical composition according to claim 11, wherein the dosage form is suitable for administration between once daily, twice daily, three times daily or four times daily to provide a therapeutically effective dose of 3,4,5- trimethoxyphenethylamine (mescaline) over a period of 6 to 24 hours.

20. The pharmaceutical composition according to claim 11, in a form suitable for oral delivery.

21. The pharmaceutical composition according to claim 20 in a form selected from a tablet, a pill, a capsule, a pellet, granules, a powder, a wafer, coated or uncoated beads, a solution, a suspension, syrup, an emulsion, and a dispersion.

22. The pharmaceutical composition according to claim 11, further comprising a pharmaceutically acceptable carrier or excipient.

23. The pharmaceutical composition according to claim 22, wherein the pharmaceutically acceptable carrier or excipient is selected from the group consisting of inert diluents, granulating and disintegrating agents, binding agents, and lubricating agents.