MDMA prodrugs to assist psychotherapy

Abstract

To provide a compound for treating an individual, for example in substance-assisted psychotherapy.SOLUTION: A compound includes a prodrug having a psychoactive base substance attached to an amino acid. The psychoactive base substance is MDMA or an MDMA-like substance.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Background of the Invention 1. Field of the Invention The present invention relates to novel substances (compositions) for substance-assisted psychotherapy, including (1) a description of the novel substances, (2) methods for the synthesis of the substances, and (3) applications of the substances in treating illnesses. [Background technology]

[0002] 2.Background technology 3,4-Methylenedioxymethamphetamine (MDMA), a psychoactive drug that alters mood and perception, is being investigated as an adjunct to psychotherapy for post-traumatic stress disorder (PTSD), social anxiety, and autism (Danforth, 2016; Danforth et al., 2018; Danforth et al., 2016; Mithoefer et al., 2019; Mithoefer et al., 2010; Oehen et al., 2013) and may be tested and used for a variety of other conditions in the future. Conditions for which MDMA or related substances may be useful include, but are not limited to, substance use disorders, depression, anxiety disorders, anxiety due to life-threatening illnesses, personality disorders including narcissistic and antisocial disorders, and obsessive-compulsive disorder. MDMA or related substances can also be used to enhance couples therapy.

[0003] MDMA and related substances are thought to have favorable long-term therapeutic effects in MDMA / substance-assisted psychotherapy settings by producing acute, positive subjective mood effects that may be beneficial in their own right and also improve the efficacy of psychotherapy. These acute, beneficial MDMA effects include, but are not limited to, feelings of happiness, feelings of connectedness with others, feelings of increased trust, feelings of love, increased emotional empathy, and feelings of prosociality and prosocial behavior (Hysek et al., 2014; Liechti et al., 2001; Schmid et al., 2014; Vollenweider et al., 1998a).

[0004] The prior art discloses the use of substances in substance-assisted psychotherapy, including MDMA, psilocybin, and LSD (Carhart-Harris et al., 2017; Liechti, 2017; Luoma et al., 2020; Nichols et al., 2017; Sessa et al., 2019; Trope et al., 2019). However, other substances with different therapeutic benefit / tolerance profiles may be more suitable. In addition, MDMA is the only empathogen-type substance currently being studied for substance-assisted psychotherapy, whereas psilocybin and LSD are hallucinogens with different effect profiles and modes of action (Holze et al., 2020). Alternatives to MDMA have been proposed (Oeri, 2020). These alternative MDMA-like substances include a number of compounds that may share some similarities with MDMA based on their in vitro pharmacological profiles and based on reports of their subjective effects by recreational users (Oeri, 2020). 3,4-Methylenedioxamphetamine (MDA) is the only MDMA-like substance that has been used in the past to aid in psychotherapy (Baggott et al., 2019; Yensen et al., 1976).

[0005] The present invention includes an alternative approach to optimizing the effects of MDMA and MDA by using a prodrug approach. This allows for the modification of MDMA and MDA effects, but at the same time, the novel compounds used are converted in the body to the known and previously used active substances MDMA and MDA, providing greater safety compared to compounds with novel structures that are the active entities. MDMA may not be the only compound suitable for substance-assisted therapy. In fact, MDMA may be contraindicated in some subjects (e.g., due to cardiovascular side effects), and some patients may require substantial characteristics that are slightly different from MDMA.

[0006] There is a need for agents that have expected benefits generally similar to MDMA in MDMA-assisted therapy, but which may improve upon some of the adverse effects of MDMA or may exhibit therapeutically beneficial properties independent of MDMA. Therefore, the present invention describes novel MDMA-like compounds that may substitute for MDMA in certain patients.

[0007] Substances with MDMA-like properties overall are those with similar in vitro pharmacological profiles overall, i.e., those that release monoamines with a preference for the release of serotonin (5-HT) over dopamine (DA) ( Liechti, 2014 ; Oeri, 2020 ; Simmler et al., 2013 ).

[0008] Although MDMA acutely induces mostly positive subjective effects, including elevated mood, openness, trust, and increased empathy, undesirable effects may also be present, including anxiety, particularly at the onset of the subjective response ( Hysek et al., 2014 ; Liechti et al., 2001 ; Schmid et al., 2014 ; Vollenweider et al., 1998a ).

[0009] A possible solution to alleviating onset anxiety consists of delaying the onset of drug effect by using sustained-release formulations of MDMA. The present invention novelly uses prodrugs that are expected to be converted slowly in the body to MDMA or MDMA-like substances, thereby resulting in a slower, attenuated response and reduced subjective onset anxiety.

[0010] Amphetamines, including MDMA, carry a risk of abuse liability. This is evidenced by the fact that MDMA, although not very potent, can be self-administered by animals (Cole & Sumnall, 2003; Creehan et al., 2015), promotes conditioned place preference (Cole & Sumnall, 2003), and, while less potent than other drugs of abuse, releases dopamine in the brain similarly (Kehr et al., 2011). The risk of abuse of substances with central nervous system effects is generally related in part to the rapid onset of subjective drug effects, which in turn is related to the rapidity of drug-plasma concentration increase in the brain (or plasma) (Busto & Sellers, 1986; Mumford et al., 1995).

[0011] One means of reducing the addictive potential of substances of abuse is by delaying the onset of action and / or increase in blood concentration, for example, by using sustained-release formulations (Mumford et al., 1995).

[0012] Another approach is to use prodrugs that slowly convert to the active substance. For example, this approach is used with the prodrug lisdexamfetamine, which converts to d-amphetamine after reaching the circulation (Jasinski & Krishnan, 2009a; Jasinski & Krishnan, 2009b).

[0013] Therefore, there remains a need for methods to safely administer MDMA to individuals while minimizing unwanted side effects. Summary of the Invention [Means for solving the problem]

[0014] Summary of the Invention The present invention provides compounds that include prodrugs having psychoactive basic substances attached to amino acids.

[0015] The present invention provides methods for treating an individual, particularly in substance-assisted psychotherapy, by administering proMDMA or a proMDMA-like compound to the individual, metabolizing the prodrug, and releasing MDMA or an MDMA-like substance in the individual.

[0016] The present invention also provides a method for reducing anxiety while administering MDMA by providing a sustained release of MDMA or an MDMA-like substance and thereby reducing anxiety in an individual at the onset of administration.

[0017] The present invention provides a method of personalized medicine by assessing an individual in need of MDMA treatment and determining whether the individual has characteristics that make them unsuitable for MDMA treatment and administering proMDMA or a proMDMA-like substance to the individual.

[0018] The present invention provides a method for reducing the abuse of MDMA by administering proMDMA or a proMDMA-like substance and slowing and attenuating the effects of MDMA or an MDMA-like substance, thereby reducing abuse.

[0019] DESCRIPTION OF THE DRAWINGS Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, in which: [Brief explanation of the drawings]

[0020] [Figure 1A] Figure 1A shows an example of an MDMA-like substance: 3,4-methylenedioxymethamphetamine (MDMA). [Figure 1B] Figure 1B shows an example of an MDMA-like substance: 3,4-methylenedioxyamphetamine (MDA). [Figure 1C] Figure 1C shows an example of an MDMA-like substance: 1-(1,3-benzodioxol-5-yl)-methyl-2-butanamine (MBDB). [Figure 1D] Figure 1D shows an example of an MDMA-like substance: 3,4-methylenedioxyethylamphetamine (MDEA). [Figure 1E] Figure 1E shows an example of an MDMA-like substance: methylone. [Figure 1F] Figure 1F shows an example of an MDMA-like substance: 5-(2-aminopropyl)-benzofuran (5-APB). [Figure 1G] Figure 1G shows an example of an MDMA-like substance: N-methyl-1-(benzofuran-5-yl)-propan-2-amine (5-MAPB). [Figure 1H] Figure 1H shows an example of an MDMA-like substance: 5,6-methylenedioxy-2-aminoindan (MDAI). [Figure 2] Figure 2 shows lysMDA and lysMDMA as representative examples of the structures of proMDMA or proMDMA-like compounds. Inactive lysMDA or lysMDMA are rapidly absorbed in the intestine after oral administration, as shown for related compounds (Hutson et al., 2014), and peptidases in the blood metabolize lysMDA or lysMDMA to lysine and active MDA or MDMA, respectively. [Figure 3] FIG. 3 is a graph showing plasma alprazolam levels following administration of immediate release (IR) and extended release (XR) formulations. [Figure 4] FIG. 4 is a graph showing the subjective effects of immediate-release (IR) and extended-release (XR) formulations of alprazolam on the subjective effect-time curve (Mumford et al., 1995). [Figure 5A] FIG. 5A is a graph showing the effect of immediate-release and sustained-release formulations of alprazolam on maximum drug preference ratings (Mumford et al., 1995). [Figure 5B] FIG. 5B is a graph showing the effect of immediate-release and extended-release formulations of alprazolam on relevant drug reinforcement measures (Mumford et al., 1995). [Figure 6]FIG. 6 is a graph showing plasma levels of d-amphetamine after administration of the prodrugs lisdexamfetamine and d-amphetamine at equal molar doses in humans (Jasinski et al., 2009b), where the drugs were administered intravenously. [Figure 7] Figure 7 is a graph showing subjective drug preference ratings as a measure of abuse liability following administration of equal molar doses of the prodrugs lisdexamfetamine and d-amphetamine (Jasinski et al., 2009b), administered intravenously. [Figure 8] FIG. 8 is a graph showing subjective peak change following oral administration of 50 mg, 100 mg, and 150 mg doses of the prodrug lisdexamfetamine and a 100 mg equivalent dose of d-amphetamine (40 mg). [Figure 9] FIG. 9 is a graph showing systolic blood pressure values ​​following oral administration of the prodrug lisdexamfetamine at doses of 50 mg, 100 mg, and 150 mg, and a 100 mg equivalent dose of d-amphetamine (40 mg). [Figure 10] FIG. 10 is a graph showing plasma concentrations of amphetamine following administration of equal doses of lisdexamfetamine and d-amphetamine (semi-log plot as inset). [Figure 11] FIG. 11 is a graph showing subjective preference rating scores over time following administration of lisdexamfetamine and amphetamine to healthy subjects. [Figure 12] FIG. 12 is a graph showing systolic blood pressure over time following administration of lisdexamfetamine and amphetamine to healthy subjects. [Figure 13] FIG. 13 is a graph showing the acute effects of MDMA and amphetamine, illustrating the stronger and shorter effect of MDMA on drug preference compared to amphetamine, and suggesting the potential for attenuating the effects of MDMA using the prodrug concept. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description of the Invention The present invention generally provides novel MDMA-like compounds, a description of their production and their uses, and advantages of use over existing substances used in substance (MDMA)-assisted psychotherapy to treat illnesses. Most generally, the present invention provides prodrug compounds comprising a psychoactive basic substance attached to an amino acid. Preferably, the compounds are prodrugs of MDMA and MDMA-like compounds.

[0022] As used herein, "prodrug" refers to a compound that contains a moiety added to an active drug substance that is metabolized after administration to an individual, converting the compound into the active drug substance. The use of a prodrug allows for improved absorption, distribution, metabolism, and excretion of the active drug. A prodrug can be used to prevent the release of the active drug in the gastrointestinal tract shortly after administration, so that the drug can be more conveniently released elsewhere in the body. The prodrug in the present invention can be referred to as "proMDMA" or a "proMDMA-like compound."

[0023] More specifically, the compounds contain an amino acid covalently attached to the psychoactive base of MDMA or an MDMA-like compound (Figures 1A-1H). The addition of the amino acid renders the active compound inactive, primarily by preventing interaction with monoamine transporters, which are the site of action and also affect the rate of bioavailability / absorption. The amino acid can be lysine or any other amino acid, such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine, and can typically be attached to the amine (N) group of MDMA or an MDMA-like substance, thereby reducing pharmacological activity at the primary site of action (cell membrane monoamine transporters, including serotonin, dopamine, and norepinephrine transporters) and also altering the degree and rate of absorption, primarily releasing the active substance into the blood circulation after absorption of the inactive compound. The amino acid can also be any other natural or synthetic amino acid. The present invention is illustrated using lysine as an example amino acid in combination with MDMA and MDA. However, the present invention can use any other amino acid covalently attached to any other MDMA-like substance via the amine group of the MDMA-like substance to form a peptide bond.

[0024] MDMA-like compounds include MDMA (Figure 1A), 3,4-methylenedioxyamphetamine (MDA) (Figure 1B), 3,4-methylenedioxyethylamphetamine (MDEA) (Figure 1D), 1-(1,3-benzodioxol-5-yl)methyl-2-butanamine (MBDB) (Figure 1C), 1-(1,3-benzodioxol-5-yl)-2-aminobutane (BDB, also known as MDB), methylone (Figure 1E), ethylone, 5,6-methylenedioxy-2-aminoindan (MDAI) (Figure 1H), 5-iodo-2-aminoindan (5-IAI), 4-(2-aminopropyl)-benzylamine (BBE), and methylone. The compounds can be benzofuran (4-APB), 5-(2-aminopropyl)-benzofuran (5-APB) (Figure 1F), 6-(2-aminopropyl)-benzofuran (6-APB), N-methyl-1-(2,3-dihydrobenzofuran-5-yl)-propan-2-amine (5-MAPDB), 6-(2-methylaminopropyl)-benzofuran (6-MAPB) (Figure 1G), or other compounds, i.e., benzofurans, aminoindans, or cathinones with MDMA-like pharmacological profiles or mixed dopaminergic and serotonergic amphetamines and their N-alkylated analogs (Rickli et al., 2015a; Rickli et al., 2015b; Simmler et al., 2013), or active metabolites of such substances (Luethi et al., 2019). 1A-1H, all of the compounds have structural similarities and contain a 3,4-substitution of the benzene ring in the phenethylamine structure, which is typical of MDMA-like compounds that preferentially act on the serotonin transporter over the dopamine transporter, releasing primarily serotonin. The compounds can be used in any suitable pharmaceutical salt form, such as hydrochloride or dimesylate, etc. Any active metabolites can also be used.

[0025] The invention described herein details two examples of materials representative of the invention relating to drugs comprising lysMDMA (lysine covalently linked to MDMA) and lysMDA (lysine covalently linked to MDA).

[0026] Compounds in the field of the present invention can generally be prepared in a similar manner to known routes, such as that described for lisdexamfetamine, which is derived from the combination of lysine as an amino acid and dextroamphetamine as a psychoactive substance (Patent Nos. WO 2005032474A2, WO 2006121552A2, U.S. Pat. No. 7223735B2, U.S. Pat. App. Pub. No. 2009234002A1, U.S. Pat. App. Pub. No. 20120157706A1, WO 2017098533A2). Briefly, a bis-N-protected lysine or another amino acid is activated at the carboxyl group by introducing a leaving group such as O-succinimide. In this example, this activated lysine derivative is then reacted with a primary or secondary amine, such as MDA or MDMA, respectively, to form the corresponding amide in the presence of a suitable aprotic base, such as triethylamine, N-methylmorpholine, or diisopropylethylamine. Tetrahydrofuran (THF) or dioxane are used as suitable solvents, but others, such as dimethylformamide (DMF) or dimethyl sulfoxide (DMSO), may also be considered. After isolation and purification, the resulting compound, such as bis-N-protected lysMDA or lysMDMA, is redissolved in a suitable solvent and treated with the corresponding deprotection conditions, for example, using acid to remove the tert-butoxycarbonyl (BOC) group or hydrogen in the presence of a catalyst such as palladium-activated carbon (Pd-C) to remove hydrogen-sensitive protecting groups. The final product can be isolated from the corresponding conditions as a salt or as its free base. Optional further purification steps and / or conversion to a salt such as the hydrochloride or mesylate salt according to known procedures leads to a final product such as lysMDA or lysMDMA or any similar combination of an MDMA-like psychoactive substance linked to an amino acid.

[0027] A problem with using MDMA in the treatment of illness is that it has some abuse liability due to its amphetamine structure and pharmacology. Namely, MDMA releases dopamine, which is associated with addiction (Kehr et al., 2011). MDMA also releases serotonin (Kehr et al., 2011), which counteracts addiction (Suyama et al., 2016). Due to its mixed dopaminergic and serotonergic properties, MDMA is considered a moderate reinforcer compared to the strong reinforcers methylphenidate, cocaine, or nicotine (Liechti, 2014). Nevertheless, MDMA abuse may be a medical concern.

[0028] A readily measurable measure of abuse liability is subjective drug liking (Jasinski, 2000; Jasinski & Krishnan, 2009a; Jasinski & Krishnan, 2009b). The subjective effect of drug liking is thought to be related to abuse liability. In particular, higher drug liking scores and more rapidly increasing scores after substance administration are predictive of greater abuse liability. Consistently, immediate-release formulations increase liking more rapidly and to higher levels than sustained-release formulations of certain centrally acting substances. For example, this has been shown for immediate- and sustained-release formulations of alprazolam, with the sustained-release formulation resulting in lower liking and less drug reinforcement compared to the immediate-release formulation (Figures 3-5) (Mumford et al., 1995).

[0029] For example, as illustrated in Figure 2, proMDMA-like compounds are inactive and, after oral administration, are well absorbed in the intestine, where they are transported into the bloodstream. In the bloodstream, proMDMA-like compounds are cleaved into an amino acid (lysine in this example) and the active MDMA-like compound (MDA in the example of Figure 2), as shown for related compounds (Hutson et al., 2014).

[0030] The truncated amino acids are physiologically available and are metabolically required substances that can be physiologically used or metabolized by the body (protein synthesis), as in the case of amino acids provided in food (meat) or food supplements.

[0031] The amino acid tryptophan can also be used and may be particularly useful in the present invention because it is a precursor amino acid used by the brain to produce the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). MDMA and MDMA-like substances release endogenous serotonin, which can lead to serotonin depletion, which in turn can lead to depressed mood several days after MDMA administration. The tryptophan contained in tryptophan-MDMA prodrugs helps prevent such serotonin depletion and the associated negative mood effects.

[0032] ProMDMA compounds have low bioavailability when used via parenteral routes such as intranasal (inhalation) or intravenous administration, limiting their abuse liability as shown for related compounds (Figures 4 and 5A-5B). This concept has already been used with d-amphetamine (U.S. Patent No. 7,655,630 B2) (Jasinski et al., 2009b), but not with MDMA or its analogs.

[0033] ProMDMA compounds can elicit lower drug preference ratings compared to equivalent doses of the parent substance. This has been shown using lisdexamfetamine and equivalent oral doses of d-amphetamine (Jasinski et al., 2009a) (Figure 8) and can be confirmed using lysMDMA / lysMDA and MDMA / MDA in clinical trials used to further support the present invention. In Figure 8, preference ratings for lisdexamfetamine were lower compared to d-amphetamine rating scores.

[0034] MDMA and related substances rapidly increase blood pressure, sometimes significantly in some subjects (Hysek et al., 2011; Vizeli & Liechti, 2017). This can be problematic for subjects or patients with cardiovascular disease. MDMA-like substances with less acute cardiovascular effects or attenuated increases in blood pressure are warranted. ProMDMA and proMDMA-like compounds exhibit attenuated cardiac stimulatory responses due to the slow production of active substances from the prodrug, as similarly shown for lisdexamfetamine and d-amphetamine (Jasinski et al., 2009a) (Figure 9). In Figure 9, blood pressure increased more slowly and later after administration of 100 mg lisdexamfetamine compared to d-amphetamine.

[0035] The ProMDMA compound exhibited attenuated acute effects, including a reduced and delayed increase in drug preference, a reduced and delayed increase in blood pressure, and a reduced and delayed increase in any anxiety at the onset of effect. This is based on existing data comparing the effects of lisdexamfetamine and d-amphetamine on abuse-related criteria such as drug preference (Jasinski & Krishnan, 2009a; Jasinski & Krishnan, 2009b) (Figures 6-9).

[0036] The present invention offers advantages of the prodrug concept not only in terms of abuse-related effects, but also due to the reduced anxiety ratings and reduced cardiovascular stimulation of the prodrug formulation, and therefore the better benefit-to-adverse effect profile of the prodrug compared to administration of the active substance. This effect is achieved by the slow release of the active substance (MDMA) from the prodrug compound (proMDMA), resulting in a moderately slow increase in plasma levels of the psychoactive substance (MDMA) compared to direct administration of the psychoactive substance. In addition, published reports of reduced drug preference with orally administered lisdexamfetamine relative to d-amphetamine were observed in only one study (Jasinski et al., 2009a) and not another (Dolder et al., 2017) (Figure 8). Unexpectedly, another very detailed and reliable experimental study showed that the onset (10% of the individual's maximum response as a threshold) and peak times of the amphetamine concentration-time curve were longer after lisdexamfetamine administration compared to d-amphetamine, but no differences were seen in the maximum concentrations (Dolder et al., 2017) (Figure 10). In addition, the subjective effect-time curve, including the drug preference assessment, was shifted to the right, resulting in a significantly longer time to effect onset (T) after lisdexamfetamine administration compared to d-amphetamine administration. onset ) and time to maximum effect (T max ) values ​​and consistent with the pharmacokinetics of the two drugs (Dolder et al., 2017) (Figure 11). However, there was a significant difference in the maximum effect (E) between lisdexamfetamine and d-amphetamine. maxNo differences in Tmax or area under the effect-time curve (AUEC) values ​​were found (Dolder et al., 2017). There was a small, non-significant decrease and delay in drug-liking responses for lisdexamfetamine versus d-amphetamine (Figure 11). Furthermore, lisdexamfetamine and d-amphetamine produced similar increases in blood pressure (Figure 12), heart rate, body temperature, and pupil size (Dolder et al., 2017). Blood pressure-time curves showed a significantly longer Tmax after lisdexamfetamine administration compared to d-amphetamine administration. onset The data has shifted to the right due to the difference in peak efficacy (Dolder et al., 2017). This conflicting data therefore indicates that there may be no relevant differences between the prodrug and its active metabolite in terms of peak efficacy, or at least that such differences may be due to dosing. Therefore, the benefits of the present invention are not clear based on the existing conflicting data (Dolder et al., 2017; Jasinski & Krishnan, 2009a; Jasinski & Krishnan, 2009b) and need to be further substantiated and documented by experimental data for the prodrugs described in this invention.

[0037] d-Amphetamine and MDMA differ in terms of molecular structure and metabolism. Importantly, lisdexamfetamine is converted to d-amphetamine, which has a relatively long half-life of 8 hours and is present in human plasma (Dolder et al., 2017). It is metabolized to the active metabolite, 4-hydroxyamphetamine, while d-amphetamine is also excreted unchanged in urine as a hippuric acid conjugate (Krishnan et al., 2008). In contrast, lysMDMA is primarily converted to MDMA, which is metabolized to the methylenedioxy group, which is absent in d-amphetamine. In particular, MDMA is primarily inactivated to 3,4-dihydroxymethamphetamine (HHMA), which is then rapidly further metabolized to 4-hydroxy-3-methoxymethamphetamine (HMMA) by the cytochrome P450 enzyme (CYP) 2D6 and catechol-O-methyltransferase (COMT) (de la Torre et al., 2000; Schmid et al., 2016b). This process occurs as early as the formation of MDMA from lysMDMA. Therefore, the kinetics of MDMA formation and metabolism after administration of lysMDMA differ from those of d-amphetamine formation and metabolism after administration of lisdexamfetamine, as characterized in the tests described in this invention and cannot be simply derived from past know-how.

[0038] A direct comparison of the response rates for the acute effects of d-amphetamine and MDMA also shows a "slower" response rate for d-amphetamine compared to MDMA, including a lower peak effect and longer-lasting subjective effects on preference ratings (Figure 13). Thus, MDMA prodrugs, unlike d-amphetamine prodrugs, likely have a lower E of preference compared to d-amphetamine. max There is more scope for lowering the dose and prolonging the effect, further supporting the novelty of the innovation of the present invention with regard to modifying the effect after oral use.

[0039] As such, the present invention includes experimental test designs and detailed protocols that experimentally support the claims made.

[0040] Clinical experimental studies can be performed in healthy participants using a randomized, balanced-order (placebo-controlled) crossover design to compare the effects of lysMDMA and lysMDA with MDMA and MDA, respectively, within the same participants. Equimolar doses of lysMDMA and MDMA or lysMDA and MDA are administered as hydrochlorides, with an active drug (MDMA or MDA) content corresponding to 125 mg of MDMA. Primary endpoints are plasma pharmacokinetics of MDMA and MDA, subjective effects including any, favorable, and unfavorable effects, and drug preference and anxiety; and autonomic nervous system effects, including heart rate and diastolic and systolic blood pressure. Relevant pharmacokinetic parameters for this invention are C max , T max , T onset , and AUC (area under the concentration-time curve). The relevant parameters for the effect of the substance are E max , T max , T onset , and AUEC. lysMDMA / lysMDA vs. MDMA / MDA resulted in a lower C for active MDMA / MDA plasma levels. max , higher T max , longer T onset , and similar AUC values ​​and lower E for subjective effect ratings and measures of autonomic nervous system response. max , longer T max , longer T onset, and similar AUEC levels. This result likely corresponds to a long-term attenuated response to administration of lysMDMA / lysMDA compared to MDMA / MDA. Crossover studies can include lysMDMA and MDMA alone, or lysMDA and MDA alone, or all four conditions, or an additional placebo condition. Relevant comparisons for the present invention are lysMDMA vs. MDMA and lysMDA vs. MDA. Studies can also include comparisons between MDMA and MDA and between lysMDMA and lysMDA to derive additional information about the differences between MDMA and MDA. In particular, where clinical experimental data on the differences between MDMA and MDA are not available from studies that legitimately compare the two, such comparisons can be incorporated into studies involving lysMDMA and lysMDA, or even performed as separate experimental studies comparing MDMA and MDA alone. Novel aspects of such experimental studies are presented below.

[0041] MDA is a psychoactive amphetamine and an MDMA analog. MDA is also the active metabolite of MDMA. Peak plasma concentrations of MDA are approximately 7-10% of those of MDMA after MDMA administration (Hysek et al., 2011; Schmid et al., 2016a). Plasma levels of MDA increase more slowly and reach a maximum later than MDMA levels after MDMA administration. maxThe values ​​are 2.6 and 4.7 for MDMA and MDA after administration of 125 mg MDMA to healthy subjects (Hysek et al., 2011). In addition, the elimination half-life of MDA is 10–16 h, longer than that of MDMA (7–10 h) (Baggott et al., 2019; Hysek et al., 2011; Kolbrich et al., 2008). This means that the effects of MDA may last longer than those of MDMA when administered as a drug. Plasma levels of MDA, an MDMA metabolite, are relatively higher compared to MDMA levels toward the end of the MDMA experience, which also means that the effects of MDA may contribute to some degree to the MDMA experience, especially toward the end of the experience.

[0042] The MDMA metabolite, MDA, is psychoactive (Baggott et al., 2019) and, like MDMA, has previously been used in MDA-assisted psychotherapy (Pentney, 2001; Turek et al., 1974; Yensen et al., 1976). The pharmacology of MDA is relatively similar overall to that of MDMA, supporting the notion that MDA is an MDMA-like compound (Hysek et al., 2012; Oeri, 2020). The relative potency of dopamine-to-serotonin transporter inhibition (DAT / SERT) is a key determinant of the type of psychoactivity produced by amphetamine compounds.

[0043] Specifically, substances with a low DAT / SERT ratio (<1) are MDMA-like empathogenic compounds, whereas substances with a high DAT / SERT ratio (>10) and thus predominantly dopaminergic effects are amphetamine / methamphetamine-like stimulants (Liechti, 2015; Simmler et al., 2013). For example, MDMA-like compounds included in the present invention, such as MDMA, MBDB, MDEA, and MDA, have DAT / SERT ratios of 0.08, 0.09, 0.14, and 0.24, respectively (Simmler et al., 2013). The benzofurans 5-APB and 6-APB have DAT / SERT ratios of 0.05 and 0.29, respectively (Rickli et al., 2015b). Aminoindan MDAI has a DAT / SERT ratio of 0.2 (Simmler et al., 2014).

[0044] All these substances also release serotonin, similar to MDMA (Rickli et al., 2015b; Simmler et al., 2013; Simmler et al., 2014). Thus, all these compounds are similar in terms of their primary action, which is to release monoamines with a preference for serotonin over dopamine.

[0045] However, there are notable differences, with MDA being slightly more dopaminergic than MDMA (Hysek et al., 2012; Rickli et al., 2015b). MDA also inhibits 5-HT 2A It also activates 5-HT receptors, which mediate its psychotomimetic effects (Preller et al., 2017; Vollenweider et al., 1998b), and is significantly more potent than MDMA (Rickli et al., 2015b). 2A Half-maximal effect of receptor activation (EC 50The concentrations producing α- and β-blockers (α-blockers) are 6.1 and 0.63 for MDMA and MDA, respectively (Rickli et al., 2015b). Therefore, based on their pharmacological profiles, MDA would be expected to exert more LSD-like psychotomimetic effects than MDMA.

[0046] Direct comparisons of MDMA and MDA within clinical experimental trials remain unresolved.

[0047] A previous study tested the effects of MDA (1.4 mg / kg orally) in 12 healthy subjects, also providing an indirect comparison with the effects of MDMA (Baggott et al., 2019). Importantly, the data were obtained in different subjects and studies and therefore are not a valid comparison. MDA's effects reportedly shared characteristics with MDMA and classic hallucinogens (Baggott et al., 2019), consistent with its in vitro pharmacological profile (Rickli et al., 2015b). MDA's self-reported effects lasted longer than MDMA, up to 8 hours, while MDMA's effects dissipated by 6 hours. MDA also produced greater perceptual changes than MDMA on the 5-Dimensions of Altered States of Consciousness Scale (Baggott et al., 2019), suggesting more hallucinogen-like properties.

[0048] Based on these previous data, differences exist between MDMA and MDA, i.e., the effects of MDA are more hallucinogen-like and longer lasting compared to MDMA.

[0049] Additionally, the use of lysMDA can further prolong and attenuate the MDA response, producing an experience distinct from MDA and MDMA that is desired in some patient populations. Specifically, lysMDA is useful in situations where a longer, more mixed empathogenic and psychotomimetic response is desired compared to the shorter, more empathogenic response to MDMA.

[0050] Other compounds with MDA-like structures or their prodrug compositions can be used within the scope of the present invention as described for MDMA or MDA. Specifically, MDA-like compounds include MBDB, BDB, and fluorine-containing analogs of MDMA, such as 2F-MDA, 5F-MDA, and 6F-MDA. BDB and fluorinated MDA compounds release 5-HT and exhibit DAT / SERT inhibition ratios between 0.1 and 1, and are therefore similar to MDMA in their primary pharmacological properties of stimulating serotonin rather than dopamine systems (data on file).

[0051] The present invention generally provides a method for treating an individual by administering proMDMA or a proMDMA-like compound to the individual, metabolizing the prodrug, and releasing MDMA or an MDMA-like substance in the individual. This method can provide a way around or avoid the metabolism of MDMA in the gastrointestinal tract, due to metabolism elsewhere in the body, such as in the liver or blood circulation. There are many advantageous effects of administering proMDMA or a proMDMA-like compound, as opposed to psychoactive substances without the prodrug, as described below.

[0052] The compositions described herein can be used in any type of substance-assisted psychotherapy similar to the intended uses of MDMA or LSD or psilocybin (Danforth et al., 2018; Luoma et al., 2020; Mithoefer et al., 2016; Mithoefer et al., 2018; Trope et al., 2019).

[0053] In particular, the compounds can be used in compound adjunctive therapy for post-traumatic stress disorder, social anxiety, autism spectrum disorder, substance use disorders, depression, anxiety disorders, anxiety due to life-threatening illnesses, personality disorders including narcissistic or antisocial personality disorders, medical disorders including obsessive-compulsive disorder, couples therapy, enhancement of any psychotherapy by inducing feelings of happiness, connectedness, trust, affection, empathy, openness, and prosociality and improving the therapeutic bond in any psychotherapy in patients or neurotic / healthy subjects.

[0054] In comparison with the use of MDMA or related psychoactive substances, the prodrug compounds described herein have slower onset of action due to their slower reaction rate characteristics, longer duration of action, a reduced peak effect, thereby resulting in a reduced effect profile, a lower anxiety at the onset of subjective efficacy, a lower anxiety at the onset of subjective efficacy, a slower increase in drug preference rating scores relative to their acute effects, a reduced risk of abuse and dependence, delayed and reduced effects when used parenterally, thereby deterring abuse, and delayed and reduced cardiac stimulant effects, making them safer for use in patients with cardiovascular disease and risk factors. Combinations of these effects may also be included.

[0055] The present invention also provides a method for reducing anxiety while administering MDMA by providing a sustained release of MDMA or an MDMA-like substance and thereby reducing anxiety in an individual at the onset of administration. The sustained release can be provided by proMDMA or proMDMA-like substances because the pro-compounds are enzymatically degraded in the body, primarily by peptidases in the circulation, to amino acids and the psychoactive substance, releasing the psychoactive substance at a slower rate compared to the level achieved by the absorption rate of the psychoactive substance administered in its direct, active form.

[0056] The present invention provides a method for personalized medicine by identifying individuals in need of MDMA treatment, determining whether the individual has characteristics that make them unsuitable for MDMA treatment, and administering proMDMA or a proMDMA-like substance to the individual. For example, if an individual has heart problems, it may be better to treat them with proMDMA instead of MDMA. Also, if an individual experiences anxiety at the start of regular MDMA treatment, proMDMA treatment may be recommended. A further example is suggested if a subject suffers from high levels of MDMA administration due to a poor metabolic condition, where proMDMA can address and / or completely prevent the onset effects. Even further suggestions can be considered if a subject has any type of gastrointestinal disorder that is expected to impair MDMA absorption. Therefore, proMDMA may be more easily absorbed and more suitable, resulting in better control of MDMA availability in the body. This method maximizes efficiency and minimizes toxicity to the individual.

[0057] The present invention provides a method for reducing the abuse of MDMA by administering proMDMA or a proMDMA-like compound and providing a delayed, attenuated effect of MDMA or a proMDMA-like compound, thereby reducing abuse. The use of a prodrug can result in delayed onset of the drug, resulting in, but not limited to, a reduced and delayed increase in drug preference, a reduced and delayed increase in blood pressure, and a reduced and delayed increase in any anxiety at the onset of effect.

[0058] In comparison to MDMA, each of the other psychoactive compounds described herein, i.e., MDA, has a unique profile of effects that is partially distinct from MDMA, making them useful alternatives to MDMA in substance-assisted therapy.

[0059] That is, MDA is different from MDMA and may exhibit a desirable effect profile in certain patients, including a longer duration of action and more psychotomimetic effects than MDMA. Such distinct effect profiles of MDA versus MDMA are predicted based on in vitro data and preliminary experimental data.

[0060] The compounds of the present invention are administered and administered in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, the administration schedule, the patient's age, sex, weight, and other factors known to physicians. A pharmaceutically "effective amount" for purposes herein is therefore determined by such factors 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 selected as appropriate criteria by those skilled in the art.

[0061] In the method of the present invention, the compound of the present invention can be administered by various means. It should be noted that the compound of the present invention can be administered as a compound, and 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 intravenously, intramuscularly, and intranasally. Implants of the compound are also useful. The patient being 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.

[0062] Doses can be single or multiple doses over the course of several days, weeks, or months. The duration of treatment is generally proportional to the duration of the disease process and drug effectiveness and the type of patient being treated.

[0063] When the compound of the present invention is administered parenterally, it is generally prepared in a unit dosage injection form (solution, suspension, emulsion). Pharmaceutical preparations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

[0064] 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 may also be used as solvent systems for composite compositions. Additionally, various additives that enhance the stability, sterility, and isotonicity of the composition, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of microbial action can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It is often desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical forms can be achieved by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. In accordance with the present invention, however, it will be understood that any excipient, diluent, or additive used would have to be compatible with the compound.

[0065] 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 other ingredients as desired.

[0066] The pharmaceutical preparations of the present invention can be administered to patients in injection formulations containing any suitable carrier, such as various excipients, adjuvants, additives, and diluents, or the compounds utilized in the present invention can be administered to patients parenterally in the form of targeted delivery systems, such as sustained-release subcutaneous implants or monoclonal antibodies, guided delivery, iontophoresis, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include U.S. Patent No. 5,225,182; U.S. Patent No. 5,169,383; U.S. Patent No. 5,167,616; U.S. Patent No. 4,959,217; U.S. Patent No. 4,925,678; U.S. Patent No. 4,487,603; U.S. Patent No. 4,486,194; U.S. Patent No. 4,447,233; U.S. Patent No. 4,447,224; U.S. Patent No. 4,439,196; and U.S. Patent No. 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0067] Throughout this application, various publications, including U.S. patents, are referenced by author and year and patent number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0068] The invention has been described by way of illustration and example, 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.

[0069] Obviously, many modifications and variations of the present invention are possible in light of the above teachings, and it is therefore to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described.

[0070] References 1.Baggott MJ, Garrison KJ, Coyle JR, Galloway GP, Barnes AJ, Huestis MA, & Mendelson JE (2019). Effects of the Psychedelic Amphetamine MDA (3,4-Methylenedioxyamphetamine) in Healthy Volunteers. J Psychoactive Drugs 51: 108-117. 2.Busto U, & Sellers EM (1986). Pharmacokinetic determinants of drug abuse and dependence. A conceptual perspective. Clin Pharmacokinet 11: 144-153. 3.Cole JC, & Sumnall HR (2003). The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA). Neurosci Biobehav Rev 27: 199-217. 4.Creehan KM, Vandewater SA, & Taffe MA (2015). Intravenous self-administration of mephedrone, methylone and MDMA in female rats. Neuropharmacology 92C: 90-97. 5.Danforth A Exploring MDMA-assisted therapy as a new pathway to social adaptabilty for autistic adults. 6.Danforth AL, Grob CS, Struble C, Feduccia AA, Walker N, Jerome L, Yazar-Klosinski B, & Emerson A (2018). Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study. Psychopharmacology 235: 3137-3148. 7.Danforth AL, Struble CM, Yazar-Klosinski B, & Grob CS (2016). MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults. Prog Neuropsychopharmacol Biol Psychiatry 64: 237-249. 8.de la Torre R, Farre M, Roset PN, Lopez CH, Mas M, Ortuno J, Menoyo E, Pizarro N, Segura J, & Cami J (2000). Pharmacology of MDMA in humans. Ann N Y Acad Sci 914: 225-237. 9.Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, & Liechti ME (2017). Pharmacokinetics and pharmacodynamics of lisdexamfetamine compared with D-amphetamine in healthy subjects. Front Pharmacol 8: 617. 10.Hutson PH, Pennick M, & Secker R (2014). Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug. Neuropharmacology 87: 41-50. 11.Hysek CM, Schmid Y, Simmler LD, Domes G, Heinrichs M, Eisenegger C, Preller KH, Quednow BB, & Liechti ME (2014). MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affect Neurosci 9: 1645-1652. 12.Hysek CM, Simmler LD, Ineichen M, Grouzmann E, Hoener MC, Brenneisen R, Huwyler J, & Liechti ME (2011). The norepinephrine transporter inhibitor reboxetine reduces stimulant effects of MDMA (”ecstasy”) in humans. Clinical pharmacology and therapeutics 90: 246-255. 13.Hysek CM, Simmler LD, Nicola V, Vischer N, Donzelli M, Kraehenbuehl S, Grouzmann E, Hoener MC, & Liechti ME (2012). Duloxetine inhibits effects of MDMA (”ecstasy”) in vitro and in humans in a randomized placebo-controlled laboratory study. PLoS One 7: e36476. 14.Jasinski DR (2000). An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol 14: 53-60. 15.Jasinski DR, & Krishnan S (2009a). Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse. J Psychopharmacol 23: 419-427. 16.Jasinski DR, & Krishnan S (2009b). Human pharmacology of intravenous lisdexamfetamine dimesylate: abuse liability in adult stimulant abusers. J Psychopharmacol 23: 410-418. 17.Kehr J, Ichinose F, Yoshitake S, Goiny M, Sievertsson T, Nyberg F, & Yoshitake T (2011). Mephedrone, compared to MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and serotonin levels in nucleus accumbens of awake rats. Br J Pharmacol 164: 1949-1958. 18.Kolbrich EA, Goodwin RS, Gorelick DA, Hayes RJ, Stein EA, & Huestis MA (2008). Plasma pharmacokinetics of 3,4-methylenedioxymethamphetamine after controlled oral administration to young adults. Therapeutic drug monitoring 30: 320-332. 19.Krishnan SM, Pennick M, & Stark JG (2008). Metabolism, distribution and elimination of lisdexamfetamine dimesylate: open-label, single-centre, phase I study in healthy adult volunteers. Clinical drug investigation 28: 745-755. 20.Liechti M (2015). Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signaling. Swiss Med Wkly 145: w14043. 21.Liechti ME (2014). Novel psychoactive substances (designer drugs): overview and pharmacology of modulators of monoamine signalling. Swiss Med Weekly 144: w14043. 22.Liechti ME, Gamma A, & Vollenweider FX (2001). Gender differences in the subjective effects of MDMA. Psychopharmacology 154: 161-168. 23.Luethi D, Kolaczynska KE, Walter M, Suzuki M, Rice KC, Blough BE, Hoener MC, Baumann MH, & Liechti ME (2019). Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems. J Psychopharmacol 33: 831-841. 24.Luoma JB, Chwyl C, Bathje GJ, Davis AK, & Lancelotta R (2020). A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy. J Psychoactive Drugs: 1-11. 25.Mithoefer MC, Feduccia AA, Jerome L, Mithoefer A, Wagner M, Walsh Z, Hamilton S, Yazar-Klosinski B, Emerson A, & Doblin R (2019). MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology. 26.Mithoefer MC, Grob CS, & Brewerton TD (2016). Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry 3: 481-488. 27.Mithoefer MC, Mithoefer AT, Feduccia AA, Jerome L, Wagner M, Wymer J, Holland J, Hamilton S, Yazar-Klosinski B, Emerson A, & Doblin R (2018). 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry 5: 486-497. 28.Mithoefer MC, Wagner MT, Mithoefer AT, Jerome I, & Doblin R (2010). The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol 25: 439-452. 29.Mumford GK, Evans SM, Fleishaker JC, & Griffiths RR (1995). Alprazolam absorption kinetics affects abuse liability. Clinical pharmacology and therapeutics 57: 356-365. 30.Oehen P, Traber R, Widmer V, & Schnyder U (2013). A randomized, controlled pilot study of MDMA (±3,4-methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic post-traumatic stress disorder (PTSD). J Psychopharmacol 27: 40-52. 31.Oeri HE (2020). Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy. J Psychopharmacol: 269881120920420. 32.Pentney AR (2001). An exploration of the history and controversies surrounding MDMA and MDA. J Psychoactive Drugs 33: 213-221. 33.Preller KH, Herdener M, Pokorny T, Planzer A, Kraehenmann R, Staempfli P, Liechti ME, Seifritz E, & Vollenweider FX (2017). The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation Curr Biol 27: 451-457. 34.Rickli A, Hoener MC, & Liechti ME (2015a). Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 25: 365-376. 35.Rickli A, Kopf S, Hoener MC, & Liechti ME (2015b). Pharmacological profile of novel psychoactive benzofurans. Br J Pharmacol 172: 3412-3425. 36.Schmid Y, Hysek CM, Simmler LD, Crockett MJ, Quednow BB, & Liechti ME (2014). Differential effects of MDMA and methylphenidate on social cognition. J Psychopharmacol 28: 847-856. 37.Schmid Y, Vizeli P, Hysek CM, Prestin K, Meyer Zu Schwabedissen HE, & Liechti ME (2016a). CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of 3,4-methylene-dioxymethamphetamine in a controlled study in healthy individuals. Pharmacogenet Genomics 26: 397-401. 38.Schmid Y, Vizeli P, Hysek CM, Prestin K, Meyer zu Schwabedissen HE, & Liechti ME (2016b). CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of MDMA in a controlled study in healthy subjects. Pharmacogenet Genom 26: 397-401. 39.Simmler L, Buser T, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener M, & Liechti ME (2013). Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168: 458-470. 40.Simmler LD, Rickli A, Schramm Y, Hoener MC, & Liechti ME (2014). Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives. Biochem Pharmacol 88: 237-244. 41.Suyama JA, Sakloth F, Kolanos R, Glennon RA, Lazenka MF, Negus SS, & Banks ML (2016). Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin. J Pharmacol Exp Ther 356: 182-190. 42.Trope A, Anderson BT, Hooker AR, Glick G, Stauffer C, & Woolley JD (2019). Psychedelic-Assisted Group Therapy: A Systematic Review. J Psychoactive Drugs 51: 174-188. 43.Turek IS, Soskin RA, & Kurland AA (1974). Methylenedioxyamphetamine (MDA)-subjective effects. J Psychoactive Drugs 6: 7-14. 44.Vizeli P, & Liechti ME (2017). Safety pharmacology of acute MDMA administration in healthy subjects. J Psychopharmacol 31: 576-588. 45.Vollenweider FX, Gamma A, Liechti ME, & Huber T (1998a). Psychological and cardiovascular effects and short-term sequelae of MDMA (”ecstasy”) in MDMA-naive healthy volunteers. Neuropsychopharmacology 19: 241-251. 46.Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, & Hell D (1998b). Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9: 3897-3902. 47.Yensen R, Di Leo FB, Rhead JC, Richards WA, Soskin RA, Turek B, & Kurland AA (1976). MDA-assisted psychotherapy with neurotic outpatients: a pilot study. J Nerv Ment Dis 163: 233-245.

Claims

1. Compounds containing prodrugs that contain psychoactive basic substances attached to amino acids.

2. The compound of claim 1 , wherein the psychoactive basic substance is MDMA or an MDMA-like substance.

3. 3. The compound of claim 2, wherein the MDMA or MDMA-like substance is selected from the group consisting of MDA, MDEA, MBDB, BDB, MDB, 2F-MDA, 5F-MDA, 6F-MDA, ethilon, MDAI, 5-IAI, 4-APB, 5-APB, 6-APB, 5-MAPDB, 6-MAPB, mixed dopaminergic serotonergic amphetamines, and N-alkylated analogs thereof and active metabolites thereof.

4. 2. The compound of claim 1, wherein the amino acid is selected from the group consisting of lysine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

5. 2. The compound of claim 1, wherein the amino acid is selected from the group consisting of natural or synthetic.

6. 1. A method for treating an individual, comprising: administering proMDMA or a proMDMA-like compound to said individual; metabolizing the prodrug in the proMDMA or proMDMA-like compound; and A method comprising the step of releasing MDMA or an MDMA-like substance in said individual.

7. 7. The method of claim 6, wherein the treatment is substance-assisted psychotherapy and the proMDMA or proMDMA-like compound provides at least one advantageous effect compared to administering active MDMA or an MDMA-like substance alone.

8. 8. The method of claim 7, wherein the beneficial effect is selected from the group consisting of reduced anxiety upon onset of subjective effects, resulting in a slower or smaller increase in cardiovascular activity, resulting in a slower or smaller increase in drug preference, resulting in a longer lasting effect, resulting in a more psychedelic effect, resulting in reduced abuse liability, and combinations thereof.

9. 7. The method of claim 6, wherein the individual is being treated for a condition selected from the group consisting of post-traumatic stress disorder, social anxiety, autism spectrum disorder, substance use disorder, depression, anxiety disorder, anxiety due to a life-threatening illness, personality disorder including narcissistic or antisocial personality disorder, obsessive-compulsive disorder, and is treated with couples therapy, and combinations thereof.

10. 10. The method of claim 6, further comprising the step of inducing an emotion selected from the group consisting of happiness, connectedness, trust, love, empathy, prosociality, and combinations thereof.

11. 10. The method of claim 6, further comprising the step of strengthening a therapeutic bond with the patient and the neurotic / healthy subject.

12. 7. The method of claim 6, wherein the metabolizing step further comprises avoiding metabolism of MDMA or MDMA-like substances in the individual's gastrointestinal tract.

13. 7. The method of claim 6, wherein the proMDMA or proMDMA-like compound comprises MDMA or an MDMA-like substance selected from the group consisting of MDA, MDEA, MBDB, BDB, MDB, 2F-MDA, 5F-MDA, 6F-MDA, ethilon, MDAI, 5-IAI, 4-APB, 5-APB, 6-APB, 5-MAPDB, 6-MAPB, mixed dopaminergic serotonergic amphetamines, and N-alkylated analogs and active metabolites thereof.

14. 7. The method of claim 6, wherein the proMDMA or proMDMA-like compound comprises an amino acid selected from the group consisting of lysine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

15. 14. The method of claim 13, wherein the amino acid is selected from the group consisting of natural or synthetic.

16. 1. A method for reducing anxiety during MDMA administration, comprising: A method comprising the step of providing sustained release of MDMA or an MDMA-like substance, thereby reducing anxiety in an individual upon initiation of administration.

17. 17. The method of claim 16, wherein the MDMA or MDMA-like substance is selected from the group consisting of MDA, MDEA, MBDB, BDB, MDB, 2F-MDA, 5F-MDA, 6F-MDA, ethilon, MDAI, 5-IAI, 4-APB, 5-APB, 6-APB, 5-MAPDB, 6-MAPB, mixed dopaminergic serotonergic amphetamines, and N-alkylated analogs and active metabolites thereof.

18. 17. The method of claim 16, wherein the MDMA or MDMA-like compound is attached to an amino acid selected from the group consisting of lysine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

19. 19. The method of claim 18, wherein the amino acid is selected from the group consisting of natural or synthetic.

20. 1. A method of personalized medicine, comprising: assessing an individual in need of MDMA treatment to determine whether the individual has characteristics that make them unsuitable for MDMA treatment; and A method comprising the step of administering proMDMA or a proMDMA-like compound to said individual.

21. 21. The method of claim 20, wherein the individual has a condition selected from the group consisting of cardiac problems, anxiety experienced at the start of regular MDMA treatment, high levels of MDMA administration due to poor metabolism, and gastrointestinal disorders that impair MDMA absorption.

22. 21. The method of claim 20, wherein the proMDMA or proMDMA-like compound comprises MDMA or an MDMA-like substance selected from the group consisting of MDA, MDEA, MBDB, BDB, MDB, 2F-MDA, 5F-MDA, 6F-MDA, ethilon, MDAI, 5-IAI, 4-APB, 5-APB, 6-APB, 5-MAPDB, 6-MAPB, mixed dopaminergic serotonergic amphetamines, and N-alkylated analogs and active metabolites thereof.

23. 21. The method of claim 20, wherein the proMDMA or proMDMA-like compound comprises an amino acid selected from the group consisting of lysine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

24. 24. The method of claim 23, wherein the amino acid is selected from the group consisting of natural or synthetic.

25. 1. A method for reducing MDMA abuse, comprising: administering proMDMA or a proMDMA-like compound; and A method comprising the step of slowing and attenuating the effects of MDMA or MDMA-like substances, thereby reducing abuse.

26. 26. The method of claim 25, wherein the proMDMA or proMDMA-like compound has low bioavailability via parenteral routes.

27. 26. The method of claim 25, wherein the effecting step is further defined as effecting an effect selected from the group consisting of a reduced and slowed increase in drug preference, a reduced and slowed increase in blood pressure, and a reduced and slowed increase in anxiety at onset of effect.

28. 26. The method of claim 25, wherein the proMDMA or proMDMA-like compound comprises an MDMA or MDMA-like substance selected from the group consisting of MDA, MDEA, MBDB, BDB, MDB, 2F-MDA, 5F-MDA, 6F-MDA, ethilon, MDAI, 5-IAI, 4-APB, 5-APB, 6-APB, 5-MAPDB, 6-MAPB, mixed dopaminergic serotonergic amphetamines, and N-alkylated analogs and active metabolites thereof.

29. 26. The method of claim 25, wherein the proMDMA or proMDMA-like compound comprises an amino acid selected from the group consisting of lysine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.

30. 30. The method of claim 29, wherein the amino acid is selected from the group consisting of natural or synthetic.

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