R-MDMA and S-MDMA to support psychotherapy

Abstract

A composition comprising R-MDMA, S-MDMA, or a specific combination of these two enantiomers (not 1:1 as in racemic MDMA), as well as R-MDA, S-MDA, and non-1:1 combinations of R-MDA and S-MDA. A method of treating an individual, particularly in substance-assisted psychotherapy, by administering the composition to the individual. A method of personalized medicine by assessing an individual in need of MDMA treatment, determining whether there are characteristics of the individual present that would make them unsuitable for MDMA treatment, and administering the composition to the individual. A method of reducing abuse of MDMA by an individual by administering R-MDMA to the individual, thereby reducing abuse.

Description

[Technical field]

[0001] 2. Background of the Invention 1. Field of the invention The present invention relates to the use of the R- and S-enantiomers of 3,4-methylenedioxymethamphetamine as a treatment for a medical condition. [Background technology]

[0002] 2. Background technology Racemic ±3,4-methylenedioxymethamphetamine (MDMA) is a psychoactive substance and prototypical empathogen that acutely induces feelings of elevated mood, empathy, trust in others, and closeness (Hysek et al., 2014a). These acute subjective effects of MDMA may be useful in supporting psychotherapy, and MDMA is currently being investigated in a Phase 3 trial as a possible treatment for post-traumatic stress disorder (PTSD) (Mitchell et al., 2021).

[0003] MDMA is a racemic substance containing equal amounts of the enantiomers S(+)- and R(-)-MDMA. To date, the enantiomers of MDMA have not been studied in humans.

[0004] Preclinical studies indicate that S-MDMA primarily releases dopamine (DA), norepinephrine (NE), serotonin (5-HT) and oxytocin, while R-MDMA acts more directly on the serotonin 5-HT2A receptor and may release prolactin (PRL). Animal studies also indicate that the two enantiomers act synergistically to produce the subjective effects of MDMA, and that S-MDMA is primarily involved in psychostimulation, while R-MDMA may have fewer adverse effects and greater prosocial effects. However, the acute effects of S-MDMA and R-MDMA have not been effectively examined in human studies.

[0005] MDMA is currently being studied in patients with PTSD, social anxiety, and autism (Danforth et al., 2018; Danforth et al., 2016; Mithoefer et al., 2019; Mithoefer et al., 2010; Oehen et al., 2013), and may later be studied and used for a variety of other conditions. Such conditions in which MDMA or R-MDMA or S-MDMA, or a combination of R-MDMA and S-MDMA, may be useful, include, but are not limited to, substance use disorders, depression, anxiety disorders, anxiety disorders with life-threatening illnesses, personality disorders including narcissistic and antisocial disorders, and obsessive-compulsive disorders. R- or S-MDMA or combinations thereof may also be used to enhance couples therapy.

[0006] MDMA and related substances are believed to provide positive therapeutic long-term benefits in the context of MDMA / substance-assisted psychotherapy by producing acute subjective positive mood effects that may also enhance the efficacy of psychotherapy and be beneficial in their own right. Such acute beneficial MDMA effects include, but are not limited to, feelings of euphoria, feelings of connectedness to others, increased trust, feelings of love, enhanced emotional empathy, and enhanced feelings of prosociality and prosocial behaviors (Dolder et al., 2018; Holze et al., 2020; Hysek et al., 2014a; Schmid et al., 2014).

[0007] The prior art discloses the use of MDMA in substance-assisted psychotherapy (Mitchell et al., 2021; Mithoefer et al., 2010; Oehen et al., 2013). However, R-MDMA and S-MDMA or their specific combinations may be more suitable with different therapeutic benefit / tolerability profiles. As further explored in the studies described in the Examples, R- and S-MDMA have different effects than racemic MDMA.

[0008] Amphetamines, including MDMA, carry a certain risk of abuse liability. This is evidenced by the fact that MDMA is self-administered by animals (Cole & Sumnall, 2003; Creehan et al., 2015), promotes conditioned place preference (Cole & Sumnall, 2003), and, although not as robust and potent as typical abused drugs such as methamphetamine, similarly releases dopamine in the brain (Kehr et al., 2011). The risk of abuse of substances with central nervous system effects is very commonly linked to their dopamine stimulating properties. Summary of the Invention [Problem to be solved by the invention]

[0009] There remains a need for further characterization of the enantiomers of MDMA and methods to optimize the effects of MDMA. [Means for solving the problem]

[0010] Summary of the Invention The present invention provides compositions that include specific combinations of these two enantiomers of R-MDMA, S-MDMA, or racemic MDMA (not 1:1 as in racemic MDMA), as well as R-MDA, S-MDA, and non-1:1 combinations of R-MDA and S-MDA. These compositions may be useful in providing a specific desired effect in an individual.

[0011] The present invention provides methods of treating an individual, particularly in substance-assisted psychotherapy, by administering to the individual a composition of R-MDMA, S-MDMA, a non-1:1 combination of R-MDMA and S-MDMA, R-MDA, S-MDA, or a non-1:1 combination of R-MDA and S-MDA.

[0012] The invention provides a method of personalized medicine by assessing an individual in need of MDMA treatment, determining whether there are any individual characteristics present that would make the individual unsuitable for MDMA treatment, and administering to the individual a composition of R-MDMA, S-MDMA, a non-1:1 combination of R-MDMA and S-MDMA, R-MDA, S-MDA, or a non-1:1 combination of R-MDA and S-MDA.

[0013] The present invention provides a method of reducing abuse of MDMA by an individual by administering R-MDMA to the individual, thereby reducing the abuse. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description of the Invention The present invention provides a method of enhancing (positively improving qualitatively) the acute subjective (emotional, therapeutic) effects of MDMA in the treatment of medical (mainly psychiatric) conditions while reducing adverse effects, i.e. optimizing the effects of MDMA. Thus, the benefit-disadvantage profile of MDMA is improved to have a form of MDMA more suitable for treating an individual.

[0015] The benefit-disadvantage profile of MDMA is improved by either increasing the positive acute effects of MDMA or decreasing the negative acute or subacute effects by administering an enantiomer of MDMA (R-MDMA or S-MDMA) or a unique combination of these two enantiomers that differs from the 1:1 combination present in racemic MDMA. This makes it possible to modify the MDMA effect to increase its therapeutic benefits or / and reduce its adverse effects. MDMA may be contraindicated in some subjects (e.g., due to cardiovascular side effects), and material properties of R- or S-MDMA, and material properties that are slightly different from those of MDMA, may be required in some patients.

[0016] R-MDMA and S-MDMA may be unexpectedly more potent than the racemic mixture of MDMA, or may have reduced toxicity, so it may be advantageous to administer the enantiomers as opposed to the racemic mixture.

[0017] Furthermore, MDMA is partially metabolized to 3,4-methylenedioxyamphetamine (MDA), which is psychoactive. Using only R-MDMA or S-MDMA instead of racemic MDMA results in the formation of only R-MDA and S-MDA, which may similarly provide advantages as opposed to the use of racemic MDMA and the formation of racemic MDA as the active metabolite.

[0018] Finally, instead of using R-MDMA or S-MDMA, the present invention can use administration of the MDMA metabolites R-MDA or S-MDA or any non-1:1 combination thereof to produce the desired effect in any of the methods described herein.

[0019] R-MDMA may have a more beneficial profile than MDMA in any subject, but may further increase its benefits in certain patients who are at higher risk of adverse reactions to racemic MDMA. In particular, R-MDMA has a pharmacological profile with less stimulant effects and more psychiatric-type effects compared to MDMA. R-MDMA may be an alternative to MDMA with reduced abuse liability, reduced cardiovascular adverse effects, and reduced risk of negative mood effects after its use. Similarly, S-MDMA may be advantageous in some patients based on its unique effect profile.

[0020] As described further below, R-MDMA can be used to provide more psychedelic-like effects compared to comparably psychoactive doses of racemic MDMA, to produce significantly lower ratings of acute subjective "stimulation," "high," and "liking" compared to comparably psychoactive doses of racemic MDMA or S-MDMA, to produce significantly less acute autonomic stimulation (blood pressure, heart rate, heart rate-systolic blood pressure product, and body temperature) than racemic MDMA or S-MDMA, to produce significantly less acute and subacute adverse effects than racemic MDMA or S-MDMA, and to produce no or less depressed mood 1-3 days after its use compared to MDMA or S-MDMA. S-MDMA can be used to produce greater stimulation of oxytocin release compared to R-MDMA, and to produce similar to greater stimulation of oxytocin release compared to MDMA.

[0021] The specific benefits are described herein and will also be investigated directly in human subjects in the ongoing clinical studies described in Example 1.

[0022] In general, R-MDMA can be administered in doses of 20-400mg, S-MDMA can be administered in doses of 20-100mg, R-MDA can be administered in doses of 20-400mg, and S-MDA can be administered in doses of 20-100mg.

[0023] The present invention provides methods of treating an individual by inducing and enhancing the positive acute and long-term therapeutic effects of MDMA in an individual, such as by administering R-MDMA, S-MDMA, or a unique combination thereof (not 1:1) to an individual, as well as by treating an individual by enhancing the positive response compared to classical racemic MDMA.

[0024] The overall objective of the present invention is to improve or maintain the positive acute and therapeutic subjective effect response of MDMA (i.e., induce a positive acute subjective drug effect) while reducing the adverse effects typically associated with MDMA.

[0025] This method can be used for any indication for MDMA drug use, and is typically applied to psychiatric disorders including (but not limited to) post-traumatic stress disorder, substance use disorders, autism spectrum disorders, anxiety disorders, eating disorders, but can also include depression, obsessive-compulsive disorder, personality disorders, addictions, or it can even be used in couples therapy.

[0026] MDMA is an amphetamine derivative that, unlike prototypical amphetamine, primarily enhances serotonergic neurotransmission via release of 5-HT by the SERT and, to a lesser extent, also releases dopamine and norepinephrine by the dopamine transporter (DAT) and norepinephrine transporter (NET) (Hysek et al., 2014b; Verrico et al., 2007). Furthermore, MDMA is known to induce oxytocin release, which may contribute to its effects of enhancing trust, prosociality, and empathy enhancement (Dumont et al., 2009; Hysek et al., 2014a). Thus, MDMA is referred to as an "entactogen" or "empathogen."

[0027] MDMA has been widely used for decades, especially among young people. Its popularity is likely related to its emotional effects, including feelings of euphoria, positive mood, enhanced feelings of love and connection to other people, increased openness, loss of anxiety, and a sense of security (Schmid et al., 2014; Wardle & de Wit, 2014). These acute subjective effects of MDMA may also help support psychotherapy.

[0028] MDMA is a racemic substance containing equal amounts (1:1 mixture) of the enantiomers S(+)- and R(-)-MDMA. Preclinical studies have shown that S-MDMA releases primarily dopamine (DA) (Acquas et al., 2007; Hiramatsu & Cho, 1990; Murnane et al., 2010; Verrico et al., 2007), norepinephrine (NE) (Steele et al., 1987; Verrico et al., 2007), serotonin (5-HT) (Verrico et al., 2007) and oxytocin (Forsling et al., 2002), whereas R-MDMA acts more directly on the 5-HT2A receptor (Fantegrossi et al., 2005; Nash et al., 1994), is more hallucinogen-like (Murnane et al., 2009) and may release prolactin (PRL) (Murnane et al., 2010).

[0029] Consistently, animal studies have shown that while S-MDMA is more stimulant-like compared to R-MDMA, R-MDMA can be more psychedelic-like (Murnane et al., 2009) and may have fewer adverse effects while still producing MDMA-typical effects at higher doses (Fantegrossi et al., 2003; Pitts et al., 2018; Young & Glennon, 2008). This more psychedelic-like profile of R-MDMA is believed to be advantageous in the present invention, as it is associated with greater positive subjective effects and less addictive and stimulant-type effects (including autonomic stimulation) compared to MDMA or S-MDMA. The clinical studies described as part of the present invention in Example 1 are used to evaluate and demonstrate this positive effect profile of R-MDMA compared to MDMA for the first time in humans, across different doses of R-MDMA. Example 1 includes a comparison of acute responses to specific doses of R-MDMA, S-MDMA, MDMA, and placebo in a crossover study in healthy subjects. Based on preclinical data and this ongoing study in humans, it is proposed that the enantiomers of MDMA have unique efficacy profiles that enable their use in the treatment of medical disorders similar to MDMA but with an improved safety profile, including efficacy profiles that are more suitable for certain disorders compared to the use of standard racemic MDMA.

[0030] Specifically, in humans, R-MDMA administered at 125 mg or 250 mg, especially the higher dose of 250 mg, is expected to produce greater psychiatric-type effects (5D-ASC total OAV score) compared to S-MDMA (125 mg). In contrast, 125 mg of S-MDMA is hypothesized to induce greater subjective arousal (VAS) than 125 mg of R-MDMA.

[0031] Hyperthermia is a lethal adverse effect of only MDMA (Liechti, 2014a) and S-MDMA, and R-MDMA does not induce hyperthermia in animals (Curry et al., 2018; Fantegrossi et al., 2003; Frau et al., 2013). Thus, in humans in Example 1, 125 mg of R-MDMA is expected to result in less autonomic stimulation (blood pressure, heart rate, heart rate-systolic blood pressure product, and body temperature) than 125 mg of MDMA or 125 mg of S-MDMA. Thus, the adverse cardiovascular effect profile and risk of hyperthermia associated with MDMA are expected to be improved by using R-MDMA in Example 1.

[0032] In humans, in Example 1, 125 mg R-MDMA is predicted to produce fewer adverse effects (LC total score) than 125 mg MDMA or 125 mg S-MDMA.

[0033] When administered repeatedly at high doses, S-MDMA is more effective at depleting serotonin (Schmidt et al., 1987) and is more neurotoxic than R-MDMA (Frau et al., 2013). Thus, in humans, in Example 1, S-MDMA is expected to cause greater mood depression on days 1-3 after administration compared to R-MDMA (BDI, SCL-90R, LC, AMRS in Example 1), similar to MDMA. Thus, the present invention includes R-MDMA as a form of MDMA, resulting in less negative subacute aftereffects, also described as midweek depression or blues (Liechti et al., 2001; Verheyden et al., 2002).

[0034] In humans, S-MDMA (125 mg) is expected to provide greater stimulation of oxytocin release compared to R-MDMA (125 mg) in Example 1. This profile may be beneficial in certain disorders associated with low oxytocin, such as, but not limited to, autism spectrum disorder or pituitary dysfunction / insufficiency.

[0035] One way to reduce the addictiveness of an abused substance is by reducing its effect on the dopamine system and relatively enhancing its serotonergic effects. This approach is used by replacing MDMA with R-MDMA, which is less dopaminergic than MDMA and stimulates the serotonin system to a greater extent. Racemic MDMA and both enantiomers have moderate reinforcing properties, and S-MDMA is more potent than R-MDMA in maintaining self-administration as tested in rhesus monkeys (Fantegrossi et al., 2002). S-MDMA, but not R-MDMA, restored amphetamine responses indicative of greater abuse liability (McClung et al., 2010; Pitts et al., 2018). Thus, in Example 1, 125 mg of S-MDMA is expected to induce abuse-related subjective effects (VAS liking) similar to racemic MDMA, but greater than 125 mg of R-MDMA, in humans.

[0036] Potential therapeutic effects may also differ for each enantiomer (Pitts et al., 2018). For example, R-MDMA, but not S-MDMA, reduced conditioned fear when extinction retention was assessed in a model of PTSD, whereas S-MDMA reduced conditioned fear during extinction training but not afterwards (Curry et al., 2018). Thus, R-MDMA may be particularly suitable for treating PTSD and maintaining therapeutic effects compared to S-MDMA.

[0037] R-MDMA also produced greater peak effects than S-MDMA on prosocial behavior in monkeys (Pitts et al., 2017) and mice (Curry et al., 2018; Pitts et al., 2018). Thus, R-MDMA may be particularly useful for aiming for maximal prosocial effects in humans, a difference that will be further evaluated in the human studies in Example 1.

[0038] The metabolism (Meyer & Maurer, 2009) and pharmacokinetic profiles of R- and S-MDMA are different in vitro and in animals, respectively (Fantegrossi et al., 2009). For example, in mice, the onset of interoceptive effects of S-MDMA and racemic MDMA was faster compared to R-MDMA, and the duration of discriminative stimulus effects was shortest for R-MDMA (Fantegrossi et al., 2009). There was also enantiomeric interconversion in mice, in that 3.5% and 9.9% of one enantiomer was converted to the other after administration of R-MDMA and S-MDMA, respectively (Fantegrossi et al., 2009). Whether this is also true in humans is examined in the Examples. Human studies have assessed the pharmacokinetics of R- and S-MDMA after administration of racemic MDMA, but not of the enantiomers (Steuer et al., 2016). After administration of racemic MDMA, plasma levels of the active metabolite S-MDA were higher and peaked earlier compared to R-MDA (Steuer et al., 2016). The concentration-time profiles of parent R- and S-MDMA were relatively similar, with minor differences including minor changes in the R / S ratio over time and after inhibition of CYP2D6 (Steuer et al., 2016). Differences in the pharmacokinetics of S-MDMA and R-MDMA are expected, including differential effects of inhibition when MDMA is administered as a racemate (Steuer et al., 2016). In humans, in Example 1, there may be different concentration-time profiles for S-MDMA and R-MDMA, as well as S-MDA and R-MDA, which may also be beneficial in certain individuals.

[0039] The acute effects of S-MDMA and R-MDMA have not been effectively examined in human studies. Therefore, the present study in Example 1 as part of the present invention compares acute responses to R-MDMA, S-MDMA, ±MDMA and placebo in a crossover study in healthy subjects.

[0040] When designing a direct comparison between a racemic drug and its enantiomer, as is done in the present invention, the administration of each substance is important. Generally, only one enantiomer of a racemic drug is active and is therefore administered at half the mg dose of the racemate. This is different for MDMA. In the case of MDMA, there is substantial evidence from animal studies and even human reports that both enantiomers are active, produce differential effects, and are reportedly even required synergistically to produce the full MDMA experience (Fantegrossi et al., 2003; Fantegrossi et al., 2002; Young & Glennon, 2008). Furthermore, the effects and potency of racemic MDMA are more likely to be different from those expected from the action of its optical isomers (Young & Glennon, 2008).

[0041] Animal studies generally indicate that the two enantiomers act synergistically to produce the subjective effects of MDMA, with S-MDMA primarily involved in psychostimulation, while R-MDMA may have fewer adverse effects and greater prosocial effects (Fantegrossi et al., 2003; Pitts et al., 2018). R-MDMA is less potent than S-MDMA in producing prokinetic and other behavioral effects in animals (Fantegrossi et al., 2003; Fantegrossi et al., 2005; Paulus & Geyer, 1992; Young & Glennon, 2008). S-MDMA has been described as roughly equivalent in potency to racemic MDMA in terms of locomotor-promoting effects in rodents, whereas R-MDMA is clearly less potent than racemic MDMA (Fantegrossi et al., 2003; Fantegrossi et al., 2005; Paulus & Geyer, 1992; Young & Glennon, 2008). Animal studies have shown roughly similar dose-response relationships for S-MDMA and racemic MDMA (Young & Glennon, 2008), with some studies indicating that MDMA responses are only partially attributable to S-MDMA, and that the locomotor response produced by racemic MDMA is greater than would be predicted by simply adding the effects of the individual isomers (Fantegrossi et al., 2003). Lethal doses were also similar for S-MDMA and R- / S-MDMA in mice (Fantegrossi et al., 2003). Racemic MDMA is typically administered in a single dose of 80–125 mg (Liechti & Holze, 2021; Mithoefer et al., 2018; Vizeli & Liechti, 2017). Some studies in patients have also used an additional dose of 40–62.5 mg MDMA 2 hours after the first dose, resulting in a total dose of 120–187.5 mg (Mitchell et al., 2021; Oehen et al., 2013). As with previous studies, we selected 125 mg racemic MDMA as a representative and safe dose (Vizeli & Liechti, 2017).Based on the animal data, S-MDMA and racemic MDMA are expected to have overall equal abilities to induce stimulant-type and adverse effects in humans. A dose of 125 mg of S-MDMA is expected to be comparable to 125 mg of racemic MDMA in terms of subjective and autonomic stimulant-type effects, but may not produce the full range of empathogenic and prosocial effects of racemic MDMA. Theoretically, if only S-MDMA were active, a dose of 62.5 mg of S-MDMA would be equivalent to 125 mg of MDMA. However, because R-MDMA is also active and based on the synergistic effects of the two enantiomers recorded in animal studies (Fantegrossi et al., 2003), it is very likely that a higher dose of S-MDMA would be required to produce the full characteristic response. Furthermore, it is hypothesized that a 125 mg dose of R-MDMA will produce significantly less stimulant-type subjective effects compared to S-MDMA or racemic MDMA, and a 250 mg dose of R-MDMA will produce empathogenic effects greater than 125 mg of S-MDMA and similar to 125 mg of racemic MDMA. S-MDMA acts primarily on the monoaminergic system, producing primarily the stimulant-type and adverse effects of MDMA (Pitts et al., 2018), and is not to be dosed above 125 mg, consistent with its similar efficacy to MDMA in animal studies (Young & Glennon, 2008). However, R-MDMA will be administered at a higher dose of 250 mg so that its efficacy characteristics can be more fully assessed based on its reported lower potency (Young & Glennon, 2008), as well as its reduced adverse effects profile and greater safety (Curry et al., 2018; Pitts et al., 2018).

[0042] A problem with the use of MDMA in the treatment of medical conditions is that it has some abuse liability due to its amphetamine structure and pharmacology. That is, MDMA releases dopamine, which is associated with addiction (Kehr et al., 2011). MDMA also releases serotonin, which counteracts dependence (Suyama et al., 2016) (Kehr et al., 2011). Due to its combined dopaminergic and serotonergic properties, MDMA is considered a moderate reinforcer compared to methylphenidate, cocaine or nicotine, which are strong reinforcers (Liechti, 2014b). Nevertheless, abuse of MDMA may be of medical concern. R-MDMA is expected to be less addictive based on in vitro and animal data, but human data is lacking and is generated herein.

[0043] A measure of abuse liability that can be easily measured is subjective drug liking (Jasinski, 2000; Jasinski & Krishnan, 2009a; Jasinski & Krishnan, 2009b). The subjective effects of drug high and drug liking are thought to be related to abuse liability. In particular, higher drug liking scores are predictors of higher abuse liability. #3875]. Thus, lower drug high and drug liking would be expected following R-MDMA compared to S-MDMA, as assessed in Example 1.

[0044] MDMA and related substances increase blood pressure, and in some subjects, significantly (Hysek et al., 2011; Vizeli & Liechti, 2017). This can be problematic for subjects or patients with cardiovascular disease. MDMA-like substances with lower acute cardiovascular effects or attenuated blood pressure increases are warranted. R-MDMA is expected to show attenuated cardiac stimulant responses based on its pharmacological profile. However, this has not yet been demonstrated prior to the present invention.

[0045] Overall, the characteristics of R-MDMA and S-MDMA relative to MDMA are known based on in vitro studies and animal data. However, such data cannot substitute for human studies, and utility and applicability must be demonstrated in humans as is done within the present invention, including the design and detailed planning of experimental studies that experimentally test, verify, and support the specific claims made for the use of R-MDMA and S-MDMA in humans.

[0046] The present invention provides a method of personalized medicine by assessing an individual in need of MDMA treatment, determining whether there are any individual characteristics present that would make them unsuitable for MDMA treatment, and administering R-MDMA, S-MDMA, or a specific combination of the two to the individual. For example, if an individual has heart problems, it is better to treat them with R-MDMA instead of MDMA. If the individual is depressed after regular MDMA treatment, treatment with R-MDMA would be recommended. This approach provides maximum efficiency and minimizes toxicity to the individual.

[0047] The present invention provides a method of reducing abuse of MDMA by an individual by administering R-MDMA to the individual, thereby reducing the abuse. EXAMPLES

[0048] Example 1 (Clinical studies with R-MDMA and S-MDMA and racemic MDMA in healthy subjects) The overall objective of the present invention was to develop R-MDMA and S-MDMA as improved forms of MDMA for treating patients. The first step involves the initial administration of R-MDMA and S-MDMA to healthy humans, studying their acute effects and comparing these effects to those of racemic MDMA in healthy humans at defined doses, and demonstrating the differences and potential advantages of R-MDMA and S-MDMA over racemic MDMA. This is the first time that the substance has been administered to humans, and the specific characteristics claimed in the present invention are verified and documented to be present in the species being treated.

[0049] Research method: Study Design: This study compares the acute subjective, physiological, and endocrine effects of S-MDMA (125 mg), R-MDMA (125 and 250 mg), and MDMA (125 mg) using a placebo-controlled, double-blind, five-period crossover design in 24 healthy subjects. Conditions are: 1) R-MDMA 125 mg, 2) R-MDMA 250 mg, 3) S-MDMA 125 mg, 4) MDMA 125 mg, 5) placebo. Treatment sequence is counterbalanced. There is a washout period of at least 10 days between substance administrations. Study days include a 10-h study session followed by a single measurement (short-term visit) the following morning (24 h after drug administration).

[0050] Research purpose: Primary research hypothesis: R-MDMA at 125 mg or 250 mg, especially the higher dose of 250 mg, is expected to produce greater psychiatric-type effects (5D-ASC total OAV score) compared to S-MDMA (125 mg). In contrast, 125 mg S-MDMA will induce greater subjective stimulation (VAS) than 125 mg R-MDMA.

[0051] Secondary research hypotheses S-MDMA at 125 mg produces greater autonomic stimulation (blood pressure, heart rate, heart rate-systolic blood pressure product, and body temperature) than R-MDMA at 125 mg. S-MDMA at 125 mg produces more adverse effects (LC total score) than R-MDMA at 125 mg, similar to racemic MDMA. S-MDMA (125 mg) is expected to produce greater transient serotonin depletion and be associated with adverse after-effects. Specifically, S-MDMA produces greater depressed mood, similar to MDMA, compared to R-MDMA (BDI, SCL-90R, LC, AMRS) on days 1-3 after administration. S-MDMA (125 mg) is expected to produce greater stimulation of oxytocin release compared to R-MDMA (125 mg). There may be different concentration-time profiles for S-MDMA and R-MDMA and S-MDA and R-MDA (descriptive endpoints). 125 mg of S-MDMA induced greater abuse-related subjective effects (VAS liking) than 125 mg of R-MDMA and similar to racemic MDMA.

[0052] Primary study endpoint: Subjective effect profile (5D-ASC, VAS stimuli).

[0053] Secondary study endpoints: autonomic effects (blood pressure, heart rate, temperature); adverse effects (LC); mood on days 1-3 (BDI, SCL-90R, LC) and day 3 (AMRS) after dosing; endocrine effects (cortisol, prolactin, oxytocin, vasopressin); plasma concentrations of S- / R-MDMA and S- / R-MDA; additional subjective effects (VAS, AMRS, SCQ).

[0054] Inclusion criteria: Age 25-65 years. Understanding of the German language. Understanding of the procedures and risks associated with the study. Participants must indicate their willingness to comply with the protocol and sign a consent form. Participants must indicate their willingness to refrain from taking illegal psychoactive substances during the study. Participants must be willing to drink only non-alcoholic liquids; coffee, black or green tea, or energy drinks must not be consumed after midnight in the evening before the study session, as well as during the study day. Participants must indicate their willingness not to drive a traffic vehicle or operate machinery within 48 hours after substance administration. Indicate their willingness to use double barrier birth control throughout their study participation. Weight between 18 and 29 kg / m 2 Body Mass Index.

[0055] Exclusion criteria: chronic or acute medical conditions. current or previous major psychiatric disorder. psychotic disorder in a first-degree relative, not including psychotic disorders secondary to obvious medical reasons, e.g. brain injury, dementia, or brain lesions. hypertension (SBP>140 / 90mmHg) or hypotension (SBP<85mmHg). use of illicit substances (not including cannabis) on more than 20 occasions or at any time during the last month. pregnant or breastfeeding women. participation in another clinical trial (currently or within the last 30 days). use of medications that may interfere with the effects of the study medication (any psychiatric medication). smoking (>10 cigarettes / day). consumption of alcoholic beverages (>15 drinks / week).

[0056] Participants: The target study sample size is 24 healthy subjects (12 men and 12 women). Dropouts during the study will be replaced to reach a final study sample of at least 20 subjects. Based on previous similar studies, approximately 36 potential participants are expected to be screened to include 24 subjects, with approximately 4 dropouts expected during the study. In case of increased dropouts or insufficient recruitment, the study period will be extended. Subjects will be recruited via advertisements displayed on the website and noticeboards at the University of Basel and University Hospital of Basel. In case of insufficient recruitment, the study period will be extended.

[0057] Screening Procedures: Physical Health: Subjects will be examined by a study physician. Baseline health will be ensured by a general medical examination including medical history, physical examination, weight and blood chemistry determination, and hematological analysis. Mental Health: Subjects will be screened using a semi-structured clinical interview for DSM-IV to exclude those with a history of personal axis I major psychiatric disorders (acute or past) or drug dependence. Axis I major psychiatric disorders also include addictive disorders. In case of psychiatric findings during the screening procedure, study personnel will provide subjects with information on where to find specialist help and suggest an appointment if necessary. Drug Use History and Drug Screening: Past occasional recreational drug use is not an exclusion criterion if no adverse reactions occurred and use was moderate and controlled. Subjects will be excluded if they have a past history of more than 20 times in their lifetime. Subjects will be asked to refrain from any illicit drug use during the study, and drug screens will be randomly performed during screening and before the session. A positive screen for stimulants, opioids or tranquilizers at the screening visit and / or on the study day will result in exclusion from the study. A positive screen for tetrahydrocannabinol (THC, cannabis) will be recorded but will not result in study exclusion as THC consumption can be detected in urine for up to several weeks and THC consumption prior to the study date is unlikely to affect the results. Few, if any, positive screens are expected based on previous studies conducted in this study group. Subjects will be asked to refrain from excessive alcohol intake between study sessions (<15 standard drinks / week) and to limit use to one standard drink the day prior to the study session. Screening Laboratory Tests: Routine laboratory blood tests including creatinine, ALAT, hemoglobin, hematocrit, white blood cell count, red blood cell count, and platelet cell count will be performed at screening examination. A urine drug screen and pregnancy test will be performed in women.

[0058] Study Procedure: The study will take place at the University Hospital of Basel. Each test session will last from 08:00 to 18:00, with a short visit the following morning (24 hours after application). An indwelling intravenous catheter will be inserted into a subcutaneous vein in the forearm and baseline psychometric measures will be obtained. Substance administration will take place at 09:00. Outcome measures (see below) will be assessed repeatedly during the study session. Subjects will be under continuous medical monitoring until any altered consciousness has subsided completely and they have left the study facility.

[0059] Psychometric ratings: Visual Analogue Scale (VAS): The VAS is used repeatedly to rate subjective changes in consciousness over time. A single scale is presented as a 100 mm horizontal line marked "not at all" on the left and "extremely" on the right. The following VAS items are used: "any drug effect", "good drug effect", "bad drug effect", "stimulated", "liking", "happy", "contented", "talkative", "open", "trusting", "feeling close to others", "anxiety", "changes in vision", "changes in hearing", "sounds seem to affect what you see", "changes in perception of time", "the boundaries between me and my surroundings seem blurred", "want to be with others", and "want to be alone". The scale is administered repeatedly before and after substance administration and takes approximately 2 minutes to complete. Maximum score (E max , 0–100) and areas under the effect-time curve (AUEC) were compared between treatments using analysis of variance for each VAS value and E maxThe 5D-ASC scale is a questionnaire that includes a 94-item visual analogue scale (Studerus et al., 2010). The method includes five scales that assess mood, anxiety, derealization, depersonalization, perceptual changes, auditory changes, and attention deficits. The scale is well validated (Studerus et al., 2010) and is used internationally to evaluate the effects of many other psychoactive substances. The overall psychedelic experience is reflected by the total 3D-ASC score. Each item of the scale is scored on a VAS ranging from 0 to 100 mm. The attribution of the individual items to the 5D-ASC subscales is analyzed according to (Studerus et al., 2010). The 5D-ASC scale is applied once at the end of the session, and subjects are instructed to retrospectively evaluate the peak changes they experienced during the study session. Adjective Mood Rating Scale (AMRS): The Adjective Mood Rating Scale (AMRS or EWL60S) is a 60-item Likert scale that allows repeated ratings of mood on six dimensions: activation, deactivation, happiness, anxious / depressed mood, extroversion and introversion, and emotional excitability. The German EWL60S version is used. The AMRS consists of subscales measuring "activation", "positive mood", "extroversion", "introversion", "deactivation", and "emotional excitability". The scale has been used previously to assess the effects of many other psychoactive substances. E maxand AUEC scores are defined for each subscale and compared between treatments using analysis of variance. The AMRS is administered repeatedly throughout the study sessions and once 3 days after each session. The States of Consciousness Questionnaire (SCQ): The SCQ has 100 items rated on a 6-point scale. The 43 items embedded in this questionnaire include the Mystical Experiences Questionnaire (MEQ) (MacLean et al., 2011), which is sensitive to the effects of psychiatric substances such as LSD. The 43 items provide a scale score for each of the seven domains of mystical experience: internal unity (pure awareness, merging with ultimate reality), external unity (all things are one, all things are alive, all is one), sense of the sacred (reverence, sacred), cognitive qualities (encounter with an ultimate reality that is more real than everyday life), transcendence of time and space, deeply felt positive moods (joy, relief, love), and paradoxicality / ineffability (claiming that the experience is difficult to describe in words). The study also uses four scale scores derived from the newly validated and revised 30-item MEQ: mystical, positive mood, transcendence of time and space, and ineffability (Barrett et al., 2015). The MEQ is an outcome measure of mystical-type effects, as this scale has become one of the standard scales in hallucinogen research. The MEQ complements the 5D-ASC ratings and is expected to be sensitive to the partial hallucinogenic effects of MDMA and R-MDMA. Data for each domain scale are expressed as a percentage of the maximum possible score. The scale is administered once at the end of the session day. Spiritual Realm Questionnaire: The scale includes 11 main questions answered with a total of 65 suborder visual rating scales. The scale is administered once at the end of the session day. Beck Depression Scale (BDI): The BDI consists of 21 questions created to measure the severity of depression. The German BDI-II version is used as a self-rating 3 days after substance administration and refers to the last 3 days to rate any after-effects on mood. Symptom-Check-List-90-R (SCL-90-R): The SCL-90-R is a widely used psychological symptom inventory.The German version is used 3 days after substance administration and measures the aftereffects on mood with reference to the previous 3 days. The outcome measures are the Global Severity Index, the Positive Symptom Distress Index and the sum of the Positive Symptoms.

[0060] Autonomic measurements: Blood pressure, heart rate, and body temperature are recorded at baseline and repeatedly throughout the session. Blood pressure (systolic and diastolic) and heart rate are measured using automated oscillometric devices. Body temperature is measured with an ear thermometer. max are determined for each measurement and each study session. These E max Values ​​are compared between drug conditions using analysis of variance.

[0061] Adverse Effects (Complaint Inventory): The Complaint Inventory (LC) consists of 66 items providing a global score measuring physical and general discomfort (Zerssen, 1976). The LC is administered before substance administration (baseline), at the end of the session to cover 0-9 h effects, and 24 h after substance administration to cover 9-24 h after-effects. To assess adverse effects after 24 h, subjects complete an additional LC 3 days after the test session, covering adverse effects from 24 to 72 h. Subjects are further asked to report adverse events during and / or between study sessions, to be assessed at the beginning of the next session and at the EOS visit. Global LC scores are summed and compared between treatments using analysis of variance.

[0062] Drug Plasma Concentrations: Plasma levels of MDMA and MDA are measured repeatedly to determine participants' individual substance exposure. While the pharmacokinetics of racemic MDMA is well known, it has not yet been tested what the R-MDMA and S-MDMA and R-MDA and S-MDA plasma concentration-time curves would be in the absence of the other enantiomer. Maximum concentrations (C max ), C max time to 24 hours, and area under the concentration-time curve (AUC 24Findings, including kinetics, concentration, and elimination half-life values, are described narratively. Plasma concentrations of MDMA and MDA are determined in the Laboratory of Clinical Pharmacology and Toxicology, Department of Biomedical Sciences, using fully validated LC-MS / MS analytical methods. Plasma concentration data are analyzed using non-compartmental methods.

[0063] Endocrine effects: Cortisol and prolactin: Cortisol and prolactin are determined as biological markers of serotonergic activity (Seifritz et al., 1996). Plasma concentrations are determined by routine immunoassays. Oxytocin and vasopressin: MDMA increases circulating oxytocin (Hysek et al., 2014a) and vasopressin or its precursor copeptin (Simmler et al., 2011). These neurohormones are thought to mediate the neurocognitive and adverse effects of MDMA, and the role of R-MDMA vs. S-MDMA has yet to be investigated. Plasma levels of oxytocin and vasopressin are measured before and after substance administration. Concentrations are determined using immunoassays.

[0064] Formulation and Dosage: Analytically pure R-MDMA, S-MDMA and racemic MDMA are customer synthesized in Switzerland. Capsules containing the active substance (25 mg per capsule) and matching placebo capsules (containing mannitol) are prepared by a Swissmedic approved GMP facility in Switzerland. Products are manufactured according to GMP and tested for identity and content uniformity. Randomization, packaging, labeling and quality control (QC) including stability testing of the final product are performed. Randomization and Blinding: Subjects and investigators involved in overseeing the sessions are blinded to the treatment sequence. Sequences are counterbalanced. A GMP facility performs the randomization.

[0065] The compounds of the present invention are administered and dosed according to good medical practice, taking into account the clinical condition of each individual patient, the site and method of administration, the administration schedule, the age, sex, weight of the patient, and other factors known to medical practitioners.Therefore, the pharmacologic "effective amount" for the purposes of this specification is determined by such considerations as are known in the art.The amount must be effective to achieve improvement, including, but not limited to, faster recovery, or improvement or elimination of symptoms, and other indicators as selected by the skilled artisan as appropriate means.

[0066] In the method of the present invention, the compound of the present invention can be administered in various ways. It should be noted that the compound can be administered as an active ingredient, alone or in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles. The compound can be administered orally, subcutaneously, or parenterally, including intravenous, intramuscular, and intranasal administration. Implants of the compound are also useful. The patient to be treated is a warm-blooded animal, particularly a mammal, including humans. Pharmaceutically acceptable carriers, diluents, adjuvants and vehicles, as well as implant carriers, generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating materials that do not react with the active ingredient of the present invention.

[0067] Doses can be single or multiple doses over several days. Treatment generally has a length proportional to the length of the disease process and drug effectiveness as well as the patient species being treated.

[0068] When the compound of the present invention is administered parenterally, it is generally formulated in a unit dosage injection form (solution, suspension, emulsion).The pharmaceutical preparation suitable for injection includes sterile aqueous solution or dispersion, and sterile powder for reconstitution into sterile injection solution or dispersion.Carrier can be, for example, solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixture thereof, and vegetable oil.

[0069] Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Non-aqueous vehicles such as cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil, and esters such as isopropyl myristate can also be used as solvent systems for the compound compositions. In addition, various additives can be added to enhance the stability, sterility, and isotonicity of the composition, including antimicrobial preservatives, antioxidants, chelating agents, and buffers. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it is desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms can be brought about by the use of agents that delay absorption, such as aluminum monostearate and gelatin. However, according to the present invention, any vehicle, diluent, or additive used must be compatible with the compound.

[0070] Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.

[0071] The pharmacological preparation of the present invention can be administered to an individual in an injectable formulation containing any compatible carrier, such as various vehicles, adjuvants, additives and diluents, or the compounds utilized in the present invention can be administered parenterally to a patient in the form of slow-release subcutaneous implants or targeted delivery systems, such as iontophoretic agents, polymer matrices, liposomes and microspheres. Examples of delivery systems useful in the present invention include: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems and modules are known to those skilled in the art.

[0072] Throughout this application, various publications, including U.S. patents, are referenced by author and year and patents are referenced by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0073] The invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of words of description rather than of limitation.

[0074] Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

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Claims

1. A composition comprising an effective amount of a compound selected from the group consisting of R-MDMA, S-MDMA, non-1:1 combinations of R-MDMA and S-MDMA, R-MDA, S-MDA, and non-1:1 combinations of R-MDA and S-MDA.

2. 2. The composition of claim 1, wherein the compound is R-MDMA and induces more psychiatric-type effects in an individual compared to an equally psychoactive dose of racemic MDMA.

3. 2. The composition of claim 1, wherein the compound is R-MDMA and produces lower abuse-related subjective effects, including lower scale ratings of "stimulus," "high," and "liking," compared to an equally psychoactive dose of racemic MDMA.

4. 2. The composition of claim 1, wherein the compound is R-MDMA and produces lower autonomic stimulation including lower blood pressure, heart rate, heart rate-systolic blood pressure product, and body temperature compared to an equally psychoactive dose of racemic MDMA.

5. 2. The composition of claim 1, wherein the compound is R-MDMA and produces fewer acute and subacute adverse effects compared to a comparably psychoactive dose of racemic MDMA.

6. 2. The composition of claim 1, wherein the compound is R-MDMA and causes no or less depressed mood 1-3 days after use compared to comparably psychoactive doses of racemic MDMA or S-MDMA.

7. 2. The composition of claim 1, wherein the compound is S-MDMA and produces greater stimulation of oxytocin release compared to comparably psychoactive doses of racemic MDMA or R-MDMA.

8. 1. A method of treating an individual, comprising: administering to said individual a composition selected from the group consisting of R-MDMA, S-MDMA, non-1:1 combinations of R-MDMA and S-MDMA, R-MDA, S-MDA and non-1:1 combinations of R-MDA and S-MDA; Treating the individual; and A method comprising:

9. 9. The method of claim 8, wherein the treating step is further defined as inducing a positive acute effect in the individual.

10. 10. The method of claim 8, further comprising reducing adverse effects associated with MDMA.

11. 9. The method of claim 8, wherein the individual has a psychiatric disorder selected from the group consisting of post-traumatic stress disorder, substance use disorder, autism spectrum disorder, anxiety disorder, eating disorder, depression, obsessive-compulsive disorder, personality disorder, and addiction.

12. The method of claim 8 , wherein the composition is administered for couples therapy.

13. 9. The method of claim 8, wherein the composition is R-MDMA and is administered in a dose of 20 to 400 mg.

14. 9. The method of claim 8, wherein the composition is S-MDMA and is administered at a dose of 20 to 100 mg.

15. 9. The method of claim 8, wherein the composition is R-MDA and is administered in a dose of 20 to 400 mg.

16. 9. The method of claim 8, wherein the composition is S-MDA and is administered in a dose of 20 to 100 mg.

17. 1. A method of personalized medicine comprising: assessing an individual in need of MDMA treatment and determining whether there are characteristics of the individual present that would make them unsuitable for MDMA treatment; administering to said individual a composition selected from the group consisting of R-MDMA, S-MDMA, non-1:1 combinations of R-MDMA and S-MDMA, R-MDA, S-MDA, and non-1:1 combinations of R-MDA and S-MDA; A method comprising:

18. 18. The method of claim 17, wherein said evaluating step is further defined as determining whether said individual has a cardiac problem and said composition is R-MDMA.

19. 18. The method of claim 17, wherein said evaluating step is further defined as determining whether said individual had previously experienced depressed mood following treatment with MDMA, and said composition is R-MDMA.

20. 1. A method for reducing abuse of MDMA by an individual, comprising: administering R-MDMA to said individual, thereby reducing abuse; A method comprising:

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