Treatment of menstrual cycle symptoms

Abstract

The present invention relates to methods for treating menstrual cycle disorders and symptoms using cathinones, particularly methods using 3-methylmethcathinone (3-MMC). The present invention also relates to kits containing 3-MMC for use in treating subjects suffering from menstrual cycle disorders and symptoms. In particular, methods and kits for treating menstrual cycle disorders and symptoms using 3-MMC for various disorders and / or conditions, such as PMS, PMDD, and perimenstrual disorders, are provided.

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 891,438, filed August 26, 2019, the entire contents of which are incorporated herein by reference.

[0002] The contents of the above-referenced applications are hereby incorporated by reference in their entirety as if fully set forth herein. [Background technology]

[0003] Menstrual symptoms such as heavy menstrual bleeding, dysmenorrhea, and significant mood disorders around the menstrual period (premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)) are common gynecological conditions. In addition to common physical symptoms, behavioral / mood changes due to the menstrual cycle usually include depression, anger outbursts, irritability, crying (continuous / moody), anxiety, confusion, social withdrawal, poor concentration, insomnia, fatigue, and changes in libido (Amer Coll. Obstet. And Gynaecol FAQ-PMS, 2015). Interview surveys have found that 22.5%-35% of women consider their menstrual bleeding heavy, and 34%-94% of women experience menstrual pain. Menstrual symptoms have a significant impact on quality of life. Furthermore, menstrual symptoms are a burden on healthcare costs. The annual cost of heavy menstrual bleeding is estimated to exceed $2000 per patient, mainly due to absenteeism and reduced productivity. The cost of absenteeism varies from country to country, depending on national regulations regarding sick leave. For young women, menstrual symptoms can lead to absenteeism and poorer performance in school. Adolescent girls who do not attend school due to dysmenorrhea report absenteeism rates ranging from 7.7% to 57.8%, and 21.5% report missing out on social activities.

[0004] Despite the significant impact on women's lives (both collectively and individually), several studies have shown that many women with dysmenorrhea do not seek help, highlighting the public health impact of menstrual problems, including reduced quality of life and high medical and societal costs. Little is known about the prevalence of menstrual symptoms in the general unselected population, but a recent study (Schoep et al, 2019 Am J Obs Gyn 220:569) reported high rates of dysmenorrhea (85%), behavioral and mood disorders (77%), and significant physical complaints (50%) among over 40,000 women interviewed. Nearly 40% of respondents reported an overall decrease in menstrual activity.

[0005] Typical treatment options for perimenstrual symptoms are varied and include dietary and lifestyle modifications for mild to moderate symptoms, and medical and non-conventional solutions for more severe symptoms. The American College of Obstetricians and Gynecologists recommends exercise and dietary modifications (e.g., complex carbohydrates and calcium-rich foods), calcium supplementation, and improved sleep for mild to moderate perimenstrual symptoms. Pharmacological solutions for severe symptoms (hormonal contraceptives, diuretics, NSAIDS) primarily address the physical aspects, while antidepressants, dopamine agonists, anxiolytics, and other psychotropic medications are prescribed for behavioral / mood symptoms. However, the pharmacologically active agents currently used to treat menstrual cyclic symptoms are not ideal due to their high cost and significant side effects. Medications such as serotonin reuptake inhibitors (e.g., fluoxetine and sertraline, both FDA-approved for PMDD), anti-inflammatories, anti-anxiety medications, hormones, dopamine agonists, and diuretics are sometimes suggested for the treatment of PMS, but the cost, efficacy, and side effects of such treatments are major concerns. (Most antidepressants have fairly serious side effects, such as palpitations, hallucinations, loss of coordination, severe dizziness, severe nausea / vomiting / diarrhea, and muscle spasms.)

[0006] Other proposed treatments for menstrual cycle symptoms include, among others, a combination of α-tocopherol and omega-3 polyunsaturated fatty acids, nerve growth factor, 2C 5-HT receptor agonists, calcium and vitamin D supplementation, GABA-A receptor agonists, pyridoxine, pindolol, magnesium, oxytocin releasers, and a combination of phosphatidyl-L-serine and magnesium (U.S. Patent Application Publication Nos. 2014 / 0356424, 2016 / 0058428, 2013 / 0171269, 2008 / 023126, 2009 / 023126, 2010 / 023126, 2011 / 023126, 2012 / 023126, 2013 / 023126, 2014 / 023126, 2015 / 023126, 2016 / 023126, 2015 ... (See specifications Nos. 2008 / 0160083, 2007 / 0255278, 2007 / 0203078, 2007 / 0098819, 2006 / 0241172, 2006 / 0241176, 2004 / 0127409, 2004 / 0048919, 2019 / 0099399 and 2016 / 0367614).

[0007] Psychostimulants and 3-MMC: Certain psychoactive drugs have been proposed to alleviate menstrual cycle symptoms and disorders related to behavior and mood. Traditional psychostimulants such as amphetamines, cocaine, and methylenedioxymethamphetamine (MDMA) all primarily target the monoaminergic system, increasing extracellular levels of serotonin (5-HT), dopamine (DA), and / or noradrenaline (NA). Although the experience of MDMA, cycloserine, and other psychoactive compounds has been suggested to be beneficial in treating mood and behavioral disorders, drawbacks have also been identified for their therapeutic use. In general, amphetamines are associated with the risk of amphetamine psychosis, depression, and cognitive impairment. In particular, serotonergic drugs such as MDMA, by stimulating excessive release of serotonin (and thus possibly also downregulating serotonin receptors in the brain), can cause rebound serotonin depletion and decreased sensitivity to neurotransmitters after use, which users experience as depression, often lasting for more than a few days (for reviews, see Danforth et al, Prog Neuro-Psych and Biol Psych, 2016, 64:237-249, or Amoroso et al, J. Psychopharm 2016, 30:595-600).

[0008] The present invention relates to the use of 3-methylmethcathinone (3-MMC) for menstrual cycle symptoms. Cathinones are substituted amphetamines that differ in the nature and location of side chain residues around the central ring. 2-, 3- and 4-methyl-methcathinone (2-, 3- and 4-MMC) are all psychoactive drugs that produce increased alertness, wakefulness, euphoria and appetite suppression. The therapeutic use of 4-MMC as a psychostimulant has been proposed in U.S. Patent Publication Nos. 2011 / 0207718, 2010 / 0172916 and 2016 / 0000815. The therapeutic use of 3-MMC has been proposed in WO 2019 / 026019. Summary of the Invention

[0009] According to one aspect of some embodiments of the present invention, there is provided a method of treating at least one menstrual cyclic symptom (i.e. a symptom resulting from the menstrual cycle) in a subject in need of such treatment, comprising identifying a time when at least one menstrual cyclic symptom is expected to occur or has occurred, and administering a therapeutically effective amount of 3-methylmethcathinone (3-MMC) to treat the menstrual cyclic symptom.

[0010] According to some embodiments of the present invention, the at least one menstrual cyclic symptom is expected to occur or has occurred 1-15 days before the onset of menstruation.

[0011] According to some embodiments of the present invention, the at least one menstrual cyclic symptom is expected to occur or has occurred 1-7 days before the onset of menstruation.

[0012] According to some embodiments of the present invention, the at least one menstrual cyclic symptom is expected to occur or has occurred 1-10 days after the onset of menstruation.

[0013] According to some embodiments of the present invention, the at least one menstrual cyclic symptom is expected to occur or has occurred 1-7 days after the onset of menstruation.

[0014] According to some embodiments of the invention, at least one menstrual cyclic symptom is expected to occur or has occurred 1-7 days before and 1-7 days after the onset of menstruation.

[0015] According to some embodiments of the invention, administration occurs prior to the time when menstrual cyclic symptoms are expected to occur.

[0016] According to some embodiments of the invention, administration occurs 1-5 days prior to anticipated onset of menstrual cyclic symptoms.

[0017] According to some embodiments of the invention, administration occurs 1-3 days prior to anticipated onset of menstrual cyclic symptoms.

[0018] According to some embodiments of the invention, administration occurs at the time when menstrual cyclic symptoms are expected to occur or have occurred.

[0019] According to some embodiments of the invention, administration is discontinued once menstrual cyclic symptoms have been alleviated.

[0020] According to some embodiments of the invention, administration is discontinued 1-7 days after the onset of menstruation.

[0021] According to some embodiments of the invention, administration is discontinued 2-5 days after the onset of menstruation.

[0022] According to some embodiments of the invention, administration is discontinued 1 to 7 days after the end of menstruation.

[0023] According to some embodiments of the invention, administration is discontinued 2-5 days after the end of menstruation.

[0024] According to some embodiments of the invention, the at least one menstrual cyclic symptom is a symptom of a menstrual cycle-related condition selected from the group consisting of perimenstrual disorder, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD).

[0025] According to some embodiments of the invention, the at least one menstrual cycle symptom is a physical symptom.

[0026] According to some embodiments of the invention, the at least one menstrual cycle symptom is a mood and / or behavioral symptom.

[0027] According to some embodiments of the invention, the at least one menstrual cycle symptom is selected from the group consisting of lethargy, eating disorders, forgetfulness, sleep disorders, appetite changes, poor concentration, loss of interest, social withdrawal, irritability, mood swings, anxiety, tension, depression, and a sense of loss of control.

[0028] According to some embodiments of the present invention, the at least one menstrual cyclic symptom comprises at least two or more symptoms.

[0029] According to some embodiments of the present invention, 3-MMC is administered in an amount ranging from 5 to 100 mg per administration.

[0030] According to some embodiments of the present invention, 3-MMC is administered in an amount ranging from 10 to 65 mg per administration.

[0031] According to some embodiments of the invention, 3-MMC is administered in amounts of 12.5 mg, 25 mg, 35 mg, 40 mg, or 50 mg per administration.

[0032] According to some embodiments of the invention, 3-MMC is administered in an amount of 25 mg per administration.

[0033] According to another aspect of some embodiments of the present invention, there is provided a kit for treating at least one menstrual cycle symptom in a subject, the kit comprising at least one unit dosage containing a therapeutically effective amount of 3-methylmethcathinone (3-MMC), instructions for administering 3-MMC before, at, or after a time when a menstrual cycle symptom is expected to occur or has occurred, and packaging material.

[0034] According to some embodiments of the invention, the kit further comprises a device for ascertaining the time when at least one menstrual cyclic symptom is expected to occur or has occurred in the subject.

[0035] According to some embodiments of the invention, the kit is accompanied by a digital computer interface for recording the timeline and characteristics of at least one menstrual cycle symptom.

[0036] According to some embodiments of the invention, the interface is a mobile phone application interface and the kit further comprises a barcode for downloading or activating the application.

[0037] According to some embodiments of the invention, the dosage unit contains 5-100 mg of 3-MMC.

[0038] According to some embodiments of the invention, the dosage unit contains 10-60 mg of 3-MMC.

[0039] According to some embodiments of the invention, the dosage unit contains 12.5 mg of 3-MMC.

[0040] According to some embodiments of the invention, the dosage unit contains 25 mg of 3-MMC.

[0041] According to some embodiments of the invention, the dosage unit contains 50 mg of 3-MMC.

[0042] According to some embodiments of the invention, the kit comprises at least one dosage unit of 12.5 mg of 3-MMC and at least one dosage unit of 25 mg of 3-MMC.

[0043] According to some embodiments of the invention, the kit comprises at least one dosage unit of 25 mg of 3-MMC and at least one dosage unit of 50 mg of 3-MMC.

[0044] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting.

[0045] Certain embodiments of the present invention are described herein, by way of example only, with reference to the accompanying drawings, in which it is emphasized that the details shown hereinafter, with particular reference to the drawings, are for the purposes of illustration and for the purpose of detailed description of embodiments of the present invention. Similarly, from a reading of the description together with the drawings, it will become apparent to those skilled in the art how embodiments of the present invention may be practiced. [Brief description of the drawings]

[0046] [Figure 1] FIG. 1 is a histogram showing common symptoms due to the menstrual cycle that were most frequently cited as motivating factors for 3-MMC use among study subjects. [Diagram 2] 1 is a histogram showing the most commonly reported effects of 3-MMC among study subjects. [Diagram 3] 1 is a histogram showing the most commonly reported undesirable effects of 3-MMC among study subjects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The present invention relates to methods of treating menstrual cycle symptoms and disorders with 3-methylmethcathinone (3-MMC), and also to kits comprising 3-MMC for use in treating menstrual cycle symptoms and disorders.

[0048] The signs and symptoms of menstrual cycle disorders are physical and psychological or behavioral, and have a temporal relationship to the menstrual cycle and a recurring characteristic with each new cycle. Physical symptoms commonly associated with PMS include dysmenorrhea, acne, abdominal bloating, breast tenderness, dizziness, fatigue, headache, hot flashes, nausea, diarrhea, constipation, heart palpitations, swelling of the hands and feet, and cramps. Emotional and cognitive symptoms include mood swings, angry outbursts, violent tendencies, anxiety, irritability, tension, poor concentration, depression, crying easily, depression, food cravings, forgetfulness, irritability, increased appetite, mood swings, and increased emotionality.

[0049] PMDD is a more severe form of PMS. The behavioural and mood-related symptoms of PMS and PMDD, as well as the physical symptoms, can be debilitating, resulting in lost work time, expenses and disruption to family and social life.

[0050] Some methylmethcathinones, particularly 2-MMC and 4-MMC, are potent psychostimulants but are considered inappropriate for use in relieving symptoms of the menstrual cycle due to the pronounced anxiety, stress and other undesirable characteristics of their psychoactive effects.

[0051] Surprisingly, the inventors have shown that 3-MMC, when administered in anticipation of, at or after the onset of menstrual cycle symptoms (e.g., PMS, PMDD), is effective in alleviating the most frequently cited symptoms, even at relatively low doses and in limited regimens, and also results in sustained improvements in quality of life for patients with behavioral and mood-related menstrual cycle symptoms, particularly women who have been refractory to conventional treatments, with minimal risk of undesirable side effects. In particular, the inventors have shown that 3-MMC can be effective in reducing the severity of some of the physical symptoms attributable to the menstrual cycle.

[0052] Before describing at least one embodiment of the present invention in detail, it should be understood that the invention is not necessarily limited in its application to the details set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0053] As mentioned above, absence from work or school is a major part of the personal and social / economic costs of menstrual cycle symptoms for patients, their families, and society at large.In fact, the inventors found that mental distress, irritability, agitation, fatigue, or exhaustion were the most frequent indications for taking 3-MMC for menstrual cycle symptoms among women in the sample population.For these women, 3-MMC reportedly increased their overall sense of well-being, raised their energy levels, promoted calm and relaxation, and improved their ability to concentrate.

[0054] Surprisingly, the inventors have observed that 3-MMC can have a cumulative positive effect on women: after two or more doses over a relatively short period of time (approximately 24 hours), the positive effects of 3-MMC are reported to persist and the effects of subsequent doses are apparently enhanced.

[0055] Thus, according to some embodiments, the present invention provides a method of treating at least one menstrual cyclic symptom in a subject in need of such treatment, comprising identifying a time when at least one menstrual cyclic symptom is expected to occur or has occurred, and administering a therapeutically effective amount of 3-methylmethcathinone (3-MMC) to treat the menstrual cyclic symptom.

[0056] The term "treating" as used herein means inhibiting, preventing or arresting the onset of a symptom and / or causing the alleviation, remission or regression of that symptom. Those skilled in the art will appreciate that a variety of methods and assays can be used to assess the onset of a symptom, and similarly, a variety of methods and assays can be used to assess the alleviation, remission or regression of a symptom. As used herein, the terms "amelioration," "alleviation" or "alleviation" of a symptom refer to an improvement in the condition of the symptom in a subject, where the improvement, alleviation or alleviation of the symptom (e.g., fatigue, mental distress) is offset by the negative aspects of the symptom. Improvement, alleviation or alleviation includes, but does not necessarily include, a complete recovery or complete prevention of menstrual cyclic symptoms. In the context of the present invention, amelioration, alleviation or relief is a reduction of at least about 10%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% of the reported or measured levels of menstrual cyclical symptoms.

[0057] As used herein, the phrase "menstrual cycle symptoms" refers to symptoms experienced by a woman that occur periodically (recur) in association with a particular portion of the menstrual cycle. In certain embodiments, the symptoms occur in association with a particular portion of the menstrual cycle and remit with the transition to another portion of the menstrual cycle. In some embodiments, menstrual cycle symptoms include, but are not limited to, symptoms of perimenstrual behavioral and mood disorders, such as premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), and perimenstrual physical symptoms, such as dysmenorrhea and abdominal bloating.

[0058] As used herein, PMS means "the cyclical recurrence of distressing physical, emotional and behavioral symptoms that affect a woman's health, relationships and / or occupational functioning." Premenstrual dysphoric disorder (PMDD) is a severe, distressing extension of PMS. PMS and PMDD symptom patterns vary from low symptom severity, to increased frequency and severity of symptoms during the premenstrual phase of the cycle, to a sudden absence of symptoms after the onset of menstruation. The severity, number and duration of symptoms affect the intensity of PMS or PMDD.

[0059] Both PMS and PMDD are associated with mood and behavioral symptoms. In some embodiments, mood and / or behavioral symptoms resulting from the menstrual cycle include, but are not limited to, lethargy, eating disorders, forgetfulness, sleep disorders, appetite changes, poor concentration, loss of interest, social withdrawal, irritability, mood swings, anxiety, tension, depression, and a sense of loss of control.

[0060] Both PMS and PMDD include periodic recurring mood swings, irritability or anger, depressed mood, anxiety or tension, decreased interest in usual activities, difficulty concentrating, lethargy, changes in appetite, disrupted sleep patterns and feeling overwhelmed.

[0061] In some embodiments, the menstrual cyclic symptoms are symptoms of PMDD. In some embodiments, PMDD is diagnosed by the presence of at least five of the following eleven symptoms (including at least one of the first four symptoms) during the last week before the onset of menstruation, which begin to improve within a few days after the onset of menstruation, and are minimal or absent one week after menstruation.

[0062] Symptoms: 1. Marked instability (e.g. mood swings) 2. Marked irritability or anger 3. Significantly depressed mood 4. Significant anxiety and tension 5. Decreased interest in usual activities 6. Poor concentration 7. Lethargy, noticeable lack of energy 8. Significant changes in appetite (e.g. overeating or cravings for certain foods) 9. Hypersomnia or insomnia 10. Feeling overwhelmed or out of control 11. Physical symptoms (e.g. breast tenderness or swelling, joint or muscle pain, feeling of "bloating" or weight gain)

[0063] In some embodiments, PMDD is defined according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). According to DSM-V, the diagnosis of PMDD requires additional criteria: at least five of these symptoms must be present, one of which must be symptoms 1-4 (marked instability, irritability, depressed mood, anxiety and tension). These symptoms will develop one week before menstruation and will remit after menstruation begins. To meet the criteria for diagnosis, symptoms must be charted in advance for two consecutive ovulation cycles to confirm the temporal and cyclical nature of symptoms. Also, the symptoms must be severe enough to affect normal work, school, social activities, or relationships with others.

[0064] It is noted that menopause (the cessation of menstruation in female mammals due to the reduction and eventual cessation of estrogen production from the ovaries) and pre- and perimenopause (the period in female mammals during which the signs and symptoms of menopause begin and increase) are often accompanied by physical and behavioral / emotional symptoms characteristic of menstrual cycle symptoms (e.g., mood swings, weight gain, loss of libido, sleep disorders, fatigue, headaches). Pre- and perimenopause also often results in an increased severity of PMS, PMDD, menstrual discomfort and dysmenorrhea. Another common symptom of pre-, perimenopause and menopause is migraine headaches. Currently available treatments for menopausal, pre- and perimenopause symptoms are also similar to those commonly prescribed for menstrual cycle symptoms (e.g., hormone therapy, antidepressants, NSAIDS, painkillers, acupuncture, herbal supplements). Thus, the application of the methods, compositions and kits of the present invention to the treatment of women suffering from the physical and behavioral / emotional symptoms of pre- and perimenopause, as well as to menopause itself, is also envisioned.

[0065] Thus, in some embodiments, the subject is a female mammal suffering from PMS, PMDD, perimenstrual disorder, or other menstrual cycle-related condition, hi certain embodiments, the subject is a female human.

[0066] As used herein, the phrase "menstrual cycle" refers to the monthly cycle of changes in the ovaries and endometrium. The four phases of the menstrual cycle are menstruation, the follicular phase, ovulation, and the luteal phase.

[0067] Menstruation is the shedding of the thickened uterine lining outside the body. The average duration of menstruation is 3 days to 1 week. In some embodiments, menstruation may last less than 3 days, more than 1 week, or up to 2 weeks or more.

[0068] The follicular phase begins with the onset of menstruation and ends with ovulation, which is characterized by the release of hormones that stimulate the production of follicles and thickening of the uterine lining. Ovulation is the release of a mature egg from the surface of the ovary, stimulated by luteinizing hormone (LH), by the rupture of an ovarian follicle. Ovulation usually occurs midway through the menstrual cycle, around day 14 of the 28-day menstrual cycle, but this varies from person to person. The released egg is transported to the uterus in preparation for fertilization.

[0069] Luteal phase: At ovulation, an egg is released from the follicle, but the ruptured follicle transforms into a glandular tissue (corpus luteum) that secretes progesterone and estrogen, maintaining the endometrium in preparation for fertilization and implantation. Unless fertilization occurs, the corpus luteum atrophies around the 22nd day of the 28-day cycle, and the menstrual cycle ends. After that, a drop in progesterone causes part of the endometrium to peel off, which is menstruation. In this specification, the start of the menstrual cycle, designated as "day 1" of the menstrual cycle, is defined as the start of menstruation.

[0070] Although there are individual differences, a normal human female menstrual cycle is 28 days. In other embodiments, the menstrual cycle is 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, or up to 40 days. In some embodiments, the subject's menstrual cycle is irregular, with some months being about 28 days, other months being less than 28 days from menstruation start to menstruation start, and / or other months being more than 28 days from menstruation start to menstruation start. In some embodiments, the subject's menstrual cycle is 24 to 38 days.

[0071] According to some aspects of the invention, the menstrual cyclic symptoms may occur during any one of four phases of the menstrual cycle: In certain embodiments, the menstrual cyclic symptoms occur during the luteal phase and / or at the onset of menstruation and several days (1-3 days, 1-5 days, 1-7 days) after the onset of menstruation.

[0072] In some embodiments, at least one menstrual cyclic symptom is expected to develop or has developed before the onset of menstruation. In some embodiments, the menstrual cyclic symptom is expected to develop 1-15 days, 1-7 days, or 1-10 days before the onset of menstruation. In other embodiments, the menstrual cyclic symptom is expected to develop or has developed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 15 days before the onset of menstruation. In certain embodiments, the menstrual cyclic symptom is expected to develop or has developed 3-7 days before the onset of menstruation.

[0073] In some embodiments, at least one menstrual cyclic symptom is expected to develop or has developed after the onset of menstruation. In some embodiments, the menstrual cyclic symptom is expected to develop 1-7 days, 1-10 days after the onset of menstruation. In other embodiments, the menstrual cyclic symptom is expected to develop or has developed 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 15 days after the onset of menstruation. In certain embodiments, the menstrual cyclic symptom is expected to develop or has developed 2 days, 3 days, 4 days, 5 days, or 6 days after the onset of menstruation.

[0074] In some embodiments, symptoms are expected to occur or have occurred 1 to 7 days before and 1 to 7 days after the onset of menstruation (days -7 to +7). In certain embodiments, menstrual cyclic symptoms are expected to occur or have occurred on days -5 to +5 of the menstrual cycle, days -4 to +5 of the menstrual cycle, days -3 to +4 of the menstrual cycle, days -2 to +3 of the menstrual cycle, and days -1 to +4 of the menstrual cycle.

[0075] It should be noted that the recurrent nature of menstrual cyclic symptoms provides an opportunity for subjects suffering from such menstrual cyclic symptoms to anticipate the onset of such symptoms and administer 3-MMC prior to the onset of the symptoms to provide relief. The inventors have determined that administering 3-MMC in anticipation of menstrual cyclic symptoms can significantly reduce the intensity and duration of many menstrual cyclic symptoms and improve the quality of life of perimenstrual women. Thus, in some embodiments, administration of 3-MMC occurs prior to the time when menstrual cyclic symptoms are expected to occur. In some embodiments, administration of 3-MMC occurs 1-5 days, 1-4 days, 1-3 days, 1-2 days, 5 days, 4 days, 3 days, 2 days, or 1 day prior to the time when menstrual cyclic symptoms are expected to occur. In other embodiments, 3-MMC is administered 48 hours, 40 hours, 36 hours, 32 hours, 28 hours, 24 hours, 18 hours, 12 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4.5 hours, 4 hours, 3.5 hours, 3 hours, 2.5 hours, 2 hours, 1.5 hours, 1 hour, 45 minutes, 30 minutes, or 15 minutes before the expected onset of menstrual cyclic symptoms.

[0076] The inventors also confirmed a significant positive effect of 3-MMC when administered when symptoms were expected or had occurred, and some subjects reported that 3-MMC was also effective when administered after the onset of menstrual cyclic symptoms.

[0077] Thus, in some embodiments, 3-MMC is administered 1 to 5 days, 1 to 4 days, 1 to 3 days, 1 to 2 days, 1 day, 2 days, 3 days, 4 days, or 5 days after the onset of menstrual cyclic symptoms. In other embodiments, 3-MMC is administered 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, 24 hours, 28 hours, 36 hours, or 40 hours after the onset of menstrual cyclic symptoms (onset of menstrual cyclic symptoms).

[0078] 3-MMC can be administered as a single dose or in a regimen of repeated administration to a subject. The inventors have observed a cumulative, and in some cases sustained, effect of repeated administration of 3-MMC. In some embodiments, 3-MMC is administered repeatedly at intervals of 1-12 hours, 1-2 days, 1-4 days, or 1-6 days. In other embodiments, 3-MMC is administered repeatedly at intervals of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

[0079] In some embodiments, administration of 3-MMC is discontinued once menstrual cyclic symptoms have been alleviated. In other embodiments, administration of 3-MMC is discontinued for 1-7 days, 2-5 days, 3-6 days, or 4 days after the onset of menstruation. In certain embodiments, administration of 3-MMC is discontinued for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or 1-7 days, or 2-5 days after the end of menstruation.

[0080] Many subjects reported taking 3-MMC in anticipation of or in response to the mood and / or behavioral symptoms caused by menstrual cycle, while some subjects reported relief from physical symptoms previously experienced with menstrual cycle.Thus, in some embodiments, at least one menstrual cycle symptom is mood and / or behavioral symptom.In certain embodiments, mood or behavioral symptom is selected from the group consisting of lethargy, eating disorder, forgetfulness, sleep disorder, appetite change, poor concentration, poor interest, withdrawal, irritability, mood swings, anxiety, tension, depression, and feeling of being out of control.

[0081] A non-limiting list of suitable devices for diagnosing, monitoring and evaluating a subject's menstrual cycle symptoms and changes therein before, during or after treatment with the methods of the present invention is provided in Table 1.

[0082] [Table 1-1]

[0083] [Table 1-2]

[0084] In certain embodiments, a subject's progress before, during or after treatment for menstrual cyclic symptoms using the methods of the invention is assessed using at least one of the Beck Depression Scale, Beck Anxiety Scale, and Beck Hopelessness Scale for PMDD (DSM V).

[0085] In other embodiments, the at least one menstrual cycle symptom is a physical symptom, including, but not limited to, breast tenderness or swelling, joint or muscle pain, "belly bloating," headaches, weight gain, and abdominal cramps.

[0086] Many subjects reported that two or more of the reported menstrual cycle symptoms were alleviated by 3-MMC.Thus, in some embodiments, the at least one menstrual cycle symptom comprises at least two or more symptoms (see above for a partial list of characteristic symptoms).In some embodiments, the at least one menstrual cycle symptom comprises two or more of depression, lethargy, irritability, anxiety, social withdrawal, and mood swings.

[0087] It will be appreciated that in some embodiments, a subject may suffer from more than one menstrual cycle condition, in which case the treatment methods of the invention may be directed to treating a single one of the conditions, according to a priority order determined by the therapist and / or the subject, and in some embodiments, it may be preferable to treat multiple conditions simultaneously.

[0088] 3-MMC is effective in relieving menstrual cycle symptoms at various concentrations.

[0089] In some embodiments, a therapeutically effective amount of 3-MMC is administered to the subject, hi some embodiments, 3-MMC is administered to the subject in an amount ranging from 5 mg to 1000 mg per administration. In some embodiments, 3-MMC is administered to a subject in an amount of about 7 mg to about 950 mg per administration, about 7 mg to about 950 mg per administration, about 10 mg to about 900 mg per administration, about 15 mg to about 850 mg per administration, about 20 mg to about 800 mg per administration, about 25 mg to about 780 mg per administration, about 30 mg to about 750 mg per administration, about 35 mg to about 700 mg per administration, about 40 mg to about 650 mg per administration, about 45 mg to about 600 mg per administration, about 50 mg to about 550 mg per administration, about 52 mg to about 500 mg per administration, about 57 mg to about 480 mg per administration, about 60 mg to about 45 ...0 mg to about 550 mg per administration, about 52 mg to about 500 mg per administration, about 57 mg to about 480 mg per administration, about 60 mg to about 450 mg per administration, about 50 mg to about 550 mg per administration, about 50 mg to about 550 mg per administration, The dose is within the range of about 63 mg to about 430 mg, about 70 mg to about 400 mg per administration, about 75 mg to about 370 mg per administration, about 77 mg to about 350 mg per administration, about 80 mg to about 330 mg per administration, about 85 mg to about 300 mg per administration, about 90 mg to about 280 mg per administration, about 95 mg to about 250 mg per administration, about 100 mg to about 230 mg per administration, about 105 mg to about 200 mg per administration, about 110 mg to about 190 mg per administration, about 115 mg to about 175 mg per administration, about 120 mg to about 165 mg per administration, about 125 mg to about 160 mg per administration, or about 130 mg to about 155 mg per administration. In some embodiments, 3-MMC is administered to a subject in an amount within the range of 20 mg to 500 mg, 22 mg to 490 mg, 27 mg to 470 mg, 30 mg to 450 mg, 33 mg to 435 mg, 40 mg to 410 mg, 47 mg to 390 mg, 50 mg to 375 mg, 55 mg to 360 mg, 57 mg to 350 mg, 60 mg to 320 mg, 63 mg to 300 mg, 67 mg to 290 mg, 70 mg to 270 mg, 75 mg to 260 mg, 77 mg to 250 mg, 80 mg to 240 mg, 85 mg to 220 mg, 90 mg to 210 mg, or 100 mg to 200 mg per administration.It will be understood that each range of amounts of 3-MMC to be administered represents a single separate embodiment.

[0090] In some embodiments, the administration of 3-MMC to a subject is at least 5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 73 mg, 75 mg, 77 mg, 80 mg, 83 mg, 85 mg, 87 mg, 90 mg, 93 mg, 95 mg, 97 mg, 100 mg, 103 mg, 107 mg, 110 mg, 113 mg, 115 mg, 117 mg, 120 mg, 130 mg, 135 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 172 mg, 175 mg, 176 mg, 17 mg, 123mg, 125mg, 127mg, 130mg, 133mg, 137mg, 140mg, 143mg, 145mg, 147mg, 150mg, 153mg, 155mg, 157mg, 160mg, 163mg, 167mg, 170mg, 173mg, 175mg, 177mg, 180mg, 183mg, 185mg, 187mg, 190mg, 193mg, 195mg, 197mg, 200mg, 220mg, 240mg, 250mg, 275mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. In certain embodiments, 3-MMC is administered in an amount of 12.5 mg per dose, 25 mg per dose, 35 mg per dose, 50 mg per dose, or 60 mg per dose, hi certain embodiments, 3-MMC is administered in an amount of 25 mg per dose.

[0091] In some embodiments, 3-MMC is administered to a subject at a dose calculated based on mass per kg of body weight, e.g., mg of 3-MMC per kg of subject body weight. In some embodiments, 3-MMC is administered to a subject at a dose of about 0.1 mg / kg body weight to about 1 mg / kg body weight per administration, about 0.5 mg / kg body weight to about 7 mg / kg body weight per administration, about 0.75 mg / kg body weight to about 6.5 mg / kg body weight per administration, about 1.0 mg / kg body weight to about 6.0 mg / kg body weight per administration, about 1.25 mg / kg body weight to about 5.5 mg / kg body weight per administration, about 1 ... to about 5.5 mg / kg body weight per administration, about 1 mg / kg body weight to about 5.5 mg / kg body weight to about 5.5 mg / kg body weight per administration, about 1 mg / kg body weight to about 5.5 mg / kg body weight to about 5.5 mg / kg body weight to about 5.5 mg / kg body weight to about The dosage ranges are from about 0.5 mg / Kg body weight to about 5 mg / Kg body weight, from about 1.75 mg / Kg body weight to about 4.5 mg / Kg body weight per administration, from about 2.0 mg / Kg body weight to about 4.25 mg / Kg body weight per administration, from about 2.25 mg / Kg body weight to about 4.0 mg / Kg body weight per administration, from about 2.5 mg / Kg body weight to about 3.75 mg / Kg body weight per administration, and from about 2.75 mg / Kg body weight to about 3.5 mg / Kg body weight per administration. It will be understood that each range of 3-MMC per Kg of body weight administered represents a single, separate embodiment.

[0092] In some embodiments, 3-MMC is administered to a subject at a dose of 0.1 mg / kg body weight, 0.2 mg / kg body weight, 0.3 mg / kg body weight, 0.4 mg / kg body weight, 0.5 mg / kg body weight, 0.75 mg / kg body weight, 1.0 mg / kg body weight, 1.25 mg / kg body weight, 1.5 mg / kg body weight, 1.75 mg / kg body weight, 2.0 mg / kg body weight, The dosage is 2.25mg / kg body weight, 2.5mg / kg body weight, 2.75mg / kg body weight, 3.0mg / kg body weight, 3.25mg / kg body weight, 3.5mg / kg body weight, 3.75mg / kg body weight, 4.0mg / kg body weight, 4.25mg / kg body weight, 4.5mg / kg body weight, 4.75mg / kg body weight, 5.0mg / kg body weight, or 5.5mg / kg body weight. In a specific embodiment, the subject is administered 3-MMC at a dosage of 0.1mg / kg body weight, 0.2mg / kg body weight, 0.3mg / kg body weight, 0.4mg / kg body weight, 0.5mg / kg body weight, 1mg / kg body weight, 1.5mg / kg body weight, 2mg / kg body weight, 2.5mg / kg body weight, or 3mg / kg body weight per administration.

[0093] 3-MMC can be administered to a subject by a variety of methods, including, but not limited to, oral administration, intravenous administration, insufflation (intranasal administration), mucosal administration, rectal administration, transdermal administration, and inhalation (e.g., dry powder or vapor inhalation). In certain embodiments of the methods of the present invention, 3-MMC is administered to a subject by oral administration. In certain embodiments, 3-MMC is orally administered to a subject in an amount of 10 mg per dose, 12.5 mg per dose, 25 mg per dose, 35 mg per dose, 50 mg per dose, 100 mg per dose, 150 mg per dose, 200 mg per dose, 250 mg per dose, 300 mg per dose, 350 mg per dose, or 400 mg per dose.

[0094] In some embodiments, sequential administration of 3-MMC can be by equal amounts per administration (e.g., two or more administrations of 12.5 mg or 25 mg or 35 mg). In other embodiments, the amount of 3-MMC can be gradually increased between administrations (e.g., an initial dose of 12.5 mg, followed by 25 mg, and finally 35 mg or 50 mg of 3-MMC) or gradually decreased between administrations (e.g., an initial dose of 35 mg or 50 mg, followed by 25 mg, and finally 12.5 mg or 10 mg of 3-MMC). In certain embodiments, sequential administration of 3-MMC for menstrual cyclic symptoms involves one or two administrations of 25 mg, followed by a dose of 12.5 mg.

[0095] Safety and pharmacokinetic studies in animal models have shown that peak serum concentrations of 3-MMC are evident within 5-10 minutes of oral administration, with an apparent plasma half-life of approximately 0.8 hours after oral ingestion. The inventors have determined that in some embodiments, human subjects begin to perceive the effects of 3-MMC approximately 30-90 minutes after oral administration, depending on whether 3-MMC is administered on an empty stomach (earlier onset) or after a meal (later onset). In some cases, the peak effects of 3-MMC are perceived in human subjects 10-30 minutes after the effects of 3-MMC first begin to be perceived. The inventors have further determined that for some subjects, the time period in which human subjects perceive the effects of 3-MMC is most often within 6-8 hours after oral administration.

[0096] Thus, in some embodiments, 3-MMC is administered at least twice to a cyclical symptom. In some embodiments, 3-MMC is administered twice to a cyclical symptom with an interval of 1 to 12 hours. In other embodiments, 3-MMC is administered twice or three times to a cyclical symptom with an interval of 2 to 8 hours. In other embodiments, 3-MMC is administered twice or three times to a cyclical symptom with an interval of 3 to 6 hours. In other embodiments, 3-MMC is administered twice or three times to a cyclical symptom with an interval of 1 to 4 hours. In other embodiments, 3-MMC is administered twice or three times to a cyclical symptom with an interval of 1 to 3 hours. In yet other embodiments, 3-MMC is administered twice or more times to a cyclical symptom with an interval of 1 to 2 hours.

[0097] In some embodiments, 3-MMC is administered multiple times (e.g., two or more times), with each administration containing the same dose of 3-MMC (e.g., 3 x 25 mg, 2 x 25 mg, 2 x 12.5 mg, etc.). In other embodiments, 3-MMC is administered multiple times (e.g., two or more times) for menstrual cyclic symptoms, with each administration containing a different dose of 3-MMC (e.g., 1 x 12.5 mg followed by 1 x 25 mg, 1 x 25 mg followed by 1 x 12.5 mg followed by a third dose of 1 x 12.5 mg, 1 x 12.5 mg followed by 1 x 50 mg, etc.). Combinations of an initial high dose followed by a lower dose, an initial low dose followed by a higher dose, and alternating doses of lower or higher than the initial dose are also contemplated.

[0098] It is understood that the method of the present invention can be combined with other treatment methods. A common treatment for menstrual cycle symptoms is drug therapy. Thus, in some embodiments, the subject is treated with at least one drug selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, serotonin-dopamine antagonists, analgesics, antihypertensives, antiallergic drugs, anxiolytics, anti-inflammatory drugs, oral contraceptives, dietary supplements (e.g., calcium, vitamin B6, vitamin E, magnesium, L-tryptophan), agnus castus and / or chasteberry extract, muscle relaxants, and local anesthetics. In certain embodiments, the method of the present invention further comprises administering to the subject at least one drug selected from the above-mentioned group.

[0099] Additionally, non-pharmacological approaches have recently become popular and can be incorporated into the methods of the present invention. Thus, in some embodiments, the methods of the present invention further comprise administering to the subject a complementary treatment, non-pharmacological method, e.g., selected from the group consisting of at least one of music, exercise, acupuncture, visual stimulation, audio stimulation, thermal comfort, and "body therapy" (e.g., massage, chiropractic).

[0100] The 3-MMC of some embodiments of the present invention can be administered to a subject per se, or it can be administered to a subject as a pharmaceutical composition in which it is mixed with a suitable carrier or excipient.

[0101] As used herein, a "pharmaceutical composition" refers to a preparation of one or more active ingredients as described herein with other chemical components, such as physiologically suitable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0102] The term "active ingredient" herein refers to 3-MMC that is responsible for the biological effect.

[0103] Hereinafter, the terms "physiologically acceptable carrier" and "pharmaceutical acceptable carrier" may be used interchangeably and refer to a carrier or diluent that does not cause significant irritation to an organism and does not impair the biological activity or properties of the administered compound. Adjuvants are also included in these terms.

[0104] The term "excipient" as used herein refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0105] Techniques for formulation and administration of drugs are described in the latest edition of "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, which is incorporated herein by reference.

[0106] Suitable routes of administration can include, for example, oral, rectal, transmucosal, particularly nasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections, as well as intrathecal, direct intraventricular, intracardiac, e.g., into the normal right or left ventricular cavity, intracoronary, intravenous, intraperitoneal, intranasal or intraocular injections.

[0107] Pharmaceutical compositions of some embodiments of the present invention can be manufactured by processes well known in the art, e.g., by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0108] Thus, pharmaceutical compositions for use in some embodiments of the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, which facilitate processing of the active ingredient into a pharma- ceutically usable preparation. The appropriate formulation will depend on the chosen route of administration.

[0109] For injection, the active ingredients of the pharmaceutical composition can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, physiological saline buffer, etc. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0110] For oral administration, pharmaceutical compositions can be easily formulated by combining the active compounds with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the pharmaceutical compositions to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient. Pharmacological preparations for oral use can be prepared using solid excipients, the resulting mixture can be milled as necessary, and the mixture of granules can be processed to obtain tablets or dragee cores, after adding suitable auxiliaries as required. Suitable excipients are, in particular, fillers, such as sugars, e.g., lactose, sucrose, mannitol, or sorbitol, cellulose preparations, e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carbomethylcellulose, and / or physiologically acceptable polymers, e.g., polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof (eg, sodium alginate).

[0111] The dragee cores are provided with suitable coatings.For this purpose, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and concentrated sugar solutions, which may contain appropriate organic solvents or solvent mixtures as required, can be used.Dyes or pigments can be added to the tablets or dragee coatings to identify or characterize different combinations of administration of active compounds.

[0112] Orally administrable pharmaceutical compositions include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers can also be added. All preparations for oral administration should be in a form suitable for the chosen route of administration.

[0113] In some embodiments, the composition can be formulated to control the release of the active ingredient. In some embodiments, 3-MMC or compositions thereof are formulated for "immediate release". The term "immediate release" (IR) as used herein means that the active agent is released into the environment over a period of a few seconds to about 30 minutes once release begins, and begins within 1 second to about 15 minutes after exposure to an aqueous environment. Immediate release compositions that do not have a substantial delay in drug release should be considered a subset of rapid release compositions. Immediate release compositions release drug in the buccal cavity, esophagus, and / or stomach.

[0114] In some embodiments, 3-MMC or compositions thereof are formulated for "rapid release". The term "rapid release" (RR) as used herein means that the active agent is released into the environment over a period of time ranging from a few seconds to about 59 minutes once release has commenced, and may begin within a few seconds or minutes after exposure to an aqueous environment or after the end of a delay period (lag time) after exposure to an aqueous environment. Generally, a rapid release composition will release the drug in the stomach, jejunum or duodenum after oral administration, provided that the composition does not contain a delayed release material or delayed release coating. In such cases, the rapid release composition will release the drug in the upper, middle and / or lower intestine or colon.

[0115] In some embodiments, 3-MMC or compositions thereof are formulated for "extended release". As used herein, the term "extended release" (ER) refers to the controlled release of an active agent from a dosage form to an environment over (throughout or during) an extended period of time (e.g., one hour or more). As used herein, the term "extended release" profile is subject to the definition widely recognized in the pharmaceutical arts. An extended release dosage form releases a drug at a substantially constant rate over an extended period of time or releases a substantially constant amount of drug incrementally over an extended period of time. The term "extended release" with respect to drug release encompasses the terms "controlled release", "prolonged release", "sustained release" or "delayed release" used in the pharmaceutical arts.

[0116] In some embodiments, 3-MMC or compositions thereof are formulated for "controlled release." As used herein, the term "controlled release" (CR) refers to the release of an active agent into an environment over a period of about 8 hours to about 12 hours, 16 hours, 18 hours, 20 hours, 1 day, or more than 1 day. The onset of controlled release can occur within minutes after exposure to an aqueous environment or after the end of a delay period (lag time) after exposure to an aqueous environment.

[0117] In some embodiments, 3-MMC or compositions thereof are formulated for "sustained release." As used herein, the term "sustained release" (SR) refers to a controlled release of an active agent to maintain constant drug levels in the blood or target tissue of a subject to which the pharmaceutical composition is administered.

[0118] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0119] According to some embodiments, enteral coating of the composition is further used for oral or buccal administration. As used herein, the term "enteric coating" refers to a coating that controls the location of absorption of the composition in the digestive system. Non-limiting examples of materials used for enteral coating are fatty acids, waxes, vegetable fibers or plastics.

[0120] For administration by nasal inhalation, the active ingredients used in some embodiments of the present invention are conveniently delivered in the form of an aerosol spray from pressurized packs or nebulizers with a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules or cartridges of, for example, gelatin for use in a dispenser can be formulated containing a powder mix of the compound and a suitable powder base (e.g., lactose or starch).

[0121] The pharmaceutical compositions described herein can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Preparations for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, and preservatives can be added as necessary. The compositions can be suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0122] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Furthermore, suspensions of the active ingredient can be prepared as appropriate oil- or water-based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate, triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. If necessary, the suspension can also contain suitable stabilizers or agents that increase the solubility of the active ingredient to allow for the preparation of highly concentrated solutions.

[0123] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, a sterile, pyrogen-free water-based solution, before use.

[0124] Pharmaceutical compositions of some embodiments of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.

[0125] Pharmaceutical compositions suitable for use in the context of some embodiments of the present invention include compositions in which the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of 3-MMC effective to treat, prevent, alleviate or ameliorate the symptoms of a menstrual cycle-related disorder or condition in a subject.

[0126] Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0127] For any formulation used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from animal models. Such information can be used to more accurately determine useful doses in humans.

[0128] Toxicity and therapeutic efficacy of the active ingredients described herein can be confirmed by standard pharmaceutical procedures in vitro in cell cultures or experimental animals. Data obtained from such in vitro and cell culture assays and animal studies can be used in formulating various dosages for use in humans. Dosages may vary depending on the dosage form and route of administration used. The exact formulation, route of administration and dosage can be selected by the individual physician in view of the patient's condition (see, for example, Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.1).

[0129] Dosage and interval can be individualized to obtain levels of 3-MMC sufficient to induce or inhibit a biological effect (minimal effective concentration, MEC). The MEC varies from formulation to formulation but can be estimated from animal models. The dose required to obtain the MEC varies with individual characteristics and route of administration. Plasma concentrations can be measured using detection assays.

[0130] As detailed above, depending on the severity and responsiveness of the condition being treated, administration can be a single dose or multiple doses, with the course of treatment lasting from several days to several weeks, or until a cure is effected or the injury or condition is abated.

[0131] The amount of composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0132] Compositions of some embodiments of the invention can be provided in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing 3-MMC as an active ingredient, if desired. The pack can, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser can also bear a notice on the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by the agency of the composition in its form or for administration to humans or animals. Such notice can be, for example, a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions comprising the formulations of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition, as further detailed above.

[0133] Thus, in some embodiments, a kit for use in treating at least one menstrual cycle symptom in a subject is provided, comprising at least one dosage unit containing a therapeutically effective amount of 3-methylmethcathinone (3-MMC), instructions for using 3-MMC before, at or after the time when the menstrual cycle symptom is expected to occur or has occurred, and packaging material. The types of menstrual cycle symptoms suitable for combination with administration of 3-MMC according to the methods of the present invention are detailed above. In some embodiments, the instructions indicate that the menstrual cycle symptom is a symptom of PMS in the subject. In other embodiments, the instructions indicate that the menstrual cycle symptom is a symptom of PMDD. In still other embodiments, the instructions indicate that the menstrual cycle symptom is a symptom of a perimenstrual disorder or condition.

[0134] As discussed above, the cyclical nature of menstrual cyclic symptoms provides an opportunity to estimate or predict the time of onset of the symptoms, and thus preemptively administer 3-MMC to treat and alleviate the symptoms. Thus, in some embodiments, the kit includes a specific dosage unit of 3-MMC along with instructions for administration at a specified time within the subject's menstrual cycle. Appropriate timing for preemptive or prophylactic administration of 3-MMC for menstrual cyclic symptoms is discussed in detail above. Examples of dosage units of 3-MMC suitable for use in the kits of the present invention include 5-100 mg, 10-80 mg, 12.5-75 mg, 20-60 mg, and 25-50 mg of 3-MMC. In certain embodiments, the dosage unit of the kit comprises 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, or 100 mg of 3-MMC. In certain embodiments, the dosage unit of the kit comprises 12.5 mg, 25 mg, 35 mg, or 50 mg of 3-MMC.

[0135] In one non-limiting example, the kit can include one, two or more 12.5 mg, 25 mg, 35 mg or 50 mg dosage units of 3-MMC, instructions for administration 0.5 to 5 days prior to the expected onset of menstrual cyclic symptoms, and packaging materials. An exemplary kit of the invention can include instructions for administration of a dosage unit of 3-MMC on the day when the onset of menstrual cyclic symptoms is expected, the expected day being expressed as n days from the onset of the previous menstruation, where n is a characteristic interval from the onset of menstruation to the onset of at least one menstrual cyclic symptom. In some embodiments, the instructions provide a specific interval or range of intervals for sequential administration of multiple dosage units of 3-MMC. In further embodiments, the instructions provide an increase ("tapering") or decrease ("tapering") in the dosage units for sequential administration of multiple dosage units of 3-MMC. Suitable intervals between unit administrations are detailed above.

[0136] In some embodiments, to improve the accuracy of the timing of administration of 3-MMC, the kit further comprises a device for identifying the time when at least one menstrual cyclic symptom is expected to occur in the subject. Thus, a subject suffering from a menstrual cyclic symptom can record the periodic recurrence of the menstrual cyclic symptom and adjust the timing of administration of 3-MMC dosage units accordingly. Furthermore, such a subject can record the response to or timing of administration of previous administrations of 3-MMC to better calibrate the timing and dosage of future administrations of 3-MMC.

[0137] Such a device can be a conventional manual recorder, such as a chart, or a digital recorder. Thus, in some embodiments, a kit of the present invention is provided with a digital computer interface for recording the timeline and characteristics of at least one menstrual cycle symptom. Such a digital computer interface can allow for manual input of parameters of the timing, duration, and characteristics (e.g., severity) of symptoms, and response to administration of 3-MMC. In some embodiments, the digital computer interface is of a mobile phone application ("app"), and the kit further includes a bar code for downloading and / or activating the application. Appropriate configuration of mobile phone applications and accompanying bar codes for activation and / or downloading are well known in the art.

[0138] It is expected that many related methods for treating subjects suffering from menstrual cyclical symptoms with 3-MMC will be developed during the life of any patent continuing from this application, and the scope of the term "administering 3-MMC to a subject suffering from menstrual cyclical symptoms" is intended to encompass all such new technologies a priori.

[0139] Throughout this specification, the term 3-MMC or 3-methylmethcathinone includes compounds of the formula:

[0140] [ka] (Including its deuterated forms.)

[0141] As used herein, the term "deuterated form" of a compound refers to a compound in which one or more hydrogen atoms have been replaced with a deuterium isotope.

[0142] According to any of the embodiments described herein, 3-MMC or a deuterated form thereof may be in the form of a pharma- ceutically acceptable salt thereof.

[0143] As used herein, the phrase "pharmaceutically acceptable salt" refers to a charged species of the parent compound and its counterion, which is typically used to modify the solubility characteristics of the parent compound and / or reduce significant irritation to an organism by the parent compound and / or improve its stability, while not impairing the biological activity and properties of the administered compound. Alternatively, pharmaceutically acceptable salts of the compounds described herein can be formed during the synthesis of the compounds, for example, during the process of isolating the compounds from a reaction mixture or during the process of recrystallizing the compounds.

[0144] In some circumstances of this embodiment, the pharma- ceutically acceptable salts of 3-MMC described herein may optionally be acid addition salts that include a protonated amine in combination with at least one counterion derived from a selected acid to form a pharma- ceutically acceptable salt.

[0145] Thus, an acid addition salt of a compound described herein can be a complex formed between an amine group of the compound and one or more equivalents of an acid.

[0146] The acid addition salt of 3-MMC is usually a mono-addition salt.

[0147] As used herein, the phrase "mono-addition salt" refers to a salt in which the stoichiometric ratio of counterion to the charged form of the compound is 1:1, thus the addition salt contains one molar equivalent of counterion per one molar equivalent of the compound.

[0148] Acid addition salts can include anions derived from a variety of organic and inorganic acids, including, but not limited to, hydrochloric acid resulting in hydrochloric acid addition salts, hydrobromic acid resulting in hydrobromic acid addition salts, acetic acid resulting in acetic acid addition salts, ascorbic acid resulting in ascorbic acid addition salts, benzenesulfonic acid resulting in besylic acid addition salts, camphorsulfonic acid resulting in camphorsulfonic acid addition salts, citric acid resulting in citric acid addition salts, maleic acid resulting in maleic acid addition salts, malic acid resulting in malic acid addition salts, methanesulfonic acid resulting in methanesulfonic acid (mesylic acid) addition salts, naphthalenesulfonic acid resulting in naphthalenesulfonic acid addition salts, oxalic acid resulting in oxalic acid addition salts, phosphoric acid resulting in phosphoric acid addition salts, toluenesulfonic acid resulting in p-toluenesulfonic acid addition salts, succinic acid resulting in succinic acid addition salts, sulfuric acid resulting in sulfuric acid addition salts, tartaric acid resulting in tartrate addition salts, and trifluoroacetic acid resulting in trifluoroacetic acid addition salts.

[0149] This embodiment further encompasses any enantiomers, diastereomers, prodrugs, solvates, and hydrates of 3-MMC (or its deuterated forms).

[0150] The term "enantiomer" as used herein refers to a stereoisomer of a compound that can be superimposed on its counterpart only by complete inversion / reflection (mirror image) of each other. Enantiomers are said to have "handedness" because they point to each other like right and left hands. Enantiomers have identical chemical and physical properties except when they are present in an environment that itself has handedness (e.g., all living systems). In the context of the present embodiment, 3-MMC or its deuterated forms can exhibit one or more chiral centers, each of which may exhibit an R or S configuration and any combination.

[0151] The term "diastereomers" as used herein refers to stereoisomers that are not enantiomers of each other. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more (but not all) of the equivalent (related) stereocenters and are not mirror images of each other. If two diastereomers differ from each other at only one stereocenter, they are epimers. Each stereocenter (chiral center) gives rise to two different configurations, and therefore two different stereoisomers. In the context of the present invention, the embodiments of the present invention encompass compounds with multiple chiral centers that occur in any combination of configurations, i.e., any diastereomers.

[0152] The term "prodrug" refers to an agent that is converted into an active compound (the active parent drug) in vivo. Prodrugs are usually useful for facilitating administration of the parent drug. For example, a prodrug may be bioavailable by oral administration whereas the parent drug is not. A prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs are also often used to provide a sustained release of an active compound in vivo.

[0153] The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) formed by a solute (a compound of the invention) and a solvent whereby the solvent does not interfere with the biological activity of the solute. Suitable solvents include, for example, ethanol, acetic acid, and the like.

[0154] The term "hydrate" means a solvate as defined above wherein the solvent is water.

[0155] It is anticipated that related forms of 3-MMC (e.g., purified enantiomers, deuterated forms, salts, etc.) will be developed during the life of any patent continuing from this application, and the scope of the term "3-MMC" is intended to encompass all such new technologies a priori.

[0156] As used herein, the term "about" or "approximately" means ±10%.

[0157] The terms "comprises," "comprising," "includes," "including," "having" and conjugations thereof mean "including but not limited to." This term encompasses the terms "consisting of" and "consisting essentially of."

[0158] The phrase "consisting essentially of" means that a composition or method may include additional components and / or steps, provided that the additional components and / or steps do not materially alter the basic and novel characteristics of the claimed composition or method.

[0159] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" or "at least one compound" includes a plurality of compounds, and may also include mixtures thereof.

[0160] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and is not an inflexible limitation of the scope of the invention. Thus, the description of a range should be considered to specifically disclose all of the possible subranges and individual numerical values ​​within that range. For example, description of a range such as 1 to 6 specifically discloses not only subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., but also individual numerical values ​​within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the magnitude of the range.

[0161] Whenever a numerical range is given herein, it is intended to include any recited number (fractional or integer) within the range given. The phrases "range between" a first indicated number and a second indicated number and "range from" a first indicated number to a second indicated number are used interchangeably herein and are intended to include the first indicated number and the second indicated number, and all fractional and integer numbers therebetween.

[0162] As used herein, the term "method" means manner, means, techniques, and procedures for accomplishing a given task, including, but not limited to, those known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine, or those that can be readily developed by practitioners from known manners, means, techniques, and procedures.

[0163] As used herein, the term "treating" includes arresting, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the worsening of clinical or cosmetic symptoms of a condition.

[0164] It will be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in a single embodiment in any combination of those features. Conversely, several features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or with respect to other described embodiments as appropriate. Certain features described in the context of various embodiments should not be construed as essential to that embodiment, unless the particular embodiment is inoperable without that element.

[0165] As noted above, various embodiments and aspects of the present invention as described and claimed herein find experimental support in the following examples. EXAMPLES

[0166] The following examples, together with the above description, are non-limiting examples of some embodiments of the present invention. In general, the nomenclature used herein includes medical, pharmacological and pharmaceutical techniques. Such techniques are fully described in the literature. See, for example, DSM-V and ICD10, both of which are incorporated herein by reference as if fully set forth herein. Other general references are provided throughout the specification. The procedures therein are believed to be well known in the art, but are provided for the convenience of the reader. All information contained therein is incorporated herein by reference as if fully set forth herein.

[0167] The following case studies illustrate some aspects of some embodiments of the methods of the present invention for treating perimenstrual disorders in subjects suffering from at least one menstrual cycle symptom by administering 3-MMC.

[0168] Closed-label clinical trial of 3-MMC for menstrual cycle symptoms A detailed report of 11 women's experiences with the use of unlabelled 3-MMC ("the pill") for menstrual cyclic symptoms.

[0169] Example I - "Gertie" Gertie is a 41-year-old Dutch woman (1.70m, 57kg) who had previous, albeit unstructured, experience with 3-MMC for the relief of menstrual symptoms (mainly PMS) and had used it on various occasions during the previous year. Based on her description and positive experience, she initiated a clinical trial to confirm the positive effect of 3-MMC on menstrual symptoms in other women.

[0170] Gertie is in a good relationship with her four children. In addition to being a mother, she is also a businesswoman and busy mother with multiple activities and responsibilities. She has no underlying medical conditions other than moderate to severe PMS symptoms for the past two years, especially after ceasing oral contraceptives.

[0171] menstrual cycle symptoms Common PMS symptoms: Gertie often or very often suffers from the following: Mental distress (past 2 years) Frustration / upset (last 2 years) Tension (past 2 years) Feelings of loneliness / helplessness (past 2 years) Hypersensitivity (past 2 years) Indecisive (last 2 years) Decreased concentration (over the past 2 years) Desire to argue or argue (last 2 years) Interpersonal conflicts (recent)

[0172] background Gertie used oral contraceptives until she was 38 years old. Over the past 2 years, after ceasing oral contraceptives, she has become increasingly aware of symptoms due to menstruation and her PMS distress has gradually increased in severity. In the days preceding her menstrual period, Gertie feels an increased need to be around other people and to be with others, perhaps to relieve the distress of her PMS.

[0173] Gertie's PMS symptoms begin 1-2 days before her period and she finds it a very stressful experience, making it hard for her to cope with her job, family and children. PMS also makes it hard for Gertie to enjoy weekends and free days.

[0174] Gertie is very open and talks candidly about menstruation and PMS, and she feels that loneliness is part of the problem, so sharing with others helps.

[0175] PMS makes Gertie argumentative, agitated, and hyper-conscious of her condition. Somehow, being aware of her menstrual cycle makes her more observant and in touch with her emotions. Gertie recognizes the monthly recurrence of tensions caused by menstruation, notices her increasing irritability, and knows when her anxiety eases.

[0176] Gertie has been experimenting with various doses of 3-MMC for PMS for about two years, about 20 times for 15 menstrual periods.

[0177] dose Gertie has tried 3-MMC consistently for the past 15 menstrual periods, usually taking only one or two tablets a few days before her period. After trying doses higher and lower than 25 mg, Gertie has concluded that a dose of 20 to 25 mg works best.

[0178] motive Gertie decided to take the pills during a particularly distressing time. She was prone to arguments on days when she began to feel irritable "for no reason." She felt particularly uncomfortable in relationships, indecisive, anxious, and lonely. Having a heart-to-heart discussion about her feelings posed a difficult challenge.

[0179] Dosage and Regimen Gertie usually takes her pills in the morning, after breakfast and before lunch, because at that time she can already foresee a difficult day.

[0180] She has tried various doses. She felt no effect at 10mg-20mg. She felt positive effects at 20mg-30mg. She tried 40mg in one dose but thought it was a bit too much and has not tried higher doses.

[0181] Pharmacodynamics Gertie begins to feel the effects after 30 minutes to an hour, with the desired peak effect occurring at 1.5 to 2 hours. The effect begins to wane after 4 hours, and is gone after 6 hours.

[0182] response Gertie feels less tense, which can be seen in the way she breathes: she breathes easier, oxygen doesn't "sink into her body" even when she is excited, and the pills allow her to take larger, deeper breaths.

[0183] Psychological effects Gertie feels "back to normal" (as on a non-PMS day) and is able to make decisions again. It is as if her mind has "cleared" and she felt confused and indecisive before taking the pill. After taking the pill, she is not necessarily more focused than usual, but she feels more comfortable with herself. Gertie no longer feels the need to cry and is able to have good interactions and interpersonal relationships. She feels more stable.

[0184] side effects She says she has never noticed any unwanted side effects, but there is a relationship between the amount of pills taken and body temperature, so you may feel a little hotter than usual or experience a change in appetite.

[0185] Example II - "Ana" Ana is a healthy 25-year-old woman (68 kg, 1.78 m) from Estonia. Ana works part-time and is a university student. She lives alone but is in a relationship, takes oral contraceptives, has never been pregnant, and has regular menstrual cycles.

[0186] menstrual cycle symptoms Ana reports physical and emotional complaints related to her menstrual periods. Her cyclical symptoms usually last 2-3 days before bleeding, but she still experiences symptoms during the first few days of her period, which usually lasts up to 7 days.

[0187] Normal Menstrual Symptoms: Ana chronically suffers from the following symptoms: Acute hypersensitivity (for at least the past 8 years) Eating disorder / cravings (for at least the past 8 years) Expressive behavior (for at least the past 8 years) Crying (for no reason) (for at least the past 8 years) Feeling out of control (for at least the past 8 years) Mood swings (for at least the past 5 years) Mental distress (for at least the past 5 years) Decline (for at least the past 5 years) Irritability / upset (for at least the past 5 years) Exhaustion and fatigue (for at least the past 5 years) Lethargy / fatigue (for at least the past 5 years) Decreased interest in usual activities (for at least the past 5 years)

[0188] Infrequent (occasionally) symptoms that persist for many years Restlessness or nervousness (last 8 years) Forgetfulness (past 8 years) · Confusion (last 8 years) Indecisiveness (for the past 8 years) Sleep disorders (past 8 years) Anxiety (past 5 years) Tension (last 5 years) ·Feelings of loneliness / helplessness (for the past 5 years) Depression (past 5 years) Feelings of impatience (past 5 years)

[0189] background Ana had her first period at age 16, but did not experience any stress or distress then or afterwards. Serious symptoms began when she was 19. For Ana, it is very difficult to cope with menstrual symptoms, and the same is true for her sister, who suffers from PMS (but their mother has no complaints).

[0190] Ultimately, these symptoms make Ana anxious, moody, and crave food. These symptoms put her in a dilemma: wanting to be alone, but also wanting company. This puts stress on her relationships; she wants to be closer to her boyfriend, but at the same time, she undervalues ​​herself on those days. Ana can feel ugly, unfeminine, and overweight, making her miserable. Ana does not believe that oral contraceptives can affect her mood swings, since she suffers from the symptoms even after stopping the pills.

[0191] Ana sometimes misses school or work due to the severity of her symptoms. She takes painkillers and has tried other homeopathic remedies to ease the physical discomfort, but she feels that they are not really effective. She has never discussed her emotional problems with a doctor. Ana believes that menstrual symptoms are a "personal issue" that she should deal with alone, with no reason to involve others or use it as an excuse for not continuing her "normal life" (normal life before and after menstruation).

[0192] summary Ana is a healthy 25-year-old young woman suffering from moderate to severe menstrual cyclic symptoms. Ana's symptoms are compatible with PMS, but also with PMDD (dysphoric mood disorder) depending on the number of indicators and their duration.

[0193] 3-MMC Clinical Trial Period period 60 days spanning three menstrual periods (2nd half of 2018) Number of clinical trials 3 times

[0194] Clinical Trial I Date of menstrual period: The first day of Anna's menstrual period Main motivation for taking pills: Physical pain and general anxiety / discomfort (when her diary showed the highest scores for the following: mental distress, mood swings, anxiety). Time: 7pm, no food (hungry). Dosage: 25 mg taken once. Physical response: After 1 hour already felt calm, this sensation peaked after 2 hours and remained so for 6 hours. The pills did not help ease the stomach pain. Psychological response: After one hour, psychological distress, mood swings and anxiety were reduced. After two hours, Anna reported feeling calmer and more relaxed, a feeling that lasted for 24 hours. Side effects: None

[0195] Clinical Trial II Day of menstrual period: Day 2 of menstrual period Main motivation for taking the pills: When her menstrual calendar showed high scores for: mental distress, depression, mood swings, helplessness, anxiety and nausea. Time of day: 1st pill taken at 3pm, 2nd pill taken at 8pm. Dose: 12.5 mg taken in two doses, 5 hours apart. Physical Reaction: After taking the first dose, I was still in pain and anxiety for the first 4 hours, so I decided to take a second dose afterwards to try and ease the symptoms. Psychological response: After the second dose, she felt "calmer" and experienced less mental distress, depression, mood swings, helplessness, and anxiety. The feeling of calm lasted until she fell asleep. Side effects: None

[0196] Clinical Trial III Trial date during menstrual period: last day of menstruation (1 day before the trial bleeding in the second month) Main motivator for taking the pills: Emotional distress and pain (her highest scores on the diary were irritability, anger and sleep problems). Time of day: 1st pill taken at 6pm, 2nd pill taken at 11pm. Dosage: Two doses: one 12.5mg and the other 25mg, 5 hours apart. Physical Reaction: After the first dose, Ana felt the pain subside, and the pain in her stomach seemed to have subsided, but she still felt a bit emotional. Psychological response: After the second dose, Ana's mental distress was reduced and she felt significantly calmer. Two hours after the last dose, she fell asleep. The high dose of 25 mg proved beneficial on a psychological level. Side effects: Ana reported an onset of acne after her last dose (25 mg), after which she stopped taking the drug due to fear of further acne outbreaks.

[0197] response: A dose of 12.5 mg was ineffective for this subject, but a dose of 25 mg was found to be beneficial. The primary reason for taking the medication was physical symptoms, not psychological symptoms (self-reported). Ana reported feeling relief from both physically and mentally trying situations. Ana stated that her physical pain was relieved, and that on an emotional level, 3-MMC made her feel more calm and relaxed, reducing mood swings, anxiety and tension.

[0198] The feeling of relaxation began one hour after ingestion and was highest after two hours, but Ana reported that the effects may last a day or longer. After taking 37.5 mg, Ana developed unexplained acne and decided to stop taking 3-MMC.

[0199] Example III: "Bea" Bea is a 21-year-old female (78 kg, 1.73 m) full-time university student. Bea currently lives in the Netherlands with other international roommates. Bea is an only child and lives far away from her parents in her country of origin, Italy. She has a Dutch boyfriend, uses oral contraception, and has never been pregnant. Bea does not use or abuse drugs. She is a healthy young woman with moderate to severe PMS symptoms that occur throughout most, if not all, of her menstrual cycle.

[0200] menstrual cycle symptoms Bears often suffer from the following conditions: Mood swings (last 3 years) Irritability / agitation (after menarche) Feeling exhausted or fatigued (after menarche) Hypersensitivity (after menarche) Lethargy (after menarche) Crying (after menarche)

[0201] Less common symptoms: ·Mental pain (after menarche) Decline (past 5 years) Depression (past 6 years) Changes in sexual desire (over the past 2 years)

[0202] background Baer's symptoms have been quite severe and have fluctuated over time since her first period. Baer noted that while she naturally stops taking oral contraceptives during her period, she still experiences high levels of psychological distress and, like the other women in the study, was unaware of the relationship between oral contraceptives and mood swings. Baer reported that the same was true for her mother, who became very emotional during her period.

[0203] Bear has regular periods and has been keeping track of her menstrual cycle ever since her gynaecologist suggested she pay attention to them. This seems to help her understand how her emotions are related to hormonal changes. Bear is therefore very aware that worries about her menstrual period interfere with her daily life. She mainly suffers from symptoms related to her menstrual cycle, one day before and the first two days of her period. Bear feels very irritable and unmotivated to do anything (apathy), especially regarding normal household chores, as well as with her university studies and other responsibilities. Bear often experiences problems with deadlines, as she knows when her next period is coming and she has to adjust her study and assignment deadlines to fit her period. Bear is convinced that PMS interferes with her work performance, so she tries to get things done quickly. However, Bear is aware that she cannot always control external factors and that she must sometimes take responsibility, despite the psychological and physical pain she feels. For example, on an important exam day, Bear may feel irritable (psychologically) or bloated or heavy (physically).

[0204] Thus, the anticipation of her period causes her stress and anxiety, both consciously and unconsciously. However, Bea also recognizes that the distress caused by menstruation does not actually affect her friendships much, although she reports frequent arguments with her boyfriend about her menstrual cycle. Nevertheless, Bea tries not to let menstruation interfere with her sentimental life. For physical pain, Bea takes painkillers, but would prefer to avoid medication if possible.

[0205] summary: Although never formally diagnosed with an apparent menstrual cycle-related condition, Baer meets the criteria for PMS: all symptoms she experiences before her period are compatible with PMS, including possibly dysphoria (there are more than five of them), and she has experienced them regularly (sometimes with symptoms of moderate to severe severity) for years. Furthermore, Baer acknowledges that the psychological distress associated with menstruation reduces her performance at both work and school.

[0206] 3-MMC Clinical Trial Period period Two months, the equivalent of three menstrual periods. Bear only took the pills during one menstrual period, because that was the only time she experienced extreme symptoms. Number of clinical trials 2 times

[0207] Clinical Trial I Menstrual period trial date: 3rd day of menstruation Main motivators for taking pills: Crying for no reason, irritability, anxiety, fatigue, pain. Time: 9am, after breakfast. Dose: 1 tablet of 12.5 mg. Physical response: Fatigue before taking the pill. Less fatigue after taking the pill (started to feel the positive effects after 1.5 hours). After 2 hours, Bear was definitely more alert. After 6 hours, body pain was completely relieved. Psychological response: Bear felt emotionally stable after one hour, less irritable, less anxious, and less likely to cry for the rest of the day. Positive emotions continued for most of the day, not just six hours after taking the drug. Side effects: Bear did not notice any unpleasant physical reactions or side effects. She also took paracetamol for pain but did not notice any unwanted interactions with 3-MMC.

[0208] Clinical Trial II Trial date during menstrual period: 15th day of menstruation (ovulation period) Main motives for taking pills: anger, frustration, emotional distress, confusion. Time: 10am, after breakfast. Dosage: 25 mg taken once. Physical reactions: Before taking the drug, Bear reported feeling "kind of drowsy," but this went away after an hour, and he felt "normal" again. The feeling of "happiness" lasted throughout the day. Psychological response: Thirty minutes after taking the drug, Bear felt less angry and irritable. After about an hour and a half, she felt more in control and experienced less mental distress and confusion. After two hours, she began to feel really relaxed, a feeling that lasted for six hours. For the rest of the day, she reported feeling "just stable." Side effects: None

[0209] Response: A definite relief of mental distress was observed with the lowest dose of 12.5 mg. At this dose, Bea was already able to feel "stable" or back to normal. At the 25 mg dose, she felt more in control and relaxed. In the first trial, she was relieved mainly of feelings of sadness, and in the second dose, of irritability and anger. Bea only tried the pills during one menstrual period, because the next menstrual period she did not experience any symptoms that would have made taking the pills worthwhile. As can be inferred from her own description, she is often in distress during her menstrual period, but not always.

[0210] Example IV - "Katy" Katie is a 24-year-old woman (58 kg, 1.70 m) from Ukraine, living with a roommate / friend, not dating, not using contraception, and never been pregnant. Her menstrual cycles are regular. She has always experienced severe physical and psychological symptoms associated with menstruation.

[0211] menstrual cycle symptoms Chronic conditions: Irritation (2 years) Mood swings (2 years) ·Mental distress (2 years) · Impatience (2 years) Hypersensitivity (2 years) Anger (2 years) A strong desire to be alone (for 2 years) Silent Desire (2 years) Feeling like crying for no reason (for 2 years) Changes in libido (which increases during menstruation)

[0212] Occasional symptoms: Nervous (2 years) Fatigue Depression (occasionally) Feeling out of control Physical problems or pain (headaches, abdominal bloating, breast tenderness, etc.)

[0213] background Katie is a healthy person, but was diagnosed with depression a few years ago and was treated with antidepressants for six months, which were also intended to address the mood swings she felt were related to her menstrual cycle. In her case, the antidepressants were not helpful, so she decided to discontinue their use. However, Katie also acknowledged that she is generally not very sensitive to medication, and often requires higher doses to get a positive effect.

[0214] Katie had her first period at age 11 and had no problems until she was 22. One day, without warning, she noticed that she would get angry and upset around the time of her period. Since then, Katie has associated her moods with her menstrual cycle. Now, she experiences mood swings starting a week before her period begins. She also experiences significant pain during the first few days of her period. Usually, on the first night Katie wakes up and needs to take painkillers, and on the second day her symptoms get worse, affecting her work performance. A few days before her period, Katie becomes very irritable, prefers to be alone, and avoids social interactions. She admits that her social interaction problems are subjectively perceived, and her perception is that people are "slow" and irritable. Her mental distress began two years ago, and the severe pain and cramps began a year ago.

[0215] Before and after "those days," Katie prefers to deal with her problems alone. But while she is open with close friends and warns them in advance of her mood changes and possible aggressive behavior, she holds herself back at work and wears a "social mask." The physical pain she feels during the first few days of menstruation makes her angry.

[0216] She is an only child, and there is no information as to whether her mother suffers from (or has suffered from) similar mood swings during her period, as Katie has not been very open about the topic with her mother.

[0217] summary Katie is a physically healthy young woman who has previously been diagnosed with depression, but for the past two years has been suffering from severe mental and physical distress caused by her menstrual cycle. Her main symptoms are anger and irritability. She has previously tried antidepressants, but these did not alleviate her depression or menstrual symptoms. Katie claims that she is not very responsive to medication.

[0218] 3-MMC Clinical Trial Period period 60 days spanning three menstrual periods (2nd half of 2018) Number of clinical trials 7 times

[0219] Clinical Trial I Trial date of menstrual period: 27th day (1 day before the next menstruation) Main motivation for taking pills: Extreme irritability (also mood swings and mental distress) Time: 11am, after breakfast Dosage: 12.5 mg once and 25 mg once (total 37.5 mg) Physical reactions: After 30 minutes, Katie felt her heart rate accelerate, after an hour she felt slightly dizzy, relaxed, and "high," which lasted for another hour. Three hours after taking the drug, she felt hot and sweaty. Her appetite decreased, which remained so for the rest of the day. Psychological response: After 30 minutes, Katie felt more self-aware and focused. After an hour, she was more proactive and had more energy for up to four hours, after which she returned to normal. However, despite feeling relaxed, she sometimes felt angry and irritated, which she now felt more in control. Side effects: accelerated heart rate, dizziness, feeling hot and sweating.

[0220] Clinical Trial II Trial date of menstrual period: 28th or first day of menstrual cycle Main motivation for taking pills: Extreme irritability and anger (also mood swings, tension and restlessness) Time: 11:30am, after breakfast Dosage: 12.5 mg once and 25 mg once (total 37.5 mg) Physical reactions: After 30 minutes, Katie noticed a slight acceleration in her heart rate, and an hour later she could still feel her heart beating and sweating (stickiness). These symptoms continued for another 2 hours, after which they subsided, but she began to feel a loss of appetite. Psychological response: After one hour, Katie was more energetic and eager to talk, less irritable and angry, and felt more relaxed. Side effects: accelerated heart rate, sweating, loss of appetite.

[0221] Clinical Trial III Menstrual period trial date: Day 2 of the menstrual cycle Main motives for taking pills: Annoyance, anger, discomfort Time: 17:30 Dose: 12.5mg x 1 + 25mg x 1 (total 37.5mg) Physical Reactions: There were no noticeable physical reactions. Psychological effects: No noticeable psychological effects. Side effects: None.

[0222] Clinical Trial IV Menstrual period trial date: Day 3 of the menstrual cycle Main motivation for taking 3-MMC: Irritability (mood swings, mental distress, restlessness) Time: 19:30 Dose: 25mg x 1 + 12.5mg x 1 (total 37.5mg) Physical Reactions: Within one hour of taking the drug, Katie began to experience a slight increase in heart rate and began to sweat. The sweating continued for another two hours. Three hours after taking the drug, she lost her appetite, a sensation that continued until six hours after taking the drug. Psychological response: After one hour, Katie felt much calmer and much more relaxed than normal. She was less agitated and irritable, and felt energized and motivated to work. Side effects: sweating and loss of appetite.

[0223] Clinical Trial V Trial date during menstrual period: 5 days before the menstrual cycle (2nd month of trial) Main motives for taking pills: Irritation and anger (emotional distress) Time: 15:30 Dose: 25 mg in two doses (1 hour apart). Total: 50 mg. Physical reactions: Slight increase in heart rate after the first dose and increased heart rate after the second dose. Sweating and loss of appetite after 3 hours. Psychological response: I was in an "in-flow" state of mind, I was focused, very sharp and energetic, I still felt irritated but not angry. This energy continued for the rest of the day. Side effects: increased heart rate, sweating and loss of appetite.

[0224] Clinical Trial VI Menstrual trial date: 4 days before the menstrual cycle Main motives for taking pills: Anger and frustration Time: 11:30am Dose: 25 mg taken twice (total of 50 mg within 1 hour) Physical Reactions: No physical reactions after first dose, but after second dose, Katie experienced slightly increased heart rate and sweating for several hours. Four hours after taking the drug, Katie noticed a loss of appetite. Psychological response: After the second dose, Katie was energetic, enthusiastic, outgoing, and talkative, but still agitated. After 3 hours, she was still hyperactive and only calmed down after 4 hours. Irritability and anger were reduced, but she felt a sense of depression or "down" for an hour afterwards. Afterwards, she felt "OK" for the rest of the day. Side effects: increased heart rate, sweating, loss of appetite, and a brief feeling of "down."

[0225] Clinical Trial VII Menstrual period trial date: 2 days before the menstrual cycle Main motivations for taking pills: Annoyance, anger and impatience Time: 17:30 Dosage: 25 mg taken in two doses, 1 hour apart (total 50 mg) Physical Reactions: No noticeable physical reactions. Psychological response: After the second dose, Katie had more energy, was less irritable, and after two hours was significantly calmer. Her anger and agitation also decreased after the second dose. However, after one hour she felt irritable again, and after four hours Katie felt stable again. Side effects: No noticeable side effects.

[0226] Response: Katie was initially aware and comfortable that she was not sensitive to the effects of the medication, so she chose to start with a dose of 37.5 mg. She tried this dose 4 times, taking it for at least 2 consecutive days before and after her menstrual period. The main physical reactions were increased heart rate, sweating (first few hours), and loss of appetite afterwards and for the rest of the day. Psychologically speaking, she said she felt "high," more self-aware, more focused, energetic, bold, and calm, but still could get irritable and angry. Since anger was the main sensation she wanted to overcome, she decided to increase the dose to 50 mg for the last 3 trials. The main reason for this was that she had developed a perceived tolerance to 3-MMC and her physical symptoms (side effects) were decreasing or disappearing. With the 50 mg dose, Katie again experienced increased heart rate, sweating, feeling hot, and loss of appetite the first time (first 2 times), but did not experience these physical reactions the third and last time. Emotionally, Katie noticed that she was calmer and no longer felt angry in situations that would have previously annoyed her, but this calmness was short-lived. She also reported that she became briefly depressed (1 hour) but this went away once the effects of the 3-MMC wore off (note that Katie had been diagnosed with depression a year prior).

[0227] Example V - "Diana" Diana is a healthy 21-year-old woman from Austria (weight 43-45 kg, height 1.60 m), working part-time and studying at a local university. She lives alone and is in a relationship. Diana has stopped taking oral contraceptives, which she had been using to regulate her mood swings, but now wants to try 3-MMC. Diana has never been pregnant and has a regular menstrual cycle.

[0228] menstrual cycle symptoms Diana participated in the trial because she had psychological and psychiatric complaints related to her menstrual period. Her cyclical symptoms usually begin about four days before the start of her period and persist throughout her menstrual period. Once her period ends, she "starts to feel like herself again." Cyclical symptoms have been a part of her cycle since her first menstruation.

[0229] Typical symptoms: (chronic) Mood swings Depression ·anxiety Irritability / upset Exhaustion or fatigue ·Hypersensitivity Lethargy / fatigue Changes in sexual desire Feeling like crying / crying for no reason

[0230] Occasional symptoms: · Feeling of loneliness / helplessness ·depression ·Feeling helpless Eating Disorders / Cravings Diana has experienced all of these symptoms since her first period.

[0231] background Diana is an overall healthy person, but her menstrual cyclic symptoms have been consistent since menarche. About 4 days before her period, she begins to feel irritable and argue with her partner / boyfriend. Her symptoms continue for the first few days of her period, when she still feels irritable and tired. At the end of her period, she feels normal again.

[0232] She tried using oral hormonal contraception to control her symptoms, but it triggered migraines, so she began looking for other solutions. She felt bothered and inconvenienced before and during her period, and wanted more control over her menstrual cycle.

[0233] Diana's symptoms have a negative impact on her social life. They affect her romantic relationships, as she becomes irritable, emotional, tired, and conflicts with her partner. She forces herself to go out and be social, even though she would rather sleep all day. She does not want her menstrual symptoms to interfere with her daily life, so she keeps them hidden from others. The only people she discusses her symptoms with are the women in her college class. She feels that her experience is not that different from other girls, so she feels that it is easy and normal for all women to go through this. However, she finds experiencing all the symptoms "distressing." Diana's experience varies depending on the activities she does during her menstrual period. For example, if she spends more time at home relaxing, she feels better because she is able to rest. On busy days, the symptoms can become a problem or a burden. To get more control, she has tried homeopathic drops to ease her mental and physical difficulties. However, in her experience, the homeopathic drops did not work. Therefore, she was interested in participating in this clinical trial.

[0234] summary A petite woman with symptoms compatible with moderate to severe PMS. She has suffered from menstrual related distress since her youth and continues to do so into the present. Overall, she is a healthy young adult.

[0235] 3-MMC Clinical Trial Period period 60 days including one menstrual period Number of clinical trials 3 times

[0236] Clinical Trial I Trial date of menstrual period: Diana's period was late but she experienced PMS symptoms on the 21st day of the trial. Main motivations for taking pills: Feeling out of control, fatigue. Time: Around 19:00 in the evening. On an empty stomach. I was worried that the capsules would keep me from sleeping, but they didn't cause me insomnia. Dosage: 25 mg taken once. Physical response: After 30 minutes, she felt more energized and no longer fatigued. She noticed an increase in her heart rate and felt more awake, and felt the same after 1 hour. After 1.5 hours, she felt more energized and the effects of the capsule began to wear off. Psychological response: After 30 minutes, she felt more focused, her mood was elevated, less helpless and in control (she went from feeling depressed to happy and energized again). She was more proactive and less likely to act impulsively ("I have to go out!"). After 1.5 hours, she began to feel calmer and more stable and continued to feel happy and calm. Side effects: stomach pain (when hungry) and increased heart rate, which she describes as feeling like a "caffeine stimulant."

[0237] Symptoms specifically alleviated: She was less distracted than usual and did not feel any mental distress, depression or tension. Normally during the menstrual period in her menstrual cycle, she feels helpless, tired, cries for no reason and has a desire to be alone. When using the capsules, she did not feel any of these symptoms.

[0238] *Notes after 1st trial: "I was very pleased with the first time I used the pills. There was an extreme change in my mood and sense of well-being that I noticed shortly after taking them. However, the psychological effects were so strong that I think a small pill would have been enough. I may consider taking a lighter dose in the future. Also, despite the increased energy, I had no problems falling asleep" (Diana).

[0239] Clinical Trial II Trial date of menstrual period: 1st day of menstruation (late menstruation) Main motivation for taking the pills: Feeling tired, depressed and down all day. Zero energy on the first day of menstruation. Time of day: Evening. No food was eaten before taking the capsule. Dose: 12.5 mg taken once. Physical Reaction: Stomach pain, she took the pill on an empty stomach and felt a slight stomach pain for the first 30 minutes. After 1 hour she felt more energetic but not as strong as with the initial 25mg intake. She felt her normal self again after 2 hours but perhaps more energetic than normal. After 4 hours there were no further effects. Psychological response: After 30 minutes, she felt a little elated, not as happy as the first dose, but not as depressed as before. She felt more stable and was able to start her homework. After 1.5 hours, she felt less able to concentrate, but still mentally stable. After 2 hours, she felt more awake than before taking the pill. After 3 hours, she felt depressed again, but still less lethargic than before. After 4 hours, the effects of the capsule wore off. Side effects: Stomach pain.

[0240] The participants were definitely less depressed, less lethargic, and less likely to feel down or fatigued.

[0241] *Note after second dose: "The effect of the low dose was quite mild. After 2 hours, it felt like the pill's effects had almost completely worn off. I had gone home early that day due to menstrual symptoms. I felt like I could have continued to work if I hadn't had the cramps after taking the pill (which the pills had no effect on)" (Diana).

[0242] Clinical Trial III Trial date during menstrual period: second day of menstruation. Main motivation for taking the pills: I felt depressed and fatigued, just like the day before. Time of day: Early afternoon, had something to eat before taking the pill. Dose: 12.5 mg taken once. Physical response: Feels better awake and more alert. After 3 hours, she felt normal again, like she was not menstruating, and felt like herself again. Psychological response: She was no longer depressed or fatigued. The participant felt more productive, more in control, and more optimistic, and did not experience the sudden feeling of happiness that occurred the first time around (as occurred with the 25 mg dose). After one hour, she felt more focused, productive, and stable. After three hours, she began to feel a bit fatigued again. Side effects: None

[0243] Specific symptoms relieved: fatigue, depression, mood swings, feelings of loneliness and helplessness, irritability, helplessness, forgetfulness, feeling like crying, poor concentration, feeling of loss of control.

[0244] *Note after 3rd dose: "Taking the pill two days in a row made the effects of the second day seem to last longer. 24 hours after taking the pill, I felt much calmer and more comfortable than I would during a normal period, even though I had not taken an additional pill." (Diana)

[0245] Results: This participant was quite skeptical before the trial began. She thought she was in the placebo group and did not expect any effect from the capsules. She hoped it would help her get through things and get things under control. Diana was amazed by how well the pills worked for her. She tried different doses in three trials (25mg the first time, then 12.5mg the next two times). The first time, she took one pill around the day she would normally feel her menstrual symptoms, but her period was late. The second and third doses were taken during the first few days of her (late) period. The main side effects were an increased heart rate and stomach pains when hungry. Psychologically, she admitted to feeling more focused and energized, and her mood was elevated and impulsive. She noticed a higher heart rate. After this, she wanted to try a lower dose to see if it would have a more dramatic effect. At the low dose of 12.5mg, she felt more energetic, less lethargic and fatigued, and her heart rate seemed to normalize. Emotionally, she felt more focused, calm, more controlled and more stable.

[0246] Example VI - "Emma" Emma is a 23-year-old woman, originally from India and raised in Saudi Arabia (60 kg, 1.68 m) (average height and weight), a full-time student and well-educated. She lives alone and is in a relationship. She does not use any form of contraception. Her menstrual cycle is regular and she has several psychological symptoms associated with the menstrual cycle. These symptoms have worsened over the past few years.

[0247] menstrual cycle symptoms Emma took part in the trial because of the psychological distress she experienced during menstruation, some of which had been present since childhood.

[0248] Usually chronic menstrual cyclic symptoms (occurring all the time or almost all the time) Mental distress (after age 12 when menarche begins) Mood swings (age 12 and up) Eating Disorders / Cravings (Ages 12 and up) Feeling like crying for no reason (for at least a year) Depression (at least in the last 5 years) Feelings of loneliness / helplessness (for at least one year) Depression (last 2 months)

[0249] Infrequent (occasionally) symptoms that develop over time Irritability / upset (ages 12 and up) Restlessness / nervousness (5 years) Anxiety (past 5 years) Wanting to be alone (last 5 years) Burst of vitality (last 5 years) Feeling out of control (last 2 months)

[0250] background Emma's reactions and attitudes towards her symptoms have changed over time. As a child she was introverted and reserved. As she got older this changed and she noticed how emotional she became around her period. She started noticing the changes already a week before her period and it got worse 2-3 days before her period.

[0251] Irritability is the most common symptom. She is always anxious and questions herself a week before her period, but once it is over everything goes back to "normal". Her periods come regularly, usually lasting 7-10 days. If they come too late or too early, she associates this phenomenon with her stress levels. She is very aware of her period and keeps track of it.

[0252] Her premenstrual anxiety is not only noticeable to her, but also to others around her, who notice changes in her personality. She discusses these issues with those close to her, basically everyone except her father. What's interesting is that her sisters also experience similar symptoms around the time of their periods and become similarly upset and angry.

[0253] While Emma believes her personality changes are normal for her menstrual cycle, she would prefer to think differently because when she is on her period, she feels more "inside her shell" even though she is actually a very sociable and outgoing person. She forces herself to be with friends and do the things she enjoys during her period.

[0254] She also suffers from body aches and cramps, so she has tried various remedies, including comfort foods (chocolate) and painkillers. She loves coffee, but coffee makes her cramps worse. She also tries to forget the discomfort by moving around, whether it's walking, running or going to the gym.

[0255] summary Emma is a healthy 23-year-old woman who suffers from moderate to severe cyclical symptoms (probably PMS), some of which have been present since menarche. She is very aware of the impact her menstrual cycle has on her personality and is very open about it and tries to adopt a positive attitude. PMS symptoms appear to run through all the women in her family.

[0256] 3-MMC Clinical Trial Period period 60 days spanning three menstrual periods (2nd half of 2018) Number of clinical trials 7 times

[0257] Clinical Trial I Day of menstrual period: Day 5 of menstrual period Main motives for taking pills: Depression, wanting to cry for no reason, anxiety Time: 15:00 pm. Dose: 12.5 mg taken once. Physical reaction: Body became warm and felt a little hot. This reaction was very rapid and occurred after 30 minutes. Psychological response: Emma felt calmer, less anxious, and more in control of her behavior. She was no longer depressed. This feeling began after 1 hour, peaked after 4 hours, and began to subside by 6 hours. Side effects: None (except feeling warm).

[0258] Clinical Trial II Menstrual period trial date: 6th day of menstruation Main motivation for taking pills: Anxiety and nervousness Time of day: Take at 13:00. After lunch Dosage: 12.5 mg per dose Physical response: Feels warm and comfortable, but this time the response was slower and I only started to feel the change after 2 hours. Psychological response: Less anxiety and tension, felt calmer; this response occurred an hour later, but the sensation was weaker. Side effects: None

[0259] Clinical Trial III Trial date during menstrual period: 1 week before menstrual period, PMS Main motivation for trying the pills: Depression, sadness, anxiety, intense pain. This time, she decided to take a higher dose to get a stronger, more desirable effect. Time of day: Taken at 15:00. Dosage: 25 mg taken once. Physical reactions: Feeling of warmth (perceived increase in body temperature) 30 minutes after taking the pill, lasting for 2-3 hours. Psychological response: Emma no longer felt depressed, anxious or distressed. She felt calmer and more peaceful, which she called a "Zen moment." These changes began occurring 30 minutes after taking the pill. Side effects: None

[0260] Clinical Trial IV Menstrual period trial date: 5th day of menstruation Primary motivation for taking 3-MMC: Emma wanted to try the pills on a more "normal" day because she was not in any particular distress but was curious about the possible effect of the pills in that situation. Time of day: Taken at 13:00. Before lunch. Dosage: 25 mg once Physical response: After 1 hour I felt hot (warm), after 2 hours I felt very hungry. Psychological response: They felt motivated to concentrate and study, and this response peaked after 2 hours and lasted for another 2 hours. Side effects: None

[0261] Clinical Trial V Day of menstrual period: 10th day of menstruation Main motivation for taking the pills: She wanted to feel more in control, focused, and motivated to study. Time: Taken at 13:00. No lunch Dosage: 25 mg once Physical response: After 2 hours I felt hot and hungry, ate a lot, but after an hour I felt hungry again. Psychological response: I felt that my concentration was improved and I was able to read or study energetically for about four hours. Side effects: None

[0262] Clinical Trial VI Day of menstrual period: 11th day of menstruation Main motivation for taking the pills: She needed to study like the day before (for the second day in a row). Time: Taken at 13:00. No lunch Dosage: 12.5 mg per dose Physical response: less hungry (probably cumulative effect: she had taken the pills the day before), felt a little warmer, but not as much as before. Psychological response: Couldn't concentrate very well, slight (low dose this time). Side effects: None

[0263] Clinical Trial VII Date of menstrual period: 1 week before the predicted menstrual period Primary motivation for taking the pills: Emma reports that she was feeling a bit emotional and needed to study and concentrate. Time of day: Take at 4:00 p.m. with food Dosage: 25 mg once Physical Reaction: After an hour she started to feel really cold (mainly body, hands and feet) and hungry even though she had eaten before taking the pill. Psychological response: Emma achieved what she wanted, was more focused and motivated in her studies. The positive effects peaked at 2 hours, lasted for another 2 hours, and faded away after 6 hours. Side effects: cold hands and feet

[0264] Results: Emma started with a dose of 12.5 mg, which already had a positive effect in terms of calming and relaxing her. This effect increased with the higher dose of 25 mg, and Emma also noticed that she was able to concentrate better and had more motivation to do things. Her first three trials were related to the distress caused by her menstrual cycle, but afterwards she said that she was not particularly anxious, but would like to try taking the pills at a time when she needed to study. She said that she was very happy with the discovery that the pills helped her to concentrate on reading, improved her concentration and increased her motivation to study. Thus, in the last four trials, she took one low dose and three high doses, with the higher dose having a noticeable effect on her concentration levels. With all doses (low or high) and with all trials, Emma noticed a change in her body temperature. It almost always felt warm, but this was not unpleasant for her. Only once, Emma suddenly felt that she was cold, especially in her hands and feet. It is possible that the pills caused a change in appetite, but she is not sure. The effects of the pills began after an hour on average, lasted for two to three hours, and wore off completely after six hours.

[0265] Example VII - "Fanny" Fanny is a 21-year-old student from Finland (height 1.60 m, weight approx. 50 kg) who is in a relationship and lives with her boyfriend. She is healthy and uses an intrauterine device. She menstruates regularly, always with unpleasant symptoms attributable to the menstrual cycle.

[0266] menstrual cycle symptoms Fanny entered the trial because of mainly psychological complaints related to her menstrual period. Her symptoms usually begin a week before her period, but her pre- and post-menstrual distress can also occur during her now longer menstrual periods.

[0267] Typical menstrual cyclic symptoms (chronic): Depression (for years, not specified how many) Mood swings (for years) Exhaustion and fatigue (for years) Hypersensitivity (for years) Feeling like crying for no reason (for years)

[0268] Less common symptoms (occasionally seen): Forgetfulness (over the past few years) Irritability / upset (over the past few months) Restlessness or nervousness (over the past few months) Feelings of impatience (for several months) Lethargy (over the past few months) Decreased concentration (over the past few months) Expressive behavior (past few months)

[0269] background At the start of her period, Fanny often feels depressed, moody, exhausted, irritable, and sometimes tearful. She has had many of these symptoms for many years. Over the past year, the symptoms have worsened and Fanny sometimes feels nervous, restless, agitated, impatient, forgetful, tired, and inattentive. All of these feelings and states are usually felt a week before and sometimes a few days after her period. In the last few years, her periods have become longer, up to seven days in length.

[0270] Fanny has suffered from menstrual symptoms for many years but her symptoms worsened after she left school and went to university. She says her symptoms began long before she decided to use an intrauterine device and are therefore not related to her choice of contraception method.

[0271] She usually has few physical problems associated with her period, and most of the pain is mild enough to be relieved with over-the-counter painkillers.

[0272] She has an open and frank attitude towards menstruation. She got her first period at 12 and took it very naturally. Her mother also suffers from severe period-related symptoms, as does her sister, and she says it's hereditary. Sure, by this time it can affect her relationships with boyfriends and friends, but she's not an indoor person and carries on with her life. When things get really bad, horse riding is always good medicine for Fanny.

[0273] summary Fanny is a healthy 21-year-old young woman who suffers from moderate to severe symptoms associated with PMS. Other women in her family also suffer from severe PMS symptoms. Her psychological distress has been consistent since menarche.

[0274] 3-MMC Clinical Trial Period period 60 days between two menstrual periods (2nd half of 2018) Number of clinical trials 5 times

[0275] Clinical Trial I Clinical trial date during menstrual period: 20th day of menstruation, 9 days before menstruation Main motivation for trying 3-MMC: Irritability and lack of focus Time: 11:30am, after breakfast Dose: 12.5 mg taken once. Physical reactions: Fanny reported muscle relaxation after 30 minutes, muscle tingling and a tingling sensation in the tongue / back of the throat after 1 hour. These sensations lasted for up to 2 hours. She also reported feeling drowsy, which disappeared after 2 hours. Psychological response: She was still irritable for the first hour after taking it, but after that her mood improved and she was less irritable, but not by much. The next day she felt agitated again. Side effects: tingling tongue, slight drowsiness

[0276] Clinical Trial II Trial date during menstrual period: 24th day of menstruation, 4 days before menstruation (PMS) Primary motivation for trying 3-MMC: General discomfort and irritation. Time: 10:50am, after breakfast Dose: 25mg. Physical reactions: After 30 minutes, relaxation and drowsiness, slight fatigue or drowsiness, increased muscle pain, increased tension in certain muscles around the shoulders, after 1 hour the muscle pain was gone, stomach pain for a few minutes (after 1 hour), sore throat that lasted for about 2 hours. Psychological response: Fanny felt a change, relaxed and calm. One hour after taking the drug she felt happier and more focused (up to 4 hours). She felt good for the rest of the day and no longer irritable or uncomfortable. From then on she felt great. Side effects: drowsiness, slight muscle pain and tension

[0277] Clinical Trial III Trial date during menstrual period: 27th day of menstruation, 1 day before menstruation (PMS) Main motivation for trying 3-MMC: Stress and frustration (very busy time in undergraduate studies) Time: 10:35am, after breakfast Dosage: 25 mg taken once. Physical reactions: After 30 minutes, muscles relaxed, slight stomach pain (possibly related to menstruation), no change in appetite. After 1.5 hours, muscle tension in the shoulders and increased energy were reported. After 2 hours, Fanny felt drowsy and still had muscle tension. The drowsiness and muscle tension eased after 3 hours. 24 hours after taking the drug, Fanny still felt well. Psychological response: 30 minutes after taking the drug, Fanny felt calm and stable, 1 hour later she was able to concentrate fully, 1 hour and 30 minutes later she was fully focused and happy to study, no longer felt stressed, irritated or anxious, and she was fine for the rest of the day. Side effects: No desire to go to the gym or fit for any physical challenge. Temporary mild stomach and muscle pain.

[0278] Clinical Trial IV Menstrual period trial date: 3rd day of menstruation Primary motivation for trying 3-MMC: Extreme discomfort and anxiety (upsetting news) Time: 13:45, after lunch Dosage: 25 mg once Physical reactions: After 30 minutes, no change, after 1 hour, numbness and relaxation, after 1.5 hours, goosebumps and chills, change in body temperature. After 2 hours, chills disappeared, but muscle tension and tingling remained. Psychological response: After 30 minutes she felt calm and, despite the very upsetting news, Fanny had no physical reaction and felt her body was "under control", even though she recognized that she was very worried. She was upset, but she accepted the situation and it was easy to deal with it. After 2 hours she felt better and decided to stop procrastinating and study. She was less concentrated, but no longer upset and was very calm. After 6 hours she was still focused and felt "calm". Side effects: noticed change in body temperature, tingling sensation in throat.

[0279] Clinical Trial V Trial date during menstrual period: 3-4 days before menstruation (PMS) Primary motivation: Irritability, wanting to cry, feeling emotionally unwell Time: 21:50, after dinner Dosage: 25 mg once Physical reactions: No reaction after 1 hour, then increased scalp sensitivity, tingling in the back of the throat, and cold hands and feet around 11pm. After 1.5 hours she felt stomach pain and irritability, after 2 hours Fanny felt better again but had difficulty falling asleep. It took Fanny an hour to fall asleep. After 24 hours she felt "normal" again. Psychological response: After 30 minutes, Fanny was less emotional. After an hour, she was still upset but no longer wanted to cry. After an hour and a half, she was emotional again. Her mood improved slightly but temporarily. Side effects: Difficulty falling asleep.

[0280] Response: The subject took the pill five times, three times a few days before her menstrual period and two times during her menstrual period. Fanny suffered from mental distress throughout the entire trial. The first time she took 12.5 mg, the other four times the dose was 25 mg.

[0281] The 12.5 mg pill had a mild effect on Fanny, but she was already able to talk calmly and emotionally relaxed. On all other occasions, when she took the 25 mg dose, she felt significantly calmer, in control, more focused and contained. She felt more active and energetic on a mental level. On one occasion, she was so distressed by some unfortunate news about her family that she felt completely out of control, so she took the pill. Fanny realised how much the pill controlled her reaction. She was still very worried about the situation, but was able to sit and work instead of crying. This resulted in a good mood afterwards.

[0282] Physical reactions could be considered "mild" side effects, some of which were seen in all trials even at low doses. There was an unidentified tingling sensation in the tongue and back of the throat for about 2 hours after taking the pill. Fanny felt generally relaxed, but had certain muscle tension in the shoulder area, and occasionally experienced very brief stomach pains (lasting 5-10 minutes). Fanny reported feeling too sleepy and numb to perform physical activities, but feeling very alive to perform mental activities. At one point, Fanny experienced a change in body temperature, cold hands and feet, and goosebumps. When taking the pill at night, she had trouble falling asleep, even though she felt calmer.

[0283] Example VIII - "Ines" Ines is a 19-year-old student of Hungarian origin living in the Netherlands (height 1.62 m, 47 kg). She is not in a relationship and does not use any form of contraception. She lives alone and shares her home only with her landlord. Her menstrual cycle is regular and has no problems other than emotional distress.

[0284] menstrual cycle symptoms A few days before her period, Inés begins to feel anxious; her symptoms are not severe enough to interfere with her daily life, but are strong enough to remind her that her period is about to begin.

[0285] Recognized cyclical symptoms, chronic: Hypersensitivity (after the first menstrual period) Mental distress (constantly) Mood swings (constantly) Indecisiveness (over the past few years)

[0286] Occasional menstrual symptoms: Fatigue and tiredness (over the last few years) ·Feeling helpless (in recent years) Lethargy / fatigue (in recent years) Feeling like crying / crying (after menarche)

[0287] background A few days before her period, Ines usually feels emotional distress and very tired. She has no sisters to compare her symptoms to, but her mother never complained about the difficult days around her period. Therefore, Ines says, "Maybe this problem is not hereditary." When she feels anxious as her period approaches, she usually takes it easy by taking a nap. Because PMS affects her mood and motivation, Ines tends not to exercise or exert herself.

[0288] Her menarche occurred at the age of 12 and was a natural, uncomplicated event, without any stress. However, as she got older, Ines noticed that she was becoming more irritable and emotional. The psychological distress she felt was usually a reminder that her period was about to begin. Her menstrual periods are regular, lasting 28 days and usually lasting about 5 days. Ines has never been formally diagnosed with PMS. She attributes the worsening of her symptoms to changes in her life, for example, going from school to university. Ines considers herself to have a normal social life and has no problems with her relationships or social interactions, even while experiencing menstrual cyclical symptoms. Ines is very open about discussing menstruation.

[0289] summary Inés is a healthy 19-year-old young woman suffering from moderate menstrual cyclic symptoms. There is no record of other women in her family being affected. Her psychological distress has gradually worsened over time.

[0290] 3-MMC Clinical Trial Period period 60 days between two menstrual periods (2nd half of 2018) Number of clinical trials 7 times

[0291] Clinical Trial I Trial date during menstrual period: 27th day of menstruation, 1 day before menstruation Main motivation for taking the pills: Emotional distress and curiosity about how the pills would help her. Time: 17:00 pm Dose: 12.5 mg taken once. Physical reaction: None Psychological response: Feeling safer, more relaxed and less emotionally distressed after 1 hour. This feeling lasted for up to 3 hours. Side effects: None

[0292] Clinical Trial II Date of menstrual period: First day of menstruation Main motivation for taking pills: Feeling a little nervous Time: Evening 18:00 Dose: 25mg. Physical reaction: None in particular. Psychological response: After the first 30 minutes, Inez already felt relaxed and less tense, after a few hours she felt more energetic, and after 4 hours she was back to normal, feeling the way she always did, but calmer. Side effects: There were no side effects and they were not related to how much sleep I got that night.

[0293] Clinical Trial III Menstrual period trial date: 2nd day of menstruation Main motivation for taking the pills: Feeling a bit nervous and having a headache. Time: 10:00, after breakfast (less than 24 hours after last pill) Dose: 12.5 mg taken once. Physical response: Headache subsided after an hour. Psychological response: felt calmer and more stable 30 minutes after taking the drug, and more satisfied and relaxed 1 hour later. Was more motivated to undertake mental tasks than physical tasks. Side effects: None

[0294] Clinical Trial IV Trial date during menstrual period: 26th day of menstruation, 2 days before menstruation Main motivation for trying 3-MMC: Feeling "down," upset, unmotivated Time: 10:00am, after breakfast Dose: 1 dose, 25 mg. Physical Reaction: None Psychological response: 30 minutes after taking the drug there was little reaction, and after an hour the patient felt significantly less agitated and sad, a feeling that continued for the rest of the day. They also had more energy. The effects of 3-MMC lasted for up to 6 hours. Side effects: None

[0295] Clinical Trial V Trial date during menstrual period: 27th day of menstruation, 1 day before menstruation Main motive for taking pills: Emotional distress Time: 10:00am, after breakfast Dose: 12.5 mg taken once. Physical reaction: None. Psychological response: Less mood swings, agitation, emotional discomfort and fatigue 30 minutes after taking the drug (possible cumulative effect: Inez took the drug consistently for several days prior to her menstrual period). Side effects: None

[0296] Clinical Trial VI Date of menstrual period: First day of menstruation Main motives for taking pills: Mental distress and tension. Time: 11:00am, after breakfast Dosage: 12.5 mg per dose Physical response: None, possibly decreased tension. Psychological response: Inez was calm, not nervous, and not emotional after taking the pill, but once the pill's effects wore off, her tension returned, but she remained calm. Side effects: None

[0297] Clinical Trial VII Menstrual period trial date: 2nd day of menstruation Main motives for taking pills: mental distress, tension, helplessness. Time: 10:00am, after breakfast Dosage: 12.5 mg per dose Physical reaction: None. Psychological response: Inez felt immediately better and less distressed and tense. She felt calmer and more content, the pills seemed to work better than they had the day before, and her tension subsided rapidly, possibly a cumulative effect. Side effects: None

[0298] Response: The subject used the pills seven times (alternating between 12.5 mg and 25 mg), and throughout that time she continued her normal busy university life, so her "rhythm of life" was not altered by any disruptive events. However, Ines still felt emotional distress during her menstrual cycle symptoms, so she used the pills three times in a row, each time before her period. She did not experience any significant side effects or physical reactions. The main effect was to feel calm and relaxed, but not really concentrate (as other participants said). Ines felt more accepting of those around her, although her peers may not have noticed the change in her. Although no significant dose-response was observed, there may have been some kind of cumulative positive effect within 24 hours of taking the pills (this needs to be supported by further research). However, it should be noted that Ines herself acknowledged that the effect of the pills lasted no more than 4-6 hours.

[0299] Example IX - "Jenny" Jenny is a 24-year-old woman of mixed (German-Turkish) ancestry. She is 1.70m tall and weighs 65Kg. She participated in the study because she suffers from moderate to severe menstrual cyclic symptoms a few days before her menstrual period. She studies and works in the Netherlands. She lives with a flatmate and is in a long-distance relationship with her boyfriend. She does not use any contraception and her menstrual periods are regular, around 24 days, lasting 3-4 days.

[0300] menstrual cycle symptoms Jenny has suffered (for at least several years) from several distinct chronic menstrual cyclical symptoms.

[0301] Common symptoms: Mental distress (over the last few years) Feeling "depressed" Eating Disorders: Cravings

[0302] She also occasionally experiences the following symptoms: Fatigue or tiredness (for 2-3 years) ·depression Feelings of loneliness and helplessness I want to be alone I want to be silent Crying for no apparent reason (for several months)

[0303] background Jenny feels severe symptoms 4-5 days before her period. She has emotional problems, which are also associated with body pain and digestive problems. Her symptoms are getting worse every year. Most of the time, Jenny is aware that she experiences physical and psychological pain, as well as other changes around the time of her period, which in turn helps her to raise awareness about the symptoms and monitor her menstrual cycle. She has not taken any special measures to overcome her problem, but usually goes for a run to relax. This is something she likes to do during her period, but on the contrary, she feels that she does not want to exercise at that time.

[0304] Once her period subsided, Jenny felt normal again, free of emotional burden, and "happy" again. This flow of emotions comes regularly every month.

[0305] Her first period was a natural process. She recalls it as an overall positive experience and remembers being excited about it. She also remembers that there were periods when her period stopped or was irregular and she felt sick. Although Jenny does not like the days before her period starts, she also feels that it is a natural, healthy and necessary experience.

[0306] Jenny acknowledges that her social and professional relationships may be affected by her cyclical symptoms. She has been open about this with her close family and has also counselled her mother and sister, who appear to experience the same cyclical symptoms.

[0307] summary Jenny is a healthy 24-year-old young woman who suffers from moderate to severe menstrual cyclic symptoms. Some of these symptoms began several years ago, but have gradually worsened over the past few months. Her mother and sister also suffer from psychological distress around the time of their menstrual period.

[0308] 3-MMC Clinical Trial Period period 60 days between two menstrual periods (December 2018 / January 2019) Number of clinical trials 4 times

[0309] Clinical Trial I Trial date during menstrual period: 21st day of menstruation, 4 days before menstruation (PMS) Main motives for taking pills: unhappiness, confusion, emotional distress. Time: 8:30am, after breakfast Dosage: 25 mg taken once. Physical Reaction: None Psychological response: After 30 minutes, Jenny felt better, less anxious, less frustrated, and "normal" again (i.e., no menstrual cycle symptoms). The good mood lasted for 2-3 hours and then faded away. Side effects: None

[0310] Clinical Trial II Trial date of menstrual period: 4th day of menstruation, last day of menstruation Main motivation for taking the pills: Jenny felt completely exhausted, had headaches, no energy and was depressed. Time: 17:00 Dose: 12.5 mg taken twice, equivalent to 25 mg. Physical Reaction: The headache lingered deep within and Jenny felt physically exhausted even after the effects of the 3-MMC had worn off. Psychological response: After 30 minutes she began to feel better, after 1 hour Jenny felt more energetic and was no longer depressed or sad, and this positive effect lasted for approximately 2 hours. Side effects: None.

[0311] Clinical Trial III Trial date during menstrual period: 12th day of menstruation (possible ovulation) Main motivation for trying 3-MMC: Feeling exhausted, helpless, tired, and wanting to cry Time: 18:00, after work Dosage: 25 mg taken once. Physical response: A fundamental feeling of physical fatigue remained. Psychological response: 30 minutes after taking the drug, Jenny felt better and more relaxed, and after 1.5 hours she felt much better and more motivated to do things. She no longer felt helpless and did not want to cry anymore. Side effects: None

[0312] Clinical Trial IV Menstrual trial date: 21st day of menstrual cycle, 7 days before menstruation Main motivations for taking the pills: Extreme sadness for no apparent reason, lack of motivation and energy, strong desire to be isolated, loss of appetite, headaches. Time: 10:00am, after breakfast Dosage: 25 mg taken once. Physical Response: Jenny's appetite returned within an hour of taking the drug and she began to feel better psychologically. By the end of the day, she no longer felt sad or had a headache. Psychological response: 30 minutes after taking the drug, Jenny began to have a little more energy and was no longer depressed. Her sadness was fading. After 1 hour, she had more energy, was able to complete some tasks and interact with people (she no longer wanted to be alone). After 1.5 hours, she was at the peak of her disposition and abilities. Side effects: None

[0313] Response: This subject took the pills four times, all four times at the same dose (25 mg). She had a positive experience in all four trials. In all four trials, she had a normal work and study life without any particularly painful situations, but in the last case, she was especially depressed, sad, and wanted to isolate herself. Overall, it was a surprisingly good experience for her. At first, she thought the pills would not help her, but somehow they made her feel better. She said that there was a clear difference in her mood before and after taking the pills. However, in Jenny's case, the effect did not last long, only a few hours. However, with the crisis over, she felt energized again and, as she put it, "normal." Normal for her means that she no longer has strange thoughts or anxiety. Overall, the pills helped her to be more focused and positive about her life, which was very pleasant, especially since the good mood lasted for the rest of the day.

[0314] Example X - "Rebecca" Rebecca is a healthy 21-year-old woman (50 kg, 1.60 m tall) from the Netherlands, studying and working part-time. She is in a relationship and shares her home with another person. She stopped taking oral contraceptives due to side effects and tried an intrauterine device. Currently, she is not using hormonal contraception. She has used the abortion pill once and her menstrual period is regular, about 28 days.

[0315] menstrual cycle symptoms Rebecca participated in the study because of psychological and psychiatric complaints related to her menstrual cycle. Her cyclic symptoms usually begin about two days before her period, but she may also experience symptoms during her period. These cyclic symptoms have been a part of her cycle for the past few months.

[0316] Typical menstrual cyclic symptoms: (chronic) ·Mental pain Mood swings Depression Irritability / upset Restlessness / tension ·tension Feelings of loneliness and helplessness ·Hypersensitivity ·confusion Indecisiveness Desire to be alone · Desire to remain silent or to speak (emphasizing the desire to remain silent) · Poor concentration or distractibility Changes in sexual desire Decreased interest in normal activities Other: Mental non-presence / absence

[0317] Less common symptoms: ·depression ·anxiety Exhaustion or fatigue Lethargy / fatigue Expressive behavior Crying for no reason

[0318] background Rebecca is a generally healthy person, but had an ovarian cyst removed when she was 15 years old. Her menstrual symptoms began approximately six months ago, and she notices them getting heavier a few days before the start of her period. Symptoms include physical symptoms (e.g., lower back pain) as well as psychological / emotional symptoms such as feeling "down" and aversion to social interactions. Social avoidance and lack of interest in social contact are normal manifestations of the emotional symptoms due to her menstrual cycle.

[0319] People around Rebecca notice her mood swings before and during her period. These symptoms affect her daily life and her work. Her boss sometimes notices her moodiness because she only does what is truly necessary at work. Her boyfriend knows that she has mood swings around her period and although they sometimes argue about it, they do discuss her symptoms. Rebecca sometimes thinks that what she experiences is actually worse than what others perceive it to be.

[0320] A few years ago, Rebecca tried birth control pills, but they made her depressed and she felt less joy in life. She then tried an intrauterine device, but removed it when it reduced her libido. To better control her symptoms, Rebecca tried microdosing LSD, but eventually stopped for fear of addiction and unwanted side effects.

[0321] summary Rebecca is a healthy 21-year-old female who suffers from moderate to severe menstrual cyclical symptoms (e.g., PMS).

[0322] 3-MMC Clinical Trial Period period 60 days between two menstrual periods (December 2018 / January 2019) Number of clinical trials 3 times

[0323] Clinical Trial I Trial date of menstrual period: 3rd day of menstruation, during menstruation Main motivation for taking the pills: Already feeling depressed, fatigued, and irritable a few days before. Time: 13:00, after meals Dose: 25 mg once + 12.5 mg once (total 37.5 mg). Physical response: After 1 hour, legs felt lighter, after 3 hours tension around head was relieved. Psychological response: After one hour, Rebecca was more awake, had more energy, felt more alive, and was less tired and irritable. She was more willing to do things. Negative feelings began to change to positive ones, and the positive feeling persisted even after the effects of the pills had subsided. Side effects: None

[0324] Clinical Trial II Menstrual period trial date: 2nd day of menstruation Main motives for taking pills: Mood swings, mental distress. Time: 17:00 Dose: 12.5mg. Physical Reaction: None Psychological response: None (she felt no effect at this low dose). Side effects: None

[0325] Clinical Trial III Menstrual period trial date: 3rd day of menstruation Main motivation for taking pills: Feeling obviously depressed and unhappy Time: 14:00 Dosage: 25 mg taken once. Physical Reaction: None Psychological response: After one hour, she felt less stressed, "really at ease," her mood was "upper," she felt less sad, less depressed and less stressed. These positive feelings lasted for three hours. Side effects: None

[0326] result: Rebecca tried the pills in three different trials (the first at 37.5 mg, the second at 12.5 mg, and the last at 25 mg). Rebecca decided to try the pills during the first few days of her period (when symptoms are heavier) because she suffers from symptoms (e.g., distress, "low mood," and social avoidance) not only a few days before her period, but also during her period. In the first trial, at the highest dose, Rebecca actually felt very good, to the point that she recalls feeling a little anxious as her dark mood was replaced by a feeling of elation and happiness. The second time, because she somehow felt that this was not actually her, she tried the smallest possible dose (12.5 mg), but had no significant reaction, neither positive nor negative. In the third trial with 25 mg, a pleasant and positive change occurred, she naturally calmed down and felt better. 25 mg seems to be the ideal dose for Rebecca. She did not want to continue trying the pills, as she felt that she was prone to addiction and was afraid of "liking them too much."

[0327] Rebecca didn't experience any physical reactions or unwanted side effects at any of the doses. She just said that it wasn't that easy to fall asleep that day (due to the lateness of the trial).

[0328] Example XI - "Pamela" Pamela is a 20-year-old woman (81 kg, 1.80 m) from Slovenia, a university student living with her boyfriend in the Netherlands. She does not use any contraception and has never been pregnant. Her menstrual periods are often regular, but can be shorter or longer than 28 days. Her periods are generally very painful, and she also has distressing psychological symptoms a few days before her period.

[0329] menstrual cycle symptoms Chronic symptoms: Decreased interest in daily activities (over a 3-year period) Anxiety (2 years) Food cravings (2 years) Desire to remain silent or to speak (2 years) Helplessness (2 years) ·Decreased concentration (1 and a half years)

[0330] Common symptoms: Mood swings (3 years) ·Mental pain (3 years) · Impatience (2 years) Hypersensitivity (2 years) Irritation (1 year) Physical problems or pain (headaches, abdominal bloating, breast tenderness, etc.) (for 5 years)

[0331] Occasional symptoms: Decline (3 years) Desire to be alone (3 years) Forgetfulness (2 years) · Confusion (2 years) Changes in sexual desire (over a 2-year period) Nervous (1 year) Fatigue (1 year)

[0332] background Pamela is a healthy person and generally avoids medications except during menstruation. She takes painkillers for physical symptoms and homeopathic substances (e.g., valerian leaf, which has a sedative effect) to help her relax and feel in control.

[0333] She had her first menstruation at age 14. It was a normal and natural experience, but in recent years it has become uncomfortable due to stress and the daily activities demanded by her studies. Pamela's symptoms worsened when she left school. Her psychological state appears to affect her physiology; for example, periods of stress can make Pamela's periods longer or shorter, depending on how worried and affected she is by the emotional stressor. Changes in her sleep patterns can also affect the regularity of her menstrual cycle.

[0334] She is very lethargic during her menstrual period and prefers to stay home and rest if possible. Her boyfriend has always noticed changes in her behavior around her menstrual period and is conscious of how this affects their relationship. There is no record of her sisters (2) or mother possibly suffering from menstrual symptoms. She has openly discussed this topic with her mother, other family members, and the general public.

[0335] summary Pamela is a healthy young woman who for the past few years has suffered from silent, stressful psychological symptoms associated with her menstrual cycle. She also suffers from physical pain. Pamela does not tolerate medication well, but manages her symptoms with painkillers and occasionally sedatives. Her primary symptoms are mood swings, fatigue, pain, confusion, and irritability, the number and duration of which are consistent with menstrual cyclic symptoms.

[0336] 3-MMC Clinical Trial Period period 60 days spanning three menstrual periods (2nd half of 2018) Number of clinical trials 4 times

[0337] Clinical Trial I Date of menstrual period trial: Day 26, 3 days before the next menstruation, symptoms experienced. Main motives for taking pills: Stress, anxiety, lack of concentration. Time: 12:00am, after breakfast Dosage: 12.5 mg per dose Physical Reaction: None Psychological response: None Side effects: None

[0338] Clinical Trial II Date of study during menstrual period: 27th day of menstruation or 2 days before experiencing symptoms. Main motives for taking pills: Feeling overwhelmed, hopeless, suffering, stress, having a really hard day Time: 13:00, after breakfast Dosage: 25 mg taken once. Physical response: No reaction Psychological response: After 1.5 hours, she felt a little less tense, after 2 hours she felt a little more relaxed and less distressed. Pamela was no longer obsessed with her problems. Four hours after taking the pill, she felt more stable but still felt the pressure of a difficult day. Side effects: None

[0339] Clinical Trial III Clinical trial date during menstrual period: Day 2, during menstrual period. Main motives for taking pills: feeling unwell, mental distress, helplessness, lack of motivation, lack of energy. Time: 11:00am, after breakfast Dose: 12.5 mg taken once. Physical Reaction: None Psychological response: None, neither good nor bad Side effects: None

[0340] Clinical Trial IV Day of menstrual trial: 27th day of cycle, 2 days before menstruation, experiencing symptoms Main motives for taking pills: Emotional distress, crying for no reason. Time: 18:00, after meals Dosage: 25 mg once Physical reactions: After 1.5 hours, felt colder than usual, then felt very hot while in the bath, after 3 hours felt fatigued, after 4 hours could not sleep. Psychological response: After 1.5 hours she calmed down a little, after 2 hours she was very relaxed and not crying anymore, after that she felt a little numb, then she stabilized, but after 6 hours she felt low energy and was unmotivated again. Side effects: Some fatigue and changes in body temperature.

[0341] result Pamela took four doses of the pill, two doses of 12.5 mg, and two doses of 25 mg. The 12.5 mg dose had no physical or psychological effects on her. The effects of the 25 mg dose were also not as relevant as those of the other subjects. She felt a little more relaxed and calm, but did not actually experience any positive effects. (Note: Pamela was the heaviest and tallest of all the subjects, so her weight may have influenced her response.) Pamela also experienced some mild, unwanted effects, such as changes in body temperature.

[0342] Example XII - Summary of all cases Between late 2018 and the first few months of 2019, 11 women participated in a blinded clinical trial of 3-MMC (the "pill") taken to relieve menstrual cycle symptoms. Each subject tried various doses ranging from 12.5 mg to 50 mg.

[0343] Ten of the 11 reported fairly good to very positive experiences, meaning that 3-MMC was effective for its intended purpose and made them feel better, in some cases, much better.

[0344] Although 3-MMC is not specifically targeted to relieve the physical pain or discomfort associated with the menstrual cycle (e.g., headaches, bloating, cramps), it should be noted that some of the normal physical menstrual cycle symptoms (e.g., headaches) may be exacerbated as a result of tension or other mental / psychological distress. Thus, in many participants in this trial, taking 3-MMC resulted in the disappearance of physical symptoms (e.g., headaches).

[0345] One of the women in the study combined 3-MMC treatment with paracetamol without any significant substance interactions or undesirable effects. The approach to menstrual symptoms is usually physical. Combining 3-MMC with the usual medications for physical menstrual symptoms (e.g. painkillers) could broaden the scope of treatment and, for example, reduce the cause of work disability for millions of women every month around the world.

[0346] With the exception of "Gertie" (Example I), all women in the study reported moderate to severe menstrual cyclic symptoms (e.g., PMS). In some cases, due to the number of years of suffering and the severity and amount of symptoms, the clinical picture could be interpreted as dysphoric mood syndrome (PMDS) according to the DSM-5 manual.

[0347] Each woman used 3-MMC for relief for at least 2-3 consecutive menstrual periods, with the number of trials ranging from 2-7 per woman, for a total of 45 trials. One of the subjects ("Gertie") had tried 3-MMC for menstrual cyclic symptoms (e.g., PMS) and had taken 3-MMC for the past 15 menstrual periods to date ("Gertie" reports radically positive life changes).

[0348] Thus, the experience with 3-MMC for menstrual cyclic symptoms reported here is derived from approximately 60 separate trials.

[0349] FIG. 3 shows an overview of the indications for treatment with 3-MMC according to the invention, ie the most typical complaints women mention before the clinical trial.

[0350] result Note: This study presents exclusively case studies and the results are qualitative in nature. Therefore, no statistics were applied in presenting these data. Mental distress in the form of anxiety, irritability and fatigue top the list of motivations for taking 3-MMC (see Figure 1). According to the case studies, the following effects were observed:

[0351] Most trials have produced desirable positive effects. Low doses (12.5 mg) of 3-MMC have been inconsistently but often effective in alleviating symptoms. In a few cases, higher doses (35-50 mg) of 3-MMC have been associated with undesirable side effects. In general, doses of 20-25 mg of 3-MMC have been shown to be effective, with no serious side effects reported. At 30-35 mg, some undesirable side effects, such as tachycardia and temperature changes, have been occasionally noticeable.

[0352] The most commonly reported psychological and emotional effects of 3-MMC were feelings of relaxation and calm, often combined with increased energy and focus, usually beginning 30 minutes to an hour after ingestion, lasting up to four hours, and fading after six hours, followed by a persistent feeling of calm. Figure 2 shows the terms used to describe the positive effects of 3-MMC, listed in order of frequency.

[0353] From some women's accounts, it can be inferred that feeling calm may also reduce physical symptoms (e.g., bodily pain).

[0354] This response suggests that 3-MMC may have a "cumulative positive effect." The positive effects of 3-MMC appear to persist after two or more consecutive trials (a second dose within 24 hours of the first, and a third dose within 24 hours of the second). Furthermore, the successive doses appear to be reduced with repeated dosing, with favorable results (e.g., an initial dose of 25 mg followed by 12.5 mg for two days appeared to provide more durable relief). A similar phenomenon was observed for undesirable effects, with repeated use of 3-MMC tending to reduce side effects over time.

[0355] The most commonly reported side effects include tachycardia, sensation of temperature change (usually feeling warm, sometimes feeling cold), and sweating. Changes in appetite (loss of appetite may be cumulative after several consecutive doses) or sleep patterns may also be possible. Some subjects reported improved sleep, while others reported difficulty falling asleep. Others reported brief stomach pains when fasting, and changes in skin condition (rashes and breakouts) (see Figure 3).

[0356] While the present invention has been described in conjunction with specific embodiments thereof, 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.

[0357] All publications, patents, and patent applications mentioned in this specification are incorporated herein in their entirety to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention, nor should it necessarily be construed as limiting, to the extent that section headings are used. Additionally, the priority documents of this application are incorporated herein in their entireties as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

1. A kit for treating at least one menstrual cycle symptom in a subject, comprising at least one dosage unit containing a therapeutically effective amount of 3-methylmethcathinone (3-MMC), instructions for administering the 3-MMC before, at, or after a time when the menstrual cycle symptom is expected to occur or has occurred, and packaging material.

2. 2. The method of claim 1, wherein the at least one menstrual cycle symptom is a symptom of a menstrual cycle condition selected from the group consisting of perimenstrual disorders, premenstrual syndrome (PMS), and premenstrual dysphoric disorder (PMDD).

3. 2. The treatment kit of claim 1, further comprising a device for determining when the at least one menstrual cyclic symptom is expected to occur or has occurred in the subject.

4. 10. The treatment kit of claim 1, accompanied by a digital computer interface for recording the timeline and characteristics of said at least one menstrual cycle symptom.

5. The therapeutic kit of claim 4 , wherein the interface is a mobile phone application interface, the kit further comprising a bar code for downloading or launching the application.

6. The therapeutic kit of any one of claims 1 to 5, wherein the dosage unit contains 5 to 100 mg of 3-MMC.

7. The therapeutic kit of any one of claims 1 to 5, wherein the dosage unit contains 10 to 60 mg of 3-MMC.

8. The therapeutic kit of any one of claims 1 to 5, wherein the dosage unit contains 12.5 mg of 3-MMC.

9. The therapeutic kit of any one of claims 1 to 5, wherein the dosage unit contains 25 mg of 3-MMC.

10. The therapeutic kit of any one of claims 1 to 5, wherein the dosage unit contains 50 mg of 3-MMC.

11. The therapeutic kit of any one of claims 1 to 5, comprising at least one dosage unit of 12.5 mg of 3-MMC and at least one dosage unit of 25 mg of 3-MMC.

12. The therapeutic kit of any one of claims 1 to 5, comprising at least one dosage unit of 25 mg of 3-MMC and at least one dosage unit of 50 mg of 3-MMC.

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