MDMA response prediction

Abstract

To provide a method of dosing an empathogen / entactogen (such as MDMA) in treating patients.SOLUTION: The present invention provides a method of determining a dose of an empathogen / entactogen based on body weight, sex, and CYP2D6 activity by assessing patient characteristics of body weight, sex, and CYP2D6 activity before empathogen / entactogen use, administering the empathogen / entactogen to the patient based on the patient characteristics, and producing maximum positive subjective acute effects in the patient.SELECTED DRAWING: None

Description

Technical Field

[0001] Background of the Invention 1. Technical Field The present invention relates to a method for predicting the response to (±) 3,4-methylenedioxymethamphetamine (MDMA) and optimizing the induction of specific acute effects in the treatment of medical conditions.

Background Art

[0002] 2. Background Art MDMA is a psychotropic drug that alters mood and cognition, and has been considered as an adjunct in psychotherapy for post-traumatic stress disorder and has later also been tested for various other medical conditions (Mithoefer et al., 2019; Mithoefer et al., 2010; Oehen et al., 2013).

[0003] What the ideal dose of MDMA is in this treatment modality is unclear. Specifically, the dose can vary depending on many factors including, but not limited to, gender, weight, age, metabolic differences, mood and mental state before MDMA administration, and personality trait factors. Therefore, it is a challenge to find the exact dose of MDMA in an individual.

[0004] While MDMA acutely induces positive subjective effects including mainly mood elevation, openness, trust, and increased empathy, negative drug effects can also occur (Hysek et al., 2014a; Schmid et al., 2014).

[0005] In some prior studies, single variables affecting the response to MDMA have been defined. Variables affecting drug experience are classically divided into set and setting (Leary et al., 1963). Set consists of factors related to the individual such as personality, age, and previous drug experience, and the individual's expectations and intentions regarding drug effects. Setting relates to environmental factors such as the place of drug intake, the people present at the time of intake, and the cultural environment (Hartogsohn, 2016).

[0006] The drug effects of MDMA have been shown to be dose-dependent (Bedi & de Wit, 2011; Vizeli & Liechti, 2017). However, in addition to dosing helping to predict the individual response to MDMA, it is unclear how additional factors such as set and setting can be used.

[0007] In the case of other substances such as psilocybin, acute effects have been found to be mainly dose-dependent (Haijen et al., 2018; Studerus et al., 2012). Also, additional variables such as personality traits and mood before drug intake have been found to influence the acute effects of psilocybin (Haijen et al., 2018; Studerus et al., 2012).

[0008] "Bad trips" (moderately, also referred to as "challenging experiences") are of particular interest when using psychotropic substances including MDMA. Personality traits may predict such bad trips. For example, "neurotic tendencies" (Ormel et al., 2012), which reflect an individual's emotional instability and poor coping with stressors, have been shown to be associated with "challenging experiences" after psilocybin intake (Barrett et al., 2017).

[0009] In several previous studies, potential pharmacological and non-pharmacological factors contributing to the response to MDMA, including gender (Bedi & de Wit, 2011; Liechti et al., 2001; Pardo-Lozano et al., 2012; Simmler et al., 2011), pharmacokinetics (Pardo-Lozano et al., 2012; Vizeli et al., 2017), personality traits (White, 2017), and genetics (Bershad et al., 2016; Schmid et al., 2016; Vizeli & Liechti, 2018; Vizeli et al., 2018; Vizeli et al., 2019; Vizeli et al., 2017) have been examined.

Summary of the Invention

Problems to be Solved by the Invention

[0010] However, all of these tests evaluated only a few potential predictors, each without adjusting for potential confounding variables and without assessing the importance of different variables. In addition, the sample sizes of previous tests were rather small, precluding such analyses. Therefore, there remains a need for a method to predict response to MDMA considering multiple variables.

Means for Solving the Problems

[0011] Summary of the Invention The present invention provides a method of administering an empathogen / entactogen (such as MDMA) in the treatment of a patient by evaluating patient characteristics before use of the empathogen / entactogen, administering the empathogen / entactogen to the patient based on the patient characteristics, and achieving the greatest positive subjective acute effects in the patient.

[0012] The present invention provides a method of determining the dosage of an empathogen / entactogen based on body weight, gender, and CYP2D6 activity by evaluating patient characteristics of body weight, gender, and CYP2D6 activity before use of the empathogen / entactogen, administering the empathogen / entactogen to the patient based on the patient characteristics, and achieving the greatest advantageous subjective acute effects in the patient.

[0013] The present invention also provides a method of improving the administration of an empathogen / entactogen by using a questionnaire including the NEO-FFI, STAI-T, and AMRS scales in a patient, evaluating the questionnaire responses, and improving the administration of the empathogen / entactogen to the patient based on the questionnaire.

[0014] The present invention provides a method for predicting future administration of an empathogen / entactogen by measuring the plasma concentration of the empathogen / entactogen in a patient after administration of a certain dose of the empathogen / entactogen, adjusting the dose of the empathogen / entactogen in the patient, thereby optimizing the positive response to the empathogen / entactogen, and optimizing the efficacy and safety of the empathogen / entactogen treatment.

[0015] The present invention provides a method for assessing the likelihood that a patient will receive an empathogen / entactogen as a treatment by evaluating patient characteristics and assessing the likelihood that the patient will receive an empathogen / entactogen as a treatment.

[0016] The present invention further provides a method for optimizing the empathogen / entactogen treatment in a patient by evaluating the openness in the patient before the use of the empathogen / entactogen, predicting a positive response that causes further openness, optimizing the empathogen / entactogen treatment including repeated administration, and bringing about an expansion of openness and an expansion of the treatment response over a long period.

[0017] Description of the Drawings Other advantages of the present invention will be readily understood since they will become more fully understood by referring to the following detailed description when considered in connection with the accompanying drawings to be attached below.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Figure 3

DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description of the Invention The present invention generally provides a method for predicting the response to empathogen / entactogen (such as MDMA) treatment by analyzing various predictor variables in a patient. More specifically, patient characteristics are evaluated prior to the use of an empathogen / entactogen, and an empathogen / entactogen is administered to a patient in a therapeutic setting or in a legal regulatory context, including but not limited to clinical trials, use for training treatment specialists, or any other legal regulatory context in healthy subjects, and the maximum positive subjective acute effect in the patient is brought about, thereby providing a method for administering an empathogen / entactogen in the treatment of a patient. Using this method, the dose range in an individual can be better targeted, increasing the likelihood of bringing about a positive acute response to the empathogen / entactogen.

[0020] "Positive subjective acute effects", as used herein, include, but are not limited to, "good drug effects", "drug craving", "trust", "intimacy", "openness", things similar to 5D-ASC scale or Mystical Effects scale ratings or Oceanic Boundlessness, experience of unity, spiritual experience, bliss, insight, connectedness, mystical experience, mystical-type effects, positive mood, transcendence of time / space, ineffability, well-being, and peak experience, and refer to any desired effects of MDMA such as self-ratings on a visual analog scale.

[0021] The present invention provides a solution to the dosing problems experienced in the prior art by characterizing predictive variables that can be used for accurate dosing and optimization of dosing, enabling better and safer choices for patients and dosing in patients to be treated with MDMA. In the present invention, a large dataset (contrary to the prior art which used solely single variables and small datasets) is used to elucidate the influence of multiple variables and their interdependencies and to derive dosing recommendations and predictive variables for physiological and psychological responses to MDMA. The present invention is based on data from 10 controlled experimental trials with a total sample size of 194 healthy subjects tested in the same laboratory over a 10-year period.

[0022] Predictive variables / patient characteristics can include, but are not limited to, age, gender, drug dose, weight, previous drug experience, genetics, personality, and mood prior to ingestion. From the tests, several predictive variables were found to be most important in predicting the effects.

[0023] While MDMA is referenced herein, any empathogen / entactogen or MDMA-like compound that produces similar MDMA-type acute subjective effect characteristics, for example, but not limited to, 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), 5,6-methylenedioxy-2-aminoindane (MDAI), mephedrone, methylone, 3-MMC, its homologs, its analogs, or novel compounds or prodrugs, may be used in the methods herein. Any other compound that provides similar MDMA-type acute subjective effect characteristics may also be used. In the methods herein, MDMA is preferably administered at a dose of 20-200 mg.

[0024] The dose / kg body weight of MDMA plasma concentration and its surrogate variables after administration to an individual are the most important predictors of the acute response to MDMA and the intensity of the response to MDMA. The dose of MDMA per body weight is a surrogate measure corresponding to the plasma concentration of MDMA. This surrogate measure is notified before MDMA administration and can be used for accurate dosing. A high dose of MDMA per body weight (within the absolute dose range of 75-125 mg) causes a more positive additional cardiac stimulatory effect along with a more potent response to MDMA (as shown in Figure 1).

[0025] In dosing, when body weight is considered, there is no need to consider the gender of the individual (Figure 2). However, in controlled trials, some gender differences in the MDMA experience have been previously reported (Liechti et al., 2001; Simmler et al., 2011; Vizeli & Liechti, 2017), even after adjustment for differences in dosing. When dosing is performed independent of body weight, women need to be dosed approximately 20-30% lower than men (125 mg for men and 100 mg for women) to account for the difference in body weight between genders.

[0026] Cytochrome P450 (CYP) 2D6 activity (genetically or phenotypically determined; Schmid et al., 2016) affects the plasma concentration of MDMA (Figures 1 and 2). Subjects with low CYP2D6 activity show higher MDMA concentrations and more potent MDMA responses compared to the CYP2D6 extensive metabolizer group. Consistent with this finding, the CYP2D6 poor metabolizer group has previously been shown to have higher MDMA plasma concentrations than the extensive / normal metabolizer group (de la Torre et al., 2005; Schmid et al., 2016). The present invention additionally makes it possible to define dosages in patients with different CYP2D6 functions and suggests a dosage reduction of MDMA in subjects with CYP2D6 poor metabolizer status. For example, if MDMA is first used in a patient with known 2D6 activity, without considering further dosing parameters based on the present invention, a dosage of 100 mg as an alternative to 125 mg would be used in male poor metabolizers, and a dosage of 80 mg as an alternative to 100 mg would be used in female patients.

[0027] Accordingly, the present invention provides a method for determining the dosage of MDMA based on body weight, gender, and CYP2D6 activity, by evaluating patient characteristics such as body weight, gender, and CYP2D6 activity prior to MDMA use, administering MDMA to the patient, and providing the maximum positive subjective acute effect in the patient.

[0028] Psychological factors such as "openness to new experiences", "neurotic tendencies", or "trait anxiety" are significant predictors of the acute subjective drug effects of MDMA after adjustment for dosage / kg.

[0029] The "openness" personality trait enables an increase in "intimacy" in response to MDMA, which strengthens the therapeutic alliance. "Openness to experience" (NEO-FFI) predicts higher "intimacy" (VAS) after MDMA (Figure 2). This prediction is consistent with higher favorable drug effects in individuals who seek greater stimulation, which is related to "openness to experience" (Roberti, 2004) (Harvanko et al., 2016). Intimacy and openness after MDMA were found to be related to the reduction of PTSD symptoms (Wagner et al., 2017).

[0030] "Openness to experience" (NEO-FFI) predicts higher 5D-ASC ratings of "visionary restructuralization" after MDMA (Figure 2). Consistently, "absorption" / openness predicted the visual effects of psychedelic drugs (Haijen et al., 2018). Also consistently, "openness to experience" was the strongest predictor of the emotion of "intimacy" (VAS) and had high 5D-ASC ratings of "visionary restructuralization" after MDMA (Figure 3).

[0031] Subjects with high scores on "trait anxiety" and "neuroticism" experience more negative MDMA effects. These personality traits are likely to lead to a greater fear of loss of control.

[0032] Higher "neuroticism" (NEO-FFI) predicts greater anxiety ("fear of ego loss" in 5D-ASC) (Figure 2). Consistently, neuroticism (NEO-FFI) was the best predictor of the increased ratings of fear of ego loss in 5D-ASC after MDMA (Figure 3).

[0033] Consistently, more pronounced "neuroticism" was related to more "challenging experiences" after psychedelic drug intake (Barrett et al., 2017; Haijen et al., 2018; Studerus et al., 2012).

[0034] Higher "trait anxiety" (STAI-T) predicts greater anxiety ("fear of ego loss" in the 5D-ASC) (Figure 2).

[0035] Previous MDMA experience was consistent with another study (Bedi & de Wit, 2011) and showed no effect on the response to MDMA. However, it is important to note that this dataset mainly included subjects who were MDMA-naive or had a maximum of only 5 past MDMA experiences. Therefore, the effects of more severe past MDMA use could not be evaluated. In particular, patients in clinical trials using MDMA are likely to have little or no experience with MDMA, similar to this test population.

[0036] Using this method, a score can be designed to predict the response to MDMA.

[0037] Using this method, it is possible to predict a positive response to MDMA in future sessions or adjust the dosage based on measuring the concentration of MDMA in one session.

[0038] Once the full dosage of MDMA has been determined based on body weight and CYP2D6 status (and gender), this method can be used to further optimize or predict the response to MDMA. Also, once a patient has been selected as suitable for treatment with MDMA, this method can be used to find the optimal dosage.

[0039] Once the MDMA dosage has been determined, or to determine the likelihood that a promising patient will receive MDMA, the important predictive variables in the response are as follows: Openness to experience (NEO-FFI) that predicts a more positive acute response, including higher intimacy, oceanic feeling (5D-ASC), and hallucinatory restructuring (5D-ASC) (Figure 2); Neuroticism (NEO-FFI) that predicts negative experiences, including fear of ego loss (5D-ASC) and control and cognitive impairment (5D-ASC) (Figure 2); Trait anxiety (STAI) (Figure 2) that predicts negative experiences, including fear of ego loss (5D-ASC) and control and cognitive impairment (5D-ASC).

[0040] Therefore, scores can be formed using the NEO-FFI and STAI before the session to predict the likelihood of positive and / or negative acute effects of MDMA during the session.

[0041] Furthermore, pre-intake mood including the following can be used as predictor variables: Anxiety / depression (AMRS) predicts anxiety (5D-ASC) (Figure 2); Introversion (AMRS) predicts anxiety (5D-ASC) (Figure 2).

[0042] Therefore, the AMRS can be used before MDMA administration to predict the likelihood of negative acute effects of MDMA including anxiety during the session.

[0043] Therefore, the present invention provides a method for improving the administration of MDMA by using a questionnaire including the NEO-FFI, STAI-T, and AMRS scales in a patient, evaluating the questionnaire responses, and improving the administration of MDMA in the patient based on the questionnaire. For example, in patients with a low NEO-FFI openness rating, a high neuroticism tendency NEO-FFI rating, and a high STAI trait anxiety rating, a reduction in the dose of MDMA is recommended. High pre-drug anxiety / depression (AMRS) and introversion (AMRS) ratings predict higher anxiety after MDMA, and a dose reduction is recommended based on the present invention and will be subject to further improvement and implementation of the present application.

[0044] In summary, in the present invention, administration parameters such as the dose of MDMA per body weight, CYP2D6 genotype, data obtained from the NEO-FFI, STAI, and AMRS are utilized to optimize the administration, predict that it is more positive over the negative experience by MDMA, thereby enhancing the safety and effectiveness of its administration in patients.

[0045] In tests on patients with PTSD, a relationship was found between a decrease in PTSD symptoms and an increase in "openness" after MDMA treatment (Wagner et al., 2017). The traits of "openness" and "neuroticism" increased and decreased respectively after MDMA treatment. Similar lasting effects on personality traits were also observed after the use of psilocybin or LSD (MacLean et al., 2011; Schmid & Liechti, 2018).

[0046] Furthermore, since MDMA increases openness and openness predicts a more positive response to MDMA including a greater therapeutic effect, this indicates that patients may gradually benefit from multiple MDMA-assisted psychotherapy sessions as they are likely to become more open over time to experience.

[0047] Accordingly, the present invention provides a method for optimizing MDMA treatment in a patient by evaluating the patient's openness prior to MDMA use, predicting a positive response that causes further openness, optimizing MDMA treatment including repeated dosing, and causing an expansion of openness and an expansion of the treatment response over time.

[0048] The present invention also provides a method for predicting future administration with MDMA by measuring the plasma concentration of MDMA in a patient after administration of a certain dose of MDMA, adjusting the dose of MDMA in the patient, thereby optimizing the positive response to MDMA, and optimizing the effectiveness and safety of MDMA treatment.

[0049] The present invention provides a method for evaluating the likelihood that a patient will receive MDMA as a treatment by evaluating patient characteristics and evaluating the likelihood that the patient will receive MDMA as a treatment.

[0050] The present invention will be described in more detail by referring to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to be limiting unless otherwise specified. Therefore, the present invention should not be construed as being limited to the following examples by any means. Instead, it should be construed as encompassing all modifications that will become apparent as a result of the teachings provided herein.

Example

[0051] Example 1 Materials and Methods Study Design A pooled analysis of raw data from 10 double-blind placebo-controlled crossover trials in healthy human subjects was performed, all of which have been previously described (Dolder et al., 2018; Holze et al., 2020; Hysek et al., 2012a; Hysek & Liechti, 2012; Hysek et al., 2012b; Hysek et al., 2011; Hysek et al., 2012c; Hysek et al., 2014b; Schmid et al., 2015a; Schmid et al., 2015b).

[0052] The trials conducted at the University Hospital Basel between 2009 and 2018 included a total of 194 healthy subjects. Seven trials included 16 subjects each (112 subjects in total) who received MDMA at 125 mg twice, once alone, and once after pretreatment with a drug (Hysek et al., 2012a; Hysek & Liechti, 2012; Hysek et al., 2012b; Hysek et al., 2011; Hysek et al., 2012c; Hysek et al., 2014b; Schmid et al., 2015b). In three additional trials, subjects received MDMA alone, placebo, and one or two other substances (Dolder et al., 2018; Holze et al., 2020; Schmid et al., 2015a). Of these, one used a MDMA dose of 75 mg (n = 30) (Schmid et al., 2015a), and the other two used 125 mg (n = 24 and n = 28) (Dolder et al., 2018; Holze et al., 2020).

[0053] In this analysis, only data from MDMA-alone and placebo sessions were used. In all of the pooled trials, the washout period between single-dose administrations of MDMA was at least 7 days to exclude carry-over effects. All of the trials were registered on ClinicalTrials.gov (NCT00886886, NCT00990067, NCT01136278, NCT01270672, NCT01386177, NCT01465685, NCT01771874, NCT01951508, NCT01616407, NCT03019822).

[0054] Detailed pharmacokinetic and safety data from these trials have been published elsewhere (Schmid et al., 2016; Vizeli & Liechti, 2017; Vizeli et al., 2017).

[0055] The test sessions were conducted in a quiet research ward, with no more than 2 subjects per session. The participants lay comfortably in their beds, mainly listened to music, and did not engage in physical activities. At 8:00 - 9:00 AM in the morning, MDMA was administered on an empty stomach without food. At 12:00 - 1:00 PM, a light, pre - determined lunch was served.

[0056] Participants A total of 194 healthy subjects (97 females) aged 18 - 45 years (mean ± standard deviation = 25.1 ± 4 years) participated in the study. One genotype sample was missing, and 3 participants did not consent to genotype identification. The mean ± standard deviation of body weight was 69 ± 10 kg (range: 46 - 97 kg). Exclusion criteria included a history of mental disorders, physical diseases, a lifetime history of more than 10 illegal drug uses (except for past cannabis use), illegal drug use within the past 2 months, and illegal drug use during the study. As reported in detail elsewhere, drug screening was performed before the test sessions (Hysek et al., 2012a; Hysek & Liechti, 2012; Hysek et al., 2012b; Hysek et al., 2012c). 75 subjects had prior illegal drug experience (1 - 8 times), among which 41 subjects had previously used MDMA (1 - 5 times), 18 subjects had previously used amphetamine or methamphetamine (1 - 2 times), 15 subjects had previously used cocaine (1 - 4 times), 10 subjects had previously used lysergic acid diethylamide (1 - 2 times), and 15 subjects had previously used psilocybin (1 - 4 times).

[0057] Test drug (±)-MDMA hydrochloride (Lipomed AG, Arlesheim, Switzerland) was administered orally in single doses of 75 or 125 mg, prepared as gelatin capsules. Male and female subjects received the same dose of MDMA, regardless of their body weight, as in the therapeutic trials (Mithoefer et al., 2010; Oehen et al., 2013). The dose per body weight (mean ± standard deviation) was 1.7 ± 0.4 mg / kg (range: 0.8 - 2.7 mg / kg).

[0058] Predictor variable The effects of MDMA were expected to be dose - and body weight - dependent (Schmid et al., 2014; Vizeli & Liechti, 2017). Therefore, the dose divided by body weight was included as a covariate in the analysis. This also explained that, since body weight is lower in women compared to men, the mg / kg dose of MDMA in women is higher compared to men.

[0059] From the domain of sociodemographic predictor variables, gender and age were included as predictor variables. Gender was included because differences in MDMA experience have been reported to be adjusted for differences in administration even in some control trials (Liechti et al., 2001; Simmler et al., 2011; Vizeli & Liechti, 2017).

[0060] Age was included because a younger age has been associated with more unpleasant acute effects of psilocybin (Studerus et al., 2012), while data on MDMA were not available.

[0061] Individual metabolic differences in the enzymes that metabolize MDMA affect exposure to MDMA and, in turn, its acute effects. Specifically, the activity of cytochrome P450 enzymes has been shown to vary MDMA concentrations and the associated subjective cardiovascular responses (de la Torre et al., 2012; Schmid et al., 2016; Vizeli et al., 2017). Therefore, the CYP2D6 gene activity score (Hicks et al., 2013; Schmid et al., 2016) was included as an additional predictor variable.

[0062] Other measures of CYP enzyme activity were not included because they have been shown to have no effect or only a very small effect on responses to MDMA (Vizeli et al., 2017). Similarly, other promising pharmacogenetic predictor variables were not included because they also showed no effect or only a minimal effect on acute responses to MDMA (Bershad et al., 2016; Vizeli & Liechti, 2018; Vizeli et al., 2018; Vizelis et al., 2019).

[0063] All subjects had no or only very limited previous experience with psychotropic substances (0 - 5 times), but the MDMA effects have been reported to change with long-term use, and more experienced users have been reported to experience fewer drug effects than naive users. Therefore, the number of previous MDMA consumptions before participation was included in the analysis (Kirkpatrick et al., 2014). This study did not include subjects with extensive previous drug experience, and all subjects were physically inactive during drug response, so it was not possible to address the potential effects of high previous substance use (>5 times) or the moderate effects of physical activity on cardiovascular and febrile responses to MDMA (Liechti, 2014).

[0064] The mood state before the administration of the psychoactive substance can affect the response, as previously shown for psilocybin in similar studies (Studerus et al., 2012). Therefore, to assess the mood state before MDMA administration, ratings on the Adjective Mood Rating Scale (AMRS) (Janke & Debus, 1978) were included. Sixty adjectives were rated on a 4-point Likert scale, and the items were grouped into six main scales: "Performance-Related Activity", "General inactivation", "Extraversion-Introversion", "General well-being", "Emotional excitability", and "Anxiety-Depression". "Extraversion" and "Introversion" were analyzed separately.

[0065] Personality traits were assessed using the NEO-FFI (Borkenau & Ostendorf, 2008), which included 60 self-reported statements reflecting the self, rated on a 4-point Likert scale. The NEO-FFI encompasses personality traits of "Neuroticism", "Extraversion", "Openness to experience", "Agreeableness", and "Conscientiousness". Subjects completed the questionnaire at the start of the study as part of the screening procedure. Finally, the trait scale of the State-Trait Anxiety Inventory (STAI-T) (Spielberger et al., 1970) was included. This self-assessment questionnaire included 20 statements describing anxiety as a stable personality trait.

[0066] Response variable Blood samples for pharmacokinetic responses were collected in lithium heparin tubes 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, and 6 hours after the administration of MDMA or placebo and immediately centrifuged.

[0067] Plasma was stored at -20 °C until analysis. The plasma concentration of MDMA was determined as described above (Hysek et al., 2012c). The area under the concentration-time curve (AUC) from 0 to 6 hours after administration was calculated according to the trapezoidal rule as a measure of total exposure to MDMA.

[0068] The subjective responses to MDMA were evaluated using psychometric scales. Visual analogue scales (VAS) (Hysek et al., 2011; Hysek et al., 2012c) were used before and 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours after MDMA or placebo administration. The VAS for “any drug effect”, “good drug effect”, “bad drug effect”, “euphoric mood”, “drug craving”, and “stimulating” were presented as a 100-mm horizontal line (0–100%) and marked from “none” on the left to “extreme” on the right. The VAS for “intimacy”, “concentration”, “openness”, and “” were bidirectional (±50%). In addition, the AMRS was performed 1.25, 2, and 5 hours after the administration of MDMA or placebo. The responses to each of the VAS and AMRS subscales were included in the analysis as the area under the effect-time curve (AUEC) values, which reflect the overall effect throughout the test day.

[0069] Blood pressure, heart rate, and body temperature were repeatedly evaluated before and 0, 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 hours after MDMA or placebo administration. Systolic and diastolic blood pressure and heart rate were measured using an automated oscillometric device (OMRON Healthcare Europe NA, Hoofddorp, Netherlands). The measurements were performed in duplicate, after at least a 5-minute break. The mean was calculated for analysis. Core (tympanic) temperature was measured using a Genius (trademark) 2-ear thermometer (Tyco Healthcare Group LP, Watertown, NY, USA). Mean arterial pressure (MAP) was calculated as diastolic blood pressure + (systolic blood pressure - diastolic blood pressure) / 3. As a measure of different autonomic responses, the maximum value (Emax) was used as an outcome variable in the analysis because high cardiovascular stimulation or body temperature are clinically important potentially harmful outcomes associated with MDMA use (Liechti, 2014; Liechti et al., 2005; Vizeli & Liechti, 2017).

[0070] To retrospectively assess the changes in MDMA-induced arousal, the 5D-ASC scale (Dittrich, 1998; Studerus et al., 2010) was administered 6 hours after drug administration.

[0071] Statistical analysis All data were analyzed using the R language and environment for statistical computing (R Core Team, 2019). Since some of the predictor and response variables contained missing data (Table 1), multiple imputation (MI) was first performed using the MICE package for multiple imputation by chained equations in R (Buuren & Groothuis-Oudshoorn, 2010). This method was chosen because it yields unbiased parameter estimates and standard errors under the missing data mechanisms of “missing at random” (MAR) or “completely at random” (MCAR), and maximizes the power of the test by using all available information (Enders, 2010). The MAR assumption was valid in this study because the missing data were mostly obtained from different study designs during the pooled trials. Twenty imputations of the missing values were generated, resulting in 20 completed datasets, protecting against potential power loss from too few imputations (Graham et al., 2007). Next, the target analysis was performed in each completed dataset, and the parameter estimates were pooled according to Rubin's rule (Little & Rubin, 2019), except for the LASSO model (see below).

[0072]

Table 1

[0073]

Table 2

[0074] To explain the clustering in the data obtained from pooling through the trial, a linear mixed effects model was used, where the intercept was allowed to vary randomly through the trial. For each combination of predictor and response variables, adjusted and unadjusted models were fit using the R package nime (Pinheiro et al., 2019). In the unadjusted model, only the predictor of interest was included as a fixed effect in part of the model, while in the adjusted model, "dose per body weight" was further included. The predictor and response variables were z-transformed before inclusion in the model so that the estimated regression coefficients were normalized and comparable across predictors and responses. To account for multiple testing, P-values were adjusted using the Benjamini-Hochberg method (Benjamini & Hochberg, 1995) across all significance tests.

[0075] To identify the best subset of predictors for each response variable, the Least Absolute Shrinkage and Selection Operator (LASSO) was applied using a penalized R package (Goeman, 2018). LASSO performs both variable selection and regularization (i.e., shrinking of regression coefficients), optimizing the predictive accuracy and interpretability of the model. It has been shown that variable selection by LASSO is often more accurate than traditional methods such as stepwise methods (Tibshirani, 1997). For each response variable, the LASSO model was developed following the steps below. First, the optimal shrinkage parameter for each model was determined by performing a grid search. For each lambda in the grid, bootstrapping with 50 replications was performed, and the average predictive performance (i.e., mean squared error) across all out-of-bag samples was calculated using machine learning in the R (mlr) package (Bischl et al., 2016). Second, the lambda value that yielded the highest out-of-bag predictive performance was selected as the optimal lambda value and used as the final LASSO model fitted to all samples. Since the way to combine LASSO models across multiple imputed datasets is currently unknown and the amount of missing data in our datasets was relatively small, only a single imputation was used for the LASSO model. Furthermore, simply, no promising clustering was observed in the data in these analyses.

[0076] Results The most important predictor in most of the MDMA response variables was the MDMA plasma concentration, as shown in the unadjusted linear mixed effects model in Figure 1. The smaller asterisks indicate uncorrected P-values. The larger asterisks are P-values corrected for multiple testing through 20 * 25 = 500 significance tests. * p < 0.05, ** p < 0.01, *** p < 0.001.

[0077] The most important predictors of MDMA plasma concentration were drug dose, body weight, gender, and genetically determined CYP2D6 activity (Figure 1).

[0078] Specifically, the 6-hour MDMA plasma AUC is a measure of total exposure to the drug. The MDMA plasma AUC is strongly and highly significantly correlated with the dose of MDMA (Figure 1). The MDMA plasma AUC is also strongly and highly significantly inversely correlated with the body weight of the subjects taking MDMA (Figure 1). Furthermore, the MDMA plasma AU is also inversely correlated with CYP2D6 activity (Figure 1). Thus, individuals with low (genetically determined) CYP2D6 activity have higher MDMA plasma levels. Finally, when the total dose of MDMA is the same and not related to body weight, women show a significantly higher MDMA plasma AUC than men.

[0079] In summary, the data (Figure 1) show that the parameters related to MDMA exposure (MDMA plasma AUC, drug dose per body weight, and secondarily CYP2D6 activity) are the most powerful and significant predictors of the response to MDMA, including any drug effects as visual analogue scale (VAS), good drug effects, euphoria, liking, stimulation, introversion (AMRS) and oceanic feeling (5D-ASC), and the increase in mean arterial pressure.

[0080] In line with the above, Figure 3 shows that the dose per body weight is the strongest predictor in the following outcome effects after MDMA administration: MDMA plasma AUC, mean arterial pressure (MAP) increase, introversion (AMRS), mood excitability (AMRS), anxiety (AMRS), any drug effect (VAS), good drug effect (VAS), euphoria (VAS), liking (VAS), stimulation (VAS), oceanic feeling (5D-ASC), and control and cognitive impairment (5D-ASC). The LASSO model was applied to identify the best subset of predictors for each response variable (Goeman, 2018).

[0081] Analysis showed that being older was the best predictor of lower heart rate increase and lower temperature increase after MDMA, as well as higher adverse drug effects (Figure 3). This means that in older individuals, the likelihood of an increase in blood pressure is higher compared to an increase in heart rate.

[0082] The finding that MDMA exposure or related measures in the body (MDMA dose and body weight and CYP2D6 activity) do not often predict the acute response to MDMA is clinically important and indicates that the elements of the set and setting are not as relevant in predicting the response as the dose of MDMA. Therefore, it is presumed that the accurate dose per body weight within a controlled setting is not only decisive in bringing about a positive acute effect, but also more decisive than the elements related to the set and setting. As a result, it is presumed that the present invention can maximize the positive effect of MDMA by mainly determining the accurate dose to be used based on the patient's body weight, gender, and CYP2D6 activity.

[0083] Findings regarding the relationship between dose and good drug effect (within the range of doses tested here) indicate that a high dose of MDMA (>75 mg) is required to bring about a higher positive effect.

[0084] Since the MDMA plasma concentration is a variable that becomes known only after drug administration, it was classified as a response variable rather than a predictor variable in further mixed effect model analysis.

[0085] Since the MDMA dose per body weight has an impact on the response variable via the MDMA plasma level, the results of the MDMA dose per body weight were adjusted to understand the predictor variables that are independent of the MDMA dose.

[0086] The results of the dose adjustment are shown in Figure 2. The smaller asterisks indicate uncorrected P-values. The larger asterisks indicate all 17 using the Benjamini-Hochberg method (Benjamini & Hochberg, 1995). *It is the P value corrected for multiple testing through the significance test of 25 = 425. * p < 0.05, ** p < 0.01, * p < 0.001.

[0087] Gender lost its predictive variable value when adjusted for dose and body weight (Figure 2).

[0088] Genetically determined CYP2D6 activity was also inversely correlated with MDMA plasma concentration (p < 0.01) (Figure 2). In addition, the inverse correlation between heart rate and age maintained significance (p < 0.05) (Figure 2).

[0089] “Openness to experience” in the NEO-FFI was positively correlated with the VAS rating of “intimacy” after MDMA, and the 5D-ASC ratings of “oceanic feeling” and “hallucinatory restructuring” (p < 0.05, p < 0.05, and p < 0.01, respectively) (Figure 2).

[0090] Subjects with higher scores on “neurotic tendency” (NEO-FFI) and “trait anxiety” (STAI-T) were more likely to experience “fear of ego dissolution” and “control and cognitive impairment” in the 5D-ASC (both p < 0.01 and both p < 0.05, respectively) (Figure 2).

[0091] Furthermore, prior use of MDMA within the range of 0 - 5 had no significant effect on the response to MDMA (Figures 2 and 3). This means that no significant difference was observed between those with no previous experience and those with some (up to 5) experiences.

[0092] Furthermore, pre-MDMA well-being (AMRS) had no significant effect as a predictor variable for the response to MDMA. This means that regardless of the current mood, MDMA produces relatively similar effects and does not need to be very good at experiencing an additional sense of well-being after MDMA (Figure 2). This is an important factor to be considered within the scope of the invention described herein for predicting a positive response to MDMA.

[0093] The most important predictor variables in each response variable of the multivariate analysis are shown in Figure 3 by the use of the LASSO model.

[0094] Limitations The limitations of this study and of the present invention include, firstly, a healthy study population that is young and mainly MDMA-naïve. Thus, their findings can only be partially interpreted for psychiatric patients, who show clearly more severe psychopathology and, presumably, a greater likelihood of adverse psychological responses to MDMA.

[0095] Secondly, only two doses were considered, and the majority of subjects received a 125 mg MDMA dose, which is also commonly used in clinical trials with MDMA.

[0096] In addition, adverse events are relatively rare under controlled experimental conditions after MDMA administration (Hysek et al., 2014b; Kirkpatrick et al., 2014; Vollenweider et al., 2002), do not fit well into the analysis as such, and are furthermore rarely reported during testing in patients (Mithoefer et al., 2010; Oehen et al., 2013), and thus were not tested.

[0097] Furthermore, the “physical and social environment” may be important, but showed little variability in this study (Hartogsohn, 2016; Leary et al., 1963).

[0098] Throughout this application, various publications, including U.S. patents, are referenced by the author and year and patent number. Adequate citations for the publications are listed below. The entire disclosures of these publications and patents are hereby incorporated by reference into this application to more fully explain the state of the art relevant to the present invention.

[0099] The present invention has been described in an illustrative manner, and it should be understood that the terminology used is of the nature of descriptive terms and is not intended to be limiting.

[0100] Obviously, in light of the above teachings, many modifications and variations of the present invention are possible. Therefore, it should be understood that the present invention can be practiced within the scope of the appended claims, except where otherwise specifically described.

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Claims

1. 1. A method of administering an empathogen / entactogen in treating a patient, comprising: assessing patient characteristics prior to use of an empathogen / entactogen; administering an empathogen / entactogen to the patient based on the patient characteristics; producing a maximal positive subjective acute effect in said patient; A method comprising:

2. 10. The method of claim 1, wherein the administering step is performed in a healthy subject and in a setting selected from the group consisting of a therapeutic setting or a regulatory setting.

3. 2. The method of claim 1, wherein the positive subjective acute effect is selected from the group consisting of good drug effect, drug liking, trust, intimacy, openness, oceanic feeling, integrative experience, spiritual experience, blissful state, insight, connection, mystical experience, mystical effect, positive mood, time / space transcendence, indescribable sensation, euphoria, peak experience, and combinations thereof.

4. 2. The method of claim 1, wherein the patient characteristics are selected from the group consisting of age, sex, drug dosage, weight, previous drug experience, genetics, personality, pre-ingestion mood, and combinations thereof.

5. 2. The method of claim 1, wherein the patient characteristics include adjusting the dose based on cytochrome P450 2D6 activity, and patients with insufficient CYP2D6 activity exhibit higher MDMA concentrations and stronger MDMA responses compared to CYP2D6 extensive metabolizers.

6. 2. The method of claim 1, wherein the empathogen / entactogen is selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), 5,6-methylenedioxy-2-aminoindan (MDAI), mephedrone, methylone, 3-MMC, homologs, analogs, and prodrugs thereof.

7. 7. The method of claim 6, wherein the empathogen / entactogen is MDMA and is administered at a dose of 20-200 mg.

8. 1. A method for determining an empathogen / entactogen dose based on body weight, sex, and CYP2D6 activity, comprising: assessing patient characteristics prior to empathogen / entactogen use: weight, sex, and CYP2D6 activity; administering the empathogen / entactogen to the patient based on the patient characteristics; producing a maximal positive subjective acute effect in said patient; A method comprising:

9. 9. The method of claim 8, wherein administering a higher dose of the empathogen / entactogen per body weight results in a more positive cardio-stimulatory effect with a stronger response to the empathogen / entactogen.

10. 9. The method of claim 8, wherein patients with low CYP2D6 activity have higher empathogen / entactogen plasma levels than patients with high CYP2D6 activity.

11. 9. The method of claim 8, wherein females have a higher empathogen / entactogen plasma AUC than males.

12. 9. The method of claim 8, wherein the positive subjective acute effect is selected from the group consisting of good drug effect, drug liking, trust, intimacy, openness, oceanic feeling, integrative experience, spiritual experience, blissful state, insight, connection, mystical experience, mystical effect, positive mood, time / space transcendence, indescribable sensation, euphoria, peak experience, and combinations thereof.

13. 9. The method of claim 8, wherein the empathogen / entactogen is selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), 5,6-methylenedioxy-2-aminoindan (MDAI), mephedrone, methylone, 3-MMC, homologs, analogs, and prodrugs thereof.

14. 14. The method of claim 13, wherein the empathogen / entactogen is MDMA and is administered at a dose of 20-200 mg.

15. 1. A method for improving administration of an empathogen / entactogen, comprising: using questionnaires including the NEO-FFI, STAI-T, and AMRS scales with patients; evaluating the questionnaire responses; refining the administration of said empathogen / entactogen in said patient based on said questionnaire; A method comprising:

16. 16. The method of claim 15, wherein openness to experience on the NEO-FFI predicts more positive acute responses, neuroticism on the NEO-FFI predicts negative experiences, trait anxiety on the STAI-T predicts negative experiences, and the AMRS predicts the likelihood of negative acute effects.

17. 16. The method of claim 15, wherein the empathogen / entactogen is selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), 5,6-methylenedioxy-2-aminoindan (MDAI), mephedrone, methylone, 3-MMC, homologs, analogs, and prodrugs thereof.

18. 18. The method of claim 17, wherein the empathogen / entactogen is MDMA and is administered at a dose of 20-200 mg.

19. 1. A method for predicting future administration of an empathogen / entactogen, comprising: measuring the plasma concentration of said empathogen / entactogen in the patient after administration of a dose of said empathogen / entactogen; adjusting the dose of said empathogen / entactogen in said patient, thereby optimizing a positive response to said empathogen / entactogen and optimizing the efficacy and safety of said empathogen / entactogen treatment; A method comprising:

20. 20. The method of claim 19, wherein the empathogen / entactogen is selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), 5,6-methylenedioxy-2-aminoindan (MDAI), mephedrone, methylone, 3-MMC, homologs, analogs, and prodrugs thereof.

21. 21. The method of claim 20, wherein the empathogen / entactogen is MDMA and is administered at a dose of 20-200 mg.

22. 1. A method for assessing the feasibility of a patient to receive an empathogen / entactogen as a treatment, comprising: assessing patient characteristics; assessing the feasibility of said patient receiving said empathogen / entactogen as a treatment; A method comprising:

23. 23. The method of claim 22, wherein the patient characteristics are selected from the group consisting of age, sex, drug dosage, weight, previous drug experience, genetics, personality, pre-ingestion mood, and combinations thereof.

24. 23. The method of claim 22, wherein the empathogen / entactogen is selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), 5,6-methylenedioxy-2-aminoindan (MDAI), mephedrone, methylone, 3-MMC, homologs, analogs, and prodrugs thereof.

25. 25. The method of claim 24, wherein the empathogen / entactogen is MDMA and is administered at a dose of 20-200 mg.

26. 1. A method for optimizing empathogen / entactogen therapy in a patient, comprising: assessing patency in said patient prior to empathogen / entactogen use; predicting a positive response that will result in greater openness; optimizing empathogen / entactogen therapy, including repeated administration in different treatment sessions, resulting in increased openness and therapeutic response over time; A method comprising:

27. 27. The method of claim 26, wherein the empathogen / entactogen is selected from the group consisting of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), 5,6-methylenedioxy-2-aminoindan (MDAI), mephedrone, methylone, 3-MMC, homologs, analogs, and prodrugs thereof.

28. 28. The method of claim 27, wherein the empathogen / entactogen is MDMA and is administered at a dose of 20-200 mg.

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